Pharmacology Test Prep 1500 USMLE-Style Questions & Answers First Edition,None Edition 2014 {PRG}

Pharmacology Test Prep 1500 USMLE-Style Questions & Answ ers

Mar io Babb in i, MD, Ph D Professor Depar t m en t of Ph arm acology Ross Medical Sch ool Mar y Th om as, Ph D Professor Em erit us Depar t m en t of Ph arm acology Un iversit y of Texas Medical Bran ch at Galveston

Th iem e New York • St ut tgar t • Delh i • Rio

Vice Presiden t an d Editorial Director, Educat ion al Produ ct s: An n e Vin n icom be Develop m ent al Editor: Julie O’Meara Ed itorial Assist an t: Huvie Wein reich Sen ior Vice Presiden t , Editorial an d Elect ron ic Produ ct Developm en t: Corn elia Sch ulze Produ ct ion Editor: Barbara A. Ch ern ow In tern at ion al Product ion Director: An dreas Sch aber t In tern at ion al Market ing Director: Fion a Hen derson Director of Sales, North Am erica: Mike Rosem an In tern at ion al Sales Director: Lou isa Tu rrell Vice Presiden t , Fin an ce an d Accoun t s: Sarah Van derbilt President: Brian D. Scanlan Com positor: Carol Pierson , Ch ern ow Editorial Ser vices, In c.

Librar y of Con gress Cat alogin g-in -Pu b licat ion Dat a Babbin i, Mario, auth or. Ph arm acology test p rep : 1500 USMLE-st yle qu est ion s & an sw ers / Mario Babbin i, Mar y Th om as. p. ; cm . ISBN 978-1-62623-041-5 (alk. p ap er) — ISBN 978-1-62623-042-2 (eISBN) I. Th om as, Mar y (Professor of ph arm acology), au th or. II. Title. [DNLM: 1. Ph arm acological Ph en om en a—Exam in at ion Qu est ion s. QV 18.2] RS97 615.1076—dc23 2014027117

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Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Sectio n I: Gen eral Prin ciples of Ph arm acology Qu est ion s I-1

Ph arm acokin et ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

I-2

Ph arm acodyn am ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

I-3

Adverse E ects of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

An sw ers an d Exp lan at ion s I-1

Ph arm acokin et ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

I-2

Ph arm acodyn am ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

I-3

Adverse E ects of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Sectio n II: Auton om ic Ner vou s System Qu est ion s II-1

In t rodu ct ion to Au ton om ic Ph arm acology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

II-2

Adren ergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

II-3

An t iadren ergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

II-4

Ch olin ergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

II-5

An t ich olin ergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

An sw ers an d Exp lan at ion s II-1

In t rodu ct ion to Au ton om ic Ph arm acology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

II-2

Adren ergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

II-3

An t iadren ergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

II-4

Ch olin ergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

II-5

An t ich olin ergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Sectio n III: Cen t ral Ner vous System Qu est ion s III-1

In t rodu ct ion to Cen t ral Ner vou s System Ph arm acology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

III-2

Sedat ive an d Hypn ot ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

III-3

Gen eral An esth et ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

III-4

Local An esth et ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

III-5

Skeletal Mu scle Relaxan ts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

III-6

An t iseizu re Dr ugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

III-7

Drugs for Degen erat ive Disorders of th e Cen t ral Ner vou s System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

III-8

Neu rolept ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

III-9

Drugs for Dep ressive an d An xiet y Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

III-10

Drugs for Bipolar Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

III-11

Drugs for Ch ildh ood Beh avioral Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

III-12

Op ioid An algesics an d An tagon ists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

III-13

Drugs of Abu se . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

v

vi Contents

An sw ers an d Exp lan at ion s III-1

In t rodu ct ion to Cen t ral Ner vou s System Ph arm acology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

III-2

Sedat ive an d Hypn ot ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

III-3

Gen eral An esth et ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

III-4

Local An esth et ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

III-5

Skeletal Mu scle Relaxan ts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

III-6

An t iseizu re Dr ugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

III-7

Drugs for Degen erat ive Disorders of th e Cen t ral Ner vou s System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

III-8

Neu rolept ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

III-9

Drugs for Dep ressive an d An xiet y Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

III-10

Drugs for Bipolar Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

III-11

Drugs for Ch ildh ood Beh avioral Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

III-12

Op ioid An algesics an d An tagon ists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

III-13

Drugs of Abu se . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Sectio n IV: Cardiovascu lar an d Ren al System s Qu est ion s IV-1

Diuret ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

IV-2

Drugs for Isch em ic Hear t Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

IV-3

Drugs for Cardiac Failu re . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

IV-4

An t ihyp er ten sive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

IV-5

An t iarrhyth m ic Dr ugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

IV-6

An t ihyp erlip idem ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

IV-7

Drugs A ect ing Hem ostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

An sw ers an d Exp lan at ion s IV-1

Diuret ics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

IV-2

Drugs for Isch em ic Hear t Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

IV-3

Drugs for Cardiac Failu re . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

IV-4

An t ihyp er ten sive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

IV-5

An t iarrhyth m ic Dr ugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

IV-6

An t ihyp erlip idem ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

IV-7

Drugs A ect ing Hem ostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

Sectio n V: En docrin e System Qu est ion s V-1

Drugs for Hyp oth alam ic an d Pit u itar y Disord ers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

V-2

Drugs for Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

V-3

Cor t icosteroid s an d An t agon ist s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

V-4

Drugs for Gon adal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

V-5

Drugs for Bon e Hom eostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

V-6

Drugs for Diabetes Mellit us . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

An sw ers an d Exp lan at ion s V-1

Drugs for Hyp oth alam ic an d Pit u itar y Disord ers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

V-2

Drugs for Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

V-3

Cor t icosteroid s an d An t agon ist s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

Content s vii V-4

Drugs for Gon adal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

V-5

Drugs for Bon e Hom eostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321

V-6

Drugs for Diabetes Mellit us . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

Sectio n VI: Respirator y, Gast roin test in al, an d Hem atopoiet ic System s Qu est ion s VI-1

Drugs for Bron ch osp ast ic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

VI-2

Drugs for Gast roin test in al Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

VI-3

Drugs for Hem atopoiet ic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

An sw ers an d Exp lan at ion s VI-1

Drugs for Bron ch osp ast ic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

VI-2

Drugs for Gast roin test in al Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354

VI-3

Drugs for Hem atopoiet ic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359

Sectio n VII: In am m at ion an d Im m un om odulat ion Qu est ion s VII-1

Hist am in e an d Seroton in : Agon ists an d An tagon ists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

VII-2

Eicosan oids: Agon ist s, An tagon ists, an d In h ibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

VII-3

Non steroidal An t iin am m ator y Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

VII-4

Im m un om odu lat ing Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

VII-5

Drugs for Ar th rit is an d Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

An sw ers an d Exp lan at ion s VII-1

Hist am in e an d Seroton in : Agon ists an d An tagon ists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

VII-2

Eicosan oids: Agon ist s, An tagon ists, an d In h ibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

VII-3

Non steroidal An t iin am m ator y Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

VII-4

Im m un om odu lat ing Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392

VII-5

Drugs for Ar th rit is an d Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

Sectio n VIII: Ch em oth erapeut ic Drugs Qu est ion s VIII-1

Bacterial Cell Wall Syn th esis In h ibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400

VIII-2

Bacterial Protein Syn th esis In h ibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

VIII-3

In h ibitors of Bacterial Nu cleic Acid Syn th esis or Fun ct ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415

VIII-4

An t im ycobacterial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420

VIII-5

An t ifu ngal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

VIII-6

An t iviral Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

VIII-7

An t ip rotozoal Dr ugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

VIII-8

An th elm in t ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

VIII-9

An t in eop last ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439

An sw ers an d Exp lan at ion s VIII-1

Bacterial Cell Wall Syn th esis In h ibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446

VIII-2

Bacterial Protein Syn th esis In h ibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455

VIII-3

In h ibitors of Bacterial Nu cleic Acid Syn th esis or Fun ct ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462

VIII-4

An t im ycobacterial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466

viii Contents

VIII-5

An t ifu ngal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469

VIII-6

An t iviral Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473

VIII-7

An t ip rotozoal Dr ugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478

VIII-8

An th elm in t ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481

VIII-9

An t in eop last ic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484

Preface Th is book is a collect ion of m u lt ip le ch oice qu est ion s (MCQs) to p rom ote th e lear n ing of p h ar m acology in th e fram ew ork of preclin ical an d clin ical discip lin es. Th e m ain feat u res of th e book are th e follow ing: • Th e MCQs are all of th e t ype th at is used for th e step 1 m ed ical board exam s in th e Un ited St ates an d are w r it ten accord in g to Un ited St ates Med ical Licen sin g Exam in at ion (USMLE) gu id elin es (i.e., pat ien t-cen tered vign et tes). All qu est ion s are “on e best an sw er”; in m ost cases, th ere are ve an sw er ch oices, bu t in som e cases six or seven an sw er ch oices are given . • Becau se th e MCQs are abou t ph arm acology, each quest ion m en t ion s a dr ug or a dr ug class eith er in th e stem or as th e an sw er ch oices. • Each MCQ is provided w ith a level of di cu lt y, a learn ing object ive, th e correct an sw er, an d an explan at ion . • Th ere are th ree levels of di cu lt y: easy, m ediu m , an d h ard. • Th e learn ing object ive is a brief beh avioral statem en t w rit ten using an act ion verb. If a st u den t can perform th at act ion , t h en h e or sh e sh ou ld be able to an sw er the question correctly. The explanation in cludes both the reason s w hy a given an sw er is correct an d w hy th e dist ractors are w rong. • Many quest ions are related to th e highest levels of Bloom ’s taxon om y (e.g., in terpret at ion of data an d solut ion of problem s) rath er th an being sim ple recall quest ion s. • For each drug or drug class, th e con cept s asked by th e MCQs are related to m ode of act ion , ph arm acokin et ics, ph arm acodyn am ics, adverse e ects, interactions, or clinical u ses. • Most MCQs are in tegrated quest ion s, an d a good kn ow ledge of th e relevan t h u m an physiology, bioch em ist r y,

pathology, m icrobiology, and/or elem entary clinical m edicin e is a n ecessar y p rerequ isite to determ in e th e righ t an sw er to t h e qu est ion . Th erefore, t h e qu est ion w it h it s an sw er explan at ion can also be u sed as a p ow erfu l tool for review ing an d in tegrat ing th e m edical scien ce disciplin es. • Th e MCQs are grou ped in ch apters covering m ost topics p resen ted in st an d ard p h ar m acology text books. Th ere are 20 to 50 MCQs in each ch apter, tot aling over 1500 quest ion s. MCQs are th e learn ing tool m ost frequen tly used by m edical st uden ts. Th is book is in ten ded as an in tegrated tool for both course st udy an d board exam preparat ion . Because th e book is organ ized alon g clin ical rat h er t h an st r ict ly p h ar m acological lin es, it sh ou ld be u sefu l for both step1 an d step 2 exam preparat ion . Pharm acology is a fast-evolving disciplin e. The authors have ch ecked sou rces believed to be reliable, in order to provide in form at ion th at is in accordan ce w ith th e cu rren tly accepted st an dards. How ever, th e au th ors are aw are th at in several in st an ces th e ph arm acoth erapy of disease is st ill con t roversial. Th ey h ave t ried, as m u ch as p ossible, to avoid qu est ion s addressing con t roversial issu es. Th is book is n ot in ten ded to be a subst it u te for ph arm acology textbooks. St u den t s are st rongly advised to con su lt th eir textbooks of ph arm acology for m ore in -d epth coverage of th e su bject m at ter. Mario Babbini, MD, PhD Mary Thom as, PhD

ix

I General Principles of Pharm acology Questions: I-1 Pharm acokinetics Di cult y level: Easy

Di cult y level: Easy

1. A 22-year-old w om an su ering from asth m a w as prescribed

4. A 12-year-old boy recen tly diagn osed w ith t ype 1 diabetes

albu terol by in h alat ion . Albu terol is a bron ch od ilat in g d r ug

started a therapy w ith t w o daily subcutan eous adm inistrations

w it h a m olecu lar w eigh t of 239 dalton s. W h ich of t h e fol-

of in sulin . W h ich of th e follow ing perm eat ion processes best

low in g p er m eat ion p rocesses m ost likely accou n ted for t h e

explain s th e absorpt ion of in sulin from th e site of inject ion ?

t ran sfer of th e d rug th rough th e bron ch ial m u cosa?

A. Bu lk ow t ran sp or t

A. Aqu eou s di u sion

B. Lipid di usion

B. Lipid di u sion

C. Facilit ated di usion


D. En docytosis

D. En docytosis

E. Act ive t ran sp or t

E. Act ive t ran sp or t

Di cult y level: Hard Di cult y level: Easy

5. An 85-year-old m an w as recen tly adm it ted to a n ursing facil-

2. A 34-year-old m an on vacat ion in Mexico w as adm it ted to th e

it y. Diseases listed in h is m edical record on adm ission w ere

h ospital because of vom it ing, double vision , an d m uscular pa-

dep ression w ith an xiet y sym ptom s, at rial brillat ion , ch ron ic

ralysis. Th e m an reported th at h e h ad eaten som e can n ed food

obst ruct ive pulm on ar y disease, an d osteoar th rit is. Medica-

from a local ven dor th e previous day. After a physical exam -

t ion s taken orally by th e p at ien t in clu ded th e follow ing:

in at ion , a presu m pt ive diagn osis of bot u lism w as m ade. It is

Ser t ralin e (base, pKa = 9.5)

kn ow n th at bot ulin um toxin cau ses paralysis by get t ing in -

Diazepam (base, pKa = 3.0)

side th e axon term in als of m otor n er ves, w h ere it in h ibits th e release of acet ylch olin e. Bot u lin u m toxin is a p rotein w ith a

Am iodaron e (base, pKa = 7.4)

m olecular w eigh t greater th an 100,000 dalton s. W h ich of th e

Th eop hyllin e (acid, pKa = 8.8)

follow ing perm eat ion processes m ost likely accoun t s for th e

Ibuprofen (acid, pKa 4.8)

t ran sfer of th e toxin th rough th e n er ve cell m em bran e? A. Aqu eou s di u sion B. Lipid di u sion C. Facilit ated di usion D. En docytosis E. Filt rat ion

Di cult y level: Easy 3. A 51-year-old w om an su ering from hyperthyroidism w as adm in istered an oral solut ion of radioact ive iodin e to dest roy h er thyroid glan d. W h ich of th e follow ing perm eat ion pro cesses m ost likely accoun ted for th e t ran sfer of th e drug across th e thyroid cell m em bran e? A. Act ive t ran sp or t B. Lipid di u sion C. Facilit ated di usion D. En docytosis E. Aqu eou s di u sion

Sh ortly after adm inist rat ion, w hich of the follow ing drugs w as m ost likely con cen t rated in side th e p at ien t’s gast ric cells? A. Ser t ralin e B. Diazepam C. Am iodaron e D. Th eophyllin e E. Ibuprofen

Di cult y level: Medium 6. A 17-year-old boy took a tablet of n aproxen for a h eadach e. Nap roxen is a w eak acid w it h a p Ka of 5.2. W h at p ercen t age of t h e d r ug w as m ost likely w ater solu ble in t h e p at ien t ’s plasm a? A. 1% B. 24% C. 50% D. 76% E. 99% F.

> 99%

1

2

General Principles of Pharm acology

Di cult y level: Medium


7. A 69-year-old w om an w as brough t to a local h ospit al em er-

10. Du r in g a p h ase 1 clin ical t r ial, fou r d i eren t oral d osage

gen cy dep ar t m en t by h er son , w h o rep or ted th at h is m oth er

for m s of t h e sam e d ose of a d r ug w ere ad m in istered to a

w as fou n d leth argic, disorien ted, an d com bat ive a few h ou rs

h ealt hy volu n teer on fou r sep arate occasion s. Th e p lasm a

earlier. Addit ion al h istor y revealed th at sh e h ad ingested a

con cen t rat ion −t im e cur ves are plot ted below.

large n u m ber of aspirin tablet s in a su icide at tem pt . An ap propriate th erapy w as in st it u ted, w h ich in clu ded th e adm in -

W

ist rat ion of sodiu m bicarbon ate to in crease th e elim in at ion of salicylate. W h ich of th e follow ing best exp lain s th e m ech a-

[

A. Decreased t ubular act ive t ran sport of salicylate

D

r

u

g

]

n ism of th is in creased elim in at ion ?

X

B. Decreased ren al biot ran sform at ion of salicylate

Y Z

C. Decreased bioavailabilit y of salicylate D. Urin ar y ion t rap p ing of salicylate E. In creased glom erular lt rat ion of salicylate

Tim e

W h ich of th e follow ing feat ures best explain s w hy form u la-

Di cult y level: Medium 8. A 63-year old m an recen t ly d iagn osed w it h hyp er ten sion st ar ted a th erapy w ith hydroch loroth iazide, on e t ablet daily. Hydroch loroth iazide is an acidic dr ug w ith a pKa of abou t 9.

tion W produces the largest plasm a concentration−tim e cur ve of th e drug? A. High est absorpt ion th rough gu t w all

W h ich of th e follow ing part s of th e digest ive t ract m ost likely

B. Low est rst-pass e ect

rep resen t s th e m ain site of absorpt ion of th at dr ug?

C. Low est h epat ic clearan ce D. High est volu m e of dist ribu t ion

A. Oral m ucosa

E. Low est d rug elim in at ion

B. Stom ach C. Sm all in test in e


D. Colon

11. A 26-year-old m an becam e in ebriated after drin king several

E. Rect u m

glasses of alcoh olic beverages at a p art y. Eth an ol is a polar, n on ion izable drug w ith an approxim ate m olecular w eigh t of

Di cult y level: Easy 9. Th e ph arm acokin et ic proper t ies of ve n ew drugs (P, Q, R, S, an d T) w ere st udied in h ealthy volun teers. Th e sam e dose of

46 dalton s. W h ich of th e follow ing p erm eat ion processes m ediated th e m an’s in test in al absorpt ion of eth an ol?

each dr ug w as adm in istered in t raven ously (IV) an d orally to


th e sam e su bject on t w o separate occasion s. Th e result s w ere

B. Bulk ow t ran spor t

th e follow ing:

C. Facilit ated d i u sion D. Act ive t ran sp or t

Drug

E. En docytosis

AUCOral (mg h/ L)

AUCIV (mg h/ L)

P

50

600

Q

200

2000

12. A 44-year-old m an took a large dose of acetam in oph en in

R

30

400

aqu eou s solu t ion to t reat an excr u ciat in g h eadach e. Tw o

S

100

120

h ou rs later, t h e p ain w as n ot dim in ish ed . Becau se acet -

T

45

90

am in op h en sh ou ld be e ect ive in abou t 30 m in u tes after

Abbreviations: AUC, area under the curve; IV, intravenous.

W h ich of th e follow ing drugs m ost likely h as th e h igh est oral bioavailabilit y? A. Drug P B. Drug Q C. Drug R D. Drug S E. Drug T

Di cult y level: Hard

it s oral ad m in ist rat ion , w h ich of t h e follow ing con d it ion s m ost likely d elayed t h e oral absor pt ion of t h e d r ug in t h is p at ien t? A. A m oderate in crease in in test in al perist alsis B. Th e p resen ce of st rong p ain C. Th e ad m in ist rat ion of th e drug in aqu eou s solu t ion D. A large volum e of dist ribut ion of th e drug E. A ver y low clearan ce of th e drug

Questions: I-1 Pharm acokinetics 3 Di cult y level: Medium

W h ich of th e follow ing statem en t s best explain s w hy several

13. A 22-year-old w om an w as adm it ted to th e em ergen cy de-

drugs, including m ethotrexate, cann ot easily enter the brain?

partm ent after a car accident. The w om an had extensive brain

A. Cerebrospin al u id pressure is low er th an cerebral per-

t rau m a an d m u lt iple fract u res. Sh e com p lain ed of severe

fu sion p ressu re.

p ain , an d th e at ten ding physician plan n ed to adm in ister

B. Th e p H of cerebrospin al u id is low er th an p lasm a p H.

m orp h in e. Th e physician kn ew th at th e dose sh ou ld be care-

C. Many drugs are bou n d to protein an d can n ot cross brain

fu lly t it rated becau se th e en t r y of m orph in e in to th e p at ien t’s cen t ral n er vou s system (CNS) w as m ost likely h igh er

cap illaries. D. En doth elial cells of brain capillaries an d ch oroid plexus

th an n orm al. W h ich of th e follow ing factors is m ost likely to h ave increased m orphine entry into the CNS of this patient?

h ave t igh t ju n ct ion s. E. Most drugs are com p letely ion ized in blood.

A. Th e h igh rst-pass e ect of th e drug B. Th e brain t raum a of th e pat ien t


C. Th e young age of th e pat ien t

17. Th e abilit y of ve di eren t drugs (P, Q, R, S, an d T) to cross

D. Th e low clearan ce of th e drug

th e p lacen ta w as st u died in laborator y an im als. Th e follow -

E. Th e h igh ion izat ion of th e drug

ing data w ere obtain ed.


Drug

14. A 67-year-old w om an recen t ly d iagn osed w it h at r ial br il-

Molecular Weight (daltons)

Protein Bound in Maternal Plasma (%)

Ionized in Maternal Plasma (%)

lat ion st ar ted t reat m en t w it h aten olol, 100 m g/d . W it h t h is

P

20

0

100

d ose, t h e p ercen t age of aten olol bou n d to p lasm a p rotein s

Q

250

99

50

is about 5%. W h ich of th e follow ing w ou ld h ave been th e

R

4500

25

10

bou n d percen t age of aten olol if a d ose of 50 m g/d h ad been

S

500

10

90

T

2000

15

30

adm in istered to th e sam e p at ien t? A. 2.5% B. 5%

W h ich of th e follow ing drugs m ost likely crossed th e pla-

C. 10%

cen t a at th e fastest rate?

D. 1.25%

A. Drug P

E. 2%

B. Drug Q C. Drug R


D. Drug S

15. A 34-year-old m an recen tly diagn osed w ith gran d m al epi-

E. Drug T

lep sy st ar ted t reat m en t w it h valp roic acid , an an t iseizu re d rug w ith a pKa of 5. W h at percen tage of th e drug w as m ost


likely lipid solu ble in th e p at ien t’s du oden al lu m en (assu m -

18. A 52-year-old w om an su ering from rh eum atoid ar th rit is

ing pH = 7 in th e lu m en )?

star ted a t reat m en t th at in clu ded in ixim ab, a m on oclon al

A. 1%

an t ibody again st t u m or n ecrosis factor-α (TNF-α ). Th e drug

B. 24%

h as a volum e of dist ribut ion of about 3 L. W h ich of th e fol-

C. 50%

low in g is m ost likely t h e m ain site of d ist r ibu t ion of t h is

D. 76%

d rug?

E. 99%

A. Fat t issu e B. Plasm a


C. Ext racellular uids

16. A 4-year-old boy su ering from acu te lym ph oblast ic leu ke-

D. Cell cytosol

m ia w as abou t to receive an in t rath ecal inject ion of m eth ot rexate, a drug th at can n ot cross th e blood−brain barrier.

E. Tot al body w ater

4




19. A 36-year-old w om an recen t ly diagn osed w it h t r ich om on i-

22. A n ew d r ug w as st u d ied in a h ealt hy volu n teer d u r ing a

asis st ar ted a t reat m en t w it h m et ron idazole. Th e d r ug h as

p h ase 1 clin ical t r ial. Ur in e an d p lasm a sam p les w ere col-

a h ep at ic clearan ce of 4.86 L/h an d a ren al clearan ce of

lected 1 h ou r after t h e in t raven ou s ad m in ist rat ion of a test

0.54 L/h . On th e assu m pt ion th at on ly th e liver an d kid n ey

dose. Drug concentration was 40 m g/m L in urine and 1 m g/m L

are involved in th e elim in at ion of th is d rug, w h at p ercen tage

in p lasm a. Th e u r in e ou t p u t of t h is su bject w as 1.44 L/d .

of th e adm in istered drug w ill be elim in ated by th e liver?

W h ich of th e follow ing w as m ost likely th e ren al clearan ce of

A. 20%

th e drug, in m L/m in ?

B. 40%

A. 40

C. 50%

B. 30

D. 60%

C. 20

E. 70%

D. 50

F.

E. 60

90%

F.

10

Di cult y level: Medium 20. Th e p h arm acokin et ic propert ies of ve n ew drugs (P, Q, R, S, an d T) w ere st u died in laborator y an im als. Th e drugs w ere given orally, an d th e results are sh ow n below.

Di cult y level: Easy 23. A 10-m g dose of a n ew drug th at follow s

rst-order, on e-

com p ar t m en t m od el kin et ics w as given in t raven ou sly to h ealthy subject s in a ph ase 1 clin ical t rial. Th e volu m e of dis-

Drug

Percentage of Drug Reaching the Portal Vein

Hepatic Clearance (mL/min)

t ribu t ion (Vd ) of th e drug t urn ed out to be 80 L. W h ich of th e follow ing w ould h ave been th e volum e of dist ribut ion of th e drug (in liters) if th e adm in istered dose w ere 20 m g?

P

90

20

Q

86

1000

A. 40

R

50

450

B. 80

S

2

100

C. 240

T

10

30

D. 160 E. 120

W h ich of th e follow ing drugs m ost likely h as th e h igh est oral bioavailabilit y?


A. Drug P

24. A 45-year-old m an su ering from epilepsy h ad been receiv-

B. Drug Q

ing carbam azep in e, on e t ablet daily. Th e d r ug h as a tot al

C. Drug R

clearan ce of 63 L/h an d a h ep at ic clearan ce of 62 L/h . Th e

D. Drug S

m an w as recen t ly d iagn osed w it h a skin in fect ion d u e to

E. Drug T

Mycobacterium m arinum , an d t reat m en t w ith rifam pin an d eth am butol w as st ar ted. Kn ow ing th at rifam pin is a poten t

Di cult y level: Medium 21. W h en st udied in h ealthy volun teers, th e oral bioavailabilit y of a n ew drug t urn ed out to be 20%. Kn ow ing th at in th is case

in ducer of m icrosom al en zym es, w h ich of th e follow ing ch anges m ost likely occurred to th e ph arm acokin et ics of carbam azep in e?

th e en t ire adm in istered dr ug reach ed th e p or tal circu lat ion ,

A. Th e h epat ic clearan ce of th e drugs decreased .

w h ich of th e follow ing w ill be th e h epat ic clearan ce (in m L/

B. Th e rst-pass loss of th e drug decreased .

m in ) of th e drug?

C. Th e ren al clearan ce of th e drug decreased.

A. 500 B. 800 C. 1200 D. 1500 E. 2000

D. Th e volu m e of d ist ribu t ion of th e drug in creased. E. Th e h alf-life of th e drug d ecreased .

Di cult y level: Medium 25. A 59-year-old Japan ese m an w ith at rial

brillat ion pre-

sen ted to h is p hysician com p lain ing of red u rin e. Th e m an h ad been receiving a stan dard dose of w arfarin , w h ich is an an t icoagu lan t drug biot ran sform ed by CYP2C9 isozym e. W h ich of th e follow ing w as th e m ost likely cause of th e pat ien t’s disord er?

Questions: I-1 Pharm acokinetics 5 A. In creased protein bin ding of w arfarin


B. Decreased ren al excret ion of w arfarin

29. A 22-year-old m an su ering from adult aut ism an d violen t

C. Gen et ic polym orph ism of CYP2C9

beh avior st ar ted a t reat m en t th at in clu ded bu sp iron e, a drug

D. Decreased m etabolism of CYP2C9

w ith a large

E. In creased CYP2C9 syn th esis in a person of Asian origin

m acokin et ic prop er t ies of th e drug w as m ost likely a ected

rst-pass e ect . W h ich of th e follow ing ph ar-

by th is large rst-pass e ect?

Di cult y level: Easy 26. Th e p h arm acokin et ics of a n ew drug w as st u died in labora-

A. Volum e of dist ribu t ion B. Oral bioavailabilit y

tor y an im als. Th e drug w as given orally, an d th e follow ing

C. Ren al clearan ce

results w ere obt ain ed:

D. Su blingu al bioavailabilit y

Percen t reach ing th e port al circu lat ion : 40%

E. In t ram uscular bioavailabilit y

Liver clearan ce: n egligible Liver blood

ow in th e an im al w as 1000 m L/m in . W h ich of

th e follow ing w ou ld be th e oral bioavailabilit y of th e dr ug? A. 1.0 B. 0.4 C. 0.1 D. 2.2 E. 0.6 F.

0.8

Di cult y level: Easy 30. A 47-year-old m an recen tly diagn osed w ith systolic h ear t failure st arted a t reat m en t th at in cluded furosem ide. Th e d rug h as a tot al clearan ce of abou t 136 m L/m in , an d about 66% of th e drug is excreted as su ch in th e u rin e. On th e assum ption that, in this case, only the liver and kidneys are involved in drug elim ination, w hich of the follow ing w as m ost likely th e ren al clearan ce of fu rosem ide (in m L/m in )? A. 90

Di cult y level: Medium 27. A 35-year-old Cau casian m an com plain ed to h is physician of t ingling sen sat ion in h is lim bs an d n oted th at h is arm s som et im es felt h eavy. Th e m an , recen tly diagn osed w ith pu lm on ar y t uberculosis, h ad been receiving ison iazid an d rifam pin for 2 m on th s. He w as diagn osed w ith periph eral n europ athy, a kn ow n adverse e ect of ison iazid. W h ich of th e follow ing even t s m ost likely caused th e pat ien t’s sym ptom s an d sign s? A. Rifam pin -in duced in h ibit ion of ison iazid m etabolism B. Worsen ing of th e disease, despite th e th erapy C. Allergic react ion to rifam pin D. In h erited de cien cy of N-acet ylt ran sferase E. Allergic react ion to ison iazid

B. 70 C. 110 D. 25 E. 81 F.

16

Di cult y level: Hard 31. The pharm acokinetics of a new drug that followed rst- order, on e-com par t m en t m odel kin et ics w as st udied in a h ealthy volunteer. A 20-m g dose w as given intravenously. The plasm a con cen t rat ion of t h e d r ug t u r n ed ou t to be 2 m g/L in it ially an d 1 m g/L 2 h ou rs later. W h ich of th e follow ing w as m ost likely th e total clearan ce of th e drug (in L/h )? A. 2.5

Di cult y level: Medium 28. A 49-year-old obese m an recen tly diagn osed w ith vasospast ic angin a st arted a t reat m en t w ith n ifedip in e. Th e d rug h as a volu m e of dist ribu t ion (Vd ) of about 55 L in a 70-kg person , bu t in th is obese p at ien t , th e Vd t u rn ed ou t to be 110 L. Th e stan dard load ing dose of n ifedip in e for a p at ien t w eigh ing 70 kg is 30 m g. W h ich of th e follow ing sh ou ld be th e th erapeu t ic loading dose adm in istered to th is p at ien t (in m g) in order to ach ieve th e sam e t arget con cen t rat ion ? A. 20 B. 40 C. 60 D. 90 E. 120 F.

150

B. 8.4 C. 5.5 D. 6.7 E. 3.5 F.

4.9

6



A. 250

32. Th e p h arm acokin et ic propert ies of ve n ew drugs (P, Q, R, S,

B. 390

an d T) w ere st u died in laborator y an im als. A 100-m g dose of

C. 420

each drug w as adm in istered in t raven ously to th e sam e an i-

D. 315

m al on

E. 180

ve sep arate occasion s. Th e plasm a con cen t rat ion −

t im e cu r ves for each drug are depicted in th e gu re below : 100

F.

115


P

10

(

g

/

m

L

)

35. A 23-year-old h ealthy m ale volun teer received an intraveQ

n ous dose of 2 m g of a n ew drug during a clin ical t rial. Th e

R

d rug follow ed a rst-order, on e-com part m en t m odel kin etics an d h ad a volu m e of dist ribu t ion of 10 L. After 6 h ou rs th e p lasm a con cen t rat ion of th e drug w as 50 µg/L. W h ich of th e

1

follow ing w as m ost likely th e h alf-life of th e drug (in h ours)?

T

A. 1

C

o

n

c

e

n

t

r

a

t

i

o

n

S

B. 2 C. 3 0.1

D. 4

Tim e (h)

E. 5 W h ich of t h e follow in g d r ugs h as t h e largest volu m e of

F.

6

d ist ribut ion ? A. Drug P


B. Drug Q

36. Th e

gu re below dep ict s th e p lasm a con cen t rat ion −t im e

C. Drug R

cu r ves for fou r drugs (W, X, Y, an d Z) given by IV in fu sion to

D. Drug S

th e sam e laborator y an im al on fou r sep arate occasion s.

E. Drug T 50

W

be 1 m g/L. W h ich of th e follow ing w as m ost likely th e oral bioavailabilit y of th e drug? A. 0.1 B. 0.5

L m / g m ( n o i t a r t n

th e th eoret ical p lasm a con cen t rat ion at t im e 0 t u rn ed ou t to

Z

20

e

t ribu t ion of 100 L. After th e oral adm in ist rat ion of 200 m g,

Y

c

on e-com par t m en t m odel kin et ics an d h ad a volum e of dis-

X

30

n

rst-order,

40

o

volun teers. It w as foun d th at th e drug follow ed

C

33. Th e ph arm acokin et ics of a n ew drug w as st u died in h ealthy

)


10 0

0

1

2

C. 0.8

3

4 5 6 Tim e (h)

7

8

9

10

D. 1.0

W h ich of th e follow ing drugs h as th e sh or test h alf-life?

E. 2.3

A. Drug W

F.

B. Drug X

1.6

C. Drug Y


D. Drug Z

34. A 32-year-old m ale cocain e addict w as brough t un con scious to th e em ergen cy depar t m en t . A frien d stated th at th e m an


h ad intravenously self-injected an u n kn ow n d ose of cocain e

37. Th e p h arm acokin et ics of a n ew drug w as st u died in a h ealthy

2 h ou rs earlier. An im m ediate lab an alysis in dicated th at th e

volu n teer. Th e d r ug w as given by in travenous in fu sion at a

p lasm a level of cocain e w as 0.75 m g/L. Cocain e h as a volum e

rate of 30 m g/h . Th e plasm a con cen t rat ion −t im e cur ve of

of dist r ibu t ion of abou t 130 L an d a h alf-life of abou t 1 h ou r.

th e drug is dep icted below.

W h ich of th e follow ing w as m ost likely th e injected dose of cocain e (in m g)?

Questions: I-2 Pharm acodynam ics 7 Di cult y level: Medium

4

2

e

m

n

L

t

)

r

a

t

i

o

n

(

m

m in istered to a laborator y an im al.

/

c

g

1

a

t

i

o

n

(

n o C

gu re below depict s th e con cen t rat ion −t im e cu r ve of a

n ew drug after a single in t raven ous dose of 20 m g w as ad-

3

g

/

m

L

)

39. Th e

e

n

12 14 16

c

6 8 10 Tim e (h)

n

4

o

2

C

0

t

r

0

W h ich of th e follow ing is m ost likely th e tot al clearan ce of th e drug (in L/h )?

10 9 8 7 6 5 4 3 2 1 0

0

A. 4

2 4 6 8 10 12 Tim e (h)

B. 6

W h ich of t h e follow ing dr ugs d oes t h e n ew agen t m ost

C. 2

resem ble?

D. 10

A. At ropin e

E. 14

B. Propran olol

F.

C. Eth an ol

16

D. Ph enyleph rin e


E. Clon idin e

38. Th e p h arm acokin et ics of a n ew drug follow ing zero-order

F.

Dobutam in e

kinetics w as studied in a healthy volunteer. Three hours after th e in t raven ou s adm in ist rat ion of a test dose, th e plasm a


con cen t rat ion of th e drug w as 8 m g/L, an d 1 h our later it w as

40. Th e p h arm acokin et ics of a n ew drug w as st u died in a h ealthy

7 m g/L. W h ich of t h e follow in g w as m ost likely t h e p lasm a

volun teer. Th e drug follow ed

con cen t rat ion of t h e d r ug (in m g/L) im m ed iately after d r ug

m od el kin et ics an d h ad a h alf-life of 3 h ou rs. An in t raven ou s

adm in ist rat ion ?

in fusion of th e drug w as st ar ted at 8:00 a.m . A blood sam ple

A. 9

t aken at 2:00 p .m . of th e sam e day sh ow ed a p lasm a dr ug

B. 32

con cen t rat ion of 60 µg/m L. W h ich of th e follow ing w as m ost

C. 11

likely th e p lasm a con cen t rat ion of th at dr ug (in µg/m L) at th e

D. 16

steady st ate?

E. 64

A. 100

F.

B. 60

5

rst-order, on e-com par t m en t

C. 80 D. 30 E. 40 F.

120

Questions: I-2 Pharm acodynam ics Di cult y level: Medium

C. Th e β-receptor n um ber in creased.

1. A 68-year-old m an recen tly diagn osed w ith at rial brillat ion

D. Most β receptors becam e p h osp h or ylated .

star ted th erapy w ith aten olol, a β-receptor blocker. W h ich of th e follow ing ch anges m ost likely occu rred in cardiac m yocytes du ring th e rst 2 w eeks of th erapy? A. Sp are β receptors becam e act ivated. B. Th e G-protein n um ber decreased.

E. Th e abilit y to respon d to in t racellular cyclic aden osin e m on oph osph ate (cAMP) declin ed.

8




2. A n ew drug w as tested in an in vit ro system . It w as fou n d th at

6. A 2-year-old boy w as adm it ted to th e em ergen cy depar t m en t

on ly on e en an t iom er of th e racem ic pair bou n d substan t ially

after a gen eralized ton ic-colon ic seizure. His m oth er reported

to a speci c receptor, w h ereas th e oth er en an t iom er sh ow ed

that the boy apparently ingested several tablets of propranolol,

n egligible bin ding. W h ich of th e follow ing term s best de n es

a β-blocker, w h ich h e h ad foun d in h is fath er’s dresser draw er.

th is propert y?

Vital sign s on adm ission w ere blood pressure 85/50 m m Hg,

A. In t rin sic act ivit y

h ear t rate 40 beat s per m in u te (bpm ), respirator y rate 20/m in .

B. A n it y

Th e boy received an in t ram u scu lar inject ion of glu cagon , a

C. Stereoselect ivit y

horm one that activates glucagon receptors in the h eart, caus-

D. Poten cy

ing a sign i can t in crease in h ear t con t ract ilit y. W h ich of th e

E. Variabilit y

follow ing term s best de n es th e an t agon ism bet w een gluca-

F.

Maxim al e

cacy

gon an d β-blockers? A. Ch em ical


B. Fu n ct ion al

3. A 14-year-old girl su ering from season al rh in it is star ted a

C. Com p et it ive

t h erapy w it h lorat ad in e, a d r ug t h at bin d s to H 1 h ist am in e receptors. W h ich of th e follow ing term s describes a ch aracterist ic of loratadin e bin ding to th e H1 receptor? A. In t rin sic act ivit y

E. Ph arm acological

Di cult y level: Medium 7. Th e e ect of a n ew auton om ic drug w as tested on a h ealthy

B. Poten cy C. Maxim al e

D. Ph arm acokin et ic

cacy

volun teer du ring a clin ical t rial. Th e subject w as t reated w ith

D. A n it y

salin e or w ith th e drug, an d cardiac rate w as recorded at rest

E. Receptor act ivat ion

or after exercise. Th e result s are reported below. Heart Rate (bpm)


Treatment

4. Tw o n ew drugs w ere tested in laborator y an im als. W h ich of th e follow ing drug param eters w as m ost likely recorded to est im ate th e relat ive poten cy of both drugs? A. Th e th erapeut ic in dex of both drugs

At Rest

After Exercise

Saline

70

150

Drug

85

100

Abbreviation: bpm , beat s per m inute.

B. Th e m axim al respon ses produ ced by each drug

W h ich of th e follow ing term s best de n es th e tested dr ug?

C. Th e graded log dose−respon se cur ve of both drugs

A. Non com p et it ive an tagon ist

D. Th e volum e of dist ribut ion of both drugs

B. Com p et it ive an t agon ist

E. Th e clearan ce of both dr ugs

C. Par t ial agon ist D. Physiologic an t agon ist


E. Fu ll agon ist

5. A 65-year-old m an su ering from osteoar th rit is h as been t ak-

F.

Ch em ical an tagon ist

ing n ap roxen , 500 m g daily for 1 m on th . Th e drug w as e ect ive, bu t th e p at ien t su ered from n au sea an d h ear tbu rn . Th e


physician decided to t r y an oth er n on steroidal an t iin am m a-

8. A 65-year-old w om an su er in g from at r ial

br illat ion h ad

tor y drug (NSAID) an d prescribed celecoxib, a drug ~5 t im es

been t aking a drug to t reat th is con dit ion for 6 m on th s. Th e

m ore poten t th an n aproxen , w ith n egligible gast roin test in al

drug h ad n o in t rin sic act ivit y an d bou n d reversibly to β 1 re-

sid e e ect s. W h ich of t h e follow ing w ou ld be t h e m ost ap p rop r iate daily d ose of celecoxib (in m g) to p rescr ibe to t h e pat ien t?

ceptors. W h ich of th e follow ing term s best de n es th is drug? A. Par t ial agon ist B. Fu n ct ion al an tagon ist

A. 50

C. Inverse agon ist

B. 1000

D. Non com p et it ive an tagon ist

C. 10

E. Com p et it ive an t agon ist

D. 25

F.

E. 100 F.

75

Fu ll agon ist

Questions: I-2 Pharm acodynam ics 9 Di cult y level: Medium


9. A n ew β-blocker w as tested in h ealthy volun teers. Th e cu -

12. Th e

gu re below d ep ict s th e in vit ro log dose−respon se

m u lat ive frequ en cy dist ribu t ion of su bject s sh ow ing a de-

cu r ves of ve di eren t drugs (P, Q, R, S, an d T) act ing on th e

crease of 10 bp m in th e h eart rate w as p lot ted again st th e log

sam e receptor.

d ose. W h ich of th e follow ing drug param eters can be determ in ed from th is cu m u lat ive frequ en cy d ist ribu t ion ?

P

Q

R

S

T

t

n it y

e

f

f

e

B. Median e ect ive dose

u

m

C. Th erapeut ic in dex

60 40

a

x

i

m

D. Th erapeut ic w in dow cacy

M

E. Maxim al e

80

c

A. Receptor a

(%

)

100

20 0

log dose

Di cult y level: Easy 10. In th e

gu re below , cu r ve X d ep ict s t h e in vit ro log d ose−

respon se cu r ve for a full α 1 agon ist on con t ract ion of vascu -

W h ich of th e follow ing drugs h as th e h igh est ED50 ? A. Drug P

lar sm ooth m u scle. W h ich of th e cu r ves best dep ict s th e log

B. Drug Q

dose−resp on se cu r ve of th at agon ist w h en a

C. Drug R

xed dose of a

100

e f f e m u m i x a M

P

60

Q

R

13. A 65-year-old w om an w h o h ad been adm it ted to the hospital

S

w ith a m yocardial in farct ion developed ven t ricu lar t achycardia and received an intravenous injection of lidocaine. Her

20

card iologist kn ew t h at t h e d ose given m u st be w it h in t h e range of d oses t h at h ave a h igh p robabilit y of t h erap eu t ic

log dose

success. W hich of the follow ing term s best de nes this range?

A. Cu r ve P

A. In t rin sic act ivit y

B. Cu r ve Q

B. E cacy

C. Cu r ve R

C. Poten cy

D. Cu r ve S

D. Th erapeut ic in dex

E. Cu r ve T

E. Th erapeut ic w in dow F.

Di cult y level: Medium 11. The gure below depicts the in vitro log dose−response curves of ve di eren t drugs (P, Q, R, S, an d T). W h ich of th e follow ing pairs of drugs can fully act ivate th e sam e receptors? P

R

S

Q

% ( t c x a M

14. A 67-year-old m an su ering from term in al can cer st arted an algesic t reat m en t w ith an opioid dr ug. Kn ow ing th at toleran ce to op ioid s is pron ou n ced, w h ich of th e follow ing dr ug

T

t reat m en t? A. Maxim al e

cacy

B. Median e ect ive dose

20

C. Th erapeut ic in dex

0

A. Drugs P an d Q B. Drugs P an d R C. Drugs P an d S D. Drugs Q an d T E. Drugs Q an d S F.


40

i

m

u

m

e

f

f

e

80 60

Resp on se variabilit y

param eters w as m ost likely in creased after a few days of

)

100

E. Drug T


40

0

D. Drug S

T

X

80

c

t

(

%

)

com pet it ive α 1 an t agon ist is given con com it an tly?

Drugs R an d S

D. Poten cy log dose

E. Half-life

10



A. Addit ive e ect

15. A 17-year-old girl star ted sm oking 1 m on th ago, an d n ow

B. Poten t iat ion

sh e is sm oking 5 to 10 cigaret tes daily. Sh e h as n ot iced th at

C. Syn ergism

th e

D. Sen sit izat ion

rst cigaret te of th e day often cau ses m ild tachycardia,

w h ich does n ot usually occur w ith th e follow ing cigaret tes.

E. Reverse toleran ce

W h ich of t h e follow ing ter m s best de n es t h is toleran ce p at tern ?


A. Cross-toleran ce

19. A 45-year-old w om an recently diagnosed w ith a urinary tract

B. Tachyp hylaxis

in fect ion st ar ted t h erapy w it h a t r im et h op r im −su lfam e-

C. Ph arm acokin et ic toleran ce

thoxazole com bination. Both trim ethoprim and sulfam ethox-

D. In n ate toleran ce

azole are bacteriost at ic dr ugs w h en given alon e. How ever, a

E. Sen sit izat ion

bactericidal e ect is obt ain ed w h en th e t w o drugs are given in com bin at ion . W h ich of th e follow ing term s best de n es


th is drug in teract ion ?

16. A 64-year-old m an w ith term in al can cer h ad been su ering

A. Addit ive e ect

from con t in u ou s p ain an d star ted t reat m en t w ith m orp h in e.

B. Poten t iat ion

After a few days of t reat m en t , th e in it ial dose w as n o longer

C. Syn ergism

e ect ive, an d th e physician gradu ally in creased th e dose,

D. Reverse toleran ce

kn ow ing th at ph arm acodyn am ic toleran ce m ost likely h ad

E. Sen sit izat ion

occurred. W h ich of th e follow ing best explain s th e m ech an ism of toleran ce in th is pat ien t?


A. Accelerated m orph in e m etabolism

20. A 2-year-old girl w as ru sh ed to th e em ergen cy depar t m en t

B. In creased a

n it y of receptors to m orph in e

after ingest ing several tablet s of a m edicat ion con t ain ing

C. Decreased bin ding of m orph in e to plasm a protein s

iron . An em ergen cy t reat m en t w as st arted th at in clud ed th e

D. Decreased m orph in e receptor den sit y

intraven ous adm inistration of deferoxam ine. This drug is able

E. Decreased con cen t rat ion of m orph in e in th e brain

to com bin e w it h iron in p lasm a to for m an in act ive com p lex an d th erefore to an t agon ize iron e ects. W h ich of th e


follow ing term s best de n es th is an tagon ism ?

17. A 17-year-old boy drank increasing am ounts of alcohol w hen

A. Com p et it ive

at ten ding parties. He noticed that lately h e w as able to bet ter

B. Non com p et it ive

tolerate alcoh ol e ect s an d asked h is physician th e reason

C. Fu n ct ion al

for th is. Th e physician said th at ph arm acodyn am ic toleran ce

D. Ch em ical

h ad probably occurred. W h ich of th e follow ing act ion s m ost

E. Ph arm acokin et ic

likely m ediated th is toleran ce? A. Decreased concentration of the drug at the site of action B. Hom eost at ic adapt ive ch anges th at cou n teract th e drug e ect

Di cult y level: Easy 21. A n ew dr ug w as tested in an in vit ro system . Th e relat ion sh ip bet w een th e con cen t rat ion of th e drug an d th e associat ion

C. Decreased bioavailabilit y of th e drug

and dissociation of the drug−receptor com plex w as evaluated.

D. In creased biot ran sform at ion of th e drug

W h ich of th e follow ing factors regulates th is relat ion sh ip?

E. In creased n u m ber of drug receptors

A. Th e p h arm acological respon se B. Th e volu m e of d ist ribu t ion of th e drug


C. Th e tot al clearan ce of th e drug

18. A 46-year-old w om an com plain ed to h er physician th at th e

D. Th e law of m ass act ion

sedat ive e ect of th e drug sh e w as t aking h ad in creased su b stan t ially. Th e w om an , w h o w as su ering from gen eralized an xiet y disorder, h ad been t aking diazepam , on e tablet daily. A few days earlier, sh e h ad st arted t aking cim et idin e to t reat h er h eartburn . Cim et idin e is an in h ibitor of th e cytoch rom e P-450 system in th e liver. W h ich of th e follow ing term s best d e n es th is cim et idin e−diazepam in teract ion ?

E. Th e rate of sign al t ran sd u ct ion

Questions: I-2 Pharmacodynamics 11 Di cult y level: Easy


22. An 83-year-old w om an su er ing from over ow u r in ar y

25. A series of n ew β agon ists w as tested in laborator y an im als.

in con t in en ce star ted a th erapy w ith a ch olin ergic drug th at

Heart rate w as m easured after treatm en t w ith di erent doses

w as able to relieve leaking. W h ich of th e follow ing best de-

of each drug. Th e result s are given below :

n es th e m olecu lar even t in it iated by drug−receptor bin ding Drug

an d en ding w ith th e th erapeu t ic e ect in th is pat ien t? A. Receptor u p regu lat ion B. Drug e

cacy

C. Sign al t ran sdu ct ion p ath w ay D. Drug−receptor in teract ion E. Drug poten cy

ED50 (mg)

Maximal Increase in Heart Rate (bpm)

A

2

+15

B

10

+22

C

15

+30

D

5

+40

E

20

+55

Abbreviations: bpm , beats per m inute; ED50 , e ective dose that produces a response in 50% of subject s.

Di cult y level: Easy 23. A 9-year-old boy su ering from m ild asth m a u sed a β 2 agon ist “as n eeded” by in h alat ion . W h ich of th e follow ing w as

W h ich of th e follow ing drugs w as th e m ost poten t?

m ost likely th e im m ediate con sequen ce of th e act ivat ion of

A. Drug A

β 2 receptors?

B. Drug B C. Drug C

A. Open ing of ligan d-gated K+ ch an n els

D. Drug D

B. In creased syn th esis of cAMP

E. Drug E

C. Decreased syn th esis of cAMP D. Con form at ion al ch ange of a G protein


E. Ph osp h or ylat ion of a G p rotein

26. Tw o n ew diu ret ics w ere tested in h ealthy volu n teers. Th ey w ere given singly or togeth er on sep arate occasion s. Th e re-

Di cult y level: Easy 24. A 57-year-old m an w h o w as in th e h ospital after a surgical p rocedu re com plain ed of a severe abdom in al pain . Th e physician d ecid ed to st art an algesic t reat m en t w ith an op ioid.

su lt s are given below : Drug

Dose (mg )

Daily Urine Output (L)

Th e drugs h e w as con sidering w ere m orp h in e (10 m g IM)

A

20

5

an d bu p ren orp h in e (0.3 m g IM). Morph in e is a fu ll agon ist at

B

5

3

20 (A) + 5 (B)

8

m u (µ) opioid receptors, w h ereas bu p ren orp h in e is a p ar t ial agon ist at th e sam e receptors. Th e above-m en t ion ed doses

A+ B

of th e t w o drugs are equie ect ive. W h ich of th e follow ing

W h ich of th e follow ing term s best de n es th e t ype of drug−

p airs of statem en ts correctly de n es th e poten cy an d e

d rug in teract ion th at h as occu rred?

-

cacy of m orp h in e an d bu p ren orp h in e? A. Mor p h in e is m ore p oten t . Bu p ren or p h in e is m ore effect ive. B. Mor p h in e is m ore p oten t . Bu p ren or p h in e is less effect ive.

A. Syn ergism B. Poten t iat ion C. Addit ive D. Fu n ct ion al an tagon ism E. Ph arm acokin et ic an t agon ism

C. Mor p h in e is less p oten t . Bu p ren or p h in e is m ore effect ive. D. Morp h in e is less p oten t . Bu p ren orp h in e is less e ect ive.

Di cult y level: Medium 27. A 45-year-old w om an recen tly diagn osed w ith lupus er yth em atosu s star ted a t reat m en t w ith a syn th et ic steroid. W h ich of th e follow ing is th e m ost likely t im e lapse expected bet w een receptor act ivat ion an d th erapeu t ic respon se? A. Few m illisecon ds B. Few secon ds C. Few m in u tes D. On e or 2 h ours E. Several h ou rs or days

12


Di cult y level: Medium 28. Th e

• Drug Z w as able to an t agon ize th e e ects of both drug X

cu r ves of di eren t drugs act ing on th e sam e receptor. R

S

% ( t u

m

e

f

f

e

c

80

P

W h ich of th e follow ing term s best de n es drug X? A. Com p et it ive an t agon ist

T

)

100 Q

60

B. Par t ial agon ist C. Inverse agon ist D. Irreversible an tagon ist E. Fu ll agon ist

40

M

a

x

i

m

an d drug Y.

gu re below d ep ict s th e in vit ro log dose−resp on se

20 0

Di cult y level: Medium log dose

W hich of the drugs has the highest a nit y for the receptor?

30. A clin ical t r ial w as con d u cted by orally adm in ister ing a n ew an algesic d r ug to a grou p of p at ien t s su er ing from ar t h r it ic p ain . On e h ou r after adm in ist rat ion , th e pat ien ts

A. Drug P

w ere qu est ion ed abou t p ain relief, an d a sam p le of blood w as

B. Drug Q

collected from each pat ien t to m easure plasm a drug levels.

C. Drug R

Pain relief gen erally correlated w ell w ith plasm a levels, but

D. Drug S

th ree p at ien ts w h ose p lasm a levels w ere equ al to zero re-

E. Drug T

p orted good pain relief. W h ich of th e follow ing is th e m ost likely explan at ion of th e an algesic e ect of th e d rug in th ose


th ree p at ien t s?

29. Som e n ew drugs act ing on th e sam e receptor w ere st u died

A. High bioavailabilit y of th e drug

in laborator y an im als. It w as foun d th at

B. Sm all volu m e of dist ribu t ion of th e dr ug

• Drug X w as able to decrease th e con st it ut ive level of act iv-

C. Ver y low clearan ce of th e drug

it y of th e receptor. • Drug Y w as able to in crease th e con st it u t ive level of act iv-

D. Poor pat ien t com plian ce E. Placebo e ect

it y of th e receptor.

Questions: I-3 Adverse E ects of Drugs Di cult y level: Easy 1. A 23-year-old w om an com plain ed to h er physician th at th e diph en hyd ram in e sh e u sed to preven t m ot ion sickn ess w h en t raveling by boat w as e ect ive in preven t ing vom it ing bu t cau sed d row sin ess an d dr y m ou th . W h ich of th e follow ing term s best explains the underlying cause of these drug-related adverse e ects? A. Gen et ic predisposit ion

Drug

Median Ef ective Dose (mg )

P

3

Q

10

R

24

S

35

T

50

B. Non sp eci c cytotoxicit y

W h ich of th e drugs m ost likely h as th e h igh est risk of over-

C. Drug−receptor in teract ion

dose toxicit y?

D. Im m u n ologic respon se E. Preexist ing path ology

Di cult y level: Medium 2. Five n ew an t iconvu lsan t drugs (P, Q, R, S, an d T) w ere tested in laborator y an im als. It w as fou n d th at all of th e dr ugs h ad ap proxim ately th e sam e leth al dose th at produ ces death in 50% of subjects (LD50 ). Th e m edian e ect ive dose of each drug is rep or ted below :

A. Drug P B. Drug Q C. Drug R D. Drug S E. Drug T

Questions: I-3 Adverse E ects of Drugs 13 Di cult y level: Easy 3. A 51-year-old m an repor ted to h is physician th at in th e m orn -

Plasma Concentration (mg/ L) Drug

ing h e n ot iced h is u rin e w as clou dy an d red. Th e m an h ad

Minimum ef ective

Minimum toxic

been t aking an oral an t icoagu lan t for 3 w eeks to t reat a deep

P

5

20

ven ous th rom bosis. If th e pat ien t’s sym ptom s w ere caused by

Q

1

10

th e an t icoagu lan t , w h ich of th e follow ing adverse drug reac-

R

30

60

t ion s w as m ost likely involved?

S

A. Overdose toxicit y

T

0.6 20

3 80

B. Au toim m u n e react ion C. Idiosyn crat ic react ion

W h ich of th e drugs h as th e h igh est probabilit y of th erapeu t ic

D. Pseudoallergic react ion

su ccess?

E. Im m ediate allergic react ion

A. Drug P B. Drug Q


C. Drug R

4. A 23-year-old w om an sch eduled for su rgical dilat ion an d cu-

D. Drug S

ret tage w as an esth et ized w ith th iop en tal. Sh or tly after recov-

E. Drug T

er y from th e an esth esia, th e w om an h ad gen eralized seizu res follow ed by a deep com a. Fur th er in form at ion given by h er


husband indicated th at th e patien t’s m other had su ered from

7. A 32-year-old African Am erican m an w h o w orked as a Peace

acute in term it ten t porphyria. If th e com a w as caused by th io-

Corp s volu n teer in Gh an a p resen ted w ith w eakn ess, fat igu e,

pen tal, w h ich of th e follow ing drug react ion s w as m ost likely

yellow ing of h is skin an d sclera, an d sligh t fever. He recen tly

involved?

w as given ch loroqu in e as a prophylaxis for m alaria. Labora-

A. Typ e II allergic react ion

tor y

B. Delayed allergic react ion

likely du e to ch loroqu in e t reat m en t . Th is pat ien t’s disease

C. Idiosyn crat ic react ion

w as m ost likely m ediated by gen et ic p olym orp h ism of w h ich


of th e follow ing en zym es?

E. Overdose toxicit y

A. N-acet ylt ran sferase

n dings con rm ed th e diagn osis of h em olyt ic an em ia

B. Glu cose-6-ph osph ate dehydrogen ase

Di cult y level: Medium 5. A 28-year-old w om an w h o h ad h ad a m it ral valve replace-

C. Red u ced for m of n icot in am id e ad en in e d in u cleot id e (NADH)−m eth em oglobin redu ctase

m en t for rh eum at ic h eart disease 2 years ago h ad h er sus-

D. Pseudoch olin esterase

pected p regn an cy con rm ed by a p osit ive pregn an cy test . Her

E. Glu curon osylt ran sferase

cu rren t m edicat ion s in clu d e th e an t icoagu lan t w arfarin (U.S. Food an d Drug Adm in ist rat ion [FDA] categor y for teratogen ic


risk D) an d am oxicillin (FDA categor y B). W h ich of th e follow -

8. A 61-year-old w om an com plain ed to h er physician of a burn -

ing w ou ld be th e best cou rse of act ion to be im plem en ted by

ing sen sat ion w h en sh e urin ated. Past h istor y of th e p at ien t

h er fam ily physician ?

w as sign i can t for seriou s hypersen sit ivit y to su lfa drugs. Uri-

A. Stop all m edicat ion s th rough ou t p regn an cy

n alysis revealed abun dan t gram -n egat ive bacteria, an d a sen -

B. Su sp en d w arfarin for th e rst t rim ester of p regn an cy

sit ivit y test sh ow ed th at th ey w ere sen sit ive to am ikacin ,

C. Rep lace w arfarin w ith h eparin an d con t in u e am oxicillin

piperacillin , trim ethoprim -sulfam etoxazole, cipro oxacin, an d

D. Con t in u e w ar far in an d rep lace am oxicillin w it h p en icil-

ceft riaxon e. A diagn osis of urin ar y t ract in fect ion w as m ade,

lin G E. Red u ce th e dose of w arfarin an d con t in u e am oxicillin

an d an an t ibiot ic th erapy w as prescribed. W h ich of th e follow ing an t ibiot ics sh ou ld be avoided in th is p at ien t? A. Trim eth op rim -su lfam eth oxazole


B. Piperacillin

6. Five n ew an t ihyper ten sive drugs w ere tested in h ealthy vol-

C. Am ikacin

u n teers. All of th e dr ugs w ere foun d to be equally e ect ive

D. Cipro oxacin

in con t rolling hyp er ten sion . Th e m in im u m e ect ive p lasm a

E. Ceft riaxon e

con cen t rat ion s an d th e m in im u m toxic plasm a con cen t rat ion s w ere determ in ed for each drug. Th e resu lts are rep or ted below :

14



w as m ad e. W h ich of t h e follow in g adverse d r ug react ion s

9. A new hypnotic drug w as tested in laborator y anim als. It w as

best exp lain s th e disease of th is pat ien t?

fou n d th at th e ED50 for in du cing sleep w as 2 m g/kg. W h ich

A. Overd ose toxicit y

of th e follow ing best explain s th e m ean ing of th at dose?

B. Tachyp hylact ic react ion

A. Th e m ean dose able to elicit sleep in duct ion


B. Th e dose w ith a 50% probabilit y of causing sleep

D. Allergic react ion

C. Th e dose th at elicit s sleep in 50% of an im als

E. Pseudoallergic react ion

D. Th e m ean d ose w it h a good p robabilit y of sleep in -


du ct ion E. Th e dose th at elicit s a m edian th erapeut ic sleep respon se in m ost an im als

13. A 15-year-old boy w as adm it ted to th e h ospital w ith fever (103.1°F, 39.5°C), a m orbilliform skin eru pt ion , lym ph aden op athy, angioedem a, an d ar th ralgia. Th e boy h ad been re-


ceiving am picillin for a pu lm on ar y in fect ion for 2 w eeks. Lab

10. A n ew born boy w h ose m oth er h ad epilepsy presen ted w ith

data revealed elevated circulating im m une com plexes. W h ich

m icroceph aly, a broad n asal bridge, sh or t n ose, cleft p alate,

of th e follow ing adverse drug react ion s best explain s th e pa-

an d hyp op lasia of th e d istal p h alanges. Drugs u sed by th e

t ien t’s disord er?

m oth er d u ring pregn an cy in clu ded p h enytoin for seizu res,

A. Overd ose toxicit y

m ethyldopa for pregnancy-induced hypertension, and er yth -

B. An aphylactoid react ion

rom ycin for an u p per resp irator y in fect ion du ring th e

rst


t rim ester. Du ring th e deliver y, th e w om an w as t reated w ith

D. Au toim m u n e react ion

d iazepam an d h ad epidural an esth esia w ith lidocain e. W h ich

E. Seru m sickn ess

of t h e d r ugs t aken by t h e m ot h er m ost likely cau sed t h e baby’s p resen t ing syn drom e?


A. Methyld op a

14. A 69-year-old m an presen ted to th e h ospit al w ith a skin

B. Ph enytoin

eru pt ion over h is n eck, arm s, an d legs. Th e p at ien t reported

C. Er yth rom ycin

th at h e w as diagn osed w ith sen ile pr u rit u s 3 w eek earlier,

D. Lidocain e

an d h e h ad been app lying a top ical doxep in cream to relieve

E. Diazepam

itch ing. Physical exam in at ion revealed red, sw ollen skin covered w ith blisters, an d a p atch test con rm ed th at th e skin


eru pt ion w as d u e to doxep in . W h ich of th e follow ing ad-

11. A 75-year-old w om an com plain ed to h er physician of in -

verse drug react ion s best explain s th e pat ien t’s disorder?

creased n eed to u rin ate du ring th e n igh t . Th e w om an h ad

A. Typ e I allergic react ion

been receiving gen t am icin for 2 m on th s to t reat a u rin ar y

B. Typ e II allergic react ion

t ract in fect ion . Lab tests revealed a seru m creat in in e level of


5 m g/dL (n orm al 0.5−1.2 m g/d L). Seru m gen t am icin con cen -


t rat ion obtain ed ju st before th e last dose w as 9 m g/dL (n or-

E. Typ e IV allergic react ion

m al < 2 m g/dL). Th e p at ien t w as m ost likely su ering from w h ich of th e follow ing adverse drug react ion s?



15. A 38-year-old w om an w en t to h er p hysician becau se of a

B. Typ e III allergic react ion

blu ish d iscolorat ion of h er lip s. Med ical h istor y w as sign if-


ican t for an in h er ited de cien cy of t h e red u ced for m of n ic-


ot in am id e ad en in e d in u cleot id e (NADH)−m et h em oglobin


reductase. On e w eek earlier, sh e h ad star ted th erapy w ith t rim eth op rim -su lfam eth oxazole to t reat a u rin ar y t ract in -


fect ion . Physical exam in at ion sh ow ed cyan osis of th e oral

12. A 34-year-old m an w as adm it ted to th e h ospital because of

m u cosa, an d a blood test revealed a h igh level of m eth em o-

su d den on set of fever (102.2°F, 39.0°C), oligu ria, an d a skin

globin em ia. Th e p hysician su spected th at su lfam eth oxazole

rash . Th e m an h ad been receiving am picillin for prim ar y

w as t h e cau se of t h e p at ien t ’s cyan osis. W h ich of t h e fol-

syphilis. Laborator y ndings show ed eosinophiluria, protein -

low in g adverse d r ug react ion s best exp lain s t h e p at ien t ’s

u ria, an d in creased serum levels of urea n it rogen an d creat i-

d isord er?

n in e. A diagn osis of drug-in duced t ubuloin terst it ial n eph rit is

Answers and Explanations: I-1 Pharm acokinetics 15 A. Typ e I allergic react ion

A. De cien cy of th e reduced form of n icot in am ide aden in e

B. Typ e IV allergic react ion

d in ucleot ide (NADH)−m eth em oglobin redu ctase


B. Product ion of autoan t ibodies again st red blood cells


C. Drug-in duced de cien cy of folic acid


D. Drug-in duced bon e m arrow suppression E. De cien cy of glucose-6-ph osph ate dehydrogen ase

Di cult y level: Easy 16. A 32-year-old w om an com plain ed to h er physician of ur t i-


caria. Th ree days earlier, the w om an h ad started therapy w ith

19. A 64-year-old m an w as h ospit alized for t reat m en t of Staph-

am oxicillin for in fect iou s ton sillit is. Th e p hysician su sp ected

ylococcus aureus bacterem ia an d w as given an in t raven ous

an allergic react ion to th e drug. W h ich of th e follow ing w as

in fusion of van com ycin . A few m in utes later h e d evelop ed

m ost likely th e m ain determ in an t of th at drug react ion ?

sym ptom s of an an aphylact ic-like react ion . Th e p at ien t w as

A. Dose of th e drug

n ot aw are of previou s exposure to van com ycin , an d a search

B. Ch em ical st ruct ure of th e drug

for an t ibodies to th e su spected drug w as n egat ive. W h ich of

C. Oral bioavailabilit y of th e drug

th e follow ing t yp es of drug react ion w as m ost likely experi-

D. Gen et ic pedigree of th e pat ien t

en ced by th e p at ien t?

E. Liver an d kidn ey fun ct ion s of th e pat ien t

A. Typ e I allergic react ion B. Au toim m u n e react ion


C. Gen et ically m ediated react ion

17. An 85-year-old w om an w as adm it ted to th e h ospital w ith an


infected decubitus ulcer. Cult ures revealed Staphylococcus au-

E. Overd ose toxicit y

reus th at w as sen sit ive to som e β-lactam an t ibiot ics, n am ely, oxacillin , cep h alexin , an d im ip en em . W h ich of th e follow ing


w ou ld be th e rst p roced u re to u n der take in order to m in i-

20. A 43-year-old m an h ad to un dergo surger y to rem ove a bili-

m ize th e risk of an allergic react ion to th ese an t ibiot ics?

ar y calcu lu s. Th e an esth esiologist ch ose to su pp lem en t th e

A. St art th e th erapy w ith a ver y sm all dose

an esth esia w ith su ccinylch olin e, a p aralyzing agen t th at h as

B. Perform a skin sen sit ivit y test

a rapid on set an d a sh or t du rat ion of act ion . In th is p at ien t ,

C. Pret reat th e pat ien t w ith an an t iallergic drug

h ow ever, th e drug-induced paralysis lasted several hours, n e-

D. Use an oth er β-lact am an t ibiot ic act ive again st S. aureus

cessit at ing th e an esth esiologist to con t in ue th e an esth esia

E. Get a detailed drug h istor y

an d con t in u e ar t i cial resp irat ion . W h ich of th e follow ing adverse drug react ion s best explain s th e pat ien t’s disorder?



18. A 32-year-old pregn an t w om an w as foun d to h ave a red

B. Im m ediate allergic react ion

blood cell cou n t of 3.2 × 10 6 /m m 3 (n orm al 3.5−5.5 × 10 6 ) an d


a posit ive direct Coom bs test du ring a regu lar clin ic visit. Th e


w om an h ad st arted a t reat m en t w ith m ethyldop a 4 m on th s

E. Overd ose toxicit y

earlier because of st age 1 hyper ten sion . W h ich of th e follow ing m ech an ism s m ost likely m ediated th e drug-in duced react ion of th is p at ien t?

Answers and Explanations: I-1 Pharm acokinetics Learning objective: Describe the m ain features of lipid di usion of drugs across cell m em branes. 1. B Lipid di u sion is by far th e m ost com m on t ran sp or t system of drugs across cell m em bran es. Because albuterol h as a low

m olecular w eigh t , lipid di u sion m ost likely accoun ts for th e t ran sfer of albu terol th rough th e bron ch ial m u cosa. A, C−E See correct an sw er explan at ion .

16


Learning objective: Identify the m echanism of perm eation of botulinum toxin through nerve cell membranes.

lu m en is less th an 2, ibup rofen , an acid drug w ith a pKa of 4.8,

2. D Ver y large m olecu les can n ot p erm eate cell m em bran es by

ily pen et rate th e gast ric m u cosal cell m em bran es. In side th e

di u sion or lt rat ion . Th e on ly w ay th ey can cross cell m em -

m ucosal cells, h ow ever, th e pH is about 7, an d th e dr ug w ill

bran es is by en d ocytosis, a p rocess by w h ich a su bst an ce is

becom e m ain ly ion ized becau se n ow th e pKa is less th an th e

bou n d to th e cell su rface, engu lfed by th e cell m em bran e, an d

pH. Con sequen tly, th e con cen t rat ion gradien t of th e n on ion -

carried in to th e cytosol, w h ere th e su bst an ce can be released

ized, lipid-solu ble form w ill rem ain h igh , an d th e drug w ill

by breakdow n of th e vesicle m em bran e.

con t in ue crossing cell m em bran es. At equilibrium , th e con -

A–C, E See correct an sw er explan at ion .

w ill be m ain ly n on ion ized in th e gast ric lu m en an d w ill read -

cen t rat ion of th e n on ion ized m oiet y of th e drug w ill be th e sam e on both sides, bu t th e con cen t rat ion of th e ion ized m oi-

Learning objective: Describe the m ain features of active transport of drugs across cell m em branes. 3. A Abou t on e fth of th e iodides ingested w ith foods are selectively rem oved from the circulating blood by the Na +-dependent secon dar y act ive t ran sp ort system th at con cen t rates iodide in thyroid cells 30 to 100 t im es it s con cen t rat ion in th e blood. Because radioact ive iodin e is essen t ially th e sam e as iodide t aken w ith foods, it is t ran sp or ted in to th e thyroid cells by th e sam e secon dar y act ive t ran sp or t system . B−E See correct an sw er explan at ion .

Learning objective: Describe the m ain features of bulk ow transport of drugs across cell barriers. 4. A A d r ug ad m in istered su bcu t an eou sly w ill in it ially be located p r im ar ily in t h e ext racellu lar

u id . In ord er to be ab -

sorbed , t h e dr ug m u st en ter t h e gen eral circu lat ion ; t h at is, it m u st cross th e cap illar y w all. Cap illaries h ave ver y w ide fen est rae th at perm it th e passage of m olecules w ith a m olecu lar w eigh t as h igh as 30,000 dalton s (D). Th erefore, m ost d r ugs given by th e su bcutan eous or in t ram u scu lar routes w ill en ter th e gen eral circu lat ion by bu lk ow t ran sp or t (or lt rat ion ; also kn ow n as solven t drag) th rough cap illar y fen est rae. Moreover, in su lin is a p rotein w ith a m olecu lar w eigh t of

et y in side th e cell can be 15 to 20 t im es h igh er th an th at in th e gast ric lu m en , as th e ion ized m oiet y is “t rapp ed ” in side th e cell (ion -t rapping m ech an ism ). Th erefore, th e tot al drug con cen t rat ion in side th e cell w ill be h igh . A−C Basic dr ugs are m ain ly ion ized w h en the pKa is h igh er th an th e pH; th erefore, m ost of th e drug w ill st ay in th e stom ach lu m en . D Th eophyllin e, an acidic drug w ith a pKa of 8.8, is m ain ly n on ion ized in th e stom ach lum en an d th erefore can readily p en et rate th e gast ric cell m em bran es. In side th e gast ric cells, h ow ever, th e dr ug rem ain s m ain ly n on -n on ion ized (i.e., lipid solu ble) becau se th e pKa is greater th an th e p H. Th erefore, th e drug w ill be able to di u se th rough th e basolateral m em bran e of th e cell, th us reach ing th e ext racellular uids. No ion t rap ping occurs, an d th e drug w ill n ot con cen trate in side th e cells.

Learning objective: Explain why the lipid and water solubilities of a drug are related to their pKa and to the pH of the solvent. 6. F An acid ic dr ug is m ain ly w ater solu ble w h en it s pKa is low er th an th e pH of th e m ediu m . Th e am ou n t of w ater solubilit y is p roport ion al to th e d i eren ce bet w een pH an d pKa , according to th e follow ing t able

abou t 6000 D, so it can n ot cross th e capillar y w all by lipid or

Dif erence betw een pH and pKa

> 2.0

2.0

1.0

0.5

0.0

aqu eou s di usion th rough aquaporin s (w ater ch an n els) of cell

Percentage

> 99

99

90

76

50

m em bran es. Bulk

ow t ran spor t is a passive process an d is

directly p rop or t ion al to th e p ressu re gradien t across th e cap -

Because th e pH of plasm a is abou t 7.4, th e drug w ill be greater

illar y w all. It d oes n ot d ep en d on t h e st r u ct u re of t h e d r ug

th an 99% w ater soluble in th e pat ien t’s plasm a.

bu t on ly on it s m olecu lar size (both lip idan d w ater-solu ble

A−E See correct an sw er explan at ion .

drugs can be ltered p rovided th e m olecu le is n ot too large). B See correct an sw er exp lan at ion .

Learning objective: Describe the ion-trapping mechanism of drugs.

C−E Facilitated di usion , en docytosis, an d act ive t ran spor t

7. D Aspirin is an acidic drug. As a rule, th e excret ion of an acidic

do n ot seem to be involved in th e absorpt ion of in su lin from

drug can be accelerated by alkalin izing th e u rin e, becau se an

th e site of inject ion .

acidic drug dissociates to it s ch arged, polar form in alkalin e solu t ion . Th is form , being w ater solu ble, is “t rapp ed” in th e

Learning objective: Explain the m ain m echanistic features of ion trapping.

t u bu lar lu m en an d can n ot be t ran sp or ted back in to th e blood

5. E Th e Hen derson -Hasselbalch equ at ion predicts th at a w eak

t ion of a w eak base m ay be accelerated by acidifying th e u rin e.

across th e ren al t u bular cells. Conversely, th e urin ar y excre-

acid w ill be m ore nonionized, and therefore m ore lipid soluble,

A Salicylates do n ot un dergo act ive t ran spor t .

w h en p Ka is greater th an pH. Because th e pH of th e stom ach

B Salicylate biot ran sform at ion by th e kidn ey is n egligible.

Answers and Explanations: I-1 Pharm acokinetics 17 C Asp ir in w as already absorbed , so bioavailabilit y is n ot relevan t . E Glom eru lar

Learning objective: Describe the m ain characteristics of drug permeation across cell membranes.

lt rat ion of a drug is st rictly related to th e

11. A Being a polar drug, eth an ol is readily w ater soluble. Be-

ren al glom erular lt rat ion rate (GFR). It is ver y rare for drugs

cau se its m olecu lar w eigh t is sm all, it can cross cell m em -

to sign i can tly in crease GFR.

bran es by aqu eou s di u sion th rough aqu aporin s. B−E See correct an sw er explan at ion .

Learning objective: Identify the m ain site of absorption of drugs administered by the oral route. 8. C All drugs given by th e oral rou te are p rim arily absorbed by

Learning objective: List the m ain factors a ecting the absorption of drugs adm inistered by the oral route.

th e sm all in test in e. Th is is becau se of th e ver y large su rface

12. B St rong pain can substan t ially decrease gast ric em pt ying,

area of th e sm all in test in e, w h ich is abou t 250 m 2 an d rep -

likely becau se of th e act ivat ion of th e sym p ath et ic n er vous

resen t s abou t 80% of th e tot al area of th e gast roin test in al

system . Becau se th e absorpt ion of drugs by th e stom ach is

t ract . Hyd roch lorot h iazid e is an acid ic d r ug w it h a p Ka of

ver y sm all, gast ric em pt ying is a m ajor factor in u en cing th e

abou t 9, so it w ill be m ore lip id solu ble in t h e stom ach

rate of in test in al dr ug absorpt ion , an d its decrease can sig-

(w h ere t h e p H is less t h an 2) t h an in th e sm all in test in e

n i can tly delay th is absorpt ion .

(w h ere th e pH is aroun d 7). Neverth eless, absorpt ion w ill t ake p lace m ain ly in th e sm all in test in e becau se of it s en orm ou s absorpt ive su rface area. A Because a drug given orally is sw allow ed, th e oral m u -

A, C Th ese factors u su ally speed u p, n ot delay, th e in test in al absorpt ion of drugs. D, E Th e dist ribut ion an d elim in at ion (clearan ce) of dr ugs h ave n oth ing to do w ith absorpt ion .

cosa does n ot con t ribu te to absorpt ion . B, D, E See correct an sw er explan at ion .

Learning objective: Describe the m ain factors that can increase the entry of drugs into the central nervous system.

Learning objective: Calculate the oral bioavailabilit y of a drug, given su cient data.

13. B Th e p er m eabilit y of t h e blood −brain bar r ier can be in -

9. D Oral bioavailabilit y is m easu red by th e rat io AUCOral/AUCIV.

(t rau m a, in fect ion s, t u m ors, m et abolic d isord ers, cerebro -

Drug S gives an oral bioavailabilit y of 0.83, th e h igh est of all

vascu lar d isord ers) is on e of t h e m ost com m on cau ses of

th e listed drugs.

in creased blood−brain barrier p erm eabilit y.

A−C, E See correct an sw er explan at ion .

creased by several factors. Dam age to th e brain by any cau se

A, D Th e rst-p ass e ect is related to th e bioavailabilit y of a drug. Clearan ce is related to th e elim in at ion of a drug. Pas-

Learning objective: Explain why the dosage form of a drug form ulation can a ect the oral bioavailabilit y of that drug.

sage in to th e brain is related to th e dist ribu t ion of th e drug.

10. A Th e am ou n t of drug reach ing th e port al circu lat ion after

p rocesses.

oral adm in ist rat ion can be st rongly in uen ced by th e dosage form u lat ion . Because on ly single m olecules of th e drug can p ass th rough th e gut w all, th e drug m u st be in solut ion in order to en ter th e in test in al epith elial cells. For exam ple, a

Bioavailabilit y, distribution, an d elim ination are indepen dent C Th e perm eabilit y of th e blood−brain barrier is physiologically in creased on ly in th e fet u s an d th e n ew born . E Th e h igh ion izat ion of th e drug decreases, n ot in creases, th e drug en t r y in to th e brain .

t ablet m u st be disin tegrated an d d issolved before reach ing th e port al circu lat ion . Th e e

cien cy of th is process dep en ds

on several factors, in cluding th e w ay th e t ablet is m an ufact u red an d th e excip ien t s u sed. On ce in th e p or tal circu lat ion , th e drug can be m et abolized by th e liver, bu t th e h ep at ic

Learning objective: Describe the m ain features of drug−protein binding. 14. B Drugs bin d prim arily to album in (if acidic) or to α 1 acid glycop rotein (if basic).Th e exten t to w h ich d rugs are bou n d

clearan ce w ill be th e sam e, regardless of th e di eren t dosage

to protein is h igh ly variable (e.g., 0%for lith ium , 99%for w ar-

form s. Because in th is case th e sam e dose of th e drug w as

farin). Drugs ordinarily bind to protein in a reversible fashion

adm in istered , th e con cen t rat ion of th e drug in th e p or t al

an d in dyn am ic equilibrium , according to th e law of m ass

vein w ill be directly proport ion al to th e oral bioavailabilit y

act ion , as sh ow n by th e equat ion

of th e di eren t form u lat ion s, w h ich is in dicated by th e differen t AUCs depicted in th e gure. B−D See correct an sw er exp lan at ion .

[Free drug] + [Protein ]

[Drug−protein com plex]

Mass act ion kin et ics predicts th at a con stan t p ercen tage of th e drug is boun d; th erefore, bin ding is in depen den t of th e dose (i.e., th e kin et ics of bin ding is rst order). A, C−E See correct an sw er explan at ion .

18


Learning objective: Calculate the degree of ionization of a drug in cell uids using the Henderson-Hasselbalch equation.

drug factors a ect ing placen t al t ran sp or t in clu de th e m olec-

15. A The answ er can be found using the Henderson-Hasselbalch

th an 1500 D cross th e placen ta poorly), it s physicoch em ical

ular size of th e dr ug (drugs w ith m olecu lar w eigh t greater propert ies (lip op h ilic drugs di u se readily; h igh ly ion ized

equ at ion : Weak acid:

Non ion ized log ———————— = pKa – p H Ion ized

In th e presen t case, th e equat ion becom es Non ion ized Log ———————— = − 2 Ion ized Taking th e an t ilog on both sides, th e equ at ion becom es Non ion ized 1 ———————— = ——— Ion ized 100 an d rem em bering th at th e tot al drug (i.e., 100% = 1) is th e su m of th e ion ized an d n on ion ized form : 1 − Ion ized 1 ———————— = ——— Ion ized 100

drugs w ith m olecu lar w eigh t greater th an 200 D cross th e placen t a slow ly), an d it s degree of protein bin ding (drugs h igh ly protein boun d cross th e placen t a slow ly). Drug P h as a ver y sm all m olecu lar w eigh t an d is n ot protein boun d. Because it is 100% ion ized, it w ill be com pletely w ater solu ble an d w ill easily cross th e placen t a by aqu eou s di u sion th rough aqu ap orin s. B Drug Q w ill cross th e p lacen ta slow ly becau se it is h igh ly protein bou n d . C, E Drugs R an d T w ill cross th e placen ta w ith di cult y becau se of th eir h igh m olecu lar w eigh t . D Drug S w ill cross th e placen t a w ith di cult y because it is p rim arily ion ized (i.e., w ater solu ble) an d is too big to perm eate th e m em bran es by aqueous di usion .

th at is:

Th erefore, th e ion ized form w ill be 99%, an d th e n on ion ized,

Learning objective: Explain why the volum e of distribution (Vd ) can predict, to a certain extent, the pat tern of distribution of a drug in the body.

lip id-solu ble form w ill be 1%.

18. B Because th e volum e of plasm a in a person w eigh ing 70 kg

100 Ion ized = ———= 0.99 101

B−E See correct an sw er explan at ion .

is abou t 3 L, it can be deduced th at drugs w ith a volum e of d ist ribut ion of abou t 3 L dist ribu te in plasm a. In fact , in ix-

Learning objective: Describe the main factors that can hinder the entry of drugs into the central nervous system.

im ab is a large m olecu le th at can n ot leave th e vascu lar com -

16. D Drugs m ay en ter th e cen t ral n er vous system (CNS) by

th u s p reven t ing th e act ion s of th is cytokin e.

crossing th e cerebral capillaries (i.e., from p lasm a to th e ext racellu lar u id [ECF]) or by crossing th e ch oroid p lexu s (i.e., from p lasm a to th e cerebrospin al u id [CSF]). Th e com p osit ion of CSF is essen t ially th e sam e as th at of brain ECF, an d th ere ap pears to be free com m u n icat ion bet w een th e brain ECF an d CSF. In both of th ese cases, th e drug m ust cross th e

p ar t m en t . It bin ds to an d n eu t ralizes TNF-α in th e blood, A, D In th ese cases, th e volu m e of dist ribu t ion w ou ld be greater th an 42 L. C In th is case, th e volu m e of dist ribut ion w ould be about 13 L. E In th is case, th e volum e of dist ribut ion w ould be about 42 L.

blood−brain barrier (BBB). Th e m ain reason s th at th is barlial cells of brain capillaries are con n ected to each oth er by

Learning objective: Calculate the percentage of a drug elim inated by the liver, given su cient data.

occluding zon u lae an d do n ot h ave fen est rae, an d (2) epith e-

19. F Becau se th e total clearan ce is 5.4 L/h , an d th e h epatic clear-

lial cells of th e ch oroid p lexu s are con n ected by occlu ding

an ce is 4.86 L/h , th e h epat ic clearan ce w ill be 90%of th e total

zon u lae.

clearan ce (4.86/5.40 = 0.9, or 90%). Th erefore, 90% of th e

rier lim it s th e t ran sfer of d rugs in to th e CNS are (1) en d oth e-

A, B Th ese statem en ts are correct , bu t th ey do n ot exp lain th e low drug perm eabilit y of th e blood−brain barrier.

drug w ill be elim in ated by th e liver. A, C−F See correct an sw er explan at ion .

C Drugs are variably boun d to plasm a protein s; because th e bou n d an d free drugs are in equ ilibriu m , even ver y exten sively boun d drugs can appreciably en ter th e brain . E Ver y few drugs are com pletely ion ized in th e blood.

Learning objective: Outline the m ain drug factors that can a ect the placental transport of a drug. 17. A Th e m em bran es sep arat in g fet al blood from m ater n al

Learning objective: Describe the factors a ecting the oral bioavailabilit y of a drug. 20. A A large fract ion of drug P reach es th e por tal vein an d is p oorly m et abolized by th e liver (as seen by th e low h ep at ic clearan ce). Th is m ean s th at a large fract ion of th e drug can reach th e system ic circulat ion ; th at is, th e oral bioavailabilit y of th e drug is h igh .

blood in t h e in ter villou s sp ace resem ble cell m em bran es

B Abou t t h e sam e fract ion of bot h d r ug P an d d r ug Q

elsew h ere in th eir gen eral perm eabilit y beh avior. Th erefore,

reach es th e port al vein . How ever, th e h epat ic clearan ce of

Answers and Explanations: I-1 Pharm acokinetics 19 drug Q is m u ch h igh er th an th at of drug P. Th erefore, th e oral

clearan ce of th e d rug w ill also in crease su bst an t ially. Re-

bioavailabilit y of drug Q w ill be low er th an th at of drug P.

m em bering th at

C−E A low er fract ion of th ese drugs reach es th e por tal vein . Th erefore, th eir oral bioavailabilit y m ust be low er th an th at of drug P.

t ½ = 0.7 Vd /CL, w h ere t ½ = h alf-life, Vd = volu m e of dist ribu t ion , an d CL = clearan ce, th e h alf-life of th e drug w ill decrease. A−C Th ese param eters are in creased, n ot decreased, w h en

Learning objective: Calculate the hepatic clearance of a drug, given su cient data.

m icrosom al en zym es are in du ced .

21. C By de n it ion , clearan ce is th e volu m e of blood from w h ich

w h en th e am oun t of drug reach ing th e gen eral circulat ion

all th e drug is rem oved per u n it of t im e. If all of th e drug

D Th e volum e of distribut ion of a drug does n ot ch ange ch anges.

w ere rem oved by th e liver, th e liver clearan ce w ou ld equ al th e liver blood

ow (volu m e p er u n it of t im e), th at is, 1500

m L/m in . Becau se 20% of th e drug can reach th e gen eral circu lat ion , it follow s th at 80% of th e drug is rem oved by th e liver, th at is, th e drug con tain ed in 80% of th e blood

ow.

Th erefore, th e liver clearan ce w ill be 80% of th e liver blood ow (0.8 × 1500 m L/m in = 1200 m L/m in ). A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Calculate the renal clearance of a drug, given su cient data. 22. A If t h e daily u rin e ou t p u t is 1.44 L/d (24 h ), th e u r in e ow in th at subject w ill be

Learning objective: Describe how the genetic polym orphism of P450 isozymes can in uence the e ects of drugs. 25. C P450 isozym es sh ow gen et ic polym orph ism , an d di eren t subgroups have been characterized as poor, interm ediate, extensive, and ultra-rapid m etabolizers. In the case of CYP2C9 isozym e, m ore th an 20% of Asian s are poor m et abolizers. Th erefore, th e h em at u ria of th e p at ien t w as m ost likely related to th e fact th at h e w as a p oor m et abolizer of w arfarin , so th e an t icoagu lan t e ect of th e drug w as too pron ou n ced . A, D, E All th ese reason s w ou ld cau se a decrease, n ot an in crease, in th e w arfarin e ect . B Th eoret ically, d ecreased ren al excret ion of w ar far in

Urin e ow 1440 m L/1440 m in = 1 m L/m in

w ou ld cau se an in crease in th e w arfarin e ect . How ever,

Rem em bering th at th e ren al clearan ce (CLr ) of a su bst an ce

m ore th an 95%of w arfarin is m etabolized, so adverse e ect s

is given by CLr = (Urin e ow × Urin e con cen t rat ion )/Plasm a con cen t rat ion th e ren al clearan ce of th at drug w ill be CLr = (1 m L/m in × 40 m g/m L)/1 m g/m L = 40 m L/m in B−F See correct an sw er explan at ion .

of w arfarin du e to variat ion in ren al excret ion are u n likely.

Learning objective: Calculate the oral bioavailabilit y of a drug, given su cient data. 26. B Th e liver clearan ce w as n egligible, so all of th e drug reach ing th e p or tal circu lat ion w ill reach th e system ic circu lat ion . Because on ly 40% of th e drug reach es th e port al circulat ion , th e oral bioavailabilit y of th e d rug is 0.4. (Note th at th e liver

Learning objective: Calculate the volum e of distribution (Vd ) of a drug, given su cient data. 23. B Th e volum e of dist ribu t ion (Vd ) of a drug is in depen den t of th e dose. In fact , Vd = D × F/Cp 0 , w h ere D = dose, F = fract ion absorbed, an d Cp 0 = p lasm a con cen t rat ion at t im e 0. If th e dose is in creased by a cert ain proport ion , th e plasm a con cen t rat ion w ill also be in creased by th e sam e propor t ion , an d th e Vd w ill rem ain th e sam e. A, C−E See correct an sw er explan at ion .

Learning objective: Explain the consequences of drug induction or inhibition of m icrosom al enzym es. 24. E W h en m icrosom al en zym es are in d u ced , t h e h ep at ic clearan ce of a drug in creases. Becau se th e h ep at ic clearan ce of carbam azepin e is close to th e total clearan ce, th e tot al

blood ow rate is n ot n eeded to solve th e problem .) A, C−F See correct an sw er explan at ion .

Learning objective: Explain the reason for increased toxicit y of drugs biotransform ed by acet ylation. 27. D Ison iazid is biot ran sform ed m ain ly by h ep at ic acet ylat ion , w h ich is u n der gen et ic con t rol. About on e h alf of people of Caucasian origin are slow acet ylators because th ey h ave an in h erited de cien cy of N-acet ylt ran sferase. Slow acet ylators h ave a h igh er risk of adverse e ects w ith ison iazid. A Rifam pin can in crease, n ot reduce, th e biot ran sform ation of m any drugs by in creasing the synthesis of m icrosom al en zym es. B, C, E Th ese path ologic con dit ion s do n ot cause periph eral n eu rop athy.

20


Learning objective: Calculate the therapeutic loading dose of a drug, given su cient data.

Learning objective: Estim ate the m agnitude of a volum e of distribution of a drug using inform ation from a graph.

28. C Th e dose of a drug can be calculated using th e equat ion

32. E Th e volu m e of d ist ribu t ion (Vd ) of a drug is given by

Dose = Vd × Cp 0 /F

Vd = D/Cp 0 ,

w h ere Vd = volu m e of dist ribu t ion , Cp 0 = p lasm a con cen t ra-

w h ere D = dose an d Cp 0 = th eoret ical p lasm a con cen t rat ion

t ion at t im e 0, an d F = fract ion absorbed. Becau se th e Vd of

at t im e 0. Becau se th e dose is th e sam e for all drugs, th e drug

t h e obese p at ien t is t w ice t h e Vd of a n or m al-w eigh t p er-

w ith th e low est Cp 0 (d rug T, as seen in th e grap h ) w ill h ave

son , th e dose m ust be doubled to 60 m g to ach ieve th e sam e

th e largest Vd .

plasm a con cen t rat ion .

A−D See correct an sw er explan at ion .

A, B, D−F See correct an sw er explan at ion .

Learning objective: Explain the relationship bet ween rst-pass e ect and oral bioavailabilit y.

Learning objective: Calculate the oral bioavailabilit y of a drug, given su cient data. 33. B Th e bioavailabilit y can be calcu lated as

29. B If an orally adm inistered drug is extensively biotransform ed d uring it s rst p ass th rough th e gu t w all an d/or th e liver, less d rug w ill reach th e gen eral circulat ion . Th at is, its oral bioavailabilit y w ill be redu ced. In fact , bu sp iron e h as an oral bioavailabilit y of abou t 5%. A Absorpt ion (m easured by bioavailabilit y) an d dist ribu -

Vd = D × F/Cp 0 , w h ere Vd = volu m e of dist ribut ion , D = dose, F = oral bioavailabilit y, and Cp 0 = th eoret ical plasm a con cen t rat ion at t im e 0. Th erefore, rearranging: F = (Vd × Cp 0 )/D = (100 L × 1 m g/L)/200 = 0.5

t ion (m easu red by volu m e of d ist ribu t ion ) are in depen den t

A, C, D See correct an sw er exp lan at ion .

p rocesses; th erefore, volum e of dist ribut ion is n ot a ected

E, F Th ese opt ion s are irrat ion al. Bioavailabilit y can n ot be

by th e absorpt ion of th e drug.

h igh er th an 1 (or 100%).

C Ren al elim in at ion (m easu red by ren al clearan ce) an d bioavailabilit y are in d ep en d en t p rocesses; t h erefore, ren al clearan ce is n ot a ected by th e absorpt ion of th e dr ug. D, E Sublingual an d in t ram uscular adm in ist rat ion s avoid th e rst-p ass e ect .

Learning objective: Calculate the adm inistered dose of a drug, given su cient data. 34. B Becau se th e h alf-life of cocain e is 1 h ou r, th e p lasm a con centration of the drug should have been 1.5 m g/L 1 hour after th e inject ion an d 3 m g/L im m ediately after th e inject ion . To

Learning objective: Calculate the renal clearance of a drug, given su cient data. 30. A If 66% of th e d rug is excreted as su ch in th e u rin e, it s ren al clearan ce w ill be 66% of th e tot al clearan ce (0.66 × 136), or abou t 90 m L/m in . B−F See correct an sw er explan at ion .

Learning objective: Calculate the total clearance of a drug, given su cient data. 31. E Th e plasm a con cen t rat ion (Cp) of th e drug is 2 m g/L in it ially an d 1 m g/L after 2 h ou rs; th erefore, th e h alf-life (t ½ ) of th e drug is 2 h ours. Th e volu m e of dist ribut ion of th e drug (Vd ) is given by Vd = 20 m g/2 m g/L = 10 L Th us, th e total clearan ce (CL) w ill be CL = 0.7 × Vd /t ½ , CL = 0.7 × 10 L/2 h = 3.5 L/h A−D, F See correct an sw er explan at ion .

d eterm in e th e dose, D = Cp × Vd = 3 m g/L × 130 L = 390 m g, w h ere D = dose, Cp = plasm a con cen t rat ion , an d Vd = volu m e of dist ribu t ion . The lethal dose of cocaine is about 500 m g in a nonaddicted person . Hen ce th e dose t aken by th e pat ien t w as m ost likely h igh en ough to in duce com a. A, C−F See correct an sw er exp lan at ion .

Learning objective: Calculate the half-life of a drug, given su cient data. 35. C Th e in it ial plasm a con cen t rat ion (Cp) of th e drug w ou ld be Cp = D/Vd = 2000 µg/10 L = 200 m g/L, w h ere D = dose an d Vd = volum e of dist ribut ion . Th erefore, th e Cp w ill be 100 µg/L after on e h alf-life an d 50 µg/L after t w o half-lives. Because this is the concen tration after 6 h ours, th e h alf-life of th e drug w ill be 3 h ours. A, B, D−F See correct an sw er exp lan at ion .

Answers and Explanations: I-2 Pharm acodynamics 21 Learning objective: Identify the half-life of a drug from a graph.

th e adm in ist rat ion , 10 m g/L 1 h our after th e adm in ist rat ion ,

36. B W h en a drug is given by in t raven ou s in fu sion , it w ill reach

an d 11 m g/L im m ediately after th e adm in ist rat ion .

50% of steady st ate after 1 h alf-life. Th e steady-st ate p lasm a

A, B, D−F See correct an sw er exp lan at ion .

con cen t rat ion for dr ug X is abou t 30 m g/m L. From th e graph it can be seen th at 15 m g/m L is reach ed in 1 h our. A Th e steady st ate for drug W is about 47 m g/m L. Half of th is value (abou t 23 m g/m L) is reach ed in 2 h ours. C Th e steady state for drug Y is abou t 25 m g/m L. Half of th is value (about 12 m g/m L) is reach ed in 2 h ours. D Th e steady state for drug Z is about 20 m g/m L. Half of th is value (about 10 m g/m L) is reach ed in 2 h ours.

Learning objective: Estim ate the order kinetics of a drug from a graph. 39. C Th e con cen t rat ion −t im e cu r ve is a st raigh t lin e, w h ich in d icates th at a con st an t am ou n t of a drug is elim in ated per u n it of t im e. Th erefore, th e drug follow s zero-order kin et ics. The three m ain drugs that follow zero-order, rather than rstorder, kin et ics are eth an ol, salicylic acid, an d ph enytoin . A, B, D−F All th ese drugs, like m ost drugs used clin ically,

Learning objective: Calculate the total clearance of a drug, given su cient data.

follow

rst-order kin et ics.

w h en th e rate of in fu sion is equal to th e rate of elim in at ion ,

Learning objective: Calculate the plasm a concentration of a drug at the steady state, given su cient data.

th at is,

40. C Because th e h alf-life of th e drug is 3 h ours, 75% of th e

37. D Th e steady-state plasm a con cen t rat ion (Css) is reach ed

D/T = Css × CL, w h ere D = dose, T = t im e, an d CL = clearan ce. From th e graph , w e h ave Css = 3 m g/L. Th erefore, CL = (D/T)/Css, 30 m g/h /3 m g/L= 10 L/h A−C, E, F See correct an sw er explan at ion .

p lasm a con cen t rat ion of th e drug at th e steady st ate w ill be reach ed in t w o h alf-lives, th at is, at 2:00 p.m . Th e plasm a con cen t rat ion of th e dr ug at 2:00 p.m . is 60 µg/m L. Th is rep resen t s 75% of th e plasm a con cen t rat ion of th e drug at th e steady state. Th erefore, at th e steady st ate th e p lasm a con cen t rat ion w ill be 80 µg/m L (60 ÷ 0.75). A, B, D−F See correct an sw er exp lan at ion .

Learning objective: Calculate the plasm a concentration of a drug, given su cient data. 38. C Th e kin et ics of drug absorpt ion , d ist ribu t ion , an d elim in at ion is de n ed as zero order (or sat u rat ion kin et ics) w h en a con stan t am ou n t of th e drug is absorbed, dist ribu ted, or elim in ated per un it of t im e. If th e plasm a con cen t rat ion of t h e d r ug w as 8 m g/L 3 h ou rs after t h e ad m in ist rat ion an d 7 m g/L 1 h ou r later, t h is m ean s t h at 1 m g/L of t h e d r ug is lost ever y h our. Th erefore, th e dr ug w as 9 m g/L 2 h ours after

PHARMACOKINETICS Answ er key 1. 2. 3. 4. 5.

B D A A E

6. 7. 8. 9. 10.

F D C D A

11. 12. 13. 14. 15.

A B B B A

16. 17. 18. 19. 20.

D A B F A

21. 22. 23. 24. 25.

C A B E C

26. 27. 28. 29. 30.

B D C B A

31. 32. 33. 34. 35.

E E B B C

36. 37. 38. 39. 40.

B D C C C

Answers and Explanations: I-2 Pharm acodynam ics Learning objective: Explain the m ost likely consequence of chronic blockade of drug receptors

after repeated act ivat ion of th e receptor, n ot after repeated

1. C W hen receptors are chronically blocked, the num ber of those

blockade.

D Ph osph or ylat ion desen sit izes th e receptor. Th is can occur

receptors m ay in crease over t im e, a p rocess called receptor

E Beta-receptor blockade can a ect th e syn th esis of cAMP

u pregu lat ion . Th e e ector respon se w ill be greater th an usual

bu t n ot t h e abilit y of t h e cell to resp on d to cAMP t h at h as

if th e blockade is abru ptly rem oved .

already been syn th esized.

A By de n it ion , spare receptors are n ot involved in receptor act ivat ion or blockade. B G-protein synthesis is not under β-receptor control. Blockade of β receptors preven t s th e act ivat ion , n ot th e syn th esis, of G protein s.

22


Learning objective: De ne the term stereoselectivity. 2. C A p eculiar prop er t y of receptors is stereoselect ivit y, m ean ing t h at t h ey often bin d on ly on e en an t iom er of a racem ic

A Un less th e toxic doses of th e t w o drugs are th e sam e, th erapeut ic in dex can tell n oth ing abou t th e relat ive poten cy of th e t w o drugs. B Th e m axim al respon se of each dr ug is term ed its m axim al

pair. A In t rin sic act ivit y refers to th e abilit y of a drug (on ce bou n d to a receptor) to in it iate ch anges th at lead to a biologic

e

cacy. Poten cy an d e

cacy are in d epen den t variables.

D, E Volum e of dist ribut ion an d clearan ce are ph arm acokin et ic variables. Poten cy is a ph arm acodyn am ic variable.

resp on se. B A n it y refers to t h e st rengt h of d r ug bin d in g to a receptor. D Poten cy refers to th e dose of a drug required to produ ce a given e ect . E Variabilit y refers to th e fact th at th e n um ber of receptors can var y w ith t im e. F Maxim al e

Learning objective: Calculate the equie ective dose of a new drug given to a patient when the old drug m ust be suspended because of adverse e ects. 5. E Because n aproxen w as th erapeut ically e ect ive, it is rat ion al to star t th e th erapy w ith an equie ect ive dose of th e n ew

cacy refers to th e m axim al e ect th at can be

produ ced by a drug.

drug. Celecoxib is ~5 t im es m ore p oten t th an n aproxen , so a dose 5 t im es low er, or 100 m g, sh ou ld be equ ie ect ive. A−C, D, F See correct an sw er explan at ion .

Learning objective: De ne the term a nity (of a drug). 3. D A n it y is t h e ten d en cy of a d r ug to bin d to a receptor.

Learning objective: De ne the term functional antagonism.

According to th e occupat ion th eor y, bin ding to a receptor is

6. B Glu cagon is som et im es u sed to t reat β-blocker overd ose. By

driven by th e law of m ass act ion ; th at is, th e n u m ber of bou n d

blocking β 1 receptors in the heart, β-blockers lead to a dose-

receptors in creases w h en th e n u m ber of available drug m ole-

d ep en den t decrease in h ear t con t ract ilit y. Glu cagon -in d uced

cu les in creases. Su p pose th at 100 receptors are exposed to

act ivat ion of glu cagon receptors leads to an in crease in h eart

1000 m olecu les of drug A or to 1000 m olecu les of drug B. Also

con t ract ilit y. W h en a d r ug resp on se m ediated by t h e act i-

su p p ose th at , in th is in st an ce, 40 m olecu les of d rug A are

vat ion of a receptor is an t agon ized by an op p osite resp on se

fou n d to be boun d to th e receptors, but on ly 10 m olecu les of

p rod u ced by an ot h er d r ug act ing on a d i eren t set of recep -

drug B are bou n d to th e receptors. It can be con clu ded th at

tors, th e an t agon ism is de n ed as fun ct ion al (also called

receptor a

physiologic).

n it y of drug A is greater th an th at of d rug B.

A In t rin sic act ivit y (often in t rin sic e

cacy is used as a syn -

A, C−E See correct an sw er explan at ion .

onym ) refers to th e abilit y of a drug (on ce boun d to a recep tor) to in it iate ch anges th at lead to a biologic respon se.

Learning objective: De ne the term partial agonist.

B Poten cy refers to th e dose of a drug requ ired to produ ce a

7. C Becau se, by de n it ion , a p ar t ial agon ist can act ivate each

given e ect . Th e low er th e dose requ ired to p rod u ce th e ef-

receptor on ly part ially, it w ill produce less th an th e fu ll e ect

fect , th e h igh er th e poten cy.

even w h en it h as occupied 100%of receptors. Moreover, in th e

C Maxim al e

cacy refers to th e m axim um e ect produ ced

by th e drug. E Receptor act ivat ion is related to th e drug’s in t rin sic act ivit y (th e h igh er th e in t rin sic act ivit y of a drug, th e h igh er th e am oun t of receptor act ivat ion brough t about by th at drug).

presen ce of a fu ll agon ist , a par t ial agon ist w ill beh ave as an agon ist w h en th e con cen t rat ion of th e fu ll agon ist is low, bu t it w ill beh ave as an an t agon ist w h en th e con cen t rat ion of th e fu ll agon ist is h igh . Th e tested dr ug w as m ost likely a par t ial agon ist at β 1 receptors. At rest , w h en th e n orepin eph rin e levels are low, th e

Learning objective: Explain how the graded log dose−response curve can be used to determine the relative potency of t wo drugs.

d rug cau ses a lit tle in crease in h eart rate by p ar t ially act ivat -

4. C By de n it ion , poten cy refers to th e dose n eeded to produce

n ep h r in e are h igh , t h e dr ug beh aves as an an t agon ist , t h u s

a given e ect . In a graded log dose–respon se cur ve, poten cy can be readily est im ated by reading th e dose on th e abscissa (x-axis) correspon ding to a given e ect read on th e ordin ate (y-axis). Poten cy is inversely propor t ion al to th e dose n eeded to produce a given e ect; th e low er th e dose, th e greater th e poten cy.

ing β 1 receptors. After exercise, w h en t h e levels of n orep idecreasing th e h ear t rate. A, B, D−F See correct an sw er exp lan at ion .

Answers and Explanations: I-2 Pharm acodynamics 23 Learning objective: De ne the term competitive antagonist. 8. E By de n it ion , a drug w ith ou t in t rin sic act ivit y is on e th at

Learning objective: Identify the log dose−response curves of t wo drugs that can fully activate the sam e receptors.

is able to bin d receptors bu t is n ot able to act ivate th em .

11. B Drugs P, R, an d S can all p rod u ce th e sam e m axim al e ect .

Th erefore, it is de n ed as an an tagon ist. W h en th e bin ding is

How ever, cu r ves P an d R are parallel, w h ereas cu r ve S is n ot .

reversible, th e an t agon ism is referred to as com pet it ive, an d

Th is suggest s th at dr ugs P an d R act on th e sam e receptors,

th e drug is a com pet it ive an t agon ist .

w h ereas drug S m ost likely acts th rough di eren t receptors.

A−D, F See correct an sw er explan at ion .

A, C−F See correct an sw er explan at ion .

Learning objective: Describe the drug param eters that can be determined from a plot of a cumulative frequency distribution of responders versus log dose.

Learning objective: Identify the highest ED50 of a drug from a graph of multiple log dose−response curves.

9. B Th e cu m u lat ive frequ en cy d ist ribu t ion of su bject s sh ow -

th is t yp e of cu r ve, th e ED50 of a drug is de n ed as th e dose

ing a desired e ect w h en t reated w ith in creasing doses of a

producing 50% of th e m axim u m e ect . It can be est im ated

d rug is called a quan tal log dose−respon se cu r ve. From th is

from th e dose on th e abscissa (x-axis) th at corresp on ds to

cu r ve, th e dose th at can p rodu ce th at e ect in 50% of in di-

th e 50% of m axim u m e ect on th e ord in ate (y-axis). From

vidu als (called th e m edian e ect ive dose) can be read on th e

th e grap h it can be seen th at drug T h as th e h igh est ED50 .

abscissa (x-axis).

12. E Th e dep icted cu r ves are graded log dose−e ect cu r ves. In


A A n it y is th e ten den cy of a drug to bin d to a receptor. It can be m easu red by p lot t ing th e fract ion of receptors bou n d

Learning objective: De ne the therapeutic window of a drug.

by a drug again st th e log of th e drug con cen t rat ion . It can n ot

13. E Th e th erap eu t ic w in dow is th e in ter val bet w een th e m in i-

be m easu red from a qu an t al log dose−respon se cu r ve.

m um th erapeut ic dose (or plasm a con cen t rat ion ) an d th e

C, D Th e th erapeut ic in dex is a rat io bet w een th e toxic

m in im um toxic dose (or plasm a con cen t rat ion ) of a drug.

(TD50 ) an d th e e ect ive (ED50 ) dose of a drug. Th e th erapeu -

Becau se doses below th e m in im um th erapeu t ic dose are by

t ic w in dow is th e in ter val bet w een th e m in im u m e ect ive

de n it ion in e ect ive, an d d oses above th e m in im u m toxic

dose (ED1) an d th e m in im um toxic dose (TD1 ). In order to

dose are, by de n it ion , toxic, th is w in d ow de n es th e range

m easu re th ese variables, t w o qu an tal log dose−e ect cu r ves

of doses th at h ave a h igh probabilit y of th erapeut ic su ccess.

are n eeded. E Maxim al e

A In t rin sic act ivit y refers to th e abilit y of a drug (on ce cacy is th e m axim al e ect a drug can pro-

du ce. It can be m easu red w ith a grade log dose−respon se cu r ve, bu t n ot w ith a qu an tal log dose−resp on se cu r ve.

bou n d to a receptor) to in it iate ch anges th at lead to a bio logic respon se. B E cacy refers to th e m axim al e ect th at a drug can produ ce.

Learning objective: Identify the log dose−response curve of an agonist when a xed dose of a competitive antagonist is given concom itantly.

a given e ect .

10. E W h en a dose of a com pet it ive an tagon ist is given in th e

an d an e ect ive dose of a drug. Like th e th erapeut ic w in dow,

C Poten cy refers to th e dose of a drug requ ired to produ ce D Th e th erapeut ic in dex is a rat io bet w een a toxic dose

n it y of

it is an in dex of th e safet y of a drug, but it is a single valu e

t h e agon ist for it s receptor is d ecreased , as som e receptors

an d th erefore can n ot predict th e range of doses th at are both

w ill be occu p ied by t h e an t agon ist . Th erefore, t h e d ose−

safe an d e ect ive.

p resen ce of a dose of a full agon ist , th e apparen t a

respon se cur ve of an agon ist in th e presen ce of a xed dose of a com pet it ive an tagon ist w ill be sh ifted to th e righ t , but th e m axim al respon se w ill n ot be a ected becau se th e com p et it ive an t agon ism is su rm ou n t able. In oth er w ords, all th e receptors can be occupied by th e agon ist even in th e presen ce of a com pet it ive an t agon ist , p rovided th at th e am ou n t of th e agon ist is h igh en ough to displace all of th e an t agon ist that is present (rem em ber that the interaction bet ween drugs an d receptors is driven by th e law of m ass act ion ). A−D See correct an sw er explan at ion .

F Respon se variabilit y refers to th e range of respon ses, n ot to th e doses elicit ing th e respon ses.

24


Learning objective: Identify the drug param eter that is increased when a drug e ect undergoes tolerance.

Ot h er listed m ech an ism s refer to h om eost at ic adapt ive ch anges of th e organ ism th at coun teract th e drug e ect .

14. B By de n it ion , toleran ce is a decreased respon siven ess to

A, E Tolerance due to increased m etabolism of the drug and

the action of a drug. Therefore, a higher dose of that drug w ill

to decreased con cen t rat ion of th e dr ug at th e site of act ion is

be n ecessar y to obt ain th e given e ect in 50% of th e p op u la-

called ph arm acokin et ic, n ot p h arm acodyn am ic, toleran ce.

t ion (th e m edian e ect ive dose [ED50 ]) w h en toleran ce h as occurred. A Th e m axim al e

e ect s of m orp h in e.

cacy refers to th e m axim u m e ect

ach ievable if th e dose is t aken to ver y h igh levels. In toleran t su bjects, m axim al e

B, C Th ese even ts w ou ld h ave in creased, n ot decreased, th e

cacy m ay st ill be ach ieved, even if

h igh er doses are n eeded to obt ain it .

Learning objective: Explain the m echanism s of pharm acodynam ic tolerance. 17. B Toleran ce can be de n ed as a st ate of d ecreased resp on -

C Th e th erapeut ic in dex is th e rat io bet w een a toxic dose

siven ess to th e act ion of a dr ug th at resu lt s from p rior exp o-

an d an e ect ive dose. Becau se th e e ect ive dose is in creased

su re to th at drug or to a related dr ug. Drug toleran ce can

as a resu lt of toleran ce, th e th erap eut ic in dex is exp ected

involve a d ecreased con cen t rat ion of th e dr ug at th e site of

to decrease or to rem ain th e sam e (if th e toxic dose is also

act ion , du e m ain ly to an in creased biot ran sform at ion of th e

in creased).

d rug (ph arm acokin et ic toleran ce), or it can occu r even w h en

D Poten cy, w h ich refers to th e dose of th e drug n eed ed

t h e con cen t rat ion of t h e d r ug at t h e site of act ion is n ot

to produce a given e ect , is decreased w h en toleran ce h as

m od i ed (ph arm acodyn am ic toleran ce). In th e lat ter case,

occurred.

th e u n derlying m ech an ism can be eith er a d ecreased n u m -

E Toleran ce can be due to in creased m et abolism of th e

ber of receptors (th e m ost com m on ), a ch ange in th e p ost re-

drug. In th is case, h ow ever, th e h alf-life w ould be decreased,

ceptor m ech an ism s, or h om eost at ic adapt ive ch anges th at

n ot in creased.

cou n teract t h e d r ug e ect . Hom eost at ic adapt ive ch an ges seem esp ecially im p or t an t in toleran ce to et h an ol. In fact ,

Learning objective: Explain the meaning of the term tachyphylaxis.

cen t ral n er vous system (CNS) e ect s are m ore pron oun ced

15. B Tachyphylaxis refers to a drug toleran ce th at ap p ears rap -

w h en eth an ol con cen t rat ion s reach es a cert ain level th an

idly (in a m at ter of h ou rs) an d also disappears rapidly w h en

w h en th e sam e con cen t rat ion is presen t during recover y

th e d rug is w ith draw n . So, th e

rst cigaret te cau sed t achy-

from d ru n ken n ess. Th is in dicates th at h om eostat ic adapt ive

cardia because tolerance to nicotine e ects disappeared over-

ch anges occurred in th e CNS during th e in toxicat ion period.

n igh t , but toleran ce to th ose e ect s w as rapidly resum ed

A, C, D Th ese m ech an ism s exp lain ph arm acokin et ic, n ot p h arm acodyn am ic, toleran ce.

w h en sm oking w as rein stated. A Cross-toleran ce refers to toleran ce to a drug th at is sh ared by oth er drugs w ith sim ilar ch em ical st ru ct u re an d/

E A decreased, n ot in creased, n um ber of receptors can exp lain ph arm acodyn am ic toleran ce.

or sim ilar ph arm acological e ects. C Toleran ce is called ph arm acokin et ic w h en it is d u e to a d ecrease in th e e ect ive con cen t rat ion of th e drug at th e site of act ion .

18. B Alth ough ben zodiazep in es are n o longer

rst-lin e agen ts

for gen eralized an xiet y disorder, th ey are st ill used w h en

D In n ate toleran ce refers to a gen et ically determ in ed lack of sen sit ivit y to a drug th at is obser ved th e

Learning objective: De ne the term drug potentiation.

rst t im e th e

d rug is adm in istered. E Sen sit izat ion refers to a dr ug respon se th at in creases w ith th e repet it ion of th e sam e dose of th at drug.

oth er drugs are poorly tolerated or in e ect ive, as m ost likely occurred in th is case. Poten t iat ion occurs w h en a drug en h an ces th e e ect of an oth er drug but is devoid of th at e ect w h en given alon e. Cim et idin e is devoid of sedat ive e ects bu t can in crease th e sedat ive e ect of d iazepam by in h ibiting h ep at ic m etabolism of diazepam m etabolism .

Learning objective: Explain the m echanism s of pharm acodynam ic tolerance.

com bin ed drugs is equal to th e com bin ed respon ses of th e

16. D Opiates exh ibit ph arm acodyn am ic toleran ce, w h ich can be

in dividu al drugs.

A Addit ive e ect occurs w h en th e respon se elicited by

d e n ed as th e decreased respon siven ess to th e act ion of a

C Syn ergism occurs w h en th e respon se elicited by com -

d rug w h ose con cen t rat ion at th e site of act ion rem ain s th e

bin ed drugs is greater th an th e com bin ed respon ses of th e

sam e. Th e m ost com m on m ech an ism u n derlying p h arm aco -

in dividu al drugs.

dyn am ic toleran ce is receptor d ow n regu lat ion ; a d ecrease in receptor den sit y.

D, E Th ese term s refer to drug e ect s th at in crease over t im e w h en th e drug is given ch ron ically.

Answers and Explanations: I-2 Pharm acodynamics 25 Learning objective: De ne the term drug synergism.

pharm acological e ect, often through the activation of di er-

19. C A d rug in teract ion is de n ed as syn ergist ic w h en th e re-

ent protein kin ases.

spon se elicited by com bin ed drugs is greater th an th e com -

A, B, D, E See correct an sw er exp lan at ion .

bin ed resp on ses of th e in dividu al drugs. In oth er w ords, th e p ly addit ive. In th e presen t case, th e e ect s of th e in dividu al

Learning objective: Describe the im m ediate consequence of the activation of m etabotropic receptors.

d rugs are bacteriost at ic, w h ereas th e e ect of th e com bin ed

23. D W h en a m et abot rop ic receptor, e.g., t h e β 2 receptor, is

d rugs is m ore th an an addit ive bacteriost at ic e ect (by de -

act ivated, it bin ds to a G p rotein , w h ich u n dergoes a con for-

n it ion , a bactericidal e ect is greater th an a bacteriostat ic

m at ion al ch ange leading to a free guan osin e t riph osph ate

e ect). Th e in teract ion is th erefore de n ed as syn ergism .

(GTP)-α su bun it th at can regulate a m em bran e en zym e or an

respon se elicited by th e drug com bin at ion is m ore th an sim -

A Ad d it ive e ect s occu r w h en t h e resp on se elicited by com bin ed d r ugs is equ al to t h e com bin ed resp on ses of t h e in d ivid u al dr ugs. B Poten t iat ion occurs w h en a drug en h an ces th e e ect of an oth er d rug bu t is devoid of th at e ect w h en given alon e. D, E Th ese term s refer to drug e ect s th at in crease over t im e, w h en th e d rug is ch ron ically given .

Learning objective: De ne the term chemical antagonism.

ion ch an n el. A−C Th ese are con sequen ces of G-protein act ivat ion , n ot th e im m ediate even t follow ing th e act ivat ion of m etabot rop ic receptors. E Act ivat ion of a G protein can ult im ately cause ph osph orylat ion of m any p rotein s, th u s con t rolling th eir fu n ct ion , bu t th e G protein does n ot un dergo ph osph or ylat ion.

20. D Ch em ical an tagon ism is said to occu r w h en a drug com -

Learning objective: Identify which drug is m ore potent and which drug is m ore e ective, given su cient data.

bin es ch em ically w ith th e drug to be an tagon ized, m aking

24. D Poten cy of a drug refers to th e dose of th at drug n eeded to

th at d rug p h arm acologically in act ive, as in th e presen t ex-

obt ain a given e ect . Because 10 m g of m orph in e is n eeded

am ple. A ch em ical an t agon ist does n ot act on receptors or on

to get an analgesic e ect equal to that given by 0.3 m g of bu-

th e p h arm acokin et ics of th e drug to be an t agon ized.

pren orph in e, m orph in e is less poten t th an bupren orph in e.


E cacy refers to th e m axim al e ect produced by a dr ug. By de n it ion , par t ial agon ist s h ave a m axim al e

Learning objective: Identify the law that regulates the relationship bet ween drug concentration and the association and dissociation of the drug−receptor complex. 21. D According to th e law of m ass act ion , th e n u m ber of recep -

cacy low er

th an th at of fu ll agon ist s. Becau se m orp h in e is a fu ll agon ist an d bu p ren orp h in e a p ar t ial agon ist at th e sam e receptor, bu p ren orp h in e is less e ect ive th an m orph in e. A–C See correct an sw er explan at ion .

tors occupied by a drug depen ds on th e drug con cen t rat ion the higher the concentration (i.e., m ass) of the drug, the higher

Learning objective: Identify the m ost potent am ong di erent drugs, given su cient data.

th e n u m ber of receptors occu pied by th e drug.

25. A Poten cy refers to th e dose n eeded to ach ieve a given e ect .

and the a nit y of the drug−receptor com plex. In other w ords,

A, E Th ese factors depen d on receptor act ivat ion an d on

Th erefore, th e low er th e dose, th e h igh er th e p oten cy. Be-

th e associat ion an d d issociat ion of th e drug−receptor com -

cau se th e ED50 is th e dose n eeded to obt ain a given e ect

p lex, but th ey do n ot regulate th em .

in 50% of in dividuals receiving th e drug, drug A is th e m ost

B, C Th ese are p h arm acokin et ic param eters. Ph arm acokin etic changes do not regulate pharm acodynam ic properties.

poten t . Poten cy h as n oth ing to do w ith e

cacy, w h ich refers

to th e m axim um at t ain able e ect , irrespect ive of th e dose given . In fact , in th e p resen t case, drug A is th e m ost p oten t

Learning objective: De ne the process initiated by drug−receptor binding and ending with the therapeutic e ect.

an d th e least e ect ive. B−E See correct an sw er explan at ion .

22. C Th e d et ailed m olecu lar p at h w ay t h at st ar t s from t h e d r ug bin ding to it s receptor an d leads to a m easurable ph ar-

Learning objective: De ne the term additive ef ects.

m acological e ect is called th e sign al t ran sdu ct ion path w ay.

26. C In th e presen t case, th e respon se elicited by com bin ed

It can in clu d e several step s t h at occu r follow in g t h e act i-

d rugs (8 L of u rin e) is equ al to th e com bin ed resp on ses of th e

vat ion of th e receptor an d are ter m ed post receptor m echa-

in dividu al drugs (5 L + 3 L). W h en th is occu rs, th e drug−d rug

nism s. An exam p le of a p ost receptor m ech an ism is t h e

in teract ion is referred to as addit ive. In oth er w ords, th e ef-

open ing of ion ch an n els, or th e act ivat ion of G protein s,

fect of th e t w o drugs used togeth er is th e sum of th eir in di-

w h ich in t urn causes th e in creased or decreased syn th esis of

vidu al e ects.

secon d m essengers. These m essengers ultim ately produce a


26


Learning objective: Identify the response tim e to activation of steroid receptors. 27. E Drugs th at act ivate n u clear receptors to a ect t ran scrip -

• De n ed as antagonists if th ey do n ot ch ange th e level of con st it ut ive act ivat ion but can an t agon ize th e e ects of both agon ist s an d inverse agon ists (e.g., drug Z)

t ion u su ally h ave a relat ively long resp on se t im e follow ing

Con st it u t ive act ivat ion is a relat ively recen t discover y an d

receptor act ivat ion . Th ese drugs regulate gen e t ran script ion ,

m ay prove to be of greater ph arm acological sign i can ce in

w h ich in t urn causes an in crease or decrease of syn th esis of

th e fut ure.

speci c p rotein s. Th is is con sisten t w ith th e obser vat ion th at


th ere is a t im e lag of h ou rs or days bet w een drug adm in is-

Learning objective: Describe the placebo e ect of a drug.

t rat ion an d th e th erapeu t ic e ect of th ese d rugs. B−E See correct an sw er explan at ion .

30. E W h en a plasm a level of a drug adm in istered 1 h our previously is equal to zero, a ph arm acological e ect of th e drug is

Learning objective: Identify the drug with the highest a nit y for the receptor from a graph of multiple log dose−response curves.

exceedingly u n likely. Th erefore, th e p ain relief m u st be du e

28. A A n it y is de n ed as th e ten den cy of a drug to bin d to its

act ion of th e drug an d op erates th rough psych ological m ech -

receptor. For drugs act ing on th e sam e receptors, a

to an e ect th at is in depen den t from th e ph arm acological

n it y is

an ism s (i.e., a placebo e ect). Placebo e ect is com m on in

d irectly proport ion al to th e poten cy of th e drug. From th e

d rug th erapy. It is alw ays p resen t (m ore or less p ron ou n ced)

graph it can be seen th at drug P is th e m ost poten t an d th ere-

in any dr ug e ect , even for drugs w h ose e

fore h as th e greatest a

p uted. On average, 35% of diseases are favorably in u en ced

n it y for th e receptor.


cacy is u n dis-

by a placebo t reat m en t . A–C All th ese factors w ould h ave caused a sign i can t

Learning objective: De ne the term inverse agonist. 29. C Although m ost receptors are activated only w h en an agon ist m olecule is bound, it has been show n th at som e receptors

p lasm a level of th e drug. D Poor pat ien t com plian ce can n ot explain a good ph arm acological e ect .

can sh ow an appreciable level of act ivat ion (called con st it ut ive act ivat ion ) even w h en n o ligan d is p resen t . Exam p les

PHARMACODYNAMICS Answ er key

in clu d e receptors for gam m a-am in obu t yr ic acid (GABA), can n abin oids, an d seroton in . Drugs act ing on th ese recep tors are • De n ed as agonists if th ey in crease th e level of con st it u t ive act ivat ion (e.g., drug Y) • De n ed as inverse agonists if th ey decrease th e level of con st it ut ive act ivat ion (e.g., drug X)

1. 2. 3. 4. 5.

C C D C E

6. 7. 8. 9. 10.

B C E B E

11. 12. 13. 14. 15.

B E E B B

16. 17. 18. 19. 20.

D B B C D

21. 22. 23. 24. 25.

D C D D A

26. 27. 28. 29. 30.

C E A C E

Answers and Explanations: I-3 Adverse E ects of Drugs Learning objective: Describe the m echanism of adverse side effects of drugs.

Learning objective: Estimate the risk of overdose toxicit y, given su cient data.

1. C Accord ing to th e m ost accepted d e n it ion , a sid e e ect is

2. E Th e r isk of overd ose toxicit y can be est im ated from t h e

an u n in ten ded but n ot toxic ph arm acological respon se to a

t h erap eu t ic in d ex of a d r ug, w h ich is t h e rat io bet w een a

n orm al th erapeut ic dose of a drug. Th erefore, th e adverse ef-

h arm ful dose (leth al, in th is case) an d an e ect ive dose of th at

fect s of th e drug in th is pat ien t are classic side e ect s an d are

drug (m ed ian e ect ive dose, in th is case). Th e low er th e th er-

a con sequen ce of a drug−receptor in teract ion . In fact , all an t i-

apeu t ic in dex, th e h igh er th e risk of overdose toxicit y. Be-

h istam in es used for m ot ion sickn ess h ave sedat ive e ects th at

cau se th e leth al d ose is th e sam e for all drugs, th e drug w ith

resu lt from act ivat ion of cen t ral H 1 receptors, as w ell as an t i-

th e h igh est m edian e ect ive dose w ill be th e drug w ith th e

ch olin ergic e ect s th at are due to blockade of periph eral ch o-

low est th erapeu t ic in dex an d th u s th e h igh est risk of over-

lin ergic receptors.

dose toxicit y.



Answers and Explanations: I-3 Adverse E ects of Drugs 27 Learning objective: Explain the m eaning of overdose toxicit y of a drug.

m alfor m at ion s, in clu ding eye an om alies, dw ar sm , congen i-

3. A Bleeding is th e m ajor adverse e ect of an t icoagu lan t s an d

Heparin is a paren teral an t icoagu lan t th at is n ot h arm fu l to

is a direct con sequ en ce of th eir ph arm acological act ion . It is

th e fet us because it is a large m olecu le (m olecu lar w eigh t

th erefore du e to a dose th at is too h igh for th at pat ien t (i.e.,

15,000 dalton s [D]) an d th erefore does n ot cross th e placen t a.

overd ose toxicit y). Th is risk can be decreased by carefu l con -

All pen icillin s are con sid ered safe du ring p regn an cy.

t rol of dosage an d close m on itoring w ith ap p rop riate lab tests. Hem at u ria (m icroscop ic, or less frequ en tly, m acroscop ic, as

tal h eart disease, an d deafn ess. Fet al death can also occu r.

A Th is ch oice is irrat ion al. Pat ien t s w ith ar t i cial h eart valves m u st receive an t icoagu lan t th erapy.

in th e p resen t case) is usually th e rst sign of overdosage, bu t

B Th e teratogen ic r isk of w ar far in exten d s to t h e secon d

bleeding in th e n ose, oral p h ar yn x, or in test in al t ract is also

an d th ird t rim esters of pregn an cy. Exposu re in th ese p eriods

com m on .

m ay cau se cen t ral n er vous system an om alies, in cluding hy-


d rocep h alu s, m en t al ret ardat ion , seizu res, an d sp ast icit y. Moreover, w h en given sh ortly before deliver y, it m ay cau se a

Learning objective: Describe the idiosyncratic reaction to thiopental in a patient with a genetic de ciency of hem e biosynthetic pathway enzym es. 4. C Barbit urate-in duced at t acks of acu te porphyria in gen et ically susceptible people are a well-know n exam ple of idiosyncrat ic drug react ion . Th ese pat ien t s h ave a gen et ic de cien cy of h em e biosyn th et ic path w ay en zym es. Th e h em e n orm ally fu n ct ion s as a rep ressor of d-am in olevu lin ate syn th ase (ALA syn th ase), th e en zym e th at regu lates th e rate-lim it ing step in porp hyrin biosyn th esis. Barbit u rates in du ce th e syn th esis of

h em orrh agic e ect in th e n ew born . D See correct an sw er explan at ion . E Red u cin g t h e d ose of w ar far in cou ld red u ce t h e r isk to t h e fet u s (teratogen ic e ect s are also related to th e dose of th e o en ding drug) but does n ot avoid it . Moreover, redu cing th e dose w ill m ost likely redu ce th e e ect iven ess of th e th erapy for th e m oth er.

Learning objective: Compare the therapeutic windows of di erent drugs, given su cient data.

cytoch rom e P-450 in th e liver. Th is leads to an en h an ced con -

6. B By de n it ion , th e th erap eu t ic w in d ow of a dr ug is th e range

sum ption of h em e, w hich is a com pon en t of cytochrom e P-450,

bet w een th e m in im u m th erap eu t ic dose (or plasm a con cen -

an d th e con cen t rat ion of h em e in th e liver cells decreases. Th e

t rat ion ) an d th e m in im u m toxic d ose (or p lasm a con cen t ra-

low er con cen t rat ion of h em e en h an ces th e syn th esis of ALA

t ion ) of a drug. Th e w ider th is range, th e h igh er th e probabilit y

syn th ase (derepression ), w h ich in t u rn st im u lates th e syn th e-

of th erapeu t ic su ccess. How ever, because th e range is a rela-

sis of p orphyrin s. Th ese in term ediates accu m u late, as th ey

t ive m easu re, in order to com p are th erap eu t ic w in dow s of

can n ot be t ran sform ed in to h em e du e to th e de cien cy of an

di eren t drugs, th e rat io bet w een th e m in im u m toxic con cen -

en zym e in th e h em e biosyn th et ic path w ay.

tration an d th e m in im um th erapeutic con cen t rat ion of each

At t acks of acu te in term it ten t p orphyria can be ver y seriou s

drug n eeds to be calcu lated, w h ich m ean s calcu lat ing th eir

an d (rarely) fatal. Th e pat ien t’s fam ily h istor y is th e best in di-

therapeutic index. A large therapeut ic index represents a w ide

cator of th e risk of acu te in term it ten t porp hyria.

th erapeut ic w in dow ; a sm all th erapeut ic in dex represen t s a

A, B, D, E All of th ese opt ion s are un likely.

n arrow th erapeut ic w in dow. Th erefore, th e th erapeut ic in dex can be th ough t of as a w ay to qu an t ify th e th erapeu t ic w in -

Learning objective: Describe the best course of action for a patient under warfarin therapy who becomes pregnant. 5. C Warfarin is a teratogen ic drug (categor y D in cludes drugs w it h a p osit ive evid en ce of h u m an p ren at al r isk). Exp o su re to w ar far in d u r ing t h e rst t r im ester m ay cau se several

dow of a drug. In th is exam p le, drug Q n eed s a dose 10 t im es h igh er th an th e m in im um th erapeut ic dose in order to sh ow toxicit y. For all oth er drugs, a dose 2 to 4 t im es h igh er th an th e m in im um th erapeu t ic dose is en ough to cau se toxicit y. A, C–E See correct an sw er explan at ion .

28


Learning objective: Identify the enzym e involved in an idiosyncratic reaction to chloroquine.

can lead to fet al inju r y an d death , t reat m en t w ith secon d

7. B Th e gen et ic polym orph ism of glucose-6-ph osph ate dehy-

A Methyldopa is th e an t ihyper ten sive of ch oice during

d rogen ase (G6PD) is pron oun ced; over 400 m u tan t form s of

pregn an cy becau se ver y few adverse e ect s h ave been re-

th e en zym e h ave been iden t i ed. On ly som e of th ese m u ta-

ported in n eon ates exp osed to th is drug in u tero, desp ite its

t ion s cau se clin ical sym ptom s becau se th eir act ivit y is 1 to

exten sive use.

15% of n orm al. G6PD de cien cy is X-lin ked an d is th e m ost com m on disease-producing enzym e abnorm alit y in hum ans;

gen erat ion an t iconvu lsan t s is gen erally advisable.

C Er yth rom ycin is con sidered safe during pregn an cy (FDA pren at al risk categor y B).

m ore th an 200 m illion p eop le are est im ated to carr y th e

D, E Th ese drugs w ere given du ring th e d eliver y, so th ey

t rait . Th e defect is fu lly exp ressed in m ales an d a ect s abou t

could n ot be associated w ith th e m alform at ion s of th e n ew -

10% of African Am erican m ales. Dim in ish ed G6PD act ivit y

born baby.

im pairs th e abilit y to form NADPH, th e redu ced form of n ict ial in detoxi cat ion of free rad icals an d p eroxides form ed

Learning objective: Describe the m ain features of overdose toxicit y of a drug.

w ith in cells. Alth ough th e de cien cy occurs in all cells, it is

11. E Th e ver y h igh seru m creat in in e level in dicates ren al fail-

m ore severe in er yth rocytes, w h ere th e h exose m on op h os-

u re. Th e n oct u r ia rep or ted by t h e p at ien t is often an early

p h ate provides th e on ly m ean s of gen erat ing NADPH. Th u s,

sym ptom , p r in cip ally d u e to a failu re to con cen t rate t h e

red blood cells are especially sen sit ive to factors such as in -

u r in e. Am in oglycosid e an t ibiot ics su ch as gen t am icin can

fect ion s, diabet ic acidosis, an d oxidan t drugs th at cau se oxi-

cau se n ep h rotoxicit y w h en given at h igh d oses, an d t h e

dat ive dam age of th e cell an d lead to h em olysis. Com m on ly

gen tam icin seru m level poin ts ou t th at th e d rug h ad reach ed

u sed dr ugs th at produce h em olyt ic an em ia in pat ien ts w ith

a too-h igh steady-state con cen t rat ion . Th e m ech an ism of

G6PD de cien cy are som e an t im alarials (e.g., prim aquin e,

am in oglycoside-in du ced ren al failu re is com p lex bu t seem s

ch loroquin e, an d quin in e), som e sulfon am ides (e.g., su lfa-

to be m ain ly related to a dest ruct ion of brush border cells of

m eth oxazole), an d som e salicylates.

th e ren al t u bu le.

ot in am ide aden in e din ucleot ide ph osph ate, w h ich is essen -


A, B Cer t ain ren al diseases (e.g., t u bu loin terst it ial n eph rit is) m ay be cau sed by drug hypersen sit ivit y, bu t am in ogly-

Learning objective: Identify the antibiotic contraindicated in a patient with a previous serious allergic reaction to sulfa drugs. 8. A Becau se t h e w om an h ad a ser iou s hyp ersen sit ivit y to su lfa drugs, any agen t h aving a sulfur atom in it s m olecule

cosid e an t ibiot ics rarely cau se sen sit izat ion , an d t h e h igh gen t am icin con cen t rat ion in d icates t h at overd ose toxicit y is th e m ost likely drug react ion . C, D See correct an sw er explan at ion .

(sulfam eth oxazole, in th is case) sh ou ld be avoided, as crosssen sit ivit y u su ally occu rs in d r ugs w it h sim ilar ch em ical st ru ct u re. B−E See correct an sw er explan at ion .

Learning objective: Identify the m ain t ype II allergic reactions to penicillins. 12. D Th e sign s of th e pat ien t (skin rash , eosin op h ilu ria) suggest th at h is disease w as cau sed by an allergic react ion . Th e m ost

Learning objective: De ne the ED 50 of a drug.

frequ en t cau se of t u bu loin terst it ial n ep h rit is is a t ype II al-

9. C By de n it ion , th e dose able to elicit a speci c respon se

lergic drug react ion . Allergic t u bu loin terst it ial n eph rit is is

(sleep, in th is case) in 50% of in dividu als receiving th e drug

rat h er com m on an d is t h e u n derlying cau se of u p to 3% of

is called th e m edian e ect ive dose (ED50 ).

all cases of acu te ren al failu re. Th e d isease can be cau sed by


m any d i eren t d r ugs, in clu d in g an t ibiot ics, d iu ret ics, an d n on steroidal an t iin am m ator y drugs (NSAIDs), but pen icil-

Learning objective: Describe the fetal phenytoin syndrom e. 10. B Many

rst gen erat ion an t iconvu lsan t drugs are classi ed

categor y D or X by th e U.S. Food an d Drug Adm in ist rat ion (FDA). Th e syn drom e exh ibited by th is n ew born baby is called fetal ph enytoin syn drom e an d m ay in clu de n early all p ossible t ypes of m alform at ion s. It is n ow recogn ized th at th is syn drom e h as been lin ked to oth er rst gen erat ion an t i-

lin s are m ost frequ en tly im p licated . Recogn it ion of a drugrelated cau se is im por t an t , because severe ren al dam age is often preven t able an d reversible. A−C, E See correct an sw er explan at ion .

Learning objective: Describe the m ain t ype III allergic reactions to drugs.

convulsan t s an d occurs in about 4%of th e ch ildren of epilep -

13. E Th e p at ien t w as m ost likely su ering from seru m sickn ess,

t ic w om en w h o receive th is th erapy d uring pregn an cy. Yet ,

a t yp e III allergic react ion to drugs ch aracterized by acu te

because uncontrolled generalized seizures during pregnancy

urticaria and angioedem a or by m orbilliform eruptions, often accom p an ied by p olyar th rit is, m yalgia, an d fever, du e to an

Answers and Explanations: I-3 Adverse E ects of Drugs 29 excessive form at ion of im m u n e com p lexes. Th e an t igen -

th e occurren ce an d th e severit y of an allergic react ion are

an t ibody com p lex u su ally p recip it ates ver y qu ickly an d ,

n ot dose-depen den t in m ost cases.

being p h agocytosed by m acrop h ages, elicit s n o react ion . If

C Th e bioavailabilit y refers to th e fract ion of th e dr ug

th e an t igen is in excess to th e an t ibody, h ow ever, th e im -

reach ing th e gen eral circu lat ion . Because allergy is n ot re-

m u n e com p lexes m ay rem ain solu ble in th e blood an d con -

lated to dose, bioavailabilit y is n ot an im p or t an t factor for an

t in u e to circu late. Even t u ally th ey m ay dep osit on th e w alls

allergic drug react ion . Moreover, th e oral rou te carries th e

of blood vessels at basem en t m em bran es, causing com ple-

low est risk of allergic react ion .

m en t act ivat ion an d local in am m at ion . Pen icillin s are t ypical cau sat ive agen ts of seru m sickn ess. A−D See correct an sw er explan at ion .

D Th e gen et ic pedigree is im por tan t for idiosyn crat ic dr ug react ion s. E Th e pat ien t’s liver an d kidn ey fun ct ion s are im port an t factors for drug overdose toxicit y.

Learning objective: Describe the m ain t ype IV allergic reactions to drugs. 14. E Th e pat ien t w as likely su ering from con tact derm at it is, w h ich is an adverse e ect com m on to m any dr ugs given

Learning objective: Describe the appropriate procedure to m inimize the risk of an allergic drug reaction. 17. E A det ailed p erson al an d fam ily h istor y sh ould be th e

rst

locally. Top ical doxepin , w h ich is e ect ive in m any cases of

p rocedu re to u n d er take in order to m in im ize th e risk of an

p ru rit us, is especially pron e to cause th is adverse e ect .

allergic drug reaction. This should include inform at ion about

Con tact derm at it is is th e m ost com m on m an ifestat ion of

p rior allergic an d m edicat ion en cou n ters, prior exposu re to

t ype IV (cell-m ediated) allergic react ion . Pat ien ts m ay be-

th e sam e or st ru ct u rally related m edicat ion s, an d th e n at u re

com e allergic to drugs u sed to t reat skin diseases. It t akes

an d severit y of th e react ion . Th is in form at ion can alert th e

6 to 10 days (in th e case of st rong sen sit izers) to years (for

p hysician abou t cert ain t ypes of com p oun ds to w h ich th e

w eaker sen sit izers) for pat ien ts to becom e sen sit ized. Con -

p at ien t is likely to react .

t act derm at it is m ay resem ble oth er t ypes of derm at it is, bu t

A Giving a sm all dose is n ot a safeguard again st allergic

skin ch an ges an d t h e h istor y of exp osu re facilit ate t h e

react ion to a drug because th e seriousn ess of an allergic re-

d iagn osis.

act ion is n ot related to th e dose given .

A−D All of th ese opt ion s are un likely because of th e h istor y of exposu re an d th e result of th e patch test .

B Skin test s are reliable m eth ods for th e diagn osis of allergy to β-lact am an t ibiot ics, bu t th ey sh ould be perform ed on ly after th e h istor y h as determ in ed th e likelih ood of an

Learning objective: Describe the idiosyncratic drug reactions due to a genetic de ciency of the reduced form of nicotinam ide adenine dinucleotide (NADH)−methemoglobin reductase.

allergic react ion to th em .

15. C Th e p at ien t w as m ost likely su ering from a gen et ically

bu t th ey are n ot e ect ive for p reven t ion of any su pp osed

d eterm in ed abn orm al react ion to su lfam eth oxazole. Several

C Antiallergic m edication s (corticosteroids, antihistam ines, etc.) can be used for th e th erapy of speci c allergic react ion s, (an d st ill un kn ow n ) hypersen sit ivit y react ion .

drugs, including sulfonam ides, som e local anesthetics, nitrites,

D To ch ange th e drug th e pat ien t is allergic (or is supposed

p rim aquin e, an d dapson e, can cau se m eth em oglobin em ia.

to be allergic) to w ith an oth er dr ug belonging to th e sam e

Pat ien ts w ith a gen et ic de cien cy of NADH−m eth em oglobin

ch em ical class does n ot decrease th e risk of an allergic reac-

reductase are especially sen sit ive to drug-in duced m eth e-

t ion becau se cross-sen sit ivit y is ver y com m on am ong di er-

m oglobin em ia, becau se th ey lack th e en zym e th at redu ces

en t drugs belonging to th e sam e class.

m eth em oglobin to h em oglobin . A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Describe the allergic reaction to m ethyldopa. 18. B Th e p osit ive Coom bs test in d icates th at th e pat ien t w as

Learning objective: Outline the m ost important determ inant of allergic drug reaction.

m ost likely su ering from au toim m u n e h em olyt ic an em ia.

16. B Som e drugs cause allergic react ion s ver y rarely, w h ereas

t reated for 3 to 6 m on th s w ith m ethyldop a, w ith h em olyt ic

oth er com poun ds (obviously n ot used as dr ugs) can cause

an em ia occu rring in 1 to 5% of cases. Th is is a t yp e II allergic

sen sit izat ion in all exp osed su bject s. Th erefore, t h e d r ug

d rug react ion . Th e drug is able to in du ce th e form at ion of

st r u ct u re is t h e m ajor d eter m in an t of t h e frequ en cy of an

au toan t ibodies (im m u n oglobu lin G) to red blood cells, th u s

allergic react ion to a drug.

cau sing cell lysis. Th e an em ia u su ally ceases w ith in 3 w eeks

A Even if in som e rare occu rren ces th e dose can be a factor predisposing to allergy (i.e., pen icillin -in duced h em olyt ic an em ia requ ires h igh an d su stain ed drug con cen t rat ion s),

Posit ive Coom bs react ion occurs in up to 30% of pat ien t s

after w ith draw al of th e drug, bu t a Coom bs test can rem ain p osit ive for m ore th an 1 year. A, C−E See correct an sw er explan at ion .

30


Learning objective: Identify a pseudoallergic reaction to drugs.

m u scu lar blockade by th ese drugs m ay be exceedingly p ro-

19. D Th e sign s an d sym ptom s of th e p at ien t in dicate th at h e

longed in p at ien t s w h o h ave a gen et ically abn orm al varian t

w as su er in g from a t yp e I−like allergic react ion , bu t cir-

of ch olinesterase. Also, because th is varian t is m u ch less e

cu lat ing an t ibod ies can n ot be d etected . In t h ese cases, t h e

cien t th an th e n orm al en zym e, it can take 2 to 3 h ou rs for

react ion is called pseu doallergic, an d th e clin ical sym ptom s

th e p aralysis to disapp ear. In th is case, th e an esth esiologist

are du e to a drug-in du ced direct form at ion an d/or release of

m u st con t in u e th e gen eral an esth esia an d ar t i cial resp ira-

m ediators n orm ally involved in allergic react ion s.

t ion u n t il cessat ion of th e drug e ect .


A, B, D, E Th ese oth er opt ion s are u n likely.

Learning objective: Identify an idiosyncratic reaction to drugs.

ADVERSE EFFECTS OF DRUGS Answ er key

20. C An id iosyn crat ic react ion is com m on ly d e n ed as a gen et ically determ in ed abn orm al react ion to a drug. Succinylch olin e an d m ivacurium are n eurom uscular blocking drugs th at are p rim arily m etabolized by p lasm a ch olin esterase (but yr ylch olin esterase). Because of th is exten sive an d rapid m et abolism , t h e act ion of t h ese d r ugs is br ief. Th e n eu ro -

1. 2. 3. 4. 5.

C E A C C

6. 7. 8. 9. 10.

B B A C B

11. 12. 13. 14. 15.

E D E E C

16. 17. 18. 19. 20.

B E B D C

-

II Autonom ic Nervous System Questions: II-1 Introduction to Autonom ic Pharm acology Directions for questions 1−5


Match each e ect w ith th e act ivat ion of th e ap p rop riate receptor

7. A 43-year-old m an recen t ly d iagn osed w it h p h eoch rom o -

(each let tered opt ion can be selected on ce, m ore th an on ce, or n ot

cytom a (an adren al glan d t um or) st ar ted a t reat m en t w ith a

at all).

drug th at can cau se a p ron ou n ced decrease in n orep in ep h rin e

A. α 1 adren ergic B. α 2 adren ergic

an d epin eph rin e by blocking th e rst rate-lim it ing step in cat ech olam in e biosyn th esis. W h ich of th e follow ing en zym es

C. β 1 adren ergic

w as m ost likely in h ibited by th e drug?

D. β 2 adren ergic

A. Arom at ic l -am in o acid decarboxylase

E. β 3 adren ergic

B. Dopam in e-β-hydroxylase

F.

C. Tyrosin e hydroxylase

D1 dopam in ergic

G. D2 dopam in ergic

D. Ph enyleth an olam in e m ethylt ran sferase

H. M 2 ch olin ergic

E. Mon oam in e oxidase

I.

M 3 ch olin ergic

J.

Nm ch olin ergic

K. Nn ch olin ergic

Di cult y level: Medium 8. A 14-year-old boy w ith t ype 1 diabetes n ot iced sym ptom s of p alpit at ion s, inw ard t rem blin g, sw eat ing, h u nger, w eakn ess,


an d n er vou sn ess ju st after h is p ar t icip at ion in a basketball

1. Mydriasis

gam e. His m edicat ion in clu ded t w ice daily inject ion s of in sulin . Most of th e boy’s sym ptom s likely resu lted from in creased

Di cult y level: Easy 2. In creased glu con eogen esis

ring of w h ich of th e follow ing n euron s? A. Som at ic m otor n eu ron s B. Pyram idal n eu ron s


C. Preganglion ic parasym path et ic n eu ron s

3. Select ive dilat ion of ren al vessels

D. Preganglion ic sym path et ic n euron s E. Postganglion ic parasym path et ic n euron s

Di cult y level: Easy 4. Con st rict ion of bladder in tern al sp h in cter

Di cult y level: Easy 9. A 55-year-old w om an su ering from post u ral hyp oten sion

Di cult y level: Easy 5. Decreased at rioven t ricular con du ct ion

Di cult y level: Medium 6. A 2.1-kg (4.6-lb) baby boy w as bor n at 34 w eeks gest at ion by vagin al deliver y. On e h our after bir th , th e baby appeared hyp oth erm ic an d leth argic. Apgar scores w ere low, an d blood pressu re w as 55/35 m m Hg. Lab test s revealed th at th e n ew -

star ted a t reat m en t w ith an α 1 -adren ergic drug. W h ich of th e follow ing is a body site w h ere au ton om ic receptors are prim arily α 1 adren ergic? A. Bron ch ial m uscle B. Sp h in cter m u scle of th e iris C. At rioven t ricu lar n ode D. Pu rkinje bers E. Skin vessels

born h ad a gen et ic dopam in e β-hydroxylase de cien cy. Lab test s w ould h ave also sh ow n w h ich of th e follow ing results? A. Ver y low plasm a levels of n orepin eph rin e B. Ver y low plasm a levels of dopam in e C. High p lasm a levels of ep in ep h rin e D. High u rin ar y levels of n orm etan eph rin e E. Low urin ar y levels of h om ovan illic acid

31

32

Autonomic Nervous System



10. A 24-year-old w om an adm it ted to th e h ospit al after a car

13. Th e cardiovascular e ects of a n ew au ton om ic drug th at does

acciden t w as d iagn osed w ith n eu rogen ic sh ock du e to a sp i-

n ot cross th e blood−brain barrier w ere evaluated in a h ealthy

n al cord inju r y. An em ergen cy t reat m en t w as st ar ted th at

volu n teer. Th e drug w as adm in istered in t raven ou sly, an d th e

in clu ded th e adm in ist rat ion of n orepin ep h rin e. W h ich of

results are presen ted below :

t h e follow ing exp ected e ect s of th e d r ug w as m ost likely m ediated by th e act ivat ion of p eriph eral p ost syn apt ic β 1

Parameter

Control

Drug X

receptors?

Systolic BP (m m Hg)

120

130

A. Bron ch odilat ion

Diastolic BP(m m Hg)

80

100

B. Uterin e relaxat ion

Heart rate (bpm )

70

60

Abbreviations: BP, blood pressure; bpm , beats per m inute.

C. In creased liver glucon eogen esis D. In creased ren in secret ion

W h ich of th e follow ing receptors did th e dr ug m ost likely

E. Decreased in sulin secret ion F.

act ivate?

In creased sw eat ing of th e palm s of th e h an ds

A. α 1 adren ergic B. β 2 adren ergic

Di cult y level: Medium 11. A 28-year-old w om an presen ted to th e em ergen cy depar tm en t w ith breath ing di cu lt y an d in creasing sw elling of h er face, eyes, lips, an d tongue. An h our earlier sh e h ad received an in t ram u scu lar inject ion of am p icillin to t reat acu te ph aryngit is. A diagn osis of an aphylact ic react ion w as m ade, an d an in t ram u scu lar inject ion of ep in ep h rin e w as given . W h ich of th e follow ing expected e ect s of th e drug w as m ost likely m ed iated by t h e act ivat ion of p er ip h eral p ost syn apt ic α 2 receptors?

(cGMP)

12. A n ew auton om ic drug w as adm in istered locally in th e con jun ct ival sac of a h ealthy volun teer. Tw en t y m in u tes later, m easu rem en t of several eye param eters gave th e follow ing results:

C. Nn an d Nm ch olin ergic D. M 2 an d M 3 ch olin ergic E. β 1 an d β 2 adren ergic

Di cult y level: Hard 15. Th e cardiovascu lar e ect s of a n ew au ton om ic drug th at d oes n ot cross th e blood−brain barrier w ere evaluated in a h ealthy m ale volun teer. Th e drug w as adm in istered in t ra-

Before Drug

After Drug

3.0

3.5

Norm al

Norm al

20

15

W h ich of th e follow ing pairs of receptors did th e dr ug m ost

B. α 2 an d β 2 adren ergic

m ost likely m ediated th e th erap eu t ic e ect of th e drug in

E. In creased syn th esis of cyclic guan osin e m on oph osph ate


A. α 1 an d α 2 adren ergic

ceptors. W h ich of th e follow ing post receptor m ech an ism s

D. Blockade of voltage-gated Ca 2+ ch an n els

Dilat ion of skelet al m uscle vessels

likely act ivate?

st ar ted th erapy w ith a drug th at select ively act ivates α 1 re-

C. Open ing of ligan d-gated K+ ch an n els

E. In creased h ear t rate

Intraocular pressure (m m Hg)

14. A 62-year-old m an su er ing from p ost u ral hyp oten sion

B. In creased act ivat ion of ph osph olipase C

D. Con st rict ion of skin vessels

Lens curvature


diacylglycerol (DAG)

C. In creased secret ion of ren in

Pupillary diam eter (m m )

E. β 1 adren ergic

A. Decreased syn th esis of in ositol t riph osph ate (IP3 ) an d

B. Decreased secret ion of in sulin

Parameter

D. M 2 ch olin ergic

th is p at ien t?

A. Mydriasis

F.

C. D1 dopam in ergic

ven ou sly, an d th e resu lts are presen ted below : Parameter

Control

Drug


120

130

Diastolic BP (m m Hg)

75

55

Heart rate (bpm )

70

115


Questions: II-1 Introduction to Autonom ic Pharmacology 33 W h ich of th e follow ing pairs of receptors w ere m ost likely


act ivated by th e drug?

18. A n ew auton om ic drug w as adm in istered locally in th e con -

A. α 1 an d α 2 adren ergic

jun ct ival sac of a h ealthy volun teer during a ph ase 1 clin ical

B. α 1 an d β 1 adren ergic

t rial. Tw en t y m in u tes later, m easu rem en t of several eye pa-

C. Nm an d Nn ch olin ergic

ram eters gave th e follow ing results:

D. M 2 an d M 3 ch olin ergic

Pu pillar y diam eter: decreased

E. β 1 an d β 2 adren ergic

Len s cur vat ure: in creased

Di cult y level: Hard 16. Th e bron ch ial e ect s of a n ew alp h a-bet a agon ist th at does

In t raocular pressure: decreased W h ich of th e follow ing receptors did th e drug m ost likely

n ot cross t h e blood −brain bar r ier w as st u died in labora-

act ivate?

tor y an im als. It w as foun d th at th e drug caused relaxat ion of

A. α 1

bron ch iolar sm ooth m u scle. Th e act ivat ion of w h ich of th e

B. α 2

follow ing pairs of adren oceptors m ost likely m ediated th e

C. Nm

e ect of th e drug?

D. M 3

A. β 2 p ostsyn apt ic an d α 2 presyn apt ic

E. β 2

B. β 1 p resyn apt ic an d α 1 post syn apt ic C. α 2 post syn apt ic an d β 3 post syn apt ic D. α 1 presyn apt ic an d β 2 presyn apt ic E. β 1 p ostsyn apt ic an d α 2 presyn apt ic

Di cult y level: Hard 19. A 54-year-old w om an com plain ed to h er physician of palp it at ion s, dr y m ou th , blurred vision , an d con st ipat ion . Th e w om an h ad a long h istor y of en dogen ou s depression an d h ad


recen tly st ar ted a n ew an t idep ressan t th erapy. Th e p at ien t’s

17. Th e m et abolic e ect s of a n ew au ton om ic drug w ere st u d ied

sym ptom s m ost likely resu lted from a blockade of w h ich of

in laborator y an im als. Th e follow ing result s w ere obtain ed: Liver glucon eogen esis: in creased Ren in secret ion : u n a ected Plasm a K+: decreased Degran u lat ion of m ast cells: in h ibited

th e follow ing pairs of receptors? A. α 1 an d α 2 B. α 1 an d β 1 C. M 2 an d M 3 D. β 1 an d β 2 E. Nm an d β 2

Lipolysis in fat cells: in creased W h ich of th e follow ing pairs of receptors w ere m ost likely act ivated by th e drug? A. α 1 an d β 1 B. β 2 an d β 3 C. β 1 an d β 2 D. M 3 an d β 3 E. M 2 an d M 3 F.

α 1 an d M 2

Di cult y level: Hard 20. A 35-year-old far m er w as brough t to t h e em ergen cy dep ar t m en t w ith severe abd om in al cram p s an d vom it in g. He repor ted th at h e w as w orking in th e

eld w ith an organ o-

p h osph ate pest icide. Th e p hysician obser ved all of th e t ypical sym ptom s of acet ylch olin e excess. W h ich of th e follow ing sym ptom s of th e p at ien t w ere m ost likely du e to th e act ivat ion of n icot in ic Nm receptors on ly? A. Salivat ion , decreased blood p ressu re B. Di cult y in breath ing, m iosis C. Diarrh ea, sw eat ing D. Bradycardia, urin ar y urgen cy E. Diplopia, di cu lt y in sw allow ing

34


Questions: II-2 Adrenergic Drugs Directions for questions 1−5


Match each ad ren ergic d r ug w it h t h e ap p rop r iate d escr ipt ion

7. A 35-year-old m an w as adm it ted to th e h ospital follow ing a


car acciden t , an d a blood t ran sfu sion w as st arted. A few m in -

at all).

u tes later, h e com plain ed of n au sea an d p rurit us an d devel-

A. Albuterol

oped dyspn ea w ith audible w h eezing. His skin w as m ot tled

B. Apraclon idin e

an d cold, h ear t rate w as 120 bpm , an d blood pressu re fell to

C. Cocain e

80/40 m m Hg. An in t ram u scu lar inject ion of epin eph rin e w as

D. Dext roam ph etam in e

given . W h ich of th e follow ing act ion s of th e drug m ost likely

E. Dobutam in e

con t ributed to it s th erapeu t ic e

F.

A. In creased glycogen olysis

Dopam in e

cacy in th is pat ien t?

G. Epin eph rin e

B. β 2 receptor−m ediated vasodilat ion

H. Isoproteren ol

C. St im u lat ion of p latelet aggregat ion

I.

Methyld op a

D. In hibit ion of in sulin secret ion

J.

Norep in ep h rin e

E. In hibit ion of m ast cell degran ulat ion

K. Ph enylep h rin e L.

F.

St im u lat ion of eicosan oid biosyn th esis

Salm eterol

Di cult y level: Medium Di cult y level: Easy

8. A 34-year-old w om an w as at th e den t ist for an en dodon t ic

1. An α 2 select ive adren oceptor agon ist

procedu re. Before st art ing th e procedu re, th e den t ist injected a solut ion of lidocain e plus epin eph rin e n ear th e tooth in


order to provide local an esth esia. Th e epin eph rin e-in duced

2. A long-act ing β 2 select ive adren oceptor agon ist

in creased duration of th e lidocain e e ect w as m ost likely m e-


ceptors?

3. An in d irect -act ing ad ren ergic agen t som et im es u sed as an

A. β 1

diated by th e act ivat ion of w h ich of th e follow ing ad ren o-

B. β 2

an t ihyper ten sive

C. β 3 D. α 1

Di cult y level: Easy 4. A n on select ive β 1 adren oceptor agon ist

E. α 2


Di cult y level: Easy 5. A select ive α 1 adren oceptor agon ist

9. A 51-year-old m an w as adm it ted to th e coron ar y care un it w it h a d iagn osis of m yocardial in farct ion . Tw o h ou rs later, h e developed ven t ricular brillat ion an d w as de brillated im -

Di cult y level: Medium 6. A 75-year-old -w om an , h osp it alized for breast can cer, w as fou n d u n con sciou s in h er bed by a n u rse. A d iagn osis of card iac ar rest w as m ad e, an d card iop u lm on ar y resu scit at ion w as st arted w ith ou t su ccess. Th e elect rocardiogram sh ow ed th at th e pat ien t w as in asystole. An in t racardiac inject ion of ep in ep h rin e w as given . W h ich of th e follow ing post receptor m ech an ism s m ost likely m ediated th e e ect of epin eph rin e on cardiac con t ract ilit y in th is pat ien t? +

A. Open ing of ligan d-gated K ch an n els +

B. Open ing of ligan d-gated Na ch an n els C. Act ivat ion of ph osph olipase C D. Act ivat ion of ph osph olipase A2 E. Act ivat ion of adenylyl cyclase

m ed iately, bu t w ith out success. Cardiopu lm on ar y resu scitat ion (CPR) w as star ted, an d t w o ad dit ion al sh ocks w ere given at a h igh er en ergy, but th e p at ien t rem ain ed un respon sive. At th is t im e a bolu s of in t raven ou s epin eph rin e w as given , w h ile con t in uing th e CPR. W h ich of th e follow ing receptor act ion s of th e drug best describes th e rat ion ale for adding epin eph rin e in th is set t ing? A. α 1 receptor−m ediated vasocon st rict ion B. β 2 receptor−m ediated vasodilat ion C. β 2 receptor−m ediated in crease in cardiac contractilit y D. β 1 receptor−m ediated in crease in ren in secret ion E. β 2 receptor−m ediated bron ch odilat ion

Questions: II-2 Adrenergic Drugs 35 Di cult y level: Medium


10. A 60-year-old m an h ospitalized follow ing a m yocardial in -

13. A 43-year-old m an w as brough t to th e em ergen cy room fol-

farct ion sh ow ed a pron ou n ced decrease in blood pressure

low ing a car acciden t . He received an in lt rat ion of a local

an d u rin e ou t p u t 2 h ou rs after th e adm ission . A diagn osis of

an esth et ic arou n d a skin w ou n d in preparat ion for su t u ring.

cardiogen ic sh ock w as m ad e, an d an em ergen cy th erapy w as

A few m in utes later, th e m an appeared

star ted. An adren ergic d rug w ith both direct an d in direct ac-

plain ed of di cult y breath ing. Blood pressure w as 90/50 m m

t ion s w as given by in t raven ou s in fu sion . W h ich of th e fol-

Hg, h eart rate 92 bp m . Ch est au scu lt at ion revealed rest ric-

low ing d rugs t t ing th is p ro le w ou ld be appropriate for th e

t ive air

p at ien t?

given . W h ich of th e follow ing act ion s m ost likely con t rib -

A. Dopam in e

u ted to th e th erapeu t ic e

B. Norep in ep h rin e

d isorder?

C. Isoproteren ol

A. An tagon ism of h istam in e e ects on th e h ear t

D. Dobutam in e

B. An t agon ism of bradykin in e ect s on skelet al m u scle

ush ed an d com -

ow an d st ridor. An inject ion of ep in ep h rin e w as cacy of th e drug in th e pat ien t’s

vessels

E. Ph enylep h rin e

C. An t agon ism of leu kot r ien e e ect s on t h e resp irator y


system

11. A n ew auton om ic drug th at does n ot en ter th e brain w as

D. Act ivat ion of α 1 receptors on bron ch ial m uscles

given in t raven ou sly to h ealthy volu n teers in a p h ase 1 clin i-

E. Act ivat ion of β 2 receptors on lu ng vessels

cal t rial. Th e resu lts are p resen ted below :

F.

Parameter

Control

Peak Drug Ef ect


125

145

Diastolic BP(m m Hg)

75

95

Heart rate (bpm )

70

51

Cardiac output (L/m in) Ejection fraction (%)

5.5 60

5.1 75

Act ivat ion of α 2 receptors on platelet s

Di cult y level: Medium 14. A 16-year-old girl was treated topically w ith eye drops during a rou t in e op h th alm oscop ic exam in at ion . After 15 m in u tes, th e op h th alm ologist m easu red an in crease in p u p illar y d iam eter w ith n egligible ch anges in len s cu r vat u re an d in t raocular pressu re. W h ich of th e follow ing drugs w as m ost likely adm in istered to th e p at ien t?

Abbreviations: BP, blood pressure; bpm , beats per minute.

A. Ph enyleph rin e


B. Tim olol

resem ble?

C. Acet ylch olin e D. Apraclon idin e

A. Dobutam in e

E. Epin eph rin e

B. Epin eph rin e C. Isoproteren ol


D. Norep in ep h rin e

15. A 15-year-old boy su er ing from ast h m a rou t in ely self-

E. Ph enylep h rin e F.

adm in istered albu terol th rough a m etered-dose in h aler.

Propran olol

W hich of the follow ing actions m ost likely contributed to the


th erap eu t ic e

cacy of th e drug in th e p at ien t’s disorder?

12. A 54-year-old m an w as about to receive local an esth esia be-

A. In creased m icrovascular perm eabilit y

fore a tooth ext ract ion . On e year ago th e pat ien t u n der w en t

B. Decreased bron ch ial secret ion s

an ep isode of ven t ricu lar

C. Release of h ist am in e from m ast cells

brillat ion th at w as su ccessfu lly

t reated w ith elect rical cardioversion . Th e den t ist d ecid ed to

D. In creased residual respirator y volu m e

avoid a local an est h esia w it h ep in ep h r in e becau se t h e p a-

E. In creased m ucociliar y clearan ce

t ien t w as esp ecially at risk of w h ich of th e follow ing drugin duced adverse e ect s? A. Cerebral h em orrh age B. Nausea an d vom it ing C. Pu lm on ar y edem a D. Ven t ricular tachycardia E. Hyp erglycem ia

36




16. A n ew auton om ic drug th at does n ot en ter th e brain w as

19. A 57-year-old h om eless alcoh olic m an w as brough t to th e

given in t raven ou sly to h ealthy volu n teers in a p h ase 1 clin i-

h ospital by th e police, w h o h ad foun d h im lying on a side-

cal t rial. Th e cardiovascu lar e ect s are p resen ted below :

w alk. Physical exam in at ion sh ow ed clear sign s of alcoh ol w ith draw al. Th erapy w as star ted th at in cluded clon idin e.

Parameter

Control

Peak Drug Ef ect


125

145

Diastolic BP (m m Hg)

75

95

Heart rate (bpm )

70

58


5 60

4.5 60


W h ich of th e follow ing best explain s th e m ost likely m ech an ism of act ion of clon idin e in th is pat ien t? A. Decreased cen t ral sym path et ic ou t ow B. Act ivat ion of perip h eral α 1 receptors C. Decreased cen t ral parasym path et ic out ow D. Act ivat ion of perip h eral α 2 receptors E. Blockade of α receptors on th e t ract u s solitarius F.

Blockade of α receptors on th e locus ceruleus

W h ich of t h e follow ing dr ugs d oes t h e n ew agen t m ost resem ble?


A. Dobutam in e

20. A 7-year-old girl recen tly diagn osed w ith persisten t asth m a

B. Epin eph rin e

star ted t reat m en t w ith in h aled albu terol “as n eeded .” W h ich

C. Isoproteren ol

of th e follow ing adverse e ect s w as m ost likely to occur


d uring th e th erapy?


A. At rioven t ricu lar block B. Restlessn ess


C. Sleepin ess

17. A 72-year-old m an su ering from prostatic hyperplasia com -

D. Post ural hypoten sion

p lain ed to h is p hysician th at h e h ad in creased di cu lt y an d

E. Ven t ricular tachycardia

p ain in voiding h is bladder. Th e pat ien t h ad h ad been taking an over-th e-cou n ter oral n asal decongestan t for 3 days be-

Di cult y level: Medium.

cau se of an an n oying com m on cold . W h ich of th e follow ing

21. A 52-year-old w om an su ering from severe bronchial asthm a

d rugs m ost likely con t ributed to h is dysuria?

w as recen tly d iagn osed w ith open -angle glau com a. An ap -

A. Albuterol

p ropriate local th erapy w as p rescribed . W h ich of th e follow -

B. Ph enylep h rin e

ing drugs m ost likely w ou ld be in clud ed in th e glau com a

C. Clon idin e

t reat m en t of th is p at ien t?


A. Carbach ol

E. Dopam in e

B. Epin eph rin e

F.

C. Propran olol

Salm eterol

D. Pilocarp in e


E. Tim olol

18. A 65-year-old w om an su ering from open -angle glaucom a w as prescribed a t reat m en t regim en th at in clu ded ap raclon -


idin e eye drops. W h ich of th e follow ing act ion s on aqueous

22. A 33-year-old m an w as brough t to th e em ergen cy room

h um or m ost likely m ediated th e th erapeut ic e ect of th e

after a car acciden t . Up on adm ission , th e pat ien t w as lu cid

d rug in th e pat ien t’s disease?

bu t com p letely p aralyzed, w ith loss of all sen sat ion an d re-

A. In creased out ow th rough th e Sch lem m can al

ex act ivit y below th e th orax. Vit al sign s w ere blood pres-

B. Decreased product ion by th e t rabecular m esh w ork

su re 80/40 m m Hg, h ear t rate 42 bp m , resp irat ion s 36/m in .

C. In creased out ow th rough th e uveoscleral route

A prelim in ar y diagn osis of spin al sh ock, due to spin al cord

D. Decreased product ion by eye vessel con st rict ion

inju r y, w as m ade, an d an in t raven ou s in fusion of an app ro-

E. Decreased product ion by th e ciliar y epith elium

p riate drug w as st ar ted. W h ich of th e follow ing drugs w as m ost likely adm in istered?

Questions: II-2 Adrenergic Drugs 37 A. Isoproteren ol

80/70 m m Hg, an d respirat ion w as sh allow w ith a rate of 30

B. Clon idin e

breath s/m in . Th e

C. Norep in ep h rin e

in th is p at ien t w ould h ave been an in t raven ou s in fu sion of

D. Albuterol

w h ich of th e follow ing agen t s?

E. Salm eterol

A. Norep in ep h rin e

rst ap p rop riate th erap eu t ic in ter ven t ion

B. Epin eph rin e


C. Dobutam in e

23. Th e card iovascu lar e ect s of a n ew au ton om ic d r ug t h at

D. Isoton ic salin e

d oes n ot cross th e blood−brain barrier w ere evalu ated in a

E. Dopam in e

h ealthy m ale volun teer. Th e drug w as adm in istered in t ra-

F.

Isoproteren ol

ven ously, an d th e results are presen ted below :

Di cult y level: Hard Parameter

Control

Peak Drug Ef ect

Mean BP (m m Hg)

90

80

Heart rate (bpm )

70

110


5.5 60

6.5 80

26. A 53-year-old m an w as brough t to th e em ergen cy depar tm en t after su ering cru sh ing su bstern al p ain for th e past h our. Vital sign s on adm ission w ere blood pressure 88/50, p ulse 115 bpm , respirat ion s 30/m in . Fu r th er exam s led to th e diagn osis of cardiogen ic sh ock du e to m yocardial in farct ion , an d th erapy w as star ted th at in clu ded an in t raven ou s

Abbreviations: BP, blood pressure; bpm , beat per m inute.

in fusion of an approp riate drug. W h ich of th e follow ing m o-


lecu lar act ion s m ost likely m ediated th e th erapeu t ic e ec-

resem ble?

t iven ess of th e drug in th is p at ien t?

A. Albuterol

A. Act ivat ion of ph osph olipase A2

B. Cocain e

B. In creased syn th esis of in ositol t riph osph ate (IP3 ) an d diacylglycerol (DAG)

C. Isoproteren ol D. Norep in ep h rin e

C. In creased syn th esis of cyclic aden osin e m on ophosph ate (cAMP)


D. In creased syn th esis of cyclic guan osin e m on ophosph ate (cGMP)

Di cult y level: Medium 24. A 51-year-old m an received an in t raven ous in fusion of isop roteren ol at t h e con clu sion of h ear t t ran sp lan t su rger y. W h ich of th e follow ing act ion s m ost likely occurred a few m in u tes after th e st ar t of th e in fu sion ? A. St im u lat ion of ren in secret ion B. In h ibit ion of in sulin release C. In creased tot al periph eral resist an ce. D. Re ex tachycardia E. St im u lat ion of p latelet aggregat ion

Di cult y level: Medium 25. A 34-year-old m an w as brough t to th e em ergen cy room w ith a gun sh ot w oun d to th e abdom en . Extern al blood loss an d in ter n al h em or rh age w ere sign i can t , an d h e w as an xiou s an d d isor ien ted . On exam in at ion , h is skin w as p ale an d cool, p u lse w as th ready at 130 bp m , blood p ressu re w as

E. Open ing of ligan d-gated Na + ch an n els F.

Open ing of ligan d-gated K+ ch an n els

Di cult y level: Medium 27. A 25-year-old h ealthy m ale volun teer received an in t raven ous in fusion of a n ew drug in a ph ase 1 clin ical t rial. It w as fou n d th at th e drug causes an in crease in cardiac con t ract ilit y, a sligh t in crease in h ear t rate, an d n o m ajor ch anges or a d ecrease in system ic vascular resist an ce. W h ich of th e follow ing drugs does th e n ew agen t m ost resem ble? A. Ph enyleph rin e B. Norep in ep h rin e C. Isoproteren ol D. Epin eph rin e E. Dobutam in e

38




28. A 58-year-old m an becam e con fused an d disorien ted 5 days

31. A 16-year-old m ale sn or ted cocain e for th e

rst t im e at a

after h e u n der w en t su rger y to rem ove n ecrot ic bow el t issu e.

p ar t y. A few m in u tes later h e felt eu ph oric, an d frien ds n oted

Physical

th at h is pu p ils w ere dilated. W h ich of th e follow ing m olecu -

n d in gs w ere h igh fever (103°F, 39.4°C), blood

p ressure 90/50 m m Hg, pulse 130 bpm , respirat ion s 30/m in .

lar act ion s m ost likely m ediated th e m ydriasis?

Per t in en t lab values w ere part ial pressure of arterial carbon

A. In h ibit ion of m on oam in e oxidase A

d ioxide (Pa CO2 ) 30 m m Hg (n orm al 33−45 m m Hg), bicar-

B. Blockade of α 2 receptors in sym p ath et ic term in als

bon ate

(HCO3-

) 18 m Eq/L (n orm al 22−28 m Eq/L), serum pH

7.31, w h ite blood cell cou n t (W BC) 22,000 cells/m m 3 . Arte-

C. In h ibit ion of norepin eph rin e reupt ake in to sym path et ic term in als

rial an d p u lm on ar y arter y cath eters w ere in ser ted, revealing

D. Stim ulation of epinephrin e release from adrenal m edulla

a cardiac out put of 6 L/m in an d a pron oun ced decrease of

E. St im u lat ion of n orepin eph rin e release from sym p ath et ic

system ic vascu lar resistan ce. Flu id th erapy w as in it iated, bu t

term in als

1 hour later m ean blood pressure w as still 60 m m Hg. An in travenous infusion of an appropriate drug was started. Which of th e follow ing drugs w as m ost likely adm in istered?

Di cult y level: Hard 32. A 41-year-old m an presen ted to th e clin ic com plain ing of an

A. Isoproteren ol

im pairm en t in h is abilit y to volun t arily raise h is left eyelid .

B. Epin eph rin e

Physical exam in at ion sh ow ed m iosis, ptosis,

C. Norep in ep h rin e

skin, and loss of sw eating over the left side of the face. Further

D. Albuterol

exam s led to th e diagn osis of Horn er syn drom e. To deter-

E. Clon idin e

m in e th e site of th e au ton om ic lesion , a hydroxyam p h et-

ush ed facial

am in e solu t ion w as in st illed in to th e conju n ct ival sac of th e


left eye. A few m in u tes later, m ydriasis w as obser ved. Th e

29. A 13-year-old girl w ith m ild persistent allergic asthm a started

p hysician correctly con cluded th at th ere w as a localized le-

a t reat m en t th at in clu ded an in h aled bron ch odilator “as

sion in w h ich of th e follow ing n er vou s st ru ct u res?

n eeded.” A drug w ith w h ich of th e follow ing m ech an ism s of

A. Preganglion ic sym path et ic n er ves in n er vat ing th e face

act ion w ou ld be m ost app ropriate for th is p at ien t’s in h aler?

B. Postganglion ic sym path et ic n er ves in n er vat ing th e face

A. Blockade of α 1 adren oreceptors

C. Preganglion ic p arasym path et ic n er ves in n er vat ing th e

B. Blockade of M 2 ch olin ergic receptors C. Act ivat ion of β 2 adren oreceptors D. Act ivat ion of H1 h ist am in e receptors

face D. Postganglion ic parasym p ath et ic n er ves in n er vat ing th e face

E. Act ivat ion of leukot rien e receptors F.

Blockade of Nm ch olin ergic receptors

Di cult y level: Medium 33. A 37-year-old m an w as adm it ted to th e h ospital after a w ork


acciden t . An adm it t ing diagn osis of sp in al cord inju r y w as

30. A 42-year-old w om an com plain ed to h er physician of t rem -

m ade, an d em ergen cy th erapy w as in it iated , w h ich in clu d ed

ors, m u scle cram ping, palp it at ion s, an d an xiet y. Th e w om an ,

th e in t raven ou s in fu sion of a low dose of dopam in e. W h ich

w h o w as recen tly diagn osed w ith severe bron ch ial asth m a,

of th e follow ing e ect s of th e dr ug w ere m ost likely m edi-

h ad st ar ted an ap p rop r iate t h erapy 2 w eeks earlier. W h ich

ated by th e act ivat ion of dopam in e D1 receptors?

of t h e follow in g d r ugs m ost likely cau sed t h e p at ien t ’s

A. In creased diu resis

sym ptom s?

B. Nausea an d vom it ing

A. Isoproteren ol

C. Con st rict ion of skin vessels

B. Salm eterol

D. In creased h ear t rate

C. Propran olol

E. In creased st roke volum e

D. Dobutam in e E. Prazosin

Di cult y level: Medium 34. A 46-year-old w om an ad m it ted to t h e h osp it al w it h t h e p resum pt ive diagn osis of sept ic sh ock w as given em ergen cy th erapy. Th e t reat m en t in cluded an adren ergic d rug th at can d ecrease tot al perip h eral resist an ce at low er d oses an d can in crease it at h igh er doses. W h ich of th e follow ing drugs w as m ost likely adm in istered?

Questions: II-2 Adrenergic Drugs 39 A. Norep in ep h rin e


B. Albuterol


C. Isoproteren ol

partm ent because of dyspnea, gen eralized itching, an d sw ell-

D. Dobutam in e

ing of th e lip s, eyelids, an d tongu e. Th e sym ptom s st arted a


few m in utes after an in t ram uscu lar (IM) inject ion of a vac-

F.

cin e. An ap p rop riate th erapy w as st ar ted , w h ich in clu d ed

Dopam in e

an IM inject ion of epin eph rin e. W h ich of th e follow ing ex-


p ected e ects of th e drug w ere m ost likely m ediated by act i-

35. A 51-year-old p at ien t su ering from post u ral hyp oten sion

vat ion of β 2 adren oceptors?

w as ad m it ted to th e h osp it al for evalu at ion . A t yram in e in -

A. In h ibit ion of in sulin release

fu sion did n ot raise th e blood pressure, w h ereas a ver y sm all

B. Skin vasocon st rict ion

d ose of n orep in eph rin e caused a large, t ran sien t elevat ion of

C. Mydriasis

blood pressu re. Th ese resu lt s w ou ld suggest a degen erat ion

D. Con t ract ion of th e bladder sp h in cter

of w h ich of th e follow ing n er vous st ruct ures?

E. In creased glycogen olysis

A. Postganglion ic sym path et ic n eu ron s B. Preganglion ic sym path et ic n euron s


C. Postganglion ic parasym path et ic n euron s

39. An in t raven ou s inject ion of drug X w as given to a laborator y

D. Preganglion ic parasym path et ic n er ves n euron s

an im al before an d after th e adm in ist rat ion of at ropin e, an d

E. Medu lla oblongata

th e h ear t rate w as record ed. Th e resu lt s are dep icted below : 90

Di cult y level: Easy 36. A 47-year-old w om an su ering from post m en opau sal h ot

80

m

)

ash es t ried d i eren t d r ugs w ith lit t le su ccess. Her p hysi-

e

(

b

p

cian d ecid ed to t r y an ot h er d r ug th at d ecreases th e release

70

r

a

t

of n orepin eph rin e from adren ergic n er ve term in als. W h ich

H

e

a

r

t

of th e follow ing drugs w as m ost likely prescribed? A. Prazosin

60

drug X

atropine

drug X

B. Clon idin e C. Albuterol D. Isoproteren ol E. Labet alol

50

W h ich of th e follow ing drugs w as m ost likely dr ug X? A. Epin eph rin e

Di cult y level: Hard 37. A 48-year-old w om an su er ing from lu p u s er yt h em atosu s w as ad m it ted to t h e h osp it al becau se of severe m u scle w eakn ess. Per t in en t laborator y dat a on ad m ission w ere K+ 7.9 m Eq/L, creat in in e 5 m g/dL, blood u rea n it rogen (BUN) 60 m g/d L. An elect rocard iogram (ECG) revealed in creased PR in ter vals an d w iden ed QRS com plexes. In sulin w ith dex-

B. Norep in ep h rin e C. Prazosin D. Albuterol E. Isoproteren ol F.

Dobutam in e


t rose w as given in t raven ou sly to red u ce th e h igh p ot assiu m

40. A 43-year-old w om an w as in th e em ergen cy depart m en t for

level. An oth er drug w as also given becau se it h as an addit ive

th e t reat m en t of sh ock du e to sp in al t rau m a. Desp ite

e ect w ith in su lin in decreasing seru m p otassiu m . W h ich of

th erapy, sh e w as st ill hypoten sive (80/50 m m Hg) an d tachy-

th e follow ing drugs w as m ost likely ad m in istered?

cardic (125 bp m ). An in t raven ou s in fu sion of n orep in eph -

A. Ph enylep h rin e B. Albuterol C. Clon idin e D. Isoproteren ol

rin e w as st arted, an d a few m in u tes later th e blood p ressu re w as 120/85 m m Hg, an d th e h eart rate decreased to 85 bp m . W h ich of t h e follow ing act ion s best exp lain s t h e d r ugin duced decrease of h ear t rate in th is p at ien t?

E. Epin eph rin e

A. Act ivat ion of cardiac β 2 receptors

F.

B. Decreased ring rate of vagal n euron s

Dobutam in e

u id

C. In creased ring rate of aor t ic baroreceptors D. Act ivat ion of cardiac α 2 autoreceptors E. Decreased ring rate of carot id ch em oreceptors

40


Questions: II-3 Antiadrenergic Drugs Directions for questions 1−5


Match each an t iadren ergic drug w ith th e ap p rop riate descript ion

7. Ph en oxyben zam in e w as given to rats du ring a lab experi-


m en t . W h ich of th e follow ing sets of e ect s m ost likely oc-

at all).

cu rred after t reat m en t?

A. Aten olol B. Esm olol C. Met yrosin e

Firing Rates of Carotid Baroreceptors

Cardiac Contractility

Cardiac Rate

D. Ph en oxyben zam in e

A

↓

↑

↑

E. Pin dolol

B

↑

↑

↓

F.

C

↑

↓

↑

D

↓

↑

↓

E

↓

↓

↓

Propran olol

G. Sotalol H. Tam su losin I.

Tim olol

Di cult y level: Easy 1. Th is drug is a part ial agon ist at β 1 an d β 2 receptors.

Di cult y level: Medium 8. A 51-year-old m an , recen tly diagn osed w ith ph eoch rom ocytom a, w as sch edu led for su rger y to rem ove th e t u m or.


One w eek before surger y, phenoxybenzam ine w as prescribed.

2. Th is dr ug is a select ive β 1 an t agon ist frequen tly used for th e

W h ich of th e follow ing act ion s m ost likely m ediated th e

ch ron ic t reat m en t of at rial brillat ion .

th erap eu t ic e ect of th e drug in th e p at ien t’s disease? A. Decreased periph eral vascular resistan ce


B. In creased cardiac out put

3. Th is d r ug is a β-blocker t h at can also block p ot assiu m

C. Decreased epinephrine release from the adrenal m edulla

ch an n els.

Di cult y level: Easy 4. Th is drug is frequ en tly used in th e t reat m en t of prostat ic hyp erplasia.

Di cult y level: Easy 5. Th is drug is som et im es given in cardiovascular em ergen cies by in t raven ou s in fusion because of its ext rem ely sh ort h alflife.

E. Decreased ring from th e vasom otor cen ter

Di cult y level: Medium 9. A 58-year-old m an com plain ed to h is physician of w eakn ess, d row sin ess, dizzin ess, an d p alpit at ion s. He w as recen tly diagn osed w ith bladder obst ruct ion du e to ben ign p rostat ic hyp erplasia an d h ad been t aking a drug for 2 w eeks. W h ich of t h e follow in g d r ugs m ost likely cau sed t h e p at ien t ’s sym ptom s? A. Beth an ech ol

Di cult y level: Hard 6. A 25-year-old m an com plain ed to h is physician of pain ful erect ion an d im p aired ejacu lat ion du ring in tercou rse. Th ree w eeks earlier, h e h ad been diagn osed w ith Rayn au d disease an d h ad started an app rop riate th erapy. A drug w ith w h ich of th e follow ing m ech an ism s of act ion s m ost likely caused th e pat ien t’s sym ptom s? A. β 2 -receptor blockade B. M 3 -receptor act ivat ion C. β 1 -receptor blockade D. α 2 -receptor act ivat ion E. α 1 -receptor blockade F.


Nm -receptor act ivat ion

B. Tam su losin C. Propran olol D. Flu t am ide E. Albuterol F.

Ph enyleph rin e

Di cult y level: Medium 10. A 28-year-old w om an presen ted to th e out pat ien t clin ic w ith a 5-day h istor y of left h an d an d arm pain . Sh e n oted th at th e ngers of h er left h an d becam e cold an d som ew h at blu e, esp ecially w h en exp osed to cold. Physical exam in at ion sh ow ed th at th e p at ien t’s ext rem it ies h ad app ropriate sen sat ion . W h en h er h an ds w ere placed in cold w ater, several w h ite splotch es appeared, an d t ingling w as felt in th e h an ds.

Questions: II-3 Antiadrenergic Drugs 41 W h ich of th e follow ing dr ugs w ould be appropriate to t reat

To w h ich of th e follow ing drug classes did th e tested drug

th e pat ien t’s disorder?

m ost likely belong?

A. Neost igm in e

A. Beta adren oceptor blockers

B. Propran olol

B. Ch olin ergic agon ist s

C. Prazosin

C. Ch olin ergic an t agon ist s

D. Clon idin e

D. Ganglion ic blockers


E. Alph a-1 adren oceptor blockers



11. A 64-year-old w om an , recen tly diagn osed w ith open -angle

14. A 58-year-old m an recen tly diagn osed w ith exert ion al an -

glau com a, st ar ted a top ical t h erapy w it h t im olol an d ap ra-

gin a started t reatm en t w ith aten olol. W h ich of th e follow ing

clon id in e. W h ich of t h e follow in g w as t h e m ost likely site

cardiovascular param eters w as m ost likely decreased in th is

of act ion of both drugs?

p at ien t?

A. Ciliar y m u scle

A. En d-systolic volum e

B. Uveoscleral vessels

B. Ven t ricular eject ion t im e

C. Conju n ct ival vessels

C. Cardiac eject ion fract ion

D. Ciliar y ep ith elium

D. En d-diastolic volum e

E. Ret in al vessels

E. Ven ou s ton e

F.

Sch lem m can al

Di cult y level: Medium Di cult y level: Hard

15. A 57-year-old, w om an recen tly diagn osed w ith open -angle

12. A 22-year-old m an w as adm it ted to th e h ospit al for evalua-

glau com a, st ar ted t reat m en t w ith t im olol eye drop s. W h ich

t ion of a fain t systolic m u rm u r an d an u n u su al elect rocar-

of th e follow ing sets of e ect s m ost likely occurred sh or tly

d iogram reading. After clin ical an d lab evaluat ion , a diagn osis

after th e adm in ist rat ion of th e dr ug?

of hypert roph ic cardiom yopathy w as m ade, an d propran olol Pupillary Diameter

Lens Curvature

Intraocular Pressure

A

+

−

0

B

0

0

−

C

+

0

−

D

0

+

0

E

−

0

+

w as p rescribed. W h ich of th e follow ing act ion s m ost likely con t ributed to th e th erapeut ic e

cacy of th e drug in th e pa-

t ien t’s d isease? A. Decreased ren in secret ion B. In creased du rat ion of diastole C. Blockade of an abn orm al pacem aker D. Decreased eject ion fract ion

+ = increased − = decreased 0 = negligible e ect

E. Coron ar y vasodilat ion

Di cult y level: Medium 13. A n ew auton om ic drug w as tested in a h ealthy volun teer.


Th e m an w as t reated w ith salin e or w ith th e drug, u n d er

16. Propran olol w as given by in t ram uscular inject ion to several

rest ing or exercise con dit ion s. His h ear t rate w as m easured

d ogs d u r ing a lab exper im en t . On e h ou r later, each dog re-

in both con dit ion s. Th e results w ere th e follow ing:

ceived a d i eren t au ton om ic d r ug, an d th e e ect s of th at d r ug w ere record ed . W h ich of th e follow ing d r ug-in d u ced

Heart Rate (bpm)

e ect s w as m ost likely best cou n teracted by p ropran olol

Saline

Drug

Resting

70

68

A. Isoproteren ol-in duced hyperglycem ia

Exercise

150

80

B. Nicot in e-in du ced decrease in skin blood ow

p ret reat m en t?

C. Norep in ep h rin e-in du ced re ex bradycardia D. Ph enyleph rin e-in du ced m ydriasis E. Pilocarp in e-in du ced con t ract ion of bron ch ial m u scle

42




17. A n ew drug w as st udied in laborator y an im als. Epin eph rin e

20. A 47-year-old m an w h o h ad been su ering from diabetes for

w as given eith er alon e or after th e adm in ist rat ion of th e n ew

10 years w as adm it ted to th e h ospit al follow ing a m yocardial

d rug X. Som e p lasm a values w ere th en recorded, as reported

in farct ion . He w as disch arged 10 days later w ith a p ostdis-

in th e t able below :

ch arge th erapy th at in cluded aten olol. Th e pat ien t w as in st ru cted to m on itor h is blood glu cose level carefu lly for both Epinephrine Alone

Epinephrine after Drug X

Renin (m U/ L)

250

70

Blood glucose (m g/dL)

160

155

hyp eran d hypoglycem ia after th e d rug w as in it iated. W h ich of th e follow ing statem en t s abou t aten olol best explain s th e reason for glucose m on itoring? A. It can dangerously in crease blood sugar levels.

W h ich of t h e follow ing d r ugs d id t h e n ew agen t m ost

B. It can blu n t som e sym ptom s of hypoglycem ia.

resem ble?

C. It can in crease in sulin secret ion .

A. Albuterol B. Tim olol C. Aten olol D. At ropin e E. Propran olol F.

Prazosin

Di cult y level: Medium 18. A 44-year-old m an w h o h ad been su ering from m igrain e for 3 m on th s com plain ed to h is physician th at h is m igrain e

D. It can im pair lipid m etabolism . E. It decreases ren in release.

Di cult y level: Hard 21. A 57-year-old w om an w as disch arged from th e h ospital after an acu te m yocardial in farct ion . Th e w om an h ad been su ering from m ild season al asth m a for 15 years. Her post d isch arge th erapy in clu ded aten olol, on e t ablet daily. W h ich of th e follow ing w as th e m ost likely rat ion ale beh in d prescribing aten olol to th is p at ien t?

at t acks w ere e ect ively abor ted by su m at r ipt an , bu t t h ey

A. It can coun teract pulm on ar y vasocon st rict ion .

w ere n ot reduced in frequen cy. Th e physician decided to

B. It blocks β 1 adren oceptors on ly.

star t a t reat m en t to redu ce th e frequ en cy of at t acks an d

C. It h as an t iin am m ator y e ect s in asth m at ics.

ch ose propran olol as th e in it ial agen t . W h ich of th e follow -

D. It can block pulm on ar y α adren oceptors.

ing pairs of adverse e ect s w ould be expected to be m ost

E. It h as an in term ediate h alf-life (about 6 h ours).

likely du ring th e rst days of th erapy? A. Post ural hypoten sion an d fain t ing B. Palp itat ion s an d u sh ing C. Im pairm en t of far vision an d ph otoph obia D. In som n ia an d n igh t m ares E. Severe con st ip at ion an d gast roesop h ageal re u x

Di cult y level: Medium 22. A 47-year-old m an w as d iagn osed w it h ben ign p rost at ic hyp erp lasia. Su rgical ablat ion of th e p rostate w as con t rain d icated, an d a drug su it able for th e t reat m en t of th e pat ien t’s im p aired blad d er em pt ying w as p rescr ibed . W h ich of t h e follow in g m olecu lar act ion s m ost likely con t r ibu ted to t h e


th erap eu t ic e ect of th at d rug in th e pat ien t’s disease?

19. A 42-year-old m an cam e to th e clin ic for a follow -up visit

A. Decreased blood ow in prostat ic vessels

2 m on th s after bein g d iagn osed w ith essen t ial hyp er ten -

B. Relaxat ion of prost ate cap su le

sion . Th erapy w ith p rop ran olol an d hyd roch lorot iazid e w as

C. Relaxat ion of th e det ru sor m uscle

started at th e t im e of d iagn osis. His blood p ressu re rem ain ed

D. Decreased system ic blood pressure

poorly con t rolled, an d h e adm it ted h e h ad been taking th e

E. Decreased diu resis

pills on ly on ce in a w h ile, becau se of a dist u rbing adverse e ect . W h ich of th e follow ing w as m ost likely th e e ect


m en t ion ed by th e pat ien t?

23. A 25-year-old m an com plain ed to h is physician of a

A. Palp itat ion s B. Sexu al dysfu n ct ion C. Migrain e h eadach e D. Trem or E. Angin al pain

n e,

slow t rem or of th e h an d s elicited by perform ing skilled act s. Th e p at ien t n ot iced t h at th e t rem or w as get t in g w orse, esp ecially w h en h e felt ten se an d an xiou s. Med ical h istor y sh ow ed t h at t h e p at ien t ’s fat h er h ad a sim ilar sym ptom . Neu rologic exam in at ion of t h e p at ien t w as u n rem arkable. A prelim in ar y diagn osis w as m ade, an d a th erapy w as prescribed. W h ich of th e follow ing drugs w ou ld be app ropriate for th is pat ien t?

Questions: II-3 Antiadrenergic Drugs 43 A. Prazosin


B. Clon idin e

27. A 32-year-old m an com plain ed to h is physician th at h e felt

C. Albuterol

an xiou s an d ten se. Histor y revealed th at h e w as a m u sician

D. Physost igm in e

an d h ad to give an im p or tan t pian o con cert th at even ing. Th e

E. Propran olol

p hysician told t h e p at ien t t h at h e w as su er ing from p erfor m an ce an xiet y an d p rescribed a drug to be t aken 2 h ou rs


before th e p erform an ce. W h ich of th e follow ing drugs w as

24. A 31-year-old m an w as brough t to th e em ergen cy depar t-

m ost likely p rescribed ?

m en t after th e police fou n d h im sh ou t ing an d act ing irrat io-

A. Diazepam

n ally in th e st reet . Th e m an adm it ted th at for th e past few

B. Propran olol

h ours he had been using am phetam ines that h e had obtained

C. Flu oxet in e

from a n ew dealer. He w as agit ated an d an xiou s an d exh ib -

D. Ven lafaxin e

ited psych ot ic beh avior. Vital sign s w ere blood pressu re

E. Buspiron e

230/150 m m Hg, heart rate 160 bpm , respirations 20/m in. An em ergen cy th erapy w as star ted , an d th e pat ien t w as t reated w ith in t raven ous diazepam , bu t 30 m in utes later h is blood p ressure w as st ill 210/130. W h ich of th e follow ing pairs of d rugs w ould be appropriate to in clu de in th e pat ien t’s t reat m en t at th is t im e? A. Ph en tolam in e follow ed by p rop ran olol B. Ph en oxyben zam in e follow ed by esm olol C. Met yrosin e follow ed by n eost igm in e D. Beth an ech ol follow ed by ph enyleph rin e E. Clon idin e follow ed by albuterol

Di cult y level: Medium 25. A 57-year-old alcoh olic m an w ith liver cirrh osis w as adm itted to t h e in ten sive care u n it w it h a 2-w eek h istor y of in ter m it ten t m elen a. Esop h agoscopy revealed t h ree ch ain s of large varices in th e low er esop h agu s w ith sign s of recen t bleeding. An ap p rop riate t reat m en t w as perform ed th at in cluded a drug aim ed at redu cing th e por tal pressure. W h ich of th e follow ing drugs w as m ost likely given ? A. Albuterol B. Propran olol C. Methyld op a D. Clon idin e E. Prazosin

Di cult y level: Medium 26. A 51-year-old w om an presen ted to th e clin ic w ith a 1-m on th h istor y of palpitat ion s, in som n ia, n er vousn ess, fat igue, diarrhea, and heat intolerance. The physical exam ination revealed hyperre exia, lid lag, and m ild trem or. Vital signs w ere blood p ressure 160/60, h ear t rate 95 bpm . W h ich of th e follow ing d rugs w as m ost likely ap propriately in cluded in th e th erap eu t ic m an agem en t of th is pat ien t? A. Albuterol B. Propran olol C. Labet alol D. Prazosin E. Ph en oxyben zam in e

Di cult y level: Easy 28. A 65-year-old m an , recen t ly d iagn osed w it h p rost at ic hyp er p lasia, st arted t reat m en t w ith prazosin , on e tablet daily. W h ich of th e follow ing adverse e ects w ould be m ost likely to occur du ring th e rst days of th erapy? A. Mydriasis B. Im paired m ict urit ion C. Pale an d cold skin D. Bron ch ocon st rict ion E. Post ural hypoten sion

Di cult y level: Easy 29. A 44-year-old w om an su ering from open -angle glaucom a h ad been receiving topical t im olol for 3 m on th s. Th e disease w as w ell con t rolled, an d th e t reat m en t stopp ed th e p rogression of opt ic n er ve dam age. W h ich of th e follow ing m olecu lar act ion s m ost likely m ediated th e th erap eut ic e

cacy of

th e drug in th e p at ien t’s disease? A. Open ing of ligan d-gated K+ ch an n els B. In creased syn th esis of diacylglycerol (DAG) C. Decreased synthesis of cyclic guanosine m onophosphate (cGMP) D. Decreased act ivit y of adenylate cyclase E. In creased syn th esis of t yrosin e kin ase F.

Open ing of ligan d-gated Na + ch an n els

Di cult y level: Easy 30. A 33-year-old m an recen t ly d iagn osed w it h p h eoch rom ocytom a w as sch ed u led for su rger y. Th e w eek before t h e op erat ion h e received a t reat m en t w ith a drug th at act s by d ecreasing catech olam in e biosyn th esis. W h ich of th e follow ing drugs w as m ost likely adm in istered? A. Ph en oxyben zam in e B. Propran olol C. Met yrosin e D. Dexam eth ason e E. Levothyroxin e

44


Questions: II-4 Cholinergic Drugs Directions for questions 1−5


Match each ch olin ergic d r ug w it h t h e ap p rop r iate d escr ipt ion

7. A 62-year-old m an su ering from open -angle glau com a u n -

(each let tered opt ion can be selected on ce, m ore t h an on ce, or

der w en t ocular su rger y for can aloplast y. Before th e opera-

n ot at all).

t ion , th e op h th alm ologist in st illed a few d rop s of carbach ol in

A. Acet ylch olin e

th e conjun ct ival sac. W h ich of th e follow ing an atom ical st ruc-

B. Beth an ech ol

t u res rep resen t s th e p rim ar y site of act ion of th e drug in th is

C. Carbach ol

pat ien t?

D. Don epezil

A. Ganglion ic n eu ron s

E. Edroph on ium

B. Ciliar y m u scle

F.

C. Len s

Mu scarin e

G. Neost igm in e

D. Radial m u scle of th e iris

H. Parath ion

E. Brain stem

I.

Pilocarpin e

J.

Pralidoxim e

K. Physost igm in e

Di cult y level: Hard 8. A 51-year-old diabet ic w om an presen ted to th e em ergen cy room w ith severe ocular pain an d redn ess, decreased vision ,


colored h alos, an d n au sea an d vom it ing. Oph th alm oscopy re-

1. In h ibit ion of ch olin esterases by th is drug is ver y sh ort (2−10

vealed an terior ch am ber in am m at ion , an d ton om et r y m ea-

m in utes).

su red an in t raocu lar p ressu re of 48 m m Hg in th e righ t eye (n orm al 10−20 m m Hg). A diagn osis of an acu te glaucom a at -


tack w as m ade, an d t w o d rugs w ere in st illed in th e conju n ct i-

2. Th is drug can in h ibit ch olin esterases equally w ell in th e pe-

val sac. An oth er drug w as given by th e sam e route 15 m in utes

rip h er y as in th e cen t ral n er vou s system .

later. W h ich of t h e follow ing t h ree d r ugs w ere m ost likely adm in istered?


A. Tim olol, apraclon idin e, an d pilocarpin e

3. Th is com pou n d can be absorbed e ect ively th rough th e in t act

B. Hom at ropin e, carbach ol, an d t im olol

skin .

C. Scop olam in e, dorzolam ide, an d ph enyleph rin e D. Hom at ropin e, carbach ol, an d d orzolam ide

Di cult y level: Easy 4. Th is drug is able to regen erate ch olin esterases blocked by organ oph osph ates.

E. Prazosin , physost igm in e, an d m an n itol

Di cult y level: Medium 9. A 62-year-old w om an h ad n o bow el m ovem en ts 4 days after

Di cult y level: Easy 5. Th is d r ug can in h ibit ch olin esterases an d d irect ly act ivate Nm ch olin ergic receptors.

Di cult y level: Medium 6. A n ew au ton om ic d r ug w as given in t raven ou sly to d ogs du ring a lab experim en t . It w as fou n d th at th e drug w as able to in crease ch olin ergic t ran sm ission in both th e periph eral an d cen t ral n er vous system s. W h ich of th e follow ing drugs does th e n ew agen t m ost resem ble? A. Acet ylch olin e B. Carbach ol C. Beth an ech ol D. Neost igm in e E. Physost igm in e

su rger y to rem ove a colon can cer. A diagn osis of adyn am ic ileu s w as m ad e, an d an in t ram uscu lar inject ion of n eost igm in e w as given . Th e act ivat ion of w h ich of th e follow ing pairs of receptors m ost likely m ediated th e th erapeut ic e ect of th e drug in th e pat ien t’s disorder? A. Nm an d M 2 ch olin ergic B. Nn an d M 3 ch olin ergic C. β 2 adren ergic an d M 3 ch olin ergic D. β 2 adren ergic an d Nn ch olin ergic E. Nn ch olin ergic an d α 1 adren ergic F.

Nm ch olin ergic an d α 1 adren ergic

Questions: II-4 Cholinergic Drugs 45 Di cult y level: Easy


10. A 74-year-old m an com plain ed to h is physician of m em or y

13. A 79-year-old fem ale residen t of a n u rsing h om e w as re-

im pairm en t th at h ad w orsen ed over th e past 2 m on th s. He

cen tly diagn osed w ith urin ar y over ow in con t in en ce due to

also rep or ted th at h e h ad in creasin g d i cu lt y in recogn iz-

an aton ic bladd er, an d a t reat m en t w ith beth an ech ol w as

ing fam iliar object s an d in plan n ing ever yday act ivit ies such

p rescribed. W h ich of th e follow ing act ion s m ost likely m edi-

as sh opp ing. Physical exam in at ion revealed n o n eu rologic

ated th e th erap eut ic e ect iven ess of th e drug in th e pat ien t’s

d e cits, but th e m an perform ed ver y poorly in th e Folstein

d isorder?

Min i-Men tal St at u s Exam . Don epezil w as p rescribed. W h ich

A. In creased bladder sph in cter ton e

of the follow ing m olecular m echanism s m ost likely m ediated

B. Decreased ureteral perist alsis

th e th erap eu t ic e ect of th e drug in th e p at ien t’s disease?

C. Decreased com plian ce of th e bladder

A. In h ibit ion of n orepin eph rin e reu ptake

D. Decreased diu resis

B. St im u lat ion of n orep in ep h rin e release

E. In creased ton e of th e bladder t rigon e

C. Blockade of n icot in ic n eu ron al receptors D. In h ibit ion of ch olin esterase


E. Blockade of m u scarin ic M 1 receptors

14. A 58-year-old w om an w ith a long h istor y of depression w as

F.

In h ibit ion of ch olin e acet ylt ran sferase

brough t to th e em ergen cy dep ar t m en t w ith vom it ing, u rin ar y in con t in en ce, profuse salivat ion , cold sw eat , rapid an d


irregular pulse, t achypn ea, an d m en tal con fu sion . Sh e ad-

11. A 71-year-old m an su ering from m yasth en ia gravis w as ad-

m it ted at tem pt ing su icide by ingest ing several t ablets fou n d

m it ted to th e h osp it al for evalu at ion . His th erapy in clu d ed

in h er h usban d’s bu reau d raw er. Soon after adm ission , th e

n eost igm in e, th ree t ablet s daily. It w as foun d th at th e pa-

w om an exp erien ced a ton ic-clon ic seizu re. W h ich of th e fol-

t ien t h ad a slow h ear t rate (46 bpm ), w h ich th e p hysician

low ing drugs m ost likely caused th e p at ien t’s poison ing?

th ough t w as related to n eost igm in e th erapy. W h ich of th e

A. Clon idin e

follow ing m olecular m ech an ism s m ost likely m ediated th is

B. Scop olam in e

adverse e ect of th e drug?

C. Nicot in e

A. Open ing of ligan d-gated K+ ch an n els

D. Beth an ech ol

B. Open ing of voltage-gated Na + ch an n els

E. Neost igm in e

C. In creased syn t h esis of in ositol t r ip h osp h ate (IP3 ) an d


d iacylglycerol (DAG) D. Open ing of ligan d-gated Ca 2+ ch an n els

15. A 65-year-old m an su ering from open -angle glaucom a h ad

E. In creased syn th esis of adenylyl cyclase

been receivin g several d r ugs over t h e p ast 6 m on t h s, bu t t h e con t rol of in t raocu lar p ressu re proved in adequ ate. Th e


oph th alm ologist decided to add a drug an d prescribed ech o-

12. A 67-year-old w om an su ering from glaucom a un der w en t

th iop h ate. W h ich of th e follow ing act ion s m ost likely m edi-

t rabecu lectom y, a surgical procedu re to rem ove p ar t of th e

ated th e th erap eu t ic e ect of ech oth iop h ate in th e pat ien t’s

t rabecu lar m esh w ork of th e eye. Before th e op erat ion , th e

d isease?

oph th alm ologist in st illed a few drops of pilocarpin e in th e

A. Con t ract ion of th e radial m u scle of th e iris

conjun ct ival sac. W h ich of th e follow ing set s of e ects m ost

B. Con t ract ion of th e sph in cter of th e iris

likely occu rred sh or tly after th e adm in ist rat ion of th e d rug?

C. Decreased product ion of aqueous h um or

Pupillary Diameter

Lens Curvature

Ocular Pressure

A

0

0

−

B

−

+

−

C

+

0

0

D

+

0

−

E

+

−

+


D. Dilat ion of th e episcleral ven ous plexus E. Dilat ion of ret in al vessels F.

Con t ract ion of th e ciliar y m u scle

46



A. Mydriasis

16. A 49-year-old farm er cam e to th e em ergen cy depar t m en t

B. Con st ip at ion

com plain ing of blurred vision , n au sea, an d pain ful m uscle

C. Over ow in con t in en ce

con t ract ion s in h is legs. He said th e sym ptom s star ted soon

D. Sialorrh ea

after com ing in from h is soybean eld. Th e at ten ding p hysi-

E. Near vision im p airm en t

cian ap propriately adm in istered pralidoxim e in t raven ou sly soon after t h e m an ar r ived . An agen t from w h ich of t h e


follow in g d r ug classes m ost likely cau sed t h e p at ien t ’s

20. A 63-year-old w om an u n der w en t a tot al hysterectom y to re-

sym ptom s?

m ove a u terin e leiom yom a. Gen eral an esth esia w as in du ced

A. Adren ergic an tagon ist s

w it h t h iop en t al sod iu m , m ain t ain ed w it h h alot h an e an d

B. Carbam ates

n it rous oxide, an d supplem en ted w ith t ubocu rarin e. W h ich

C. Ch olin ergic an t agon ist s

of th e follow ing drugs did th e pat ien t m ost likely receive

D. Organ oph osph ates

after th e op erat ion to reverse th e skelet al m u scle p aralysis?

E. Alcoh ols

A. Physost igm in e B. Edroph on ium


C. Neost igm in e


D. Beth an ech ol

m en t becau se of severe vom it ing an d diarrh ea th at star ted

E. Pralidoxim e

abou t 1 h ou r after a m eal. Th e pat ien t sh ow ed p rofu se salivat ion , lacrim at ion , an d w h eezing. His skin w as m oist , an d


h is pu pils w ere m iot ic. Skelet al m u scle m ovem en t s w ere

21. A 74-year-old m an w ith a long h istor y of t ype 2 diabetes

n orm al. Blood pressure w as 80/50 m m Hg, pulse 46 bpm .

com plain ed to h is physician of di cult urin at ion . Fur th er

Poison ing of th is pat ien t w as m ost likely du e to w h ich of th e

exam in at ion led to th e diagn osis of a disorder, an d t reat-

follow ing agen t s?

m en t w ith beth an ech ol im p roved th e sym ptom s. W h ich of

A. Mu scarin e-con tain ing m u sh room s

th e follow ing w as m ost likely th e p at ien t’s disorder?

B. Nicot in e-con tain ing in sect icide

A. Prost at ic hyperplasia

C. Organ oph osph ate-con tain ing in sect icide

B. Im paired diuresis

D. At ropin e-con t ain ing m u sh room s

C. Det rusor hyperre exia

E. Carbam ate-con t ain ing in sect icide

D. Neu rogen ic atony of th e bladder E. Urin ar y t ract in fect ion

Di cult y level: Easy 18. A 61-year-old m an com plain ed to h is physician of brow


ach e, d i cu lt y w ith far vision , an d p roblem s seeing in dim

22. A 47-year-old m an w as adm it ted to th e em ergen cy depar t-

ligh t . Th e m an h ad a long h istor y of open -angle glaucom a.

m en t becau se of ext rem e m u scle w eakn ess, ptosis, dip lopia,

On e m on th earlier, h e h ad ch anged h is oph th alm ic m edica-

an d di cu lt y in sw allow ing, sp eaking, an d breath ing. Th e

t ion . W h ich of th e follow ing w as m ost likely h is n ew drug?

m an , recen tly diagn osed w ith severe m yasth en ia gravis, h ad

A. Pilocarpin e

been receiving n eost igm in e for th e p ast 3 m on th s. W h ich of

B. Tim olol

the follow ing responses to 2 m g of intravenous edrophonium

C. Apraclon idin e

w ou ld in dicate a ch olin ergic crisis?

D. Epin eph rin e

A. No fascicu lat ion s, in creased m u scle st rength


B. Fascicu lat ion s, decreased m u scle st rength

F.

C. No fascicu lat ion s, n o ch ange in m u scle st rength

Neost igm in e

D. No fascicu lat ion s, decreased m u scle st rength


E. Fascicu lat ion s, in creased m u scle st rength

19. A 64-year-old m an , recen tly diagn osed w ith m yasth en ia gravis, st ar ted t reat m en t w ith n eost igm in e. W h ich of th e fol-


low ing adverse e ects w ould be m ost likely in th is pat ien t?

23. A 60-year-old m ale pat ien t presen ted for rout in e oph th alm ic exam in at ion . Ton om et r y m easu red an in t raocu lar p ressu re of 28 m m Hg in both eyes (n orm al 10−20 m m Hg). Th e p at ien t h ad been su ering from com plete at rioven t ricular

Questions: II-4 Cholinergic Drugs 47 (AV) block for 2 years. Th e oph th alm ologist prescribed ap -

A. Acet ylch olin e

propriate eye drops. W h ich of th e follow ing drugs w as m ost

B. Ph enyleph rin e

likely in clu ded in th e t reat m en t?

C. Prazosin

A. Tim olol

D. Don epezil

B. Prazosin

E. Pilocarp in e

C. Isoproteren ol D. Pilocarpin e


E. Albuterol

27. A 59-year-old m an u n d er w en t su rger y to rem ove a colon

F.

carcin om a. Th ree days after su rger y, h e d evelop ed fever

Hom at ropin e

(103°F, 39.4°C), abd om in al d isten t ion , an d vom it in g. Palp a-


t ion sh ow ed ten dern ess over th e en t ire abdom en , an d au s-

24. A 3-year-old boy w as r ush ed to th e em ergen cy depar t m en t

cu ltat ion revealed n o bow el sou n ds. W h ich of th e follow ing

w it h m en t al con fu sion , rest lessn ess, in coh eren ce, an d h al-

th erap eu t ic m easu res w ou ld be absolu tely con t rain dicated

lu cin ator y beh avior. His m ot h er st ated t h at t h e ch ild h ad

in th is case?

eaten several black berries of a w ild p lan t w h ile playing w ith

A. Paren teral adm in ist rat ion of an an t ipyret ic

frien ds in th e w oods. Physical exam in at ion revealed m ydria-

B. Nasogast ric in t ubat ion an d suct ion

sis; dr y, h ot , an d scarlet skin ; an d a disten ded abdom en w ith

C. Paren teral an t ibiot ic th erapy

n o bow el soun ds. Vit al sign s w ere tem perat ure 104.5°F

D. Su bcu tan eou s adm in ist rat ion of n eost igm in e

(40.3°C), h ear t rate 145 bpm , blood pressure 105/60 m m Hg.

E. In t raven ous adm in ist rat ion of uid an d elect rolytes

W h ich of th e follow ing drugs w ould an t agon ize m ost of th e sym ptom s exh ibited by th e p at ien t?


A. Neost igm in e

28. A 6-year-old boy, on vacat ion w ith h is paren t s in Mexico,

B. Albuterol

w as brough t u n con sciou s to th e em ergen cy d ep art m en t . His

C. Physost igm in e

p aren t s rep or ted t h at t h e boy h ad eaten an ap p le bough t

D. Epin eph rin e

from a local ven d or 2 h ou rs earlier. Physical exam in at ion

E. Prazosin

sh ow ed th at th e boy w as salivat ing profu sely an d w as in con -

F.

t in en t w ith regard to both u rin e an d feces. He h ad p inp oin t

Ph enylep h rin e

p up ils, m oist skin , an d sh allow respirat ion . A diagn osis w as


m ade, an d t w o ap prop riate drugs w ere adm in istered in t ra-

25. A h igh dose of n icot in e w as adm in istered in t raven ously to

ven ou sly. W h ich of th e follow ing p airs of drugs w ere m ost

d ogs in a laborator y exp erim en t . An in it ial in crease in blood

likely given ?

p ressure w as soon follow ed by a profou n d decrease of blood

A. Physost igm in e an d at ropin e

pressure. W h ich of the follow ing m olecular m echan ism s m ost

B. Physost igm in e an d pralidoxim e

likely m ediated th e decrease in blood pressure?

C. Physost igm in e an d propran olol

A. Long-last ing act ivat ion of n icot in ic n euron al receptors

D. Pralidoxim e an d propran olol

B. Long-last ing blockade of m u scarin ic M 2 receptors

E. At ropin e an d p rop ran olol F.

C. Long-last ing blockade of m u scarin ic M 1 receptors

At ropin e an d p ralidoxim e

D. Preven t ion of acet ylch olin e release from p resyn apt ic


term in als E. Preven t ion of catech olam in e release from ch rom a

n

cells

29. A 13-year-old boy st ar ted sm oking h is rst cigaret te. W h ich of th e follow ing e ect s w as m ost likely elicited by n icot in e soon after sm oking?



26. A 55-year-old w om an presented to a clinic because of a grad-

B. Dilat ion of th e skin an d splan ch n ic vessels

ual onset of a scratchy sensation on both eyes and extrem e d r yn ess of th e m outh an d lip s. Lab test s sh ow ed elevated

C. In creased ep in ep h r in e secret ion from t h e ad ren al m ed u lla

levels of an t ibodies again st gam m a globulin . A diagn osis of

D. In h ibit ion of gast roin test in al secret ion s

Sjögren syn drom e w as m ad e, an d a d rug w as prescribed to

E. Relaxat ion of th e det ru sor m uscle

relieve th e pat ien t’s xerostom ia. W h ich of th e follow ing d rugs w as m ost likely adm in istered?


48

Di cult y level: Easy 30. A 12-year-old girl st ar ted sm oking h er

A. Sym p ath et ic ganglia rst cigaret te. A few

B. Ch em oreceptor t rigger zon e

m in u tes later, sh e h ad t w o ep isodes of n au sea an d vom it ing.

C. Locu s ceru leu s

Act ivat ion of receptors located in w h ich of th e follow ing

D. Adren al m edu lla

sites m ost likely m ediated th is adverse e ect of n icot in e?

E. Vest ibular n uclei

Questions: II-5 Anticholinergic Drugs Directions for questions 1−5


Match each an t im u scarin ic or ganglion ic d rug w ith th e app ropri-

7. A 33-year-old wom an su ering from irritable bow el syndrom e

ate descript ion (each let tered opt ion can be selected on ce, m ore

w as p rescribed glycopyrrolate. Blockad e of w h ich of th e fol-

th an on ce, or n ot at all).

low ing pairs of receptors m ost likely m ediated th e th erap eu -

A. At ropin e

t ic e ect of th e drug in th e p at ien t’s disease?

B. Ben zt ropin e

A. β 2 an d Nm

C. Darifen acin

B. M 2 an d Nn

D. Glycopyrrolate

C. M 3 an d Nn

E. Hom at ropin e

D. α 1 an d M 2

F.

E. M 1 an d M 3

Iprat ropium

G. Mecam ylam in e H. Scop olam in e

Di cult y level: Hard 8. A 62-year-old w om an w h o w as on vacat ion in Gu atem ala


p resen ted to th e local h ospit al w ith n ausea, vom it ing, an d

1. Th is drug is cu rren tly used in bron ch ospast ic disorders.

profu se, w ater y diarrh ea. Th e sym ptom s h ad ap peared after eat ing raw oysters. Sh e w as prescribed at ropin e, w h ich re-


lieved h er diarrh ea. W h ich of th e follow ing m olecu lar act ion s

2. Th is drug alm ost exclusively blocks m uscarin ic M 3 receptors.

m ost likely m ediated th e th erapeut ic e ect of at ropin e in th e


A. In h ibit ion of h ist am in e secret ion by gast ric cells

3. Th is drug is m ain ly used in parkin son ism .

B. Decreased cytosolic Ca 2+ in sm ooth m uscle cells

pat ien t’s disorder?

C. Open ing of Na + ch an n els in sm ooth m u scle cells

Di cult y level: Easy 4. Th is drug can block on ly n icot in ic n euron al receptors.

Di cult y level: Easy 5. Th is drug is u sed alm ost exclusively to diagn ose or t reat eye disorders.

Di cult y level: Medium 6. A 25-year-old m an experien ced severe m otion sickness w hen ever h e t raveled by air or sea. He felt m uch bet ter after using a t ran sd erm al p atch to app ly a drug before t raveling. Blockade of w h ich of th e follow ing receptors m ost likely m ediated th e th erapeut ic e ect of th e drug in th e pat ien t’s disorder? A. H1 h ist am in ergic B. β 2 adren ergic C. D2 dopam in ergic D. 5-HT3 seroton in ergic E. M 1 ch olin ergic F.

Nn ch olin ergic

D. In creased ring disch arge of th e vagu s n er ve E. Act ivat ion of presyn apt ic ch olin ergic au toreceptors

Di cult y level: Hard 9. A 42-year old m an w as h ospit alized w ith th e adm it t ing diagn osis of m yocardial in farct ion . Vit al sign s w ere blood pressure 100/60 m m Hg, h ear t rate 40 bp m , resp irat ion s 12/m in . Th e bradycardia disapp eared after an in t ram u scu lar inject ion of atropin e. The in creased heart rate w as m ost likely due to counteraction by atropine of w hich of the follow ing acet ylcholin ein duced act ion s? A. Release of n it ric oxide B. Open ing of K+ ch an n els in sin oat rial n od e C. Decrease in cardiac con t ract ilit y D. Open ing of Na + ch an n els in ganglion ic n eu ron s E. Act ivat ion of cardiac p resyn apt ic au toreceptors

Questions: II-5 Anticholinergic Drugs 49 Di cult y level: Medium


10. A 5-year-old girl w h o w as on vacat ion in Ven ezu ela w it h

13. A 77-year-old w om an w as found to have elevated intraocular

h er paren ts w as adm it ted to th e local h ospit al w ith fever

pressure during a routin e eye exam in ation . Histor y indicated

(103.7°F, 39.8°C), m en tal con fu sion , restlessn ess, an d h allu -

th at sh e h ad recen tly been t aking several an t im u scarin ic

cin ator y beh avior. Histor y revealed th at th e girl h ad eaten

m edicat ion s to t reat h er bladder hyp erre exia. Th e op h th al-

som e honey bought from a local ven dor. Physical exam ination

m ologist told h er th at h e believed th e in creased in t raocu lar

revealed m ydriasis; dr y, h ot , an d red skin ; an d a disten ded

p ressure w as an adverse e ect of th ose m edicat ion s. W h ich

abdom en . A diagn osis of at rop in e p oison ing w as m ade, an d

of t h e follow in g ocu lar act ion s m ost likely m ed iated t h is

an ap p ropriate th erapy w as star ted. W h ich of th e follow ing

adverse e ect?

m olecu lar act ion s m ost likely con t ribu ted to th e at rop in e-

A. Relaxat ion of th e ciliar y m uscle

in duced hyper th erm ia in th is pat ien t?

B. In creased aqueous h um or produ ct ion

A. Skin vasocon st rict ion

C. Dilat ion of ciliar y body vessels

B. Blockade of prostaglandin synthesis in the hypothalam us

D. Relaxat ion of th e radial m u scle of th e iris

C. Un cou p ling of oxidat ive p h osp h or ylat ion in skelet al

E. Decreased episcleral aqueous h um or ou t ow

m uscle

F.

Relaxat ion of th e t arsal m u scle

D. Blockade of m u scarin ic receptors in th e hypoth alam u s


E. Blockade of m u scarin ic receptors of sw eat glan ds

14. An 85-year-old m ale resid en t of a n u rsing facilit y com -


p lain ed of frequen t u rin ar y u rges th at often resu lted in u rin e

11. A 54-year-old m an, recently diagnosed w ith chronic obstruc-

leakage. Darifen acin w as prescribed to m an age th e pat ien t’s

t ive p u lm on ar y d isease, st arted a th erapy w ith iprat ropiu m

in con t in en ce. W h ich of th e follow ing act ion s m ost likely

brom ide u sing a m etered-dose in h aler. W h ich of th e follow -

m ediate th e th erap eu t ic e ect of th e drug?

ing st atem en ts best explain s w hy drugs from th e iprat ro-

A. Decreased bladder in tern al sph in cter ton e

p iu m class are th e on ly an t im uscarin ic d rugs used to t reat

B. Relaxat ion of th e prostate cap su le

bron ch ospast ic disorders?

C. Con t ract ion of th e d et ru sor m u scle

A. Th ey are m ore poten t th an oth er an t im uscarin ic drugs.

D. Decreased diu resis

B. Th ey h ave an oral bioavailabilit y h igh er t h an t h at of

E. In creased com plian ce of th e bladder

oth er an t im uscarin ic drugs. C. Th ey h ave excellen t in h alator y bioavailabilit y.


D. Th ey h ave n egligible e ect s on bron ch ial secret ion s an d

15. A 77-year-old m an su ering from ch ron ic obst ruct ive pul-

m ucociliar y clearan ce.

m on ar y disease h ad been taking ip rat rop iu m by in h alat ion .

E. Th ey h ave n egligible e ect s on t h e cen t ral n er vou s system .

Sh ortly after in adver ten tly spraying th e m edicat ion on h is face, w hich of the follow ing e ects did the patient m ost likely experien ce?


A. Urge in con t in en ce

12. A 25-year-old m an w en t to h is oph th alm ologist’s o

ce for

B. Drow sin ess

a rou t in e visit . He received on e drop of h om at rop in e in th e

C. Salivat ion

conjun ct ival sac to prepare th e eye for exam in at ion . W h ich

D. At rioven t ricu lar (AV) block

of th e follow ing set s of e ect s did th e drug m ost likely cau se

E. Di cult y in n ear vision

in th e pat ien t’s eye, a few m in u tes after th e adm in ist rat ion ?

F.

Pupillary Diameter

Lens Curvature

Intraocular Pressure

A

+

−

−

B

+

0

C

0

−

0

D

−

0

−

E

+

−

+


Hallu cin at ion s

50




16. An 8-year-old boy w as in an oph th alm ologist’s o

ce for th e

19. A 67-year-old m an recen tly diagn osed w ith ben ign prost at ic

rst t im e an d received op h th alm ic drop s of a drug to p re-

hyp erplasia w as sch eduled for su rger y. W h ich of th e follow -

p are h is eyes for m easu rem en t of refract ive errors. A h alf

ing drug classes w ou ld be absolu tely con t rain dicated in th is

h our later, h e sh ow ed m en tal con fusion , restlessn ess, in co-

p at ien t?

h eren ce, an d h allucin ator y beh avior. His pulse rate w as 120

A. Alph a-1 blockers

bp m . W h ich of th e follow ing drugs m ost likely cau sed th e

B. An t im uscarin ics

p at ien t’s adverse e ects?

C. Beta blockers

A. Ph enylep h rin e

D. Alph a-2 agon ists

B. Epin eph rin e

E. Beta-1 agon ists

C. At ropin e D. Tim olol


E. Pilocarpin e

20. A 55-year-old w om an w as adm it ted to th e h ospit al w ith sh allow breath ing, w h eezing, p rofu se rh in orrh ea, lacrim a-


t ion , ocu lar p ain , an d d im in ish ed vision . Sh e reported th at brillat ion presen ted to th e

th e sym ptom s star ted w h en sh e w as in h er garden sp raying

clin ic because of dizzin ess, palpit at ion s, dyspn ea, an d an ur-

ow ers w ith an in sect icide con t ain ing carbar yl, a reversible

gen t n eed to u rin ate. Th e m an w as on vacat ion in Mexico,

ch olin esterase in h ibitor. W h ich of th e follow ing drugs w ou ld

an d th e sym ptom s st arted 1 h ou r after taking an over-th e-

be ap prop riate to t reat th is p at ien t’s disorder?

coun ter preparat ion bough t at a local ph arm acy to t reat di-

A. Pralidoxim e

arrh ea. W h ich of th e follow ing drugs m ost likely cau sed th e

B. Terbu t alin e

p at ien t’s sym ptom s?

C. Epin eph rin e

A. Ph enylep h rin e

D. Glycopyrrolate

B. Epin eph rin e

E. At ropin e

17. A 73-year-old m an w ith at rial

C. At ropin e D. Propran olol


E. Albuterol

21. A 64-year-old m an com plain ed to h is physician of a recen t on set of diarrh ea. Th e physician believed th e diarrh ea w as


related to aspirin and m isoprostol that the patien t had started


t aking 1 w eek earlier for th e t reat m en t of join t p ain d u e to

m en t w ith p alp it at ion s, restlessn ess, an d h allu cin ator y be-

osteoar th rit is. W h ich of th e follow ing drugs w ould be m ost

h avior. He adm it ted th at h e w as a h eroin addict an d th at 1

app ropriate to t reat th e p at ien t’s d iarrh ea?

h our earlier, h e h ad self-injected h is usual dose of “sm ack,”

A. Ph enyleph rin e

bough t from a n ew ven dor. Physical exam in at ion sh ow ed a

B. Iprat ropium

d ist ressed m an w ith th e follow ing sign s:

C. Propran olol

Blood p ressu re: 160/80 m m Hg

D. Glycopyrrolate

Pu lse 135

E. Prazosin

Pu pils: dilated

F.

Don epezil

Skin : h ot an d dr y


Bow el sou n ds: decreased

22. A 63-year-old m an underwent surger y to rem ove a laryngeal

W h ich of th e follow ing drugs m ost likely caused th e pat ien t’s

carcin om a. Before su rger y, th e an esth esiologist adm in istered

sign s an d sym ptom s?

a d rug in t ram u scu larly to decrease bron ch ial secret ion s an d

A. Nicot in e

to preven t bradycardia due to m an ipulat ion of th e vagus

B. Beth an ech ol

n er ve. W h ich of th e follow ing drugs w ou ld be m ost appro-

C. Scop olam in e

p riate in th is sit u at ion ?

D. Pralidoxim e

A. Iprat ropium

E. Neost igm in e

B. Dopam in e C. At ropin e D. Isoproteren ol E. Epin eph rin e

Questions: II-5 Anticholinergic Drugs 51 Di cult y level: Hard

A. Physost igm in e-in du ced sw eat ing

23. A 44-year-old m an collapsed at w ork an d w as foun d to be

B. Epin eph rin e-in duced hyper ten sion

u n respon sive. W h en th e param edics arrived, h e h ad ven t ric-

C. Nicot in e-in du ced skin vasocon st rict ion

u lar

D. Prazosin -in duced re ex t achycardia

brillat ion an d w as cardiover ted su ccessfu lly. He w as

adm it ted to th e coron ar y u n it , bu t sh ortly th ereafter h e d e-

E. Glycopyrrolate-in duced bron ch odilat ion

veloped asystole. Cardiopulm onar y resuscitat ion w as started, an d escalat ing d oses of epin eph rin e w ere given w ith ou t su c-


cess. W h ich of th e follow ing drugs w ould be m ost appropri-

27. A 23-year-old m an com plain ed to h is physician of ph oto-

ately adm in istered at th is poin t?

p h obia an d di cult y in reading th e n ew sp ap er. A few days

A. Neost igm in e

earlier, th e m an h ad star ted u sing a n asal spray of iprat ro-


p iu m to m an age p rofuse rh in orrh ea associated w ith a cold .

C. Dopam in e

W h ich of th e follow ing m olecular act ion s m ost likely m edi-

D. At ropin e

ated th e adverse e ects of th e dr ug?

E. Iprat ropium

A. Blockade of M 3 m uscarin ic receptors B. Act ivat ion of M 3 m uscarin ic receptors


C. Blockade of β 2 adren oceptors

24. In a laborator y experim en t , a m ecam ylam in e pret reat m en t

D. Act ivat ion of β 2 adren oceptors

w as given in t ram u scu larly to several dogs. On e h ou r later,

E. Blockade of α 1 adren oceptors

each dog received an au ton om ic drug, an d th e e ect of th at

F.

Act ivat ion of α 1 adren oceptors

d rug w as recorded. W h ich of th e follow ing exp ected dr ugin du ced e ect s w as m ost likely best coun teracted by m e-


cam ylam in e p ret reat m en t?

28. A 55-year-old m an w as adm it ted to th e coron ar y u n it fol-

A. Neost igm in e-in du ced in crease in in test in al perist alsis

low ing a m yocardial in farct ion . Four h ours after adm ission ,

B. Nicot in e-in du ced con t ract ion of skeletal m u scle

the electrocardiogram indicated bradycardia that disappeared

C. Norep in ep h rin e-in du ced bradycardia

after an in t ram u scu lar inject ion of at rop in e. W h ich of th e

D. Epin eph rin e-in duced tachycardia

follow ing act ion s m ost likely m ediated th e th erapeut ic ef-

E. Propran olol-in duced hypoten sion

fect of at ropin e in th e pat ien t’s disorder? A. Dilat ion of capacitan ce vessels


B. In creased h ear t con t ract ilit y

25. A 43-year-old m an cam e to th e h ospit al for a radiologic

C. Decreased blood pressure

exam in at ion of th e colon . Before st ar t ing t h e exam , h e re-

D. In creased at rioven t ricu lar (AV) con duct ion

ceived an in t ram u scu lar inject ion of scopolam in e to relax

E. Con st rict ion of resistan ce vessels

th e in test in e. W h ich of th e follow ing adverse e ects did th e

F.

In creased h ear t refractorin ess

pat ien t m ost likely exp erien ce a few m in u tes after th e adm in ist rat ion ?


A. Salivat ion

29. A 25-year-old w om an com plain ed to h er p hysician of ex-

B. Abdom in al pain

cessive a xillar y sw eat in g an d a sw eat y foreh ead , p rim arily

C. Palp itat ion s

w h en sh e w as an xious or excited. Th e w om an stated th at th e

D. Pain fu l erect ion

sym ptom w ere ver y dist u rbing an d asked for a t reat m en t .

E. Urge u rin ar y in con t in en ce

Th e physician p rescribed glycopyrrolate cream , to ap ply to th e a ected areas. Blockade of w h ich of th e follow ing recep -

Di cult y level: Easy 26. At ropin e w as given in t ram u scu larly to several dogs du ring a

tors m ost likely m ediated th e th erapeut ic e ect of th e drug in th e p at ien t’s d isorder?

lab experim en t . On e h ou r later each dog received an in t ra-

A. β 2 adren ergic

m u scu lar inject ion of an au ton om ic drug, an d th e e ects of

B. Nn ch olin ergic

th at drug w ere recorded . W h ich of th e follow ing exp ected


d rug-in duced e ect s w as m ost likely best an tagon ized by

D. α 2 adren ergic

at rop in e pret reat m en t?

E. M 3 m u scarin ic


52


A. 70

30. In a clin ical experim en tal set t ing, a 33-year-old h ealthy m an

B. 50

received an in t ram uscular inject ion of a ganglion ic blocker

C. 100

w ith a fast on set of act ion . A few m in utes after th e inject ion ,

D. 130

w hich of the follow ing heart rates, in beats per m inute (bpm ),

E. 150

w as m ost likely obser ved in th e m an ?

Answers and Explanations: II-1 Introduction to Autonom ic Pharm acology Questions 1−5 1. A

Learning objective: Explain the autonom ic activation that follows hypoglycemia.

2. D

8. D The described sym ptom s are m ost likely due to sym pa-

3. F

thet ic act ivat ion that occurs any tim e sign i cant hypoglyce-

4. A

m ia is present. In insulin -dependent diabetics, hypoglycem ia

5. H

is com m on after physical exercise that increases sugar m etab olism , as in th e presen t case. Sym path et ic act ivat ion in clu des

Learning objective: Describe the m etabolism of catecholam ines.

an in creased

6. A Dop am in e β-hydroxylase is th e en zym e th at cat alyzes th e

w h ich in t u rn w ill in crease

ring of preganglion ic sym p ath et ic n eu ron s, ring in postganglion ic sym pa-

conversion of d op am in e in to n orep in ep h r in e. Becau se t h e

th et ic n eu ron s an d ep in eph rin e secret ion from th e adren al

en zym e is lackin g, p lasm a levels of n orep in ep h r in e w ill be

m edu lla.

ver y low. B Plasm a levels of dop am in e w ould be h igh , n ot low.

A−C, E Th ese n euron s are n ot involved in sym path et ic act ivat ion .

C Ep in ep h rin e is syn th esized from n orepin eph rin e in th e adren al m edulla. Because plasm a levels of n orepin eph rin e are low, p lasm a levels of epin eph rin e w ill also be low, n ot h igh .

Learning objective: Identify the vessels where autonom ic receptors are primarily α 1 adrenergic.

D Nor m et an ep h r in e is a u r in ar y m et abolite of n orep i-

9. E Th e vascu lar system h as both α 1 an d β 2 receptors. Alp h a-1

n ep h rin e. Because plasm a levels of n orepin eph rin e are low,

receptors p redom in ate in th e vessels of th e skin an d th e

n orm etan eph rin e w ill also be low, n ot h igh .

gast roin test in al an d gen itou rin ar y system s. Bet a-2 receptors

E Hom ovan illic acid is th e m ain urin ar y m et abolite of dopa-

predom in ate in th e vessels of skelet al m u scle an d liver. Para-

m in e. Because plasm a levels of dopam in e are h igh , h om ovan -

sym path et ic receptors are n ot w idely rep resen ted in th e vas-

illic acid w ill also be h igh , n ot low.

cu lar system . A Au ton om ic receptors in th e bron ch ial m uscle are pri-

Learning objective: Identify the enzym e that controls the ratelim iting step in norepinephrine biosynthesis.

m arily M 3 an d β 2 .

7. C Th e hydroxylat ion of t yrosin e to dopa is th e rate-lim it ing

are p rim arily M 3 .

step in n orepin ep h rin e biosyn th esis an d is cat alyzed by th e en zym e t yrosin e hydroxylase. Th e in h ibit ion of th is en zym e w ill th erefore cause a big redu ct ion in biosyn th esis of th e

B Auton om ic receptors in th e sph in cter m uscle of th e iris C Auton om ic receptors in th e at rioven t ricular n ode are prim arily M 2 an d β 1 . D Auton om ic receptors in Purkinje bers are prim arily β 1 .

n al produ ct . A Arom at ic l -am in o acid decarboxylase t ran sform s dopa in to dopam in e. B Dop am in e-β-hyd roxylase t ran sfor m s d op am in e in to n orepin eph rin e. D Ph enyleth an olam in e m ethylt ran sferase t ran sform s n orep in ep h rin e in to ep in ep h rin e. E Mon oam in e oxidase t ran sform s n orepin eph rin e an d epin ep h r in e in to dihyd roxym an d elic acid an d d op am in e in to d ihydroxyph enylacet ic acid.

Learning objective: Describe the e ects of the activation of peripheral postsynaptic β 1 receptors. 10. D Beta-1 receptors are abundant in ju xtaglom erular cells, and th e act ivat ion of th ese receptors in creases ren in secret ion . A Bron ch odilat ion is due m ain ly to act ivat ion of bron ch ial β 2 receptors. B Uterin e relaxat ion is due m ain ly to act ivat ion of u terin e β 2 receptors.

Answers and Explanations: II-1 Introduction to Autonom ic Pharm acology 53 C In creased liver glucon eogen esis is du e m ain ly to act ivat ion of liver β 2 receptors. E Decreased in sulin secret ion is due m ain ly to act ivat ion of pan creas α 2 receptors. F In creased sw eat ing of th e palm s of th e h an ds is due m ain ly to act ivat ion of th e p alm s’ α 1 receptors.

Learning objective: Describe the e ects of activation of α 1 receptors of the cardiovascular system . 13. A Act ivat ion of α 1 receptors con t ract s vascu lar sm ooth m u scle. Th is w ill in crease th e systolic blood pressure (w h ich is dep en d en t on both card iac ou t p u t an d tot al p er ip h eral resistan ce [TPR]), as w ell as diastolic blood pressure (w h ich is dep en den t m ain ly on TPR). Th e in crease in m ean blood pres-

Learning objective: Describe the e ect s of the activation of pancreatic α 2 receptors.

su re cau ses an act ivat ion of th e baroreceptor re ex, w h ich in

11. B Act ivat ion of α 2 receptors located on p an creat ic β cells

B Act ivat ion of β 2 receptors w ould cau se a decrease, n ot an

in h ibit s in sulin secret ion . Th is is on e of th e act ion s th at con -

in crease, of TPR, because β 2 receptors are abu n dan t in skele-

t ribu te to th e n al hyp erglycem ic e ect of ep in ep h rin e.

tal m u scle vessels, an d ap proxim ately on e h alf of th e body

A, D Th ese e ect s are d u e to act ivat ion of α 1 , n ot α 2 , receptors.

t u rn w ill decrease th e h eart rate.

w eigh t is skelet al m u scle. C Act ivat ion of D1 receptors w ou ld cau se a dilat ion of

C, E Th ese e ect s are due to act ivat ion of β 1 receptors.

splan ch n ic an d ren al vessels; th erefore, th e d iastolic blood

F Th is e ect is due to act ivat ion of β 2 receptors.

pressure w ou ld decrease, n ot in crease. D Act ivat ion of M 2 receptors w ou ld decrease th e h ear t

Learning objective: Describe the e ects of the activation of α 1 and α 2 receptors on the eye.

con t ract ilit y an d rate, w h ich in t u rn w ou ld decrease cardiac

12. A Pupillar y diam eter can be in creased eith er by th e act iva-

n ot in crease.

t ion of α 1 receptors (w h ich con t racts th e radial m uscle of th e iris) or by th e blockade of M 3 receptors (w h ich relaxes th e

output. Therefore, the systolic blood pressure w ould decrease, E Act ivat ion of β 1 receptors w ou ld in crease, n ot decrease, th e h eart rate.

sph in cter m u scle of th e iris). Th e qu est ion asks for an act ivaocular pressure can be decreased by a decreased product ion

Learning objective: Describe the postreceptor m echanism s of α 1 receptor activation.

or by an in creased out ow of aqueous h um or. A decreased

14. B Alpha-1 receptor activation m ay initiate several postrecep -

p rodu ct ion can follow eith er t h e act ivat ion of α 2 receptors

tor m ech an ism s, dep en d ing on th e t issu e w h ere th e recep -

or th e blockade of β 2 receptors. Th e quest ion asks for an ac-

tors are located. Am ong th ese, on e of th e m ost com m on is

t ivat ion of a receptor, so th e α 2 receptor m ust be involved.

th e act ivat ion of p h osph olipase C, w h ich in t u rn resu lts in

t ion of a receptor, so th e α 1 receptor m u st be involved. In t ra-

B Bet a-2 receptor act ivat ion w ou ld cau se an in creased

th e gen erat ion of t w o secon d m essengers, IP3 an d DAG. IP3

produ ct ion of aqu eou s h u m or an d th erefore w ou ld in crease,

st im u lates th e release of calciu m from en d op lasm ic stores.

n ot decrease, th e in t raocular pressu re.

DAG is a poten t act ivator of protein kin ase C, w h ich in t u rn

C Act ivat ion of Nn receptors w ou ld cause an in crease in

in creases in t racellular Ca 2+. Th e

n al e ect is th erefore in -

sym pathetic as w ell as parasym pathetic ring. Because in the

creased Ca 2+ availabilit y, w h ich en h an ces sm ooth m u scle

eye th e parasym path et ic system is predom in an t , th is w ould

con t ract ion .

lead to an act ivat ion of M 3 receptors in th e ciliar y m uscle,

A Th e syn th esis of IP3 an d DAG is act u ally in creased, n ot

w h ich w ould in crease th e len s cur vat ure an d an act ivat ion

d ecreased , by α 1 receptor act ivat ion (see cor rect an sw er

of th e iris sph in cter m uscle, w h ich w ould decrease, n ot in -

explan at ion ).

crease, th e p u p illar y d iam eter. Act ivat ion of Nm receptors

C Alp h a-1 receptors are m ain ly excit ator y, so th e op en -

cau ses th e con tract ion of skeletal m uscles on ly an d th erefore

ing of K+ ch an n els (w h ich w ou ld lead to a hyp er p olar iza-

can a ect th e ext rin sic, n ot th e in t rin sic, eye m u scles.

t ion of t h e m em bran e) is u n likely. In fact , t h ey can close K+

D See an sw er explan at ion for item C. E See an sw er explan at ion for item B.

ch an n els. D Blockade of volt age-gated Ca 2+ ch an n els is th e m ech an ism of act ion of Ca 2+ ch an n el blockers E In creased syn th esis of cGMP is th e post receptor m ech an ism t riggered by bet a-, n ot by alph a-, receptor act ivat ion .

54


Learning objective: Describe the e ects of activation of β 1 and β 2 receptors

Learning objective: Describe the e ects of the activation of M3 receptors on the eye.

15. E Th e act ivat ion of β 1 receptors in creases cardiac con t ract il-

18. D Pupillar y diam eter an d len s cur vat ure are m ain ly un der

it y an d rate, th u s in creasing cardiac out put , w h ich in t u rn

t h e con t rol of t h e p arasym p at h et ic n er vou s system . Act i-

in creases systolic blood pressu re. Th e act ivat ion of β 2 recep -

vat ion of M 3 receptors on t h e ir is sp h in cter m u scle cau ses

tors causes periph eral vasodilat ion , th us decreasing th e dia-

con t ract ion of t h e m u scle, d ecreasing p u p illar y diam eter.

stolic blood p ressu re. Th e m ean blood p ressu re (diastolic

Act ivat ion of M 3 receptors on ciliar y m u scle cau ses con -

plu s on e th ird of pulse p ressure [th e di eren ce bet w een th e

t ract ion of t h e m u scle, w h ich lead s to (1) rela xat ion of t h e

systolic an d diastolic p ressu re read ings]) of th e volu n teer

zon ula bers, w h ich in t urn in creases th e len s cu r vat ure, an d

w as 90 m m Hg u n der con t rol con dit ion s an d 80 m m Hg after

(2) op en ing th e pores of th e t rabecu lar m esh w ork, w h ich

t h e d r ug ad m in ist rat ion . Th e d ecreased blood p ressu re ac-

in creases th e ou t ow of th e aqu eou s h u m or, decreasing th e

t ivated th e baroreceptor re ex, cau sing re ex tachycard ia.

in t raocular p ressure.

Moreover, th e act ivat ion of both β 1 an d β 2 receptors also

A Act ivat ion of α 1 receptors w ou ld con t ract th e iris radial

cau sed a direct in crease in h ear t rate, so th e n al e ect w as

m u scle, cau sing an in crease, n ot a d ecrease, in p u p illar y

a pron oun ced t achycardia.

diam eter.

A−D Act ivat ion of n on e of t h ese p airs of receptors can

B Act ivat ion of α 2 receptors w ould decrease th e produc-

explain th e cardiovascular act ion s of th e au ton om ic drug

t ion of th e aqu eou s h u m or. Th is w ou ld lead to a decrease in

un der st udy.

in t raocular pressu re, but p up il diam eter an d len s cu r vat u re w ou ld n ot be a ected.

Learning objective: Identify the autonom ic receptors that m ediate the relaxation of bronchial sm ooth m uscle.

of skelet al m uscles on ly an d th erefore w ould a ect th e ex-

16. A Alph a-beta agon ist s in duce relaxat ion of m ost sm ooth

t rin sic, n ot th e in t rin sic, eye m u scles.

m u scles both directly, by act ivat ing post syn apt ic β 2 recep tors, an d in directly, by act ivat ing presyn apt ic α 2 receptors

C Act ivat ion of Nm receptors w ould cau se th e con t ract ion

E Act ivat ion of β 2 receptors w ou ld cau se relaxat ion , n ot con t ract ion , of ciliar y m uscle.

on ch olin ergic term in als, w h ich in t urn in h ibit acet ylch olin e release. B−E See correct an sw er explan at ion .

Learning objective: Describe the e ect s of activation of M2 and M3 receptors. 19. C Th e n ew drug th e w om an w as taking w as m ost likely am i-

Learning objective: Describe the e ect of the activation of β 2 and β 3 receptors.

t ript ylin e, an an t id ep ressan t m ed icat ion w ith p ron ou n ced

17. B Act ivat ion of β 2 receptors in creases liver glucon eogen esis,

M 2 receptors, w h ereas dr y m ou th , blu rred vision , an d con -

in h ibit s degran ulat ion of m ast cells, an d decreases plasm a K+ (becau se of in creased K+ u pt ake by skelet al m u scle). Act ivat ion of β 3 receptors in fat cells in creases lip olysis w ith

an t im u scarin ic e ect s. Palp it at ion s are d u e to blockad e of st ipat ion are du e to blockade of M 3 receptors. A, B, D, E Blockade of th ese p airs of receptors w ou ld n ot cau se th e sym ptom s reported by th e p at ien t .

en h an ced release of free fat t y acids in to th e blood. C Beta-1 receptor act ivat ion is n ot involved, as th e secret ion of ren in is u n a ected . A, D−F Th ese p airs of receptors can m ediate som e, bu t n ot all, of th e e ects listed.

Learning objective: Describe the e ect s of activation of nicotinic Nm receptors. 20. E Nm receptors are foun d on ly in th e m otor en d plate; th erefore, th e sym ptom s m u st refer to skelet al m u scles. W h en Nm receptors are act ivated by acet ylch olin e, th e ion ch an n el op en s, allow in g Na + to en ter t h e cell. Th e en d -p late m em bran e becom es d ep olar ized ; t h is d ep olar izat ion is called en d-p late p oten t ial. If it s am p lit u d e reach es th e th resh old for excitat ion , voltage-gated Na + ch an n els open , gen erat ing

Answers and Explanations: II-2 Adrenergic Drugs 55 an act ion poten t ial th at propagates th e depolarizat ion an d

is n ot du e to th e blockade of Nm receptors bu t to th e p er-

cau ses th e con t ract ion of th e skeletal m u scle. Th e en d-p late

sisten t act ivat ion of th ose receptors. W h en th e paralysis in -

dep olarizat ion is sh or t-last ing, as acet ylch olin e is rap idly

volves th e ext rin sic m uscles of th e eye, diplopia result s. Th e

m etabolized. How ever, w h en an excessive am oun t of acet yl-

paralysis of th e st riated m u scles of th e p h ar yn x cau ses d i -

ch olin e causes a persisten t act ivat ion of Nm receptors, a loss

cu lt y in sw allow ing.

of elect rical excit abilit y of th e m uscle cells occurs. Th e m ain reason for th is loss is th at , even if th e m em bran e is st ill de-

A−D All of t h ese e ect s are d u e to t h e act ivat ion of m u scarin ic receptors.

polarized becau se of th e act ivation of Nm receptors, voltagesen sit ive Na + ch an n els becom e in act ivated an d th erefore n ot INTRODUCTION TO AUTONOMIC PHARMACOLOGY Answ er key

able to open in respon se to a brief depolarizing st im ulus. Th is loss of elect rical excitabilit y in th e presen ce of a depolarized m em bran e is called depolarizat ion blockade. Th e m ain con sequen ce of th is block in skeletal m u scle cells is th e paralysis of the m uscle. It sh ould be n oted th at th is paralysis

1. 2. 3. 4. 5.

A D F A H

6. 7. 8. 9. 10.

A C D E D

11. 12. 13. 14. 15.

B A A B E

16. 17. 18. 19. 20.

A B D C E

Answers and Explanations: II-2 Adrenergic Drugs Questions 1−5 1. B

Learning objective: Describe the actions that m ediate the therapeutic e ect of epinephrine in allergic reactions.

2. L

7. E Th e sym ptom s an d sign s of th e p at ien t suggest th at h e h ad

3. I

an acu te an aphylact ic react ion , w h ich som et im es occurs fol-

4. H

low ing a blood t ran sfu sion . On e of th e u sefu l act ion s of ep i-

5. K

neph rine in this disorder is the β 2 receptor−m ediated inh ibition of degran ulat ion of m ast cells, w h ich preven t s th e release of

Learning objective: Describe the postreceptor m echanism that mediates the therapeutic e ect of epinephrine in cardiac arrest.

h istam in e an d oth er in am m ator y m ediators.

6. E Ep in ep h rin e e ects on th e h ear t are du e to th e act ivat ion of

any, to th e th erapeu t ic e

β 1 an d β 2 receptors. Th e post receptor m ech an ism com m on to all β receptor act ivat ion is th e st im u lat ion of adenylyl cyclase, w h ich in t urn in creases th e am ou n t of cyclic aden osin e m on oph osphate (cAMP) in t arget t issues. A Th is post receptor m ech an ism is t riggered by th e act ivat ion of M 2 receptors. B Th is post receptor m ech an ism is t riggered by th e act ivat ion of n icot in ic receptors. C Th is post receptor m ech an ism is t riggered by th e act ivat ion α 1 an d M 3 receptors. D Th is post receptor m ech an ism is t riggered by th e act ivat ion of α 1 receptors.

A−D, F All th ese act ion s of epin eph rin e con t ribu te lit tle, if cacy of th e drug in an ap hylaxis.

Learning objective: Identify the adrenoceptors that m ediate the e ect of epinephrine to increase the duration of the local anesthetic e ect of lidocaine when the t wo drugs are given concomitantly. 8. D Ep in ep h rin e is often u sed togeth er w ith local an esth et ics to prolong th e act ion of th e an esth et ic. Th is in creased du rat ion is du e to th e epin eph rin e-in du ced vasocon striction (m ediated by α 1 receptor act ivat ion ), w h ich localizes th e an esth et ic at th e desired site, th u s slow ing dow n it s system ic dist ribu t ion . A−C, E See correct an sw er explan at ion .

56


Learning objective: Explain the action that m ediates the therapeutic e ect of epinephrine in cardiac arrest.

terproductive, but it does n ot occur in cardiac arrest (see

9. A Th e m ost appropriate m an agem en t of cardiac arrest in -

correct an sw er explan at ion ).

B Th e β 2 receptor−m ediated vasodilat ion w ould be coun -

brillat ion is a 200-jou le de brillat ion .

C Th is act ion of th e drug cou ld add a ben e t (see correct

Addit ion al sh ocks at h igh er en ergy sh ou ld be given in case of

an sw er explan at ion ), but it is m ain ly related to β 1 receptor

in it ial failu re. If ven t ricu lar brillat ion persists, th e Am erican

act ivat ion (th e in crease in cardiac con t ract ilit y due to β 2 re-

Hear t Associat ion in dicates th at ep in ep h rin e sh ou ld be ad -

ceptor act ivat ion is m in or). In any case, th e m ain epin eph -

m in istered. Most likely th e t w o m ajor m ech an ism s th rough

r in e m ech an ism is m ost likely t h e α 1 receptor−m ed iated

w hich epin ephrine in creases blood ow to the brain and heart

vasocon st rict ion .

du ced by ven t ricu lar

D, E The bene cial e ects of epinephrine-induced increase

du ring CPR are th e follow ing: • It preven ts carot id ar terial collapse at th e th oracic in let . Collapse results from h igh extravascular intrath oracic pressu re cou pled w ith low in t ravascu lar p ressu re an d loss of arteriolar ton e. By con st rict ing ar terial vessels (an α 1 act ion ) an d by in creasing ven ou s ret u rn , ep in ep h rin e in creases th e aort ic diastolic p ressu re du ring closed ch est

t ion are, at th e m ost , on ly m argin al.

Learning objective: Describe the direct and indirect m echanism s of action of dopam ine. 10. A Dop am in e is a m ixed -act ing ad ren ergic d r ug t h at can d irect ly act ivate α , β, an d d op am in e receptors. It can also

com pression . • Preferen t ial red u ct ion of blood

in ren in secret ion an d of epin ep h rin e-in d uced bron ch od ila-

ow to th e ren al an d

sp lan ch n ic beds, du e to α 1 receptor act ion , facilit ates th e d ist ribut ion of th e lim ited cardiac out pu t to th e cerebral an d coron ar y circulat ion during extern al cardiac m assage.

in crease t h e release of n orep in ep h r in e from ad ren ergic term in als. B−E All of th ese drugs are adren ergic agon ist s (i.e., directact ing adren ergic agen t s).

Because cerebral blood vessels are relat ively in sen sit ive to th e vasocon st rict ing e ect of α agon ist s, p erfu sion of th e brain is in creased. It seem s, therefore, that the m ain bene cial e ects of epineph rin e in cardiac arrest are related to its α 1 receptor act ivat ion .

Learning objective: Describe the cardiovascular e ects of norepinephrine. 11. D Th e invest igat ion al drug causes a parallel in crease in both systolic an d diastolic p ressu re an d a con com itan t decrease

It is w or th w h ile to n ote th at , u n like w h at h appen s un der

in h eart rate. Th is pat tern suggest s th at th e decrease in h eart

n or m al con dit ion s, ep in ep h r in e in creases tot al p er ip h eral

rate is due to a re ex vagal disch arge. Drugs th at cause th is

resist an ce in p eop le w it h card iac ar rest . Du r ing cardiac ar-

e ect m u st be vasocon st rict ing agen ts (e.g., n orepin ep h rin e

rest , t h ere is a com p lete loss of ar ter iolar ton e; t h erefore, β 2 -

and phenylephrine) devoid of vasodilating activit y. In this case,

m ed iated vasodilat ion can n ot occu r, w h ereas th e α 1 -m ediated vasocon st rict ion is st ill op erat ive. Addit ion al ben e cial e ect s of ep in ep h rin e th at are p ri-

h ow ever, st roke volum e is subst an t ially in creased (st roke volum e = cardiac ou t put/h eart rate, 78.6−100 m L). Ph enylep h rin e w ou ld in crease th e st roke volu m e on ly sligh tly (if

ne

ven ous con st rict ion causes an in crease in ven ous ret urn ) or

brillat ion in to a coarse on e, w h ich is m ore sus-

n ot at all, as it h as n o β-adren ergic act ivit y. Moreover th e

cept ible to elect rical de brillat ion , an d st im ulat ing spon t a-

eject ion fract ion is in creased, w h ich con rm s th at th e drug

n eous ven t ricular con t ract ion in case of asystole.

d oes in crease card iac con t ract ilit y. (Th e eject ion fract ion is

m arily related to β 1 receptor act ivat ion are ch anging a ven t ricu lar

Becau se t h e ben e t s of ep in ep h r in e are m ain ly d u e to

th e rat io of th e st roke volu m e to th e en d diastolic volu m e.

α 1 -m ediated vasocon st rict ion , n orepin eph rin e could also be

Rem em ber th at th e on ly w ay to in crease th e eject ion frac-

u sed. In fact a large preclin ical t rial failed to iden t ify any difference in survival follow ing treatm ent w ith norepinephrin e or stan dard d oses of ep in ep h rin e. Oth er vasocon st rict ing agen ts

t ion is to in crease cardiac con t ract ilit y). A−C Dobut am in e, epin eph rin e, an d isoproteren ol w ould in crease, n ot decrease, th e cardiac ou t p ut of th e h ear t .

h ave been evalu ated. Recen tly, vasopressin h as been tested ,

E See correct an sw er explan at ion .

w ith prom ising result s.

F Propran olol w ould decrease, n ot in crease, th e eject ion

Th e fact th at epin eph rin e is st ill th e agen t of ch oice in car-

fract ion of th e h ear t .

d iac arrest is likely related to th e long experien ce ach ieved w ith this drug, as well as to the additional bene ts listed above. For exam p le, ep in eph rin e act ivates both β 1 an d β 2 receptors;

Learning objective: Describe the cardiac adverse e ects of epinephrine in patients at risk.

t h erefore, it is likely m ore e ect ive t h an n orep in ep h r in e

12. D Ep in ep h r in e can cau se several card iovascu lar adverse ef-

in st im u lat ing sp on t an eou s con t ract ion of t h e h ear t d u r ing

fect s, in clu d in g an gin a, hyp er ten sion , an d card iac ar rhyt h -

asystole.

m ias, an d is t h erefore con t rain d icated in p at ien t s at r isk.

Answers and Explanations: II-2 Adrenergic Drugs 57 Becau se th e pat ien t h ad an ep isode of ven t ricu lar

brilla-

t ion , h e w as at h igh risk of ven t ricu lar arrhyth m ias.

th us im proving th e

ow of th e coat of m ucus tow ard th e

ph ar yn x.

A−C, E Th ese are adverse e ect s of epin eph rin e but are

A−C Bet a-2 receptor agon ist s act u ally decrease m icrovas-

less likely in th is pat ien t becau se h e did n ot h ave speci c risk

cular perm eabilit y, in crease bron ch ial secret ion , an d preven t

factors for th ese e ect s.

th e release of h ist am in e from m ast cells. All th ese act ion s are useful in t reat ing bron ch osp ast ic disorders.

Learning objective: Relate the therapeutic e cacy of epinephrine to its m echanism of action.

in n orm al in dividuals but is act u ally decreased in asth m at ic

13. C Th e sym ptom s an d sign s of th e p at ien t in dicate th at h e

pat ien ts.

D Residual respirator y volum e is n ot sign i can tly a ected

w as m ost likely su ering from an acu te an ap hylact ic reacst rict ion of an an ap hylact ic react ion is kn ow n to be cau sed

Learning objective: Describe the cardiovascular e ects of phenylephrine.

by both h ist am in e an d leukot rien es, but today leukot rien es

16. E Th e drug causes a parallel in crease in both systolic an d di-

(on ce kn ow n as th e slow -react ing subst an ce of an aphylaxis)

astolic p ressu re an d a con com it an t decrease in h eart rate.

are t h ough t to be t h e m ain bron ch ocon st r ict in g agen t s.

Th is p at tern suggest s th at th e decrease in h ear t rate is du e to

Ep in eph rin e, a

rst-lin e agen t for an ap hylaxis, w orks as a

a re ex vagal disch arge. Drugs th at cau se th is e ect m u st be

fu n ct ion al an tagon ist of th e m ediators of th e disorder. It

vasocon st rict ing agen t s (e.g., n orepin ep h rin e an d ph enyl-

coun teract s th e h ist am in e-m ediated vasodilat ion by act ivat-

ep h rin e) devoid of vasodilat ing act ivit y. In th is case, h ow -

ing α 1 receptors an d coun teract s th e leukot rien e-m ediated

ever, th e st roke volu m e h as in creased on ly sligh tly (st roke

bron ch ocon st rict ion by act ivat ing β 2 receptors. Epin eph rin e

volum e [SV] = cardiac ou t put/h eart rate; th erefore, con t rol

also in h ibit s t h e release of m ed iators from basop h ils an d

SV = 5/70 = 71.4 m L; SV after drug = 4.5/58 = 77.6 m L), an d

m ast cells by act ivat ing β 2 receptors.

the ejection fract ion has not changed. Norepinephrine w ould

t ion to th e injected local an esth et ic. Th e st rong bron ch ocon -

A Hist am in e e ect s on th e h eart are w eak an d are m ain ly

su bst an t ially in crease th e st roke volu m e an d th e eject ion

excit ator y. Ep in eph rin e w ould en h an ce, n ot an tagon ize, h is-

fract ion , as it h as β-adren ergic act ivit y (rem em ber th at th e

t am in e e ect s on th e h eart .

on ly w ay to in crease th e eject ion fract ion is to in crease th e

B Bradykin in h as gen eralized vasodilat ing act ivit y. Epin eph rin e w ould en h an ce, n ot an t agon ize, bradykin in s e ect

con t ract ilit y of th e h eart). A−D See correct an sw er explan at ion .

on skelet al m uscle vessels by act ivat ing β 2 receptors. D Alph a-1 receptors are n ot located in bron ch ial sm ooth m u scles.

Learning objective: Describe the m ain adverse e ect s of phenylephrine.

E Act ivat ion of β 2 receptors in bron ch ial vessels w ould

17. B Ph enylep h rin e is u sed as a n asal decongestan t both topi-

cau se vasodilat ion , w h ich w ou ld be det rim en tal by dim in -

cally and orally even th ough its e ectiven ess is controversial.

ish ing th e ven t ilat ion /p erfu sion rat io.

W h en taken orally, it can reach th e gen eral circu lat ion an d

F Epin eph rin e act ivat ion of α 2 receptors on platelet s prom otes p latelet aggregat ion , bu t t h is e ect h as n egligible relevan ce in th e th erapy of an aphylaxis.

act ivate α 1 receptors of th e in tern al sp h in cter of th e bladder. Th is in t u rn leads to sp h in cter con st rict ion , th u s cau sing difcult y in voiding, especially in m en su ering from prost at ic hyp erplasia, as in th is case.

Learning objective: Describe the e ect of phenylephrine given topically in the eye. 14. A Ph enylep h rin e is a select ive α 1 agon ist frequ en tly u sed to facilitate th e exam in at ion of th e ret in a. Th e drug causes m ydriasis by con t ract ing th e radial m u scle of th e iris, w h ich receives on ly sym path et ic in n er vation . Because M 3 , α 2 , an d

A, C−F Th ese drug are n ot u sed as n asal decongestan t s.

Learning objective: Explain the reason for the therapeutic use of apraclonidine in glaucoma. 18. E Apraclon idin e is a select ive α 2 agon ist th at can decrease th e p rodu ct ion of aqu eou s h u m or by th e ciliar y ep ith eliu m .

β 2 receptors are n ot act ivated, len s cur vat ure an d in t raocu lar

Th e aqu eou s h u m or of th e eye is p rodu ced by th e ep ith elial

pressu re are n ot a ected.

cells of th e ciliar y body an d is under th e con t rol of α 2 an d

B−E Each of t h ese d r ugs, given locally, w ou ld a ect t h e in traocu lar pressu re.

β receptors (m ain ly β 2 ) located on t h ese cells. Act ivat ion of α 2 receptors decreases t h e p rod u ct ion , w h ereas act ivat ion of β receptors in creases t h e p rod u ct ion .

Learning objective: Describe the pharm acological actions of albuterol. 15. E Albuterol is a β 2 -select ive agon ist . Act ivat ion of β 2 recep tors in th e respirator y t ract in creases m ucociliar y clearan ce,


58


Learning objective: Explain the m echanism of the therapeutic effect of clonidine in alcohol withdrawal.

such as norepinephrin e, phenyleph rine, and dopam in e are

19. A Clon idin e is often used to decrease th e sym ptom s of sym -

decreased blood p ressu re.

used to restore th e ar teriolar ton e, th u s coun teract ing th e

p ath et ic act ivat ion , w h ich are prom in en t du ring w ith draw al

A, B, D Th ese drugs are devoid of α 1 -adren ergic act ivit y.

from m any sedat ive drugs, in clu d ing alcoh ol an d opioids.

E Salm eterol is an an t iadren ergic drug.

Many of th ose sym ptom s are du e to an in creased ring from th e locu s ceru leu s, a brain n u cleu s w ith a ver y h igh con cen t rat ion of α receptors. By act ivat ing α 2 presyn apt ic receptors, clon idin e decreases th e cen t ral sym path et ic out ow, an tagon izing th e in creased ring of th e locus ceruleus. B, D Clon idin e act ivates periph eral adren oceptors on ly w h en ver y h igh doses are given . C Clon idin e in creases, n ot decreases, cen t ral parasym path et ic ou t ow. E, F Clon idin e act ivates, n ot blocks, th ese receptors.

Learning objective: Describe the cardiovascular e ect s of isoproterenol. 23. C Th e d r ug cau ses a su bst an t ial in crease in h ear t rate, cardiac ou t p u t , an d eject ion fract ion an d a con com it an t d ecrease in m ean blood p ressu re. An in crease in eject ion fract ion in dicates th at th e con t ract ilit y of th e h ear t is in creased. Th e fact th at m ean blood p ressu re is decreased d espite th e in creased cardiac ou t p u t in dicates th at th e drug m u st decrease total p eriph eral resistan ce (TPR). Th e t w o listed drugs th at can decrease TPR are isoproteren ol an d al-

Learning objective: Describe the adverse e ect s of albuterol.

bu terol. How ever, becau se albu terol is a select ive β 2 agon ist ,

20. B Restlessn ess an d an xiet y are com m on adverse e ect s of β 2

it w ould h ave caused a decrease in TPR an d a re ex in crease

adren oceptor agon ists. Th ey occur in 10 to 20% of ch ildren

in th e h eart rate, bu t th e eject ion fract ion w ou ld h ave been

receiving in h alator y th erapy. Th is poin t s ou t th at β agon ists

m in im ally a ected.

are m ain ly excit ator y d r ugs in t h e cen t ral n er vou s system .


In fact , toxic doses u su ally cause convulsion s. A Beta-2 receptor activation in creases at riovent ricular (AV) con duct ion , so AV block is un likely. C Beta-2 receptor act ivat ion act u ally causes in som n ia.

Learning objective: Describe the pharm acological actions of isoproterenol. 24. A Isoproteren ol is often u sed in th e operat ing room after

D Hypoten sion can rarely occur w ith β 2 agon ist s, but pos-

h ear t t ran splan t , because con t ract ilit y an d sin us n ode fun c-

t u ral hypoten sion is u n likely, as th e baroreceptor re ex is

t ion of th e n ew h ear t are tem p orarily im p aired to var ying

n ot a ected.

d egrees, based on th e con dit ion of th e don or h ear t , qu alit y

E Arrhyth m ias can occur w ith β 2 agon ist s, bu t ven t ricu lar tachycard ia is rare.

of preser vat ion , an d so on . Isoproteren ol is a n on select ive β agon ist (i.e., it act ivates all β receptors). Act ivat ion of β 1 receptors in th e ju xtaglom eru lar cells of th e m acu la d en sa

Learning objective: Describe the therapy of open-angle glaucom a in a patient with a concom itant disease.

st im u lates ren in secret ion .

21. B Epin eph rin e is som et im es u sed in op en -angle glau com a

creases in su lin release.

B Act ivat ion of β 2 receptors in th e pan creas act u ally in -

because it decreases aqueous hum or production by activating

C Act ivat ion of β 2 receptors in th e vessels causes vasodila-

α 2 receptors in th e ciliar y ep ith eliu m , an d it also in creases

t ion , w h ich in t u rn decreases, n ot in creases, total perip h eral

aqu eou s h u m or ou t ow th rough th e uveoscleral rou te.

resist an ce.

A, C−E All of th ese drugs are e ect ive in op en -angle glau-

D Isoproteren ol causes t achycardia, w h ich is, in a n orm al

com a but are con t rain dicated in th is case becau se of severe

person , both d irect (du e to act ivat ion of cardiac β receptors)

asth m a. In fact , even w h en given top ically, β-blockers an d

an d re ex (due to drug-in du ced periph eral vasodilat ion ). In

cholin ergic agon ists can in crease th e risk of bron ch ospast ic

th is pat ien t , h ow ever, th e n ew h ear t is den er vated, so re ex

d isord ers from system ic absor pt ion via t h e n asolacr im al

tachycard ia can n ot occu r.

system .

E Th is e ect is m ediated by th e act ivat ion of α 2 receptors. Isoproteren ol h as n o act ivit y on α receptors.

Learning objective: Describe the therapeutic uses of norepinephrine. 22. C Th e sh ock du e to th e spin al cord inju r y is vasodilator y

Learning objective: Describe the rst therapeutic intervention for a patient with hypovolemic shock.

(also called n eurogen ic or dist ribut ive sh ock), w h ich occurs

25. D Th e sym ptom s an d sign s of th e p at ien t in dicate th at h e

because the injured sym pathetic nervous system fails to m ain-

w as m ost likely su er in g from hyp ovolem ic sh ock d u e to

t ain th e ar teriolar ton e. Drugs w ith α 1 -adren ergic activit y

t h e exten sive h em or rh age. Th e m ost im p or t an t t h erap eu t ic in ter ven t ion in hyp ovolem ic sh ock is th e in fu sion of

Answers and Explanations: II-2 Adrenergic Drugs 59 in t raven ou s u ids. Cr ystalloids (isoton ic solut ion s th at con -

a decreased system ic periph eral resist an ce. In fact , th e pa-

tain eith er n orm al salin e or salin e equ ivalen t s) or colloid

t ien t h as m et abolic acidosis, in dicat ing an aerobic m etabo-

solu t ion s (w h ich con tain large on cot ically act ive m olecu les,

lism an d lact ic acidosis. Even if u id adm in ist rat ion is st ill

e.g., album in an d carbohydrates) can be given . Th e ch oice

th e m ain st ay th erapy in sept ic sh ock, recen t eviden ce sug-

bet w een th e t w o rem ain s con t roversial, bu t n orm al isoton ic

gests th at early aggressive vasop ressor su p port m ay be th e

salin e is exten sively u sed .

key to a p osit ive ou tcom e. Dop am in e is frequ en tly th e in it ial

A Norepin eph rin e is u sed in n eu rogen ic sh ock.

ph arm acological agen t ch osen for th e t reat m en t , bu t w h en

B Epin eph rin e is th e rst-lin e agen t in an ap hylact ic sh ock.

th e system ic vascu lar resistan ce is ver y low, as in th is case,

C Dobutam in e is u sed in cardiogen ic sh ock.

n orepin eph rin e w as foun d to be superior to dopam in e.

E Dopam in e is used in n eurogen ic an d cardiogen ic sh ock F Isoproteren ol is con t rain dicated in any t ype of sh ock.

A, B, D, E All of th ese dr ugs ten d to decrease th e system ic vascular resist an ce an d are th erefore n ot in dicated in th is case.

Learning objective: Describe the postreceptor m echanism of drugs used to treat cardiogenic shock. 26. C Th e th erapy of cardiogen ic sh ock requires a rapid-act ing

Learning objective: Explain the m echanism of action of antiasthmatic β agonists.

in ot ropic drug to in crease m yocardial con t ract ilit y an d car-

29. C Accord ing to t h e Exp er t Pan el Rep or t of t h e Nat ion al In -

d iac ou t pu t . Dobu tam in e an d dopam in e are th e t w o drugs

st it u tes of Health , all p at ien t s w ith asth m a sh ou ld receive a

m ost frequ en tly u sed. In both cases, th e th erapeu t ic e

cacy

sh ort-act ing β 2 agon ist on an “as n eeded” basis. Th erefore,

is m ediated m ain ly by th e direct (dobu tam in e) or in direct

th e m ost app ropriate drug for th is pat ien t’s in h aler w ou ld be

an d direct (dopam in e) act ivat ion of β 1 receptors, w h ich in

a drug like albuterol.

t u rn in crease th e syn th esis of cAMP. A, B, D−F See correct an sw er exp lan ation .

B Act ivat ion of M 2 receptors in n onvascu lar sm ooth m u scle can cause sm ooth m uscle con t ract ion . Th erefore, blockad e of M 2 receptors (w it h an an t ich olin ergic d r ug, e.g.,

Learning objective: Describe the cardiovascular e ect s of dobutam ine.

iprat rop ium ) cou ld cause a bron ch odilat ing e ect . How ever,

27. E Dobu tam in e is a select ive β agon ist th at act ivates m ain ly

an d th e bron ch ocon st rict ing act ion of M 2 receptors is less

β 1 receptors. Th is sh ou ld cau se an in crease of all th e param eters of h ear t act ivit y, but for u n kn ow n reason s, frequ en cy

an t ich olin ergics are less e ect ive th an β 2 agon ist s in asth m a, e ect ive th an th at of M 3 receptors. A, D−F See correct an sw er exp lan at ion .

and autom aticit y are increased only slightly. A nit y of dobut am in e for α 1 an d β 2 receptors is sligh t (h igh doses are

Learning objective: Describe the adverse e ects of salm eterol.

n eeded); m oreover, the con sequen ces of th is act ivat ion on

30. B Bet a-2 agon ist s ad m in istered by in h alat ion are

rst-lin e

th e vessel caliber can balan ce each oth er. Th is can exp lain

d rugs for asth m a. Trem or is th e m ost frequen t adverse e ect

w hy th ere are n o m ajor ch anges or a decrease (w h en th e

of β 2 agon ist s (in u p to 40% of pat ien t s). It likely occurs be-

β 2 -m ediated vasodilat ion overrides th e α 1 -m ediated vaso-

cau se β 2 -receptor act ivat ion accelerates th e sequ est rat ion of

con st rict ion ) in total periph eral resistan ce.

cytosolic Ca 2+ (by open ing Ca 2+ ch an n els in th e sarcop lasm ic

A−D All of th ese drugs cause substan t ial ch anges in h ear t rate an d system ic vascular resist an ce.

reticulum of skeletal m uscle) and increases discharge in m uscle spin dles. An xiet y is th e secon d m ost frequen t adverse e ect of th ese drugs (in u p to 20% of p at ien t s). Palp itat ion s

Learning objective: Describe the therapeutic uses of norepinephrine.

can occu r in u p to 10% of p at ien t s an d are related to th e car-

28. C Th e sign s an d sym ptom s of th e p at ien t st rongly suggest

m oreover, β 2 -receptor act ivat ion also in creases h ear t con -

th e diagn osis of sept ic sh ock. Sign s con sisten t w ith th is diag-

t ract ilit y an d rate). Mu scle cram p ing is likely a con sequ en ce

n osis are th e h igh fever, h igh W BC, hypoten sion , t achycardia,

of hypokalem ia (β 2 agon ists st im u late Na/K+ ATPase, th u s

elevated cardiac out put , an d low system ic vascular resis-

facilitat ing K+ en t r y in to cells), as K+ is n eeded for vasodila-

t an ce. Sept ic sh ock is a vasodilator y sh ock (vasodilat ion m ay

t ion in th e skelet al m u scle.

diac e ect s of th ese drugs (β 2 sp eci cit y is n ever absolu te;

be par tly du e to th e vasodilator y e ects of en dotoxin s or

A Isoproteren ol can cause th e pat tern of adverse e ect s

oth er ch em ical m ediators). In th is kin d of sh ock, even if car-

repor ted by th e p at ien t bu t is ver y rarely u sed today in asth -

d iac ou t pu t is in creased, it is in adequate to m ain tain a blood

m at ic pat ien t s.

p ressure th at w ill perfu se th e essen t ial organ s in th e face of

C−E Th ese drugs are n ot u sed to t reat asth m at ic p at ien ts.

60


Learning objective: Explain the m ain m echanism of action of cocaine.

Learning objective: Describe the pharm acological e ect s of dopam ine.

31. C Cocain e is an in direct-act ing adren ergic drug th at blocks

34. F Dopam in e decreases tot al periph eral resist an ce (TPR) at

catech olam in e u ptake in both th e cen tral an d periph eral n er-

low d oses by select ively act ivat ing D1 receptors (m ain ly in

vous system s. Th erefore, th e adren ergic act ion s of cocain e

m esen teric an d ren al beds). At h igh er doses, dopam in e can

are d u e to th e in creased availabilit y of n orep in ep h r in e in

also act ivate α receptors an d in crease n orepin eph rin e re-

t h e syn apt ic cleft .

lease from adren ergic term in als. Th e α -m ediated vasocon -

A, B, D, E All of th ese listed m ech an ism s can in crease th e availabilit y of n orep in eph rin e or ep in ep h rin e, bu t th ese are n ot m ech an ism s of act ion of cocain e.

st rict ion overrides th e vasodilat ing e ects on th e kidn ey, an d TPR in creases. A, E Norep in ep h rin e an d p h enyleph rin e h ave on ly vasocon st rict ing e ects m ediated by act ivat ion of α 1 receptors.

Learning objective: Describe the diagnostic uses of cholinergic drugs.

e ects m ediated by th e act ivat ion of β 2 receptors.

32. A Horn er syn d rom e resu lt s w h en th e cer vical sym p ath et ic

D Dobut am in e h as n egligible e ect s on TPR.

B, C Albu terol an d isop roteren ol h ave on ly vasod ilat ing

p ath w ay r u n n ing from th e hypoth alam us to th e eye is disr u pted. Th e lesion cau ses vasodilat ion (loss of α 1 receptor−

Learning objective: Describe the diagnostic uses of t yram ine.

m ediated vascular ton e), ptosis (loss of α 1 receptor−m ediated

35. A Tyram in e is a n orm al by-product of t yrosin e m etabolism

con t ract ion of th e superior tarsal m uscle), m iosis (loss of th e

in th e body an d is also fou n d in h igh con cen t rat ion in fer-

α 1 receptor−m ediated d ilat ion of th e p u p il), an d an h idrosis

m en ted food . It is n orm ally in act ive w h en ingested, becau se

(loss of sym p ath et ic ch olin ergic ring to th e sw eat glan d s).

of a very large rst-pass e ect (m etabolism by hepatic m ono-

Th e u se of ad ren ergic d r ugs can h elp to d eter m in e if t h e

am in e oxidase [MAO]). If adm in istered p aren terally, it h as

lesion is pre- or postganglion ic. Hydroxyam ph etam in e is an

an in direct sym p ath om im et ic act ion du e to th e release of

in direct-act ing adren ergic drug th at st im ulates th e release

stored catech olam in es. Th is is th e basis of th e t yram in e test ,

of n orepin eph rin e from adren ergic n er ve en dings. Because

som et im es u sed clin ically for th e diagn osis of som e au to-

m ydriasis w as obser ved , th e postganglion ic n eu ron is in tact

n om ic n er vous system (ANS) diseases.

an d th erefore able to release n orep in ep h rin e. Dam age to th e

In t h is case, t h e p at ien t is m ost likely a ected by p u re

postganglion ic n eu ron w ould results in less or n o n orepi-

au ton om ic failu re, a rare degen erat ive d isorder of th e ANS

n eph rin e being released, an d m ydriasis w ould be in com -

p resen t ing in m iddle to late life. In th is disease, th ere is a

plete or absen t . Th e con clusion is th at th e lesion m u st be on

d egen erat ion of p ostganglion ic sym path et ic n eu ron s, w h ich

th e preganglion ic n eu ron .

can exp lain th e post u ral hyp oten sion . An in t raven ou s injec-

B See correct an sw er explan at ion .

t ion of t yram in e n orm ally cau ses an elevat ion of blood p res-

C, D A lesion of eit h er p re- or p ostganglion ic p arasym -

su re du e to th e release of stored catech olam in es. In th is case,

p at h et ic n er ves w ou ld cau se a com p letely di eren t clin ical

h ow ever, th e elevat ion did n ot occur because catech olam in es

p ict ure (m ydriasis, n o ptosis, etc.).

h ad been lost from th e n er ve en dings. On th e con t rar y, an in t raven ou s inject ion of ep in eph rin e cau sed a big elevat ion

Learning objective: Describe the mechanism of dopamine-induced diuresis.

in blood pressu re, as epin ep h rin e directly act ivates adren o-

33. A Act ivat ion of D1 receptors in th e kidn ey cau ses vasodila-

a d ecreased availabilit y of th e n eu rot ran sm it ter (den er va-

t ion an d in h ibit ion of Na + reabsorpt ion by th e proxim al t ubu le. Both act ion s con t ribu te to th e in creased diu resis th at can occu r w ith low doses of d op am in e. B Th is e ect occu rs w ith h igh dose of dopam in e, w h ich act iviates D2 recept ion s in th e area post rem a. C−E Th ese e ect s occu r w it h an in ter m ed iate d ose of d op am in e, w h ich st ill act ivates D1 receptors, bu t also act ivates β 1 receptors an d release of n orepin eph rin e from n er ve term in als.

ceptors. Moreover, th ese receptors w ere upregulated, du e to t ion su persen sit ivit y). B A lesion of th e preganglion ic sym path et ic n er ve w ould h ave caused orth ost at ic hypoten sion , bu t t yram in e w ou ld h ave caused hyper ten sion , as th e postganglion ic adren ergic n euron s w ere in tact . C, D In case of a lesion of either pre- or postganglionic parasym path et ic n er ves, t yram in e w ou ld h ave been e ect ive. E Lesion s of th e sym path et ic path w ays in th e m edulla ob longat a w ould h ave caused sym ptom s sim ilar to th ose du e to lesion s of th e preganglion ic sym path et ic n er ves. In th is case, t yram in e w ou ld h ave been e ect ive.

Answers and Explanations: II-2 Adrenergic Drugs 61 Learning objective: Describe the pharm acological action of clonidine.

Learning objective: Explain the reversal of norepinephrine e ect on heart rate by atropine.

36. B Hot ash es are sym ptom at ic of a disord er in th erm oregu-

39. B Th e drug causes a decrease in h ear t rate th at is reversed by

lat ion du e to th e com plex h orm on al ch anges th at accom -

a p ret reat m en t w ith at ropin e. Th is suggest s th at th e brady-

p any est rogen w ith draw al. Several ch em ical m ediators are

cardia is cau sed by a re ex vagal disch arge. Norepin ep h rin e

th ough t to be involved, in clu ding n orep in ep h rin e, ep in eph -

is th e on ly listed drug th at cau ses a vagal re ex bradycardia

rin e, seroton in , an d p rostaglan din s. Clon idin e is som et im es

st rong en ough to overcom e its ow n direct t achycardic e ect .

u sed to t reat h ot ash es, even if it is n ot a rst-lin e agen t for

W h en th e re ex vagal disch arge is blocked by at ropin e, th e

th at disorder. In fact , it is less e ect ive com pared to oth er

direct tachycardic e ect of norepin eph rine becom es evident.

n on h or m on al t h erap ies (gabap en t in , ven lafa xin e, an d

u-


oxet in e). By act ivat ing presyn apt ic α 2 receptors, clon idin e cau ses a d ecrease of n orepin eph rin e release from adren ergic term in als. How ever, h ow th is m ech an ism decreases h ot ash es is st ill un kn ow n . A, C−E Th ese drugs do n ot act ivate α 2 receptors.

Learning objective: Explain the reason for the decrease in heart rate caused by an intravenous injection of norepinephrine. 40. C Norepin eph rin e u su ally cau ses a re ex bradycardia in pat ien t s w ith in tact in n er vat ion of th e h eart for th e follow ing reason : th e in crease in blood pressu re du e to act ivat ion of α 1

Learning objective: Identify the drugs used to treat hyperkalem ia.

receptors act ivates baroreceptors located in th e carot id sin us

37. B Th is p at ien t’s lab dat a in dicate th at sh e is su ering from

in creases th e

an d aor t ic arch (baroreceptors are st retch receptors). Th is ring rate to th e n u cleus of th e t ract u s soli-

ren al failure, w h ich frequen tly leads to hyperkalem ia. Hyper-

t ariu s in th e m edu lla, w h ich in t u rn in creases it s ring to th e

kalem ia w ith ECG ch anges requ ires em ergen cy t reat m en t .

vagal m otor n euron s (dorsal m otor n euron an d n ucleus am -

Th e th erapy in clu des

bigu u s). W h en th is vagal excit at ion is st rong en ough , it can

• Agen t s th at an tagon ize th e cardiac e ect s of hyperkale-

overcom e the norepinephrin e-induced tachycardia due to ac-

m ia (e.g., calciu m , w h ich cou n teract s t h e d ep olar izin g

tivation of cardiac β receptors; therefore, bradycardia ensues.

e ect of hyperkalem ia) • Drugs th at sh ift K+ from th e ext racellular to th e in t racellu lar sp ace (e.g., in su lin an d β 2 agon ists) • Dr ugs t h at en h an ce K+ elim in at ion (e.g., ion -exch ange resin s th at bin d K+ in th e bow el lu m en ) Albuterol is th e on ly dr ug in th e list th at h as on e of th ese e ect s (β 2 agon ist) w ith ou t oth er act ion s th at w ou ld be deleterious in th is pat ien t .

A, B Th ese act ion s w ou ld cau se an in crease, n ot a d ecrease, in h eart rate. D Act ivat ion of α 2 autoreceptors causes a decrease of n orep in ep h rin e release, bu t th is is n ot th e m ain m ech an ism of n orepin eph rin e-in duced bradycardia. E Decreased

ring rate of carot id ch em oreceptors occurs

on ly in severe path ologic con dit ion s an d w ould cause an in crease, n ot a decrease, in h eart rate.

A, C, F Ph enylep h rin e, clon idin e, an d dobu t am in e do n ot a ect K+ con cen t rat ion .

ADRENERGIC DRUGS Answ er key

D, E Isoproteren ol an d epin eph rin e can cause hypokalem ia, bu t th ey are n ot u sed th erapeu t ically for th is p u rp ose becau se of m any oth er u nw an ted e ects.

Learning objective: Relate the e ect s of epinephrine to the activation of speci c receptors. 38. E Act ivat ion of β 2 receptors by epin eph rin e in creases cyclic aden osin e m on oph osp h ate (cAMP), w h ich in t u rn act ivates the cAMP-dependent protein kinase A. This enzym e activates a cascade of en zym es th at prom ote glycogen degradat ion . A Th is act ion is m ediated by act ivat ion of α 2 receptors. B−D Th ese act ion s are m ed iated by act ivat ion of α 1 receptors.

1. 2. 3. 4. 5.

B L I H K

6. 7. 8. 9. 10.

E E D A A

11. 12. 13. 14. 15.

D D C A E

16. 17. 18. 19. 20.

E B E A B

21. 22. 23. 24. 25.

B C C A D

26. 27. 28. 29. 30.

C E C C B

31. 32. 33. 34. 35.

C A A F A

36. 37. 38. 39. 40.

B B E B C

62


Answers and Explanations: II-3 Antiadrenergic Drugs Questions 1−5 1. E

Learning objective: Describe the m ain adverse e ect s of tam sulosin.

2. A

9. B Tam su losin is a select ive α 1 an t agon ist frequ en tly u sed to

3. G

cou n teract blad d er obst r u ct ion d u e to p rost at ic hyp er p la-

4. H

sia. Fat igue, sleepin ess, an d dizzin ess are com m on adverse

5. B

e ect s m ost likely related to th e drug-in du ced hypoten sion . Palp it at ion s are in frequ en t ly rep or ted an d are m ost likely

Learning objective: Explain the m echanism of impaired ejaculation caused by α 1 antagonists.

related to t h e re ex t achycard ia t r iggered by t h e d r ug-

6. E Vasospasm in th e ngers, w h ich is th e m ost com m on sign of

D Flut am ide is an an drogen receptor blocker th at is used

Rayn au d disease, is t reated by a vasodilator, u su ally a calciu m

in p at ien t s w ith p rostat ic hyperp lasia. How ever, it does n ot

ch an n el blocker, such as n ifedipin e, or an α 1 an t agon ist , su ch

cau se th e sym ptom s reported by th e p at ien t .

as prazosin . Th e pat ien t m ost likely received prazosin because h e com p lain ed of im p aired ejacu lat ion . Th e in creased

r ing

in duced vasodilat ion .

A, C, E, F Th ese dr ugs are n ot u sed for p rost at ic hyp erplasia.

of th e sym path et ic n er vous system th at occurs du ring sex act ivates α 1 receptors located on th e vas deferen s an d prostate

Learning objective: Describe the therapeutic uses of prazosin.

cap su le. Th e con t ract ion of sm ooth m u scles of th ese organ s

10. C Th e p at ien t’s sign s an d sym ptom s suggest th e diagn osis of

p ut s th e sem en in to th e u reth ra, th us causing ejaculat ion .

Rayn au d d isease. In th is disease, w h ich is idiopath ic an d is

Prazosin blocks α 1 adren oceptors, so ejaculat ion is im paired.

m ost com m on in young w om en, the threshold for vasospastic


respon se is low ered by local cold or anyth ing th at act ivates th e sym p ath et ic ou t ow or th e release of catech olam in es. By

Learning objective: Describe the pharm acological e ects of phenoxybenzamine.

blocking α 1 receptors, prazosin is often h elp fu l in redu cing

7. A Ph en oxyben zam in e is a n on select ive α -adren ergic blocker.

A, B, D, E Th ere is n o rat ion ale for th e u se of any of th ese

Th e blockade of α 1 adren oceptors cau ses p erip h eral vasodila-

vasospast ic episodes. drugs in Rayn au d disease.

t ion , w h ich in t u rn decreases th e blood pressu re. A red u ct ion ceptors. Because the baroreceptor discharge increases the vagal

Learning objective: Identify the site of action of apraclonidine and timolol in open-angle glaucoma.

out ow to th e h eart , a decreased ring rate w ill h ave th e op -

11. D Open -angle glaucom a is ch aracterized in m ost cases by

p osite e ect; th at is, it w ill in crease th e sym path et ic ou t ow,

in creased in t raocu lar pressu re, w h ich in t urn is du e to an

causing t achycardia an d in creased cardiac con t ract ilit y.

excessive am oun t of aqueous h um or in th e an terior ch am ber

in blood pressu re decreases th e

ring rate of carot id barore-


of t h e eye. Ph ar m acological t h erapy for t h is d isease aim s to d ecrease t h is volu m e, eit h er by low er in g aqu eou s h u m or

Learning objective: Identify the action m ediating the therapeutic e ect of phenoxybenzamine.

p roduct ion or by in creasing aqu eous h u m or ou t ow. In th e

8. A Phenoxyben zam ine is a nonselective α antagonist frequen tly

ep ith eliu m an d is u n der th e con t rol of both β adren ocep -

used in pheochrom ocytom a both in th e preoperative m anage-

tors (w h ich in crease th e product ion ) an d α 2 adren oceptors

m en t of th e disease an d to h an dle in operable or m etastat ic

(w h ich decrease th e product ion ). Product ion of aqueous

cases. By blocking α 1 receptors, th e drug decreases p erip h eral

h u m or can be reduced eith er by drugs th at block β receptors

eye, aqu eous h um or is m an ufact u red by th e cells of ciliar y

vascular resistan ce, th us coun teract ing th e hyperten sion th at

(e.g., t im olol) or by drugs th at act ivate α 2 receptors (e.g.,

is a prom in en t sym ptom of th e t um or.

apraclon idin e).Th e site of act ion of both drugs is th e ciliar y

B, D Th ese are act ion s of ph en oxyben zam in e, but th ey m ediate u nw an ted e ects, n ot th e th erap eu t ic e ect of th e drug. C By blocking α 2 presyn apt ic receptors, p h en oxyben zam in e act u ally in creases, n ot decreases, ep in ep h rin e release from th e adren al m edu lla. E Alph a-2 agon ists redu ce ring from th e vasom otor cen ter, so an α 2 an t agon ist such as ph en oxyben zam in e w ould in crease, n ot decrease, ring from th e vasom otor cen ter.

ep ith eliu m . A−C, E, F See correct an sw er explan at ion .

Answers and Explanations: II-3 Antiadrenergic Drugs 63 Learning objective: Explain the m echanism of action of β-blocker in hypertrophic cardiomyopathy. 12. B In hypert rop h ic cardiom yopathy, th e st i , n on com p lian t ven t ricle resist s diastolic

lling. Th is can cause in su

Learning objective: Describe the ocular e ects of tim olol. 15. B Bet a-blockers decrease aqueous h u m or product ion by blocking β receptors in th e ciliar y ep ith eliu m . Th e con se-

cien t

qu en t reduct ion in in t raocu lar pressure usually can be de-

en d-diastolic volu m e an d th erefore diastolic failu re. Beta-

tected w ith in 30 m in utes after a single dose. Bet a-blockers

blockers slow th e h ear t rate, w h ich allow s an in creased du-

h ave n egligible e ect s on pupillar y diam eter (w h ich is un der

rat ion of diastole an d th us m ore com plete diastolic

lling.

th e con t rol of M 3 receptors on th e sp h in cter m u scle of th e

Th ey also decrease m yocardial con t ract ilit y, w h ich in creases

iris an d of α 1 receptors on th e radial m u scle of th e iris) an d

ven t ricle com plian ce.

on len s cu r vat u re (w h ich is m ain ly u n d er t h e con t rol of

A, C, D All of th ese e ect s can be cau sed by prop ran olol, bu t th ey d o n ot m ed iate th e e

cacy of th e d r ug in hyp er-

M 3 receptors on th e ciliar y m uscle). A, C−E See correct an sw er explan at ion .

t roph ic cardiom yopathy. d ilat ion . Th e e ect is du e prim arily to th e decrease in car-

Learning objective: Describe the interactions bet ween propranolol and isoproterenol.

d iac con t ract ilit y an d, to a lesser exten t , to th e blockade of

16. A Isop roteren ol-in d u ced hyp erglycem ia is m ain ly d u e to

E Propran olol causes coron ar y vasocon st rict ion , n ot vaso-

β 2 receptor−m ediated vasodilat ion .

β 2 receptor−m ediated glucon eogen esis an d glycogen olysis. Because of th is, it can be e ect ively coun teracted by pro-

Learning objective: Describe the cardiovascular actions of β-blockers.

pran olol, w h ich blocks β 2 receptors. Non e of th e oth er listed

13. A Th e act ion s of a β-blocker on th e cardiovascular system

n ot m ediated by act ivat ion of β receptors.

are m u ch m ore pron ou n ced w h en sym path et ic ton e is h igh .

act ion s can be an t agon ized by propran olol, because th ey are B Nicot in e-in du ced act ivat ion of Nn receptors in ganglia

Th erefore, u n d er rest in g con d it ion s, t h e d r ug-in d u ced d e-

in creases th e

ring of postganglion ic sym path et ic n er ves,

crease of h ear t rate is m in im al, w h ereas it is p ron ou n ced

w h ich in t u rn causes skin vasocon st rict ion by act ivat ing α 1

d uring exercise, w h en th e sym path et ic ton e is h igh .

receptors.

B A ch olin ergic agon ist w ould cau se a m ore pron oun ced

C Norepin eph rin e-in duced re ex bradycardia is m ediated

d ecrease of th e h ear t rate u n der rest ing con dit ion s, because

by t h e act ivat ion of M 2 card iac receptors. Moreover, p ro -

it fur th er in creases th e parasym path et ic act ivit y th at is al-

pran olol itself can cau se bradycardia.

ready predom in an t un der rest ing con dit ion s. C−E All of these drugs tend to increase the h eart rate under rest ing con dit ion s.

D Ph enyleph rin e-in duced m ydriasis is m ediated by th e act ivat ion of α 1 receptors. E Pilocarpin e-in duced con t ract ion of bron ch ial m usculat u re is m ediated by th e act ivat ion of M 3 receptors. Moreover,

Learning objective: Describe the cardiovascular e ects of atenolol.

propran olol it self can cau se bron ch oconst rict ion .

14. C Aten olol is a select ive β adren oceptor blocker. By blocking best in dex of cardiac con t ract ilit y is th e eject ion fract ion ,

Learning objective: Describe the pharm acological e ect s of atenolol.

w hich is th e fract ion of th e en d-diastolic volu m e th at is

17. C Th e n ew drug com pletely an tagon izes th e epin eph rin e-

ejected du ring systole (rem em ber th at st roke volu m e is n ot

in duced in crease in ren in (w h ich is m ediated by β 1 receptor

the best in dex of cardiac con t ract ilit y, as it also dep en ds on

activation) but does not antagonize the epinephrine-induced

preload).

hyp erglycem ia (w h ich is du e to several act ion s, in clu ding β 2

β 1 receptors, aten olol decreases cardiac con t ract ilit y. Th e

A, D Becau se con t ract ilit y is decreased, th ese volu m es are act u ally in creased, n ot decreased. B Beta-blockers actually increase ventricular ejection tim e. E Ven ous ton e (w h ich is m ain ly depen den t on α 1 -receptor act ivat ion ) is m in im ally a ected by β-blockers.

adren oceptor−m ediated glycogen olysis). Th erefore, th e drug m u st be a select ive β blocker, su ch as aten olol. A, D, F Albu terol, at rop in e, an d p razosin can n ot an tagon ize eith er of th e epin ep h rin e-in du ced e ect s. B, E Tim olol an d propran olol are n on select ive β–blockers, so th ey w ou ld an t agon ize both e ects of ep in eph rin e.

64


Learning objective: Describe the adverse e ects of propranolol on the central nervous system.

blocking β 2 -m ediated in crease in in sulin secret ion , but th is

18. D Propran olol is a

e ect is m ild an d is n ot sh ared by select ive β 1 -blockers, such

rst-lin e agen t for m igrain e prophylaxis,

an d a large n u m ber of st u dies su p port its e ect iven ess. Adverse e ect s of propran olol in clude in som n ia, vivid dream s, an d n igh t m ares (in u p to 5% of pat ien ts). Th e m ech an ism

A Bet a-2 blockers occasion ally can in crease sugar levels by

as aten olol. C Bet a-2 blockers can decrease, n ot in crease, in su lin secret ion .

u n derlying th ese cen t ral e ects is st ill un cert ain , but pro-

D, E Beta-blockers h ave th ese e ects, but th is is n ot th e

p ran olol is a h igh ly lipoph ilic drug an d con cen t rates in th e

reason w hy diabet ic pat ien t s receiving β-blockers m u st

brain .

carefu lly con t rol th eir sugar levels.

A Beta-blockers do n ot cause post ural hypoten sion , as th e p reload an d th e baroreceptor re ex are n ot a ected by th ese d rugs.

Learning objective: Explain the rationale of prescribing selective β 1 -blockers in asthmatics.

B Bet a-blockers d ecrease t h e h ear t rate an d h ave an t i-

21. B Bet a-blockers are usually con t rain dicated in asth m at ics

ar rhyt h m ic p rop er t ies, so p alp it at ion s are u n likely. Bet a-

becau se of th eir bron ch ocon st rict ing act ivit y d u e to block-

blockers block β adren oceptor−m ediated vasodilat ion , so

ad e of bron ch ial β 2 receptors. How ever, th ey are

ush ing is also un likely.

rst-lin e

t h erapy after a m yocard ial in farct ion , as th ey su bst an t ially

C Bet a-blockers h ave n o sign i can t e ect on eye accom -

decrease m orbid it y an d m or t alit y. In deciding w h eth er to

m odat ion an d do n ot cau se m ydriasis, so im p airm en t of far

at tem pt to u se β-blockers in asth m at ic p at ien ts w ith previ-

vision an d ph otoph obia are un likely.

ous MI, w eigh ing th e risk versus ben e t is im perat ive. In th is

E Beta-blockers com m on ly cau se diarrh ea, w h ich is likely

case, asth m a w as m ild an d in term it ten t , so on e cou ld m ake

related to th e blockade of β 2 receptors in th e gut an d do n ot

a case for cau t iou sly adm in istering a β-blocker. A select ive

cau se gast roesoph ageal re u x. Even if con stipation can occur

antagonist such as atenolol w as a rational choice, as blockade

w ith som e β-blockers, it is un com m on an d n ever severe.

of β 2 receptors is n egligible at th erap eu t ic doses. How ever, cau t ion m u st be u sed, becau se at h igh er doses select ivit y

Learning objective: Describe the main adverse e ects of β-blocker/ diuretic com bination.

m ay be lost .

19. B Bet a-blockers can cau se dose-related sexu al dysfu n ct ion ,

pu lm on ar y vasocon st rict ion , bu t th is is n ot th e reason for

A By decreasing ren in secret ion , β-blockers can coun teract

w h ich is m ore frequen t w h en diuret ics are given con com i-

th e ch oice of select ive agen t s in asth m at ics.

tan tly, as in th is case. Th e dysfun ction in cludes erectile prob-

C, D Aten olol does n ot h ave th ese e ect s.

lem s, decreased libido, an d an orgasm ia. Th e m ech an ism

E Aten olol h as a h alf-life of abou t 6 h ou rs, bu t t h is is

u n derlying th ese e ects is st ill un cer tain but probably re-

n ot th e reason for t h e ch oice of th e d r ug in an ast h m at ic

lated to th e hyp oten sive e ect an d to cen t ral e ect s.

pat ien t .

A, C−E All of th ese disorders are gen erally relieved, n ot cau sed, by β-blockers.

Learning objective: Explain the mechanism of action of α 1 -blockers in the treatment of impaired bladder empt ying.

Learning objective: Explain why β-blockers are relatively contraindicated in a diabetic patient.

22. B Th e p at ien t m ost likely received a select ive α 1 an tagon ist .

20. B Historically, th e presen ce of diabetes w as a con t rain dica-

for th e t reat m en t of im paired bladder em pt ying in prost at ic

t ion for β-blockade, du e to th e adverse e ect s on in su lin re-

hyp erplasia. By blocking α 1 receptors, th ey relax th e prost ate

lease an d blu n t ing of hypoglycem ia-associated tachycard ia.

capsule an d th e in tern al sph in cter of th e bladder, w h ich h ave

How ever, diabet ics com prise a large p or t ion of in farct pa-

plen t ifu l α 1 receptors, allow ing a bet ter u rin e ow.

t ien t s, an d m any st u d ies h ave fou n d th at pat ien ts t reated w ith β-blockers follow ing m yocardial in farct ion experien ce a 30 to 35%redu ct ion in m ort alit y. Th erefore, β-blockers can be given to diabet ic p at ien t s, bu t th ey m u st carefu lly con t rol

Th ese d rugs (p razosin , t am su losin , etc.) are rst-lin e agen ts

A By blocking vascular α 1 receptors, α 1 an tagon ist s w ould in crease, n ot d ecrease, blood ow. C Th e det rusor m uscle is m ain ly un d er th e con t rol of th e parasym p ath et ic system .

th eir sugar levels. In fact , hyp oglycem ia-associated tachycar-

D Alph a-1 an tagon ists decrease blood pressure, but th is

d ia can be blun ted by β-blockers, depriving th e pat ien t of an

is n ot t h e reason for t h eir t h erap eu t ic e ect in p rost at ic

im port an t diagn ost ic sign .

hyp erplasia. E Alph a-1 an tagon ists h ave n egligible e ects on diuresis.

Answers and Explanations: II-3 Antiadrenergic Drugs 65 Learning objective: Describe the therapeutic uses of propranolol. 23. E Th e p at ien t w as m ost likely su ering from ben ign essen t ial

A Act ivat ion of β 2 receptors by albuterol w ould w orsen th e varices by in creasing th e por tal pressu re.

t rem or, a disord er th at is often in h erited (au tosom al dom i-

C−E Methyldopa, clon idin e, an d p razosin can red u ce th e

n an t in 50% of cases), as in th is case. Propran olol (an d oth er

system ic blood p ressu re, bu t th ey h ave u np red ict able e ect s

n on select ive β-blockers) is e ect ive in t reat ing th e disorder.

on th e perfusion pressu re of liver arterial vessels.

Th e m ech an ism of th is th erapeu t ic e ect is st ill u n cert ain , in crease in sequ est rat ion of cytosolic Ca 2+ an d en h an ced dis-

Learning objective: Describe the therapeutic use of propranolol in hyperthyroidism.

ch arge of m uscle spin dles.

26. B Th e sym ptom s an d sign s of th is pat ien t in d icate th at th e

bu t it seem s related to blockad e of th e β 2 receptor−m ediated

A−D Non e of th ese drugs are of value for th e t reat m en t of essen t ial t rem or.

w om an w as m ost likely su ering from hyperthyroidism . In addit ion to th e sp eci c th erapy (an t ithyroid drugs an d rad ioiod in e), th e t reat m en t of th is disease alm ost alw ays in -

Learning objective: Describe the therapeutic uses of α- and β-blockers in amphetam ine poisoning.

cludes th e adm in ist rat ion of β-blockers th at rapidly decrease

24. A Th e p at ien t ’s h istor y an d sym ptom s p oin t ou t t h at h e

hyp er ten sion , m ost likely becau se m any of th ese sign s an d

w as m ost likely su ering from am phetam ine poisoning. Most

sym ptom s are du e to sym path et ic overact ivit y. Propran olol

sym ptom s, in clu ding hyp er ten sion , can be m an aged w ith

is th e drug of ch oice.

th e n er vou sn ess, palp it at ion s, h eat in toleran ce, t rem ors, an d

gen erou s t it rat ion of ben zod iazepin es. If sedat ion fails to re-

A, C−E All of th ese d r ugs are con t rain d icated in hyp er-

d uce blood pressure, a cardiovascular t reat m en t is n eeded,

t hyroidism , as th ey can fu r th er decrease th e diastolic blood

as in th is case. Am p h etam in es st im u late n orepin eph rin e re-

p ressure, w h ich is abn orm ally low in th is disease.

lease from adren ergic term in als, in creasing n orepin eph rin e availabilit y in th e syn apt ic cleft . Th erefore, both α - an d β

Learning objective: Describe the therapeutic uses of β-blockers.

blockers can be u sed to e ect ively cou n teract n orep in ep h -

27. B Bet a-blockers are e ect ive in t reat ing n ongen eralized so-

r in e-in d u ced act ivat ion of α an d β receptors. Paren teral

cial p h obias involvin g p er for m an ce-related sit u at ion s, al-

α -blockers, su ch as p h en tolam in e (or vasod ilators, e.g., n i-

t h ough t h ey are n ot ap p roved by t h e U.S. Food an d Dr ug

t rop ru sside an d n it roglycerin ), m u st be given

rst . W h en

Adm in ist rat ion for th is pu rp ose. Th ey are often u sed by m u-

th e blood p ressu re is back to n orm al lim its, a β-blocker is

sician s an d h ave been called “th e m u sician s’ u n dergrou n d

u su ally adm in istered to con t rol tachyarrhyth m ias th at are

d rug.” Th e an t ian xiet y e ect of β-blockers in sit u at ion al

frequ en t w h en circu lat ing levels of catech olam in es are h igh .

an xiet y seem s to be related to th eir blocking of n orep in ep h -

B Th is drug com bin at ion could an t agon ize n orepin eph rin e

rin e e ects, th u s redu cing p hysical sym ptom s of an xiet y

e ect s, bu t p h en oxyben zam in e is an irreversible an t agon ist

(p alpit at ion , t rem or, an d blu sh ing). In fact , even β-blockers

w ith a ver y long durat ion of act ion an d is n ot available for

th at do n ot cross th e blood−brain barrier are e ect ive in per-

p aren teral use. It is th erefore n ot suit able for an em ergen cy

form an ce an xiet y.

t reat m en t . C−E Th ese d r ugs can n ot an t agon ize n orep in ep h r in e e ect s.

A Ben zod iazep in es su ch as d iazep am are e ect ive an t ian xiet y agen t s bu t are n ot in dicated in th is sit u at ion , as th ey can h ave depressive e ect s on th e cen t ral n er vou s system th at cou ld n egat ively a ect th e perform an ce.

Learning objective: Describe the therapeutic uses of β-blockers in esophageal varices.

tin e) and serotonin -n orepinephrine reuptake inh ibitors (e.g.,

25. B Th e creat ion of arterioven ous an astom oses, w h ich occu rs

ven la axin e) are curren tly

C, D Select ive seroton in reupt ake in h ibitors (e.g., uoxerst-lin e agen t s for an xiet y dis-

in cirrh osis, allow s th e perfusion pressu re of th e h epat ic ar-

orders, but th ey are n ot in dicated in th is sit uat ion , as e ect s

ter y to be partly t ran sm it ted in to th e por t al vein . Th erefore,

occur gradu ally over several days.

arterioven ou s an astom oses are a prim ar y cau se of p or tal hyp er ten sion in cirrh osis. Becau se th e esop h ageal vein s are t ribu taries of th e p ort al vein , port al hyp er ten sion cau ses th e esoph ageal vein s to dilate an d becom e varicose. By blocking β 2 receptors (particularly abundant in the liver vascular bed), liver ar terial vessels are con st ricted, an d th e pressu re t ran sm it ted in to th e port al vein decreases.

E Buspiron e is an e ect ive an xiolyt ic agen t , but its in it ial e ect s are obser ved after 7 to 10 days of th erapy.


66

Learning objective: Describe the main adverse e ects of prazosin. 28. E Post u ral hyp oten sion is a com m on adverse e ect of α 1

Learning objective: Explain the m echanism of action of m et yrosine.

an t agon ist s su ch as prazosin , esp ecially du ring th e rst days

30. C Met yrosin e in h ibit s th e en zym e t yrosin e hydroxylase,

of th erapy. Th e e ect is due to an im pairm en t of barorecep -

w h ich cat alyzes th e hydroxylat ion of t yrosin e to dopa. Th is

tor re ex, as th e α 1 blockade h in ders th e vasocon st rict ion

is th e rate-lim it ing step in catech olam in e biosyn th esis, an d

th at n orm ally occu rs w h en th e body assu m es a stan ding

th e in h ibit ion of th e en zym e can cau se u p to a 70% decrease

posit ion .

of catech olam in e con ten t in adren ergic term in als. Th e on ly

A Blockade of α 1 receptors in th e radial m u scle of th e iris w ou ld cau se m iosis, n ot m ydriasis. B Mict urit ion is facilitated, n ot im paired, w h en an α 1 blocker is adm in istered to a m an w ith prostatic hyperplasia. C Th e blockade of α 1 receptors in skin vessels w ou ld cau se

th erap eu t ic u se of th is drug is for th e sh ort-term m an agem en t of p at ien t s w ith p h eoch rom ocytom a w h o are aw ait ing su rger y or for long-term m an agem en t of m align an t ph eoch rom ocytom a w h en surger y is con t rain dicated. A, B, D, E See correct an sw er exp lan at ion .

red an d h ot , n ot pale and cold, skin . D Bron ch ocon st rict ion is caused by blockade of β 2 , n ot α 1 ,

ANTIADRENERGIC DRUGS Answ er key

receptors.

Learning objective: Explain the m olecular m echanism of action of timolol. 29. D Tim olol is a n on select ive β-receptor blocker. Act ivat ion of all β receptors in creases th e syn th esis of cyclic aden osin e m on op h osp h ate (cAMP) t h rough in creased act ivit y of t h e ad enylate cyclase en zym e. By blockin g t h ese receptors, all β-blockers d o t h e op p osite (i.e., t h e act ivit y of ad enylate

1. 2. 3. 4. 5.

E A G H B

6. 7. 8. 9. 10.

E A A B C

11. 12. 13. 14. 15.

D B A C B

16. 17. 18. 19. 20.

A C D B B

21. 22. 23. 24. 25.

B B E A B

26. 27. 28. 29. 30.

B B E D C

cyclase is decreased). A−C, E, F See correct an sw er explan at ion .

Answers and Explanations: II-4 Cholinergic Drugs Questions 1−5 1. E

Learning objective: Identify the sites of action of carbachol given locally in the conjunctival sac.

2. K

7. B Carbach ol is used in ocular surger y to decrease th e in t raoc-

3. H

u lar p ressu re by in creasing th e ou t ow of th e aqueou s h u m or.

4. J

Th e drug can act ivate both m u scarin ic an d n icot in ic n euron al

5. G

receptors located on th e body of auton om ic ganglia. How ever, w h en th e drug is given locally, it can reach th e ciliar y m u scle

Learning objective: Describe the m echanism of action of physostigm ine.

bu t can n ot reach th e ciliar y ganglion th at is located on th e

6. E To in crease ch olin ergic t ran sm ission in th e cen t ral n er vou s

drug given locally in th e conju n ct ival sac is th e ciliar y m u scle.

system , th e drug m u st act ivate (directly or in directly) cen t ral

Act ivat ion of m u scarin ic M 3 receptors leads to th e con t ract ion

acet ylch olin e receptors. Physost igm in e is an an t ich olin es-

of th e ciliar y m u scle, w h ich in t urn cau ses th e open ing of t ra-

terase drug th at is able to cross th e blood−brain barrier. Th e

becu lar m esh w ork, th u s in creasing th e ou t ow of th e aqu e-

in creased acet ylch olin e availabilit y in th e cen t ral n er vou s

ous h um or.

system accou n t s for th e in creased ch olin ergic t ran sm ission . A−D Th ese drugs do n ot a ect ch olin ergic t ran sm ission in th e cen t ral n er vous system because th ey ver y poorly cross th e blood−brain barrier.

posterior orbit . Th erefore, th e p rim ar y site of act ion of th e

C, D Th e len s an d th e radial m u scle of th e iris are devoid of Nn an d M 3 receptors. A, E See correct an sw er exp lan at ion .

Answers and Explanations: II-4 Cholinergic Drugs 67 Learning objective: Identify the drugs used in an acute glaucom a at tack. 8. A An acute glaucom a at tack is usually th e

Learning objective: Explain the m olecular m echanism of neostigmine-induced bradycardia.

rst sym ptom of

11. A By in h ibit ing ch olin esterase, n eost igm in e in creases acet yl-

acu te angle-closu re glau com a, a disease associated w ith a

ch olin e availabilit y in th e syn apt ic cleft of ch olin ergic bers.

closed an terior ch am ber angle. W h en th is occu rs, in t raocu -

Th is can in crease th e act ivit y of both sym path et ic an d p ara-

lar pressu re rises, because th e obst ru ct ion of th e perip h eral

sym path et ic ganglia su p plying th e h eart an d can act ivate

iris preven ts th e n orm al drain age of aqueous h um or from

m u scar in ic M 2 receptors, w h ich are t h e m ost abu n dan t

th e eye. An acu te glau com a at t ack is a m edical em ergen cy

acet ylch olin e receptors in t h e sin oat r ial (SA), at r iu m , an d

because vision can be lost quickly. Aqu eou s h u m or p rod u c-

at r ioven t ricular (AV) n odes. Th is act ivat ion in t urn open s

t ion m u st be decreased. Th erefore, a top ical β-blocker (e.g.,

acet ylch olin e-sen sit ive K+ ch an n els, in creasing th e hyper-

t im olol) an d an α 2 agon ist (e.g., ap raclon id in e) are im m e-

polarizat ion of SA an d AV cardiac bers. Th e n al resu lt is a

d iately adm in istered. Th en pilocarpin e is given to in crease

n egat ive ch ron ot ropic an d drom ot ropic e ect .

aqu eou s h u m or ou t ow (ch olin ergic drugs alon e are gen er-


ally in e ect ive w h en th e in t raocu lar pressu re is m ore th an B−D Hom at rop in e an d scop olam in e are con t rain d icated

Learning objective: Describe the pharm acological e ects of pilocarpine on the eye.

in an gle-closu re glau com a becau se t h ey in d u ce m ydr iasis,

12. B Pilocarpin e is a m u scarin ic agon ist . Th e drug-in du ced ac-

40 m m Hg).

w h ich in creases th e risk of closing th e an terior ch am ber. E Prazosin is in e ect ive in glaucom a. Man n itol is n ot given

t ivat ion of M 3 receptors cau ses con t ract ion of th e sp h in cter m u scle of th e iris (decreasing p u p illar y diam eter) an d con -

topically, bu t in t raven ously, an d is u sed to low er th e in t ra-

t ract ion of th e ciliar y m u scle (in creasing len s cu r vat u re).

ocular pressu re on ly if th e respon se to th e rst t reat m en t is

Ocu lar p ressu re is decreased becau se th e con t ract ion of th e

in adequate.

ciliar y m u scle op en s th e p ores of th e t rabecu lar m esh w ork, facilitat ing th e out ow of aqueous h um or in to th e Sch lem m

Learning objective: Identify the receptors m ediating the neostigmine-induced increase in bowel movements.

can al. A, C−E See correct an sw er explan at ion .

9. B Neost igm in e is a reversible ch olin esterase in h ibitor som eileus or atony of th e urin ar y bladder. Th e drug in creases th e

Learning objective: Describe the pharm acological action of bethanechol.

availabilit y of acet ylch olin e at ch olin ergic term in als, w h ich

13. C Over ow in con t in en ce occu rs w h en th e w eigh t of u rin e in

in t urn act ivates both th e n icot in ic n euron al receptors on

a disten ded bladder overcom es ou tlet resist an ce. It resu lts

p arasym path et ic ganglia an d th e m uscarin ic M 3 receptors

from an an atom ical ou tlet obst ru ct ion or an aton ic bladd er,

on sm ooth m uscle.

as in th is case. Beth an ech ol is a ch olin ergic agon ist th at pri-

t im es u sed to in crease sm ooth m u scle act ivit y in adyn am ic

A, C−F See correct an sw er exp lan at ion .

m arily act ivates m u scarin ic M 3 receptors. Th is act ivat ion cau ses a con t ract ion of th e det ru sor m u scle of th e bladder;

Learning objective: Explain the mechanism of action of donepezil in Alzheim er disease.

t h erefore, t h e am ou n t of blad d er sp ace t h at can be

10. D Th e patient’s sym ptom s an d the results of th e Mini-Men tal

decreased

St at u s Exam in dicate th at h e w as m ost likely in th e early stages of Alzh eim er d isease (AD). To date, n o drugs are available th at can h alt or reverse th e p rogression of th e disease, bu t drugs are app roved for th e t reat m en t of m em or y de cit associated w ith AD. Acet ylch olin e is sign i can tly redu ced in AD, an d drugs th at can in crease it s levels in th e brain h ave sh ow n m oderate su ccess in slow ing th e p rogression of th e d isease. Don epezil select ively in h ibit s ch olin esterase in th e cen t ral n er vou s system w ith less e ect on ch olin esterase in p erip h eral t issu es. A−C, E, F See correct an sw er explan at ion .

lled

(i.e., t h e d isten sibilit y of t h e blad d er, or it s com p lian ce) is A, B, E Act ivat ion of M 3 receptors cau ses e ect s op posite to th ose described D Diu resis refers to th e produ ct ion of urin e by th e kidn ey. Beth an ech ol does n ot a ect diu resis.

68


Learning objective: Describe the pharm acological actions of nicotine.

Learning objective: Describe the poisoning by organophosphate insecticides.

14. C Th e h istor y of th e pat ien t , togeth er w ith h er sym ptom s

16. D Th e h istor y an d th e p at ien t’s sym ptom s an d sign s in dicate

an d sign s, is con sisten t w ith th e diagn osis of n icot in e poi-

t h at h e w as m ost likely su er in g from organ op h osp h ate

son ing, likely du e to lozenge tablet s u sed by h er h u sban d to

p oison ing. Serious poison ing from organ oph osph ate pest i-

qu it sm oking. Nicot in e causes a rapid act ivat ion of both th e

cides is rare today becau se of en forced occu p at ion al h ealth

sym p ath et ic an d p arasym p ath et ic n er vou s system s, as w ell

an d safet y stan dards, bu t m ild p oison ing is st ill su rp risingly

as st im u lat ion of di eren t areas of th e brain . Sign s in th is

com m on .

p at ien t du e to parasym path et ic act ivat ion are vom it ing, u rin ar y in con t in en ce, an d profu se salivat ion . Sign s of sym pa-

A, C, E Poison ing by th ese drugs does n ot cau se th e sym p tom s an d sign s sh ow n by th e pat ien t .

th et ic act ivat ion are cold sw eat (sw eat glan ds are st im u lated

B Sym ptom s of poison ing from carbam ates, w h ich are re-

an d skin vessels con st ricted) an d rapid an d irregu lar pu lse

versible ch olin esterase in h ibitors, are usually in dist inguish -

(act ivat ion of n icot in ic n euron al [Nn ] receptors releases epi-

able from th ose cau sed by organ op h osp h ates. How ever, in

n eph rin e from adren al m edulla). Cen t ral st im ulat ion ac-

case of p oison ing from reversible ch olin esterase in h ibitors,

counts for the m ental confusion and the tonic-clonic seizure.

p ralidoxim e is useless (an d can also be dangerous). Th e fact

A Clon idin e does n ot cause m ost of th e sym ptom s exh ib -

th at th e at ten ding p hysician adm in istered pralidoxim e in di-

ited by th e pat ien t . B Scop olam in e is u sed for t h e p reven t ion of m ot ion sick-

cates th at h e or sh e w as su re, from th e p at ien t’s in form at ion , th at an organ op h osp h ate w as th e cu lp rit drug.

n ess. Th e d r ug is a m u scar in ic an t agon ist; t h erefore, t h e sym ptom s of overdose w ou ld be th e opp osite of th ose exh ibited by th e pat ien t . D Beth an ech ol is a m uscarin ic agon ist . Sym ptom s of overd ose w ould be lim ited to parasym path et ic act ivat ion .

Learning objective: Describe the signs and symptom s of m uscarine poisoning. 17. A Th e p at ien t ’s sign s an d sym ptom s are con sisten t w it h t h e d iagn osis of m u scar in e p oison in g. High con cen t rat ion s

E Neost igm in e is a ch olin esterase in h ibitor. Many sym p -

of m u scar in e are p resen t in var iou s sp ecies of Inocybe an d

tom s of poison ing by ch olin esterase in h ibitors are sim ilar to

Clitocybe m u sh room s. Th e sym ptom s of m u scarin e in toxi-

th ose of n icot in e overdose (both d rugs can act ivate, directly

cat ion star t w ith in 1 h ou r after th e ingest ion an d are all at-

or in d irect ly, n icot in ic receptors). How ever, in t h e case of

t ribu table to act ivat ion of m u scarin ic receptors.

n eost igm in e p oison in g, cen t ral e ect s w ou ld be m in im al,

B Nicot in e poison ing results from th e act ivat ion , an d later

as th e am ou n t of drug crossing th e blood −brain barrier is

th e blockade, of n icot in ic n eu ron al (Nn ) an d n icot in ic m u s-

n egligible.

cu lar (Nm ) receptors. Act ivat ion of Nn receptors in ganglia an d ad ren al m edu lla cau ses in creased sym p ath et ic

ring

Learning objective: Describe the ocular actions of echothiophate.

an d in creased release of n orep in ep h rin e. Early sign s in clu de

15. F W h en con t rol of glau com a is n ot ach ieved w ith st an dard

cold sw eat , rapid an d irregular pulse, an d hyperten sion , fol-

p h ar m acot h erapy, an t ich olin esterase agen t s m ay be p re-

low ed by hyp oten sion an d collap se. Moreover, th e act ivat ion

scr ibed as a last top ical t h erapy opt ion . Ech ot h iop h ate is

of Nm receptors at th e m otor en d plate w ould cau se m uscle

an irreversible ch olin esterase in h ibitor. W h en given locally

p aralysis du e to d epolarizat ion blockade, w h ich is absen t in

in th e subconjun ct ival sac, it in creases th e availabilit y of ace-

th is p at ien t .

t ylch olin e at ch olin ergic syn apses. By act ivat ing m u scarin ic

C Poison ing by organ oph osph ates causes sym ptom s due

M 3 receptors, acet ylch olin e con t racts th e ciliar y m uscle,

to act ivat ion of m uscarin ic receptors; in addit ion , th ere are

w hich in t urn open s th e t rabecu lar m esh w ork an d Sch lem m

sym ptom s du e to act ivat ion of n icot in ic receptors (i.e., skele-

can al, in creasing th e out ow of aqueous h u m or. In th is w ay,

t al m u scle paralysis du e to dep olarizat ion blockade).

th e in t raocular pressure is decreased. Being an irreversible

D Som e m ush room species con tain at ropin e. Th e sym p -

in h ibitor, th e drug h as a long d urat ion of act ion th at a ords

tom s of at ropin e poison ing are due to blockade of m usca-

good con t rol of glau com a.

rin ic receptors an d are th e opp osite of th ose exh ibited by th e

A, C−E Acet ylch olin e does n ot cause th ese e ects.

p at ien t .

B By act ivat ing M 3 receptors, acet ylch olin e can con t ract

E Carbam ate in sect icid es are reversible ch olin esterase

th e sph in cter of th e iris, bu t th is act ion h as n egligible e ect s

in h ibitors. Sym ptom s of poison ing by th ese agen t s are th e

on th e in t raocular pressure.

sam e as th e sym ptom s of p oison ing by organ op h osph ates.

Answers and Explanations: II-4 Cholinergic Drugs 69 Learning objective: Describe the ocular adverse e ect s of pilocarpine. 18. A Pilocarpin e is a ch olin ergic agon ist th at act ivates on ly m u scarin ic M 1 , M 2 , an d M 3 receptors (act ivat ion of n icot in ic receptors is n egligible). Act ivat ion of M 3 receptors in t h e

B Edroph on iu m is n ot in dicated becau se it h as a ver y sh or t du rat ion of act ion (its h alf-life is 1 to 10 m in u tes). D, E Beth an ech ol an d pralidoxim e do n ot act at Nm receptors.

ciliar y m u scle cau ses cyclosp asm , w h ich in t u rn in creases

Learning objective: Describe the therapeutic uses of bethanechol.

th e len s cur vat ure. Th e eye is accom m odated for n ear vision ,

21. D Th e fact th at beth an ech ol w as able to im p rove th e p a-

an d far vision becom es di cult . Act ivat ion of M 3 receptors

t ien t’s sym ptom s p oin t s ou t th at h e su ered from over ow

in th e sph in cter m u scle of th e iris causes m iosis, w h ich im -

in con t in en ce du e to an acon t ract ile bladder. Neu rogen ic

pairs vision in p oor ligh t .

atony of th e bladder is com m on in diabet ic n eu rop athy an d

B, C Tim olol an d ap raclon id in e d ecrease t h e prod u ct ion

w as m ost likely th e cau se of th e p at ien t’s disorder. By act i-

of aqu eou s h u m or bu t h ave a n egligible e ect on accom m o -

vating m uscarinic M 3 receptors, bethan ech ol causes increased

dat ion .

det ru sor m uscle con tract ilit y, w h ich can facilit ate voiding of

D, E Epin eph rin e an d ph enyleph rin e act ivate α 1 receptors in th e radial m uscle of th e iris. Th is w ould cause m ydriasis, w h ich w ould favor, n ot im pair, vision in poor ligh t .

th e bladder. A Prostat ic hyperplasia can cause over ow in con t in en ce du e to ureth ral st rict u re, bu t beth an ech ol is con t rain d icated

F Neost igm in e is a ch olin esterase in h ibitor th at could h ave

in any case of over ow in con t in en ce du e to u reth ral obstruc-

cau sed e ects sim ilar to th ose of p ilocarp in e. How ever, it

tion, as the in creased detrusor con tractilit y can not overcom e

h as been ap p roved on ly for t h e t reat m en t of m yast h en ia

the obstruction, thus causing painful bladder spasm s.

gravis an d som e gast roin test in al an d u rologic problem s. It is n ot used to t reat glaucom a.

B Diuresis refers to th e p rodu ct ion of u rin e by th e kidn ey. A drug act ing on th e bladder h as n oth ing to do w ith urin e product ion .

Learning objective: Describe the m ain adverse e ect s of neostigm ine.

con dit ion s, as th e act ivit y of th e det ru sor m u scle is already

19. D Neost igm in e is a ch olin esterase in h ibitor an d th erefore

in creased.

C, E Beth an ech ol is con t rain dicated, n ot in dicated, in th ese

in creases th e availabilit y of acet ylch olin e at all ch olin ergic syn apses, elicit ing m u scarin ic e ects, m ain ly in th e gast roin test in al t ract . A−C, E By in creasing acet ylch olin e availabilit y, n eost igm in e cau ses e ect s opp osite to th ose listed.

Learning objective: Describe the use of edrophonium to diagnose a cholinergic crisis. 22. B Myasth en ic pat ien ts u n der t reat m en t w ith ch olin esterase in h ibitors m ay exh ibit decreased m u scle st rength becau se of an excessive con cen t rat ion of acet ylch olin e th at cau ses de-

Learning objective: Describe the therapeutic uses of neostigm ine.

p olarizat ion blockade of th e m otor en d plate. Th is is referred

20. C Reversible ch olin esterase in h ibitors su ch as n eost igm in e

creased m u scle st rength becau se of a su dd en exacerbat ion

can reverse th e paralysis in du ced by n on dep olarizing n eu ro-

of th e disease. Th is is called a m yasth en ic crisis. Edroph o-

m u scu lar blocking drugs su ch as t u bocu rarin e. Tu bocu rarin e

n ium can be used to dist ingu ish bet w een th e t w o syn -

blocks n icot in ic m u scu lar (Nm ) receptors at th e m otor en d

d rom es. In fact , in cases of ch olin ergic crisis, edroph on iu m

p late, w h ereas acet ylch olin e act ivates th ese receptors. Th e

adm in ist rat ion w ill produ ce n o relief or w orsen th e syn -

t w o drugs com pet it ively an t agon ize each oth er, an d th e in -

d rom e. (a decrease in m uscle st rength ), w h ereas in cases of

creased availabilit y of acet ylch olin e brough t abou t by ch o-

m yasth en ic crisis, th e drug w ill im prove th e syn drom e (an

lin esterase in h ibitors can t h erefore reverse t h e m u scle

in crease in m u scle st ren gth ). Moreover, an ed rop h on iu m -

p aralysis in d u ced by t u bocu rar in e. Th is an t agon ism is ex-

in d u ced d ecrease of m u scle st rengt h is accom p an ied by

p loited clin ically, an d reversible ch olin esterase in h ibitors

fascicu lat ion s (br ief m u scle con t ract ion s before t h e p araly-

are often u sed to speed recover y from th e n eu rom u scu lar

sis), as acet ylch olin e brie y act ivates n icot in ic receptors,

blockade rem ain ing after com plet ion of su rger y. Neost ig-

w h ereas an in crease in m uscle st rength is n ot accom pan ied

m in e is th e p referred drug, as it does n ot en ter th e brain an d

by fascicu lat ion s.

is th erefore free of cen t ral adverse e ect s. A Physost igm in e is n ot in dicated because it can cross th e blood−brain barrier.

to as a ch olin ergic crisis. Th ese pat ien ts m ay also exh ibit de-


70


Learning objective: Describe the therapeutic uses of pilocarpine in glaucoma.

poten t ial, t h e d ep olar ized m em bran e is resist an t to fu r t h er

23. D Th e pat ien t w as m ost likely su ering from open -angle

larizat ion blockade). Im pairm en t of n eu ron al t ran sm ission

glau com a. Pilocarp in e h istorically w as th e in it ial t reat m en t

in sym path et ic ganglia decreases th e sym path et ic ton e, th u s

of ch oice, but today it is u sed on ly as an altern at ive th erapy

cau sing a decrease in blood pressu re.

w h en oth er drugs are con t rain dicated, as in th is case (see an sw er exp lan at ion s below ).

depolarizat ion , an d n euron al t ran sm ission is blocked (dep o-

B, C Blockade of ganglion ic M 2 an d M 1 receptors w ould preven t th e p rod u ct ion of in h ibitor y postsyn apt ic poten t ial

A Beta-blockers are rst-lin e th erapy for glaucom a bu t are

an d early slow excit ator y p ostsyn apt ic p oten t ial. Th ese po-

con t rain dicated in th is case because of th e AV block. In fact ,

ten t ials are n ot involved in th e product ion of th e act ion

system ic e ect s can occu r even after a top ical ad m in ist ra-

poten t ial.

t ion , especially in th e elderly, secon dar y to in adverten t overd ose du e to poor adm in ist rat ion tech n iqu e. In pat ien ts w ith

D, E Nicot in e does n ot preven t acet ylch olin e or catech olam in e release.

com plete AV block, th e h ear t rate is m ain t ain ed by a rhyth m th at is d riven by a ven t ricu lar p acem aker an d is abou t 50

Learning objective: Describe the therapeutic uses of pilocarpine.

bp m . By blocking β receptors in th e ven t ricle, a β-blocker

26. E Sjögren syn drom e is a di use con n ect ive t issue disease

can redu ce th is barely su

cien t h ear t rate, cau sing h ear t

in w h ich lym p h ocytes in lt rate m u cosal an d oth er t issu es.

failure. Pilocarpine is not dangerous because in a patient w ith

Lym ph ocyt ic in lt rat ion in salivar y glan ds cau ses glan d at -

a com p lete AV block, th e AV con du ct ion is, by de n it ion , al-

rop hy. Saliva dim in ish es, resu lt ing in ext rem e dr yn ess of th e

ready com pletely blocked, an d th e parasym path et ic con t rol

m ou th an d lip s. If glan d s are n ot severely at roph ied, p ilocar-

of th e ven t ricle is n egligible, due to lack of in n er vat ion .

p in e can be u sed to st im u late salivar y produ ct ion .

B, C, E Th ese drugs are n ot used for t reat ing glau com a.

A Acet ylch olin e is n ot used for system ic th erapy because of it s ver y sh or t durat ion of act ion .

Learning objective: Describe the therapeutic uses of physo stigm ine.

B−D Ph enyleph rin e, p razosin , an d don ep ezil h ave lit tle effect on salivar y product ion .

24. C Th e pat ien t’s sym ptom s, sign s, an d h istor y in dicate th at h e sh ade (At ropa belladonna), a plan t containing antim uscarinic

Learning objective: Describe the absolute contraindications of neostigmine.

alkaloids (m ain ly at ropin e an d scop olam in e). An t im u sca-

27. D Th e pat ien t’s sign s an d sym ptom s suggest th e diagn osis

rin ic syn drom e is du e to com p et it ive blockade of m u scarin ic

of adyn am ic ileus due to in t raperiton eal in fect ion (see th e

receptors all over th e body. Physost igm in e is an an t ich olin -

h igh -grade fever). Ileus m ean s paralysis of th e gut . W h en

esterase in h ibitor th at can cross th e blood−brain barrier, in -

th is p aralysis is du e on ly to a lack of au ton om ic n eu rot ran s-

creasing th e availabilit y of acet ylch olin e both in th e cen t ral

m ission (as in m ost cases of p ostoperat ive ileu s), a drug su ch

n er vou s system an d in th e periph er y. Alth ough th eoret ically

as n eost igm in e, w h ich in creases th e levels of acet ylch olin e,

a ch olin esterase in h ibitor w ou ld be th e ideal th erapy for an -

can h elp to restore th e m otor act ivit y of th e gu t . On th e oth er

t im u scarin ic p oison ing, physost igm in e can h ave dangerou s

h an d, w h en th e paralysis is due to obst ruct ion or in am m a-

cen t ral n er vous system e ects. Th erefore, it is used on ly in

t ion of th e gu t , ch olin ergic drugs are absolu tely con t rain di-

p at ien ts w ith dangerou s hyperth erm ia or severe t achycar-

cated, as an in crease in gu t m ot ilit y in th ese con dit ion s can

d ia, as in th is case.

exacerbate th e in am m at ion an d lead to perforat ion of th e

w as m ost likely p oison ed by black berries of deadly n igh t-

A Neost igm in e, a quatern ar y am m on ium com poun d, is a

in test in e.

ch olin esterase in h ibitor th at can n ot cross th e blood−brain

A−C, E All of t h ese t h erap eu t ic m easu res are in dicated ,

barrier an d th erefore is u n able to cou n teract th e cen t ral ef-

n ot con t rain dicated, in case of ileus due to in t raperiton eal

fect s of at ropin e an d scopolam in e.

in fect ion .

B, D−F Th ese drugs in teract w ith th e adren ergic system an d are th erefore u seless, or even dangerou s, in an t im u scarin ic p oison ing.

Learning objective: Describe the therapy of organophosphate poisoning. 28. F Th e p at ien t ’s sym ptom s an d sign s in d icate t h at h e w as

Learning objective: Explain the m echanism of hypotension that occurs after the hypertensive e ect induced by nicotine.

m ost likely p oison ed by an organ op h osp h ate in sect icid e.

25. A Prolonged act ivat ion of n icot in ic receptors causes a per-

m any cou n t ries, bu t th ey are st ill com m on ly u sed in u n der-

Th e u se of t h ese p est icid es is n ow ban n ed or rest r icted in

sisten t dep olarizat ion of th e postju n ct ion al cell m em bran e

d eveloped cou n t ries. Th e t w o

t h at p reven t s t h e ret u r n to t h e rest in g st ate. Becau se it is

son ing are at ropin e an d a ch olin esterase react ivator su ch as

t h e ch ange in th e rest ing p oten t ial th at t riggers th e act ion

p ralidoxim e. At ropin e is essen t ial to cou n teract m u scarin ic

rst-lin e agen ts for th is p oi-

Answers and Explanations: II-5 Anticholinergic Drugs 71 e ect s on th e cen t ral n er vou s system , as pralidoxim e does

th e a eren t st im u lat ion of th e vom it ing cen ter by sen sor y

n ot appreciably cross th e blood−brain barrier.

receptors presen t in th e tongue an d lu ngs.


A, C, D Nicot in e can act on th ese sites, bu t th ey are n ot in volved in th e m ech an ism of n ausea an d vom it ing.

Learning objective: Describe the pharm acological actions of nicotine.

E Nicot in e does n ot in terfere sign i can tly w ith vest ibular fu n ct ion .

29. C By activating n icotin ic neuronal receptors, n icotine increases th e release of epin eph rin e from ch rom a

n cells of th e adre-

CHOLINERGIC DRUGS Answ er key

n al m edulla, w h ich is th e on ly periph eral organ able to syn th esize epin eph rin e. A, B, D, E Nicot in e cau ses e ect s op p osite to th ose listed

Learning objective: Explain the m echanism of the em etic action of nicotine. 30. B Nicot in e can directly st im u late th e ch em oreceptor t rigger zone, and this seem s to be the m ain m echan ism of nicotineinduced nausea and vom iting. Additional m echanism s involve

1. 2. 3. 4. 5.

E K H J G

6. 7. 8. 9. 10.

E B A B D

11. 12. 13. 14. 15.

A B C C F

16. 17. 18. 19. 20.

D A A D C

21. 22. 23. 24. 25.

D B D C A

26. 27. 28. 29. 30.

E D F C B

Answers and Explanations: II-5 Anticholinergic Drugs Questions 1−5

hyp eract ivit y of th e gu t . Qu atern ar y am m on iu m an t im u sca-

1. F

rin ic drugs m ain ly block m u scarin ic receptors bu t also exh ibit

2. C

a signi cant blocking activit y on ganglionic Nn receptors. Both

3. B

the blockade of M 3 receptors in the gastrointestinal sm ooth

4. G

m uscle an d th e blockade of th e Nn receptors in th e ganglia of

5. E

th e m yen teric an d subm ucosal plexus likely con t ribute to th e relaxat ion of th e sm ooth m u scle.

Learning objective: Identify the receptors that m ediate the antiemetic action of scopolamine. 6. E Th e drug u sed by th e p at ien t w as m ost likely scop olam in e, th e on ly an t i−m ot ion sickn ess drug th at can be applied to th e


Learning objective: Explain the postreceptor m echanism m ediating the antidiarrheal e ect of atropine.

skin via a t ran sderm al patch . An t im uscarin ic drugs are used

8. B Th e h istor y an d sym ptom s of th e pat ien t in dicate th at sh e

in cer t ain vest ibu lar disorders, in clu ding m ot ion sickn ess an d

w as m ost likely su ering from t raveler’s diarrh ea, a gast ro-

Men iere d isease. Th eir m ain m ech an ism of act ion is m ost

en terit is th at is u su ally cau sed by bacteria en dem ic to local

likely related to blockade of m u scarin ic M 1 receptors located

w ater. At rop in e is st ill a com pon en t of m any over-th e-cou n ter

in th e vest ibu lar n u clei, in th e ch em oreceptor t rigger zon e,

an t idiarrh eal preparat ion s available out side th e Un ited States.

an d in th e solit ar y t ract n u cleu s. Th is blockad e d ecreases r-

Diarrh ea is m ediated, at least in par t , by an in creased act ivit y

ing from th ese region s to th e vom it ing cen ter, so n au sea an d

of th e parasym path et ic n er vous system . By act ivat ing M 3 re-

vom it ing are preven ted.

ceptors, acet ylch olin e in creases th e syn th esis of in ositol t ri-


ph osp h ate/diacylglycerol (IP3 /DAG), w h ich in t u rn in creases th e am ou n t of Ca 2+ available for m uscle con t ract ion . By block-

Learning objective: Explain the m olecular m echanism of action of antimuscarinic quaternary ammonium compounds. 7. C Glycopyrrolate is a qu atern ar y am m on iu m an t im u scarin ic drug. Drugs of th is t ype relax th e in test in al sm ooth m u scle an d are som et im es given to p at ien t s w it h ir r it able bow el syn drom e during periods of diarrh ea, in order to relieve th e

ing M 3 receptors in th e gu t , at ropin e p reven ts th is in crease an d th us relieves th e diarrh ea. A, C, D At rop in e does n ot h ave th ese e ects. E At ropin e can block presyn apt ic M 2 receptors, bu t th is act ion w ou ld in crease th e release of acet ylch olin e, w h ich w ou ld w orsen , n ot relieve, th e diarrh ea.

72


Learning objective: Explain the postreceptor m echanism that m ediates atropine-induced increase in heart rate.

Learning objective: Explain why ipratropium and tiotropium are the only antimuscarinic drugs used to treat bronchospastic disorders.

9. B By act ivat in g M 2 receptors, acet ylch olin e op en s K+ ch an -

11. D In th e p ast , an t im u scarin ic d rugs w ere u sed to t reat bron -

n els in t h e sin oat r ial (SA) n od e. Th is in creases t h e ou t w ard

ch ospast ic disorder. How ever, it w as realized th at m ost an t i-

K+ cu r ren t , an d t h e m em bran e becom es hyp er p olar ized .

m u scarin ic d rugs redu ce th e volu m e of bron ch ial secret ion s,

Th e resu lt is a d ecrease in

r in g rate of t h e SA n od e. By

w h ich th en becom e th ick. Th is viscous m aterial is di cult

blockin g M 2 re ceptors, an t im u scar in ic d r ugs cou n teract t h e

to rem ove from th e respirator y t ree an d can dangerously ob -

acet ylch olin e- in du ced op en ing of K+ ch an n els in th e SA

st ru ct air ow. Moreover, th e redu ced bron ch ial secret ion s in

n ode. Th e ring rate of th e SA n ode is in creased, causing an

t u rn decrease m u cociliar y clearan ce, an im port an t fu n ct ion

in crease in h eart rate.

for th e clean ing of th e bron ch ial t ree. Th erefore, th ese drugs

A Acet ylch olin e-in duced release of nit ric oxide causes va-

(except iprat ropium an d t iot ropium ) h ave becom e con t ra-

sodilat ion , w h ich cou ld lead to re ex tachycard ia. By cou n -

in dicated in respirator y disord ers. Ip rat ropiu m , for u n kn ow n

teract ing th is act ion , an t im uscarin ic drugs w ould decrease,

reason s, h as n egligible e ect s on bron ch ial secret ion s an d

n ot in crease, th e h ear t rate.

m u cociliar y clearan ce. Th u s, its an t ich olin ergic p rop er t ies

C An t im u scar in ic d r ugs can cou n teract acet ylch olin ein du ced decrease in cardiac con t ract ilit y, but th is h as n oth ing to do w ith th e in crease in h eart rate. D Acet ylch olin e-in duced open ing of Na + ch an n els in gan glion ic n eu ron s is m ediated by th e act ivat ion of Nn recep tors. An t im uscarin ic drugs h ave w eak or n egligible blocking act ivit y on th ese receptors. E Th e blockad e of p resyn apt ic au toreceptors in creases t h e release of acet ylch olin e from ch olin ergic term in als. Th is w ou ld decrease, n ot in crease, th e h ear t rate.

can be safely exploited in th e t reat m en t of bron ch ospast ic d isease. A Poten cy, or th e inverse of th e dose n eeded to get a pred eterm in ed e ect , is alm ost n ever th e reason for th e ch oice of a speci c drug. B Th ese drugs are given only by the in halator y route, so oral bioavailabilit y is n ot an issu e. Moreover, th e oral bioavailabilit y is ver y low, as th ese drugs are qu atern ar y am m on iu m com poun ds an d th erefore can n ot cross lipid m em bran es. C By de n it ion , bioavailabilit y is th e fract ion of drug reach ing th e gen eral circu lat ion . W h en given by in h alator y

Learning objective: Explain the m echanism of atropine-induced hyperthermia.

route, th e fract ion of iprat ropium reach ing th e gen eral circu-

10. E At ropin e poison ing can occur from h on ey m ade from th e

E Cen t ral e ects of th ese drugs are n egligible (th e drugs

p ollen of plan ts from th e n igh tsh ade fam ily. Several cases

are poorly absorbed), bu t th is is n ot th e reason w hy th ese

h ave been reported in th e literat u re. By blocking M 3 recep -

d rugs are th e preferred an t im u scarin ic agen ts to t reat bron -

tors on sw eat glan ds, at ropin e can reduce sw eat ing en ough

lat ion is n egligible.

ch ospast ic disorders.

to raise th e body tem perat ure. Th is occurs prim arily in ch ildren , becau se t h ey are esp ecially su scept ible to th e toxic

Learning objective: Describe the ocular e ects of hom atropine.

e ects of an t im u scarin ic drugs.

12. E Hom at ropin e is an an t im uscarin ic drug th at blocks M 3 re-

A Toxic doses of an t im uscarin ic drugs cause skin vasodilat ion .

ceptors in th e sph in cter m uscle of th e iris an d in th e ciliar y m uscle. Th e relaxat ion of th e sph in cter m u scle of th e iris in -

B An t im u scarin ic drugs do n ot a ect prost aglan din syn -

creases p u p illar y diam eter, th u s facilit at ing th e eye fu n du s

t h esis. Moreover, blockad e of p rost aglan d in syn t h esis in

in spect ion . Th e relaxat ion of th e m u scle st retch es th e zon u la

t h e hyp oth alam u s h as an an t ipyret ic, n ot a fever-in du cing,

bers, w h ich in t u rn pull th e len s capsule an d decrease len s

e ect .

cu r vat u re. Th e rela xat ion of t h e ciliar y m u scle also ten d s

C Un coupling oxidative phosphorylation in skeletal m uscle

to close t h e sp aces of t h e t rabecu lar m esh w ork, d ecreasing

can cau se fever, bu t th is is n ot an act ion of an t im u scarin ic

aqu eou s h u m or ou t ow , w h ich in t u r n cau ses an in crease

drugs. Un cou p ling can be cau sed by h igh doses of cer t ain

in in t raocular pressure.

ch em icals, such as din it roph en ol an d salicylates. D Th e receptors involved in tem perat ure regulat ion by th e hyp oth alam ic th erm ost at ic cen ter are st ill u n kn ow n .


Answers and Explanations: II-5 Anticholinergic Drugs 73 Learning objective: Describe the ocular actions of antim uscarinic drugs.

Learning objective: Describe the e ect s of an overdose of atropine in children.

13. A An t im uscarin ic drugs relax th e ciliar y m uscle. Th is act ion

16. C An t im uscarin ic drugs are som et im e used to prepare th e

com p resses t h e t rabecu lar m esh w ork an d Sch lem m can al,

eye for m easu rem en t of refract ive errors. Even if at ropin e is

d ecreasing t h e ou t ow of aqu eou s h u m or. Th e

adm in istered topically, it can p ass in to th e n asolacrim al du ct

n al e ect

is in creased in t raocu lar pressu re. B Aqueou s h u m or produ ct ion is prim arily un der th e con t rol of th e sym p ath et ic n er vou s system . C Vessel ton e is prim arily un der th e con t rol of th e sym path et ic n er vous system . D Th e radial m uscle of th e iris is prim arily u n der th e con t rol of th e sym p ath et ic n er vou s system . E Episcleral aqueous h um or out ow is prim arily un der th e con t rol of prost aglan din s. F Th e t arsal is a palpebral sm ooth m u scle an d h as n oth ing

an d be absorbed from th e n asal m u cosa. Ch ildren are especially sen sit ive to th e e ect s of an t im u scarin ic dr ugs an d m ay exh ibit th e classic cen t ral an d cardiovascu lar sym ptom s of at ropin e overdose, as in th is case. A, B Ph enyleph rin e an d ep in ep h rin e can also be absorbed from th e n asal m u cosa an d cou ld t ran sien tly in crease th e h ear t rate, but th ey do n ot cause cen t ral e ect s, as th ey do n ot en ter th e brain . D, E Tim olol an d pilocarpin e w ou ld cause a decrease, n ot an in crease, in h ear t rate.

to do w ith th e con t rol of in t raocular pressure.

Learning objective: Describe the adverse e ects of atropine. Learning objective: Describe the pharm acological actions of darifenacin.

17. C At ropin e is st ill a com pon en t of m any over-th e-coun ter

14. E Th e pat ien t’s sym ptom s in dicate th at h e w as su ering

By blocking M 2 receptors in th e h ear t , at rop in e in creases

from u rge in con t in en ce, th e m ost com m on form of u rin ar y

at r ioven t r icu lar con d u ct ion . In a p at ien t w it h at r ial br illa-

in con t in en ce a ect ing th e elderly. Darifen acin is a select ive

t ion , t h is in crease can cau se t achycard ia (m ore im p u lses

M 3 an tagon ist . By blocking M 3 receptors, th e drug relaxes

origin at ing in the at rium can reach th e ven t ricle), w h ich in

th e sm ooth m u scle of th e bladder, so th e com p lian ce (i.e., a

t u rn st im u lates th e release of at rial n at riu ret ic pept ide. Th is

m easu re of th e ease w ith w h ich a h ollow in tern al organ m ay

explain s th e pat ien t’s urgen t n eed to urin ate. It is in terest ing

be disten ded) of th e bladder is in creased .

to n ote th at at ropin e w ill in crease th e urge to urin ate w h ile

A Decreased ton e of th e in tern al sph in cter of th e bladder is m ediated by blockade of α 1 adren oceptors. B Relaxat ion of th e prost ate capsule is m ediated by blockade of α 1 ad ren oceptors. C Con t ract ion of th e det rusor m uscle is m ediated by act ivat ion of M 3 receptors. D Diuresis is n ot un der th e con t rol of M 3 receptors.

antidiarrheal preparations available outside the United States.

in h ibit ing th e abilit y to d o so. Th e u rge to u rin ate is du e to th e in creased diu resis th at in t u rn in creases

lling of th e

bladder. Th e con sequ en t in creased ring from st retch recep tors ascen ds th e sp in al cord to th e p eriaqu edu ctal gray, w h ere it projects both to th e pon t in e m ict urit ion cen ter an d to th e cerebrum . At th e sam e t im e, th e an t ich olin ergic act ivit y of at rop in e ten d s to relax th e det ru sor, th u s in h ibit ing th e abilit y to u rin ate.

Learning objective: Describe the ocular actions of ipratropium .

A, B, D, E Non e of th ese dr ugs are u sed to relieve diarrh ea.

15. E Ip rat rop iu m is a qu ater n ar y am m on iu m an t im u scar in ic drug. By blocking M 3 receptors in th e ciliar y m uscle, it causes cycloplegia w ith loss of accom m odat ion for n ear vision .

Learning objective: Describe the symptom s and signs of scopolamine poisoning.

A System ic e ect s are u n likely w ith local adm in ist rat ion

18. C Th e p at ien t’s sign s an d sym ptom s in dicate h e w as m ost

of th e drug. Moreover, urge in con t in en ce is due to con t rac-

likely poison ed by scopolam in e, a drug frequ en tly u sed to

t ion of th e det ru sor m u scle. By blocking M 3 receptors, an t i-

“cut” h eroin . Epidem ics of poison ing caused by h eroin adu l-

m u scarin ic dr ugs w ou ld cau se relaxat ion , n ot con t ract ion , of

terated w ith scopolam in e h ave occurred in New York an d

th e det ru sor m u scle.

th e eastern Un ited St ates. Th e m ost frequ en t sym ptom s of

B, F Quatern ar y am m on ium an t im uscarinic drugs do n ot cross th e blood−brain barrier, so th ese e ects are un likely. C By blocking M 3 receptors, an t im u scarin ic drugs w ould cau se xerostom ia, n ot salivat ion . D System ic e ect s are un likely w ith a local adm in ist rat ion of th e drug. Moreover, by blocking M 2 receptors in th e h eart , an t im u scarin ic drugs w ou ld in crease AV con du ct ion , so AV block is un likely.

an t im u scarin ic p oison ing are tachycardia, m ild hyperten sion , dilated pu pils, dr y an d h ot skin , an d d im in ish ed or ab sen t bow el sou n ds. A, B, D, E See correct an sw er exp lan at ion .

74


Learning objective: Explain the m ain contraindication of antimuscarinic drugs.

• Th ere is a clin ical im pression th at th ey h ave a relat ively

19. B An t im uscarin ic drugs relax th e det ru sor m uscle, so void-

at t r ibu ted to t h e fact t h at t h ey can also block n icot in ic

ing of th e bladder becom es m ore di cult . Th is can be espe-

receptors in parasym path et ic ganglia of m yen teric an d

cially dangerou s in p at ien t s w ith prost at ic hyperp lasia w h o

su bm u cosal p lexu s.

greater e ect on gast roin test in al act ivit y. Th is h as been

already have di cult y in m icturition, due to prostate-induced

• Becau se t h eir oral bioavailabilit y is low , w h en given

n arrow ing of th e ureth ra. In th ese pat ien t s, an t im u scarin ic

orally, t h eir e ect s are m ain ly lim ited to t h e gast roin tes-

d rugs can precipitate acute urin ar y reten t ion .

t in al w all (w h ere th ey are, in it ially, m ore con cen t rated).

A Alp h a-1 an t agon ist s su ch as p razosin are act u ally in -

B Iprat rop ium is an an t im u scarin ic quatern ar y am m o-

d icated in prostat ic hyperplasia, as th ey relax th e in tern al

n ium com pou n d but is given on ly by th e in h alator y route for

sph in cter of th e bladder.

bron ch ospast ic disorders.

C Bet a-blockers ten d to con t ract th e sm ooth m u scle, as

A, C, E Sym path et ic agon ist s an d an t agon ist s h ave lit tle ef-

th ey block β 2 receptor−m ed iated relaxat ion . How ever, th ese

fect on th e gast roin test in al system an d are n ot used to t reat

drugs h ave lit tle in u en ce on n onvascu lar sm ooth m uscles,

diarrh ea.

w h ich are m ain ly un der parasym path et ic con t rol. D Alph a-2 agon ists act ivate α 2 receptors, w h ich are m ain ly

F Don epezil is a ch olin esterase in h ibitor an d th erefore w ou ld be con t rain dicated in th is case of diarrh ea.

presyn apt ic. Th is act ivat ion in t urn can decrease th e release of n orepin eph rin e, th ereby decreasing th e con t ract ilit y of

Learning objective: Describe the therapeutic uses of atropine.

th e in tern al sp h in cter of th e bladd er.

22. C At ropin e is som et im es used to preven t vagal re exes w h en

E Bet a-1 agon ists do n ot a ect th e con t ract ilit y of sm ooth m u scle.

su rger y is p erform ed n ear th e locat ion of th e vagu s n er ve, as in th is case. A Iprat ropiu m is an an t im uscarin ic drug, bu t it is used


on ly by in h alat ion for bron ch ospast ic disease.

20. E At rop in e is alw ays u sed to t reat p oison ing by ch olin ester-

B, D, E Dopam in e, isoproteren ol, an d epin eph rin e can in -

ase in h ibitors, becau se it is able to cou n teract both th e cen -

crease th e h eart rate, bu t at rop in e is m u ch m ore e ect ive

t ral an d perip h eral sym ptom s of acet ylch olin e excess.

w h en bradycardia is due to parasym path et ic act ivat ion .

A Pralidoxim e rapidly regenerates th e ph osphorylated acet ylch olin esterase an d th erefore is u sefu l for th e t reat m en t of


p oison ing du e to organ oph osp h ates (irreversible ch olin es-

23. D Asystole is th e com p lete elect rocardiograph ic absen ce of

terase inh ibitors). How ever, the drug is cont raindicated w h en

elect rical act ivit y. Its developm en t u su ally in dicates a p ro-

p oison ing is du e to reversible ch olin esterase in h ibitors, as in

longed cardiac arrest an d carries a ver y grave progn osis.

th is case. In fact , p ralidoxim e is n ot able to regen erate th e

In th e t reat m en t of asystole, epin eph rin e is th e in it ial

acet ylch olin esterase blocked by carbam ates; it also h as w eak

agen t of choice to generate a rhyth m . Because enhanced para-

an t ich olin esterase act ivit y.

sym path et ic ton e, possibly also du e to ch est com pression ,

B, C Sym path om im et ic dr ugs such as terbut alin e an d epi-

m ay p lay a role in in h ibit ing su p raven t ricu lar an d ven t ricu -

n eph rin e are useless in th e t reat m en t of poison ing by ch o-

lar p acem akers, an t ich olin ergic drugs m ay be ben e cial, an d

lin esterase in h ibitors.

at rop in e is u su ally t ried w h en ep in ep h rin e fails.

D Glycopyrrolate is a qu ater n ar y am m on iu m an t im u scarin ic d r ug. Th erefore, it w ou ld n ot be able to cou n teract th e cen t ral e ect s of acet ylch olin e excess becau se it does n ot cross th e blood−brain barrier ver y w ell.

A Neost igm in e in creases ch olin ergic act ivit y an d is th erefore absolutely con t rain dicated in th is set t ing. B, C W h en epin eph rin e does n ot w ork, th e ch oice of oth er sym path om im et ic drugs, su ch as n orep in ep h rin e an d dopam in e, is irrat ion al.

Learning objective: Describe the therapeutic uses of glycopyrrolate. 21. D An t im u scarin ic drugs are cu rren tly u sed to t reat diarrh ea from variou s cau ses, in clu ding d rug-in du ced diarrh ea, as in th is case. Qu atern ar y am m on iu m com pou n ds, su ch as glycopyrrolate, are som et im es preferred for t w o reason s:

E Iprat ropium is an an t ich olin ergic agen t bu t is used on ly by in h alat ion for bron ch ospast ic disorders.

Answers and Explanations: II-5 Anticholinergic Drugs 75 Learning objective: Describe the interactions bet ween m ecamylamine and other autonomic drugs.

ceptors, w hich in turn decreases the blood pressure. Atropine

24. C Norepin eph rin e in creases th e m ean blood pressu re. Th is

act ually can cause tachycardia an d th erefore can in crease,

in crease causes a st im ulat ion of aor t ic baroreceptors, w h ich

D Prazosin can cause re ex tachycardia by blocking α 1 re-

n ot coun teract , th e act ion of prazosin .

act ivates th e baroreceptor re ex. Th e in creased vagal dis-

E Glycopyr rolate in d u ces bron ch od ilat ion by blockin g

ch arge overcom es th e direct e ect of n orepin eph rin e on th e

M 3 an d Nn receptors. At ropin e can block M 3 receptors an d

h ear t rate (an in crease due to th e act ivat ion of β 1 receptors),

th erefore can in crease, n ot cou n teract , th e act ion of glyco-

so th e

n al e ect is a decrease in h eart rate. Ganglion ic

pyrrolate.

blockers su ch as m ecam ylam in e im p air th e baroreceptor reA Neost igm in e is a ch olin esterase in h ibitor th at in creases

Learning objective: Explain the m olecular m echanism of action of ipratropium on the eye.

th e availabilit y of acet ylch olin e at ever y ch olin ergic syn apse.

27. A Iprat ropiu m n asal sp ray is app roved by th e U.S. Food an d

Acet ylch olin e act ivates M 3 receptors in th e gut an d Nn re-

Drug Adm inistration for the m anagem ent of rhinorrhea from

ceptors in th e auton om ic ganglia. Both act ion s con t ribute to

variou s cau ses. W h en given by th is rou te, th e drug can cau se

th e in crease in in test in al perist alsis. A ganglion ic blocker can

an t im u scarin ic e ect s on th e eye. Th e blockad e of M 3 recep -

preven t th e act ivat ion of Nn receptors bu t h as n o e ect on

tors on th e sph in cter m uscle of th e iris causes m ydriasis,

th e act ivat ion of M 3 receptors. Th erefore, p eristalsis w ill be

w h ich in t urn can lead to ph otoph obia, w h ereas th e block-

decreased bu t n ot com p letely abolish ed.

ade of M 3 receptors in th e ciliar y m uscle causes cycloplegia,

ex, th ereby abolish ing bradycardia.

B Nicot in e-in du ced con t ract ion of skeletal m uscle is du e

w h ich in t urn leads to im pairm en t of n ear vision .

to act ivat ion of Nm receptors. Ganglion ic blockers h ave n eg-

B Iprat ropium blocks, n ot act ivates, M 3 receptors.

ligible act ivit y on th ese receptors.

C−F Iprat ropiu m h as n o e ect on adrenoceptors.

D Epin eph rin e-in du ced tachycardia is due to th e act ivat ion of cardiac β 1 an d β 2 receptors. A ganglion ic blocker can n ot block th ese receptors.

Learning objective: Describe the pharm acological action that contributes to atropine-induced increase in heart rate.

E Ganglionic blockers act ually cause hypotension by block-

28. D Bradycardia th at occu rs after a m yocardial in farct ion is

ing th e sym p ath et ic disch arge to th e vessels. Th erefore, th e

often du e to an AV block, w h ich often resu lt s from in creased

p rop ran olol-in du ced hyp oten sion is in fact en h an ced , n ot

p arasym p at h et ic ton e an d u su ally resp on d s to at rop in e.

preven ted.

Som et im es t h e block resolves sp on t an eou sly, bu t at rop in e is given w h en th e h ear t rate is too low for su

Learning objective: Describe the adverse e ect s of antim uscarinic drugs.

cien t cardiac

out put . A−C, E, F See correct an sw er explan at ion .

25. C By blocking M 2 receptors, an t im u scarin ic drugs d ecrease an d at rioven t ricular n odes. Th is can lead to an in creased

Learning objective: Explain the m olecular m echanism of action of glycopyrrolate given topically to manage hyperhidrosis.

h ear t rate th at in t urn can cau se a con scious aw aren ess of

29. E Glycopyrrolate is a quatern ar y an t im uscarin ic drug som e-

th e vagal con t rol to th e h eart , w h ich is m ain ly on sin oat rial

th e h ear t beat ing (i.e., palp itat ion s). A, B, D, E By blocking m u scarin ic receptors, at ropin e ten ds to cause e ect s opposite to th ose listed.

tim es used locally to coun teract excessive sw eating. The drug blocks M 3 receptors located in t h e sw eat glan d s, t h u s relieving hyperh idrosis. How ever, relief is in com plete at best , likely becau se ap ocrin e rath er th an exocrin e glan ds are u su -

Learning objective: Describe the interactions bet ween atropine and other autonom ic drugs.

ally involved in th e excessive sw eat ing, an d th e auton om ic

26. A Physost igm in e is a ch olin esterase in h ibitor, an d th erefore

ch olin ergic.

con t rol of apocrin e glan ds seem s adren ergic rath er th an

it can in crease th e availabilit y of acet ylch olin e at ch olin ergic

A, C, D Th ese receptors do n ot m ediate sw eat ing.

n euroe ector jun ct ion s. Act ivat ion of M 3 receptors in sw eat

B Glycopyrrolate can block Nn receptors in au ton om ic

glan ds p rom otes sw eat ing. By blocking M 3 receptors, at ro-

ganglia. Th is act ion can con t ribu te to th e

pin e can coun teract th is act ion .

lieving excessive sw eat ing w h en th e drug is given paren ter-

B Epin eph rine increase blood pressure by activating α 1 and β 1 receptors. Th ese receptors are n ot a ected by at rop in e. C Nicot in e can cau se skin vasocon st rict ion by act ivat ing Nn receptors in sym path et ic ganglia. At rop in e h as n egligible e ect s on Nn receptors.

n al e ect of re-

ally. How ever, w h en given locally, th e drug can reach th e sw eat glan ds located in th e derm is bu t n ot th e sym p ath et ic ganglia located on th e sp in al cord.

76


Learning objective: Describe the action of ganglionic blockers on heart rate. 30. C Ganglion ic blocking d r ugs block Nn receptors on bot h sym p at h et ic an d p arasym p at h et ic gan glia. Th erefore, t h e h ear t is n o longer u n d er au ton om ic con t rol an d goes back to it s in t rin sic rate, w h ich is approxim ately 100 bpm . A, B, D, E See correct an sw er exp lan at ion .

CHOLINERGIC DRUGS Answ er key 1. 2. 3. 4. 5.

F C B G E

6. 7. 8. 9. 10.

E C B B E

11. 12. 13. 14. 15.

D E A E E

16. 17. 18. 19. 20.

C C C B E

21. 22. 23. 24. 25.

D C D C C

26. 27. 28. 29. 30.

A A D E C

III Central Nervous System Questions: III-1 Introduction to Central Nervous System Pharm acology Di cult y level: Easy


1. A 3-year-old boy w as brough t to th e em ergen cy depar t m en t

4. A 51-year-old m an su ering from episodic leg cram ps st arted

after eat ing som e black berries from a plan t in th e w oods.

a t reat m en t w ith a drug th at act ivates GABAB receptors both

Physical exam in at ion sh ow ed a disorien ted an d h allu cin at ing

in th e brain an d in th e spin al cord. Th is act ivation m ost likely

pat ien t w ith dilated p u p ils, dr y m ou th , red an d dr y skin , an d

open ed w h ich of th e follow ing ion ch an n els?

body tem p erat u re of 103.4°F (39.7°C). Vit al sign s w ere blood

A. K+

pressu re 90/50 m m Hg, p u lse 122 bp m , resp irat ion s 24/m in .

B. Cl−

Th e cen t ral an d periph eral sym ptom s of th is pat ien t w ere

C. Ca 2+

m ost likely m ediated by th e blockade of w h ich of th e follow -

D. Mg ++

ing receptors?

E. Na +

A. Noradren ergic B. Nicot in ic


C. Mu scarin ic

5. A 54-year-old w om an su ering from in it ial in som n ia w as

D. Dopam in ergic

prescribed a hyp n ot ic drug th at in creases th e act ivit y of a

E. Seroton ergic

m ajor n eurot ran sm it ter system in th e brain . W h ich of th e fol-

F.

low ing n eu rot ran sm it ter system s w as m ost likely involved in

GABAergic

G. Glu t am atergic

Di cult y level: Hard 2. A 33-year-old m an w h o w as a h eavy sm oker star ted a m edi-

th e th erapeu t ic act ion of th at drug? A. Ch olin ergic B. Noradren ergic C. Glu t am atergic

cally assisted p rogram to qu it sm oking. Th erapy in clu ded th e

D. GABAergic

adm in ist rat ion of an agon ist at α 2 p resyn apt ic receptors th at

E. Dopam in ergic

act s m ain ly on n oradren ergic n eu ron s in th e brain . W h ich of

F.

En dorph in ergic

th e follow ing brain region s w as m ost likely involved in th e th erap eu t ic e ect of th e drug in th is p at ien t?


A. Nucleu s basalis of Meyn er t

6. A 54-year-old w om an w as adm it ted u n con scious to th e em er-

B. Cen t ral raph e n u cleus

gen cy depar t m en t after a car acciden t . After p hysical an d lab

C. Locu s ceru leu s

exam s, a diagn osis of brain inju r y w as m ade. It is kn ow n th at

D. Su bstan t ia n igra

in brain inju r y, a rap id an d large in crease of Ca 2+ in u x in to

E. Am ygdala

dam aged n eu ron s can con t ribu te sign i can tly to n eu ron al

F.

death (a p rocess called excitotoxicit y). Act ivat ion of w h ich of

Nucleu s t ract us solitarius

th e follow ing brain receptors m ost likely cau sed th is m eta-


bolic derangem en t in th e pat ien t?

3. A 46-year-old w om an com p lain ed to h er p hysician of day-

A. Presyn apt ic α 2 adren oceptors

t im e sleep in ess. On e day earlier, sh e h ad st arted taking an an t ih ist am in e for allergic rh in it is. Th e physician explain ed

B. Post syn apt ic α 2 adren oceptors C. Presyn apt ic NMDA receptors

th at drow sin ess w as m ost likely du e to in h ibit ion of th e act ion

D. Post syn apt ic NMDA receptors

of h istam in ergic n eu ron s in th e brain . W h ich of th e follow ing

E. Presyn apt ic GABA receptors

brain region s w as m ost likely involved in th e adverse e ect of

F.

Post syn apt ic GABA receptors

th is drug? A. Nucleu s t ract us solitarius B. Caudat um C. Hip p ocam pu s D. Nucleu s basalis of Meyn er t E. Am ygdala F.

Ven t ral posterior hypoth alam us 77

78

Central Nervous System


Drug

Norepinephrine

Acet ylcholine

GABA

Serotonin

7. A 35-year-old w om an w as adm it ted to a psych iat ric h ospital

P

+

0

+

+

for evaluat ion . Sh e repor ted episodic feelings of sadn ess

Q

−−

++

0

++

R

0

0

+++

+

S

+++

−

−

+++

T

0

+++

0

0

sin ce adolescen ce, bu t sh e h ad n ot iced a gradu al w orsen ing in h er m ood over th e past 3 w eeks. Sh e h ad depressed m ood m ost of th e day, h ad lost in terest in any leisure act ivit y, an d h ad di cu lt y sleeping, poor appet ite, low en ergy, feelings of guilt , an d recurren t th ough ts of death . W h ich of th e follow ing pairs of n eu rot ran sm it ters w ere m ost likely involved in th e p at ien t’s disord er?

+ = increased availabilit y − = decreased availabilit y 0 = negligible e ect Abbreviation: GABA, gam m a-am inobut yric acid.

A. Glut am ate an d seroton in

W h ich of th e follow ing drugs is likely to be m ost e ect ive in

B. Norep in ep h rin e an d glu tam ate

th e t reat m en t of Alzh eim er disease?

C. Glut am ate an d acet ylch olin e

A. Drug P

D. Seroton in an d acet ylch olin e

B. Drug Q

E. Seroton in an d n orep in ep h rin e

C. Drug R

F.

D. Drug S

Acet ylch olin e an d n orep in ep h rin e

E. Drug T

Di cult y level: Easy 8. A 63-year-old w om an recen tly diagn osed w ith gen eralized


an xiet y disorder started a t reat m en t w ith a drug th at in -

11. A 32-year-old w om an w as brough t to th e em ergen cy de-

creases seroton in availabilit y in th e syn apt ic cleft . W h ich of

p ar t m en t because of a gen eralized ton ic-clon ic seizu re. Her

th e follow ing en zym es is th e rate-lim it ing step in seroton in

h usban d st ated th at h is w ife h ad been su ering from epi-

biosyn th esis?

lepsy sin ce ch ildh ood, but th e seizu res w ere on ly p ar t ially

A. Tyrosin e hydroxylase

con t rolled by m ed icat ion . W h ich of t h e follow in g p airs of

B. Dopam in e-ß -hydroxylase

n eu rot ran sm it ters are t h ough t to be m ost involved in sei-

C. Tr yptoph an hyd roxylase

zu re disorders?

D. Ch olin e acet yl t ran sferase

A. GABA an d seroton in

E. L-am in o acid decarboxylase

B. GABA an d glut am ate C. GABA an d acet ylch olin e


D. Seroton in an d glu tam ate

9. A 26-year-old m an w ith a long h istor y of polydrug abuse stated th at h e felt an in ten se eu ph oric sen sat ion ever y t im e

E. Seroton in an d acet ylch olin e F.

Acet ylch olin e an d glu t am ate

h e self-adm in istered any illicit drug. W h ich of th e follow ing item s cor rect ly p airs t h e n eu rot ran sm it ter an d t h e cen t ral


n er vou s system site m ost likely involved in t h e rew ard in g

12. A 34-year-old fem ale pat ien t in a psych iat ric h ospital h ad

e ect of abu sed drugs?

been stan ding im m obile for several h ou rs w ith on e of h er

A. GABA−am ygdala

arm s stretched upw ard. The patient w as m ute, unresponsive,

B. Acet ylch olin e−n u cleu s basalis of Meyn er t

an d d id n ot ap p ear aw are of h er su rrou n dings. W h en p laced

C. Histam in e−n u cleu s accu m ben s

in an oth er aw kw ard p ost ure, th e pat ien t m ain t ain ed th at

D. Dopam in e−basal ganglia

p ost u re for a long t im e w ith ou t apparen t dist ress. W h ich of

E. Seroton in −rap h e n u clei

th e follow ing n eu rot ran sm it ters h as been con sisten tly im -

F.

p licated in th e pat ien t’s syn drom e?

Dopam in e−n u cleus accum ben s

G. Seroton in −am ygdala

A. Norep in ep h rin e B. Acet ylch olin e

Di cult y level: Easy 10. Th e ph arm acological act ivit y of

C. Histam in e ve n ew cen t ral n er vou s

system (CNS) drugs (P, Q, R, S, an d T) w as st u died in labora-

D. Dopam in e E. GABA

tor y an im als. All drugs w ere able to ch ange th e availabilit y of speci c CNS n eurot ran sm it ters in th e syn apt ic cleft . Th e


results are repor ted in th e t able below.

13. Th e p h ar m acological act ivit y of

ve n ew cen t ral n er vou s

system drugs (P, Q, R, S, an d T) w as st udied in laborator y

Questions: III-1 Introduction to Central Nervous System Pharm acology 79 an im als. All drugs w ere able to ch ange th e availabilit y of


speci c cen t ral n er vou s system n eu rot ran sm it ters in th e

16. A 32-year-old m an w h o h ad been injured in a car acciden t

syn apt ic cleft . Th e resu lt s are rep or ted in th e table below. Drug

1 m on th earlier presen ted to th e h ospit al for a follow -u p visit . Neurologic exam in at ion disclosed slow n ess of in ten -

Dopamine

Acetylcholine

GABA

Serotonin

P

+++

+++

0

−−−

Q

−−

++

0

+

ron s w as m ade. W h ich of th e follow ing n eu rot ran sm it ters

R

+++

−−

0

0

w as m ost likely involved in th e p at ien t’s syn drom e?

S

+

0

+++

+++

T

+

+++

+

−

+ = increased availabilit y − = decreased availabilit y 0 = negligible e ect Abbreviation: GABA, gam m a-am inobut yric acid.

W h ich of th e drugs w ould be m ost e ect ive in th e t reat m en t

t ion al m ovem en t s an d spast icit y. A diagn osis of u pper m otor n euron syn drom e due to dam age of pyram idal m otor n eu -

A. Norep in ep h rin e B. Glut am ate C. Acet ylch olin e D. Dopam in e E. GABA

of Parkin son disease?


A. Drug P

17. A 24-year-old w om an presen ted to a psych iat rist com plain -

B. Drug Q C. Drug R D. Drug S E. Drug T

Di cult y level: Easy 14. A 71-year-old m an recen tly diagn osed w ith Alzh eim er disease star ted a th erapy w ith a drug th at acts m ain ly on th e cen t ral ch olin ergic system . W h ich of t h e follow in g brain region s w as m ost likely involved in th e th erapeu t ic e ect of th e drug in th is p at ien t? A. Nucleu s basalis of Meyn er t B. Cen t ral rap h e n u cleu s C. Locus ceru leus D. Su bstan t ia n igra E. Am ygdala F.

Nucleu s t ract us solitarius

Di cult y level: Easy 15. A 41-year-old w om an w as adm it ted to th e psych iat ric h osp it al becau se of a 1-year h istor y of ap preh en sion an d w orr y. Sh e h ad been feeling ten se m ost of th e t im e, w as often irrit able, an d fou n d it h ard to con cen t rate becau se of h er con stan t dist ress. After p sych iat ric exam in at ion , a diagn osis of gen eralized an xiet y disorder w as m ade, an d a th erapy w as p rescribed th at in cluded a drug w ith p ron ou n ced an xiolyt ic act ivit y. W h ich of th e follow ing n europhysiological act ion s m ost likely m ediated th e th erap eu t ic e ect of th at drug? A. In creased seroton ergic t ran sm ission B. Decreased seroton ergic t ran sm ission C. In creased dopam in ergic t ran sm ission D. Decreased dopam in ergic t ran sm ission E. In creased glu tam atergic t ran sm ission F.

Decreased glu tam atergic t ran sm ission

ing of a dist ressing beh avior. For th e past several m on th s sh e experien ced an irresist ible urge to ch eck th at ever yth ing w as in a cert ain order at h om e an d fou n d it h ard to get ou t of the house because she needed, again and again, to verify that th e door w as locked. Sh e adm it ted h er u rge w as irrat ion al, bu t sh e w as u n able to con t rol it . After psych iat ric exam in at ion , a diagn osis w as m ade, an d a drug w as prescribed. W h ich of th e follow ing n eu rot ran sm it ters h as been m ost con sisten tly im plicated in th e pat ien t’s disorder? A. Acet ylch olin e B. Norep in ep h rin e C. GABA D. Seroton in E. Glut am ate F.

Histam in e

Di cult y level: Easy 18. A 44-year-old m an w as adm it ted un con scious to th e em ergen cy depar t m en t . Sh ortly after adm ission , h e h ad a ton icclon ic seizu re. Fu rth er exam s led to th e diagn osis of stat us ep ilept icu s, an d h e w as t reated w ith a drug th at in creased th e act ivit y of a cen t ral n eu rot ran sm it ter able to gen erate on ly in h ibitor y post syn apt ic poten t ials (IPSPs) by in creasing Cl– or K+ con duct an ce. W h ich of th e follow ing n eurot ran sm it ters w as m ost likely a ected by th e drug t reat m en t? A. Glut am ate B. Acet ylch olin e C. Norep in ep h rin e D. GABA E. Dopam in e


80



19. A 37-year-old m an recen tly diagn osed w ith par t ial seizu res


st ar ted a t reat m en t w it h a d r ug t h at is t h ough t to act by

m en t after a seriou s car acciden t . He began to exp erien ce

blockin g N-m et hyl- d -asp ar t ate (NMDA) receptors in t h e

severe pain th rough ou t h is body. W h ich of th e follow ing

brain . W h ich of t h e follow in g cen t ral system s w as m ost

t rip let s of n eu rot ran sm it ters m ost likely acted in th e cen t ral

likely a ected by th at drug?

n er vou s system to d ecrease p ain sign alin g in t h is pat ien t?

A. Noradren ergic

A. Norep in ep h rin e, GABA, glu tam ate

B. Ch olin ergic

B. Glut am ate, n orepin eph rin e, opioid pept ides

C. Histam in ergic

C. Histam in e, acet ylch olin e, GABA

D. Dopam in ergic

D. Histam in e, acet ylch olin e, opioid pept ides

E. Seroton ergic

E. Glut am ate, GABA, seroton in

F.

F.

GABAergic

Opioid pept ides, n orepin eph rin e, seroton in

G. Glu t am atergic

Questions: III-2 Sedative and Hypnotic Drugs Directions for questions 1−6


Match each sedat ive-hyp n ot ic drug w ith th e ap prop riate descrip -

6. An an xiolyt ic drug w ith n egligible abuse liabilit y

t ion (each let tered opt ion can be selected on ce, m ore th an on ce, or n ot at all). A. Alprazolam

Di cult y level: Medium 7. A 42-year-old m an recen tly diagn osed w ith gen eralized an xi-

B. Buspiron e

et y disorder h ad st ar ted a t reat m en t w ith ser t ralin e, but th e

C. Clon azepam

drug caused som e sexual dysfun ct ion , an d th e psych iatrist de-

D. Flum azen il

cided to sw itch to a short course of alprazolam . W hich of the

E. Flun it razepam

follow ing m olecu lar act ion s on n euron al m em bran es m ost

F.

likely m ed iated t h e t h erap eu t ic e ect of alp razolam in t h e

Lorazepam

G. Midazolam

p at ien t’s disorder?

H. Ph en obarbital

A. Decreased out w ard Na + cu rren t

I.

Th iopen tal

B. In creased inw ard Cl− cu rren t

J.

Zolpidem

C. Decreased out w ard K+ cu rren t D. In creased inw ard Ca 2+ cu rren t


E. In creased inw ard H cu rren t

1. A par t ial agon ist at seroton in (5-hydroxyt r ypt am in e, 5-HT) 5-HT1A receptors

Di cult y level: Medium 8. A 63-year-old w om an w as referred to a psych iat rist because


of easy fat igue, w orr y, irrit abilit y, an d d i cu lt y con cen t rat-

2. A com pet it ive an t agon ist at ben zodiazepin e receptors

ing. Th ese sym ptom s h ad been p resen t alm ost con t in u ou sly du ring th e dayt im e sin ce sh e ret ired from h er job as a sch ool-


teach er 1 m on th ago. Sh e told th e doctor th at th ose sym ptom s

3. A hypn ot ic dr ug w ith n egligible e ect s on sleep arch itect ure

w ere u n bearable an d t h at sh e w an ted to d ie. A p relim in ar y

an d stages

d iagn osis of severe gen eralized an xiet y d isord er w as m ad e, an d a t reat m en t w ith sert ralin e an d diazepam w as prescribed.

Di cult y level: Easy 4. Th e barbit u rate m ost frequ en t ly u sed to in d u ce gen eral an esth esia

W h ich of th e follow ing adverse e ect s w ere m ost likely to occur during th e rst days of th erapy? A. Excitem en t an d irritabilit y B. Men tal con fu sion an d an terograd e am n esia

Di cult y level: Easy 5. A ben zodiazepin e w ith a ver y sh or t h alf-life (about 2 h ours)

C. Excessive sedat ion an d drow sin ess D. Resp irator y d ep ression an d ap n ea E. Dist urbing dream s an d early aw aken ing

Questions: III-2 Sedative and Hypnotic Drugs 81 Di cult y level: Medium


9. A 36-year-old m an w as referred to a psych iat rist because of

12. A 63-year-old w om an com plain ed to h er physician of dif-

irrit abilit y, w orr ying th ough ts, palpit at ion s, dr y m outh , an d

cu lt y in falling asleep. Sh e den ied n oct u rn al in som n ia or

in som n ia of 1-m on th durat ion . Th e m an h ad a past h istor y

early aw aking. Th e doctor prescribed ram elteon , on e tablet

of alcoh ol abuse, but h e w as able to qu it 1 year ago after psy-

at bedt im e. W h ich of th e follow ing m olecular act ion s m ost

ch ological coun seling an d drug th erapy. Recen tly, h e su f-

likely m ediated th e th erap eut ic e ect of th e drug?

fered from erect ile dysfun ct ion , t reated w ith silden a l. A

A. Act ivat ion of GABAB receptors

p rovision al d iagn osis of gen eralized an xiet y disord er w as m ade, an d cogn it ive beh avioral th erapy w ith a drug t reat-

B. Blockade of α 1 receptors C. Act ivat ion of m elaton in receptors

m en t w as prescribed. W h ich of th e follow ing dr ugs w ou ld

D. Blockade of glut am ate receptors

be m ost ap prop riate for th is p at ien t?

E. Act ivat ion of seroton in 5-HT3 receptors

A. Diazepam B. Fluoxet in e


C. Lorazepam

13. A 58-year-old m an w as adm it ted to th e h ospit al for a laparo-

D. Haloperidol

scopic h ern ia rep air. Gen eral an esth esia w as in du ced by in -

E. Lith ium

t raven ou s diazep am , an d th e p at ien t lost con sciou sn ess in

F.

abou t 1 m in u te. He regain ed con sciou sn ess abou t 35 m in -

Bu spiron e

u tes later. Kn ow ing th at th e h alf-life of diazepam is about 40


h ours, w h ich of th e follow ing item s best explain s th e sh or t

10. A 75-year-old w om an w as un dergoing cystoscopy for a sus-

act ion of th e drug?

p ected p ap illom a of t h e blad d er. Before t h e p roced u re, t h e an est h esiologist ad m in istered alp razolam to in d u ce con -

A. Rap id m et abolism of t h e d r ug w it h in t h e cen t ral n ervous system

scious sedat ion an d to avoid sit uat ion al an xiet y. W h en th e

B. Rapid excret ion of th e drug by th e kidn eys

cystoscopy w as over, u m azen il w as adm in istered . W h ich of

C. Red ist ribut ion of th e drug from cen t ral n er vou s system

th e follow ing term s best de n es th e m ode of act ion of th is

to oth er t issues

d rug?

D. Biot ran sform at ion of th e drug in to in act ive m et abolites

A. Fu ll agon ist

E. Developm en t of a rapid toleran ce to drug e ect s

B. Fu n ct ion al an tagon ist C. Par t ial agon ist


D. Inverse agon ist

14. A 43-year-old m an su er ing from rect al bleed ing w as ad -

E. Com p et it ive an t agon ist

m it ted to t h e h osp it al for a colon oscopy. An in t raven ou s inject ion of diazepam w as given before th e procedure to in -


d uce a con scious sedat ion . W h ich of th e follow ing sym p -

11. A 44-year-old m an com plained to his physician of being tired,

tom s did th e pat ien t m ost likely experien ce u pon recover y

irrit able, an d ten se, w ith frequen t stom ach u pset an d diar-

from sedat ion ?

rh ea. Th e m an den ied past or presen t use of any illicit drugs

A. Nausea an d vom it ing

or alcoh ol. Past m edical h istor y of th e pat ien t w as sign i can t

B. In creased respirator y rate

for pept ic ulcer, presen tly t reated w ith om eprazole, an d for

C. An terograde am n esia

m yasth en ia gravis, presen tly t reated w ith n eost igm in e. After

D. Lim b m uscle spasm s

fu r th er clin ical assessm en t , a d iagn osis of gen eralized an xi-

E. Delusion al th ough t s

et y disorder w as m ade, an d an appropriate th erapy w as prescribed. W h ich of th e follow ing dr ugs w ou ld be relat ively con t rain dicated for th is pat ien t? A. Ven lafaxin e B. Bu spiron e C. Paroxet in e D. Diazepam E. Ser t ralin e

82



A. Zolp idem

15. A 34-year-old m an exh ibited severe agit at ion , fearfuln ess,

B. Tem azep am

an d app reh en sion u p on recover y from su rger y to rem ove a

C. Ram elteon

colon cancer. He w as given an intravenous injection of a drug

D. Ch lorprom azin e

that acts by m aking the resting m em brane potentials of short

E. Buspiron e

in tern euron s in several brain areas m ore n egat ive. W h ich of

F.

Ph en obarbital

th e follow ing drugs w as m ost likely adm in istered? A. Trazodon e B. Haloperidol

Di cult y level: Easy 19. A 78-year-old m an w as adm it ted to th e h ospital because of

C. Th iopen tal

a broken leg. His w ife rep orted th at h e w as w alking in th e

D. Alprazolam

din ing room w h en he suddenly lost his balan ce and fell dow n.

E. Bu spiron e

Th e m an h ad been su ering from at rial brillat ion , in som -

F.

n ia, hyper ten sion , an d an xiet y. Th e pat ien t’s m ed icat ion s on

Im ipram in e

adm ission w ere aten olol, w arfarin , diazep am , losart an , an d

Di cult y level: Easy 16. A 16-year-old girl brough t by am bulan ce to th e em ergen cy

hydroch loroth iazid e. W h ich of th ese drugs w as m ost likely to h ave con t ributed to th e pat ien t’s acciden t?

d epart m en t w as diagn osed w ith st at u s epilept icu s an d w as

A. Aten olol

given an in t raven ou s inject ion of a drug th at bin ds to th e α

B. Warfarin

su bu n it of th e GABAA receptor com plex. W h ich of th e fol-

C. Diazepam

low ing drugs w as m ost likely adm in istered? A. Lorazepam B. Zolpidem C. Flum azen il D. Ph enytoin E. Valproic acid

D. Losar t an E. Hydroch loroth iazide

Di cult y level: Easy 20. A 45-year-old m an h ad been su ering from a cen t ral n ervou s system disorder for m any years. Recen tly, a barbit u rate w as added to h is p h arm acoth erapy. W h ich of th e follow ing

Di cult y level: Medium 17. A 67-year-old w om an su ering from prim ar y in som n ia h ad

central nervous system e ects w as m ost likely elicited by th at d rug?

star ted t reat m en t w ith zolp idem , bu t th e drug w as w ith -

A. An t idepressan t

d raw n because sh e develop ed conjun ct ivit is, apparen tly du e

B. An t iparkin son

to a hypersen sit ivit y react ion to th e drug. Her physician pre-

C. An t ipsych ot ic

scribed beh avioral th erapy and a short course of tem azepam ,

D. An t iconvulsan t

one tablet at bedtim e. W hich of the follow ing was m ost likely

E. An algesic

an act ion of th e drug on th e p at ien t’s sleep arch itect u re? A. Decreased n um ber of rapid eye m ovem en t (REM) sleep cycles

Di cult y level: Medium 21. A 66-year-old m an w ho had been a heavy sm oker for 30 years

B. Decreased laten cy of sleep on set

w as u n d ergoing bron ch oscopy for su sp ected bron ch ogen ic

C. In creased du rat ion of slow -w ave sleep

carcin om a. Before star t ing th e in ter ven t ion , th e an esth esiol-

D. In creased du rat ion of st age 1 sleep

ogist adm in istered a drug to preven t sit u at ion al an xiet y an d

E. Decreased du rat ion of stage 2 sleep

to provide an terograde am n esia of th e procedu re. W h ich of th e follow ing drugs w ou ld be ap prop riate for th is pat ien t?


A. Buspiron e

18. An 82-year-old m an w as brough t to h is physician by h is son ,

B. Ch lorprom azin e

w h o repor ted th at h is fath er appeared oversedated, spen d-

C. Zolp idem

ing th e w h ole day dozing. Fur th er quest ion ing revealed th at

D. Oxazepam

t h e m an h ad for som e t im e been t akin g a “sleep in g p ill”

E. Haloperidol

given to h im by a frien d, bu t h e did n ot rem em ber th e n am e of th e drug. W h ich of th e follow ing drugs m ost likely caused


th e p at ien t’s disorder?

22. A 37-year-old m an w as brough t un con scious to th e em ergen cy dep ar t m en t . His room m ate stated th at th e m an h ad been ver y dep ressed for th e last few days an d th at h e h ad

Questions: III-2 Sedative and Hypnotic Drugs 83 been drin king w h iskey all day. Th e room m ate also said h e


fou n d an em pt y, un labeled drug bot tle n ext to h im on th e

26. A 34-year-old w om an visited a psych iat rist because of over-

bed . W h ich of th e follow ing drugs m ost likely con t ribu ted to

w h elm ing pan ic sym ptom s th at occurred “out of th e blu e.”

th e pat ien t’s in toxicat ion ?

Sh e felt ligh t -h ead ed , d izzy, an d feared losin g con t rol or

A. Buspiron e

going crazy. Sh e also felt n au sea, a lu m p in h er th roat , sh or t-

B. Diazepam

n ess of breath , an d palpitat ion s. Th ese sym ptom s lasted

C. Ven lafaxin e

abou t 30 m in u tes. Th e w om an h ad t w o of th ese at t acks th e

D. Fluoxet in e

p reviou s m on th . Tw o days ago sh e h ad st arted a t reat m en t

E. Lith ium

w ith sertraline prescribed by her fam ily physician, but yesterday sh e su ered anoth er at tack. After furth er clin ical assess-


m ent, a prelim inary diagnosis w as m ade, and the psychiatrist

23. A 61-year-old obese m an com plain ed of di cult y in falling

d ecided to p rescribe a drug in addit ion to ser t ralin e. W h ich

asleep an d asked h is p hysician for a sleep in g p ill. Th e m an

of th e follow ing w ould be an appropriate addit ion al drug for

h ad been recen t ly d iagn osed w it h obst r u ct ive sleep ap n ea,

th e p at ien t at th is t im e?

m ost likely d u e to obesit y. W h ich of t h e follow in g d r ugs

A. Aripiprazole

w ou ld be con t rain dicated for th is p at ien t?

B. Th iopen tal

A. Tem azep am

C. Buspiron e

B. Acetazolam ide

D. Alprazolam

C. Im ipram in e

E. Eszopiclon e

D. Medroxyp rogesteron e E. Prot ript ylin e

Di cult y level: Easy 27. A 56-year-old h om eless alcoh olic m an w as brough t to th e


em ergen cy depart m en t by police, w h o fou n d h im w an der-

24. A 26-year-old w om an , su ering from cerebral palsy an d sei-

ing in th e st reet . Th e m an w as n au seated, t rem u lou s, an d

zures secon dar y to h ead injur y, w as seen in a clin ic for a

h allucin at ing. He st ated h e w as out of m on ey an d un able to

sch ed u led visit . Sh e w as sp ast ic an d u n able to w alk. Medical

buy h is usu al daily am ou n t of w h iskey. W h ich of th e follow -

h istor y in dicated th at for th e m on th prior to th e visit , h er

ing w ould be an approp riate drug to t reat th e acu te alcoh ol

seizu res h ad n ot been w ell con t rolled . W h ich of th e follow -

w ith draw al of th is pat ien t?

ing drugs w ou ld be appropriate to im prove h er seizure con -

A. Nalt rexon e

t rol an d m u scle spasm s?

B. Im ipram in e

A. Bu spiron e

C. Haloperidol

B. Lith ium

D. Buspiron e

C. Don epezil

E. Eth an ol

D. Haloperidol

F.

Diazepam

E. Fluoxet in e F.

Diazepam

Di cult y level: Easy 28. A 57-year-old m an com plain ed to h is physician th at h e h ad


di cult y in falling asleep. He w as a schoolteacher and needed

25. A 32-year-old m an com plain ed to h is physician of at tacks of

a good n igh t’s sleep to perform e ect ively during th e day.

in ten se terror w h ile h e w as asleep, such as feeling cru sh ed.

Zolp idem w as p rescribed, on e tablet at bedt im e. Th e pre-

He often w oke u p scream ing bu t w ith ou t rem em bering any

scribed drug m ost likely caused w h ich of th e follow ing e ects

speci c dream . He also felt w orried an d restless from t im e to

on ion con ductan ce of cen t ral n er vous system n euron s?

t im e du ring th e day. W h ich of th e follow ing d rugs w ou ld be

A. Decreased Na + con duct an ce

m ost likely to provid e a sh or t-term decrease in th e p at ien t’s

B. In creased Cl− con du ct an ce

sym ptom s?

C. Decreased K+ con du ctan ce

A. Lith ium

D. Decreased Ca 2+ con du ctan ce

B. Tem azep am

E. In creased K+ con du ct an ce

C. Haloperidol D. Im ipram in e E. Ph en obarbital


84



29. A 49-year-old w om an com p lain ed to h er p hysician t h at sh e


cou ld get to sleep w h en sh e w en t to bed bu t w oke u p sev-

m en t after a car acciden t . He sh ow ed on ly m in or inju ries bu t

eral t im es du ring th e n igh t an d n ever felt refresh ed in th e

w as ver y an xiou s an d excited . Th e p at ien t h ad a h istor y of

m orn ing. Th e w om an h ad n o m edical p roblem s an d took n o

epilepsy and had been stabilized on phenobarbital for several

m edicat ion s. W h ich of th e follow ing drugs w ou ld be m ost

years. Th e at ten ding p hysician adm in istered a sedat ive d rug

app ropriate for th is p at ien t?

in t raven ously. Several m in u tes later th e pat ien t becam e cya-

A. Flun it razepam

n ot ic an d apn eic, an d h is blood pressure w as 100/55 m m Hg.

B. Bu spiron e

W h ich of th e follow ing drugs m ost likely caused th ese ad-

C. Eszopiclon e

verse e ects?

D. Fluoxet in e

A. Buspiron e

E. Haloperidol

B. Haloperidol

F.

C. Diazepam

Im ipram in e

D. Flu oxet in e E. Th iopen tal F.

Ch lorprom azin e

Questions: III-3 General Anesthetics Directions for questions 1−5


Match each gen eral an esth et ic w ith th e app ropriate descript ion

4. This inhaled anesthetic substantially reduces the required con-


cen t rat ion of oth er in h aled an esth et ics given con com it an tly.

at all). A. Haloth an e


B. Sevo u ran e

5. A drug th at can cause a cat alept ic st ate called dissociat ive

C. Nit rou s oxide

an esth esia

D. Th iopen tal E. Propofol


F.

Etom idate

6. Five n ew p oten t ial in h alat ion al an esth et ics (P, Q, R, S, an d T)

G. Ket am in e

w ere tested in laborator y an im als. Som e p h ar m acological

H. Midazolam

p aram eters of each drug are recorded in th e table below :

I.

Fen t anyl Drug

MAC

Induction


P

5.5

Slow

1. A h alogen ated an est h et ic t h at cau ses fast in d u ct ion an d

Q

45.2

Fast

R

12.7

Fast

S

0.9

Slow

T

3.2

Fast

recover y

Di cult y level: Easy 2. A drug th at can t rigger an at tack of acute porphyria in at-risk pat ien ts

Di cult y level: Easy 3. Th is drug h as th e h igh est in ciden ce of post an esth et ic n ausea an d vom it ing.

Abbreviation: MAC, m inim um alveolar concentration.

W h ich of th e follow ing drugs h as th e h igh est poten cy? A. Drug P B. Drug Q C. Drug R D. Drug S E. Drug T

Questions: III-3 General Anesthetics 85 Di cult y level: Easy

A. Ket am in e

7. A 59-year-old m an un der w en t surger y to repair an ingu in al

B. Haloth an e

h ern ia. Lorazepam w as adm in istered as prean esth et ic m ed-

C. Fen t anyl

icat ion . Gen eral an esth esia w as in duced by propofol an d

D. Propofol

m ain t ain ed w ith h aloth an e an d n it rou s oxide. On dan set ron

E. Th iopen tal

w as also given to p reven t vom it ing. Fifteen m in u tes after starting the operation, the electrocardiogram m on itor sh ow ed


ven t r icu lar t achycard ia. W h ich of t h e d r ugs m ost likely

11. A 52-year-old w om an un der w en t hysterectom y to rem ove

cau sed th is adverse e ect?

an en d om et r ial carcin om a. An est h esia w as in d u ced w it h

A. Lorazepam

t h iop en t al an d m ain t ain ed w it h n it rou s oxid e an d h alo -

B. Propofol

t h an e. W h ich of t h e follow in g reason s best exp lain s w hy

C. Nit rou s oxide

an ot h er an est h et ic, in t h is case h alot h an e, w as ad d ed to

D. Haloth an e

n it rous oxide?

E. On dan set ron

A. To ach ieve a m ore com p lete an algesia B. To m ain tain u n con sciou sn ess an d m u scle relaxat ion


C. To p reven t sen sit izat ion of t h e m yocard iu m to cate-

8. A 32-year-old m an w as adm it ted to th e h ospital for reduc-

ch olam in es

t ion of a dislocated sh ou lder. Sedat ion w ith diazep am w as

D. To p reven t an esth esia-in du ced resp irator y depression

su p p lem en ted w it h a 30% con cen t rat ion of n it rou s oxid e.

E. To p reven t p ostan esth et ic n au sea an d vom it ing

W h ich of t h e follow ing e ect s m ost likely occu r red after n it rous oxide adm in ist rat ion ?


A. Excellen t skeletal m uscle relaxat ion

12. A 12-year-old boy w as ad m it ted to t h e h osp it al w it h t h e

B. Ver y pron ou n ced an algesia

ad m it t ing diagn osis of acu te app en dicit is. Fam ily h istor y of

C. Rapidly ach ieved u n con sciou sn ess

the pat ien t indicated that his father un der w ent surger y a few

D. Sh arp decrease in blood pressure

years earlier an d su ered a seriou s disorder ju st after th e

E. Profoun d respirator y depression

begin n ing of gen eral an esth esia. Fu rth er an alysis in dicated th at th e disorder w as an in h erited au tosom al dom in an t disease. Because of th is, th e an esth esiologist avoided th e use of

Di cult y level: Hard 9. A 64-year-old m an un der w en t su rger y for prostate can cer. An in t raven ous inject ion of th iopen t al w as adm in istered,

h alogen ated an esth et ics in th is boy. W h ich of th e follow ing w as m ost likely th e disorder su ered by th e pat ien t’s fath er?

an d th e p at ien t lost con sciou sn ess in abou t 10 secon ds.

A. Acu te in term it ten t p orp hyria

W h ich of th e follow ing w as m ost likely th e m ajor m ech a-

B. Malign an t hyp er th erm ia

n ism of act ion m ediat ing th e an esth et ic e ect of th is drug?

C. Acu te h ep at it is

A. In creased a

n it y of GABA for GABAA receptors

B. Enhancem ent of β-carboline a nit y for GABAA receptors C. Blockade of NMDA glu t am ate receptors in the cen t ral n er vou s system D. En h an cem en t of Cl− ch an n el open ing in th e absen ce of GABA E. Act ivat ion of GABAB receptors on presyn apt ic term in als

D. Hem olyt ic an em ia E. Myasth en ia gravis

Di cult y level: Easy 13. A 43-year-old m an un der w en t surger y to rem ove a prost at ic cancer. Sevo urane was used for general an esth esia. The drug h as a m in im um alveolar con cen t rat ion (MAC) of 2%. W h ich of th e follow ing best describes th e MAC of an in h alat ion al


an esth et ic?

10. A 34-year-old w om an w as adm it ted to th e day surger y cen -

A. Th e blood /gas par t it ion coe

cien t of th e an esth et ic

ter for st rabism u s surger y. Th is su rger y is con sidered h igh ly

B. The concentration of anesthetic needed for short surgery

em etogen ic d u e to a st im u lat ion of t h e vom it in g cen ter

C. Th e ED50 on a conven t ion al qu an t al dose−resp on se cu r ve

d u r ing t h e op erat ive m an ip u lat ion of ext raocu lar m u scles.

D. Th e m axim al e

W h ich of th e follow ing an esth et ics w ould be m ost appropri-

E. Th e con cen t rat ion of an esth et ic in th e in spired air

ate for th is pat ien t?

cacy of th e an esth et ic

86



A. Haloth an e

14. A 48-year-old w om an un der w en t su rger y to rem ove a uter-

B. Ket am in e

in e m yom a. Gen eral an esth esia w as in duced w ith propofol

C. Propofol

an d m ain tain ed by sevo u ran e an d n it rou s oxide. Th e block-

D. Th iopen tal

ade of w h ich of th e follow ing receptors m ost likely m ediated

E. Etom idate

th e e ect iven ess of n it rou s oxid e in th is pat ien t?


A. Nm ch olin ergic

18. A 4-year-old girl w h o h ad been su ering from severe asth m a

B. Alph a-1 adren ergic C. NMDA glu t am atergic

for 6 m on th s w as sch edu led for a sh or t sut ure procedure

D. GABAergic

th at w as an t icip ated to t ake ap p roxim ately 10 m in u tes. Sh e

E. 5-HT3 seroton ergic

w as brough t to th e op erat ing room by h er paren t s an d w as in d ist ress over p ar t ing from th em an d afraid of th e doctors. W h ich of th e follow ing drugs w ould be appropriate for pro-

Di cult y level: Medium 15. A 44-year-old w om an un der w en t surger y because of a pro-

viding sedat ion an d an algesia for th is girl?

lap sed in ter vertebral disk. Gen eral an esth esia w as in du ced

A. Ket am in e

w ith propofol an d m ain tain ed w ith sevo u ran e. W h en ad-

B. Th iopen tal

m in ist rat ion of sevo u ran e w as discon t in u ed, th e p at ien t

C. Fen t anyl

regain ed con sciou sn ess in a few m in utes. W h ich of th e fol-

D. Haloth an e

low ing st atem en ts best exp lain s w hy an esth et ic recover y is

E. Sevo u ran e

so rap id w h en sevo u ran e adm in ist rat ion is stop ped? A. It redist ributed rapidly to th e lipid t issue.

19. A 52-year-old m an un der w en t liver biopsy for a suspected

B. It is rapidly m et abolized. C. It h as a low m in im u m alveolar con cen t rat ion (MAC)

liver can cer. Con sciou s sedat ion w as in du ced w ith a dr ug com bin at ion th at h as t h e advan t age of being reversible by

valu e. D. It h as a low blood/gas par t it ion coe


cien t .

E. It dist ributes m ain ly in to th e cerebral cor tex.

t h e ad m in ist rat ion of sp eci c receptor an t agon ist s. W h ich of the follow ing pairs of drugs w as m ost likely adm inistered? A. Fen t anyl an d th iopen tal


B. Fen t anyl an d m idazolam

16. A 63-year-old w om an un der w en t surger y to rem ove a vul-

C. Fen t anyl an d ket am in e

var can cer. Th e pat ien t w as a h eavy sm oker an d h ad been

D. Th iopen tal an d m idazolam

su er ing from ch ron ic obst r u ct ive p u lm on ar y disease for

E. Th iopen tal an d ketam in e

20 years. Gen eral an esth esia w as in du ced w ith p rop ofol an d m ain t ain ed w ith iso u ran e. W h ich of th e follow ing e ects


m ost likely occu rred du ring su rger y?

20. A 57-year-old m an w as u n d ergoing su rger y to rem ove a

A. Decreased cardiac out put

kid n ey carcin om a. Th e an esth esia w as in d u ced w ith propo-

B. In creased ven t ilator y respon se to carbon dioxide

fol, m ain t ain ed w ith h aloth an e, an d supplem en ted by succi-

C. Bron ch odilat ion

nylch olin e. A few m in u tes in to t h e op erat ion , t h e p at ien t

D. In creased skelet al m uscle ton e

exh ibited a fever of 104°F (40°C), skelet al m u scle con t rac-

E. In creased uterin e ton e

t u re, an d p rofu se d iap h oresis. His blood p ressu re d rop p ed to 80/50 m m Hg, an d th e h ear t rate w as 125 bpm . W h ich of

Di cult y level: Easy 17. A 55-year-old m an su ering from ch ron ic h eart failure un d er w en t an explorator y laparotom y because of an abdom in al sw elling. Th e an esth esia protocol in cluded a drug th at

th e follow ing m olecular act ion s best explain s th e sign s an d sym ptom s of th e pat ien t? A. Excessive release of acet ylch olin e from m otor n euron term in als

causes rapid in duction, a very rapid rate of recovery, and m in -

B. Opening of K+ channels in the skeletal m uscle m em brane

im al ch anges in cardiovascular an d respirator y fun ct ion s.

C. Excessive release of Ca 2+ from the sarcoplasm ic reticulum

W hich of th e follow ing drugs w as m ost likely adm inistered?

D. Blockad e of Ca 2+ ch an n el in t h e skelet al m u scle m em bran e E. Open ing of Cl− ch an n els in th e m otor en d plate

Questions: III-3 General Anesthetics 87 Di cult y level: Easy

of th e follow ing reason s best exp lain s w hy gen eral an esth e-

21. A 60-year-old m an w as about to un dergo surger y to rem ove

sia in du ced by a st an dard dose of th iop en t al last s 5 to 15

a p rost ate can cer. Th e m an h ad been su ering from isch em ic

m in utes?

h ear t disease for 2 years. Th e an esth esiologist decided to use

A. Slow d ist r ibu t ion of t h e d r ug in to t h e cen t ral n er vou s

n it rou s oxide an d an oth er gen eral an esth et ic th at causes a

system (CNS)

p ron oun ced in crease in coron ar y blood ow w ith con com i-

B. Fast elim in at ion of th e dr ug from th e body

t an t d ecrease in m yocard ial oxygen con su m pt ion an d n eg-

C. Red ist ribut ion of th e drug in to p eriph eral t issues

ligible e ect s on cardiac out put . W h ich of th e follow ing

D. Rapid biot ran sform at ion of th e drug by th e brain

an esth et ics w as m ost likely given w ith n it rou s oxid e for an -

E. Poor di usion of th e drug in to th e cen t ral n eu ron s

esth esia m ain ten an ce? A. Haloth an e


B. Etom idate

25. A 29-year-old w om an w as ad m it ted to t h e h osp it al for d i-

C. Propofol

lat ion an d cu ret t age after a sp on t an eou s abor t ion . Gen eral

D. Iso uran e

an est h esia w as in d u ced by p rop ofol. W h ich of t h e follow -

E. Sevo u ran e

ing drugs w ould be m ost appropriately co-injected w ith p ropofol?


A. Th iopen tal

22. A 68-year-old h ospitalized w om an developed gen eral m al-

B. Etom idate

aise, fever (100.7°F. 38.2°C), n ausea an d vom it ing, jau n dice,

C. Paroxet in e

an d a skin rash . Th e w om an h ad u n dergon e su rger y 4 days

D. Lidocain e

earlier to rem ove a u ter in e m yom a. Em ergen cy lab exam s

E. Diazepam

sh ow ed t h e follow ing p er t in en t resu lt s: asp ar t ate am in o t ran sferase 240 U/L, alkalin e p h osp h at ase 380 U/L. Th e


p at ien t ’s con d it ion rap id ly d eter iorated, an d com a en su ed .

26. An 80-year-old w om an underw ent surger y to rem ove a blad-

W h ich of t h e follow ing d r ugs m ost likely cau sed t h e p a-

d er can cer. Medical h istor y in dicated th at sh e h ad been su f-

t ien t’s syn d rom e?

fering from gast roin test in al re u x disease presen tly t reated

A. Sevo u ran e

w ith om eprazole. Gen eral an esth esia w as m ain tain ed w ith

B. Haloth an e

n it rou s oxide an d sevo uran e. In th is pat ien t , th e sum of th e

C. Nit rou s oxide

m in im u m alveolar con cen t rat ion (MAC) of th e t w o in h ala-

D. Th iopen tal

tional an esth etics needed to obtain surgical anesthesia turned

E. Fen t anyl

out to be 0.7 MAC. In m ost pat ien ts th is total is 1.3 MAC.

F.

W h ich of th e follow ing variables m ost likely caused th e de-

Iso uran e

crease in MAC in th is case?


A. Th e can cer of th e pat ien t

23. A 22-year-old w om an w as about to un dergo surger y to re-

B. Th e u se of t w o an esth et ics

m ove a m an dibu lar can cer. Th e an esth esiologist h ad decided

C. Th e age of th e p at ien t

to use n it rous oxide an d sevo uran e for an esth esia m ain -

D. Th e ad dit ion of n it rou s oxide

ten an ce. W h ich of th e follow ing w ould be th e m in im um

E. Th e u se of om ep razole

alveolar con cen t rat ion of both drugs n eeded to provide an app ropriate gen eral an esth esia in th is pat ien t?


A. Nit rou s oxide 0.2; sevo u ran e 0.3

27. A 46-year-old m an recen tly diagn osed w ith ph eoch rom o-

B. Nit rou s oxide 0.7; sevo u ran e 0.6

cytom a w as sch eduled for su rger y to rem ove th e t u m or. He

C. Nit rou s oxide 0.4; sevo u ran e 0.1

h ad n orm al pulm on ar y an d ren al fun ct ion , but h is blood

D. Nit rou s oxide 1.0; sevo u ran e 1.6

catech olam in e levels w ere su bstan t ially elevated. W h ich of

E. Nit rou s oxide 1.0; sevo u ran e 0.7

th e follow ing drugs w ou ld be con t rain dicated for in clu sion in h is an esth et ic protocol?


A. Haloth an e

24. A 43-year-old w om an u n d er w en t d ilat ion an d cu ret t age

B. Fen t anyl

for abn orm al vagin al bleeding. Gen eral an esth esia w as per-

C. Lorazep am

form ed w ith th iopen t al. Th e pat ien t lost con sciousn ess in

D. Th iopen tal

abou t 10 secon d s an d regain ed it 15 m in u tes later. W h ich

E. Nit rou s oxide


88


A. Nausea an d vom it ing

28. A 62-year-old m an w as about to un dergo su rger y to repair

B. Delusion s

a sm all bow el closed loop obst ru ct ion . W h ich of th e follow -

C. Pron ou n ced respirator y depression

ing gen eral an esth et ics w ou ld be con t rain dicated in th is

D. Hyp er ten sion

pat ien t?

E. Decreased cardiac out put

A. Haloth an e B. Nit rou s oxide C. Th iopen tal

Di cult y level: Medium 30. A 49-year-old m an un der w en t em ergen cy su rger y because

D. Propofol

of m ult iple fract u res due to a car acciden t . Because th e pa-

E. Sevo u ran e

t ien t w as exp erien cing severe p ain , fen t anyl w as given be-

F.

fore surger y. Gen eral an esthesia w as induced by propofol and

En uran e

m ain t ain ed by n it rou s oxide an d iso u ran e. Cisat racu riu m

Di cult y level: Easy 29. A 61-year-old w om an u n der w en t colon oscopy because of rectal bleeding. Th e w om an w as ver y afraid of th e procedure an d asked for a gen eral an esth esia. Becau se sh e h ad been su ering from exer t ion al angin a for 7 years, etom idate w as

w as added to en su re a com p lete m u scle relaxat ion . After th e operat ion , th e an esth esiologist adm in istered oxygen for ve m in u tes before discon n ect ing th e face m ask. Th e procedu re w as perform ed to p reven t an adverse e ect of w h ich of th e follow ing drugs?

ch osen for an esth esia. W h ich of th e follow ing adverse ef-

A. Iso uran e

fect s w ou ld be m ost likely to occur in th is pat ien t during th e

B. Propofol

p ostan esth et ic period?

C. Fen t anyl D. Nit rou s oxide E. Cisat racurium

Questions: III-4 Local Anesthetics Directions for questions 1−3

aroun d th e w oun d to provide region al an esth esia. Blockade of

Match each local an est h et ic w it h t h e ap p rop r iate d escr ipt ion

w h ich of th e follow ing ion ch an n els m ost likely m ediated th e


ph arm acological e ect of th e drug in th e pat ien t?

at all).

A. In act ivated, volt age-gated Na + ch an n els

A. Ben zocain e

B. Rest ing, volt age-gated K+ ch an n els

B. Bup ivacain e

C. Act ivated , ligan d -gated Ca 2+ ch an n els

C. Cocain e

D. In act ivated, ligan d-gated K+ ch an n els

D. Lidocain e

E. Rest ing, ligan d-gated Na + ch an n els

E. Prilocain e

F.

F.

Act ivated , voltage-gated Ca 2+ ch an n els

Procain e

G. Tet racain e

Di cult y level: Easy 5. A 43-year-old m an un der w en t an em ergen cy m in or arm re-


pair p rocedu re after a car acciden t . A stan dard dose of lido-

1. An ester-t ype local an esth et ic w ith a sh or t durat ion of act ion

cain e w as adm in istered n ear th e brach ial plexu s for p eriph eral n er ve block. Fifteen m in u tes later, t h e an est h esia w as st ill

Di cult y level: Easy 2. Th e m ost cardiotoxic local an esth et ic

Di cult y level: Easy 3. An am ide-t ype local an esth etic w ith a long duration of action

Di cult y level: Easy 4. A 27-year-old w om an un der w en t a m in or sut ure procedure for a skin cut on h er righ t leg. A local an esth et ic w as injected

in com plete, an d an oth er dose of lidocain e w as adm in istered. W h ich of t h e follow ing adverse e ect s w ou ld m ost likely occur after th e adm in ist rat ion ? A. Ven t ricular tachycardia B. Abdom in al colic C. Drow sin ess D. Convu lsion s E. Hyp er ten sive crisis

Questions: III-4 Local Anesthetics 89 Di cult y level: Medium


6. A 53-year-old m an w as brough t to th e em ergen cy depart-

10. Th e act ion of a n ew p oten t ial local an est h et ic w as st u d ied

m en t after su ering a h an d inju r y th at requ ired im m ediate

on di erent isolated ner ve ber preparations. Mem brane po-

su rger y. Local an esth esia w as perform ed by brach ial p lexu s

ten t ial an d con du ct ion velocit y of th ose

block. Th e su rgeon est im ated th at th e p rocedu re sh ou ld last

below :

bers are repor ted

abou t 3 h ours. W h ich of th e follow ing local an esth et ics w ou ld be m ost ap prop riate for th is p at ien t? A. Prilocain e B. Procain e C. Tet racain e D. Ben zocain e E. Cocain e

Di cult y level: Medium 7. A 62-year-old m an w as u n d ergoing su rger y to rem ove a hyp er p last ic p rost ate. Sp in al an est h esia w as p er for m ed w it h lidocain e. Th e pKa of lidocain e is about 7.8. W h at fract ion of th e drug w as m ost likely lipid soluble in th e pat ien t’s cerebrospin al u id (pH = 7.3)?

C. 50%

Q

−82

25

R

−45

2

S

−60

15

T

–55

50

W h ich of th e n er ve

bers w as likely to be m ost sen sit ive to

th e act ion of th e n ew drug? A. Fiber P B. Fiber Q C. Fiber R

ce for a d en t al

u lar n er ve. W h ich of th e follow ing physiological fun ct ion s

8. A n ew poten t ial local an esth et ic drug w as st udied in th e lab ber preparat ion . W h ich of

th e follow ing n er ve proper t ies m ost likely in creased w h en th e drug w as applied to th e n er ve ber? A. Rate of rise of th e act ion p oten t ial B. Am plit ude of th e act ion poten t ial C. Refractor y p eriod of th e n er ve D. Con du ct ion velocit y of th e n er ve E. Rest ing p oten t ial of th e n er ve m em bran e

Di cult y level: Easy 9. A 2-year-old girl w as brough t to th e em ergen cy depart m en t after cut t ing h erself w ith a kitch en kn ife a few m in utes earlier. The ngers were bleeding. Exam ination revealed t w o clean w ou n ds on th e m iddle an d ring ngers of th e righ t h an d. Th e doctor decided to su t u re th e w ou n ds u n der local an esth esia using lidocain e w ith ou t epin eph rin e. Epin eph rin e w as avoided to preven t w h ich of th e follow ing possible com plicat ion s?

E. System ic toxicit y

9

ext ract ion . A local an esth et ic w as injected n ear th e m an dib -


D. Delayed w oun d repair

−90

11. A 46-year-old m an w as in t h e d en t ist ’s o

E. 90%

C. Excessive bleeding

P


D. 76%

B. Isch em ic gangren e

Conduction Velocity (m/sec)

E. Fiber T

B. 24%

A. Wou n d in fect ion

Membrane Potential (mV)

D. Fiber S

A. 10%

orator y u sing an isolated n er ve

Nerve Fiber

w as m ost likely th e last to be blocked in th at pat ien t? A. Motor fu n ct ion B. Pain sen sat ion C. Mu scle ton e D. Tou ch sen sat ion E. Vasom otor fun ct ion

Di cult y level: Easy 12. A 55-year-old diabet ic m an w as adm it ted to th e em ergen cy d epart m en t w ith fever (101.5°F, 38.6°C) an d abdom in al p ain . Physical exam in at ion disclosed a sup er cial abscess on th e righ t sid e of th e abdom en . A local an esth et ic w as in jected aroun d th e abscess in preparat ion for su rger y. W h ich of th e follow ing t issue propert ies m ost likely accoun t for th e slow er on set of local an esth et ic act ion in in fected t issu es? A. High levels of drug-m et abolizing en zym es B. Low vessel den sit y C. High er ext racellu lar K+ D. High levels of p ara-am in oben zoic acid E. Low er ext racellu ar p H

90



abou t 20 m in utes. W h ich of th e follow ing local an esth et ics

13. A 4-day-old boy w as brough t to th e em ergen cy depar t m en t

w ou ld be m ost app rop riate for th is p at ien t?

w it h blu ish d iscolorat ion of t h e lip s an d ext rem it ies. He

A. Cocain e

w as born fu ll term , h ad n o p erin at al p roblem s, an d w eigh ed

B. Ben zocain e

3.5 kg (7.7 lb). Medical h istor y of th e baby disclosed th at h e

C. Bupivacain e

h ad un dergon e a circum cision procedure w ith local an es-

D. Tet racain e

th esia th e previou s day, an d cyan osis h ad begu n 1.5 h ou rs

E. Lidocain e

after th e p rocedu re. Lab resu lt s sh ow ed m eth em oglobin em ia. W h ich of th e follow ing drugs w as m ost likely u sed for


local an esth esia?

17. A 28-year-old pregn an t w om an w h o w as n ear term decided

A. Lidocain e

to have the delivery under spinal anesthesia. The patient’s past

B. Ben zocain e

h istor y in cluded an an aphylact ic react ion 3 years earlier, ap -

C. Bu pivacain e

p aren tly du e to a su n screen con t ain ing para-am in oben zoic

D. Prilocain e

acid (PABA). W h ich of th e follow ing local an esth et ics w ou ld

E. Tet racain e

be ap prop riate for th is pat ien t? A. Procain e


B. Tet racain e


C. Lidocain e

m ent w ith extensive burns on his arm s and thorax. Pertinent

D. Ben zocain e

plasm a levels on adm ission w ere K+ 6.3 m Eq/L, Ca 13.0 m g/dL,

E. Cocain e

creat in in e 2.8 m g/dL, blood u rea n it rogen (BUN) 35 m g/dL. An em ergen cy t reat m en t w as started th at in cluded th e ad-


m in ist rat ion of a top ical local an esth et ic on th e bu rn ed area.

18. A 56-year-old w om an , w h o h ad been su er in g from at r ial

W h ich of th e follow ing m olecular even t s m ost likely m ade

br illat ion for 3 years, w as in t h e d en t ist ’s o

ce for t h e ap -

th e n er ve m em bran e m ore sen sitive to th e act ion of th e

p licat ion of an im p lan t . Th e d en t ist w as abou t to in it iate

local an esth et ic in th is pat ien t?

local an esth esia by inject ing a local an esth et ic close to th e

A. In creased ext racellu lar con cen trat ion of Ca 2+

m an dibu lar n er ve. W h ich of th e follow ing local an esth et ic

B. In creased ext racellu lar con cen t rat ion Na +

p reparat ion s w ou ld be m ost ap prop riate for th is pat ien t?

C. Decreased ext racellu lar con cen t rat ion of Cl−

A. Lidocain e alon e

D. In creased ext racellu lar con cen t rat ion of K+

B. Lidocain e plu s epin eph rin e

E. In creased ext racellu lar con cen t rat ion of Mg

2+

C. Bupivacain e plus epin eph rin e D. Ben zocain e plus epin eph rin e


E. Ben zocain e alon e

15. A 45-year-old w om an w as u n dergoing su rger y to rem ove an exten sive lipom a in h er righ t arm . Her m edical h istor y w as


sign i can t for long-term , severe ch ron ic obst ru ct ive pu lm o-

19. A 16-year-old boy com p lain ed of bu r n ing p ain du e to m u l-

n ar y disease (COPD) du e to h eavy sm oking. Local an esth esia

t ip le su p er cial skin abrasion s after a m otorcycle acciden t .

w ith a periph eral n er ve block w as plan n ed. W h ich of th e

A local an esth et ic w as applied topically to th e abraded areas.

follow ing local an esth et ics w ould be con t rain dicated in th is

W h ich of th e follow ing local an esth et ics w ould be m ost ap -

p at ien t?

p ropriate for th is pat ien t?

A. Prilocain e

A. Ben zocain e

B. Procain e

B. Procain e

C. Tet racain e

C. Cocain e

D. Lidocain e

D. Prilocain e

E. Bu pivacain e

E. Bupivacain e



16. A 60-year-old m an w as sch eduled for a lith ot ripsy to sh at ter

20. A 44-year-old w om an got a scratch on h er arm w h ile w ork-

a bladd er ston e. Lu m bar epidu ral an esth esia w as selected for

ing at h om e. Sh e p u t a cream con t ain ing a local an est h et ic

the procedure. The anticipated duration of the procedure w as

on th e w ou n d ed area. It is kn ow n t h at on t h e body, local

Questions: III-5 Skeletal Muscle Relaxants 91 an esth et ics can exist eith er as th e u n ch arged base (n on -

kn ife. Th e w om an w as agitated an d rm ly refused any injec-

ion ized form ) or as a cat ion (ion ized form ). Th e ion ized form

t ion procedu re. Exam in at ion of th e w ou n d sh ow ed a long

m ost likely m ediated w h ich of the follow ing properties of the

su per cial cu t of th e skin w ith exten sive bleeding. Th e an es-

drug?

th esiologist ch ose to apply a solut ion of a topical an esth et ic

A. Tissue redist ribut ion

th at could also cause local vasocon st rict ion . W h ich of th e

B. Liver biot ran sform at ion

follow ing drugs w as m ost likely adm in istered?

C. Blood−brain crossing

A. Cocain e

D. Receptor bin ding

B. Prilocain e

E. Half-life

C. Bupivacain e D. Tet racain e


E. Lidocain e

21. A 56-year-old w om an w as abou t to u n d ergo em ergen cy m in or skin su t u ring after an acciden t al self-inju r y w ith a

Questions: III-5 Skeletal Muscle Relaxants Directions for questions 1−4

A. Ganglion ic n eu ron m em bran es

Match each skeletal m u scle relaxan t w ith th e ap prop riate de-

B. Adren al m edu lla

script ion (each let tered opt ion can be selected on ce, m ore th an

C. Postjun ct ion al folds of m otor en d plates

on ce, or n ot at all).

D. Au ton om ic ch olin ergic n er ve term in als

A. Tubocurarin e B. Cisat racu rium C. Mivacu riu m D. Su ccinylch olin e E. Dan t rolen e F.

Gabap en t in

E. Sp in al m otor n eu ron m em bran es F.

Skelet al m u scle cell m em bran es

Di cult y level: Easy 6. A 38-year-old pat ien t w as adm it ted to th e em ergen cy depar tm en t w ith exten sive soft t issue burn s. He w as sem icon scious

G. Diazepam

an d w as art i cially ven t ilated. His un coordin ated respirator y

H. Tizan idin e

m ovem en t s w ere in terfering w ith th e m ech an ical ven t ilat ion .

I.

W h ich of t h e follow ing dr ugs w ou ld m ost likely be e ect ive

Baclofen

to decrease th e pat ien t’s spon tan eous breath ing?


A. Diazepam

1. An an t agon ist at Nn acet ylch olin e receptors in au ton om ic

B. Vecuron ium

ganglia

C. Bot ulin u m toxin D. Dan t rolen e

Di cult y level: Easy 2. An agon ist at Nm acet ylch olin e receptors

Di cult y level: Easy 3. Prim arily an agon ist at α 2 receptors located in th e spin al cord.

Di cult y level: Easy 4. An an t iconvulsan t agen t th at can reduce spast icit y in pat ien t s w ith m ult iple sclerosis

Di cult y level: Easy 5. A 63-year-old m an underwent abdom inal surgery for prostate can cer. Gen eral an esth esia w as su p p lem en ted w ith t u bocu rarin e. W h ich of th e follow ing an atom ical st ruct ures m ost likely rep resen t s th e m ain site of act ion of th e d rug for th is clin ical applicat ion ?

E. Baclofen F.

Tizan idin e

Di cult y level: Easy 7. A 57-year-old w om an w as adm it ted sem icon scious to th e em ergen cy dep art m en t after an acciden t at h om e. Art i cial ven t ilat ion w as n eeded, an d a drug w as given to facilitate in t u bat ion . Th is drug h as th e sh or test du rat ion of act ion am ong skelet al m uscle relaxan t s. W h ich of th e follow ing drugs w as m ost likely adm in istered? A. Su ccinylch olin e B. Cisat racuriu m C. Dan t rolen e D. Vecuron ium E. Tubocurarin e F.

Tizan idin e

92



A. Eye ext rin sic m u scles, lim b m u scles, diap h ragm

8. A 49-year-old m an d iagn osed w it h ingu in al h er n ia w as

B. Lim b m uscles, diaph ragm , eye ext rin sic m uscles

p repared for surger y. Sh or tly after th e in it iat ion of gen eral

C. Diaph ragm , eye ext rin sic m uscles, lim b m uscles

an esth esia w ith h aloth an e an d su ccinylch olin e, th e p at ien t

D. Diaph ragm , lim b m uscles, eye ext rin sic m uscles

d evelop ed m uscle rigidit y, t achycardia, labile blood pres-

E. Lim b m uscles, eye ext rin sic m u scles, diaph ragm

su re, p rofu se diap h oresis, an d h igh fever (104.2°F, 40.1°C). Th e an esth esia w as discon t in u ed at on ce, an d a d rug w as ad-


m in istered by rap id in t raven ou s pu sh . W h ich of th e follow -

12. A 59-year-old w om an w as u n dergoing su rger y for breast

ing w as m ost likely th e m ech an ism of act ion of th e

can cer. Gen eral an est h esia w as su p p lem en ted w it h a n on -

adm in istered drug?

d epolarizing neurom uscular blocker that has a short duration

A. Act ivat ion of GABAB receptors in th e spin al cord

of action and is m etabolized by plasm a pseudocholinesterase.

B. Blockade of excit ator y n eu rot ran sm it ter release in th e brain C. Blockad e of Ca 2+ ch an n els in t h e skelet al m u scle m em bran e

W hich of the follow ing drugs w as m ost likely adm inistered? A. Su ccinylch olin e B. Tu bocu rarin e C. Vecuron ium

D. Blockade of Ca 2+ ch an n els in th e sarcoplasm ic ret iculum

D. Mivacu riu m

E. In creased K+ con du ct an ce in th e skelet al m u scle m em -

E. Cisat racurium

bran e

Di cult y level: Easy Di cult y level: Easy

13. A 74-year-old m an un der w en t abdom in al surger y to rem ove

9. A 22-year-old m an su ering from st rabism us st ar ted t reat-

a colon carcin om a. Th e p at ien t h ad severely im p aired h e-

m en t w ith local inject ion s of bot u lin u m toxin in to th e ex-

p at ic an d ren al fu n ct ion , an d th e an esth esiologist decided to

t rin sic ocular m uscles. W h ich of th e follow ing stru ct u res w as

su p p lem en t gen eral an esth esia w ith a m u scle relaxan t th at

m ost likely th e site of th e th erap eu t ic act ion of th e dr ug?

is in act ivated p r im ar ily by a for m of sp on t an eou s break-

A. Nicot in ic m u scu lar receptors

d ow n (also kn ow n as Ho m an n elim in at ion ). W h ich of th e

B. Som at ic n er ve term in als

follow ing drugs w as m ost likely given ?

C. Mu scarin ic receptors

A. Su ccinylch olin e

D. Au ton om ic n er ve term in als

B. Dan t rolen e

E. Nicot in ic n eu ron al receptors

C. Tu bocu rarin e D. Cisat racurium


E. Mivacu riu m

10. A 73-year-old m an un der w en t th oracic surger y to rem ove a lu ng can cer. Gen eral an esth esia w as su p plem en ted w ith


vecuron ium . W h ich of th e follow ing m olecular act ion s m ost

14. A 65-year-old w om an un der w en t hysterectom y for en do-

likely m ediated th e m uscle relaxan t e ect of th is drug?

m et rial carcin om a. Th e gen eral an esth esia p rotocol in clu ded

A. St im u lat ion of p lasm a ch olin esterase

sodiu m th iop en t al, iso u ran e, n it rou s oxide, an d t u bocu-

B. Long-last ing act ivat ion of post syn apt ic Nm receptors

rarin e. Th e an esth esiologist also adm in istered an oth er drug

C. Com p et it ive blockade of p ost syn apt ic Nm receptors

to coun teract t u bocurarin e-in duced hypoten sion . To w h ich

D. Blockade of act ion poten t ial of th e m otor n er ves

of th e follow ing classes did th is drug m ost likely belong?

E. Blockade of Ca 2+ release from the sarcoplasm ic reticulum

A. β 1 agon ists

F.

B. D1 an tagon ists

Com p et it ive blockade of Nn receptors in th e brain

C. Muscarin ic agon ist s


D. Cholin esterase in h ibitors

11. A 61-year-old m an un der w en t su rger y for prostate can cer.

E. H1 an tagon ists

Th e an esth esia w as in d u ced by th iop en t al an d m ain t ain ed by h aloth an e an d n it rou s oxide. Vecu ron iu m w as added to


en su re ad equ ate m u scle relaxat ion . W h ich of th e follow in g


w as m ost likely t h e sequ en ce of th e p aralysis of skelet al

p ar t m en t follow ing a car acciden t . Su rger y w as n eeded to

m u scles in du ced by vecu ron iu m in th is p at ien t?

repair a badly dam aged leg. Medicat ion s of th e pat ien t on adm ission w ere gen t am icin an d darifen acin for u rin ar y t ract

Questions: III-5 Skeletal Muscle Relaxants 93 in fect ion , t im olol an d lat an op rost for glau com a, an d lovas-

A. Bot ulin um toxin

t at in for hyp erch olesterolem ia. Gen eral an esth esia w as in -

B. Dan t rolen e

du ced by th iop en tal sod iu m , m ain t ain ed by iso u ran e an d

C. Su ccinylch olin e

n it rou s oxide, an d supplem en ted by vecuron ium . W h ich of

D. Tu bocu rarin e

th e follow ing of th e pat ien t’s m edicat ion s m ost likely en -

E. Cisat racurium

h an ced th e act ion of vecuron ium ? A. Gen t am icin


B. Darifen acin

19. A 57-year-old w om an u n der w en t surger y for breast can cer.

C. Tim olol

Gen eral an esth esia w as in duced by th iopen tal, m ain tain ed

D. Latan oprost

by sevo uran e an d n it rous oxide, an d supplem en ted w ith

E. Lovast at in

a m u scle relaxan t th at cau ses a long last ing act ivat ion of Nm receptors. W h ich of th e follow ing dr ugs w as m ost likely


adm in istered ?

16. A 44-year-old m an brough t to th e em ergen cy depar t m en t

A. Su ccinylch olin e

after a car acciden t requ ired in t u bat ion an d m ech an ical ven -

B. Cisat racurium

t ilat ion . Th e p at ien t ’s h istor y w as sign i can t for a gen et ic

C. Tu bocu rarin e

d e cien cy of plasm a ch olin esterase. A m uscle relaxan t w as

D. Mivacu riu m

adm in istered in t raven ously. W h ich of th e follow ing m u scle

E. Vecuron ium

relaxan t s w ould be con t rain dicated in th is pat ien t?

F.

Baclofen

A. Tubocurarin e B. Cisat racurium


C. Baclofen

20. A 48-year-old w om an un der w en t h ear t surger y for place-

D. Mivacu riu m

m en t of an ar t i cial valve. An esth esia w as in du ced by th io-

E. Vecuron ium

p en tal, an d a m u scle relaxan t w as th en given in t raven ou sly

F.

to facilitate in t ubat ion . Soon after th e adm in ist rat ion of th e

Tizan idin e

d rug, th e p at ien t exh ibited t ran sien t m uscle fascicu lat ion s


t h at p rogressed to gen eralized p aralysis w ith in 1 m in u te.

17. A 56-year-old w om an w as u n d ergoing m ajor su rger y to

W h ich of t h e follow ing m u scle rela xan t s w as m ost likely

rem ove a breast carcin om a. Th e w om an , w h o w as a h eavy

given ?

sm oker, h ad been su er ing from ch ron ic obst r u ct ive p u l-

A. Cisat racurium

m on ar y d isease for 15 years. A d r ug w as ad m in istered p re-

B. Su ccinylch olin e

op erat ively, an d t h e an est h esia w as su p p lem en ted w it h

C. Dan t rolen e

a skelet al m u scle rela xan t . W h ich of t h e follow in g d r ugs

D. Vecuron ium


E. Tu bocu rarin e

A. Tubocurarin e

F.

Tizan idin e

B. Glycopyrrolate C. Clon idin e


D. Vecuron ium

21. A 10-year-old boy diagnosed w ith hereditar y spastic parapa-

E. Cisat racurium

resis 2 years ago w as treated w ith several spasm olytic drugs w ith lim ited su ccess. Recen tly, th e n eurologist p rescribed


an oth er sp asm olyt ic agen t th at act s as an α 2 -receptor ago-

18. A 49-year-old w om an required in t ubat ion an d m ech an ical

n ist in th e spin al cord. W h ich of th e follow ing drugs w as

ven t ilat ion for m an agem en t of respirator y failure du e to se-

m ost likely prescribed?

vere em physem a. Th e pat ien t w as agit ated, at tem pt ing to sit

A. Diazepam

u p in bed an d reach for th e en dot rach eal t ube. Lorazepam

B. Baclofen

w as given in t raven ou sly (IV) for sedat ion , an d th e p at ien t

C. Dan t rolen e

got drow sy, bu t m otor restlessn ess w as on ly m argin ally im -

D. Mivacu riu m

proved. An IV m uscle relaxan t w as given . Th e pat ien t relaxed

E. Tizan idin e

as paralysis developed, but 5 m inutes later her heart rate w as 160 bp m . W h ich of th e follow ing dr ugs m ost likely cau sed th is adverse e ect?

94



A few m in u tes later, t h e p at ien t d evelop ed m u scle fascicu -

22. A 54-year-old m an w h o h ad been su ering from am yo-

lat ion s, t rism u s, rigidit y, tachycard ia, an d hyp oten sion , an d

t rop h ic lateral sclerosis for 1 year com p lain ed of gen eralized

h er body tem perat u re rose to 103.8°F (39.8°C). W h ich of th e

m uscle spasm s. His physician prescribed diazepam to reduce

follow ing drugs m ost likely caused th e pat ien t’s syn drom e?

spast icit y. W h ich of th e follow ing statem en t s best explain s

A. At ropin e

th e m ech an ism of th e spasm olyt ic e ect of diazep am in th is

B. Morp h in e

p at ien t?

C. Lorat adin e

A. Blockad e of calciu m release from t h e sarcop lasm ic

D. Su ccinylch olin e

ret icu lum B. Blockade of acet ylch olin e release from m otor n er ves

E. Th iopen tal F.

Nit rou s oxide

C. Depolarizat ion blockade of Nm receptors D. Facilitation of GABAA act ion s in th e sp in al cord


E. Act ivat ion of GABA B receptors in th e spin al cord

26. A 43-year-old m an com plain ed of gen eralized m u scle soren ess upon recovering from surgery to rem ove prostate cancer.


General anesth esia had been perform ed w ith thiopental, hal-

23. A 67-year-old w om an required in t ubat ion an d m ech an ical

othan e, and a skeletal m uscle relaxant. W hich of the follow ing

ven t ilat ion for m an agem en t of respirator y failu re. Vecuro-

m uscle relaxants m ost likely caused the patient’s com plaint?

n ium w as given in t raven ously to redu ce ch est w all resis-

A. Tu bocu rarin e

t an ce an d in e ect ive sp on t an eou s ven t ilat ion . W h ich of th e

B. Cisat racurium

follow in g m em bran e p oten t ials w as m ost likely blocked by

C. Su ccinylch olin e

vecuron ium in th is pat ien t?

D. Dan t rolen e

A. Act ion p oten t ial of m otor n er ve

E. Diazepam

B. Min iat u re en d-p late p oten t ial C. Rest ing p oten t ial of sm ooth m u scle


D. Act ion p oten t ial of card iac m u scle

27. A 34-year-old wom an su ering from hem ifacial spasm s started

E. Act ion p oten t ial of cor t icosp in al t ract

t reat m en t w ith bot u lin u m toxin injected directly in to th e abn orm ally con t ract ing m u scles. W h ich of th e follow ing


m olecu lar act ion s m ost likely m ediated th e th erap eu t ic ef-

24. A 40-year-old w om an , adm it ted to th e em ergen cy depar t-

fect of th e drug in th e pat ien t’s disorder?

m en t after a car collision , h ad m u lt ip le su rgeries to rep air

A. Long-last ing act ivat ion of Nm acet ylch olin e receptors

h er injuries an d w as placed on m ech an ical ven t ilat ion to as-

B. In h ibit ion of acet ylch olin e storage in to syn apt ic vesicles

sist resp irat ion . On day 13 sh e w as sch edu led for a t ran se-

C. In h ibit ion of ch olin e acet ylt ran sferase

soph ageal elect rocardiogram (ECG) an d w as given a m u scle

D. In h ibit ion of acet ylch olin e exocytosis from ch olin ergic term in als

relaxant in t raven ously to facilitate the procedure. Soon afterw ard , t h e p at ien t su ered card iac ar rest , an d card iop u lm o -

E. St im ulat ion of acet ylch olin esterase

n ar y resu scit at ion w as p er for m ed su ccessfu lly. Th e ser u m

F.

Open ing of Ca 2+ ch an n els in ch olin ergic term in als

p ot assiu m levels record ed ju st before t h e ar rest p eaked at 7.3 m Eq/L. W h ich of th e follow ing m u scle relaxan ts m ost


likely caused th e cardiac arrest?

28. A 64-year-old w om an com plain ed to h er physician of invol-

A. Cisat racurium

u n tar y blin king an d closing of th e eyes. Sh e n ot iced th at th e

B. Vecuron ium

eyelid sp asm w as m ade w orse by fat igue an d an xiet y. Fu r-

C. Tubocurarin e

th er exam s led to th e diagn osis of ben ign essen t ial blep h ar-

D. Dan t rolen e

ospasm , an d a t reat m en t w ith local inject ion s of bot ulin um

E. Su ccinylch olin e

toxin w as prescribed. W h ich of th e follow ing adverse e ect s w as m ost likely to occu r in th is p at ien t?


A. Ret in al det ach m en t

25. A 40-year-old w om an un der w en t su rger y for ovarian can cer.

B. Visual h allucin at ion s

Sh e received at ropin e, lorat adin e, an d m orph in e as prean es-

C. Visual loss

th et ic m edicat ion . Th e an esth esia w as th en perform ed w ith

D. Eyelid ptosis

th iop en t al, sevo u ran e, n it rou s oxid e, an d su ccinylch olin e.

E. Lim b m uscle paralysis

Questions: III-6 Antiseizure Drugs 95 Di cult y level: Easy


29. A 41-year-old m an su ering from am yot roph ic lateral scle-

31. A 62-year-old w om an un der w en t su rger y to rem ove an

rosis presen ted to h is physician w ith m u scle fasciculat ion s,

ovarian can cer. Gen eral an esth esia w as in d u ced by th iop en -

lim b sp ast icit y, hyperact ive deep ten don re exes, an d ex-

tal, m aintained by sevo urane and nitrous oxide, and supple-

ten sor plan tar re exes. Baclofen w as prescribed to reduce

m ented by vecuronium , w hich is currently one of the m ost

spast icit y an d cram p s. W h ich of th e follow ing act ion s m ost

com m on ly u sed skeletal m u scle relaxan t s d u ring su rger y.

likely m ediated th e th erap eu t ic e ect of th e drug in th e p a-

W h ich of th e follow ing is a prim ar y advan tage of vecuro-

t ien t’s d isease?

n ium over t ubocurarin e?

A. Act ivat ion of GABAB receptors in th e spin al cord

A. A ver y sh or t durat ion of act ion (less th an 5 m in utes)

B. Blockade of Nm receptors of m otor en d p lates

B. Negligible e ect s on h ist am in e release

C. In creased subst an ce P release in th e spin al cord

C. No fascicu lat ion s before p aralysis

D. Blockade of Ca 2+ channels in skeletal m uscle m em branes

D. Lack of e ect s on th e cen t ral n er vou s system

E. Increased K+ conductan ce in skeletal m uscle m em bran es

E. In du ct ion of com plete an terograde am n esia



30. A 48-year-old m an presented to his physician com plaining of

32. A 79-year-old m an un der w en t surger y to rem ove a stom ach

in term it ten t lim b m uscle spasm s. Th e pat ien t w as referred

can cer. Per t in en t laborator y resu lts before su rger y w ere cre-

to th e n eurologic clin ic, w h ere th e diagn osis of st i

m an

at in in e 3.5 m g/dL (n orm al 0.6−1.2 m g/dL), alan in e am in o-

syn drom e w as m ad e. A p h arm acoth erapy w as p rescribed to

tran sferase 25 U/L (n orm al 8−20 U/L), urea nitrogen 65 m g/dL

im prove h is m u scle spasm s. W h ich of th e follow ing dr ugs

(n orm al 7−18 m g/dL). Diazepam w as given th e n igh t before

w ou ld be m ost app ropriate for th is pat ien t?

surger y. Th e gen eral an esth esia w as in duced by prop ofol,

A. Ph en obarbital

m ain t ain ed by sevo u ran e an d n it rou s oxide, an d su p ple-

B. Baclofen

m en ted by cisat racu riu m . W h ich of th e follow ing w as m ost

C. Tubocurarin e

likely th e prim ar y reason for th e u se of cisat racu riu m in -

D. Su ccinylch olin e

stead of t u bocu rarin e in th is p at ien t?

E. Ch lorprom azin e

A. Liver in su

F.

B. Advan ced age

Mivacu riu m

cien cy

C. Propofol in du ct ion D. Ren al in su

cien cy

E. Diazepam adm in ist rat ion

Questions: III-6 Antiseizure Drugs Directions for questions 1−3


For each n u m bered item select th e on e let tered opt ion th at is

1. Th is drug is e ect ive in all form s of epilepsy in all age groups.

m ost closely associated w ith it (each let tered opt ion can be selected on ce, m ore th an on ce, or n ot at all). A. Acetazolam ide

Di cult y level: Easy 2. Th is drug bin ds select ively to a syn apt ic vesicular protein , al-

B. Carbam azepin e

tering th e syn apt ic release of glut am ate an d gam m a-am in o-

C. Eth osu xim ide

bu t yric acid (GABA).

D. Felbam ate E. Gabap en t in


F.

3. This drug inhibits gam m a-am inobut yric acid (GABA) reuptake

Lam ot rigin e

G. Levet iracet am H. Ph enytoin I.

Tiagabin e

J.

Topiram ate

K. Valproic acid L.

Zon isam ide

in both n euron s an d glia, en h an cing GABAergic t ran sm ission .

96



regim en . A relat ively low dose of lam ot rigin e w as prescribed

4. A 28-year-old m an w as brough t to t h e em ergen cy d ep ar t -

becau se th e drug th e p at ien t w as already t aking can in h ibit

m en t becau se of a gen eralized ton ic-clon ic seizure. Histor y

th e m et abolism of lam ot rigin e. W h ich of th e follow ing w as

sh ow ed th at th e m an h ad been su ering from ep ilep sy sin ce

m ost likely th at drug?

ch ild h ood, bu t t h e seizu res w ere on ly p ar t ially con t rolled by

A. Ph enytoin

m ed icat ion . W h ich of t h e follow in g p airs of n eu rot ran sm it-

B. Ph en obarbital

ters are th ough t to be m ain ly involved in seizu re disorders?

C. Levet iracet am

A. Gam m a-am in obu t yric acid (GABA) an d seroton in

D. Clon azepam

B. Seroton in an d acet ylch olin e

E. Valproic acid

C. GABA an d acet ylch olin e

F.

Gabap en t in

D. Seroton in an d glu tam ate


E. GABA an d glut am ate F.

Acet ylch olin e an d glu t am ate

8. A 47-year-old w om an com plain ed to h er physician of blurred an d dou ble vision . Sh e h ad been su ering from a cen t ral


n ervous system disorder and had been receiving a drug treat-

5. A 37-year-old w om an w as at a rou t in e n eurology clin ic visit .

m en t for 6 m on th s. Physical exam in at ion sh ow ed m ild h ir-

Th e w om an h ad a long h istor y of refractor y gran d m al epi-

su t ism , broaden ing of h er lip s an d n ose, an d th icken ing an d

lepsy. Sh e w as being t reated w ith several dr ugs, but w ith poor

bleeding of h er gu m s. W h ich of th e follow ing drugs m ost

results. The neurologist decided to prescribe phenytoin . Block-

likely cau sed th ese adverse e ect s?

ade of w h ich of th e follow ing t ypes of ion ch an n els is m ost

A. Lith ium

likely to m ediate th e th erapeu t ic e

B. Flu p h en azin e

cacy of th e drug in th e

pat ien t’s disease?

C. Flu oxet in e

A. Na + ch an n els in th e rest ing state

D. Diazepam

B. Na + ch an n els th at open an d close at h igh frequen cy

E. Valproic acid

C. Na + ch an n els th at open an d close at low frequen cy

F.

D. K+ ch an n els in a rest ing st ate

G. Ph enytoin

Gabap en t in

E. K+ ch an n els th at open an d close at h igh frequen cy F.

K+ ch an n els th at open an d close at low frequen cy

Di cult y level: Medium 9. A 26-year-old w om an discovered she w as unexpectedly preg-


n an t . Sh e h ad been regularly t aking an oral con t racept ive

6. A 32-year-old w om an com plain ed to h er physician th at t w o

m edicat ion for several years. Tw o m on th s earlier, sh e w as

breakth rough seizu res occu rred last w eek. On e m on th earlier

diagnosed w ith com plex partial seizures and started th e pre-

th e w om an w as diagn osed w ith sim ple par t ial seizure an d

scribed th erapy. W h ich of th e follow ing d rugs w as sh e m ost

star ted t reat m en t w ith an an t iep ilept ic drug. Th e p hysician

likely t aking?

in creased th e d ose of th e drug, th in king th at th e decreased

A. Lam ot rigin e

e ect w as m ost likely becau se th e drug is a p oten t en zym e

B. Valproic acid

in d u cer an d can in d u ce it s ow n m et abolism . W h ich of t h e

C. Clon azepam

follow ing drugs did th e pat ien t m ost likely take?

D. Gabap en t in

A. Valproic acid

E. Levet iracet am

B. Carbam azepin e

F.

Carbam azepin e

C. Lam ot rigin e D. Eth osu xim ide


E. Clon azepam

10. A 41-year-old m an w as ad m it ted to t h e h osp it al after h e su ered a seizure w ith loss of con sciou sn ess w h ile at h om e.


Tw o w eeks earlier, th e m an w as involved in a car acciden t

7. A 45-year-old m an recen tly diagn osed w ith part ial seizures

an d h ad su ered from a closed h ead inju r y. A n eu rologic ex-

ce for a rou t in e visit . Th e m an

am ination and an electroencephalogram led to the discovery

h ad been receiving an an t iseizure drug for th e past 3 m on th s.

of an epilept ic focus in th e pat ien t’s tem poral lobe. Th e n eu-

An elect roen ceph alogram sh ow ed left tem poral sh arp w aves,

rologist ordered an an t iconvulsan t drug th at m ost likely act s

and the neurologist decided to add lam otrigine to the patient’s

w ith m ult iple m ech an ism s, in cluding blockade of N-m ethyl-

cam e to h is n eu rologist’s o

d -aspart ate

(NMDA) receptor−m ediated excit at ion , blockade

Questions: III-6 Antiseizure Drugs 97 of T-t ype Ca 2+ ch an n els in th alam ic n euron s, an d in creased

A. Levet iracet am

gam m a-am in obu t yr ic acid (GABA) con ten t in t h e brain .

B. Carbam azepin e

W h ich of th e follow ing drugs w as m ost likely prescribed?

C. Valproic acid

A. Valproic acid

D. Ph en obarbital

B. Gabap en t in

E. Clon azepam

C. Tiagabin e

F.

Zon isam id e

D. Levet iracetam E. Eth osu xim ide


F.

14. A 36-year-old w om an recen tly diagn osed w ith sim ple par-

Clon azepam

t ial seizu res started a th erapy w ith lam ot rigin e. W h ich of th e


follow ing adverse e ects is m ost likely to occur during th e

11. A 12-year-old boy w h o w as recen tly diagn osed w ith absen ce

th erapy?

seizu res st arted a th erapy w ith eth osu xim ide. W h ich of th e

A. Macrocyt ic an em ia

follow ing m olecular act ion s m ost likely m ediated th e th era-

B. Hallu cin at ion s

p eu t ic e

C. Liver cirrh osis

cacy of th e drug in th e pat ien t’s disorder?

A. Open ing of voltage-gated K+ ch an n els

D. Pan creat it is

B. Blockade of T-t ype Ca 2+ ch an n els

E. Lu poid syn drom e

C. Blockade of ligan d -gated Na + ch an n els

F.

D. Act ivat ion of GABAA receptors

Er yth em atous skin rash

E. Blockade of NMDA receptors


F.

15. A 35-year-old w om an experien ced an abrupt on set of un i-

Act ivat ion of 5-HT1 receptors

lateral clon ic con t ract ion s of h er

nger t h at p rogressively


involve h er h an d , t h en low er an d u p p er ar m . Histor y re-

12. A 14-m on th -old baby boy exh ibited jerkin ess of th e upper

vealed th at sh e h ad sustain ed a brain t raum a 5 m on th s ear-

lim bs for a few w eeks. Th e jerks n ever cau sed h im to fall bu t

lier. Sh e w as diagn osed w ith sim ple p ar t ial seizu re, an d an

w ere repeated several dozen s of t im es each day, in clu ding

app ropriate d rug w as prescribed. A drug w ith w h ich of th e

w h en falling asleep. An elect roen ceph alogram sh ow ed th at

follow ing m ech an ism s of act ion w ould be appropriate for

th e jerks w ere com bin ed in all in stan ces w ith sp ike w aves,

th e p at ien t’s disease?

and th at there w as an increase of jerks and spike w aves w hen

A. Blockade of n eurom uscu lar t ran sm ission

h e fell asleep. W h ich of th e follow ing drugs w ould be m ost

B. Blockade of in act ivated K+ ch an n els

app ropriate for th is boy?

C. Decreased release of gam m a-am in obu t yric acid (GABA) from n er ve term in als

A. Ph enytoin B. Carbam azepin e

D. Act ivat ion of glu t am ate receptor in th e m otor cor tex

C. Ph en obarbital

E. Blockade of in act ivated Na + ch an n els

D. Valproic acid E. Gabap en t in


F.

16. A 39-year-old m an diagn osed w ith ton ic-clon ic seizures 2

Acetazolam ide

years ago h ad been receiving a drug th at exh ibit s dose-


depen dent elim in ation kinetics. W h ich of the follow ing drugs

13. A 54-year-old w om an w ith a previously w ell-con t rolled sei-

d id th e pat ien t m ost likely t ake?

zu re d isorder w as brough t to t h e h osp it al becau se of re-

A. Valproic acid

cu r ren t , gen eralized ton ic-clon ic seizu res. Th e p at ien t w as

B. Lam ot rigin e

in t ubated an d m ech an ically ven t ilated. Sh e w as t reated w ith

C. Ph enytoin

in t raven ous diazepam an d fosph enytoin bu t con t in ued to

D. Topiram ate

exh ibit in term it ten t seizures an d did n ot regain con scious-

E. Carbam azepin e

n ess bet w een th em . A diagn osis of refractor y st at us epilept i-

F.

cu s w as m ade. A large dose of w h ich of th e follow ing d rugs w ou ld be ap prop riate to add to th e pat ien t’s th erapy at th is t im e?

Gabap en t in

98




17. A 54-year-old m an h ad been receiving carbam azepin e sin ce

20. A 35-year-old w om an , recen tly diagn osed w ith sim ple par-

h e w as diagn osed w ith com plex par t ial seizures 5 years ear-

t ial seizu res, star ted th e p rescribed th erapy. Her p ast h istor y

lier. Th e drug w as fu lly e ect ive in con t rolling th e seizu res.

w as un rem arkable, bu t h er m oth er w as kn ow n to su er from

Blockade of w h ich of th e follow ing m olecular targets m ost

acu te in term it ten t porp hyria. W h ich of th e follow ing an t i-

likely m ediated th e th erap eu t ic e ect of th e drug in th e p a-

convulsan t drugs w ould be appropriate for th is pat ien t?


A. Diazepam

A. Acet ylch olin e receptors

B. Eth osu xim ide

B. Glut am ate receptors

C. Valproic acid

C. Mon oam in e receptors

D. Carbam azepin e

D. Na + ch an n els

E. Ph enytoin

E. K+ ch an n els

F.

F.

Lam ot rigin e

Ca 2+ ch an n els

Di cult y level: Hard Di cult y level: Medium

21. An 81-year-old m ale residen t of a n ursing facilit y recen tly

18. A 53-year-old m an su ering from par t ial seizures h ad been

d eveloped a p ar t ial seizu re disorder secon dar y to a st roke.

receiving a h igh dose of carbam azepin e for 6 m on th s. W h ich

Th e m an h ad m u lt ip le m ed ical p roblem s, in clu ding liver cir-

of th e follow ing dose-related adverse e ects m ost likely oc-

rh osis, open -angle glau com a, t ype 2 diabetes m ellit u s, an d a

cu rred du ring th e th erapy?

h istor y of kidn ey ston es. He h ad been t aking m ult iple m edi-

A. Gingival hyperplasia

cat ion s for th ese con dit ion s. Th e n eu rologist ordered a drug

B. Hallucin at ion s

to t reat th e pat ien t’s seizure disorder. W h ich of th e follow ing

C. Ataxia

d rugs w ou ld be m ost app ropriate for th is pat ien t?

D. Steven s−Joh n son syn drom e

A. Levet iracet am

E. Hear t failu re

B. Ph enytoin

F.

C. Carbam azepin e

Dilut ion al hypon at rem ia

D. Valproic acid


E. Topiram ate

19. A 13-m on th -old boy w as brough t to th e h ospit al after h av-

F.

Zon isam id e

ing a gen eralized ton ic-clon ic convulsion last ing approxim ately 4 m in u tes. Th e ep isode occu rred in associat ion w ith


an u p per resp irator y t ract in fect ion . On adm ission h is rectal

22. A 12-year-old boy w ith a long h istor y of Len n ox−Gastau t

tem perat u re w as 103°F (39.4°C). Th e p aren t s rep or ted th at

syn drom e w as adm it ted to th e n eu rologic clin ic for evalu a-

t w o sim ilar ep isodes occu rred 8 an d 3 m on th s ago, alw ays in

t ion . In th e p ast , th e boy h ad been t reated w ith several drugs,

associat ion w ith fever. Th e boy h ad n o h istor y of n eu rologic

bu t th e resp on se to th e an t iep ilept ic th erapy w as rath er

abnorm alit y, and all laborator y and neurologic ndings w ere

p oor. After a n eu rologic exam in at ion an d an elect roen cep h -

n orm al. A presum pt ive diagn osis w as m ade, an d m easu res

alogram , th e n eu rologist decided to p rescribe an an t iep ilep -

to reduce h is elevated tem perat ure w ere in it iated. Th e par-

t ic drug w ith a broad sp ect ru m of act ion , in clu ding p ar t ial,

en t s w ere in st ru cted to give a d rug rect ally to th e boy w h en -

ton ic- clon ic, m yoclon ic, an d aton ic seizu res, as w ell as in -

ever h e h ad fever. W h ich of t h e follow in g an t iconvu lsan t

fan t ile spasm an d Len n ox−Gast au t syn drom e. W h ich of th e

d rugs w ou ld be m ost appropriate for th is boy?

follow ing drugs w as m ost likely prescribed?

A. Carbam azepin e

A. Ph en obarbital

B. Topiram ate

B. Topiram ate

C. Diazepam

C. Tiagabin e

D. Eth osu xim ide

D. Zon isam id e

E. Zon isam ide

E. Carbam azepin e

F.

F.

Felbam ate

Ph enytoin

G. Gabap en t in

Questions: III-6 Antiseizure Drugs 99 Di cult y level: Medium 23. A 52-year-old m an cam e to h is n eurologist’s o

Di cult y level: Medium ce for a rou-

26. A 44-year-old m an com plain ed to h is physician of burn ing

t in e visit . Medical h istor y revealed th at h e h ad a m yocardial

an d t ickling in h is h an ds an d feet . Th e m an w as d iagn osed

in farct ion 2 years ago an d h ad been su ering from a th ird-

w ith ton ic-clon ic seizures 3 years earlier an d h ad been re-

d egree at r ioven t r icu lar block sin ce t h en . On e m on t h ear-

ceivin g a h igh d ose of an an t iseizu re d r ug sin ce t h en . Phys-

lier, h e w as d iagn osed w it h sim p le p ar t ial seizu res an d w as

ical exam in at ion disclosed large inguin al lym ph n odes, an d

p rescribed lam ot rigin e. Th e seizure at tacks w ere d im in ish ed

re ex test ing sh ow ed a lack of kn ee an d an kle ten d on re-

but n ot com pletely con t rolled. Th e n eurologist decided to

exes. Fu r t h er lab exam s sh ow ed m egaloblast ic an em ia.

d iscon t in ue lam ot rigin e an d to st ar t an oth er drug. W h ich of

W hich of the follow ing drugs m ost likely caused the patient’s

t h e follow in g d r ugs w ou ld be ap p rop r iate for t h e p at ien t


at th is t im e?

A. Gabap en t in

A. Eth osu xim ide

B. Lam ot rigin e

B. Gabap en t in

C. Clon azepam

C. Diazepam

D. Ph enytoin

D. Acetazolam ide

E. Levet iracet am

E. Carbam azepin e

F.

F.

Tiagabin e

Ph enytoin

Di cult y level: Medium Di cult y level: Medium

27. A 44-year-old w om an com plain ed to h er physician of day-

24. A 24-year-old w om an w ith a long h istor y of absen ce sei-

t im e sedat ion an d dip lopia. Th e w om an h ad been su ering

zu res h ad been su ccessfu lly m an aged w ith valp roic acid for

from ton ic-clon ic seizu res for 1 year an d h ad been t reated

the past 5 years. The patient had recently m arried, and during

w ith ph enytoin . Recen tly, th e n eu rologist h ad sligh tly in -

h er last o

ce visit sh e expressed th e desire to st art a fam ily.

creased th e dose of th e drug becau se th e seizu res w ere n ot

W h ich of th e follow ing drugs w ould be m ost appropriate for

com pletely con t rolled. Th e physician told th e pat ien t th at

th is p at ien t to su bst it u te for valproic acid th erapy?

h er sym ptom s w ere probably due to overdose toxicit y of th e

A. Carbam azepin e

d rug. W h ich of th e follow ing st atem en ts m ost likely exp lain s

B. Clon azepam

th e reason for th is toxicit y?

C. Ph enytoin

A. Th e w om an develop ed hypersen sit ivit y to th e drug.

D. Eth osu xim ide

B. Th e rst-pass e ect of th e drug w as u n exp ectedly h igh .

E. Ph en obarbital

C. Th e volu m e of d ist ribu t ion of th e drug is ver y low.

F.

D. Th e clearan ce of th e dr ug is dose-dep en den t .

Tiagabin e

E. Th e steady st ate of th e drug w as reach ed too qu ickly.

Di cult y level: Hard 25. A 45-year-old m an visited h is p hysician’s o

ce for con su l-


t at ion regarding h is an t im igrain e m ed icat ion . Th e m an h ad

28. A 10-year-old girl w as brough t to th e n eurology clin ic by h er

a 1-m on th h istor y of disabling m igrain e h eadach es occu r-

m oth er, w h o rep or ted th at h er daugh ter h ad t w o ton ic-

r ing t w o or th ree t im es w eekly. Abou t 70% of h is h eadach e

clon ic seizures in th e past 7 days. Th e girl’s teach er h ad also

at t acks h ad been abor ted w it h on e su m at ript an t ablet an d

n oted th at th e girl h ad four episodes of “st aring” in 1 day

rest . Th e pat ien t h ad also been su ering from idiop at h ic

d uring th is sam e t im e period . Th e girl h ad a h istor y of ab -

secon d-degree at rioven t ricular block diagn osed 3 years ago

sen ce seizu res for w h ich sh e h ad been t aking eth osu xim ide

an d from op en -angle glau com a for 4 years. W h ich of th e fol-

for th e past 2 m on th s. W h ich of th e follow ing ch anges in th e

low ing p rophylact ic th erap ies w ou ld be app rop riate for th is

p at ien t’s th erapy w ou ld be m ost appropriate at th is t im e?

p at ien t to redu ce th e frequen cy of m igrain e at tacks?

A. Discontinue ethosu xim ide and substitute phenobarbital.

A. Aten olol

B. Discontinue ethosu xim ide and substitute carbam azepine.

B. Verapam il

C. In crease eth osu xim ide dose an d add diazepam .

C. Am it ript ylin e

D. In crease eth osu xim ide dose an d add ph en obarbit al.

D. Lam ot rigin e

E. Discon t in ue eth osu xim ide an d su bst it ute valproic acid.

E. Valproic acid F.

Felbam ate

100




29. A 15-m on t h -old boy w as ad m it ted to t h e h osp it al becau se

32. A 10-year-old girl su ering from Len n ox−Gast aut syn drom e

of repeated ep isodes of pow erfu l con t ract ion s of t ru n k an d

recen tly h ad felbam ate added to h er cu rren t th erapy. W h ich

lim b m u scles t h at lasted 5 to 10 secon d s. Th ese ep isod es

of t h e follow in g act ion s on brain receptors m ost likely m e-

occu rred in clu sters, frequ en tly u pon aw aken ing. A brain

d iated t h e t h erap eu t ic e ect of t h e d r ug in t h e p at ien t ’s

m agn et ic reson an ce im age sh ow ed agen esis of th e corp u s

d isorder?

callosu m . An app ropriate diagn osis w as m ade, an d a th erapy

A. Blockade of GABAA receptors

w as prescribed . W h ich of th e follow ing drugs w ou ld be ap p ropriate for th e t reat m en t of th is p at ien t?

B. Act ivat ion of GABAB receptors C. Blockade of 5-HT1 receptors

A. Carbam azepin e

D. Act ivat ion of AMPA receptors

B. Eth osu xim ide

E. Blockade of NMDA receptors

C. Ph enytoin

F.

Act ivat ion of 5-HT3 receptors

D. Ph en obarbital E. Predn ison e

Di cult y level: Medium 33. A 64-year-old m an w as brough t to th e h ospit al after t w o

Di cult y level: Hard.

con secut ive seizures at h om e. On adm ission , h e w as n oted to

30. A 50-year-old m an com plain ed of occasion al episodes of ex-

be on ly sem icon sciou s, an d sh or tly after h is arrival an oth er

cru ciat ing u n ilateral facial pain th at arose n ear th e m ou th ,

ton ic-clon ic seizure began . He w as given in t raven ous loraze-

d i u sed tow ard th e n ost rils an d eyes, an d seem ed to be t rig-

p am , an d seizu re act ivit y ceased 5 m in u tes after t h e injec-

gered by eat ing or talking. Th e pain lasted abou t 1 m in u te.

t ion w as com p leted . At t h is t im e, w h ich of t h e follow in g

He w as referred to a n eu rologist , w h o m ade a p resu m pt ive

d rugs w as m ost likely adm in istered for p rolonged con t rol of

d iagn osis an d ordered an appropriate t reat m en t . W h ich of

th e p at ien t’s seizu res?

th e follow ing drugs w ou ld be app ropriate for th is pat ien t?

A. Levet iracet am

A. Ph en obarbital

B. Tiagabin e

B. Clon azepam

C. Eth osu xim ide

C. Codein e

D. Fosph enytoin

D. Diclofen ac

E. Zon isam id e

E. Carbam azepin e

F.

Felbam ate



31. A 15-year-old boy w as in th e n eurology clin ic for a rout in e

34. A 34-year-old w om an com plain ed to h er n eu rologist of a

visit . Tw o m on th s earlier, th e boy w as diagn osed w ith ab -

p ron ou n ced skin rash . Tw o w eeks earlier, th e w om an h ad

sen ce seizu res an d st ar ted th erapy w ith eth osu xim ide. He

been diagnosed w ith sim ple partial seizure and started treat-

repor ted th at th e drug decreased th e frequen cy of h is sei-

m en t w ith lam ot rigin e. Sh e rep or ted th at ap p aren tly th e

zu res, bu t h e st ill h ad som e absen ce at t acks from t im e to

th erapy w as e ect ive, as sh e h ad n ot su ered any at tacks

t im e. After fu rth er exam s, th e n eu rologist decided to ad d a

d uring th e t reat m en t . Physical exam in at ion sh ow ed an ex-

d rug th at m ost likely act s by in creasing th e carbon dioxide

ten sive er yth em atous rash over h er t ru n k an d abdom en . Th e

con cen t rat ion w ith in brain n euron s. W h ich of th e follow ing

n eu rologist w as cer t ain t h at th e adverse e ect w as dr ug-

d rugs w as m ost likely prescribed?

related . He d ecid ed to su bst it u te t h e o en d ing d r ug w it h

A. Eth osu xim ide

an ot h er agen t t h at m ost likely act s by blockin g bot h Na +

B. Levet iracet am

ch an n els an d Ca 2+ ch an n els on brain n euron s. W h ich of th e

C. Tiagabin e


D. Acetazolam ide

A. Felbam ate

E. Zon isam ide

B. Ph en obarbital

F.

C. Clon azepam

Felbam ate

D. Zon isam id e E. Carbam azepine F.

Levet iracet am

Questions: III-6 Antiseizure Drugs 101 Di cult y level: Easy


35. A 12-year-old girl w as adm it ted to th e h ospit al because of

38. A 37-year-old m an recen tly diagn osed w ith gen eralized sei-

vom it ing, drow sin ess, leth argy, an d jau n dice of 6 h ou rs’ du -

zu res star ted t reat m en t w ith valproic acid, bu t 1 m on th later

rat ion . Th e girl h ad a long h istor y of refractor y absen ce sei-

th e frequ en cy of seizu res w as n ot sign i can tly redu ced . His

zu re an d h ad been receiving several drugs over th e p ast 2

n eurologist decided to add a secon d-gen erat ion an t iepilep -

years. Sh e w as p resen tly t reated w ith t w o an t iseizu re agen ts

t ic drug th at blocks voltage-gated Na + an d Ca 2+ ch an n els an d

an d h ad n o absen ce seizu res for 5 w eeks. Physical exam in a-

m ay in h ibit th e syn apt ic release of glut am ate. W h ich of th e

t ion sh ow ed a p at ien t in obviou s dist ress w ith exten sive


jaun dice of th e skin an d sclera. Sign i can t lab results on ad-

A. Gabap en t in

m ission w ere alan in e am in ot ran sferase 400 U/L (n orm al

B. Lam ot rigin e

10−40 U/L), tot al biliru bin 20 m g/d L (n orm al 0.3−1.0 m g/dL),

C. Ph en obarbital

an d am m on ia 190 µg/d L (n or m al for ch ild ren 36−85 µg).

D. Diazepam

W hich of the follow ing drugs m ost likely caused the pat ien t’s

E. Eth osu xim ide


F.

Felbam ate

A. Eth osu xim ide B. Valproic acid


C. Lam ot rigin e

39. A 54-year-old m an w as recen tly diagn osed w ith com plex

D. Levet iracet am

p ar t ial seizure. Th e pat ien t h ad been su ering from at rio-

E. Zon isam ide

ven t ricu lar block for 1 year an d from n eph rolith iasis for

F.

3 years. W h ich of th e follow ing an t iep ilept ic drugs w ou ld

Clon azepam


Di cult y level: Easy 36. A 6-year-old girl w as diagn osed w ith m yoclon ic seizu res. A

A. Carbam azepin e B. Ph enytoin

brain m agnetic resonance im age showed no overt neurologic

C. Valproic acid

d e cit . Her past m edical h istor y w as n egat ive for epilept ic

D. Eth osu xim ide

seizu res. W h ich of th e follow ing drugs w ou ld be ap p rop riate

E. Zon isam id e

for th is pat ien t? A. Carbam azepin e


B. Haloperidol

40. A 45-year-old m an w as in th e n eu rology clin ic for a rout in e

C. Ph en obarbital

visit . Tw o m on th s earlier, th e m an w as diagn osed w ith sim -

D. Ph enytoin

p le par t ial seizu re an d st arted th erapy w ith lam ot rigin e. He

E. Fluoxet in e

repor ted th at th e drug w as able to decrease th e frequen cy of

F.

h is at t acks, but h e st ill h ad an occasion al at tack. Th e n eurol-

Clon azepam

ogist decided to add a drug th at act s by open ing a cert ain


fam ily of pot assiu m ch an n els on brain n euron s. W h ich of th e

37. A 44-year-old w om an cam e to h er n eu rologist for a rout in e


visit . Th e pat ien t h ad a long h istor y of poorly con t rolled sim -

A. Levet iracet am

p le part ial seizures. Tw o m on th s ago, sh e st arted th erapy

B. Felbam ate

w ith valproic acid th at w as on ly part ially e ect ive. Th e n eu -

C. Topiram ate

rologist decided to add to th e ongoing th erapy a recen tly ap -

D. Peram pan el

p roved drug th at m ost likely acts w ith a n ovel m ech an ism of

E. Ezogabin e

act ion , a n on com pet it ive blockade of α -am in o-3-hydroxy-

F.

5-m et hylisoxazole-4-p rop ion ic acid (AMPA) receptors on brain n eu ron s. W h ich of t h e follow in g d r ugs w as m ost likely prescribed? A. Eth osu xim ide B. Gabap en t in C. Diazepam D. Peram pan el E. Lam ot rigin e F.

Carbam azepin e

Zon isam id e

102


Questions: III-7 Drugs for Degenerative Disorders of the Central Nervous System Directions for questions 1−5

d isease. His th erapy w ith levodopa/carbidopa h ad resu lted


in im provem en t in rigid it y, bradykin esia, an d post ure, as

m ost closely associated w ith it (each let tered opt ion can be se-

w ell as im p rovem en t in th e “on -o ” e ect s, bu t h e h ad ex-

lected on ce, m ore th an on ce, or n ot at all).

p erien ced lit tle if any im provem en t in t rem or. W h ich of th e

A. Am an t adin e B. Ben zt ropin e

follow ing th erapeut ic approach es w ou ld be appropriate to reduce th e pat ien t’s t rem or?

C. Brom ocript in e

A. Decrease th e dose of carbidopa.

D. Carbidopa

B. Su bst it u te levodopa/carbid op a w ith p ram ip exole.

E. Don epezil

C. Add ben zt rop in e to th e p resen t d rug regim en .

F.

D. Add prop ran olol to th e p resen t drug regim en .

En t acapon e

G. Levodopa

E. St art brief periods of “drug h olidays” du ring th erapy.

H. Mem an t in e I.

Selegilin e

Di cult y level: Easy 8. A 62-year-old m an com plain ed to h is physician of facial gri-


m acing, lip sm acking, an d rocking of th e t ru n k th at occu rred

1. A cen t ral m uscarin ic receptor blocker

1 to 2 h ou rs after taking h is p rescribed m edicat ion . Th e m an , w h o su ered from Parkin son d isease, h ad been receiving

Di cult y level: Easy 2. A cen t ral acet ylch olin esterase in h ibitor

Di cult y level: Easy 3. An N-m ethyl- d -aspart ate (NMDA) receptor blocker used in Alzh eim er disease

Di cult y level: Easy 4. A select ive m on oam in e oxygen ase B (MAO B) in h ibitor

Di cult y level: Easy 5. A peripheral inhibitor of catechol-O-m ethyltransferase (COMT)


an an t ip arkin son d r ug for 3 years. W h ich of th e follow in g d rugs m ost likely cau sed th e adverse e ect s rep orted by th e p at ien t? A. Selegilin e B. Levodopa C. En t acapon e D. Am an t adin e E. Ben zt ropin e

Di cult y level: Easy 9. A 75-year-old diabet ic m an w ith Parkin son disease com p lain ed of w orsen ing of h is t rem or an d rigidit y in h is arm s an d legs. His Parkin son disease h ad been resp on ding w ell to a t reat m en t w ith levodop a/carbidopa an d am an t adin e, an d h is diabetes h ad been controlled by glyburide and m etform in.

6. A 63-year-old m an recen tly diagn osed w ith Parkin son dis-

Recen tly, m etoclopram ide was prescribed to m anage diabetic

ease started treat m ent w ith levodopa/carbidopa. W h ich of th e

gast rop aresis. W h ich of th e follow ing drugs cou ld h ave t rig-

follow ing act ion s m ost likely m ediated th e th erapeu t ic e ect

gered th e w orsen ing of sym ptom s rep or ted by th e p at ien t?

of levodopa in th e pat ien t’s disease?

A. Glyburide

A. Dow n regu lat ion of d op am in ergic receptors in t h e

B. Am an t adin e

st r iat u m B. In creased syn t h esis of d op am in e in t h e su bt h alam ic n ucleus

C. Carbidopa D. Metform in E. Metoclop ram ide

C. In creased syn th esis of dopam in e in th e st riat um D. In h ibit ion of dopa decarboxylase in th e st riat um


E. In h ibit ion of catech ol-O-m et hylt ran sferase in t h e su b -

10. A 53-year-old m an com plain ed to h is physician of persisten t

stan t ia n igra


an d an n oying salivat ion . Th e m an , recen tly diagn osed w ith Parkin son disease, had started treatm en t w ith levodopa/ carbidop a th at sign i can tly im p roved h is m otor sym ptom s.

7. A 79-year-old m an w h o h ad been su ering from Parkin son

Th e p hysician d ecid ed to in clu de an oth er d rug in th e t reat-

disease for 5 years com p lain ed of a rest ing t rem or, w h ich

m en t . W h ich of th e follow ing drugs w ou ld be ap prop riate to

presen tly w as on e of th e m ost debilitat ing sym ptom s of h is

add to th e th erapy at th is t im e?

Questions: III-7 Drugs for Degenerative Disorders of the Central Nervous System 103 A. En t acapon e

A. Carbidopa

B. Selegilin e

B. En t acapon e

C. Ben zt ropin e

C. Ben zt ropin e

D. Pram ipexole

D. Pram ipexole

E. Apom orph in e

E. Clon azepam F.

Propran olol

Di cult y level: Hard 11. A 51-year-old w om an com plain ed of a rest ing t rem or in h er


left h an d, d i cu lt y in w rit ing, an d a dist ressing sen sat ion of

14. A 63-year-old w om an w ith Parkinson disease had been m ain-

in n er restlessn ess. After careful n eurologic exam in at ion , a

t ain ed on levod op a/carbidop a w ith adju n ct ive u se of a drug

diagnosis was m ade, and an appropriate therapy w as ordered

th at act s by redu cing cen t ral dopam in e m et abolism . W h ich

th at in clu ded a drug act ing as a par t ial agon ist at dop am in e

of th e follow ing drugs w as m ost likely th e adjun ct ive drug?

D2 receptors in the brain. W h ich of th e follow ing drugs w as

A. Levodopa

m ost likely prescribed?

B. Pram ipexole

A. Pram ipexole

C. Selegilin e

B. Dopam in e

D. Ph en elzin e

C. Clozapin e

E. Ben zt ropin e

D. Levodopa E. Ergotam in e


F.

15. A 57-year-old w om an w it h Parkin son d isease com p lain ed

Selegilin e

t h at h er t rem or h ad grad u ally w orsen ed over t h e p ast 2


w eeks. Sh e h ad been t akin g a levod op a/carbid op a com bi-

12. A 67-year-old m an presen ted to th e clin ic com plain ing of

n at ion for 6 m on t h s. Th e n eu rologist d ecid ed to ad d ben z-

vagu e ch est p ain s an d d i cu lt y in breath ing. Medical h is-

t rop in e to th e th erap eu t ic regim en , an d 2 w eeks later th e

tor y revealed th at th e pat ien t h ad been diagn osed w ith Par-

t rem or w as w ell con t rolled. W h ich of th e follow ing act ion s

kin son disease 10 years earlier an d h ad been using several

m ost likely m ediated th e redu ct ion in th e p at ien t’s t rem or?

an t ip arkin son drugs sin ce th en . Physical exam in at ion re-

A. In h ibit ion of levodopa m etabolism in th e st riat um

vealed prom in en t breath soun ds an d en d-in spirator y crack-

B. In h ibit ion of th e abn orm ally h igh ch olin ergic ton e in th e

les, prim arily at th e lu ng bases. An x-ray sh ow ed exten sive

st riat u m

h on eycom bing. A diagn osis of pu lm on ar y brosis w as m ade.

C. Act ivat ion of dop am in ergic receptors in th e st riat u m

W h ich of th e follow ing drugs w ould h ave been m ost likely to

D. Blockade of β 2 adren oceptors in skeletal m u scle

cau se th e p at ien t’s disorder?

E. Increased GABAergic activit y in the subthalam ic nucleus

A. Brom ocript in e B. Ben zt ropin e


C. Selegilin e

16. A 45-year-old w om an com p lain ed of blu r red vision , d r y

D. Am an t adin e

m ou t h , p alp it at ion s, an d con st ip at ion . Th e p at ien t w as d i-

E. Levodopa

agn osed w ith Parkin son disease 4 m on th s earlier an d h ad

F.

been receiving a levodopa/carbidopa com bin ation sin ce th en .

En t acapon e

Recen tly, h er n eu rologist add ed a d rug to th e th erapeu t ic


regim en becau se of an in crease in t h e p at ien t ’s rest in g

13. A 54-year-old m an com plain ed to h is physician of di cult y

t rem or. W h ich of th e follow ing drugs m ost likely cau sed th e

in w rit ing, because of un steadin ess in h is righ t h an d, an d


of t igh t n ess in h is arm s an d legs. Th ese sym ptom s star ted

A. Pram ipexole

abou t 1 w eek earlier. Physical exam in at ion sh ow ed a w ell-

B. Selegilin e

n ourish ed, an xiou s pat ien t w ith a n otable lack of n orm al

C. Levodopa

ch anges in facial expression an d w ith a soft , m on oton e voice.

D. Am an t adin e

Trem or w as presen t in h is h an ds, an d a fest in at ing gait w as

E. Ben zt ropin e

n oted. A diagn osis w as m ade, an d a single-agen t ph arm aco-

F.

th erapy w as p rescribed. W h ich of th e follow ing drugs w ou ld be ap prop riate for th is pat ien t?

Carbidopa

104



A. Blurred vision

17. A 53-year-old diabet ic w om an com plain ed to h er physician

B. Diarrh ea

of a recen t ap p earan ce of an u np leasan t , creep in g d iscom -

C. Post ural hypoten sion

for t in h er legs w h en sh e w as lyin g d ow n . Th e sen sat ion

D. Bradycardia

u rged th e w om an to m ove about , an d w alking relieved h er

E. Bradykin esia

sym ptom s. Sh e also com p lain ed of di cu lt y falling asleep an d in ter r u pted n oct u r n al sleep . A p relim in ar y d iagn osis


of restless leg syn drom e w as m ade, an d a th erapy w as p re-

21. A 52-year-old w om an w ith a long h istor y of Parkin son dis-

scribed. W h ich of th e follow ing d rugs w ou ld be m ost ap pro-

ease h ad been receiving levodopa/carbidopa. W hich of the

priate for th e p at ien t’s disorder?

follow ing adverse e ects of levodopa w ere m ost likely re-

A. Haloperidol

d uced by adding carbidop a to th e t reat m en t?

B. Ch lorprom azin e

A. Visual h allucin at ion s

C. Pram ipexole

B. Cardiac arrhyth m ias

D. Im ipram in e

C. Nigh t m ares

E. Carbidopa

D. Dyskin esias

F.

E. Mood ch anges

En t acapon e



18. A 59-year-old w om an h ad been su ering from Parkin son

22. A 53-year-old w om an presen ted to h er physician com plain -

d isease for 4 years. Her disease w as w ell con t rolled w ith a

ing of a u n ilateral rest ing t rem or an d slow ing d ow n of all

t h erapy t h at in clu d ed levod op a/carbid op a. W h ich of t h e

m ovem en t s. Her m ed ical h istor y w as sign i can t for t w o

follow in g act ion s m ost likely m ed iated t h e th erap eu t ic e

sch izop h ren ic ep isodes in h er late 40s th at w ere su ccessfu lly

-

cacy of carbidop a in th e p at ien t’s disease?

t reated w ith h alop eridol. On exam in at ion sh e sh ow ed cog-

A. Decreased dopam in e m et abolism in th e st riat um

w h eel rigidit y. A presu m pt ive diagn osis of parkin son ism

B. In creased act ive t ran spor t of dopam in e in to th e brain

w as m ade. W h ich of th e follow ing drugs w ou ld be con t rain -

C. In creased periph eral biot ran sform at ion of dopam in e

d icated for th is pat ien t?

D. Decreased periph eral biot ran sform at ion of levodopa

A. Am an t adin e

E. Decreased levodopa reuptake in th e st riat um

B. Carbidopa C. Pram ipexole


D. Ben zt ropin e

19. A 65-year-old m an com plain ed to h is physician th at recen tly

E. En t acapon e

h e felt in creasingly confused at tim es, often had vivid dream s, an d som et im es saw st range object s

oat ing in th e air. Th e


p at ien t , su ering from Parkin son disease, h ad been receiv-

23. A 62-year-old w om an w ith Parkin son disease h ad been re-

ing levodopa/carbidopa for 1 year, an d h is disease w as w ell

ceiving levodopa/carbidopa com bin at ion th erapy. Coadm in -

con t rolled. W h ich of th e follow ing act ion s could be im ple-

ist rat ion of w h ich of th e follow ing drugs w ou ld m ost likely

m en ted to redu ce th e occu rren ce of th e adverse e ects being

in crease th e availabilit y of levodop a in th e p at ien t’s brain ?

experien ced by th e pat ien t?

A. Haloperidol

A. Su bst it u te levodopa w ith selegilin e.

B. En t acapon e

B. Su bst it u te levodopa w ith p ram ip exole.

C. Ben zt ropin e

C. Add ben zt rop in e to th e p resen t regim en .

D. Pram ipexole

D. Add am an t adin e to th e p resen t regim en .

E. Brom ocript in e

E. Add clozap in e to th e presen t regim en .


24. A 68-year-old pat ien t w as recen tly diagn osed w ith Parkin -

20. A 78-year-old w om an recen tly diagn osed w ith Parkin son

son d isease. His m edical h istor y in clu ded ben ign prost at ic

d isease h ad been receiving levodopa/carbidopa for 3 w eeks.

hyp erplasia for 2 years an d ch ron ic con st ip at ion for 5 years.

W h ich of th e follow ing adverse e ect s could m ost likely

W h ich of th e follow ing an t iparkin son drugs w ould be con -

occur in th is pat ien t?

t rain dicated for th is pat ien t?

Questions: III-7 Drugs for Degenerative Disorders of the Central Nervous System 105 A. Levodopa


B. Ben zt ropin e

28. A 74-year-old w om an p resen ted to h er n eu rologist com -

C. Selegilin e

p lain ing of a recen t ap p earan ce of involu n t ar y, slow m ove-

D. Am an t adin e

m en t s involvin g h er t r u n k an d low er ext rem it ies. Th e

E. Pram ipexole

w om an , su ering from Parkin son disease, h ad been receiv-

F.

ing levodopa/carbidopa for 3 years. Furth er exam s led to th e

En t acapon e

d iagn osis of levodop a-in duced dyskin esias. W h ich of th e fol-


low ing drugs could be added to th e th erapy to decrease th e

25. A 74-year-old m an w h o h ad been su ering from Parkin son

p at ien t’s dyskin esias?

d isease for 4 years com p lain ed of a p u r p lish red m ot t ling

A. Selegilin e

of th e skin th at began on h is th igh s an d spread to h is low er

B. En t acapon e

legs. Th e erupt ion appeared 2 w eeks after a drug w as added

C. Pram ipexole

to h is th erapeu t ic regim en . A diagn osis of livedo ret icularis

D. Am an t adin e

w as m ade. W h ich of th e follow ing dr ugs m ost likely cau sed

E. Ph en elzin e

th is skin eru pt ion ? A. Levodopa


B. Carbidopa

29. A 78-year-old m an h ad been sh ow ing in creasing m em or y

C. Selegilin e

im pairm en t an d recogn it ion d e cit s over th e past 2 years.

D. Am an t adin e

Recen t ly, h e becam e d isor ien ted an d con fu sed at n igh t .

E. Pram ipexole

Physical exam in at ion revealed an aler t p erson or ien ted to

F.

p lace w ith n o focal n eu rologic de cits. His p hysician p re-

Ben zt ropin e

scribed a d rug th at m igh t h elp to slow th e p rogression of h is


sym ptom s. W h ich of th e follow ing d rugs w ou ld be app ropri-

26. A 63-year-old w om an com plain ed to h er physician of fre-


qu en t p alp it at ion s. Th e w om an , recen t ly d iagn osed w it h

A. Buspiron e

Parkin son disease, h ad been receiving levodopa/carbidop a for

B. Diazepam

3 w eeks. Su bsequ en t exam s led to th e diagn osis of sin u s

C. Rivast igm in e

tachycardia likely due to the antiparkinson therapy. W hich of

D. Haloperidol

th e follow ing act ion s m ost likely m ediate th e adverse e ect

E. Physost igm in e

repor ted by th e pat ien t? A. Act ivat ion of cardiac dop am in e receptors


B. Decreased acet ylch olin e release from ch olin ergic ter-

30. A 64-year-old m an w ith Parkin son disease com plain ed of

m in als

p eriod s of a few m in u tes of com plete im m obilit y, follow ed

C. Act ivat ion of cardiac β receptors

by a sudden sw itch to involun t ar y m ovem en t s, such as

D. Blockade of cardiac M 2 receptors

t w itch ing, n odding, an d jerking. Th e pat ien t’s cu rren t m edi-

E. In creased sym path et ic ring from th e vasom otor cen ter

cation s in clu ded levodopa/carbidopa. To reduce th ese rapid u ct u at ion s, t h e n eu rologist red u ced t h e daily d ose of


levodopa/carbidopa an d add ed a drug. W h ich of th e follow -

27. A 72-year-old w om an recen t ly d iagn osed w it h Alzh eim er

ing drugs w as m ost likely p rescribed?

d isease st ar ted a p h ar m acot h erapy w it h don ep ezil. W h ich

A. Am an t adin e

of th e follow ing set s of adverse e ect s m ost likely occurred

B. Ben zt ropin e

d uring th e rst days of t reat m en t?

C. Haloperidol

A. Hyp er ten sion , palp itat ion s

D. Pram ipexole

B. Nausea, vom it ing an d diarrh ea

E. Flu oxet in e

C. Dr y m outh , an h idrosis D. Drow sin ess, leth argy E. Mydriasis, cycloplegia

106



im m ediately after m eals an d said th at th e e ect sh ou ld su b -


sid e in a few days. W h ich of th e follow ing dr ugs m ost likely

d rugs sh e w as t aking caused a dist urbing n au sea. Medica-

cau sed th e p at ien t’s n au sea?

t ion p resen tly t aken by th e p at ien t in clu d ed om eprazole for

A. Carbidopa

h ear t bu r n an d cip ro oxacin for a u r in ar y t ract in fect ion .

B. Ben zt ropin e

On e w eek earlier, t h e w om an w as d iagn osed w it h Parkin -

C. Pram ipexole

son d isease an d st ar ted an ap p rop r iate t reat m en t . Th e p hy-

D. Om eprazole

sician advised th e pat ien t to t ake th e drug in divided doses

E. Cipro oxacin

Questions: III-8 Neuroleptic Drugs Directions for questions 1−3

A. Fron tal cor tex

Match each n eu rolept ic d rug w ith th e ap prop riate d escript ion

B. Vest ibular n uclei


C. Mesolim bic p ath w ay

at all).

D. St riat u m E. Tuberoin fun dibular path w ay

A. Aripiprazole

F.

B. Ch lorprom azin e C. Clozapin e


D. Fluph en azin e

5. An 82-year-old m an w h o w as a residen t in a n ursing facilit y

E. Haloperidol F.

Cerebellu m

presen ted w ith com p lete u rin ar y reten t ion . Th e m an h ad a

Risperidon e

G. Th ioridazin e

long h istor y of hyp er ten sion an d p rostat ic hyperp lasia an d

H. Th iot ixen e

w as cu rren tly being t reated w ith hydroch loroth iazide, captopril, an d p razosin . Tw o days earlier, h e becam e agit ated an d h ost ile, refused to cooperate, an d t ried to assault oth er resi-

Di cult y level: Easy 1. A drug w ith h igh a

n it y for dopam in e D4 receptors

Di cult y level: Easy 2. A ph en oth iazin e th at frequ en tly causes ext rapyram idal adverse e ects

Di cult y level: Easy 3. A par t ial agon ist at cen t ral dopam in ergic receptors

Di cult y level: Medium 4. A 44-year-old w om an w as adm it ted to th e psych iat ric h ospital for th e sixth t im e sin ce th e age of 36. Sh e w as con fu sed an d th reaten ing, saying th at “th e voices are back.” Th e w om an h ad been on an t ip sych ot ic t h erapy for several years, bu t sh e h ad stop p ed h er m ed icat ion s 1 m on t h p r ior to t h is ad m ission . Physical exam in at ion sh ow ed abn orm al involun tar y m ovem en t s m an ifested by tongue prot rusion , frequen t blin king, an d con t in u ou s w rith ing of h er arm s an d legs. A drugin du ced p rim ar y dysfu n ct ion in w h ich of th e follow ing brain region s w as m ost likely resp on sible for t h e p at ien t ’s syn drom e?

den t s. He received 50 m g of ch lorprom azin e in t ram u scu larly an d a secon d inject ion 8 h ou rs later. W h ich of t h e follow ing w ou ld be t h e m ost likely exp lan at ion for h is u r in ar y reten t ion ? A. Decreased diu resis due to ch lorprom azin e B. Chlorprom azine-induced relaxation of the detrusor m uscle C. Decreased diu resis due to captopril D. Prazosin -in duced relaxat ion of th e r in tern al sph in cter of th e bladder E. Prazosin -in duced relaxat ion of th e prost ate capsule

Di cult y level: Medium 6. A 34-year-old w om an recen tly diagn osed w ith u n di eren t iated schizophren ia started treatm ent w ith h aloperidol. W hich of th e pat ien t’s presen t ing sym ptom s w as m ost likely best con t rolled after 1 w eek of th erapy? A. Social w ith draw al B. Lack of em ot ion C. Low en ergy D. Persecutor y delusion s E. A ect ive at ten ing

Questions: III-8 Neuroleptic Drugs 107 Di cult y level: Easy


7. A 30-year-old m an com plain ed of dr y m outh , con st ipat ion ,

10. A 32-year-old w om an w as brough t to th e h ospital after sh e

an d blurred vision w h ile reading th e n ew spaper. Th e m an , re-

w as fou n d un con sciou s in a park on a h ot sum m er day. Th e

cen tly diagn osed w ith a sch izoid disorder, h ad st ar ted t reat-

w om an h ad been a residen t in a psych iat ric u n it for th e past

m en t w ith clozap in e 2 w eeks p reviou sly. Blockade of w h ich

year. Sh e h ad a h istor y of a ch ron ic m en t al disorder, bu t sh e

of th e follow ing receptors m ost likely m ediated th e adverse

h ad recen tly sh ow n im provem en t in h er target sym ptom s

e ect s reported by th e p at ien t?

an d enjoyed ou t side p rivileges. Sh e h ad left th e w ard to go

A. 5-HT2 seroton ergic

jogging 2 h ours before being foun d in th e park. Her rect al

B. Alph a-1 adren ergic

tem perat u re w as 105°F (40.6°C), an d a diagn osis of h eat

C. H1 h ist am in ergic

st roke w as m ade. W h ich of th e follow ing drugs m ost likely

D. Nm ch olin ergic

con t ributed to th e developm en t of th e pat ien t’s h eat st roke?

E. M 3 ch olin ergic

A. Am it ript ylin e B. Clozapin e


C. Buspiron e

8. A 23-year-old h ealthy volu n teer received a n ew poten t ial

D. Diazepam

n eurolept ic drug in t raven ously during a ph ase I clin ical t rial.

E. Lith ium

It w as kn ow n th at th e drug h ad sign i can t blocking act ivit y

F.

on d op am in e D2 , h ist am in e H 1 , an d seroton in 5-HT2A recep -

Flu oxet in e

tors. Th e volun teer w as asked about the subjective sym ptom s


h e felt during the experim ent. W h ich of th e follow ing pairs of

11. A 42-year-old w om an w h o w as residen t in a psych iat ric h os-

m en t al e ect s w ere m ost likely reported by th e su bject?

p it al for a ch ron ic m en t al illn ess h ad been m u te an d im m o-

A. Eu ph oria, in creased self-con den ce

bile for th e p ast w eek. Sh e act ively resisted any at tem pt to

B. In creased alert n ess, rapid ow of th ough t

be m oved. Occasion ally, sh e h ad brief period s of u np rovoked

C. Dysp h oria, sleepin ess

agit ated an d aggressive beh avior. W h ich of th e follow ing

D. Irrit abilit y, restlessn ess

d rugs sh ou ld be avoided in th is pat ien t?

E. Delusion s, perseverat ion s

A. Lorazep am B. Haloperidol


C. Carbam azepin e

9. A 17-year-old boy presen ted w ith brief episodes of prot rud-

D. Olan zapin e

ing tongu e, grim acing, an d spasm odic tor t icollis on day 2

E. Dan t rolen e

after adm ission to the psych iatric em ergency departm ent . The

F.

Valproic acid

pat ien t w as brough t th ere by th e p olice becau se of assau lt ive beh avior tow ard h is m oth er. He st ru ck h er after a h eavy


drin king bou t becau se h e th ough t sh e w as abou t to kill h im

12. A 28-year-old m an foun d w an dering h alf-dressed in th e

w ith a kn ife. A drug t reat m en t w as started to con t rol h is as-

st reet s com plain ed of h earing voices cu rsing h im , an d h is

sau lt ive beh avior, an d h e received th ree in t ram u scu lar injec-

repor ted th ough t s w ere bizarre. Upon adm ission to th e psy-

t ion s over 24 h ou rs. W h ich of th e follow ing d rugs m ost likely

ch iat ric w ard, h is beh avior becam e disrupt ive. He refu sed to

cau sed th e adverse e ect s reported by th e p at ien t?

cooperate an d star ted verbal assaults th at in cluded th reat s

A. Haloperidol

of physical violence. A th erapy w as plan n ed th at in clude th e

B. Lorazepam

in t raven ou s inject ion of a drug. W h ich of th e follow ing drugs

C. Buspiron e

w as m ost likely adm in istered?

D. Th e large dose of eth an ol

A. Lith ium

E. Fluoxet in e

B. Im ipram in e

F.

C. Risperidon e

Clozapin e

D. Flu oxet in e E. Zolp idem F.

Morp h in e

108




13. A 39-year-old m an , a residen t in a psych iat ric un it because

16. A 29-year-old m an w as adm it ted to th e psych iat ric h ospit al

of d isorgan ized sch izop h ren ia, p resen ted w it h p rofou n d

in a p aran oid an d h ost ile st ate. He w as diagn osed w ith

lack of m ot ivat ion , rem arkably blun ted a ect , paucit y of

ch ron ic paran oid sch izoph ren ia at th e age of 23 an d h ad

speech , an d p sych om otor retardat ion . He h ad been h osp it al-

been reh osp it alized fou r t im es in th e last 2 years, secon dar y

ized th ree t im es sin ce h is d iagn osis, an d h ad been t reated

to m ed icat ion n on com p lian ce. His m ed ical w ork-u p an d

w ith h aloperidol, ch lorprom azin e, an d risperidon e but h ad

u r in e d r ug screen w ere n egat ive. Du r ing t h e last h osp it al-

on ly a p ar t ial resp on se to each m ed icat ion . W h ich of t h e

izat ion , h e h ad been st abilized on uph en azin e w ith out any

follow ing p sych ot rop ic drugs w ou ld be m ost ap prop riate to

sign of adverse e ect s. W h ich of th e follow ing t reat m en t

t r y at th is st age?

w ou ld be app ropriate for th is p at ien t?

A. Fluph en azin e

A. In t ram uscular (IM) th ioridazin e

B. Th ioridazin e

B. Oral h aloperidol

C. Fluoxet in e

C. IM uph en azin e decan oate

D. Clozapin e

D. Oral risperidon e

E. Lith ium

E. IM olan zapin e F.

Rect al ch lorp rom azin e

Di cult y level: Easy 14. A 36-year old m an com p lain ed to h is p hysician of ir r it abil-


it y, apathy, an d th e ap pearan ce of icking m ovem en ts of h is

17. A 35-year-old m an w as adm it ted to a psych iat ric h ospital

ext rem it ies. He w as referred to a n eurologic clin ic, w h ere a

follow ing a failed suicide at tem pt . He h ad a h istor y of m ul-

d iagn osis of Hun t ington ch orea w as m ade. W h ich of th e fol-

t iple drug abu se an d w as in jail for 2 m on th s after w ou n ding

low ing drugs w ou ld be m ost approp riate to suppress, at least

a relat ive. Th e p sych iat ric in ter view disclosed a pat ien t w ith

p ar t ially, h is ch oreic m ovem en ts an d agit ated beh avior?

p ersecu tor y d elu sion s, au ditor y h allu cin at ion s, rem arkably at a ect , an d social w ith draw al. A presum pt ive diagn osis

A. Im ipram in e B. Bu spiron e

w as m ade, an d a th erapy w as prescribed . W h ich of th e fol-

C. Trazodon e

low ing drugs w ou ld be m ost ap prop riate for th is p at ien t?

D. Lith ium

A. Am it ript ylin e

E. Triazolam

B. Lorazep am

F.

C. Flu oxet in e

Haloperidol

D. Lith ium


E. Clozapin e

15. A 37-year-old w om an w as brough t to th e h ospit al after as-

F.

Th ioridazin e

sau lt ing a n eigh bor. Sh e p resen ted in an acu te p sych ot ic state an d st ru ck t w o of th e p sych iat ric u n it sta

m em bers.


Th e pat ien t h ad h ad gen eralized ton ic-clon ic seizu res sin ce

18. A 60-year-old m an com plain ed to h is physician of obst in ate

th e age of 22, bu t sh e h ad stop ped h er an t iep ilept ic th erapy

con st ip at ion . Th e m an , recen t ly d iagn osed w it h a sch izo -

2 m on th s previou sly becau se sh e h ad been seizu re-free for

a ect ive disorder, h ad star ted t reat m en t w ith olan zap in e.

3 m on th s. W h ich of th e follow ing p airs of drugs w ou ld be an

Blockade of w h ich of th e follow ing pairs of receptors m ost

app ropriate th erap eu t ic regim en for th is p at ien t?

likely m ediated th e adverse e ect of th e drug?

A. Haloperidol an d clon azepam

A. Nicot in ic an d dop am in ergic

B. Ch lorprom azin e an d lam ot rigin e

B. GABAergic an d m u scarin ic

C. Clozapin e an d eth osu xim ide

C. Nicot in ic an d α 1

D. Th ioridazin e an d eth osu xim ide

D. Dopam in ergic an d α 1

E. Fluph en azin e an d gabapen t in

E. Mu scarin ic an d seroton ergic

F.

Clozapin e an d clon azepam

Di cult y level: Medium 19. A 28-year-old m an recen tly diagn osed w ith paran oid sch izop h ren ia star ted t reat m en t w ith aripip razole. Th e th erap eu t ic e ect of th is dr ug w as m ost likely m ediated by decreased d opam in ergic t ran sm ission in w h ich of th e follow ing brain st ru ct u res?

Questions: III-8 Neuroleptic Drugs 109 A. Tuberoin fun dibular path w ay


B. Locus ceru leus

23. A 78-year-old m an w as adm it ted to th e h ospital w ith m ult i-

C. Mesolim bic m esocort ical p ath w ay

p le fract ures after falling at h om e. Tw o days after adm ission ,

D. Nigrost riatal path w ay

h is beh avior ch anged. He accu sed th e st a of tort uring h im .

E. Nucleu s basalis of Meyn er t

He w as n ot able to recall w hy h e w as ad m it ted to th e h ospit al, w as disorien ted to t im e an d place, an d t ried to p u ll ou t


h is in t raven ou s lin e. His son rep or ted t h at h is fat h er w as

20. A 24-year-old w om an com plain ed to h er physician of am en -

n e before th e acciden t . W h ich of th e follow ing d rugs w ou ld

orrh ea of 2 m on th s’ durat ion an d of a w h ite disch arge from

be m ost ap p ropriate to t reat th e acu te sym ptom s in th is

h er breast s du ring th e past w eek. Th e w om an h ad been on

p at ien t?

h aloperidol an d paroxet in e for 3 m on th s to t reat a sch izoaf-

A. Clozapin e

fect ive disorder. Sh e w as m edicat ion -com plian t , an d h er ill-

B. Haloperidol

n ess w as w ell con t rolled. W h ich of th e follow ing m ech an ism s

C. Diazepam

w as m ost likely respon sible for th e p at ien t’s sym ptom s?

D. Lith ium

A. Blockade of dopam in e receptors in th e hypoth alam u s

E. Trazodon e

B. In creased seroton in availabilit y in th e pit uit ar y

F.

Paroxet in e

C. In creased seroton in availabilit y in th e st riat u m D. Blockade of dopam in e receptors in th e pit u it ar y


E. Blockade of adren coceptors in th e locus ceru leu s

24. A 33-year-old w om an w as brough t to th e em ergen cy dep ar t m en t w ith in creased agit at ion an d con fusion . Physical


exam in at ion revealed a tem perat ure of 104°F (40°C), pu lse

21. A 34-year-old m an, recently diagnosed w ith paranoid schizo-

of 125 bpm , labile blood pressu re, profuse diaph oresis, sia-

p h ren ia, becam e in creasingly rest less, w as u n able to sit or

lorrh ea, an d m uscle rigidit y. Th e w om an , recen tly d iagn osed

lie d ow n for m ore t h an few m in u tes, an d st ated t h at h e

w ith sch izoph ren ia, h ad star ted a th erapy a few days previ-

w an ted “to ju m p ou t of m y skin .” Tw o w eeks earlier, th e p a-

ou sly. W h ich of th e follow ing drugs m ost likely cau sed th e

t ien t h ad star ted th erapy w ith

p at ien t’s syn drom e?

u ph en azin e. W h ich of th e

follow ing drug-in duced adverse e ects did th e pat ien t m ost

A. Im ipram in e

likely exh ibit?

B. Tem azep am

A. Acu te dyston ia

C. Haloperidol

B. Com p lex par t ial seizu re

D. Flu oxet in e

C. Parkin son ism

E. Lith ium

D. Akath isia

F.

Ven lafaxin e

E. Cat alon ia F.


Tardive dyskin esia

25. A 62-year-old sch izoph ren ic w om an w as h osp it alized be-


cause of palp itat ion s an d ligh t-h eadedn ess of 2 h ou rs’ du ra-

22. A 27-year-old m an com plain ed to h is physician of feeling

t ion . Physical exam in at ion sh ow ed a p at ien t in m oderate

“real slow ” an d of a bilateral h an d t rem or th at im p roved

d ist ress w ith th e follow ing vital sign s: blood p ressu re 110/85

w h en h e picked u p h is co ee cup. Th e m an , su ering from

m m Hg, h ear t rate 158 bp m , respirat ion 20 breath s/m in . An

p aran oid sch izop h ren ia, w as cu r ren t ly t reated in an ou t -

elect rocardiogram disclosed polym orph ic ven t ricular tachy-

p at ien t p rogram . Physical exam in at ion sh ow ed cogw h eel

cardia. Up on qu est ion ing, th e p at ien t adm it ted sh e h ad re-

rigidit y in both arm s, stooped post u re, an d a sh u

ing gait .

cen tly in creased th e dosage of h er prescribed psych ot ropic


d rug becau se of h er augm en t ing agit at ion . W h ich of th e fol-

verse e ects?

low ing drugs m ost likely caused th e pat ien t’s sym ptom s an d

A. Clozapin e

sign s?

B. Haloperidol

A. Trazodon e

C. Metoclop ram ide

B. Th ioridazin e

D. Olan zapin e


E. Aripiprazole

D. Paroxet in e E. Lith ium F.

Lorazep am

110



A. Flu p h en azin e

26. A 51-year-old w om an , a residen t in a psych iat ric un it , com -

B. Haloperidol

p lain ed about feeling dizzy to th e poin t of fain t ing u pon

C. Olan zapin e

stan ding up rapidly. Th e p at ien t w as h ospit alized because

D. Ven lafaxin e

over th e p ast 3 m on th s sh e h ad becom e in creasingly agi-

E. Ben zt ropin e

t ated an d afraid . Sh e w as convin ced th at p eop le n ear h er

F.

Am it ript ylin e

h ouse w ere devils, plot t ing about stealing h er m on ey an d cu t t ing h er th roat . Th e p at ien t st arted a psych ot ropic m edi-


cation 2 w eeks previously. W hich of the follow ing drugs m ost

29. A 29-year-old m an com plain ed to h is psych iat rist of abn or-

likely caused th e p at ien t’s sym ptom s?

m al grow th of h is breast . Th e m an h ad been receiving a p sy-

A. Haloperidol

ch ot ropic drug for 6 m on th s to t reat paran oid sch izoph ren ia.

B. Risperidon e

He w as m edicat ion -com p lian t , an d h is illn ess w as w ell con -


t rolled . W h ich of th e follow ing drugs m ost likely cau sed th e

D. Bu spiron e

adverse e ect rep or ted by th e pat ien t?

E. Lith ium

A. Clozapin e

F.

B. Am it ript ylin e

Trazodon e

C. Haloperidol


D. Ven lafaxin e

27. A 34-year-old m an com plain ed to h is physician th at during

E. Diazepam

in tercourse, erect ion w as di cult to ach ieve, an d ejaculat ion

F.

Flu oxet in e

w as delayed . Th e m an , recen tly diagn osed w ith p aran oid sch izop h ren ia, w as t reated in it ially w it h h alop er id ol, bu t


h e w as sw itch ed to an oth er drug because of th e appearan ce

30. A 41-year-old m an w as adm it ted to a psych iat ric h ospital

of sym ptom s of pseudoparkin son ism . W h ich of th e follow -

becau se of w orsen ing of h is p sych osis. Th e m an w as recen tly

ing drugs m ost likely caused th e pat ien t’s sym ptom s?

d iagn osed w ith paran oid sch izoph ren ia an d h ad been

A. Fluph en azin e

t reated w ith risperidon e an d arip ip razole w ith ou t su ccess. A


n ew t reat m en t w as st ar ted. On e w eek later, a blood test gave

C. Paroxet in e

th e follow ing resu lts:

D. Th ioridazin e

• W h ite blood cell cou n t: 1200/m m 3 (n or m al 4500−11,000/ m m 3)

E. Fluoxet in e F.

Trazodon e

• Neu t rop h ils 12% (n orm al 54−62%) • Red blood cell cou n t: 4.3 m illion /m m 3 (n orm al 4.0−5.5

Di cult y level: Medium 28. A 57-year-old m an w as ad m it ted to t h e h osp it al becau se

m illion /m m 3 ) • Platelet cou n t: 145,000/m m 3 (n orm al 150,000−400,000/ m m 3)

h e did n ot urin ate for th e past 10 h ours. Th e m an w as diagn osed w ith ch ron ic un di eren t iated sch izoph ren ia 8 years

• Hem oglobin (Hb): 15 g/dL (n orm al >12 g/dL)

ago an d h ad taken m any di eren t an t ipsych ot ic drugs sin ce

W h ich of t h e follow ing d r ugs d id t h e p at ien t m ost likely

th en . Recen tly, in som n ia becam e a problem , an d h is p sych i-

receive as th e n ew t reat m en t?

at rist decided to ch ange th e th erapy. On e w eek ago, th e m an

A. Clozapin e

w as diagn osed w ith p rostat ic hyp erplasia an d w as sch ed -

B. Flu ph en azin e

uled for su rger y. W h ich of th e follow ing drugs m ost likely

C. Haloperidol

con t ributed to th e pat ien t’s acute urin ar y reten t ion ?

D. Ch lorprom azin e E. Diazepam F.

Flu oxet in e

Questions: III-9 Drugs for Depressive and Anxiet y Disorders 111

Questions: III-9 Drugs for Depressive and Anxiet y Disorders Directions for questions 1−5


Match each d rug w ith th e app ropriate descript ion (each let tered

7. A 55-year-old m an su er ing from severe dep ression w as

opt ion can be selected on ce, m ore th an on ce, or n ot at all).

brough t to t h e em ergen cy d ep ar t m en t after an overd ose of


an u n kn ow n m ed icat ion . Physical exam in at ion sh ow ed a le-

B. Bup ropion

thargic patient w ith dilated pupils. Vital signs w ere blood pres-

C. Citalopram

su re 95/55 m m Hg, h ear t rate 130 bp m , respirat ion s 10/m in .

D. Fluoxet in e

An elect rocardiogram (ECG) sh ow ed tachycardia w ith w ide

E. Mir tazapin e

QRS com plex. W h ich of th e follow ing drugs m ost likely cau sed

F.

th e pat ien t’s sign s an d sym ptom s?

Ph en elzin e

G. Selegilin e

A. Ser t ralin e

H. Trazodon e

B. Lith ium

I.

C. Bu propion

Ven lafaxin e

D. Ph en elzin e


E. Am it ript ylin e

1. A drug w ith pron ou n ced an t ich olin ergic proper t ies

F.

Clon azepam



2. A n on select ive m on oam in e oxidase in h ibitor

8. A 45-year-old w om an com plain ed of dizzin ess to th e poin t of fain t ing upon stan ding. Sh e also felt drow sy for m ost of th e

Di cult y level: Easy 3. An act ive m etabolite of th is drug h as a h alf-life of about 10 days.

Di cult y level: Easy 4. Th is drug can prolong th e elect rocardiogram QT in ter val.

Di cult y level: Easy 5. A seroton in 5-HT2A presyn apt ic receptor blocker

Di cult y level: Medium 6. A 43-year-old m an recen tly diagn osed w ith m ajor depressive disorder st ar ted a p h arm acoth erapy w ith an an t idep ressan t drug. W hich of the follow ing is m ost likely the com m on m echanism un derlying th e th erapeut ic e ect iven ess of long-term th erapy w ith m ost an t idepressan t s drugs?

day. Th e p at ien t h ad been ad m it ted to a h ospit al p sych iat ric u n it 2 w eeks earlier becau se of h er th ird episode of m ajor d epressive disord er. Sh e h ad been receiving an an t idepressan t th erapy for th e past 10 days. W h ich of th e follow ing drugs m ost likely caused th e pat ien t’s sym ptom s? A. Bu propion B. Mir tazapin e C. Am it ript ylin e D. Paroxet in e E. Ven lafaxin e F.

Lith ium

Di cult y level: Medium 9. A 48-year-old m an recen tly diagn osed w ith gen eralized an xiet y disorder st arted an appropriate th erapy w ith a drug th at act s by in creasing th e availabilit y of both n orep in eph r in e an d seroton in in th e syn apt ic cleft of cen t ral n er vou s system

A. In h ibit ion of cen t ral m on oam in e m et abolism

n eu ron s. W h ich of t h e follow ing d r ugs w as m ost likely

B. Up regu lat ion of cen t ral postsyn apt ic adren oceptors

p rescribed ?

C. In creased expression of brain -derived n eurot roph ic factor


D. Decreased h ippocam pal n eurogen esis E. In creased glu tam atergic t ran sm ission

B. Citalopram C. Ven lafaxin e D. Lorazepam E. Bu propion F.

Trazodon e

112




10. A 33-year-old w om an visited a p sych iat r ist for w h at sh e

13. A 25-year-old w om an visited a psych iat rist because sh e felt

d escribed as a ver y dist urbing problem . Th e w om an , w h o

ver y an xiou s w h en sh e h ad to eat or drin k in public. Sh e ac-

d elivered a h ealthy boy 1 m on th earlier, w as dist raugh t by

kn ow ledged th at h er ideas of being w atch ed by oth ers w ere

recurren t in t ru sive th ough t s about st abbing h er baby. After

irrat ion al, bu t sh e cou ld n ot get beyon d th em . Sh e also real-

fu r th er qu est ion ing, th e p sych iat rist m ade a p relim in ar y di-

ized th at alcoh ol h elped h er cop e w ith h er an xiet y, an d sh e

agn osis an d prescribed cogn it ive beh avioral th erapy an d a

h ad st arted drin king t w o or th ree glasses of bran dy ever y

p h arm acoth erapy. A drug w ith w h ich of th e follow ing m o-

day. After fu r th er quest ion ing, a prelim in ar y diagn osis w as

lecular m ech an ism s of act ion w ou ld be appropriate for th is

m ade, an d cogn it ive beh avioral th erapy w as p rescribed, to-

p at ien t?

geth er w ith a p h arm acological t reat m en t . W h ich of th e fol-

A. In h ibit ion of m on oam in e oxidase A

low ing drugs w ou ld be app ropriate for th is pat ien t?

B. Blockade of seroton ergic receptors

A. Diazepam

C. In h ibit ion of seroton in t ran spor ter

B. Zolp idem

D. Blockade of β receptors

C. Bupropion

E. In h ibit ion of n orepin eph rin e t ran spor ter

D. Haloperidol E. Paroxet in e


F.

Flu p h en azin e

11. A 75-year-old w om an recen tly diagn osed w ith pan creat ic can cer w as sen t by h er fam ily physician to a p sych iat rist be-


cau se sh e com p lain ed of sign i can t w eigh t loss, forgetfu l-

14. A 56-year-old w om an w ith a long h istor y of m ajor depres-

n ess, in it ial in som n ia, an d sadn ess. Sh e also repor ted th at

sive disorder w as brough t u n con sciou s to th e em ergen cy

she w as discouraged, fearful, and very anxious an d that som e-

d epart m en t after h er h u sban d discovered sh e h ad t aken sev-

t im es sh e experien ced sw eat ing w ith a racing h ear t . Th e

eral p ills of am it ript ylin e in a su icide at tem pt . W h ich of th e

w om an h ad been su ering from p aroxysm al at rial tachycar-

follow ing sym ptom s did th e pat ien t m ost likely sh ow ?

d ia for 5 years. Con sidering th e clin ical pict ure an d side ef-

A. Bradycardia

fect pro les, w h ich of th e follow ing w ould be an appropriate

B. Pale skin

th erap eu t ic regim en for ad dressing th ese com plain t s?

C. Fecal in con t in en ce

A. Im ipram in e an d ch lorprom azin e

D. Hyp erpn ea

B. Am it ript ylin e an d bupropion

E. Hyp er ten sion

C. Paroxet in e an d zalep lon

F.

Mydriasis

D. Haloperidol an d buspiron e E. Fluph en azin e an d lith ium

Di cult y level: Easy 15. A 52-year-old w om an com plain ed to h er physician th at th e


d rug sh e w as taking cau sed diarrh ea. Th e w om an , recen tly

12. A 54-year-old w om an com plain ed to h er physician of dizzi-

d iagn osed w ith social an xiet y disorder, h ad st arted a th er-

n ess an d ver t igo w h en stan ding u p rapidly. Sh e h ad a long

apy w ith p aroxet in e 2 w eek earlier. W h ich of th e follow ing

h istor y of recurren t m ajor depressive disorder an d h ad t aken

m olecu lar act ion s in th e en teric n er vou s system m ost likely

var iou s an t id ep ressan t d r ugs over t h e p ast several years.

m ediated th e adverse e ect of th is drug?

Recen tly, h er psych iat rist decided to prescribe im ip ram in e.

A. Blockade of M 3 receptors

W h ich of th e follow ing receptors m ost likely m ediated th e

B. In creased seroton ergic act ivit y

adverse e ects of th e drug in th is pat ien t?

C. Act ivat ion of β 2 receptors

A. Beta-1 adren ergic

D. In creased adrenergic act ivit y

B. 5-HT3 seroton ergic

E. Decreased h istam in ergic act ivit y

C. M 1 ch olin ergic

F.

Act ivat ion of GABAA receptors

D. Alph a-1 adren ergic E. H1 h ist am in ergic


F.

16. A 37-year-old m an com plain ed to h is physician of persisten t ,

Nn ch olin ergic

in tolerable pain in h is left leg th at st ar ted about 2 days earlier. He rep or ted th at h e h ad t ried several over-th e-cou n ter p ain m ed icat ion s w it h ou t su ccess. On e m on t h earlier, t h e

Questions: III-9 Drugs for Depressive and Anxiet y Disorders 113 pat ien t u n der w en t th e am p u t at ion of h is left leg follow ing

sh ow ed a con fu sed p at ien t w it h hyp erh id rosis, hyp er re-

an acciden t at w ork. Physical exam in at ion revealed th at pain

exia, an d m yoclon us but w ith out focal n eurologic de cit s.

could be elicited by a n on n oxious st im ulus applied to th e

Vital sign s w ere blood pressure 105/60 m m Hg, h eart rate

region of am pu t at ion . Th e p hysician m ade a prelim in ar y di-

130 bp m , respirat ion s 32/m in ,, body tem perat u re 103.8°F

agn osis an d p rescribed a d rug for pain . W h ich of th e follow -

(39.8°C). Qualit at ive p lasm a tests for alcoh ol, op ioid s, ben -

ing drugs w ou ld be appropriate for th is pat ien t?

zodiazep in es, an d t ricyclic an t idep ressan t s w ere n egat ive.

A. Ph en obarbital

An elect rocardiogram in dicated sin us t achycardia. A brain

B. Acetam in op h en

com puted tom ography scan w as n orm al. W h ich of th e fol-

C. Clozapin e

low ing d isorders m ost likely cau sed th e p at ien t’s sign s an d

D. Ven lafaxin e

sym ptom s?

E. Diazepam

A. Select ive seroton in reu pt ake in h ibitor (SSRI) d iscon t in -

F.

Lith ium

u at ion syn drom e B. Mir tazapin e overdose


C. Seroton in syn drom e

17. A 41-year-old m an recen tly diagn osed w ith m ajor depres-

D. Brain glioblastom a

sive disorder com p lain ed to h is psych iat rist th at h e felt

E. Ben zodiazepin e abst in en ce syn drom e

d row sy for m ost of th e day. Th e p at ien t h ad star ted a t reat-

F.

Cerebral h em orrh age

m en t w ith paroxet in e 2 m on th s earlier, bu t h is dep ressive sym ptom s w ere m in im ally im p roved . On e w eek ago, h is psy-


ch iat rist decided to sh ift to an oth er an t idepressan t an d pre-

20. A 48-year-old w om an visited a psych iat rist because for th e

scribed a d rug th at acts by in creasing th e availabilit y of both

p ast 2 m on th s sh e h ad been dep ressed an d w as n ot in ter-

n orepin eph rin e an d seroton in in th e syn apt ic cleft of cen t ral

ested in any of h er usual act ivit ies, n or did sh e n d anyth ing

n er vou s system n euron s. W h ich of th e follow ing drugs w as

enjoyable. Sh e w as also w orried an d an xiou s an d felt ver y


sleepy n early ever y day. Her m edical h istor y w as sign i can t


for exer t ion al angin a for th e past 5 years. Th e psych iat rist

B. Trazodon e

m ade a p relim in ar y diagn osis of m ajor depressive disorder

C. Bu propion

and prescribed cognitive behavioral therapy and a drug treat-

D. Citalopram

m en t . W h ich of th e follow ing dr ugs w ou ld be ap prop riate

E. Ser t ralin e

for th is pat ien t? A. Am it ript ylin e


B. Flu oxet in e

18. A 43-year-old m an w en t to h is physician com plain ing of dif-

C. Trazodon e

cu lt y in m ain tain ing an erect ion du ring in tercou rse. Past

D. Mir tazapin e

h istor y of th e pat ien t w as sign i can t for an episode of ven -

E. Lith ium

t ricu lar tachycardia 1 year earlier. He w as recen tly diagn osed

F.

Haloperidol

w ith m ajor depressive disorder an d star ted a drug t reat m en t 2 w eeks ago. W h ich of th e follow ing drugs m ost likely cau sed


th e sym ptom reported by th e p at ien t?

21. A 34-year-old m an su ering from a m ajor depressive disor-

A. Lith ium

d er h ad star ted a th erapy w ith paroxet in e, but 1 m on th later


h is sym ptom s w ere m in im ally im proved, an d h is psych ia-

C. Fluoxet in e

t rist decided to add a dr ug to th e t reat m en t . Th e prescribed

D. Ch lorprom azin e

d rug h as a com plex m olecular m ech an ism of act ion th at in -

E. Bu propion

cludes a blockade of presyn apt ic α 2 receptors. W h ich of th e

F.

follow ing drugs w as m ost likely given ?

Mir tazapin e



B. Clon idin e

19. A 53-year-old w om an w ith a long h istor y of depression w as

C. Bupropion

adm it ted to th e h osp ital becau se of agitat ion , in som n ia, an d

D. Mir tazapin e

t rem ors. Sh e h ad been t aking

E. Ven lafaxin e

u oxet in e, lorazep am , an d

m ir tazapin e for several m on th s. Th e doses of u oxet in e an d m ir tazapin e h ad ju st been in creased. Physical exam in at ion

F.

Trazodon e

114




22. A 61-year-old w om an cam e to h er psych iat rist’s o

ce for a

B. Lith ium

rout in e visit . Sh e stated th at th e drug sh e w as t aking im -

C. Flu oxet in e

p roved h er depressed m ood, but th at sh e w as st ill su ering

D. Haloperidol

from sadn ess an d fat igu e from t im e to t im e an d from h eavy

E. Diazepam

d row sin ess, n early ever y day. Th e w om an , recen t ly d iag-

F.

Clozapin e

n osed w ith m ajor depressive disorder, h ad st arted u oxet in e 1 m on th earlier. After fu r th er qu est ion ing, th e p sych iat rist


d ecided to add to th e th erapy a drug th at is th ough t to act by

25. A 56-year-old m an com plain ed to h is physician th at h e felt

d ecreasing reu pt ake of both n orepin eph rin e an d dop am in e

like h e h ad th e

u . He w as dizzy, sh ivering, ver y irrit able,

by brain n eu ron s. W h ich of th e follow ing drugs w as m ost

an xiou s, an d n au seated . Th e m an w as su ering from a m ajor

likely prescribed ?

d epressive disorder an d h ad t aken paroxet in e for 4 m on th s,

A. Bu propion

bu t 3 days ago h e decided to stop th e dr ug, as h is d ep ression

B. Methylp h en idate

h ad been in full rem ission for th e past m on th . Medical h is-

C. Lam ot rigin e

tor y of th e pat ien t w as sign i can t for hyperten sion , pres-

D. Aripiprazole

en tly t reated w ith losart an an d hyd roch loroth iazide. W h ich

E. Lith ium

of th e follow ing disorders best explain s th e syn drom e rep orted by th e p at ien t?


A. Acu te dep ressive relap se

23. A 36-year-old w om an presen ted at an out pat ien t psych iat ric

B. Select ive seroton in reu pt ake in h ibitor d iscon t in u at ion syn drom e

clin ic com plain ing of ext rem e leth argy an d depressed m ood m ore days th an n ot , for th e p ast 5 w eeks. On in ter view sh e

C. Poorly con t rolled hyper ten sion

also rep or ted an in ten se fear of being in con n ed sp aces, an d

D. Paroxet in e−losar tan in teract ion

sh e carefu lly avoided elevators an d t raveling by airp lan e. Her

E. Seroton in syn drom e

p sych iat ric h istor y in dicated t w o sim ilar episodes in th e

F.

p ast , t reated, respect ively, w ith

Paroxet in e−hydroch lorot iazide in teract ion

uoxet in e an d ven lafaxin e,

bu t w ith n egligible resu lts. After fu r th er qu est ion ing, a diag-


n osis of depression w ith at ypical feat ures w as m ade. A drug

26. A 54-year-old m an w as ad m it ted to t h e h osp it al becau se

w as p rescribed th at act s by in act ivat ing en zym es involved in

of gen eralized sh akin g, jerkin g m ovem en t s of t h e lim bs,

n eurot ran sm it ter m et abolism . W h ich of th e follow ing dr ugs

t w itch ing of th e jaw, an d clen ch ing of th e teeth . Th e p at ien t

w as m ost likely p rescribed?

h ad been su ering from gast roin test in al re u x disease for

A. Ph en elzin e

2 years. Fou r m on th s ago, h e w as diagn osed w ith an obses-

B. En t acapon e

sive-com p u lsive disorder an d st arted cogn it ive beh avioral

C. Fluoxet in e

th erapy an d a ph arm acological t reat m en t . Th ree h ours be-

D. Am it ript ylin e

fore adm ission , h e took a t ablet of m etoclopram ide given to

E. Citalopram

h im by a frien d to decrease h is h ear tburn . W h ich of th e follow ing drugs m ost likely in teracted w ith m etoclopram ide,


th us t riggering th e adverse e ects repor ted by th e pat ien t?

24. A 22-year-old m an w as sen t by h is physician to a psych iat rist


becau se of th e on set of a d ist ressing an d em barrassing be-

B. Lith ium

h avior. For th e previous 3 m on th s, th e m an h ad being expe-

C. Zolp idem

r ien cin g an ir resist ible u rge to d isin fect any object in h is

D. Paroxet in e

room an d to w ash h is h an d s again an d again . He w as d is-

E. Bupropion

t u rbed by t h e u n reason able am ou n t of t im e sp en t on su ch

F.

Buspiron e

act ivit ies, an d h e ackn ow ledged th at h is beh avior w as tot ally in ap p rop r iate, bu t h e felt h e cou ld n ot stop it . He den ied


any su bst an ce abu se or u se of m edicat ion s. Th e p sych iat rist


m ade a p relim in ar y diagn osis an d p rescribed cogn it ive be-

p ar t m en t becau se of su dden on set of ch est pain , di cu lt y in

h avioral th erapy an d a drug t reat m en t . W h ich of th e follow -

breath ing, dizzin ess, an d n au sea. Sh e described feeling “as if

ing drugs w ould be m ost appropriate for th is pat ien t?

m y h ead is going o in sp ace an d I am out side m y body.” Sh e

Questions: III-9 Drugs for Depressive and Anxiet y Disorders 115 stated th at sh e h ad been u n der ext rem e st ress lately, w ork-

to urin ate 5 to 7 t im es du ring th e previous n igh t . Past h istor y

ing too m u ch , an d th at a sim ilar ep isode h ad occurred, “out

of th e pat ien t w as sign i can t for hyper ten sion , in som n ia,

of th e blue,” 1 m on th ago. Physical exam in at ion an d labora-

an d ch ron ic low er back pain , as w ell as for recen tly diag-

tor y an alyses revealed n o abn orm alit ies. A prelim in ar y diag-

n osed depression . Presen t m edicat ion s in cluded lovast at in ,

n osis w as m ade, an d an appropriate th erapy w as prescribed.

losar t an , hydroch loroth iazid e, am it ript ylin e, an d lorazep am .

W h ich of th e follow ing drugs w ould be appropriate for th is

Which of the drugs m ost likely triggered the patient’s anuria?

pat ien t?

A. Losar t an

A. Zolpidem

B. Lovast at in

B. Eth osu xim ide

C. Hydroch lorot iazide

C. Clozapin e

D. Am it ript ylin e

D. Haloperidol

E. Lorazep am

E. Ser t ralin e F.

Pram ipexole

Di cult y level: Easy 31. A 67-year-old w om an com plain ed to h er psych iat rist th at


th e drug sh e w as taking did n ot im p rove h er d ep ressed

28. A 17-year-old girl w as adm it ted to an eat ing disorder clin ic

m ood at all. Th ree m on th s earlier, th e w om an h ad su ered a

w it h a 3-m on t h h istor y of bin ge eat in g an d vom it in g an d

m yocardial in farct ion , an d sh e h ad been su ering from a

p u rging ep isodes occu r r ing from t w ice p er w eek to fou r

secon d-degree at rioven t ricu lar block sin ce th en . Eigh t days

t im es a day. After p hysical exam in at ion an d lab test s, p sy-

ago, sh e w as d iagn osed w it h a d ep ressive d isord er an d

ch oth erapy an d a dr ug t reat m en t w ere prescribed. W h ich of

star ted an ap prop riate t reat m en t . Th e p sych iat rist advised


th e p at ien t to con t in u e th e t reat m en t , exp lain ing th at th e

A. Fluoxet in e

th erap eu t ic e ects of th e p rescribed dr ug u su ally t ake 2 to

B. Diazepam

3 w eeks or m ore to becom e eviden t . W h ich of th e follow ing

C. Ph en obarbital

d rugs w as th e pat ien t m ost likely t aking?

D. Haloperidol


E. Clozapin e

B. Paroxet in e

F.

C. Bupropion

Lith ium

D. Ph en elzin e


E. Diazepam

29. A 38-year-old m an com plain ed to h is physician th at th e dr ug h e w as taking w as e ective in relieving his anxiet y but caused


a d ist u rbing adverse e ect . Th e pat ien t h ad been recen tly

32. A 21-year-old m an w as brough t sem icon scious to th e em er-

d iagn osed w ith a social an xiet y disorder an d st ar ted t reat-

gen cy dep ar t m en t after h e ju m ped ou t of a w in dow in a su i-

m en t w ith ven lafaxin e 2 w eeks ago. W h ich of th e follow ing

cide at tem pt . Histor y revealed th at th e p at ien t w as su ering

adverse e ects d id th e pat ien t m ost likely exp erien ce?

from Hodgkin lym ph om a an d h ad been receiving th e th ird

A. Obst in ate con st ipat ion

cycle of ch em oth erapy. On e m on th earlier, h e w as diagn osed

B. Negligible orgasm du ring in tercou rse

w ith a depressive disorder an d h ad been taking an appropri-

C. Urge u rin ar y in con t in en ce

ate ph arm acoth erapy sin ce th en . W h ich of th e follow ing

D. Dizzin ess an d ver t igo upon st an ding

d rugs t aken by th e p at ien t w ou ld be m ost likely to h ave in -

E. Dr y m outh , m ost of th e day

creased h is risk of su icide?

F.

A. Zolp idem

Di cult y in n ear vision

B. Doxor ubicin


C. Bleom ycin

30. A 54-year-old m an w as adm it ted to th e h ospit al w ith severe

D. Vin blast in e

low er abdom in al discom fort an d com plete in abilit y to u ri-

E. Flu oxet in e

n ate for th e past 6 h ours. Th e m an repor ted th at h e n eeded

F.

Dacarbazin e

116


Questions: III-10 Drugs for Bipolar Disorders Directions for questions 1−4

plasm a levels, h e h ad n ot respon ded to lith iu m . W h ich of th e

Match each dr ug u sed in bip olar disorder w ith th e ap prop riate

follow ing drugs w ould be appropriate for th e pat ien t at th is

descript ion (each let tered opt ion can be selected on ce, m ore th an

t im e?


A. Haloperidol

A. Aripiprazole

B. Bu propion

B. Carbam azepin e

C. Fluph en azin e

C. Lam ot rigin e

D. Qu et iapin e

D. Lith ium

E. Diazepam

E. Qu et iapin e

F.

F.

Am it ript ylin e

Risperidon e


G. Valproic acid

7. A 34-year-old m an w as adm it ted to a psych iat ric h ospit al


du ring an acu te m an ic at tack. Th e m an h ad h is

1. A dopam in ergic receptor par t ial agon ist e ect ive in bipolar

at tack at th e age of 27 an d h ad h ad th ree oth er m an ic at t acks

rst m an ic

sin ce th en . A diagn osis of acu te m an ia w as m ade, an d a th er-

disorders

apy w as prescribed th at in clu ded a dr ug th at acts by blocking D2 an d 5-HT2 receptors in th e brain . W h ich of th e follow ing

Di cult y level: Easy 2. Th is drug can in crease th e risk of spin a bi da in th e n ew born w h en given during pregn an cy.

drugs w as m ost likely p rescribed? A. Lam ot rigin e B. Clom ipram in e C. Valproic acid

Di cult y level: Easy 3. Th is drug is e ect ive for th e t reat m en t of both acute m an ia an d all t ypes of epilepsy.

Di cult y level: Easy 4. Th e h epat ic clearan ce of th is drug is zero.

Di cult y level: Medium 5. A 45-year-old m an w ith a long h istor y of bipolar disorder h ad been stable on a m ain ten an ce lith iu m t reat m en t for th e p ast year. W h ich of t h e follow in g best d escr ibes a cu r ren t w orking hypoth esis abou t th e m olecular m ech an ism of act ion of lith iu m ?

D. Olan zapine E. Lith ium F.

Trazodon e

Di cult y level: Medium 8. A 36-year-old w om an com plain ed to h er physician th at sh e felt t ired, su ered from con st ipat ion , an d h ad gain ed w eigh t in recen t w eeks. Sh e also com p lain ed of feeling cold an d of absen ce of m en ses during th e last 3 m on th s. Th e w om an h ad been su ering from a bip olar disorder an d h ad been m ain tain ed su ccessfu lly on lith iu m th erapy for 1 year. In addit ion to lithium , her presen t m edication in cluded cim etidine for duoden al ulcer an d loratadin e for h ay fever. W h ich of th e follow -

A. In creased syn th esis of adenylyl cyclase

ing w as th e m ost likely cau se of th e pat ien t’s sym ptom s?

B. In creased syn th esis of in ositol m on oph osph atase

A. Lith ium -in duced hypothyroidism

C. In creased seroton in reupt ake in to seroton ergic term in als D. Up regu lated β-adren oceptors E. Decreased syn th esis of in ositol t riph osph ate (IP3 ) an d diacylglycerol (DAG) F.

In creased glu tam atergic act ivit y

B. Cim et idin e-in du ced decrease in lith ium m et abolism C. Adverse e ects of cim et idin e D. Cen t ral dep ressan t e ect s of lorat adin e E. Worsen ing of t h e d isease d u e to in ad equ ate lit h iu m d osage



6. A 68-year-old m an w as adm it ted to a psych iat ric h ospital be-

9. A 57-year-old w om an com plain ed to h er physician of t rem or,

cau se of depression , h opelessn ess abou t h is con dit ion , sleep dist u rban ces, an d poor ap pet ite. He h ad a long h istor y of p reviou s h osp it alizat ion s for m an ic or dep ressive ep isodes an d h ad exp er ien ced

ve m ood sw ings in t h e p ast year, in clu d -

ing episodes of depression an d hypom an ia. Despite adequate

p olyu r ia, m en t al con fu sion , an d sp eech dist u rban ces. Th e w om an h ad a d iagn osis of bip olar d isord er an d h ad been receivin g lit h iu m for 7 m on t h s. Tw o w eeks ago, sh e w as fou n d to h ave su ccessive h igh blood p ressu re read ings, an d h e r p hysician st ar te d an an t ihyp e r t e n sive t reat m e n t w it h

Questions: III-10 Drugs for Bipolar Disorders 117 hyd roch loroth iazide an d losar tan . W h ich of th e follow ing

A. For 3 m on th s

w as m ost likely th e reason for th e adverse e ect s rep or ted

B. For 6 m on th s

by th e pat ien t?

C. For 9 m on th s

A. Th iazide-in duced dilut ion al hypern at rem ia

D. For 1 year

B. Decreased ren al elim in at ion of lith ium

E. In de n itely

C. Decreased h epat ic m et abolism of lith ium D. Th iazide-in duced hypokalem ia


E. Losar t an -in du ced hyperkalem ia

13. A 33-year-old w om an su ering from a bipolar disorder h ad been m ain t ain ed su ccessfu lly on lith iu m th erapy. Now sh e


p lan n ed to becom e p regn an t . Her psych iat rist decided to

10. A 30-year-old w om an w as brough t to a psych iat ric h ospital

stop lith iu m an d to st art an oth er m edicat ion . W h ich of th e

by h er paren t s becau se sh e h ad been in bed m ost of th e day

follow ing drugs w ould be appropriate for th is pat ien t?

for th e last 2 w eeks. Th e w om an w as adm it ted to th e h ospi-

A. Carbam azepin e

t al 4 m on th s ago becau se of an acu te m an ic episode an d w as

B. Valproic acid

d isch arged on valproic acid w ith a favorable resp on se. On

C. Qu et iapin e

qu est ion ing, sh e said sh e discon t in ued h er th erapy 2 w eek

D. Haloperidol

ago becau se sh e felt cu red, but n ow sh e adm it ted sh e w as

E. Clozapin e

d epressed m ost of th e t im e an d w an ted to die. Th e p at ien t

F.

Am it ript ylin e

w as dism issed from th e h ospit al 1 w eek later w ith an ap p rop riate m ain ten an ce th erapy. W h ich of th e follow ing drugs


w ou ld be app ropriate for th e p at ien t at th is t im e?

14. A 57-year-old m an com plain ed to h is physician th at h e w as


alw ays th irst y an d h ad frequ en t an d p rofu se m ict u rit ion .

B. Lorazepam

Th e m an , recen tly diagn osed w ith bipolar disorder, h ad been

C. Haloperidol

receiving lith ium for 3 w eeks. W h ich of th e follow ing w as

D. Bu spiron e

m ost likely th e cau se of th e p at ien t’s sym ptom s?

E. Lith ium

A. Blockade of Na + reabsorpt ion in th e th ick ascen ding loop

F.

Zolpidem

of Hen le B. Blockade of vasopressin -in duced in crease of cAMP in th e


collect ing t ubule

11. A 49-year-old w om an visited h er physician com plain ing of a

C. In creased plasm a glucose levels

n e h an d t rem or an d of an in creasing n eed to u rin ate. Th e

D. St im u lat ion of th e th irst cen ter in th e hyp oth alam u s

w om an , recen tly diagn osed w ith a p sych iat ric disorder, h ad

E. Blockade of vasopressin secret ion from th e pit uitar y

been taking a p sych ot rop ic drug for 3 w eeks. Physical exam in at ion disclosed cyst ic acn e w ith folliculit is over th e t run k


an d th orax. W h ich of th e follow ing drugs w as m ost likely to

15. A 43-year-old w om an recen tly diagn osed w ith m ajor de-

h ave caused th e pat ien t’s sym ptom s an d sign s?

p ressive d isord er h ad st ar ted a t h erapy w it h ser t ralin e, bu t

A. Fluoxet in e

1 m on t h later h er con d it ion h ad n ot ch an ged ap p reciably,

B. Haloperidol

an d h er p sych iat r ist d ecid ed to ad d a secon d m ed icat ion

C. Lith ium

(augm en t at ion th erapy). He prescribed a drug w ith m u lt iple

D. Fluph en azin e

m ech an ism s of act ion , in clu ding an in h ibit ion of glycogen

E. Valproic acid

syn th ase kin ase 3. W h ich of th e follow ing drugs w as m ost

F.

likely p rescribed ?

Trazodon e

A. Olan zapin e


B. Triiodothyron in e

12. A 49-year-old w om an w as disch arged from a psych iat ric

C. Bupropion

h ospital after an episode of acute m an ia. Over th e past 2

D. Lam ot rigin e

years, th e p at ien t h ad h ad

E. Buspiron e

ve p reviou s h osp it alizat ion s for

m ajor m an ic or dep ressive episodes. Her postd isch arge th erapy in clu ded lith iu m . How long sh ou ld th e p at ien t con t in u e to t ake lith ium ?

F.

Lith ium

118



been receiving lith iu m th erapy for 1 m on th to t reat bip olar

16. A 55-year-old m an su ering from bipolar disorder st arted a

disorder. Rou t in e lab test s sh ow ed n orm al ren al fu n ct ion

m ain ten an ce t h erapy w it h lit h iu m . W h ich of t h e follow in g

an d a plasm a lith ium level of 3 m Eq/L. Lith ium h as a volum e

adverse e ect s is m ost likely to occu r d u r in g t h e

of distribution of about 45 L and a half-life of about 20 hours.

rst days

of th erapy? A. Con st ip at ion B. Weigh t loss

How m any h ou rs sh ou ld th e p hysician w ith h old lith iu m in order to reach a safer, yet likely th erapeut ic level of 0.75 m Eq/L?

C. In som n ia

A. 10

D. Hyp er ten sion

B. 20

E. Edem a

C. 30 D. 40

Di cult y level: Hard 17. A 20-year-old m an w as accom pan ied to th e clin ic by h is m oth er, w h o st ated th at h er son h ad been exh ibit ing ver y u n usual beh avior over th e past few w eeks. He w as euph oric

E. 80 F.

100


m ost of th e day, stayed up later an d later at n igh t , an d fre-

20. A 34-year-old w om an w h o h ad been t reated for an episode

qu en tly aw aken ed h is paren t s sh out ing an d scream ing. Re-

of acu te m an ia w as n o lon ger over t ly m an ic. How ever, be-

cen tly, h e exp erien ced problem s at w ork. Upon arriving at

cau se sh e h ad h ad p ast ep isod es of d ep ression an d m an ia,

th e clin ic, h e h ad t rou ble sit t ing st ill or listen ing an d becam e

h er p sych iat r ist d ecided to in st it u te p rop hylact ic t h erapy

increasingly irritable throughout the exam ination . He repeat-

an d p rescr ibed a d r ug t h at ap p ears to a ect p r im ar ily t h e

edly said h e h eard a voice telling h im h e h ad a superpow er.

in ositol secon d m essenger system . W h ich of th e follow ing

W h ich of th e follow ing pairs of drugs w ould be m ost h elpful

d rugs w as m ost likely p rescribed?

for th e pat ien t’s con dit ion ?

A. Valproic acid

A. Fluoxet in e an d risperidon e

B. Aripiprazole

B. Im ipram in e an d lith ium

C. Lam ot igrin e

C. Fluoxet in e an d h aloperidol

D. Lith ium

D. Im ipram in e an d h aloperidol

E. Qu et iapin e

E. Risperidon e an d lith ium

F.

Risperidon e



18. A 44-year-old w om an repor ted to h er psych iat rist th at th e

21. A 63-year-old m an com plain ed to h is physician th at h e h ad

p rescribed drug im proved h er feelings, bu t th at sh e w as st ill

a con st an t , st ron g d esire to d r in k an d h ad frequ en t an d

som ew h at depressed an d leth argic alm ost ever y day. Th e

p rofu se m ict u rit ion . Th e m an w as oth er w ise h ealthy, bu t

w om an , recen tly diagn osed w ith m ajor d ep ressive disord er,

2 m on th s earlier h e w as diagn osed w ith a psych iat ric dis-

h ad been t aking ven lafaxin e for 2 m on th s. Th e psych iat rist

order an d h ad been taking an appropriate ph arm acoth erapy

d ecided to add a secon d drug to th e presen t regim en . W h ich

sin ce th en . Fu rth er exam s in dicated th at th e p at ien t’s daily

of th e follow ing drugs w ould be appropriate for th e pat ien t

u rin e ou t put w as about 12 to 15 L. His urin e osm olarit y w as

at th is t im e?

216 m Osm /kg u n der con t rol con dit ion s an d 225 m Osm /kg

A. Am it ript ylin e B. Mir tazapin e C. Haloperidol D. Lith ium E. Valproic acid F.

Diazepam

after th e adm in ist rat ion of d esm opressin . Th e p hysician decreased th e dose of th e drug th e p at ien t w as t aking for h is p sych iat ric disorder an d p rescribed an oth er drug to cu re th e p at ien t’s u rin ar y sym ptom s. W h ich of th e follow ing drugs w ou ld be m ost ap p rop r iate to t reat t h e p at ien t ’s u r in ar y sym ptom s at th is t im e? A. Fu rosem id e

Di cult y level: Easy 19. A 46-year-old m an com plained to his physician of a ne hand t rem or, diarrh ea, an d frequ en t n eed to u rin ate. Th e m an h ad

B. Hydroch loroth iazide C. Am iloride D. Sp iron olacton e E. Con ivaptan

Questions: III-11 Drugs for Childhood Behavioral Disorders 119

Questions: III-11 Drugs for Childhood Behavioral Disorders Directions for questions 1−3

m ovem en t s cou ld be related to th e ch ild’s th erapy. W h ich of


th e follow ing drugs m igh t h ave cau sed th ese adverse e ect s?


A. Fluph en azin e

A. Aripiprazole

B. Methylp h en idate

B. Atom oxet in e

C. Atom oxet in e

C. Bup ropion

D. Eth osu xim ide

D. Clon idin e

E. Paroxet in e

E. Desm opressin F.

Dext roam ph etam in e

G. Gu an facin e

Di cult y level: Easy 6. A 6-year-old boy w as in h is fam ily physician’s o

ce for a

H. Methylp h en idate

sch edu led visit . Th e boy, recen tly diagn osed w ith at ten t ion

I.

Lisdexam fetam in e

de cit hyp eract ivit y disorder (ADHD), h ad st ar ted an app ro-

J.

Risperidon e

priate p h arm acoth erapy 1 w eek earlier. Vit al sign s w ere blood p ressu re 155/88 m m Hg, h ear t rate 85 bp m , resp irat ion s 16/


m in . W h ich of t h e follow in g d r ugs m ost likely cau sed t h e

1. An agon ist at α 2 an d im idazolin e receptors

p at ien t’s h igh blood pressure? A. Atom oxet in e



2. A par t ial agon ist at cen t ral dopam in ergic receptors

C. Ph enylep h rin e D. Guan facin e

Di cult y level: Easy 3. A prodrug th at is used to t reat at ten t ion de cit hyperact ivit y disorder

E. Clon idin e

Di cult y level: Medium 7. A 24-year-old w om an w h o h ad been su ering from depres-

Di cult y level: Easy 4. An 8-year-old boy recen tly diagn osed w ith at ten t ion de cit hyperactivit y disorder (ADHD) started a treatm ent w ith m eth -

sion for 3 years w as recen tly diagn osed w ith at ten t ion de cit hyp eract ivit y disord er (ADHD). W h ich of th e follow ing p airs of drugs w ould be appropriate for th is pat ien t?

ylph en idate. W h ich of th e follow ing n eu ral p ath w ays m ost

A. Bu propion an d h alop eridol

likely represen t th e m ain site of th erap eu t ic act ion of th e drug

B. Methylp h en idate an d sert ralin e

in th is ch ild?

C. Dext roam ph etam in e an d diazepam

A. Tuberoin fun dibular B. Mesolim bic C. Cort icost riat al D. Mesocor t ical E. Sp in oth alam ic

D. Atom oxet in e an d u p h en azin e E. Guan facin e an d lorazepam

Di cult y level: Easy 8. A 12-year-old girl su er ing from at ten t ion d e cit hyp eract ivit y disorder (ADHD) w as t reated in th e past w ith di eren t

Di cult y level: Easy 5. A 7-year-old boy w as t aken to th e h ospit al by h is m oth er for a sch ed uled ch ecku p. Th e boy, recen tly diagn osed w ith at ten -

drugs w ith lit tle su ccess. Th e p hysician decided to t r y an oth er drug th at is a select ive in h ibitor of n orep in ep h rin e reu pt ake. W h ich of th e follow ing drugs w as m ost likely prescribed?

t ion d e cit hyp eract ivit y d isord er (ADHD), h ad st ar ted an

A. Cocain e

ap p rop r iate p h ar m acot h erapy 2 w eeks earlier. Th e m ot h er

B. Atom oxet in e

rep or ted th at th e ch ild w as able to focu s bet ter an d w as less

C. Methylp h en idate

hyp eract ive an d less im p u lsive. How ever, sh e w as con cern ed

D. Dext roam ph etam in e

becau se h er son frequ en t ly exh ibited eye blin kin g, gr im ac-

E. Bu propion

ing, an d t w itch ing. Th e p hysician said t h at t h ese abn or m al

120




9. An 8-year-old boy w as brough t to h is pediat rician w ith com -

12. A 7-year-old boy w as brough t by h is m oth er to h is fam ily

p lain t s of rep eated h ead jerking, blin king, an d grim acing for

p ediat rician because h e st ill w et th e bed. Th e boy ach ieved

th e past 2 m on th s. Th e boy h ad n ever h ad a t ic-free p eriod

dayt im e bladder con t rol by 3 years of age bu t w et h is bed

for m ore th an a few days an d recen tly h ad started m aking

on ce or t w ice a w eek. A con dit ion ing th erapy w ith th e aid of

gru n t ing n oises an d saying obscen it ies. W h ich of th e follow -

a bell an d pad alarm , star ted 2 w eeks p reviou sly, w as on ly

ing drugs w ould be useful to t reat th e pat ien t’s con dit ion ?

p ar t ially e ect ive. Th e p ed iat r ician ord ered a d r ug to be

A. Fluoxet in e

given by n asal sp ray. W h ich of th e follow ing drugs w as m ost

B. Aripiprazole

likely p rescribed ?

C. Clon azepam

A. Desm opressin

D. Nalt rexon e

B. Im ipram in e

E. Im ipram in e

C. At ropin e

F.

D. Flu oxet in e

Lith ium

E. Haloperidol


F.

Clon idin e

10. A 10-year-old boy recen tly diagn osed w ith at ten t ion de cit hyp eract ivit y d isord er (ADHD) st ar ted a t reat m en t w it h


d ext roam ph etam in e. Th e th erapy sign i can tly im proved th e

13. A 7-year-old boy w as refer red for p sych iat r ic evalu at ion

d isease, but th e paren t s w ere con cern ed because th e boy

because h e w as u n able to sit st ill in sch ool for m ore th an

w as n ever h u ngr y. W h ich of th e follow ing w as m ost likely a

1 m in u te at a t im e. Du ring stor y t im e, h e in terr u pted , w an -

site of th is an orect ic act ion of am ph et am in es?

dered arou n d th e classroom , or poked h is n eigh bors. After

A. Tem poral cor tex

th e psych iat ric evaluat ion , a diagn osis w as m ade, an d a dr ug

B. Pu tam en

w as p rescribed th at act s by in creasing catech olam in e re-

C. Ven t rolateral m edulla

lease in th e cen t ral n er vou s system . W h ich of th e follow ing

D. Lateral hyp oth alam u s

drugs w as m ost likely p rescribed?

E. Am ygdala

A. Cocain e

F.

B. Dext roam ph etam in e

Locus ceru leus

C. Methylp h en idate


D. Guan facin e


E. Bupropion

ing th at sh e felt fearfu l, h elpless, an d w orried alm ost con t in u ou sly during th e day. Sh e also h ad di cult y organ izing h er


th ough t s an d claim ed th at cogn it ive con cept s w ere exceed-

14. A 24-year-old m an recen tly diagn osed w ith at ten t ion de cit

ingly di cult to grasp. Past h istor y of th e pat ien t in dicated

hyp eract ivit y disorder (ADHD) st ar ted beh avioral th erapy

th at sh e w as a di cu lt ch ild to m an age an d often im p u lsive

an d t reat m en t w ith m ethylp h en idate. W h ich of th e follow -

an d u nprodu ct ive in sch ool. Sh e st ar ted sm oking at th e age

ing adverse e ect s w as th e p at ien t m ost likely to exp erien ce

of 12 an d n ow sm oked t w o packs of cigaret tes daily. Sh e

d uring th e rst w eek of th erapy?

t ried to qu it sm oking several t im es w ith n o su ccess. Th e

A. In creased appet ite

p hysician suggested t r ying a drug th at w as e ect ive in t reat -

B. Grow th suppression

ing both depressive an d at ten t ion de cit disorders, as w ell as

C. Seizu res

in sm oking cessat ion . W h ich of th e follow ing drugs w as

D. In som n ia


E. Hallu cin at ion s

A. Methylp h en idate B. Paroxet in e


C. Bu propion

15. A 12-year-old boy w as referred to a psych iat rist because h e

D. Guan facin e

recen tly becam e ver y irrit able an d w ould h it h is h ead on a


w all or fu rn it u re if th e room w as too n oisy. Th e boy lived in

Questions: III-11 Drugs for Childhood Behavioral Disorders 121 a grou p h om e an d at ten ded a special sch ool program for ad-


olescents w ith developm ental disabilities. He preferred tasks

18. An 8-year-old girl w as in her physician’s o ce for a follow -up

th at allow ed h im to be alon e an d w as described as a distan t

visit regarding h er at ten t ion de cit hyperact ivit y disorder

ch ild w h o w ou ld n ot p ar t icip ate in grou p act ivit ies. Al-

(ADHD). Sh e h ad been t reated w ith t w o di eren t drugs over

th ough h e h ad superior abilit y in m ath em at ics, h e tested in

t h e p ast 6 w eeks w it h lit t le su ccess. Th e p hysician d ecid ed

th e m edium range of m en t al ret ardat ion . Th e boy h ad been

to stop th e ongoing th erapy an d to st ar t a drug th at act s as

diagn osed as au t ist ic at age 4. Th e p sych iat r ist p rescr ibed

a cen t ral α 2 -receptor agon ist . W h ich of th e follow ing drugs

a drug to decrease irritabilit y an d self-inju riou s beh avior. W h ich of th e follow ing drugs w as m ost likely appropriately prescribed?

w as m ost likely p rescribed ? A. Dext roam ph etam in e B. Methylph en idate

A. Fluoxet in e

C. Guan facin e

B. Risperidon e

D. Bupropion

C. Atom oxet in e

E. Epin ephrin e

D. Clon idin e E. Bupropion F.

Methylp h en idate


Di cult y level: Easy 19. A 6-year-old girl h ad di cult y su stain ing at ten t ion in act ivit ies at sch ool an d at h om e. Sh e failed to pay close at ten t ion to teach ers an d often m ade careless m ist akes in sch oolw ork.

16. An 11-year-old girl recen tly diagn osed w ith at ten t ion de cit

Sh e repeatedly exh ibited hyperact ivit y an d im pu lsivit y. Sh e

hyperactivit y disorder (ADHD) started treatm ent w ith m eth-

h as h ad th ese sym ptom s sin ce st art ing kin dergar ten last

ylp h en idate. W h ich of th e follow ing m olecu lar act ion s on

year. A t reat m en t w ith gu an facin e w as st ar ted. W h ich of th e

cen t ral adren ergic n euron s m ost likely m ediated th e th era-

follow ing adverse e ect s did th e pat ien t m ost likely experi-

p eu t ic e ect of th e drug in th e p at ien t’s disease?

en ce du ring th e rst days of th erapy?

A. Blockade of dopam in e reupt ake

A. Hyp oten sion

B. St im u lat ion of n orep in ep h rin e m et abolism

B. In creased appet ite

C. Blockade of seroton ergic receptors

C. Salivat ion

D. Act ivat ion of glu t am ate receptors

D. Aggressive beh avior

E. Blockade of gam m a-am in obu t yric acid (GABA) receptors

E. An h idrosis



17. A 15-year-old girl w as recen tly diagn osed w ith at ten t ion

20. An 8-year-old boy w h o h ad been su er ing from Tou ret te

d e cit hyperact ivit y disorder (ADHD). Her physician w as

syn drom e for 1 year w as recen tly diagn osed w ith at ten t ion

con cern ed about th e abu se poten t ial of drugs used for th is

d e cit hyperact ivit y disorder. W h ich of th e follow ing drugs

d isorder, as th e girl adm it ted sm oking m arijuan a occasion -

w ou ld be app ropriate to t reat both disorders?

ally w ith h er frien ds. W h ich of th e follow ing drugs w ou ld be m ost app ropriate for th is pat ien t?

A. Methylp h en idate B. Clon idin e

A. Methylp h en idate

C. Dext roam ph etam in e

B. Paroxet in e

D. Haloperidol

C. Dext roam ph etam in e

E. Risperidon e

D. Alprazolam E. Atom oxet in e F.

Aripiprazole

122


Questions: III-12 Opioid Analgesics and Antagonists Directions for questions 1−5



7. A 22-year-old pregn an t w om an w as in labor for 12 h ou rs

m ost closely associated w ith it (each let tered opt ion can be se-

an d w as exp erien cing st rong an d ver y p ain fu l con t ract ion s.

lected on ce, m ore th an on ce, or n ot at all).

Epidural adm in ist rat ion of m orph in e w as adm in istered for

A. Bup ren orph in e

an algesia. W h ich of th e follow ing n eu ron al areas w as m ost

B. Codein e

likely t h e m ain site of t h e an algesic act ion of m or p h in e in

C. Fen t anyl

th is set t ing?

D. Heroin

A. Locu s ceru leu s

E. Loperam ide

B. Su bstan t ia gelat in osa

F.

C. Periaquedu ct al gray m at ter

Meth ad on e

G. Morp h in e

D. Nucleu s accum ben s

H. Naloxon e

E. Su bstan t ia n igra

I.

Pen t azocin e

F.

J.

Propoxyph en e

Rost ral ven t rolateral m edu lla


K. Tram ad ol

8. A 58-year-old w om an w ith m et ast asized breast can cer re-


ceived an in t ram uscular inject ion of m orph in e for pain , bu t

1. A part ial agon ist at µ (m u) opioid receptors an d an t agon ist at

sh e su ered n au sea an d vom it ing soon after th e inject ion .

κ (kappa) opioid receptors

W h ich of th e follow ing brain areas w as m ost likely th e m ain site of th ese adverse e ect s of m orp h in e?


A. Locu s ceru leu s

2. A full opioid agon ist w ith th e h igh est oral bioavailabilit y

B. Area post rem a C. Median hyp oth alam ic em in en ce



3. A drug w ith ver y w eak opioid act ivit y u sed in th e t reat m en t

E. Pu tam en F.

of diarrh ea

Rost ral ven t rolateral m edu lla


Di cult y level: Easy 4. A par t ial agon ist at µ (m u) opioid receptors an d full agon ist at κ (kappa) opioid receptors

9. A 61-year-old w om an com plain ed of severe pain a few h ou rs after su rger y for ren al can cer. An in t ram u scu lar inject ion of m orp h in e w as given . W h ich of th e follow ing act ion s m ost likely con t ributed to th e an algesic e ect of m orp h in e?

Di cult y level: Easy 5. A drug w ith h igh a

n it y but n o in t rin sic act ivit y at opioid

receptors

A. Act ivat ion of brain stem n eu ron s t h at m od u late p ain t ran sm ission B. St im ulat ion of subst an ce P release from n er ve term in als

Di cult y level: Easy 6. A 34-year-old m an w as adm it ted to th e em ergen cy depar tm en t because of a sh arp abdom in al pain for th e past 3 h ours. Fu r t h er exam s led to t h e d iagn osis of ren al colic, an d t h e p at ien t received an in t ram uscular inject ion of m orph in e. Act ivat ion of receptors in w h ich of th e follow ing brain areas m ost likely m ediated th e an algesic e ect of th e drug in th is pat ien t? A. Edinger−West ph al n ucleus B. Meyn er t n u cleu s C. Nucleu s accum ben s D. Periaquedu ct al gray m at ter E. Medial em in en ce of th e hyp oth alam u s

in th e sp in al cord C. In du ct ion of dissociat ive feeling an d dysph oria D. Inhibition of adrenergic pathways from the locus ceruleus E. Inhibition of serotonergic pathways from the raphe nuclei

Di cult y level: Easy 10. A 55-year-old m an com plain ed of severe pain after surger y to rem ove a colon can cer. Th e p hysician p rescr ibed a d r ug t h at is a p ar t ial µ (m u ) op ioid agon ist , m ore p oten t t h an m or p h in e, an d w h ose e ect s are n ot read ily an t agon ized by n aloxon e. W h ich of t h e follow ing d r ugs w as m ost likely adm in istered ?

Questions: III-12 Opioid Analgesics and Antagonists 123 A. Meth ad on e


B. Meperidin e

14. A 55-year-old w om an su ering from term in al can cer re-

C. Codein e

ceived a spin al m orph in e in fusion from a por table pum p.

D. Bupren orph in e

W h ich of t h e follow in g w as t h e m ost likely elect rop hysio-

E. Fen t anyl

logical con sequ en ce of th e act ivat ion of post syn apt ic µ (m u )

F.

opioid receptors on th e pain t ran sm ission n euron s in th e

Loperam ide

spin al cord?


A. In creased ring of th ose n euron s


B. Product ion of an excitator y post syn apt ic poten t ial

p ar t m en t becau se of m ult iple fract u res sust ain ed in a car

C. Decrease in m em bran e K+ con du ctan ce

acciden t . Th e p at ien t com p lain ed of severe p ain , an d an in -

D. In crease in m em bran e Na + con duct an ce

t ram u scu lar inject ion of m orph in e w as given . W h ich of th e

E. Product ion of an in h ibitor y postsyn apt ic poten t ial

follow ing m olecular act ion s m ost likely m ediated th e an algesic e ect of th e dr ug in th is p at ien t? A. Op en in g of Ca 2+ ch an n els on

Di cult y level: Hard p resyn apt ic n er ve

term in als

15. A 51-year-old w om an w as seen in th e em ergen cy depar tm en t becau se of st ron g abd om in al p ain for t h e p ast h ou r.

B. Closing of ch loride ch an n els on post syn apt ic n eu ron s

Physical exam in at ion sh ow ed a red -h ead ed , p ale-skin n ed

C. St im u lat ion of su bstan ce P release from n ocicept ive

w om an in obviou s dist ress, w ith severe p ain an d ten d ern ess

n er ve term in als

of th e righ t an k. A presum pt ive diagn osis of ren al colic w as

D. Open ing of K+ ch an n els on p ost syn apt ic n eu ron s

m ade, an d th e p at ien t w as given an in t ram u scu lar inject ion

E. Closing of Na + ch an n els on presyn apt ic n er ve term in als

of an opioid drug th at is a part ial agon ist at µ (m u) receptors

F.

St im u lat ion of glu t am ate release from n ocicept ive n er ve

an d a fu ll agon ist at κ (kap p a) receptors. W h ich of th e fol-

term in als

low ing drugs w as m ost likely adm in istered?

Di cult y level: Easy 12. A 52-year-old m an adm it ted to th e em ergen cy depar t m en t

A. Pen t azocin e B. Bupren orph in e C. Codein e

after a m yocardial in farct ion st ill com plain ed of severe pain

D. Meth ad on e

after an in t raven ou s inject ion of n it roglycerin . In t ram u scu -

E. Fen t anyl

lar adm in ist rat ion of m orph in e w as given . W h ich of th e follow ing m olecu lar act ion s m ost likely m ediated th e an algesic e ect of th e drug?

Di cult y level: Medium 16. A 56-year-old w om an su ering from osteoarth rit is com -

A. St im u lat ion of release of en dogen ou s op ioid pept ides

p lain ed to h er physician th at th e join t pain in h er legs an d

B. Act ivat ion of µ (m u ) receptors

sh ou lders h ad w orsen ed an d w as n ow u n bearable. Sh e h ad

C. Blockade of κ (kapp a) receptors

u sed several dr ugs in th e past , in cluding ketorolac an d ibu-

D. St im u lat ion of su bstan ce P release from n er ve term in als

p rofen , w ith lit tle success. Full doses of acet am in op h en w ere

E. Act ivat ion of glu t am ate receptors

p ar t ially e ect ive u n t il recen tly, but th ey w ere n o longer ef-

F.

fect ive. Ever y m orn ing th e pat ien t said th at sh e w as “really

Blockade of β adren oceptors

ter r i ed ” by t h e exp ected p ain an d asked for an e ect ive


an algesic. Her p hysician decided to add a drug th at can also

13. A 68-year-old m an su ering from m et ast asized n eck can cer

low er th e an xiet y, fear, an d su ering evoked by p ain . W h ich

h ad a ch aracterist ic pinpoin t pupil because of subcutan eous

of th e follow ing drugs w as m ost likely prescribed?

in fusion of m orph in e from a por table pum p. St im ulat ion of

A. In dom eth acin

w h ich of th e follow ing brain areas m ost likely m ediated th is

B. Ketorolac

d rug e ect?

C. Ser t ralin e

A. Locus ceru leus

D. Diazepam

B. Nucleu s am biguus

E. Ven lafaxin e

C. Edinger−West ph al n ucleus

F.

D. Area post rem a E. Nucleu s accum ben s F.

Hip p ocam pu s

Meth ad on e

124



A. Resp irator y depression

17. A 64-year-old m an su ering from advan ced h ear t failure

B. Miosis

w as adm it ted to th e em ergen cy d ep art m en t becau se of ex-

C. An algesia

t rem e dyspn ea over th e p ast h ou r. After physical exam in a-

D. Sedat ion

t ion , a diagn osis of im pen ding pu lm on ar y edem a w as m ade,

E. Eu ph oria

an d an app ropriate th erapy w as p rescribed th at in clu d ed th e

F.

Nausea an d vom it ing

in t ram uscular inject ion of m orph in e. W h ich of th e follow ing cardiovascu lar act ion s m ost likely con t ribu ted to th e th era-


p eu t ic e ect of th e drug in th e p at ien t’s disorder?

21. A 34-year-old w om an com plain ed to h er physician of an n oy-

A. In creased systolic pressure

ing con st ipat ion . On e w eek earlier, sh e h ad develop ed a sore

B. Con st rict ion of th e ren al vascu lar bed

th roat an d a dr y, n onp rodu ct ive cough an d w as diagn osed

C. In creased h ear t rate

w ith acute bron ch it is. A drug t reat m en t w as st arted, an d th e

D. Periph eral ven ous dilat ion

cough gradually disappeared. W h ich of th e follow ing drugs

E. In creased left ven t ricular en d-diastolic pressure

m ost likely caused the constipation reported by the patient? A. Bupren orph in e


B. Fen t anyl

18. A 67-year-old w om an com plain ed to h er physician of obst i-

C. Albuterol

n ate con st ipat ion . Th e w om an , w h o w as su ering bon e pain

D. Codein e

from m et ast at ic breast can cer, h ad st arted a th erapy w ith

E. Th eop hyllin e

m orp h in e 2 w eeks previously. W h ich of th e follow ing ac-

F.

Morp h in e

t ion s m ost likely m ediated th e adverse e ect of th e drug in th is p at ien t?


A. Decreased an al sph in cter ton e

22. A 36-year-old m an com p lain ed of severe abd om in al p ain

B. In creased colon ic ton e

after su rger y to rem ove a kidn ey ston e. An an algesic drug

C. In creased in test in al perist alsis

w as adm in istered in t ram uscu larly. Sh ortly after th e adm in -

D. In creased re ex respon se to rect al disten t ion

ist rat ion , an itchy w eal develop ed at th e inject ion site, along

E. In creased soften ing of feces

w ith gen eralized prurit us. W h ich of th e follow ing drugs w as m ost likely given to th e p at ien t?


A. Fen t anyl

19. A 39-year-old w om an w as adm it ted to th e h ospital because


of gripping an d burn ing abdom in al pain th at in creased over

C. In dom eth acin

t h e p ast 4 h ou rs. Th e p at ien t w as su er in g from st age 4

D. Clon idin e

ovar ian can cer m et ast at ic to t h e p elvis. A t reat m en t w it h

E. Ibuprofen

su stain ed release m orp h in e w as st ar ted. W h ich of th e fol-

F.

Morp h in e

low ing e ects on th e p at ien t’s resp irator y system w ou ld be expected during th e rst few days of th erapy?


A. St im u lat ion of th e cough re ex


B. Bron ch odilat ion

p ar t m en t in a st u por from w h ich sh e cou ld be arou sed on ly

C. In creased vit al capacit y

brie y by st rong an d rep eated st im u lat ion . Th e w om an h ad

D. Decreased t idal volum e

received an in t ram uscular an algesic drug 2 h ours earlier be-

E. In creased rate of breath ing

cau se of several m in or abrasion s an d w ou n ds secon dar y to a m otor acciden t . Her records sh ow ed sh e w as su ering from an an xiet y disorder p resen tly t reated w ith diazep am . W h ich

Di cult y level: Easy 20. A 52-year-old m an w as in h is physician’s o

ce for a rout in e

visit . Th e m an , su ering from m etastasized stom ach can cer,

of th e follow ing an algesic dr ugs w as m ost likely given to th e p at ien t?

h ad st ar ted a th erapy w ith m orph in e 3 w eeks ago. W h ich of

A. Acetam in op h en

th e follow ing m orph in e e ects w as m ost likely u n ch anged

B. Piroxicam

in th e pat ien t after 3 w eeks of th erapy?

C. In dom eth acin D. Morp h in e E. Ketorolac F.

Aspirin

Questions: III-12 Opioid Analgesics and Antagonists 125 Di cult y level: Medium

D. Propran olol


E. Nifedipin e

m en t becau se of severe agitat ion an d h allu cin ator y beh av-

F.

Om eprazole

ior. He ad m it ted h e h ad been u sing m ar iju an a (regu larly) an d LSD (from t im e to t im e). Sh or tly before adm ission , h e


self-injected w h at h e believed to be “sm ack” (h eroin ) sold on

28. A 62-year-old m an su ering from m et ast at ic prost ate can cer

th e st reet . W h ich of th e follow ing op ioids did th e p at ien t

com plain ed of severe bon e pain . Th e physician prescribed

m ost likely t ake?

m eth adon e. W h ich of th e follow ing w as m ost likely on e of

A. Bu pren orp h in e

th e p ost receptor m ech an ism s t riggered by th is drug?

B. Morp h in e

A. In h ibit ion of t h e syn t h esis of in ositol t r ip h osp h ate/

C. Pen t azocin e

d iacylglycerol (IP3 /DAG)

D. Fen t anyl

B. Blockade of Ca 2+ channels on presynaptic nerve term inals

E. Meth ad on e

C. Open ing of Na + ch an n els on n eu ron al cell m em bran e D. St im u lat ion of adenylyl cyclase act ivit y


E. In h ibit ion of phosph olipase C act ivit y

25. A 62-year-old w om an recovering from surgical repair of m ult iple fract u res w as com p lain ing of severe p ain . A stan dard


dose of m orphine was given intram uscularly. Which of the fol-

29. A 35-year-old m an adm it ted to t h e h osp it al becau se of a

low ing adverse e ects m ost likely occurred in th is pat ien t?

secon d -d egree bu r n on h is left forear m com p lain ed of in -

A. Dysph oria

creasin g p ain . An oral com bin at ion of acet am in op h en /

B. Im pairm en t of far vision

codein e w as adm in istered for pain con t rol. W h ich of th e

C. Diarrh ea

follow ing st atem en t s best explain th e reason for using th is

D. Hyp er ten sion

d rug com bin at ion ?

E. Dr y cough

A. Codein e cou n teracts acetam in op h en -in du ced h epatotoxicit y.

Di cult y level: Medium 26. A 63-year-old m an w ith term in al prost ate can cer developed

B. Acet am in op h en cou n teract s cod ein e-in d u ced con st ip at ion .

fever (101.7°F, 38.7°C) follow ed by severe respirator y de-

C. The com bination does not cause tolerance or dependence.

pression . For th e past w eek, th e patien t h ad been receiving an

D. Acetam in op h en speeds u p th e biot ran sform at ion of co-

an algesic m edicat ion by t ran sderm al p atch becau se of severe bon e pain . W h ich of th e follow ing drugs w as m ost likely

d ein e in to m orp h in e. E. Th e t w o drugs en h an ce each oth er’s an algesic e ects.

adm in istered to th e p at ien t? A. Pen t azocin e


B. Codein e

30. A 51-year-old w om an w as adm it ted to th e h ospit al w ith se-

C. Fen t anyl

vere, in term it ten t righ t upper quadran t pain accom pan ied

D. Ibuprofen

by n ausea, vom it ing, an d clay-colored stools. Medical h is-

E. Ketorolac

tor y of th e pat ien t in dicated th at sh e h ad been su ering

F.

from hypothyroidism for 2 years. Th e adm it t ing diagn osis

In dom eth acin

w as biliar y colic. W h ich of th e follow ing st atem en t s best ex-

Di cult y level: Easy 27. A 59-year-old w om an w ith m et ast at ic breast can cer com p lain ed of in creasing bon e pain , n o longer m an aged w ith acetam in op h en an d cod ein e. A daily t reat m en t w ith oral

p lain s w hy op ioids w ere relat ively con t rain dicated in th is p at ien t? A. Th ey can cau se sm ooth m u scle spasm in th e sph in cter of Oddi.

m orp h in e w as st arted. W h ich of th e follow ing drugs sh ou ld

B. Th ey are in e ect ive in p at ien t s w ith hypothyroidism .

be given con com it an tly to preven t on e of th e m ost com m on

C. Th ey in crease th e risk of h ep atotoxicit y in p at ien t s w ith

adverse e ects of op ioid s? A. Diazepam B. Fluoxet in e C. Lact u lose

liver disease. D. Th ey are p oorly m et abolized in p at ien t s w it h liver d isease. E. Th ey can in crease th e risk of n au sea an d vom it ing.

126



A few days later, th e pat ien t reported th at h e w as feeling

31. A 64-year-old m an w as brough t to th e em ergen cy room for

m uch bet ter an d th at th e pain seem ed to be st ill th ere, but

an ep isode of severe an d cru sh ing ch est pain th at radiated to

th at “it doesn’t both er m e so m u ch .” He also said th at h e w as

h is left arm an d jaw. Th us far th e pain h ad n ot respon ded to

a lit tle sleepy during th e day an d h ad som e di cult y in void-

ve n it roglycerin su blingu al t ablets. Oth er sign s an d sym p -

ing h is bladder. W h ich of th e follow ing drugs w as m ost likely

tom s w ere con sisten t w ith th e diagn osis of acute m yocardial

prescribed to th e p at ien t?

in farct ion , an d h is physician w as con sidering th e use of an


opioid an algesic. W h ich of th e follow ing opioids w ould be


con t rain dicated in th is pat ien t?

C. Haloperidol

A. Morp h in e

D. Morp h in e

B. Fen t anyl

E. Diazepam

C. Bu pren orp h in e

F.

Ketorolac

D. Pen t azocin e E. Meth ad on e

Di cult y level: Medium 35. A 65-year-old m an w ith term in al can cer w as su ering from


con t in uous pain th at h ad gradually in creased in in ten sit y

32. A 47-year-old m an com plain ed of severe pain 3 days after

an d n ow w as severe an d n o longer relieved by fu ll th erap eu -

su rger y to rem ove a colon can cer. Physical exam in at ion an d

t ic doses of ketorolac. His p hysician d ecid ed to ch ange th e

x-ray con rm ed th e diagn osis of postoperat ive adyn am ic

th erapy. W h ich of th e follow ing t reat m en t s w ou ld be m ost

ileus. An an algesic t reat m en t w as prescribed. W h ich of th e


follow ing an algesic drugs w ould be con t rain dicated for th is

A. Naproxen orally (PO), on ce daily

p at ien t?

B. Morp h in e in t ram u scu larly (IM), as n eeded


C. Tram adol PO, t w ice daily

B. Morp h in e

D. Fen t anyl IM, as n eeded

C. Ibuprofen

E. Meth ad on e PO, on ce daily

D. Ketorolac E. In dom eth acin

Di cult y level: Hard 36. A 34-year-old m an , brough t to th e em ergen cy depart m en t


after a car collision , w as fu lly con sciou s an d com plain ed of


ch est pain . He w as also agitated, disorien ted, m oving all h is

m en t w ith st rong pain follow ing a car acciden t . Vit al sign s

lim bs, an d aggressive. Physical exam in at ion sh ow ed h em a-

w ere blood p ressu re 190/100, p u lse 55 bp m , resp irat ion s

tom a over th e righ t orbit an d st rong pain on palpat ion of th e

12/m in . Physical exam in at ion sh ow ed severe h ead t rau m a.

5th to 9th right ribs. Re exes w ere grossly intact. A com puted

Th e pat ien t w as cu rren tly taking n it roglycerin , lovast at in ,

tom ography (CT) scan w as ordered. W h ich of th e follow ing

an d ran it idin e. W h ich of th e follow ing an algesic d rugs w ou ld

p airs of d r ugs w ou ld be ap p rop r iate to in d u ce “con sciou s

be con t rain d icated for th is pat ien t?

sedat ion ” in th is pat ien t to com plete th e CT scan ?

A. In dom eth acin

A. Ibuprofen an d codein e


B. Buspiron e an d m eperidin e

C. Aspirin

C. Zolp idem an d m orph in e

D. Morp h in e

D. Lorazep am an d fen tanyl

E. Ketorolac

E. Diazepam an d acet am in oph en



34. A 74-year-old m an w h o h ad been su ering from occlusive


ath erosclerot ic disease of th e legs for 3 m on th s com plain ed

p ain on h is ch est , especially w h en h is cloth es r u bbed again st

th at recen tly h is p ain h ad in creased an d w as n ot relieved by

it , an d an itchy feeling in t h e sam e area. Th e p at ien t w as

n onsteroidal an tiin am m ator y drugs (NSAIDs). His physician

d iagn osed w ith h erpes zoster 3 w eeks ago, but th e pain fu l

changed the therapy and prescribed an appropriate treatm ent.

r u sh on h is ch est disap p eared after 8 days. Th e p hysician

Questions: III-12 Opioid Analgesics and Antagonists 127 m ade a presum pt ive diagn osis an d ordered a dr ug to allay

ap p rop r iate t h erapy. Becau se t h e p at ien t st ill com p lain ed

pain . W h ich of th e follow ing drugs w ou ld be ap p rop riate for

of som e ep isodic abdom in al p ain , a postd isch arge an algesic

th is pat ien t?

w as prescribed . W h ich of th e follow ing drug com bin at ion s



B. Eth osu xim ide

A. Bupren orph in e/ibuprofen

C. Diazepam

B. Morp h in e/in dom eth acin

D. Tram ad ol

C. Codein e/acetam in oph en

E. Fluoxet in e

D. Fen t anyl/ketorolac

F.

E. Meth ad on e/aspirin

Ibuprofen



38. A 44-year-old m an w ho underw ent surgery to rem ove a lung

41. A 34-year-old h eroin addict w as determ in ed to “qu it th e

cancer exhibited pron ounced sh ivering upon recovering from

h abit” an d st arted a detoxi cat ion program super vised by

su rger y. An app ropriate th erapy w as st arted th at in cluded

a cer t i ed p hysician . Th e p rogram in clu ded th e ad m in ist ra-

uid w arm ing an d an in t raven ous inject ion of a drug. W h ich

t ion of a bu pren orp h in e/n aloxon e com bin at ion to be given

of th e follow ing drugs w as m ost likely adm in istered?

by th e sublingual rou te. W h ich of th e follow ing w as m ost


likely th e reason for u sing n aloxon e in th e p at ien t’s detoxi -

B. In dom eth acin

cat ion p rogram ?

C. Fluoxet in e

A. To cou n teract bu p ren or p h in e-in d u ced resp irator y d ep ression

D. Meperidin e E. At ropin e

B. To in crease th e absorpt ion of bu p ren orp h in e C. To p reven t bu p ren orp h in e overd ose


D. To discou rage th e in t raven ou s abu se of bu pren orph in e

39. A baby boy, born after n orm al deliver y, presen ted w ith re-

E. To m in im ize bu pren orph in e toleran ce

spirator y dep ression , p inp oin t pu p ils, an d low Apgar scores. His m ot h er received t w o in t ram u scu lar inject ion s of an


an algesic drug 3 an d 2 h ours before th e deliver y becau se

42. A 68-year-old w om an w ith breast can cer m etast ases com -

of st rong errat ic an d ver y pain ful con t ract ion s. W h ich of th e

p lain ed to h er p hysician of a du ll bon e p ain th at h ad been

follow ing drugs w ould be appropriate for th e baby at th is

in creasing over t h e p ast few days. Th e p ain w as in it ially

t im e?

relieved by ibu profen , bu t n ow th e drug w as u n able to con -

A. Flum azen il

t rol it . Th e pat ien t described th e pain as con t in u ou s bu t

B. Th eophyllin e

m oderate. Th e physician decided to add to ibuprofen a dr ug

C. Naloxon e

w h ose an algesic e ect is m ost likely d u e to it s conversion

D. Ca ein e

to m orph in e. W h ich of th e follow ing drugs w as m ost likely

E. Albuterol

prescribed?

F.

A. Fen t anyl

Iprat ropium

B. Codein e


C. Bupren orph in e

40. A 58-year-old w om an w as about to be disch arged from th e

D. Tram adol

h ospital after a hysterectom y. Her past m edical h istor y w as

E. Pen t azocin e

sign i can t for du oden al u lcer, w h ich h ealed 1 year ago after

F.

Meperidin e

128


Questions: III-13 Drugs of Abuse Directions for questions 1−5

th e m an rem ain ed orien ted an d alert . W h ich of th e follow ing


drugs m ost likely cau sed th e p at ien t’s syn drom e?


A. Mariju an a

A. Am ph et am in e

B. LSD

B. Bup ren orph in e

C. Cocain e

C. Can n abin oids

D. Eth an ol

D. Ca ein e

E. Ph en cyclidin e

E. Cocain e F.

Eth an ol

G. Gam m a-hydroxybu t yric acid

Di cult y level: Medium 7. A 44-year-old m an w as a regular user of h igh doses of cocain e.

H. Heroin

W h ich of th e follow ing sign s an d sym ptom s w as m ost likely

L.

prom in en t in th is p erson , sh ortly after th e ad m in ist rat ion of

LSD

M. Methylen edioxym eth am p h etam in e (MDMA)

th e drug?

N. Naloxon e

A. Disorien t at ion in t im e an d space

O. Nicot in e

B. Raven ou s ap pet ite

P.

C. Leth argy

Ph en cyclidin e

D. Stereot yp ed beh avior


E. In creased feeling of fat igue

1. Th is drug is som et im es used to decrease alcoh ol craving in alcoh olics.

Di cult y level: Easy 8. Th e m oth er of a 16-year-old boy n ot iced a ch ange in h er son’s


beh avior. W h en h e ret u rn ed h om e in th e even ing after m eet-

2. Th is drug acts m ain ly by in creasing th e n onvesicular release

ing w ith h is frien ds, h e w as alw ays ver y h u ngr y, desp ite h av-

of dopam in e from dopam in ergic n euron s.

ing eaten h is din n er. He alw ays appeared h appy, w ou ld

nd

ever yth ing am u sing, an d laugh ed a lot . Occasion ally, h is eyes


w ou ld be rath er red. In th e m orn ing h e w as relu ct an t to go to

3. Th e elim in at ion of t h is d r ug follow s m ain ly zero -ord er

sch ool an d did n ot app ear to care w h eth er h e did w ell or n ot .

kin et ics.

A drug w ith w h ich of th e follow ing m ech an ism s of act ion w as h e m ost likely abusing?


A. Act ivat ion of can n abin oid receptors

4. Th is drug is u sed in h eroin detoxi cat ion program s.

B. Blockade of n orepin eph rin e reu ptake C. Act ivat ion of seroton in receptors

Di cult y level: Easy 5. Th e cen t ral e ect s of th is drug are m ost likely m ediated by th e act ivat ion of t ype B gam m a-am in obut yric acid (GABAB) receptors.

D. Act ivat ion of µ (m u ) op ioid receptors E. Blockade of dopam in ergic receptors

Di cult y level: Easy 9. An 18-year-old girl w h o h ad n ever u sed recreat ion al d r ugs

Di cult y level: Medium 6. A 28-year-old m an w as brough t to th e psych iat ric clin ic by th e police after h e at tem pted to assault a w om an in th e st reet .

join ed in sm oking m u lt ip le m ar iju an a cigaret tes at a p ar t y. W h ich of th e follow ing sign s an d sym ptom s did th e girl m ost likely experien ce ju st after sm oking?

Th e m an presen ted w ith elevated m ood, rapid speech , m uscle

A. Hyp er ten sion

t w itch ing, an d dilated p u pils. He kept on scratch ing h im self

B. In creased h ear t rate

rep eated ly becau se h e st ated th at “bugs are craw ling u n der

C. Depressive m ood

m y skin .” Vital sign s w ere blood pressu re 170/105, h ear t rate

D. Hyp eralgesia

120 bp m , resp irat ion s 20 /m in . After a sh or t t im e, stereot yp ed

E. Im proved m em or y

beh avior develop ed accom pan ied by p aran oid d elu sion s, bu t

F.

Pale skin

Questions: III-13 Drugs of Abuse 129 Di cult y level: Easy 10. A 33-year-old m an w as in h is physician’s o

Di cult y level: Easy ce becau se h e

13. A 38-year-old h eroin addict w as determ in ed to qu it th e

star ted to perceive ash es of colors an d eet ing m ovem en t s

h abit an d w as adm it ted to a detoxi cat ion clin ic. After phys-

of st range objects as h e en tered a dark room . Th e m an , w h o

ical exam in at ion an d laborator y tests, t reat m en t w as st ar ted.

w as an alcoh olic an d an occasion al u ser of recreat ion al

Su blingu al adm in ist rat ion of w h ich of th e follow ing drugs

d rugs, took t w o t ablets of an illegal drug w h ile at a part y 2

w ou ld be m ost app ropriate for th is p at ien t?

m on th s ago. W h ich of th e follow ing syn d rom es m ost likely

A. Diazepam

accou n ted for th e p at ien t’s sym ptom s?

B. Bupren orph in e

A. Ph en cyclidin e w ith draw al

C. Nalt rexon e

B. Heroin w ith draw al

D. Ph en obarbital

C. LSD ash backs

E. Codein e

D. Cocain e-in du ced sch izop h ren ic episod e

F.

Pen t azocin e

E. Am ph et am in e-in duced sch izoph ren ic episode F.

Alcoh ol w ith draw al

Di cult y level: Easy 14. A 35-year-old m ale body builder w as brough t to th e em er-


gen cy dep ar t m en t for t reat m en t of t rau m at ic inju ries to h is

11. A 42-year-old w om an com plain ed to h er doctor abou t in -

legs as a resu lt of a m otor veh icle acciden t . He w as agitated ,

creasing anxiet y, insom nia, irritabilit y, and severe craving for

hyp eraggressive, an d in a rage. He h ad been rest rain ed by

cigaret tes. Th e p at ien t , w h o w as a t w o-pack-a-day sm oker

secu r it y gu ards follow ing an altercat ion w it h on e of t h e

for 15 years, h ad recen tly quit sm oking. Th e physician pre-

n u rses. He d en ied u se of alcoh ol or ot h er m ood -alter ing

scr ibed a d r ug t h at cou ld relieve h er sym ptom s. W h ich of

d r ugs. Physical exam in at ion sh ow ed a d ist raugh t p at ien t

t h e follow in g d r ugs w ou ld be m ost ap p rop r iate for t h is

w it h exten sive skin acn e. Vit al sign s w ere w it h in n or m al

p at ien t?

lim it s, an d th e resu lts of rou t in e drug screen tests for illegal

A. Naloxon e

su bst an ces w ere n egat ive. W h ich of th e follow ing dr ugs w as

B. Bu propion

m ost likely to h ave cau sed th e pat ien t’s beh avior?

C. Brom ocript in e

A. Diazepam

D. Bu pren orp h in e

B. Mariju an a

E. Methyld op a

C. Heroin

F.

D. Mifep riston e

Im ipram in e

E. Oxan drolon e


F.

Dan azol

12. A 22-year-old m an cam e to th e clin ic com plain ing of m uscle ach es, n au sea, an d an xiet y. He rep or ted th at h e w as a h eroin


addict an d th at h e h ad been sm oking ph en cyclidin e occa-

15. A 17-year-old girl w h o h ad n ever u sed drugs decided to join

sion ally for th e p ast 6 m on th s. He w as sw eat ing, sh aking,

in w it h h er fr ien ds w h o w ere sm oking dr ugged cigaret tes.

an d kept yaw n ing. Physical exam in at ion revealed hyp er ven -

In t h e

t ilat ion , hyp er th erm ia, h igh blood p ressu re, an d tachycard ia.

t rollable laugh ter, dep erson alizat ion , an d sh arp en ed vision .

His pu pils w ere dilated, bu t n o nyst agm u s w as obser ved .

Her con cen t rat ion becam e di cu lt , an d sh e n ot iced th at h er

W h ich of th e follow ing t ypes of drugs w ould be m ost appro-

h ear t w as “poun ding.” Her frien ds n oted redden ing of h er

p riate to provide im m ediate relief to th is pat ien t?

conjun ct iva bu t n o ch ange in pu pil diam eter. W h ich of th e

A. 5-HT receptor agon ist

follow ing drugs m ost likely caused th e girl’s sym ptom s?

B. Mu receptor agon ist

A. Ph en cyclidin e

C. Glut am ate receptor an t agon ist

B. Can n abis

D. GABA receptor agon ist

C. Cocain e

E. D2 receptor an tagon ist

D. Heroin

F.

E. LSD

Alph a 2 receptor an tagon ist

rst 5 m in u tes, sh e exp er ien ced eu p h or ia, u n con -

130



A. Irrit abilit y an d restlessn ess

16. A 40-year-old fem ale alcoh olic w as adm it ted to an alcoh ol

B. Asth en ia an d sleepin ess

reh abilit at ion cen ter becau se sh e w as determ in ed to quit th e

C. Eu ph oria an d elat ion

h abit . A dr ug w as given to facilitate avoidan ce from eth an ol

D. Tachycardia an d hyperten sion

d epen den ce, based on research suggest ing th at com pu lsive

E. Decreased appet ite an d w eigh t loss

alcoh ol d rin king is in uen ced by opiate receptor act ivit y. W hich of th e follow ing drugs w as m ost likely adm inistered?


A. Diazepam

20. A 53-year-old w om an su ered a gen eralized seizu re an d

B. Clon idin e

w as t aken to th e em ergen cy depar t m en t . On adm ission sh e

C. Disul ram

w as ext rem ely an xiou s an d agitated . Sh e rep or ted sh e h ad

D. Nalt rexon e

n o h istor y of epilepsy. Furth er quest ion ing revealed th at sh e

E. Meth ad on e

h ad a long h istor y of drug abuse, but th e day before sh e de-

F.

cided to qu it an d ceased taking th e abu sed drug. With draw al

Bu pren orp h in e

from w h ich of th e follow ing drugs m ost likely cau sed th e


p at ien t’s seizure?

17. A 27-year-old m an w ith a recen t h istor y of drug abuse pre-

A. LSD

sen ted to th e em ergen cy depart m en t w ith violen t , sh aking

B. Can n abis

ch ills. He also com plain ed of restlessn ess, in som n ia, n ausea,

C. Alprazolam

an d abdom in al cram p s an d exh ibited p rofu se sw eat ing, rh i-

D. Heroin

n orrh ea, yaw n ing, an d piloerect ion . He adm it ted h e w as out

E. Cocain e

of m on ey an d w as un able to get th e u sual supply of th e drug

F.

Meth am p h etam in e

h e h ad been using for 3 m on th s. From w h ich of th e follow ing d rugs w as h e m ost likely experien cing w ith draw al?


A. Heroin

21. A 48-year-old m ale alcoholic com plained of ushing, nausea,

B. Cocain e

a th robbing h eadach e, an d con fu sion after d rin king a glass of

C. Am ph et am in es

w in e. Th e m an w as taking a drug as par t of h is reh abilitat ion

D. LSD

t reat m en t for alcoh olism . Th e sym ptom s of th e pat ien t are

E. MDMA

m ost likely cau sed by th e accu m u lat ion in th e body of w h ich

F.

of th e follow ing substan ces?

Ph en cyclidin e

A. Dopam in e


B. Acetaldehyde

18. A 28-year-old w om an w as adm it ted u n con scious to th e

C. Eth an ol

em ergen cy depar t m en t . A frien d st ated th at th e w om an w as

D. Seroton in

a polydrug user and that she had self-injected a drug approx-

E. Meth an ol

im ately 45 m in u tes prior to adm ission . Vital sign s w ere blood

F.

Form aldehyde

pressure 100/50, heart rate 95 bpm , respirations 5/m in. Physical exam ination showed cyanosis an d pinpoint pupils. W hich


of th e follow ing drugs did th e w om an m ost likely t ake?

22. A 15-year-old boy w as adm it ted to th e h ospit al in a pan icky

A. Am ph et am in e

state, cr ying an d com plain ing of being seriou sly ill. Th e boy,

B. Heroin

w h o h ad n ever u sed recreat ion al d r ugs, h ad ju st sm oked

C. Cocain e

t w o drugged cigaret tes at a p art y w ith h is frien ds. Physical

D. Ph en cyclidin e

exam in at ion sh ow ed a con fu sed an d fear fu l p at ien t w it h

E. Diazepam

fast p u lse (120 bp m ), redden ing of th e conju n ct iva w ith n o

F.

ch ange in pu pil diam eter, an d di use t rem or. W h ich of th e

LSD

follow ing drugs did h e m ost likely t ake?


A. Am ph et am in e

19. A 41-year-old m an decided to stop sm oking cigaret tes an d

B. Cocain e

asked h is fam ily physician abou t a p ossible w ith draw al syn -

C. Gam m a-hydroxybu t yric acid

d rom e. He h ad been sm oking t w o packs of cigaret tes daily

D. Heroin

for 24 years. W h ich of th e follow ing are th e w ith draw al

E. Can n abis

sym ptom s th e m an w as m ost likely to exp erien ce?

Questions: III-13 Drugs of Abuse 131 Di cult y level: Easy

A. LSD

23. A 50-year-old h om eless m an w as brough t to th e em ergen cy

B. Im ipram in e

room by t h e p olice, w h o h ad fou n d h im d isor ien ted an d

C. Ph en obarbital

t rem blin g u n d er a br idge. Physical exam in at ion an d vit al

D. Cocain e

sign s led to th e d iagn osis of d eliriu m t rem en s. W h ich of th e

E. Heroin

follow ing sign s an d sym ptom s did th e pat ien t m ost likely

F.

Gam m a-hydroxybu t yric acid

sh ow ? A. Pinpoin t pu pils B. Profoun d hypoten sion

Di cult y level: Medium 27. A 46-year-old h om eless alcoh olic m an w as brough t to th e

C. Hyp oth erm ia

em ergen cy depar t m en t in a con fu sed an d in coh eren t st ate.

D. Skelet al m u scle relaxat ion

He con st an tly repeated th at h e cou ld n ot see clearly becau se

E. Visual h allucin at ion s

of “ ickering w h ite spot s in fron t of m y eyes.” He w as breath ing rap idly, ap peared ver y an xious, an d sh ow ed m arked

Di cult y level: Medium 24. A 48-year-old w om an becam e agitated an d visibly t rem ulous an d sh ow ed h allucin ator y beh avior 1 day after being adm it ted to th e h ospital for elect ive su rger y. Sh e also ac-

m ydriasis an d loss of p up illar y re ex. Laborator y exam s on ad m ission sh ow ed a ser u m p H of 7.2. W h ich of t h e follow ing syn d rom es m ost likely cau sed t h e p at ien t ’s sign s an d sym ptom s?

cu sed th e d octors an d h er h u sban d of being u n sym p ath et ic

A. Eth an ol poison ing

an d u n caring. W h ich of th e follow ing statem en ts m ost likely

B. Eth an ol w ith draw al

explain s th e reason for th e pat ien t’s beh avior?

C. Barbit urate poison ing

A. Ben zodiazepin e m edicat ion given before surger y B. Depressive episode t riggered by th e operat ion C. Eth an ol w ith draw al D. Opioid m edicat ion given before surger y E. Haloth an e an esth esia used during su rger y

D. Opiate w ith draw al E. Am ph et am in e w ith draw al F.

Meth an ol p oison ing

Di cult y level: Medium 28. An 18-year-old m ale p at ien t st ar ted sm oking m ar iju an a

Di cult y level: Hard 25. A 30-year-old m an w ith a long h istor y of polydrug abuse cam e to th e em ergen cy depart m en t after exp ectorat ing a “basin of blood.” Th e patien t adm it ted he w as regularly using in t raven ous h eroin an d oral am ph et am in e. He also said h e h ad sm oked m arijuan a, ph en cyclidin e, an d crack cocain e

cigaret tes 1 m on th ago. He w as h ealthy an d h ad n o previou s h istor y of u se of recreat ion al d r ugs. Th ree years earlier, h e w as in a psych iat ric h ospit al for 2 m on th s becau se of a sch izo a ect ive disorder th at d isap peared after n eu rolept ic th erapy. Th e p at ien t w as at in creased risk of w h ich of th e follow ing can n abis-in duced adverse e ects?

just prior to adm ission . A ch est x-ray sh ow ed bilateral alve-

A. Depressive episode

olar in lt rates, an d bron ch oscopy revealed di use alveolar

B. At rioven t ricu lar block

h em orrh age. W h ich of th e dr ugs h e w as t aking m ost likely

C. Psych ot ic episode

cau sed th e h em orrh age?

D. Irrit able bow el syn drom e

A. Heroin B. Ph en cyclidin e C. Mariju an a

E. Seizu res


D. Am ph et am in e

29. A 39-year-old m an h ad been using m any recreat ion al drugs

E. Crack cocain e

over several years. W h ich of t h e follow ing dr ugs t aken by t h is p olyd r ug u ser is kn ow n to be d evoid of p hysical


d epen den ce?

26. A 16-year-old girl at ten ded a part y w ith several frien ds. A

A. Cocain e

d rug w as cover tly slipp ed in to h er drin k, an d a frien d th en

B. Eth an ol

asked h er to join h im for a w alk in th e p ark. A few h ou rs later

C. LSD

sh e w as fou n d w ith a con t u sed face, bru ises on h er arm s,

D. Heroin

an d a torn dress. Sh e st ated sh e w as u n able to recall w h at

E. Can n abis

h ad h appen ed. W h ich of th e follow ing drugs w as m ost likely

F.

p ut in to h er d rin k?

Ph en cyclidin e

132



A. Cocain e

30. A 27-year-old m an w ith a long h istor y of drug abu se w as

B. Heroin

brough t u n con sciou s to th e em ergen cy depar t m en t . Vital

C. Can n abis

sign s w ere blood p ressu re 190/110 m m Hg, p u lse 150 beat s/

D. Am yl n it rite

m in , rect al tem p erat u re 104°F (40°C). Pup ils w ere m ydriat ic,

E. Ph en cyclidin e

an d h is skin w as m oist an d cold. Tw en t y m in u tes later h e

F.

LSD

experien ced a ton ic-clon ic seizure, h is respirat ion becam e sh allow, an d h is systolic blood p ressu re fell to 50 m m Hg.


Sh ortly after w ard h e died from cardiovascular collapse an d

33. A 23-year-old m an w as brough t to t h e em ergen cy dep ar t -

ven t ricu lar

brillat ion . W h ich of th e follow ing drugs m ost

m en t by p olice for violen t , com bat ive beh avior. Fr ien d s

likely caused th e p at ien t’s death ?

claim ed h e took som e t ablet s of a recreat ion al d r ug at a

A. Heroin

p ar t y. Th e p at ien t ap peared agit ated, diaph oret ic, an d dis-

B. Gam m a-hydroxybu t yric acid

orien ted. His blood pressure w as 170/100 m m Hg, pu lse 130

C. Ket am in e

bp m , an d tem p erat u re 101°F (about 38°C). His pu p ils w ere

D. LSD

m iot ic, u n react ive to ligh t , an d ver t ical an d h orizon t al nys-

E. Tet rahydrocan n abin ol

t agm u s w as n oted . W h ich of th e follow ing drugs m ost likely

F.

cau sed th e p at ien t’s sign s an d sym ptom s?

Diazepam

G. Cocain e

A. Cocain e B. Heroin


C. Ph en cyclidin e

31. A 30-year-old w om an cam e to th e em ergen cy depar t m en t

D. LSD

because sh e felt disassociated from h er body, h ad n o sen se of

E. Mariju an a

h er ego boun daries, an d foun d th at objects aroun d h er w ere grossly distorted. Th e w om an , w h o h ad been a polydrug user


for m any years, h ad sm oked th ree drugged cigaret tes bough t


on th e st reet . Physical exam in at ion sh ow ed blood pressu re

w ith severe vom iting after having ingested an antifreeze m ix-

of 168/100 m m Hg, m iosis, vert ical an d h orizon tal nystag-

t u re con tain ing ethylen e glycol. Vit al sign s w ere blood p res-

m u s, sw eat ing, an d

u sh ed skin . W h ich of th e follow ing is

su re 70/40 (n orm al at age 3: 100/67), h eart rate 115 bp m ,

m ost likely th e m ajor m ech an ism of act ion of th e d rug th at

respirat ion s 22 breath s/m in . Lab test s sh ow ed a plasm a pH

app aren tly cau sed th e p at ien t’s sign s an d sym ptom s?

of 7.2 an d oxalate cr yst als in th e urin e. An in t raven ous solu-

A. In h ibit ion of t ran sm it ter reu pt ake at n oradren ergic

t ion of 10% eth an ol w as given . W h ich of th e follow ing st ate-

syn ap ses

m en ts best exp lain s th e p u rp ose of eth an ol t reat m en t in th is

B. Act ivat ion of µ (m u )-t yp e op iate receptors

p at ien t?

C. Act ivat ion of seroton ergic p resyn apt ic receptors

A. It com bin es w ith ethylen e glycol in blood, leading to an

D. St im u lat ion of th e release of m on oam in es from th e syn apt ic vesicles E. Blockade of NMDA subt ype of glut am ate receptors

in er t p rodu ct . B. It preven ts th e absorpt ion of ethylen e glycol from th e in test in es. C. It ret ards th e oxidat ion of ethylen e glycol to its toxic

Di cult y level: Hard 32. A 16-year-old girl st ar ted feeling n er vou s an d experien ced m ild n ausea after taking a dr ug w h ile at a part y. On e h ou r later sh e becam e hysterical, cr ying an d yelling about being crazy. Tw o frien ds took h er to th e h ospit al. Physical exam -

m etabolites. D. It speeds up th e m et abolism of ethylen e glycol by th e liver. E. It speeds up th e elim in at ion of ethylen e glycol by th e kidn eys.

in at ion sh ow ed m ydriasis but n o nystagm us, m ild tachycard ia, blood pressu re of 160/98 m m Hg, sw eat ing, an d t rem or.


Sh e appeared ver y an xious an d st ated th at sh e h ad a st rong

35. A 24-year old m an , w h o h ad st ar ted sm oking m ar iju an a 5

sen se th at th e fu rn it u re in th e room w as alive an d th at su r-

years ago, h ad been sm oking 5 to 10 m ariju an a cigaret tes

roun ding soun ds w ere colored. W h ich of th e follow ing drugs

daily an d occasion ally self-inject ing p u re h ash ish oil. Th e

m ost likely cau sed th e p at ien t’s sign s an d sym ptom s?

m an w as m ost likely at in creased risk of w h ich of th e follow ing adverse even ts?

Questions: III-13 Drugs of Abuse 133 A. Death from paren teral inject ion of h ash ish oil


B. Death from acute can n abis w ith draw al

39. A 34-year-old m an w ith a long h istor y of drug abu se cam e to

C. Colon can cer

the hospital com plaining of severe som nolen ce, ravenous ap -

D. Driving or w ork acciden t s

pet ite, h eadach e, depression , an d lack of m ot ivat ion . He said

E. Alzh eim er disease

h e failed to get a supply of th e drug h e w as used to taking an d rep eated ly asked th e doctor to give h im th at drug to re-


d uce h is sym ptom s. With draw al from w h ich of th e follow ing


d rugs m ay h ave cau sed th ese sym ptom s?

m en t after t aking a large am oun t of ecst asy at a rave par t y.

A. Heroin

Physical exam in at ion sh ow ed a con fused an d agit ated pa-

B. Ph en cyclidin e

t ien t w ith p rofu se sw eat ing, jaw clen ch ing, m u scle t w itch -

C. Diazepam

ing an d rigidit y, an d tem perat ure of 103.8°F (39.8°C). Vital

D. Am ph et am in e

sign s w ere blood p ressu re 170/98 m g Hg, p u lse 115 bp m ,

E. Eth an ol

resp irat ion s 22/m in . Blood an alysis sh ow ed t h e p resen ce of m ethylen edioxym eth am ph et am in e (MDMA). W h ich of th e follow ing n eu rot ran sm it ters m ost likely m ediated th e e ect s of th e drug in th is p at ien t? A. Acet ylch olin e B. Seroton in C. Norep in ep h rin e D. Gam m a-am in obu t yric acid (GABA) E. Glut am ate F.

Dopam in e

Di cult y level: Easy 37. An 18-year-old m ale patient w ho had never previously drunk

Di cult y level: Medium 40. A 55-year-old w om an w ith a long h istor y of severe alcoh olism w as adm it ted to th e h ospital becau se of deteriorat ion of h er gen eral st at us. Physical exam in at ion an d lab tests con rm ed advan ced liver cirrh osis. W h ich of th e follow ing w as m ost likely an oth er disease fou n d in th is p at ien t? A. Stom ach can cer B. Pu lm on ar y em physem a C. Ren al in su

cien cy

D. Ulcerat ive colit is E. Dilated cardiom yopathy F.

Vasospast ic angin a

a large am ou n t of alcoh ol w as brough t u n con sciou s to th e em ergen cy depar t m en t after d rin king w h iskey in a bet t ing gam e at a par t y. His alcoh ol level on ad m ission w as 5 m g/m L. Th e volu m e of d ist ribu t ion of eth an ol is abou t 45 L. W h ich of th e follow ing (in gram s) w as m ost likely th e qu an t it y of alcoh ol presen t in th e p at ien t’s body?

Di cult y level: Easy 41. A 57-year-old h om eless m an w as brough t to th e em ergen cy d epart m en t by th e police, w h o h ad fou n d h im w an d ering th e st reet s. Th e m an h ad a long h istor y of alcoh olism ; h e also abu sed variou s in h alan ts w h en h e did n ot h ave m on ey

A. 100

to buy alcoh ol. He adm it ted th at alm ost daily over th e past

B. 225

3 m on th s, h e h ad in h aled a drug su pp lied by a local ven dor

C. 300

in car t r idges becau se it w as m u ch ch eap er th an alcoh ol.

D. 355

Per t in en t n dings on physical exam in at ion in cluded m u scle

E. 400

w eakn ess, u n steady gait , vibrator y sen se loss on low er ex-

F.

t rem it ies, an d hyp eralgesia. W h ich of th e follow ing drugs

425

m ost likely cau sed th e p at ien t’s syn drom e?

Di cult y level: Easy 38. A 24-year-old w om an w h o h ad n ever previously used recre-

A. Am yl n it rite B. Nit rou s oxide

at ion al dr ugs took on e tablet of LSD at a par t y. Th e cen t ral

C. Propan e

n er vou s system (CNS) e ect s of th is drug are prim arily re-

D. Heliu m

lated to th e act ivat ion of w h ich of th e follow ing receptor

E. Iso uran e

t ypes in th e CNS? A. GABAergic B. Mu scarin ic C. Nicot in ic D. Seroton in ergic E. Noradren ergic F.

Glut am atergic

134



A. Mariju an a

42. A 10-year-old boy w as brough t by h is m oth er to th eir fam ily

B. LSD

p hysician’s o

ce becau se sh e realized t h at recen t ly t h e

C. Eth an ol

boy’s beh avior h ad ch anged . Carefu l in qu ir y by th e p hysician

D. Am ph et am in e

even t ually m ade th e boy adm it h e h ad star ted sn i ng som e

E. Methylp h en idate

p ain t th in n ers an d st ain rem overs, follow ing a frien d ’s suggest ion . Th e p at tern of e ects cau sed by th ese in h alan ts is


m ost sim ilar to th at cau sed by w h ich of th e follow ing drugs?

44. A 16-year-old boy w as brough t by h is frien ds to th e em er-

A. LSD

gen cy dep ar t m en t becau se h e felt a gen eral m alaise, st rong

B. Cocain e

h eadach e, an d n ausea an d asked for m edical assistan ce. His-

C. Morp h in e

tor y revealed th at 6 h ou rs earlier, th e boy, w h o h ad n ever

D. Am ph et am in e

p reviou sly u sed recreat ion al drugs, sm oked t w o drugged

E. Eth an ol

cigaret tes at a par t y. Physical exam in at ion sh ow ed an agit ated an d talkat ive pat ien t w ith m ydriasis, m u scle t w itch -

Di cult y level: Easy 43. A 23-year-old m an w as foun d dead at h om e by h is room m ate. Th e room m ate said th ey w ere at a par t y th e n igh t before an d w en t h om e at about 3:00 a.m . He also repor ted th at

ing, an d a n e h an d t rem or. Vital sign s w ere blood pressu re 160/95 m m Hg, p u lse 115 bp m , resp irat ion s 24/m in . W h ich of th e follow ing drugs m ost likely caused th e pat ien t’s sign s an d sym ptom s?

t h e p at ien t w as a d r ug u ser an d t r ied d i eren t d r ugs from

A. Cocain e

t im e to t im e. Au top sy sh ow ed a blood level of m or p h in e

B. Mariju an a

su bst an t ially low er th an th e est im ated m in im u m leth al con -

C. LSD

cen t rat ion of th e drug. Th e path ologist w as qu ite sure th at

D. Am ph et am in e

th e death w as cau sed by th e con com itan t adm in ist rat ion of

E. Heroin

an oth er drug. W h ich of th e follow ing w as m ost likely th e

F.

Ket am in e

oth er drug involved in th e pat ien t’s death ?

Answers and Explanations: III-1 Introduction to Central Nervous System Pharm acology Learning objective: Describe the signs and symptom s m ediated by the blockade of cholinergic receptors.

n orad ren ergic n eu ron s is t h e lateral tegm en t al area of t h e

1. C Ingest ion of plan t s an d berries by ch ildren is on e of th e top

likely clon idin e. Th e drug act ivates presyn apt ic α 2 receptors

reason s for calls to p oison con t rol cen ters. Th e ch ild m ost

located on n oradren ergic term in als, w h ich in t urn decreases

likely ate som e black berries from At ropa belladonna, a p lan t

n orepin ep h r in e release from t h ose ter m in als. It seem s t h at

com m on in th e w oods. Th e berries con t ain at ropin e, an an t i-

t h is red u ct ion of cen t ral ad ren ergic act ivit y is t h e basis of

m uscarin ic drug. Th e boy’s sym ptom s are classic for at ropin e

t h e th erap eu t ic e ect of th e drugs for t reat m en t of w ith -

poison ing.

draw al from addict ing drugs, in clu d ing n icot in e an d op ioids.

A, B, D−G See correct an sw er exp lan at ion .

ret icular form at ion . Th e drug t aken by th e pat ien t w as m ost


Learning objective: Identify the brain area that is m ost likely the main target for the therapeutic e ect of clonidine in nicotine withdrawal.

Learning objective: Identify the brain area richest in histam inergic neurons.

2. C Most n oradren ergic n euron s in th e brain are foun d in th e

produ ce sign i can t e ects on an im al beh avior. Bioch em ical

locu s ceru leu s, a blu ish area on each side of th e m edian em i-

detect ion of h ist am in e syn th esis by n eu ron s an d direct cyto-

n en ce of t h e brain stem . Th e locu s cer u leu s sen d s a large

ch em ical localizat ion of th ese n eu ron s h ave de n ed th e h ista-

n u m ber of project ion s to th e am ygdala an d h ippocam pu s,

m in ergic system in th e cen t ral n er vous system . Most of th ese

w h ere n orepin eph rin e release is th ough t to m ediate em ot ion

n euron s are located in th e ven t ral posterior hypoth alam us.

an d m em or y form at ion . An oth er brain region th at is rich in

Th ey give rise to long ascen ding an d descen ding t racts th at

3. F Hist am in e an d an t ih istam in es h ave long been kn ow n to

Answers and Explanations: III-1 Introduction to Central Nervous System Pharmacology 135

system s. Th e cen t ral h istam in ergic system is th ough t to a ect

Learning objective: Identify the enzym e that represent s the ratelim iting step in serotonin biosynthesis.

arou sal (H1 an tagon ists cau se drow sin ess), at ten t ion , feeding,

8. C Seroton in is syn th esized by a t w o-step path w ay from th e

are t yp ical of th e p at tern s ch aracterist ic of oth er am in ergic

th erm oregulat ion , an d vascular dyn am ics. A−E See correct an sw er explan at ion .

essen t ial am in o acid t r yptoph an . Tr yptoph an hydroxylase, a m ixed fu n ct ion oxidase en zym e, is th e rate-lim it ing step in seroton in biosyn th esis. It conver ts t r yptoph an in to 5-hy-

Learning objective: Describe the postreceptor m echanism of activation of GABAB receptors.

droxyt r yptop h an , w h ich is th en conver ted in to seroton in by

4. A Th e p at ien t w as m ost likely receiving baclofen , a sp asm o-

dist ribu ted an d w ith low su bst rate speci cit y.

lyt ic drug th at likely acts by act ivat ing GABAB receptors. Th is

th e arom at ic L-am in o acid decarboxylase, an en zym e w idely A, B, D, E See correct an sw er exp lan at ion .

act ivat ion m ost likely open s K+ ch an n els, th u s in creasing cell m em bran e st abilizat ion . B−E See correct an sw er explan at ion .

Learning objective: Identify the neurotransm it ter m ost likely involved in the rewarding e ect of most abused drugs. 9. F Acute rew arding e ects of m ost abused drugs are th ough t

Learning objective: Identify the neurotransm it ter involved in the therapeutic action of hypnotic drugs.

to be m ediated by an in crease in syn apt ic levels of dopam in e

5. D Most d rugs u sed to relieve in som n ia (z-hypn ot ics, ben zodi-

st riat u m , seem s to play an im p or tan t role in rew ard, p lea-

azepin es, etc.) are GABAergic drugs; th at is, th ey in crease th e

su re, an d addict ion . Th erefore, dop am in e is th ough t to be

act ivit y of GABA, th e m ost abun dan t in h ibitor y n eurot ran s-

su bst an t ially involved in drug abu se an d add ict ion .

m it ter in th e brain .

in th e n u cleu s accum ben s. Th is n u cleu s, located w ith in th e

A−E, G See correct an sw er explan at ion .

A−C, E, F Curren tly, drugs act ing on th ese n eurot ran sm it ter system s are n ot u sed to t reat in som n ia.

Learning objective: Describe the pharm acological actions of a drug that m ay be e ective in the therapy of Alzheim er disease.

Learning objective: Identify the brain receptors that can m ediate excitotoxicit y.

10. E The m ost striking neurochem ical disturbance in Alzheim er

6. D Excitotoxicit y is th e p ath ologic p rocess by w h ich n er ve

basis of th e ch olin ergic de cit is at rop hy an d degen erat ion

cells are dam aged an d killed by excessive st im ulat ion by n eu-

of subcor t ical ch olin ergic n euron s, par t icularly th ose in th e

rot ran sm it ters su ch as glut am ate an d sim ilar su bstan ces. Th is

basal forebrain (n u cleu s basalis of Meyn er t) th at p rovide

occurs w h en receptors for glut am ate, such as th e N-m ethyl-

ch olin ergic in n er vat ion to th e cerebral cor tex. Th e select ive

d -asp ar t ate (NMDA) receptors an d α -am in o-3-hyd roxy-5-

d e cien cy of acet ylch olin e in AD, as w ell as th e obser vat ion

m ethylisoxazole-4-propion ic acid (AMPA) receptors, are over-

t h at cen t ral ch olin ergic an t agon ist s su ch as at rop in e can

act ivated. Th is act ivat ion allow s h igh levels of calcium ion s to

in duce a con fusion al st ate th at bears som e resem blan ce to

en ter th e cell. Ca 2+ in u x in to cells act ivates a n u m ber of en -

th e dem en t ia of AD, h as given rise to th e “ch olin ergic hy-

zym es, in clu d ing p h osp h olip ases, en d on u cleases, an d p ro-

p oth esis,” w h ich p rop oses th at a de cien cy of acet ylch olin e

teases, w h ich go on to dam age cell st ruct ures.

is crit ical in th e gen esis of th e AD sym ptom s. Alth ough th e

d isease (AD) is a de cien cy of acet ylch olin e. Th e an atom ical

A, B, E, F Th ese receptors do n ot cause excitotoxicit y.

“ch olin ergic de cien cy syn drom e” provides a useful fram e-

C Like m ost p resyn apt ic receptors, presyn apt ic NMDA re-

w ork, it is im port an t to n ote th at th e de cit in AD is far m ore

ceptors regulate the release of n eurot ran sm it ters an d do n ot

com p lex. Never t h eless, d r ugs cau sin g augm en t at ion of

alter Ca 2+ in u x in to th e target n euron s.

ch olin ergic t ran sm ission are cu rren tly th e m ain st ay of AD t reat m en t .

Learning objective: Identify the neurotransm it ters m ost likely involved in the pathogenesis of major depressive disorder.

th ere is a de cien cy in GABAergic n eu rot ran sm ission an d

7. E Th e pat ien t’s sym ptom s in dicate th at sh e w as m ost likely

th at in creasing GABA availabilit y cou ld im prove AD. How -

su ering from a m ajor dep ressive disorder. Both th e seroto-

ever, n o GABAergic drug h as been approved yet for th is

n ergic an d n oradren ergic system s are m ost likely involved in

in dicat ion .

th e path ogen esis of m ajor depressive disorder. Th is con clu sion d erives m ain ly from th e fact th at m ost cu rren tly available an t idepressan t s h ave th eir prim ar y act ion on th e cen t ral adren ergic an d/or th e cen t ral seroton ergic system . A−D, F See correct an sw er explan at ion .

C Recen t experim en t al research poin ts out th at in AD


136


Learning objective: Identify the t wo neurotransm it ters that are thought to be most involved in seizure disorders. 11. B Ep ilep sy is a ch ron ic recu rren t d isorder of cerebral fu n c-

of dopam in e an d to decrease th e availabilit y of acet ylch olin e sh ou ld be qu ite e ect ive in th e t reat m en t of PD. A, B, D, E See correct an sw er exp lan at ion .

t ion th at is ch aracterized by rep eated seizu res. Th e essen ce can be due to several m echanism s. A leading proposed m ech -

Learning objective: Identify the brain area that is the richest in cholinergic neurons.

an ism is th at th e cau se of seizu res is eith er th e at ten u at ion

14. A Th e p rim ar y con cen t rat ion of ch olin ergic n eu ron cell bod -

of prean d/or postsyn apt ic in h ibit ion (m ain ly due to a ge-

ies is in th e basal n u cleu s of Meyn er t , a grou p of n eu ron s in

n et ic or post path ologic hypofu n ct ion of GABA n euron s) or

th e su bst an t ia in n om in ata of th e basal forebrain th at h ave

an in creased e ect iven ess of excit ator y syn apses (m ain ly

w ide projections to the neocortex. These cholinergic neurons

du e to a gen et ic or post p ath ologic hyp erfu n ct ion of glu ta-

h ave a n u m ber of im p or t an t fu n ct ion s, in p ar t icu lar w it h

m ate n euron s).

resp ect to m em or y. A severe n eu ron al loss in th e n u cleu s of

of epilepsy is probably a ch ron ic low seizure th resh old th at


Meyn er t h as been fou n d in Alzh eim er disease, in vascu lar d em en t ia, an d in th e dem en t ia accom panying Parkin son dis-

Learning objective: Identify the neurotransm it ter m ost likely involved in the pathogenesis of catatonic schizophrenia. 12. D Th e pat ien t is m ost likely su ering from th e cataton ic sub -

ease. Occasion al involvem en t is presen t in oth er dem en t ing illn esses. B−F See correct an sw er explan at ion .

t ype of sch izoph ren ia, w h ich is ch aracterized by m otor im -

to m ajor n eurot ran sm it ter system s h ave been proposed to

Learning objective: Identify the neurophysiological action that most likely mediated the therapeutic e ect of drugs used for generalized anxiet y disorders.

exp lain t h e sym ptom s of sch izop h ren ia. Of t h ese, t h e d op a-

15. A Th e p rescribed drug w as m ost likely a select ive seroton in

m obilit y an d abn orm al p ost u re m ain tain ed for a long t im e (so -called w a xy

exibilit y). A n u m ber of t h eor ies related

m in e hyp oth esis st ates th at th e illn ess resu lts from an exces-

reu pt ake in h ibitor. Dr ugs of t h is class are

sive dop am in ergic act ivit y in m esolim bic an d m esocor t ical

for an xiet y disorders. Th eir th erapeu t ic e ect is m ost likely

p ath w ays. Th e d op am in e hypoth esis is th e m ost fu lly devel-

related to th eir in h ibit ion of th e seroton in t ran sporter th at

oped an d is suppor ted by several lin es of eviden ce, in cluding

m ed iates t h e reu pt ake of seroton in in to seroton ergic ter-

th e fact th at m ost an t ip sych ot ic drugs block dopam in e D2

m in als. As a con sequ en ce, seroton ergic t ran sm ission is

receptors, an d th ere is a ver y good correlat ion bet w een clin -

in creased .

ical p oten cy of th ese drugs an d th eir in vit ro a

n it y for

rst -lin e agen t s

B−F See correct an sw er explan at ion .

th ese receptors. Tw o oth er m ajor hyp oth eses of sch izop h rein seroton ergic fu n ct ion ing a ect s m ult iple n eurot ran sm it-

Learning objective: Identify the neurotransm it ter of pyram idal motor neurons.

ter system s) an d th e glut am ate hypoth esis, w h ich proposes

16. B Pyram idal n eu ron s are excitator y p roject ion n eu ron s th at

n ia are th e seroton in hypoth esis (it is kn ow n th at alterat ion

a hypofun ct ion al glut am ate system in sch izoph ren ia. A−C, E See correct an sw er explan at ion .

u se glut am ate as th e m ain n eurot ran sm it ter. A lesion of these neurons a ects glutam atergic transm ission to the low er m otor n eu ron s.

Learning objective: Describe the pharm acological actions of a drug that may be e ective in the therapy of Parkinson disease.


n euron s in th e subst an t ia n igra th at provide dopam in ergic

Learning objective: Identify the neurotransmit ter that most likely mediates obsessive-compulsive disorders.

in n er vat ion to th e st riat u m . Most drugs e ect ive in PD can

17. D Th e p at ien t’s sym ptom s in dicate th at sh e w as m ost likely

eith er in crease th e availabilit y of d op am in e or directly act i-

su ering from an obsessive-com p u lsive disorder (OCD) an d

vate dop am in ergic receptors. An oth er grou p of drugs th at

w as prescribed a select ive seroton in reu ptake in h ibitor. A

h ave a m odest an t iparkin son ian act ion are an t im uscarin ic

w ealth of research h as at tem pted to id en t ify a speci c bio -

d rugs. In PD, th e loss of dopam in e-producing n eu ron s re-

logical explan at ion for OCD. On e leading hyp oth esis h as fo-

su lt s in a loss of th e balan ce th at n orm ally exists bet w een

cu sed on th e role of seroton in (5-hydroxyt r ypt am in e, 5-HT)

acet ylch olin e an d dop am in e-m ediated n eu rot ran sm ission .

dysfu n ct ion , w h ich is su p ported by th e fact th at th e on ly ef-

Th e an t ich olin ergic agen ts w ork by blocking excitator y ch o-

fect ive d r ug t reat m en t s for OCD p r im ar ily in u en ce 5-HT

lin ergic st riat al in tern eu ron s, th ereby m in im izing th e e ect

t ran sm ission . How ever, t h e exact role of 5-HT u n d erlyin g

of th e relat ive in crease in ch olin ergic sen sit ivit y. Taking in to

OCD h as n ot been determ in ed.

13. C Parkin son disease (PD) is ch aracterized by a loss of th e

account these ndings, a drug able to increase the availabilit y

A−C, E, F See correct an sw er explan at ion .

Answers and Explanations: III-2 Sedative and Hypnotic Drugs 137 Learning objective: Identify the central nervous system neurotransmit ter that generates only inhibitory postsynaptic potentials.

Learning objective: Identify the m ain neurotransm it ters that act to decrease pain signaling.

18. D GABA is a n eu rot ran sm it ter th at can gen erate on ly IPSPs

20. F Opioid pept ides, n orepin eph rin e, an d seroton in are th e

by act ivat ing GABA receptors. GABAA receptors are ion o-

three m ajor neurotransm it ters that act in the central ner vous

t rop ic; th eir act ivat ion op en s ligan d-act ivated Cl− ch an n els,

system (CNS) to decrease pain sign aling, th u s p rodu cing an -

in creasing inw ard Cl− con duct an ce. GABAB receptors are m e-

algesia. En dogen ou s opioids are released at several CNS sites

tabot ropic; th eir act ivat ion op en s volt age-gated K+ ch an n els,

in respon se to n oxious st im u li, in clu ding th e spin al cord, th e

in creasing ou t w ard K+ con du ctan ce. In both cases, th e in t ra-

th alam u s, an d th e cor tex. En dogen ou s op ioids can also m od -

cellular environ m en t becom es m ore n egat ive, th u s in ducing

u late pain t ran sm ission in directly by act ivat ing th e follow -

cell m em bran e st abilizat ion .

ing path w ays th at descen d from th e brain stem to th e dorsal

A−C, E All of t h ese n eu rot ran sm it ters can act ivate bot h

h orn :

excitator y an d in h ibitor y receptors.

• A n oradren ergic p ath w ay from th e locu s ceru leu s. Norep in ep h rin e released from th ese p roject ion s in th e spin al

Learning objective: Identify the brain transm ission system that targets N-methyl-d -aspartate (NMDA) receptors.

cord act ivates α 2 receptors (th e prim ar y receptors for n or-

19. G Glutam ate is an im por tan t excit ator y n eurot ran sm it ter in

of th e dorsal h orn . Th is act ivat ion causes hyperpolariza-

ep in ep h rin e in th e CNS) located on n ocicept ive n eu ron s

th e brain . Glu t am ate receptors in clu de NMDA an d α -am in o-

t ion of th e n eu ron , in h ibit ing n ocicept ive t ran sm ission .

3-hyd roxy-5-m ethylisoxazole-4-p ropion ic acid (AMPA) re-

• A seroton ergic p ath w ay from th e raph e n u clei. Seroton in ,

ceptors. Drugs such as felbam ate th at seem to act by blocking

released from these projections in the spin al cord, activates

th ese receptors can be u sed e ect ively as an t iconvu lsan ts.

seroton ergic receptors located on n ocicept ive n eu ron s of

A−E Th ese system s are n ot exclu sively excitator y; th ere-

th e dorsal h orn . Th is act ivat ion cau ses hyp erp olarizat ion

fore, drugs a ect ing th ese system s are n ot u sed as an t i-

of n eu ron s, in h ibit ing n ocicept ive t ran sm ission .

convulsan t s.


F Th e GABAergic system is cen t ral in h ibitor y. Drugs th at in crease th e act ivit y of th is system , su ch as ben zodiazepin es an d barbit u rates, are cu rren tly u sed as an t iconvu lsan t s.

INTRODUCTION TO CENTRAL NERVOUS SYSTEM PHARMACOLOGY Answ er key 1. 2. 3. 4. 5.

C C F A D

6. 7. 8. 9. 10.

D E C F E

11. 12. 13. 14. 15.

B D C A A

16. 17. 18. 19. 20.

B D D G F

Answers and Explanations: III-2 Sedative and Hypnotic Drugs Questions 1−6

ch an n el m acrom olecu lar com plex. Th e bin ding in creases th e

1. B

a

2. D

an in creased frequ en cy of ch loride ch an n el opening. Because

3. J

extracellular chloride concentration is about 120 m M, an d in -

4. I

t racellu lar ch loride con cen t rat ion is abou t 20 m M, ch loride

5. G

ch an n el open ing w ill in crease inw ard Cl− cu rren t . Th is in t u rn

6. B

w ill in crease th e n egat ive ch arges in side th e cell, causing hy-

n it y of th e GABAA receptor for GABA, w h ich in t u rn cau ses

perp olarizat ion of th e cell m em bran e.

Learning objective: Explain the benzodiazepine-induced variation in Cl− current in the GABAA receptor−chloride ion channel macromolecular complex. 7. B Ben zodiazep in es bin d to receptors located at th e in terface bet w een α an d γ su bu n it s of th e GABAA receptor−ch loride ion

A, C−E Ben zodiazep in es do n ot a ect th ese cu rren ts. Moreover, all of t h ese act ion s w ou ld cau se d ep olar izat ion , n ot hyp erpolarizat ion , of cell m em bran es.

138


Learning objective: Describe the m ain adverse e ects of benzodiazepines.

Learning objective: Describe the m ain contraindication for benzodiazepines.

8. C Today select ive seroton in reu ptake in h ibitors (SSRIs) are

11. D Because of th eir m uscle relaxan t propert ies, ben zodiaze-

rst-lin e agen ts for gen eralized an xiet y disorder, bu t becau se th ey h ave a slow on set of act ion , a ben zodiazep in e is often given con com it an tly for th e

p in es are relat ively con t rain dicated in m yasth en ia gravis. A−C, E All of th ese agen t s are rst- or secon d-ch oice drugs

rst few days to provide

in t reat ing gen eralized an xiet y disorder. Th ey lack m u scle

acu te relief of sym ptom s w h en an xiet y is severe an d in -

relaxan t act ivit ies an d th erefore are n ot con t rain dicated in

cludes a suicide risk (pat ien t w an ted to die). Sedat ion an d

m yasth en ic p at ien t s.

d row sin ess are adverse e ect s th at occu r in m ore th an 50% of patients on long- or m edium -acting benzodiazepines. They

Learning objective: Explain the mechanism of action of melatonin.

represen t an exten sion of ph arm acological e ects an d are

12. C Melaton in receptors are th ough t to be involved in m ain -

d ose-related. Toleran ce (at least par t ial) to th ese e ect s u su -

t ain ing circadian rhyth m s u n d erlying th e sleep−w ake cycle.

ally occu rs after 2 to 3 w eeks of u se. Drow sin ess can occu r in

Ram elteon , a n ovel hypn ot ic drug p rescribed sp eci cally for

abou t 10% of p at ien t s t aking sert ralin e.

sleep -on set in som n ia, is an agon ist at m elaton in receptors

A Th ese e ect s are n ot com m on (th ey occu r in 2 to 5% of p at ien ts t aking ben zodiazepin es).

located in th e su prach iasm at ic n u clei of th e brain . A, B, D, E See correct an sw er exp lan at ion .

B, D Th ese e ect s occur on ly w ith h igh doses of ben zod iazepin es. E Ben zodiazepin es im prove th e qualit y of sleep, an d early aw aken ing is u n likely w ith long- an d m ediu m -act ing com p ou n ds. Nigh t m ares w ith ser t ralin e are exceedingly rare.

Learning objective: Describe the therapeutic uses of buspirone.

Learning objective: Explain the concept of redistribution of benzodiazepines. 13. C Redist ribu t ion of a d rug from its site of act ion in to oth er t issu es or sites is a m ain factor in term in at ing dr ug e ect , p rim arily w h en a h igh ly lipid-soluble drug th at acts on th e brain is adm in istered rap idly by in t raven ou s (IV) inject ion .

9. F Buspirone is considered a second-line agent for generalized

A good exam ple of th is is th e use of IV inject ion of diazepam

an xiet y disord ers becau se of in con sisten t rep or ts of long-

(a h igh ly lipid-soluble drug) to in duce loss of con sciousn ess.

term e

cacy. How ever, it can be th e app ropriate drug in pa-

Because blood ow to t h e brain is so h igh , t h e d r ug reach es

t ien t s w h o fail oth er an xiolyt ic th erap ies or in p at ien t s w ith

it s m a xim al con cen t rat ion in t h e brain w it h in 1 m in u te of

a h istor y of su bst an ce abu se, as in th is case.

it s IV inject ion . After th e inject ion is con cluded, th e plasm a

A, C Ben zodiazep in es can cau se dep en den ce an d th erefore are con t rain dicated in a person w ith a p ast h istor y of su b stan ce abu se.

con cen t rat ion falls as diazepam di uses in to oth er t issu es, su ch as m u scle. A, D Diazep am is exten sively m etabolized in th e liver (n ot

B Selective serotonin reuptake in hibitors are drugs of choice

in th e brain ) to desm ethyldiazep am an d oxazepam . Both

for an xiet y disorders but are relatively contraindicated in this

m etabolites are act ive. Th erefore, biot ran sform at ion can n ot

p at ien t because of th e recen t episode of sexual dysfun ct ion .

explain th e sh ort act ion of th e drug.

D, E Neurolept ics, such as h aloperidol, an d lith ium h ave n egligible an xiolyt ic proper t ies.

B Th e ren al excret ion of diazepam is about 1%. E Toleran ce can develop to th e act ion of ben zodiazepin es, bu t on ly after a ch ron ic t reat m en t of several days.

Learning objective: Describe the m echanism of action of um azenil. 10. E Flum azen il is a com p et it ive ben zodiazepin e (BDZ) receptor

Learning objective: Describe benzodiazepine-induced anterograde amnesia.

an tagon ist th at can block both th e e ect s of BDZ an d th ose

14. C A classical e ect of ben zodiazep in es (m ain ly w h en h igh

of β-carbolin e d er ivat ives, t h e inverse agon ist s at BDZ re-

d oses are given to in d u ce con sciou s sedat ion ) is an tero-

ceptors. It can also block th e e ect s of z-hyp n ot ics bu t does

grad e am n esia, t h at is, loss of m em or y for even t s occu r r in g

n ot an tagon ize th ose of oth er cen t ral n er vous system de-

d u r ing t h e d r ug’s d u rat ion of act ion . Th e e ect is exp loited

p ressan ts (barbit urates, bu spiron e, eth an ol, etc.). It is u sed

t h erapeu t ically, becau se th e p at ien t can n ot rem em ber th e

clin ically to cou n teract excessive e ects of BDZ, as in th is

u np leasan t sen sat ion s felt d u r ing en doscop ic or su rgical

case. Because it can cause several (an d som etim es serious)

p rocedu res, as in th is case.

unw an ted e ects, it is not currently used in case of BDZ

A Ben zodiazepin es h ave ver y m ild an t iem et ic proper t ies.

p oison ing.

B, D Ben zodiazepin es ten d to cause e ect s opposite to

A, B, C, D See correct an sw er exp lan at ion .

th ose listed . E Delusion an d h allucin at ion s are exceedingly rare e ects of ben zodiazepin es.

Answers and Explanations: III-2 Sedative and Hypnotic Drugs 139 Learning objective: Explain the m olecular m echanism of action of benzodiazepines.

Learning objective: Explain why a chronic benzodiazepine treatment can increase the risk of fall in the elderly.

15. D Th e pat ien t m ost likely received a sh ort-act ing ben zodiaz-

19. C Th e lin k bet w een ben zodiazep in e u se an d falls is w ell d oc-

ep in e, su ch as alprazolam , a drug u sed in th e su rgical set t ing

u m en ted an d m ay result from balan ce im pairm en t , seda-

for th e rapid relief of agitat ion in postoperat ive pat ien ts.

t ion , an d m u scle relaxan t e ects. Alth ough toleran ce can

Ben zodiazepin es in crease th e frequen cy of ch loride ch an n el

d evelop to th ese ben zodiazepin e act ion s, elderly p eop le m ay

open ing, th u s m aking th e rest ing m em bran e poten t ial of

experien ce persisten t im pairm en t . Th e ch ron ic use of ben -

GABA in tern euron s m ore n egat ive in several brain areas.

zodiazep in es is th erefore relat ively con t rain dicated in th e

A−C, E, F All of th ese drugs can cause, directly or in directly, n euron al m em bran e hyperpolarizat ion (i.e., m ore n egat ive rest ing m em bran e poten t ial), but th ey are n ot used for rapid

elderly. A, B, D, E Th ese d r ugs d o n ot in crease t h e r isk of fallrelated fract ures.

relief of post surgical agit at ion .

Learning objective: Identify the drug that binds to the α 1 subunit of GABAA receptors.

Learning objective: Describe the pharm acological e ects of barbiturates. 20. D Th e m an m ost likely su ered from ep ilepsy, an d p h en o-

16. A Ben zodiazep in es (m ain ly diazepam an d lorazepam ) are

barbital w as added to h is p h arm acoth erapy. Ph en obarbital is

rst-lin e agen ts for th e em ergen cy t reat m en t of stat u s ep i-

a barbit u ric acid derivat ive an d is con sidered a secon d-lin e

lept icu s. Th ey bin d to receptors located at th e α su bu n it of

agen t in ep ilep sy. All barbit u rates can o set convu lsion s

th e GABAA receptor−ch loride ion ch an n el m acrom olecular

w h en given at doses th at cause loss of con sciousn ess, but

com plex, near the interface bet ween α and γ subunits. GABAA

p h en obarbit al h as an t iconvu lsan t prop er t ies even in doses

receptors in di eren t areas of th e cen t ral n er vous system

th at do n ot a ect aler t n ess.

con sist of di eren t isoform s con t ain ing ve di eren t α sub u n its (α 1 , -2 , -3 , -4 , an d

-5 ).

Ben zodiazepin es can bin d to m any

of th ese subun its. B, C Zolp idem an d

A−C Barbit urates are devoid of an t idepressan t , an t ipsych ot ic, or an t iparkin son proper t ies. E Alth ough barbit urates are st ill in clu ded in an algesic

um azen il bin d to α su bu n its of GABA

receptors, but th ey are not used as an t iconvulsan t s.

com bin at ion s, th ey are devoid of an algesic proper t ies, an d th ey act u ally m ay w orsen a p at ien t’s percept ion of pain .

D, E Ph enytoin an d valproic acid are used as an t iconvulsan t s, bu t th ey do n ot bin d GABA receptor com p on en ts.

Learning objective: Describe the therapeutic uses of benzodiazepines.

Learning objective: Describe the action of benzodiazepines upon sleep architecture.

21. D In addit ion to th e an xiolyt ic e ect , ben zodiazepin es given

17. B Ben zodiazep in es alter sleep arch itect u re an d stages. Th ey

m en t of m em or y for even t s occu rring after th e adm in ist ra-

d ecrease sleep laten cy an d decrease aw aken ing du ring th e

t ion of th e drug. Th is act ion is p ar t icu larly u sefu l w h en th e

n igh t . All oth er e ect s on sleep are opposite to th ose listed.

p at ien t h as to u n d ergo a dist u rbing diagn ost ic procedu re, as

Ben zodiazepin es are less frequen tly u sed today for in som n ia

in th is case. Becau se th e in ter ven t ion is brief, a sh or t-act ing

becau se of th e risk of depen den ce. Exper ts agree th at th ese

ben zodiazep in e su ch as oxazepam is m ost ap prop riate.

d rugs sh ould be u sed at th e low est e ect ive dose for th e sh ortest du rat ion possible. A, C−E See correct an sw er explan at ion .

at h igh doses can cause an terograde am n esia, th at is, im pair-

A Buspiron e is an an xiolyt ic drug, but th e e ect develops slow ly (in 1 to 2 w eeks), an d an terograde am n esia does n ot occur. B, C, E Th ese drugs cause n egligible an xiolyt ic e ect s an d

Learning objective: Describe the m ain adverse e ects of benzodiazepines.

n egligible an terograde am n esia.

d iazepin e often u sed by pract icing physician s to t reat in -

Learning objective: Describe the interaction bet ween benzodiazepines and ethanol.

som n ia. Elderly p eople are m ore sen sit ive to th e depressive

22. B Poison ing by ben zodiazep in es, su ch as diazep am , is u su -

e ect s of th ese drugs, an d th e daily dose can easily be m is-

ally n ot life-th reaten ing bu t can be ver y seriou s w h en th ese

t aken , if th e drug is t aken w ith ou t st rict su per vision , as in

d r ugs are com bin ed w it h alcoh ol becau se of t h e ad dit ive

th is case.

d epressan t e ect s on th e cen t ral n er vou s system .

18. B Th e pat ien t h ad m ost likely t aken tem azepam , a ben zo-

A, C Zolp idem an d ram elteon h ave ver y sh or t h alf-lives, so th ey are less p ron e to cau se dayt im e sedat ion . D−F Ch lor p rom azin e, bu sp iron e, an d p h en obarbit al are n ot prescribed as hypn ot ics.

A, C−F Th ese drugs do n ot cau se addit ive sedat ive e ects w h en given con com it an tly w ith alcoh ol.

140


Learning objective: Describe the m ain contraindication of benzodiazepines.

in it ially requ ire con cu r ren t ben zod iazep in e t h erapy t h at

23. A Sleep ap n ea is a breath ing disorder ch aracterized by fre-

are eviden t .

qu en t an d p rolon ged (m ore t h an 15 secon d s) p au ses in

provides qu ick relief u n t il th e th erap eu t ic e ect s of th e SSRI A−C, E None of th ese drugs are e ective in pan ic disorders.

breath ing th at occu r du ring sleep . Typ ical sym ptom s of sleep excessive dayt im e sleepin ess, an d severe sh or t n ess of breath

Learning objective: Describe the use of benzodiazepines in ethanol withdrawal.

on exer t ion . In sleep apn ea, th e sen sit ivit y of th e respirator y

27. F Th e t im e-h on ored prin ciple of t reat ing an abst in en ce syn -

cen ter to carbon dioxide is decreased. Sedat ive-hypn ot ics

d rom e w ith an agen t to w h ich th e abu sed drug in du ces

d rugs are gen erally con t rain dicated in th is disorder, as th ey

cross-toleran ce h old s for eth an ol as w ell. A long-act ing ben -

fu r th er d ecrease th e sen sit ivit y of th e respirator y cen ter to

zodiazep in e, su ch as diazep am , is th e drug m ost com m on ly

hyp ercap n ia.

u sed in alcoh ol w ith draw al, but a sh or t-act ing agen t such as

apn ea in clu de alterat ion in sleep pat tern w ith lou d sn oring,

B−E All of th ese drugs h ave been u sed in sleep apn ea w ith m od est resu lt s.

oxazep am can be adm in istered ever y 4 to 6 h ou rs according to th e stage an d severit y of w ith draw al. Th eoret ically, eth an ol it self sh ou ld be e ect ive but is n ever u sed because of its

Learning objective: Outline the anticonvulsant and m uscle relaxant uses of benzodiazepines. 24. F All ben zod iazep in es h ave an t iconvu lsan t an d m u scle re-

sh ort du rat ion of act ion an d it s n arrow range of safet y. A−E See correct an sw er explan at ion .

m ission in th e spin al cord, because th ey are e ect ive in pa-

Learning objective: Explain the zolpidem -induced increase in Cl− conductance in the GABAA receptor−chloride ion channel macromolecular complex.

t ien t s w ith cord t ran sect ion . Becau se th e con dit ion of th e

28. B Z-hypn ot ics (zolpidem , zaleplon , an d eszopiclon e) bin d

pat ien t is a ch ron ic on e, a long-act ing ben zodiazep in e is

select ively to th e α 1 subun it of th e GABAA receptor−ch loride

m ost appropriate.

ch an n el com plex. Th is select ivit y m ay accoun t for th eir rela-

la xan t act ivit y. Th e lat ter is at least p ar t ly related to t h e en h an cem en t of GABA-in du ced in h ibit ion of syn apt ic t ran s-

A−E All of th ese drugs are devoid of m uscle relaxan t prop er t ies.

t ive lack of e ect on sleep arch itect u re an d st ages, as w ell as for th e n egligible an xiolyt ic, an t iconvu lsan t , an d m u scle relaxan t p ropert ies. Th e bin ding in creases the GABA-m ediated

Learning objective: Describe the hypnotic uses of benzodiazepines.

open ing of Cl− ch an n els, leading to an in crease in Cl− con duc-

25. B Th e p at ien t’s sym ptom s in dicate th at h e is su ering from

cau ses hyp erpolarizat ion of th e cell m em bran e.

in som n ia ch aracterized by di cult y in m ain tain ing sleep

tan ce. Th e en h an ced con cen t rat ion of Cl− in side th e cell A, C−E See correct an sw er explan at ion .

d uring th e n igh t becau se of n igh t m ares. A ben zodiazep in e hyp n ot ic is p referable in th is pat ien t becau se of th e n eed for

Learning objective: Describe the therapeutic uses of eszopiclone.

an xiolyt ic e ect in addit ion to hypn ot ic e

cacy. Moreover,

29. C Non ben zodiazep in es act ing on GABA receptors (th e so-

ben zodiazep in es ten d to decrease slow -w ave sleep th at is

called Z-hyp n ot ics) are cu rren tly preferred to t reat in som -

com m on ly associated w it h n igh t m ares. A m ed iu m -act in g

n ia, because th ey do n ot alter sleep arch itect ure an d stages,

ben zod iazep in e, su ch as tem azep am , w h ich can m ain t ain

d o n ot h ave sign i can t an xiolyt ic or an t iconvu lsan t p rop er-

sleep t h rough ou t t h e n igh t , w ou ld be ap p rop r iate for t h is

t ies, an d h ave a low er risk of dep en den ce com p ared to th e

p at ien t .

sh ort-act ing ben zod iazepin es. Th e ch oice of hyp n ot ic drugs

A, C−E Th ese drugs are devoid of hyp n ot ic p rop er t ies.

d epen ds on th e t yp e of in som n ia p resen ted by th e pat ien t . W h en th ere is di cu lt y in falling asleep, a sh or t-act ing drug

Learning objective: Describe the use of benzodiazepines in panic at tacks.

is ap propriate; w h en th ere is di cu lt y in m ain t ain ing sleep


(t ½ 4−7 h ) is app ropriate, as in th is case.

d uring th e n igh t , a m edium -act ing drug such as eszopiclon e

su ering from a p an ic disord er. A select ive seroton in re-

A Flun it razepam is a long-act ing ben zodiazepin e an d is

u pt ake in h ibitor (SSRI), such as ser t ralin e, is an appropriate

th erefore n ot ap prop riate as a hyp n ot ic becau se of th e risk of

rst-lin e t reat m en t for m ost p at ien t s w ith pan ic disorder. How ever, p at ien ts w ith severe or dist ressing sym ptom s m ay

dayt im e sedat ion an d drow sin ess. B, D−F Th ese d rugs h ave n egligible hypn ot ic act ivit y.

Answers and Explanations: III-3 General Anesthetics 141 Learning objective: Describe the interaction bet ween barbiturates and benzodiazepines. 30. C Ben zodiazepin es do n ot cause sign i can t respirator y dep ression w h en given alon e, but th ey can do so w h en th ey are given w ith oth er cen t ral n er vou s system d ep ressan t s. In th is case, th e at ten ding p hysician m ost likely did n ot take a det ailed h istor y an d th u s overlooked th e an t iep ilept ic th erapy of th e pat ien t . Because of th e in teract ion bet w een ph en obarbital an d diazep am , th e p at ien t u n der w en t severe resp irator y depression .

SEDATIVE-HYPNOTIC DRUGS Answ er key 1. 2. 3. 4. 5.

B D J I G

6. 7. 8. 9. 10.

B B C F E

11. 12. 13. 14. 15.

D C C C D

16. 17. 18. 19. 20.

A B B C D

21. 22. 23. 24. 25.

D B A F B

26. 27. 28. 29. 30.

D F B C C

A, B, D−F Th ese drugs are n ot u sed for th e rap id relief of acu te an xiet y sym ptom s.

Answers and Explanations: III-3 General Anesthetics Questions 1−5 1. B

Learning objective: Describe the pharm acological e ect s of nitrous oxide.

2. D

8. B In su ban esth et ic con cen t rat ion s, n it rou s oxid e can in d u ce

3. F

a eu ph oric st ate accom p an ied by ver y good an algesia. For

4. C

th is reason , it is frequ en tly u sed as an an algesic in m in or or-

5. G

th op ed ic an d den t al p roced u res th at do n ot requ ire gen eral an esth esia, as in th is case.

Learning objective: Explain the m eaning of the m inim um alveolar concentration of inhalational anesthetics. 6. D Du ring gen eral an esth esia, th e p ar t ial p ressu re of an an est h et ic in t h e brain equ als t h at in th e lu n g w h en equ ilibr iu m

A Muscle relaxat ion w ith n it rous oxide is n egligible. C Un con sciousn ess can n ot be ach ieved w ith n it rous oxide alon e even w h en given at 100%con cen t rat ion in th e in spired air.

is reach ed. Th erefore, th e m easu rem en t of th e steady-st ate

D Blood pressure is w ell m ain tain ed by n it rou s oxide be-

alveolar con cen t rat ion of d i eren t an est h et ics p rovid es a

cau se th e direct dep ressan t e ect u p on th e h ear t is cou n ter-

m easure of th eir relat ive poten cies. Th e m in im um alveolar

acted by sym p ath et ic st im u lat ion .

con cen t rat ion (MAC) is de n ed as th e alveolar con cen t rat ion

E Respirat ion is m in im ally a ected by n it rous oxide.

of th e an esth et ic th at result s in th e im m obilit y of 50% of pat ien t s w h en exp osed to a su p ram a xim al n oxiou s st im u lu s. Th u s, MAC rep resen t s t h e ED50 on a conven t ion al qu an t al d ose−respon se cur ve an d is th erefore a m easu re of th e po-

Learning objective: Describe the m echanism of action of barbiturates. 9. D All barbit urates in crease th e a

n it y of GABA for GABAA

ten cy of th e in h aled an esth et ic: the low er th e MAC, th e h igh er

receptors, bu t u n like ben zodiazepin es, w h en given at h igh

t h e p oten cy. Th e sp eed of in d u ct ion is a p h ar m acokin et ic

doses th ey can en h an ce Cl− ch an n el op en ing in th e absen ce

p aram eter an d can tell us n oth ing about th e poten cy of a drug

of GABA. Because th e dose of th iopen t al w as h igh en ough to

(a ph arm acodyn am ic param eter).

lose con sciou sn ess, th e m ech an ism of th is act ion w as m ost


likely an en h an cem en t of Cl− ch an n el op en ing in th e absen ce of GABA.

Learning objective: Describe the adverse e ect s of halothane.


7. D Haloth an e can cause cardiac arrhyth m ias because it in to catech olam in es. Ot h er h alogen ated an est h et ics are less

Learning objective: Explain why propofol is preferred for general anesthesia in patients at high risk of vomiting.

likely to produ ce cardiac arrhyth m ias.

10. D Propofol is an in t raven ous an esth et ic w ith an on set an d

creases th e au tom at icit y of th e h ear t an d sen sit izes th e h ear t


d urat ion of an esth esia sim ilar to th at of th iop en tal. It is th e on ly an esth et ic w ith an t iem et ic act ion , so it is th e preferred d rug in p at ien t s at h igh risk of n au sea an d vom it ing, as in th is case. A−C, E See correct an sw er explan at ion .

142


Learning objective: Explain why another inhalational anesthetic is added to nitrous oxide to maintain general anesthesia. 11. B Un con sciou sn ess, w h ich is u su ally ach ieved w ith th iop en t al, can n ot be m ain tain ed w ith n it rou s oxide alon e (th e d rug

Learning objective: Describe the relationship bet ween the blood/ gas partition coe cient and the speed of induction and recovery from general anesthesia. 15. D Sevo u ran e h as a blood/gas p art it ion coe

cien t of 0.69.

h as a m in im um alveolar con cen t rat ion h igh er th an 100%),

Haloth an e, th e protot ype of h alogen ated gen eral an esth et ics,

an d th erefore an oth er p oten t an esth et ic is n eeded. More-

h as a blood/gas part it ion of 2.4. Because th e speed of in duc-

over, n it rou s oxide h as n egligible e ect s on skeletal m u scle

t ion an d recover y of an esth esia are inversely p rop or t ion al to

ton e, so a h alogen ated an esth et ic is given w ith it m ost of th e

the blood/gas part ition coe

t im e (all h alogen ated an esth et ics cau se relaxat ion of skelet al

an esth et ic in d uct ion an d recover y.

m u scle an d en h an ce th e e ect s of n eu rom u scu lar blocking agen t s). A Nit rous oxide−in duced an algesia is excellen t , even at low con cen t rat ion of th e gas. C−E Haloth an e can cause, n ot preven t , all of th ese e ect s.

cient, sevo urane causes a rapid

A Redist ribu t ion can be a factor th at speeds up th e recover y from an esth esia, bu t sevo uran e h as low lip id solu bilit y, so redist ribu t ion in to lip id t issu e is m in im al. B Met abolism of sevo u ran e is ver y low (abou t 3%). C Th e m in im u m alveolar con cen t rat ion (MAC) of an in h alat ion al an esth et ic is a m easure of th e poten cy of th e

Learning objective: Describe anesthetic-induced m alignant hypertherm ia.

d rug; th at is, it is a ph arm acodyn am ic variable. Th e sp eed of

12. B In gen et ically suscept ible pat ien t s, all h alogen ated an es-

E In h alat ion al an esth et ics dist ribute un iform ly in to th e

th et ics can t rigger m align an t hyp erth erm ia, an au tosom al

brain . Th ey are n ot con cen t rated in a sp eci c region of th e

d om in an t disorder ch aracterized by severe m u scle con t rac-

brain .

in duct ion depen ds on ph arm acokin et ic variables.

t ion , rapid developm en t of hyperth erm ia, an d a m assive in A Acu te in term it ten t porphyria is an idiosyn crat ic disor-

Learning objective: Describe the pharm acological e ects of iso urane.

d er th at can be t riggered by barbit u rates, n ot by h alogen ated

16. C All h alogen ated an esth et ics h ave bron ch odilat ing proper-

crease in m et abolic rate. Th e syn d rom e is frequ en tly fatal.

an esth et ics. C Acute h epat it is is a rare disease th at can be in du ced by

t ies, w h ich is ben e cial in p at ien t s w ith u n d erlying air w ay p roblem s, as in th is case.

h aloth an e but n ot by oth er h alogen ated an esth et ics. More-

A Cardiac out pu t is m in im ally a ected by iso u ran e.

over, it is n ot a gen et ic disorder.

B, D, E Iso uran e h as e ects opposite to th ose listed.

D, E Th ese diseases are n ot gen et ically determ in ed an d are n ot in duced by h alogen ated an esth et ics.

Learning objective: Describe the pharm acological actions of etomidate.

Learning objective: Explain the m eaning of the m inim um alveolar concentration of inhalational anesthetics

17. E Etom idate is an in t raven ou s an esth et ic agen t th at cau ses

13. C Th e m in im um alveolar con cen t rat ion (MAC) is de n ed as

p en tal (abou t 5 to 10 m in u tes of un con sciou sn ess w ith a

th e con cen t rat ion of th e an esth et ic th at resu lts in th e im m o-

stan dard an esth et ic d ose), bu t it h as m in im al act ion s on car-

bilit y of 50% of pat ien ts w h en exp osed to a su p ram axim al

d iovascu lar an d resp irator y fu n ct ion s. It is m ain ly u sed for

n oxious st im ulus. Th us, MAC represen ts th e ED50 on a con -

in duct ion of an esth esia in pat ien t s w ith serious resp irator y

ven t ion al quan t al dose−respon se cur ve an d is therefore a

or cardiovascular disease, as in th is case.

m easu re of th e p oten cy of th e in h aled an esth et ic. A, B, D, E See correct an sw er exp lan at ion .

an esth et ic in d u ct ion an d recover y sim ilar to th at of th io-

A Haloth an e cau ses a dose-depen den t depression of th e cardiovascu lar an d respirator y system s. B Ket am in e produces cardiovascular st im ulat ion by exci-

Learning objective: Explain the m echanism of action of nitrous oxide.

t at ion of th e sym path et ic n er vou s system .

14. C Nit rous oxide is a poten t an d select ive in h ibitor of NMDA-

p rim arily due to a decrease in total perip h eral resistan ce.

act ivated cu rren t , suggest ing th at it s depressan t e ects on th e cen t ral n er vou s system are p rodu ced via n on com p et it ive an tagon ist ic act ivit y at NMDA receptors. A, B, D, E See correct an sw er exp lan at ion .

C Propofol cau ses a m arked decrease in blood pressure, D Barbit urates such as th iopen t al are respirator y an d circu lator y depressan t s.

Answers and Explanations: III-3 General Anesthetics 143 Learning objective: Outline the therapeutic uses of ketam ine.

h alogen ated an esth et ics an d/or succinylch olin e. Th e path o-

18. A Ket am in e is a gen eral an esth et ic th at in du ces a state of

gen esis of t h e d isease is t h ough t to involve a m u t at ion in

sedat ion , ch aracter ized by im m obilit y, p rofou n d an algesia,

t h e gen e en coding th e skeletal m u scle r yan odin e receptor, a

an terograd e am n esia, an d a st ron g feelin g of d issociat ion

ch an n el respon sible for th e regulat ion of Ca 2+ release from

from th e environ m en t w ith ou t com p lete loss of con sciou s-

th e sarcoplasm ic ret icu lu m . Th is m u t at ion w ou ld resu lt in

n ess. Th is state h as been term ed dissociat ive an esth esia. Be-

an excessive release of Ca 2+, w h ich w ou ld be th e m ain cau se

cau se it can provoke p ostop erat ive d isorien t at ion , p ercept u al

of th e sign s an d sym ptom s of m align an t hyper th erm ia.

illusion s, an d vivid dream s, it is n ot com m on ly used in gen eral su rger y. Th e drug cau ses n egligible respirator y dep res-

A, B, D, E Non e of t h ese act ion s cau se t h e syn d rom e exh ibited by th e pat ien t .

sion an d sign i can t sym path et ic st im u lat ion . It is u sed for in u en ced by t h e m en t al e ect s of t h e d r ug), esp ecially

Learning objective: Describe the cardiovascular e ect s of isourane.

w h en th ey h ave respirator y problem s, as in th is case.

21. D Iso uran e is a poten t coron ar y vasodilator, sim u ltan eou sly

sh or t , p ain fu l su rgical p roced u res in ch ild ren (w h o are less

B, C Th iopen tal an d fen tanyl can cause sign i can t resp ira-

p roducing in creased coron ar y blood

ow an d decreased

tor y depression an d th erefore are n ot in dicated in asth m at ic

m yocardial oxygen con su m pt ion . It is a part icu larly safe an -

p at ien ts.

esth et ic to u se for pat ien t s w ith isch em ic h ear t disease, as in

D, E Gen erally, h alogen ated an esth et ics such as h aloth an e an d sevo u ran e are n ot u sed for m in or su rgical p rocedu res.

th is case. A, E Haloth an e an d sevo u ran e cau se a dose-dep en d en t d ecrease in cardiac ou t p ut .

Learning objective: Describe the drugs used for conscious sedation and have the advantage of being reversible by the administration of speci c receptor antagonists.

B, C Etom idate an d propofol are used for in duct ion , n ot for m ain ten an ce of gen eral an esth esia.

tered con sciousn ess w ith th e follow ing feat u res:

Learning objective: Identify the general anesthetic with the highest risk of toxic hepatitis.

• Con sciou sn ess is n ot lost (th e p at ien t can respon d to ver-

22. B Th e pat ien t’s sign s an d sym ptom s in dicated th at sh e w as

19. B Con sciou s sedat ion refers to a drug-in duced state of al-

bal com m an ds). • A p aten t air w ay is m ain t ain ed (th e p at ien t does n ot h ave to be ven t ilated).

m ost likely su ering from fu lm in an t h ep at it is. Haloth an e can p rod u ce fu lm in an t h ep at ic n ecrosis in a sm all n u m ber of p at ien t s (1/10,000). Th e syn drom e t yp ically start s 3 to 5

• Cardiovascular e ects gen erally are n ot m arked.

days after an esth esia an d rap idly progresses to h ep at ic fail-

• An xiet y is alleviated .

u re. Th e progn osis is poor (death occurs in about 50% of

• Pain is relieved.

th ese pat ien ts).Th e m ech an ism of h epatotoxicit y is st ill u n -

• Som e d egree of an terograde am n esia is p resen t .

cer t ain . Th e curren t hypoth esis is th at som e h epat ic protein s

A w ide variet y of in t raven ous an esth et ic agen ts (ben zodiazep in es, prop ofol, an d opioids) h ave been u sed. Ben zodiazepin es an d opioids h ave th e advan t age th at th eir e ect s can be easily reversed by th e u se of sp eci c receptor an tagon ists ( u m azen il an d n aloxon e, resp ect ively). A, C−E Th ere are n o speci c an tagon ist s for th iop en t al an d ketam in e.

Learning objective: Describe the pathophysiology of m alignant hyperthermia. 20. C Th e sign s of th e pat ien t st rongly suggest th at h e w as suffering from m align an t hyperth erm ia, a rare autosom al dom in an t disorder th at can be t riggered by th e adm in ist rat ion of

becom e t ri u oroacet ylated by h aloth an e m et abolites an d in it iate an im m u n e resp on se. A, F Th e risk of toxic h ep at it is w ith oth er u orin ated an esth et ics is n egligible. C−E Nit rou s oxide, th iopen tal, an d fen t anyl do n ot cause liver toxicit y.

144


Learning objective: Describe the additive propert y of m inim um alveolar concentration of inhalational anesthetics.

pain on inject ion , w ith on e of th ese p at ien t s report ing se-

23. B Th e m in im u m alveolar con cen t rat ion (MAC) is de n ed as

h ave been invest igated to alleviate th e pain associated w ith

th e con cen t rat ion of th e an esth et ic th at resu lts in th e im m o-

propofol inject ion . Th e coadm in ist rat ion of several drugs,

bilit y of 50% of pat ien ts w h en exp osed to a su p ram axim al

including opioids, ketam in e, an d n on steroidal antiin am m a-

n oxiou s st im u lu s (i.e., su rgical skin in cision ). MAC valu es

tor y drugs, can be e ect ive in reducing pain , but lidocain e,

of in h alat ion al an esth et ics h ave a ver y im port an t p rop er t y:

in conjun ct ion w ith ven ous occlu sion , is th ough t to be th e

th ey are rough ly ad dit ive. Becau se th e alveolar con cen t ra-

m ost e ect ive in ter ven t ion .

t ion n eeded to p rovid e su rgical an esth esia in m ost p at ien t s

vere or excruciat ing pain . As a result , several in ter ven t ion s


is about 1.3 MAC, a 0.7 MAC of n it rou s oxide plu s 0.6 MAC of

ver y poor aesthetic w hen given alone, can enhance the e ect

Learning objective: Describe the m ain variables that can decrease the m inim um alveolar concentration (MAC) of inhalational anesthetics.

of all oth er in h alat ion al an esth et ics given con com it an tly.

26. C It is kn ow n th at MAC can be decreased by several physio-

An oth er im por tan t con sequen ce of th e addit ive propert y of

logical an d p h arm acological variables, in clu ding age, preg-

MAC is th at th e an esth et ic e ects of t w o in h alat ion al an es-

n an cy, hypoth erm ia, hyp ercalcem ia, hyp on at rem ia, an d in

t h et ics are ad d it ive, bu t t h e adverse e ect s are n ot . As n i-

th e p resen ce of cert ain drugs (acu te alcoh ol, opioids, ben zo-

t rou s oxid e h as low toxicit y, t h e m ixt u re of a large MAC

d iazepin es, barbit u rates, ket am in e, lith ium , clon idin e, etc.).

fract ion of t h is gas w it h a sm all MAC fract ion of an ot h er

One of the m ost striking is the 6%decrease in MAC per decade

in h alat ion al an esth et ic can provide surgical an esth esia w ith

of age, regardless of volat ile an esth et ic. It drops to about h alf

adverse e ects su bst an t ially low er th an th at of th e oth er an -

by age 80, as in th is case.

sevo u ran e w ill p rovide an ap prop riate su rgical an esth esia for th e pat ien t . Th is explain s w hy n it rous oxide, w h ich is a

esth et ic given alon e.


A, C Th e su m of th ese MACs is n ot en ough to en su re an D, E Th e su m of th ese MACs is above th e 1.3 level n eeded

Learning objective: Identify the general anesthetic that is contraindicated in patient s with pheochrom ocytom a.

for su rgical an esth esia. Th is m ean s th at th e alveolar con cen -

27. A Haloth an e can sen sit ize th e m yocardiu m to th e arrhyth -

t rat ion is too h igh an d can su bstan t ially in crease th e risk of

m ogen ic e ect of catech olam in es an d is th erefore con t rain -

adverse e ect s. Moreover, becau se 1 MAC of n it rou s oxide

d icated in pat ien ts w ith h igh blood catech olam in e levels, as

is m ore th an 100% of th e gas alveolar con cen t rat ion , n it rou s

in th is case.

app ropriate su rgical an esth esia.

oxid e can n ot be u sed at a con cen t rat ion above 80% (i.e., abou t 0.8 MAC), as th is w ou ld lim it th e deliver y of an ade-

B−E Non e of th ese drugs cause sen sit izat ion of th e m yocardiu m to catech olam in es.

qu ate am oun t of oxygen .

Learning objective: Explain the reason for the short duration of anesthesia induced by thiopental.

Learning objective: Identify the general anesthetic that is contraindicated in sm all bowel closed loop obstruction. 28. B In closed loop obst ru ct ion , th e lu m en of th e bow el is oc-

24. C Th iop en t al rap id ly d i u ses ou t of t h e brain an d ot h er

cluded at t w o poin t s, th us preven t ing prograde an d ret ro-

h igh ly vascu lar ized t issu es an d is red ist r ibu ted to m u scle,

grade m ovem en ts of bow el con ten t s. Becau se n it rous oxide

fat , an d even t ually to all body t issues. Th is is th e prin cipal

d i uses in to th e cavit y m ore rapidly th an th e air (prin cipally

m ech an ism lim it ing an esth et ic du rat ion after a single an es-

n it rogen ) di u ses out , th e gas can in crease th e in t ralum in al

th et ic dose.

p ressure of th e obst ru cted bow el loop , th u s in creasing th e

A, E Act u ally, th iopen tal dist ributes ver y rapidly in to th e

risk of gu t ru pt u re. Exam p les of con dit ion s in w h ich n it rou s

CNS. Because it is ver y lipid solu ble, di usion in to th e CNS

oxide m igh t be h azardou s in clu de all th e closed cavit ies

n euron s is ver y good. B, D Th iop en t al h alf-life is about 12 h ours, w h ich in dicates th at th e elim in at ion of th e drug from th e body is slow.

lled w ith air, su ch as p n eu m oth orax, p u lm on ar y air cysts, an d p n eu m ocep h alu s. A, C−E See correct an sw er explan at ion .

Learning objective: Identify the drug usually adm inistered with propofol to reduce pain on injection.

Learning objective: Describe the main adverse e ects of etomidate.

25. D Th e in t raven ou s inject ion of prop ofol is associated w ith

over barbit u rate or p rop ofol an d th erefore is m ost su ited in

p ain , m ost likely due to its alcoh ol n at u re th at irrit ates th e

p at ien ts w ith coron ar y disease, as in th is case. Etom idate h as

vascu lar en doth eliu m . Th ree ou t of ve pat ien ts exp erien ce

29. A Cardiovascular stabilit y is a m ajor advan t age of etom idate

Answers and Explanations: III-4 Local Anesthetics 145 th e h igh est in ciden ce of postoperat ive n ausea an d vom it ing

dep ression . For th ese reason s, 100%oxygen is often adm in is-

(m ore th an 30% of cases) am ong th e gen eral an esth et ics.

tered for th e rst 5 to 10 m in utes of recover y. Th is procedu re

B−E Etom idate does n ot cause delusion an d h as m in im al cardiovascu lar an d respirator y e ect s.

m ay be p ar t icu larly in d icated w h en p ostop erat ive resp irator y depression is an t icipated, as in th e presen t case (see th e adm in ist rat ion of fen tanyl).

Learning objective: Explain the m echanism of di usion hypoxia caused by nitrous oxide.

A−C, E Th ese drugs do n ot cause di usion hypoxia.

30. D On recover y from an esth esia, th e ou t pou ring of large vol-

GENERAL ANESTHETICS Answ er Key

u m es of n it rou s oxid e can cau se an e ect called d i u sion hyp oxia. Th ese volu m es m ay cau se hyp oxia in t w o w ays. First , th ey m ay directly a ect oxygen at ion by displacing oxygen . Secon d, by dilu t ing alveolar carbon d ioxide, th ey m ay d ecrease respirator y drive an d h en ce ven t ilat ion . Both of th ese e ect s requ ire th at large volu m es of n it rou s oxid e be released in to th e alveoli. Becau se th ese large volu m es are released on ly d u ring th e

rst 5 to 10 m in u tes of recover y,

t h is is th e p eriod of greatest con cern . An ad d it ion al reason

1. 2. 3. 4. 5.

B D F C G

6. 7. 8. 9. 10.

D D B D D

11. 12. 13. 14. 15.

B B C C D

16. 17. 18. 19. 20.

C E A B C

21. 22. 23. 24. 25.

D B B C D

26. 27. 28. 29. 30.

C A B A D

is th at th is period m ay be th e t im e of greatest respirator y

Answers and Explanations: III-4 Local Anesthetics Questions 1−3

A, E Lidocain e ten ds to cau se adverse e ect s op p osite to th ose listed.

1. F 2. B

B Th is adverse e ect is n ot cau sed by lidocain e.

3. B

D Th is adverse e ect can occu r on ly after h uge p lasm a levels of lidocain e.

Learning objective: Explain the m olecular m echanism of action of local anesthetic. 4. A Local an esth et ics block volt age-gated Na + ch an n els, pre-

Learning objective: Identify the local anesthetic used for long surgical procedures.

ven t ing depolarizat ion of th e m em bran e an d blocking con -

6. C Th e d u rat ion of local an est h esia after a st an dard d ose of

d uct ion of th e act ion poten t ial. Th e blockade of Na + ch an n el is

tet racain e injected n ear th e brach ial plexus is about 210 to

voltage depen den t; th at is, th e a

240 m in u tes. Th e drug is th erefore p referred for m ore lengthy

n it y of th e ch an nel for th e

local an esth et ics is h igh w h en th e ch an n el is in act ivated or act ivated (i.e., w h en th e m em bran e poten t ial is less n egat ive) an d is low w h en th e ch an n el is in th e rest ing st ate (i.e., w h en the m em brane potential is m ore negative). The sam e rule holds

su rgical p rocedu res. A, B Th e du rat ion of act ion of th ese local an esth et ics is less th an 2 h ours. D, E Th ese drugs are n ot used for n er ve block an esth esia.

for an tiarrhythm ic drugs, w hich act by blocking ion chan n els.

Learning objective: Calculate the percentage of the lipid-soluble form of lidocaine in the extracellular uids, given su cient data.


Learning objective: Describe the adverse e ect s of local anesthetics.

7. B Because local anesthetics except benzocaine are weak bases,

5. C Drow sin ess is th e m ost frequen t com plain t th at result s from

of th e body uids, as in th is case. Th e rat io bet w een th e n on -

cen t ral n er vou s system (CNS) act ion s of local an esth et ics an d

ion ized an d th e ion ized form can be determ in ed u sing th e

is u su ally an early sign of a h igh p lasm a level of th e drug. CNS

Hen derson -Hasselbalch equ at ion . W h en th e di eren ce be-

e ect s of lidocain e are com m on w h en th e drug is adm in is-

t w een th e p Ka an d th e pH is +0.5, th e percen t age of th e ion -

tered system ically as an an t iarrhyth m ic or w h en a su

ized form is 76%; th erefore, th e p ercen tage of th e n on ion ized,

cien t

con cen t rat ion of th e drug can reach th e gen eral circulat ion after being given locally for local an esth esia, as w as m ost likely in th is case.

th ey are m ain ly ion ized w h en th eir p Ka is h igh er th an th e pH

lip id-solu ble form w ill be 24%. A, C−E See correct an sw er explan at ion .

146


Learning objective: Identify nerve ber properties altered by local anesthetics.

Learning objective: Explain why local anesthesia has a slower onset in infected tissue.

8. C Local an esth et ics prim arily block in act ivated Na + ch an n els,

12. E Local an esth et ics are w eak bases; all bu t ben zocain e h ave

m aking th em take longer to ret u rn to th e rest ing state. As

a pKa in th e range of abou t 7.7 to 9.4. Th erefore, th ey are

long as th e ch an n el is blocked, th e ber is refractor y to st im -

m ain ly w ater-solu ble at t h e p hysiological p H of t h e ext ra-

u lat ion , so th e refractor y period of th e n er ve w ill increase.

cellu lar u id. How ever, on ly th e sm all, lipid solu ble p or t ion

A, B, D Th ese n er ve p ropert ies are in fact d ecreased, n ot in creased, by local an esth et ics. E Local an esth et ics h ave ver y low a

of th e drug can cross th e n er ve m em bran e. Th e ext racellular uid of th e in fected t issues h as a low er pH due to th e in -

n it y for chan n els in

creased con cen t rat ion of lact ic acid . Th e lip id solu bilit y of

th e rest ing state, so th ey h ave n egligible e ect s on th e rest-

th e drug w ill be even low er, an d less drug w ill be available

ing m em bran e poten t ial of th e n er ve.

for di usion in to th e n er ve bers. A−D See correct an sw er explan at ion .

Learning objective: Explain why epinephrine should not be used with local anesthetics when organs supplied by end arteries ( ngers, ears, nose, and penis) need to be anesthetized.

Learning objective: Describe the adverse e ects of prilocaine. 13. D Prilocain e is th e on ly local an esth et ic th at can cause m et-

9. B Epin eph rin e-con t ain ing solut ion s sh ould n ot be injected

h em oglobin em ia. Th is e ect is n ot a problem in h ealthy per-

in to organ s supplied by en d ar teries ( ngers, ears, n ose, an d

son s, bu t th e n eon ate is m ore sen sit ive to m eth em oglobin em ia

p en is) becau se th e result ing vasocon st rict ion can produ ce

d ue to decreased resistan ce of fetal h em oglobin to oxidan t

isch em ia an d even gangren e.

st ress an d im m at u rit y of th e en zym es th at convert m eth e-

A, D Ep in eph rin e does n ot a ect th e risk of w ou n d in fect ion an d d oes n ot cau se delayed w ou n d repair.

m oglobin back to th e ferrou s st ate. A−C, E See correct an sw er explan at ion .

C, E Excessive bleeding an d system ic toxicit y are in fact

Learning objective: Explain why hyperkalem ia m akes the nerve membrane more sensitive to the action of local anesthetics.

p reven ted by adm in ist rat ion of epin ep h rin e.

Learning objective: Identify the factors that increase the a nit y of Na + channels for local anesthetics.

14. D According to th e Nern st equat ion , an in crease in ext racel-

10. C Local an esth et ics act p rim arily by blocking Na + ch an n els.

n egat ive (depolarizat ion ) an d favors th e in act ivated state of

Th e blockade is volt age depen den t; th e less n egat ive th e

Na + ch an n els. Because local an esth et ics m ain ly block in act i-

m em bran e poten t ial, th e h igh er th e ch an n el a

n it y for local

vated Na + ch an n els, in creased ext racellu lar con cen t rat ion of

an esth et ics. In th e rest ing state, Na + ch an n els predom in ate

K+ m akes th e n er ve m em bran e m ore sen sit ive to th e act ion

at m ore n egat ive m em bran e p oten t ial. Th ese ch an n els h ave

of local anesthetics. Local increase in extracellular concentra-

a m uch low er a

n it y for local an esth et ics th an in act ivated

t ion of K+ is com m on in bu rn ed t issues becau se th e dam aged

or act ivated ch an n els, w h ich predom in ate at less n egat ive

cells spill th eir cytosol in to th e ext racellular u id. Alth ough

m em bran e poten t ial. Th e blockade is also t im e-depen den t

pat ien ts w ith bu rn s are kn ow n to develop hypocalcem ia, hy-

(also referred to as frequen cy depen den t); th e faster th e r-

percalcem ia h as been repor ted in abou t 20%of p at ien t s w ith

ing of t h e n er ve, t h e h igh er t h e ch an n el a

exten sive burn s.

n it y for local

an esth et ics. A, B, D, E See correct an sw er exp lan at ion .

lular K+ con cen t rat ion m akes th e m em bran e poten t ial less

A−C, E All of th ese even ts cause hyperpolarizat ion of th e m em bran e, w h ich favors th e rest ing st ate.

Learning objective: Identify the physiological function blocked last by local anesthetics.

Learning objective: Explain why bupivacaine is contraindicated in a patient with chronic obstructive pulmonary disease.

11. A Fiber sen sit ivit y to blockade by local an esth et ics dep en ds

15. E Most local an esth et ics can block Na + ch an n els in cardiac

on d i eren t factors; for exam p le, sen sit ivit y is inversely

m uscle, th ereby depressing autom at icit y an d con duct ion . At

related to diam eter an d con duct ion velocit y. Fibers w ith

ver y h igh doses th ey can also dep ress con t ract ilit y, m ost

sm aller diam eter an d slow er con d u ct ion velocit y are blocked

likely by blocking Ca 2+ ch an n els. Bupivacain e is m ore cardio-

before bers th at h ave larger diam eter an d faster con d u ct ion

toxic th an m ost oth er local an esth et ics, apparen tly becau se

velocit y. Th erefore, t ype A-alph a bers, w h ich convey m otor

th e drug dissociates m uch m ore slow ly th an oth er local an -

fu n ct ion (d iam eter 12−20 µ, con d u ct ion velocit y 70−120

esth et ics du ring diastole, so a sign i can t fract ion of Na +

m /sec) are blocked last , w h en a local an esth et ic is ap plied to

ch an n els at physiological h ear t rates rem ain s blocked w ith

a n er ve.

bu p ivacain e at th e en d of th e diastole. Bu pivacain e-in du ced


cardiac toxicit y is ver y d i cu lt to t reat an d is en h an ced by

Answers and Explanations: III-4 Local Anesthetics 147 coexist ing acidosis an d hypoxem ia, w h ich are m ost likely in

of th is, ben zocain e is in corporated in to a large n um ber of

th is case because of COPD.

topical preparat ion s. Oth er drugs u sed for topical an esth esia


are lidocain e an d tet racain e. B Procain e is used on ly for in lt rat ion an esth esia becau se

Learning objective: Explain the choice of a local anesthetic according to the anticipated duration of a surgical procedure.

of it s slow on set an d sh or t durat ion of act ion .

16. E Epidural an esth esia is adm in istered by inject ing local an -

du e to it s ad dict ive p oten t ial. Moreover, cocain e absorpt ion

esth et ic in to th e epidural space an d can be perform ed in th e sacral h iat u s or in th e lu m bar, th oracic, or cer vical region of t h e sp in e. Th e an est h esia a ect s on ly t h ose n er ves leavin g

C Cocain e is ver y rarely u sed today as a local an esth et ic, from abraded skin can be sign i can t . D, E Prilocain e an d bu pivacain e are n ot used for topical an esth esia.

th e sp in al cord at th e level of inject ion . Lidocain e is th e m ost frequ en tly u sed epid u ral local an esth et ic, esp ecially w h en th e su rgical p rocedu re is sh or t , as in th is case. A, B Cocain e an d ben zocain e are n ot su it able for spin al or ep idu ral an esth esia.

Learning objective: Identify the m olecular form of a local anesthetic that mediates receptor binding. 20. D Local an esth et ics are w eak bases, an d in th e body th ey exist eith er as th e u n ch arged base (n on ion ized form ) or as a

C, D Bu p ivacain e an d tet racain e are u sed for sp in al an d

cat ion (ion ized form ). Becau se th e n on ion ized form is lip id

ep id u ral an est h esia w h en t h e su rgical p roced u re is lon g.

solu ble, it is im p or t an t for di u sion th rough th e cell m em -

Th ey are n ot n eed ed in t h is case becau se t h e an t icip ated

bran es. How ever, th e cat ion ic form is th ough t to be th e on e

d u rat ion of th e procedure is on ly about 20 m in utes.

th at bin ds to th e receptor site, located on th e Na + ch an n el n ear th e in n er surface of th e m em bran e.

Learning objective: Explain the choice of an am ide-t ype local anesthetic for a patient allergic to para-aminobenzoic acid (PABA).

ized form of th e dr ug. In fact , t issu e redist ribu t ion u su ally

17. C Lidocain e is an am ide-t ype local an esth et ic th at can be

occurs in lipid-rich t issu es; liver biot ran sform s m ain ly lip -

em p loyed in alm ost any ap p licat ion w h en a local an esth et ic

id-solu ble drugs, an d on ly th e lipid-solu ble form of th e drug

of in term ediate durat ion is n eeded. It is w idely u sed in spi-

can easily cross th e blood−brain barrier.

n al an esth esia. A, B, D, E A seriou s allergic react ion to PABA con t rain dicates th e adm in ist rat ion of all ester-t yp e local an esth et ics

A−C All of th ese proper t ies are m ore related to th e non ion -

E Th e h alf-life of a d r ug is related to it s volu m e of d ist r ibu t ion an d its clearan ce, w h ich in t u rn dep en d on m any factors, n ot on ly on th e ion ized form of th e drug.

(p rocain e, tet racain e, ben zocain e, an d cocain e), as th ey are esters of PABA. In addit ion , procain e an d ben zocain e are n ot su it able for spin al an esth esia.

Learning objective: Describe the use of cocaine as a local anesthetic agent. 21. A Th e drug used w as m ost likely cocain e, th e on ly local an es-

Learning objective: Identify the local anesthetic preparation suitable for a patient with a concomitant cardiac disease.

th et ic th at also h as a vasocon st rict ing act ion , du e to its in -

18. A Ep in ep h r in e is u sed in local an est h et ic p rep arat ion s to

term in als. Cocain e can provide bet ter toleran ce of sut uring

localize th e an esth et ic at th e desired site an d to reduce sys-

in p at ien t s w h o are u n able to tolerate inject ion s, as in th is

tem ic toxicit y. How ever, epin ep h rin e is con t rain dicated in

case. How ever, th e d rug is ver y rarely u sed today as a top ical

p at ien ts w ith cardiac arrhyth m ias. In th is pat ien t , a p repara-

an esth et ic because of its toxicit y, expen se, an d federal regu -

t ion con t ain ing th e local an esth et ic alon e is th e m ost rat io-

lator y issues. Seriou s toxic e ects (e.g., seizu res an d cardiac

n al ch oice.

arrhyth m ias) h ave been d escribed follow ing top ical cocain e

B, C See correct an sw er explan at ion . D, E Th ere are n o inject able preparat ion s of ben zocain e, as

h ibitor y e ect on n orepin eph rin e reupt ake in to adren ergic

app licat ion , part icu larly in ch ildren . B−E See correct an sw er explan at ion .

th is drug is u sed on ly for su rface an esth esia. LOCAL ANESTHETICS Answ er key

Learning objective: Describe the therapeutic uses of benzocaine. 19. A Un like ot h er local an esth et ics, ben zocain e h as a p Ka of abou t 2.5; con sequen tly, it is pract ically in soluble in w ater. Th erefore, th e drug can n ot be injected, but it can be applied directly to w ou n d ed su rfaces, w h ere it rem ain s localized for a long t im e, producing sust ain ed an esth et ic act ion . Because

1. 2. 3. 4. 5.

F B B A C

6. 7. 8. 9. 10.

C B C B C

11. 12. 13. 14. 15.

A E D D E

16. 17. 18. 19. 20. 21.

E C A A D A

148


Answers and Explanations: III-5 Skeletal Muscle Relaxants Questions 1−4 1. A

Learning objective: Describe the pharm acokinetics of succinylcholine.

2. D

7. A Th e durat ion of act ion of succinylch olin e is abou t 8 m in u tes

3. H

after a stan dard th erapeut ic dose. Th e reason is th at th e drug

4. F

is rapid ly hydrolyzed by pseu doch olin esterase in p lasm a an d liver. Th is du rat ion of act ion is en ough to facilitate in t u bat ion .

Learning objective: Identify the site of action of tubocurarine.

W h en a longer durat ion of act ion is n eeded, th e drug is given

5. C All n eu rom u scu lar blockin g agen t s bin d to Nm receptors

by in t raven ous in fusion .

located on th e postjun ct ion al folds of m otor en d plates, act ing

B−F See correct an sw er exp lan at ion .

th ere as com pet it ive an t agon ists (n on depolarizing blockers) or as par t ial agon ists (depolarizing blockers). Th e blockade of

Learning objective: Explain the mechanism of action of dantrolene

th ese receptors m ediates th e clin ical e ects of th ese drugs,

8. D Th e clin ical pict u re of th e pat ien t suggest s th e diagn osis of

th at is, skelet al m uscle paralysis.

m alignant hypertherm ia, a rare but potentially life-threatening

A, B, D Tu bocu rar in e can block Nn receptors located on

disorder that can be triggered by a variet y of stim uli, in cluding

au ton om ic ganglia, on th e adren al m edu lla, an d on som at ic

th e adm in ist rat ion of cer tain an esth et ics (m ain ly h aloth an e)

n er ve term in als, bu t th ese sites do n ot represen t th e m ain site

an d n eurom uscular blocking agen t s (m ain ly succinylch olin e).

of act ion of th e drug. In fact , th e a

n it y of th e drug for th ese

Th e disorder is related to a h eredit ar y im pairm en t in th e abil-

receptors is m u ch low er th an th e a

n it y for Nm receptors.

it y of th e sarcop lasm ic ret iculu m to sequester calciu m ; th ere-

E Spin al m otor n euron s are located on th e an terior h orn

fore, a prolonged release of calcium occurs after th e t riggering

of th e spin al cord, th at is, in side th e cen t ral n er vous system

event through sarcoplasm ic calcium channels (som etim es called

(CNS). Curare-like dr ugs can n ot en ter th e CNS becau se th ey

r yan odin e receptors). Th is cau ses m assive m u scle con t rac-

do n ot cross th e blood−brain barrier.

t ion , hyperth erm ia, an d lact ic acidosis. Dan t rolen e is a drug of

F Nm receptors are on m otor en d plates on ly. W h en act i-

ch oice in th is disorder because it blocks Ca 2+ ch an n els in th e

vated, th ey open ligan d-gated ion ch an n els, cau sing depolar-

skelet al m u scle sarcoplasm ic ret icu lu m , th u s preven t ing th e

izat ion of th e m otor en d p late (m in iat u re en d-p late p oten t ial).

m assive release of calcium . Cardiac an d sm ooth m uscle are

Skelet al m u scle cell m em bran es h ave volt age-gated ion ch an -

m in im ally a ected by dan t rolen e because th ey h ave a di er-

nels that open w hen th e depolarization of the m otor en d plate

en t t yp e of Ca 2+ ch an n el in th eir sarcop lasm ic ret icu lu m .

reach es th e th resh old for th e p rop agat ion of th e poten t ial.


Learning objective: Describe the therapeutic uses of nondepolarizing neuromuscular blockers.

Learning objective: Identify the site of action of botulinum toxin.

6. B Th e p at ien t m ost likely received vecu ron iu m , a n on dep olar-

term in als, w h ere it preven ts th e exocytot ic release of acet yl-

izing n eu rom u scu lar blocker. Th ese drugs are often u sed in

ch olin e, causing paralysis of th e skeletal m uscles surroun ding

pat ien ts w h o n eed m ech an ical ven t ilat ion . Th ey can facilit ate

th e site of inject ion .

in t u bat ion an d can block volu n t ar y m ovem en t s th at cou ld in terfere w ith m ech an ical ven t ilat ion . Neurom uscular blockers

9. B Via en docytosis, bot u lin u m toxin en ters ch olin ergic n er ve

A, C, E Bot u lin u m toxin does n ot bin d to ch olin ergic receptors.

w it h an in ter m ed iate du rat ion of act ion su ch as vecu ron iu m

D Bot ulin um toxin also preven t s acet ylch olin e release from

(abou t 30 m in u tes after a st an dard t h erap eu t ic d ose) are

auton om ic ch olinergic n er ve term in als, but th is is n ot th e site

often preferred.

of th e th erapeut ic act ion of th e drug.

A, C−F All of th ese d rugs h ave skeletal m u scle relaxan t prop er t ies, bu t th ey act w ith di eren t m ech an ism s of act ion an d are n ot used to facilitate in t ubat ion an d decrease spon tan eou s breath ing.

Answers and Explanations: III-5 Skeletal Muscle Relaxants 149 Learning objective: Explain the m echanism of action of vecuronium .

A, C, E Su ccinylch olin e, dan t rolen e, an d m ivacu riu m are n ot m etabolized by Ho m an n elim in at ion .

10. C Vecuron iu m is a n on depolarizing n eurom u scular blocker.

B Dan t rolen e can n ot cau se skelet al m u scle paralysis (u n -

Th ese d rugs act as com p et it ive an tagon ists at Nm receptors,

less h uge d oses are given ) an d t h erefore is n ot u sed as a

p reven t ing th e act ivat ion of th e receptors by acet ylch olin e.

skelet al m u scle relaxan t du ring su rger y.

In th is w ay, th ey preven t depolarizat ion of skelet al m uscle t ion can be overcom e by in creasing th e con cen t rat ion of ace-

Learning objective: Describe the interaction bet ween tubocurarine and H1 antagonists.

t ylch olin e in th e syn apt ic cleft .

14. E Tu bocu rar in e-in d u ced hyp oten sion is p r im ar ily d u e to

cell m em bran es an d in h ibit m uscular con t ract ion . Th eir ac-

A, B, D−F Non d ep olar izin g n eu rom u scu lar blockers are d evoid of th ese e ects.

h ist am in e release, an d prem edicat ion w ith an an t ih istam in e d rug is often u sed to at ten uate th is adverse e ect . A−D Drugs from th ese classes w ould in crease, n ot de-

Learning objective: Describe the sequence of muscle paralysis induced by vecuronium .

crease, t u bocu rarin e-in du ced hyp oten sion .

n eurom uscular blocking dr ugs follow s a sequ en ce th at is re-

Learning objective: Describe the interaction bet ween am inoglycoside antibiotics and nondepolarizing neurom uscular blockers.

lated to th e in n er vat ion of th e skelet al m u scles. Mu scles th at

15. A Am in oglycosid e an t ibiot ics in h ibit acet ylch olin e release

are sm all, rapidly m oving, an d rich ly in n er vated, su ch as ex-

from ch olin ergic n er ves by blocking a sp eci c t yp e of Ca 2+

t rin sic eye m u scles, sm all m u scles of th e face, an d p h ar yn x,

ch an n el. Th erefore, th ey en h an ce th e blockade in duced by

are a ected

n on depolarizing n eurom uscular blockers.

11. A Th e skelet al m u scle p aralysis in du ced by n on dep olarizing

rst . Th e p aralysis of th e ext rin sic eye m u scles

cau ses a lack of parallelism of th e visu al axes of th e eyes th at


leads to dou ble vision . As a ru le, large m u scles (e.g., lim b m uscles) are paralyzed after sm all m uscles. Ult im ately, th e

Learning objective: Describe the pharmacokinetics of mivacurium.

intercostal m uscles and, nally, the diaphragm are paralyzed.

16. D Mivacu riu m an d su ccinylch olin e are t w o n eu rom u scu lar


blockers m etabolized by p lasm a ch olin esterase. In p at ien t s w ith a gen et ic de cien cy of n orm al plasm a ch olin esterase,

Learning objective: Describe the biotransformation of mivacurium.

th ese dr ugs can cau se ap n ea for several h ou rs an d are th ere-

12. D Mivacu riu m is th e on ly n on dep olarizing n eu rom u scu lar

fore con t rain dicated.

blocker th at is m et abolized by p lasm a p seu doch olin esterase.


Because of th is rapid m et abolism , th e act ion of th e drug is A Succinylch olin e is m etabolized by plasm a ch olin ester-

Learning objective: Describe the m ain contraindication of tubocurarine.

ase, bu t it is a depolarizing, n ot a n on dep olarizing, n eu ro-

17. A Tu bocu rarin e can cau se h ist am in e release from m ast cells.

sh ort .

m u scu lar blocker. B, C, E See correct an sw er explan at ion .

A prom in en t e ect of h istam in e is bron ch ocon st rict ion . Becau se of th is, t u bocu rarin e sh ou ld n ot be u sed in p at ien t s w ith asth m a or ch ron ic obst ruct ive pulm on ar y disease.

Learning objective: Explain the use of cisatracurium in patients with impaired hepatic and renal functions.

t ion to p reven t e ects related to vagal act ivat ion (sialorrh ea

13. D Cisat racurium is a n eu rom uscular blocking dr ug th at h as

an d bradycardia)

B Glycopyrrolate is often given as a preoperat ive m edica-

t h e u n iqu e p rop er t y of bein g in act ivated p r im ar ily by a

C Clon idin e is som et im es given as a preoperat ive m edica-

for m of sp on t an eou s breakdow n also kn ow n as Ho m an n

t ion becau se it h as sedat ive proper t ies an d poten t iates th e

elim in at ion . Because of th is, it does n ot exh ibit an in crease

act ion of an esth et ic agen ts.

in h alf-life in pat ien t s w ith com prom ised h epat ic or ren al

D, E Vecu ron ium an d cisat racurium , w h ich are n on de-

fu n ct ion , an d it is th erefore th e agen t of ch oice u n der th ese

p olarizing n eu rom u scu lar blocking drugs, could be used, as

con dit ion s, as in th e presen t case.

th ese agen ts do n ot release h ist am in e.

150


Learning objective: Describe the adverse e ect s of tubocurarine. 18. D Agit at ion is a frequ en t p roblem in pat ien ts w h o are in t u -

Learning objective: Explain the m echanism of m uscle relaxant action of tizanidine.

bated an d ar t i cially ven t ilated. Ben zodiazep in es are u sefu l

21. E Tizan idin e is a cen t rally act ing α 2 -receptor agon ist , st r u c-

agen t s for con t rolling an xiet y an d agitat ion . Th ey also cau se

t u rally an d p h ar m acologically related to clon id in e. It s

an terograd e am n esia (a u sefu l propert y in th is set t ing) bu t

sp asm olyt ic act ivit y m ost likely resu lt s from act ivat ion of

h ave n o an algesic proper t ies. W h en sedat ing drugs are n ot

presyn apt ic α 2 receptors in th e spin al cord. Th is act ivat ion

fu lly e ect ive, a m u scle relaxan t is added. Tu bocu rarin e is

decreases th e release of excit ator y am in o acids, w h ich in

a n eu rom u scu lar blocking drug w h ose act ion last s m ore

t u rn leads to in h ibit ion of sp in al m otor n eu ron s.

th an 50 m in u tes after a stan dard th erap eu t ic dose. It is st ill


som et im es u sed becau se of e ect iven ess an d low cost . Th e cu rarin e can be d u e eith er to h ist am in e release or to block-

Learning objective: Explain the m echanism of the spasm olytic action of benzodiazepines.

ade of nicotinic receptors of autonom ic ganglia or, m ost likely,

22. D Ben zod iazep in es facilit ate t h e act ion of GABA in t h e

t achycard ia th at can app ear after th e adm in ist rat ion of t u bo-

to both .

cen t ral n er vou s system by in creasing th e a

A Bot ulin um toxin is n ot used to lim it m ovem en ts in an in t ubated pat ien t . It s act ion s w ould last for m on th s.

n it y of GABAA

receptors for GABA. Th eir act ion in red u cing sp ast icit y, h ow ever, seem s to be at least partly m ediated in th e spin al

B Dan t rolen e is a spasm olyt ic drug. It can red uce spast icit y but is un able to cause n eu rom uscular paralysis w h en

cord, because th ey are e ect ive also in pat ien t s w ith cord t ran sect ion .

given at th erapeu t ic doses. Th erefore, it is n ot u sed to lim it

A Th is is th e m ech an ism of act ion of dan t rolen e.

m ovem en t s in an in t u bated p at ien t .

B Th is is th e m ech an ism of act ion of bot ulin um toxin .

C Su ccinylch oline can cause st im ulat ion of both n icot in ic receptors in auton om ic ganglia an d cardiac m u scarin ic re-

C Th is is th e m ech an ism of act ion of succinylch olin e. E Th is is th e m ech an ism of act ion of baclofen .

ceptors. Th erefore, it w ould ten d to cause bradycardia, w h ich is on ly par t ially coun teracted by its sligh t ten den cy to cause h istam in e release. E Cisat racu r iu m h as n o e ect on n icot in ic receptors of au ton om ic gan glia an d h as n egligible h ist am in e-releasin g p ropert ies.

Learning objective: Describe the action of vecuronium on m iniature m em brane potential. 23. B Th e form at ion of m in iat u re en d-plate poten t ials is caused by th e release of sm all quan t a of acet ylch olin e th at act ivate Nm receptors at th e m otor en d p late. By blocking th ese re-

Learning objective: Explain the m echanism of action of succinylcholine. 19. A Su ccinylch olin e acts as a ch olin ergic agon ist at Nm recep -

ceptors, vecu ron ium blocks th e form at ion of th is poten t ial. A, D, E Neu rom u scu lar blocking drugs h ave n egligible effect s on th e form at ion of act ion poten t ials in th e m otor n euron , cardiac m uscle, or cor t icospin al t ract .

tors. Th e Na + ch an n els open an d cause depolarizat ion of th e

C Sm ooth m uscle m em bran e h as n o Nm receptors. Th ere-

m otor en d p late, bu t becau se th e drug is n ot m etabolized as

fore, n eurom uscular blocking drugs h ave n o direct e ect s on

fast as acet ylch olin e, th e act ivat ion of Nm receptors is long

sm ooth m u scle.

last ing. Th is act ivat ion cau ses a brief p eriod of excitat ion th at m ay elicit t ran sien t an d repet it ive m u scle excitat ion (fascicu lat ion s), follow ed by block of n eu rom u scu lar t ran sm ission , as th e long-last ing depolarizat ion m akes th e m otor en d p late u n respon sive to su bsequ en t st im u li (depolarizat ion blockade).

24. E Su ccinylch olin e can rap idly release p ot assiu m from in t racellular sites. In a n orm ally h ealthy pat ien t , th is result s in a sm all, t ran sien t hyperkalem ia. In p at ien t s w ith exten sive


soft t issu e t rau m a or bu rn s, cerebral vascu lar acciden t , or

Learning objective: Describe the adverse e ects of succinylcholine. 20. B Su ccinylch olin e act ivates Nm receptors. Th is can accou n t for th e involun t ar y con t ract ion of a group of m uscle

Learning objective: Describe the adverse e ect s of succinylcholine.

p rolonged st ays in an in ten sive care u n it , th is hyp erkalem ia can be m uch m ore pronoun ced w hen succinylch oline is given at least several days after th e u n derlying con dit ion h as be-

bers,

com e establish ed. Th e hyperkalem ia can be life-th reaten ing,

called fascicu lat ion s or t w itch ing, th at occu rs before th e

as it can lead to card iac ar rest , as in t h is case. Th e cau se

m u scle paralysis. Non depolarizing n eu rom u scu lar blockers

of su ccinylch olin e-in d u ced hyp erkalem ia in t h ese p at ien t s

d o n ot act ivate Nm receptors, so con t ract ion s can n ot occu r

seem s related to u p regu lat ion of n icot in ic m u scu lar (Nm )

before p aralysis.

receptors on m otor en d plates. Pat ien t s w ith th e aforem en -


tioned conditions are deprived of n eural in uence or activit y

Answers and Explanations: III-5 Skeletal Muscle Relaxants 151

ulates th e syn th esis of n ew Nm receptors across th e m u scle

Learning objective: Explain the m echanism of action of botulinum toxin.

m em bran e. W h en th ese receptors are act ivated by succinyl-

27. D Bot u lin u m toxin m u st get in sid e th e axon term in als to

ch olin e, an act ion poten t ial occurs, an d ion ch an n els op en ,

cau se paralysis. Follow ing th e at tach m en t of th e toxin to

allow in g Na + to ow in to an d K+ to ow ou t of t h e cell. Be-

p rotein s on th e su rface of axon term in als, th e toxin can be

cau se su ccinylch olin e is m et abolized m ore slow ly than ace-

t aken in to n eu ron s by en docytosis. Th ere it is able to cleave

t ylch oline, the receptor activation is m ore prolonged, cau sing

en docytot ic vesicles an d reach th e cytoplasm . Th e ligh t

a larger in u x of Na + an d a vigorou s e

ch ain of th e toxin h as protease act ivit y an d proteolyt ically

because of prolonged im m obilization. Such deprivation stim -

u x of K+. W h en Nm

receptors are in creased in skelet al m u scle, t h is K+ e

u x can

cau se life-th reaten ing hyp erkalem ia.

d egrad es a speci c p rotein th at is required for vesicle fusion th at releases acet ylch olin e from th e axon en d ings. In th is

A−C Non depolarizing neurom uscular blockers cause block-

w ay it p reven t s n eu rosecretor y vesicles from fu sing w ith th e

ade, n ot act ivat ion , of Nm receptors. Th erefore, they do n ot

n er ve syn apse plasm a m em bran e an d releasing th e n euro-

in du ce hyperkalem ia.

t ran sm it ter.

D Dan t rolen e h as n o e ect on Nm receptors.



Learning objective: Describe the adverse e ect s of a local treatment with botulinum toxin.

25. D Th e clin ical p ict u re of t h e p at ien t suggest s t h e d iagn osis

28. D Bleph arospasm is spasm of m uscles aroun d th e eye th at

of m align an t hyp er t h er m ia, a rare bu t p oten t ially life-

causes involun tary blinking and eye closing. It a ects w om en

t h reaten in g d isord er t r iggered by t h e ad m in ist rat ion of

m ore th an m en an d ten ds to occu r w ith in fam ilies. Th e

cer t ain an esth et ics an d n eu rom u scu lar blocking agen ts. Un -

cau se is m ost often u n kn ow n . Inject ion of bot u lin u m toxin

con t rolled release of Ca + from th e sarcoplasm ic ret iculum of

in to th e eyelid m u scle is often th e preferred t reat m en t (th e

skelet al m uscle is th e init iat ing even t . Alth ough m ost cases

e ect s of each t reat m en t last abou t 3 m on th s). Th e m ost

of m align an t hyper th erm ia arise from th e com bin at ion of

com m on adverse e ect is eyelid ptosis (up to 20% of cases),

su ccinylch olin e an d h alogen ated hydrocarbon an esth et ics

w h ich represen t s an unw an ted exten sion of th e ph arm aco-

(e.g., halothane, iso urane, and sevo urane), succinylcholine

logical e ect .

or an esth et ics alon e h ave been repor ted to precipitate th e resp on se. Su scept ibilit y to m align an t hyperth erm ia is an au -

A−C, E Bot ulin u m toxin is given locally, so th e risk of system ic adverse e ect s is ver y low.

tosom al dom in an t t rait . In th e m ajorit y of cases, n o clin ical sign s are visible in th e absen ce of an esth et ic in ter ven t ion . A−C, E, F See correct answ er explan at ion .


Learning objective: Describe the mechanism of action of baclofen. 29. A Baclofen is an agon ist at GABAB receptors. Th ese are m et abot rop ic t ran sm em bran e receptors for GABA th at are lin ked via Gi protein s to potassiu m ch an n els. Act ivat ion of th ese receptors by baclofen resu lt s in in creased K+ con duc-

26. C Myalgias are com m on postoperat ive com plain t s of pa-

t an ce, w h ich in t u rn cau ses hyp erpolarizat ion of p resyn apt ic

t ien t s receiving large doses of su ccinylch olin e. Th e t ru e in -

term in als. Th is hyperpolarizat ion redu ces th e release of ex-

cid en ce of m yalgias is d i cu lt to est ablish becau se of

cit ator y t ran sm it ters in both th e brain an d th e sp in al cord.

con foun ding factors, in cluding th e t ype of surger y an d posi-

Baclofen is at least as e ect ive as diazepam in reducing spas-

t ion ing du ring th e operat ion , bu t h as been rep or ted to be u p

t icit y an d is frequ en tly u sed for th is pu rp ose.

to 20%. Th e pain is th ough t to be secon dar y to th e un syn ch ron ized con t ract ion s (i.e., fasciculat ion s) of adjacen t m uscle

B Th is is th e act ion of n on depolarizing n eurom uscular blockers.

bers just before th e on set of paralysis. W h en th ese

C Baclofen can cause blockade of su bst an ce P release from

fasciculat ion s are st rong en ough , m u scle soren ess can result

spin al cord; th is seem s to be on e of th e reason s for its an al-

on recovering from an esth esia.

gesic act ivit y in p at ien t s w ith sp ast icit y.

A, B Non d ep olarizing m u scle relaxan t s can som et im es

D, E Baclofen can in d irectly block Ca 2+ ch an n els as a con -

cau se m yalgias u p on recover y from m u scle paralysis, bu t th e

sequen ce of m em bran e hyperpolarizat ion an d can in crease

in ciden ce is m uch low er th an th at w ith succinylch olin e.

K+ con duct an ce, but th ese act ion s occur in n euron al, n ot in

D, E Dan t rolen e an d diazepam are spasm olyt ic agen t s. Th ey do n ot cau se m u scle paralysis an d are n ot u sed to in d uce com plete m uscle relaxat ion du ring gen eral an esth esia.

skelet al m u scle, m em bran es.

152


Learning objective: Describe the therapeutic uses of baclofen. 30. B St i m an syn drom e is a disorder of n eu rom u scu lar t ran s-

Learning objective: Explain why cisatracurium is preferred over tubocurarine in patients with renal insu ciency

m ission ch aracterized by th e in sidiou s on set of p rogressive

32. D Th e pat ien t’s creat in in e an d urea n it rogen levels in dicate

st i n ess in th e t ru n k, abd om en , legs, an d arm s. Th e cau se of

th at h e w as m ost likely su ering from ren al in su

th e syn drom e is u n kn ow n , bu t an au toim m u n e path ogen e-

Tu bocu rarin e is m ain ly elim in ated as su ch by th e kid n ey an d

sis is su sp ected . On ly sym ptom at ic th erapy is available, an d

is th erefore con t rain dicated in p at ien t s w ith im p aired ren al

cen t ral spasm olyt ic drugs (ben zodiazepin es an d baclofen )

fu n ct ion . Cisat racu riu m is a n eu rom u scu lar blocking d rug

con sisten tly relieve th e m uscle st i n ess.

th at is in act ivated p rim arily by a form of spon tan eou s break-


d ow n an d does n ot exh ibit an in crease in h alf-life in pat ien t s w ith ren al in su

Learning objective: Identify a prom inent advantage of vecuronium over tubocurarine.

cien cy.

cien cy.

A Th e in creased alan in e am in ot ran sferase levels are too sm all to suggest h epat ic in su

cien cy.

31. B Vecu ron iu m , a steroid-derivat ive m u scle relaxan t , is cu r-

B Even if cisat racurium could be safer th an t ubocurarin e

ren tly com m on ly u sed du ring surger y. Its m ain advan t ages

in elderly p at ien ts, th is is n ot th e prim ar y reason for th e u se

over t u bocu rarin e are n egligible e ects on h ist am in e release

of cisat racurium in th is pat ien t .

an d n o act ion on n icot in ic n eu ron al receptors of au ton om ic ganglia. Moreover, u n like t u bocu rarin e, th e drug is m ain ly

C, E Th ere are n o adverse in teract ion s bet w een p ropofol or diazep am an d t u bocu rarin e.

elim in ated by liver m et abolism , w h ich can allow it s u se in p at ien ts w ith kidn ey disease.

SKELETAL MUSCLE RELAXANTS (Answ er key)

A Th e du rat ion of act ion of vecu ron ium after a st an dard th erap eu t ic dose is 20 to 35 m in u tes. C, D Th ese act ion s are absen t w ith both vecuron ium an d t u bocu rarin e. E No skelet al m uscle relaxan ts cau se an terograde am n esia, as th ey do n ot cross th e blood −brain barrier.

1. 2. 3. 4. 5.

A D H F C

6. 7. 8. 9. 10.

B A D B C

11. 12. 13. 14. 15.

A D D E A

16. 17. 18. 19. 20.

D A D A B

21. 22. 23. 24. 25.

E D B E D

26. 27. 28. 29. 30. 31. 32.

C D D A B B D

Answers and Explanations: III-6 Antiseizure Drugs Questions 1−3 1. K

Learning objective: Explain the m echanism of action of phenytoin on ion channels.

2. G

5. B Ph enytoin p rim arily blocks in act ivated voltage-gated Na +

3. I

ch an n els. Th is blockade is frequen cy-depen den t (also called u se-depen den t). Th at is, ch an n els th at open an d close at h igh

Learning objective: Identify the t wo neurotransm it ters m ost likely involved in the pathogenesis of epilepsy.

frequ en cy are m ore su scept ible to block th an ch an n els th at

4. E Ep ilep sy is a ch ron ic recu rren t disorder of cerebral fu n ct ion

nytoin can readily su pp ress th e disch arge from an ep ilept ic

th at m ay be ch aracterized by repeated seizu res. Th e essen ce

focus (w h ere th e n eu ron s are disch arging at h igh frequen cy)

of epilepsy is probably a ch ron ic low seizu re th resh old th at

w ith n egligible e ect s on n orm al- ring n euron s.

can be du e to several m ech an ism s. A leading th eor y p ost u -

open an d close at low frequ en cy. Th is can explain w hy ph e-

A Na + ch an n els th at are in a rest ing st ate are n ot sign i -

lates th at th e cau se of seizu res is eith er th e at ten u at ion of

can tly a ected by an t iseizu re drugs.

prean d/or p ost syn apt ic in h ibit ion (m ain ly du e to a gen et ic

C See correct an sw er explan at ion .

or path ology-in duced hypofun ct ion of GABA n eu ron s) or an

D−F Phenytoin has negligible e ects on K+ channels at ther-

in creased e ect iven ess of excit ator y syn apses (m ain ly du e to a gen et ic or path ology-in duced hyperfun ct ion of glut am ate n euron s). A–D, F See correct an sw er explan at ion .

apeut ic con cen t rat ion s.

Answers and Explanations: III-6 Antiseizure Drugs 153 Learning objective: Describe the e ect of carbam azepine on the P-450 system . 6. B Carbam azep in e is a poten t en zym e in du cer an d can in du ce

• Blockade of T-t yp e Ca 2+ ch an n els in th alam ic n euron s • In creased GABA con ten t in t h e brain (m ech an ism is u n cert ain )

its ow n m et abolism ; th is appears to be m ediated via it s ef-

• Op en ing K+ ch an n els (at h igh doses)

fect s on t h e h ep at ic CYP3A4 isoen zym e. On set of en zym e

B−F Non e of th ese drugs h ave all of th e m ech an ism s m en -

in duct ion is at about 3 days, w ith m axim u m e ect at abou t

t ion ed in th e qu est ion .

30 days. A, C Valp roic acid an d lam ot rigin e are u sed to t reat sim p le par t ial seizu res bu t are n ot in du cers of th e P-450 system . D, E Eth osu xim ide an d clon azepam are n ot in du cers of

Learning objective: Explain the m echanism of action of ethosuxim ide. 11. B Eth osu xim ide is a

rst-lin e agen t for absen ce seizu res. It

th e P-450 system an d are n ot u sed to t reat sim p le p ar t ial

m ost likely act s by blocking voltage-gated T-t yp e Ca 2+ ch an -

seizu res.

n els in th alam ic n euron s. Th ese ch an n els are located on th e d en d r ites of relay t h alam ic n eu ron s, w h ich con n ect t h e

Learning objective: Describe the drug interaction bet ween valproic acid and lam otrigine.

t h alam u s to th e cortex. W h en th ese ch an n els are activated

7. E Valproic acid can in h ibit CYP2C9 an d glucuron osylt ran s-

seizu re), th e n eu ron s provide an oscillator y ring rate to th e

ferase, th us decreasing th e biot ran sform at ion of m any dr ugs,

cor tex, w h ich h as a ch aracterist ic 3-Hz spike an d w ave read-

including lam otrigine, carbam azepine, phenytoin, topiram ate,

out on an elect roen ceph alogram . Excitator y input from th e

an d felbam ate.

cor tex in t urn act ivates th e th alam ic n euron s, th u s rein it iat-

(during sleep or, for un kn ow n reason s, du ring an absen ce

A, B Phenytoin and phenobarbital act ually can induce P-450

ing th e cycle. Th erefore, th e absen ce seizu re is gen erated by

en zym es, th u s in creasing, n ot decreasing, th e biot ran sfor-

a self-su stain ed cycle of act ivit y bet w een th e th alam u s an d

m at ion of m any drugs.

th e cor tex. Drugs su ch as eth osu xim ide an d valproic acid ,

C, D, F Levet iracet am , clon azepam , an d gabapen t in do n ot cau se relevan t d rug−drug in teract ion s.

w h ich are able to block volt age-sen sit ive T-t ype Ca 2+ ch an n els in th e th alam us, are e ect ive in absen ce seizu res. A, C−F Th erap eu t ic doses of eth osu xim ide do n ot h ave

Learning objective: Describe the adverse e ect s of phenytoin.

th ese act ion s.

8. G Th e sign s of th e pat ien t are classical adverse e ect s of ph enytoin . Hirsu t ism an d gingival hyp erp lasia occu r to som e

Learning objective: Outline the therapeutic use of valproic acid.

d egree in m ost pat ien t s. Blurred vision , diplopia, an d broad-

12. D Th e pat ien t w as m ost likely su ering from m yoclon ic sei-

en ing of th e lip s an d n ose are associated in som e p at ien t s

zu res, a t ype of ep ilep sy th at occu rs m ain ly du ring ch ild-

w ith long-term use of th e drug.

h ood. Valproic acid is a rst-lin e agen t for m yoclon ic seizures

A−F Th ese drugs do n ot cause th e array of adverse e ect s exh ibited by th e pat ien t .

an d can con t rol th e sym ptom s in m ost cases. Levet iracet am , clonazepam , lam otrigine, ethosu xim ide, and topiram ate also can be e ect ive.

Learning objective: Describe the interaction bet ween carbam azepine and oral contraceptives. 9. F Th ere h ave been several rep or ts of redu ced e

cacy of oral

contraceptives in patients receiving various antiseizure drugs.

A−C Ph enytoin , carbam azep in e, an d p h en obarbit al can act u ally w orsen m yoclon ic seizu res. E, F Gabap en t in an d acet azolam id e are n ot e ect ive in m yoclon ic seizures.

Carbam azep in e, p h enytoin , p h en obarbit al, an d felbam ate t radiol an d p rogest in s by in d u cing m icrosom al en zym es.

Learning objective: Outline the therapeutic uses of phenobarbital.

Th is e ect is n ot associated w ith oth er an t iconvu lsan t dr ugs,

13. D Provision of a paten t air w ay an d adequate oxygen at ion are

in cluding lam ot rigin e, valproic acid, clon azepam , gabapen -

th e in it ial steps in m an agem en t of st at u s ep ilept icu s. Em er-

t in , an d levet iracet am .

gen cy drugs in clu de ben zodiazep in es for seizu re con t rol.

h ave been sh ow n to in crease th e m etabolism of eth inyl es-


Th e con t rol m ay be sh or t-lived, h ow ever, requ iring in t raven ous (IV) ph enytoin in fusion . If refractor y stat us epilept icus

Learning objective: Explain the m echanism of action of valproic acid.

con t in ues after in it ial t reat m en t , addit ion al IV ph en obarbi-

10. A Th e m ech an ism s of act ion of valproic acid h ave n ot been

t u rate com a.

fully established, but th ey are m ost likely m ultiple, including +

• St ate-dep en den t blockade of in act ivated Na ch an n els • Blockade of NMDA receptor−m ediated excitat ion

t al or th iop en t al m ay be given , p lacing th e pat ien t in barbiA−C, E, F Th ese drugs are n ot used to t reat stat us epilept icu s.

154


Learning objective: Describe the adverse e ect s of lam otrigine.

Th is is m ost likely th e prim ar y m ech an ism of act ion of th e

14. F Lam ot rigin e causes a gen eralized er yth em atous skin rash

drug.

in abou t 85% of pat ien t s taking th e drug. Several an t iseizure

A−C, E, F Carbam azepin e in teract ion s w ith all of th ese m o-

d rugs can cause skin hypersen sit ivit y react ion s, but lam o-

lecu lar target s h ave been p rop osed, bu t th eir role in th e n al

t rigin e is by far th e drug m ost frequ en tly involved . Th e rash

th erapeut ic e ect of th e drug is st ill u n cer tain .

is usually m ild, but severely a ected pat ien ts m ay develop Steven s−Joh n son syn d rom e. Th e in cid en ce of skin rash is

Learning objective: Describe the adverse e ects of carbamazepine.

h igh er in ch ild ren , an d som e st u d ies suggest t h at a p oten -

18. C Som e of t h e adverse e ect s of carbam azep in e are re-

t ially life-t h reaten in g d er m at it is can d evelop in 1 to 2% of

lated to cerebellar-vestibular im pairm en t. The m ost com m on

p ediat ric p at ien t s.

d ose-related adverse e ect of t h is kin d is at a xia (u p to 15%

A−E Th e risk of th ese adverse react ion s is n egligible.

of p at ien t s). A Th is w ou ld be an adverse e ect of ph enytoin . It does n ot

Learning objective: Describe a m echanism of action com m on to several antiepileptic drugs.

occur w ith carbam azepin e.

15. E A par t ial seizure results from syn ch ron ous, rapid, u n con -

of carbam azepin e.

t rolled

B, D−F All th ese are seriou s but qu ite rare adverse e ect s

r in g from a grou p of n eu ron s an d a loss of su r-

rou n d ing cell in h ibit ion . An t iseizure drugs act to en h an ce

Learning objective: Outline the antiseizure uses of diazepam .

cen t ral n er vous system (CNS) in h ibit ion (i.e., by in creasing

19. C Th e h istor y of th e p at ien t an d th e lack of n eu rologic an d

GABAergic act ivit y or by decreasing glut am atergic act ivit y)

laborator y n dings in dicate th at h e w as m ost likely a ected

an d p reven t th e sp read of syn ch ron ou s act ivit y (i.e., by

by febrile seizu res, w h ich are th e m ost com m on t ype of sei-

blocking in act ivated Na + ch an n els, th u s in creasing th e re-

zu res obser ved in th e p ediat ric p op u lat ion . An t iconvu lsan t

fractor y p eriod of n er ve

bers). Several an t iseizu re drugs

th erapy is u su ally n ot requ ired if a p at ien t h as recovered

e ect ive again st p art ial seizu res act by blocking in act ivated

from an isolated seizu re, bu t a p reven t ive t reat m en t can be

Na + ch an n els.

app ropriate if th e pat ien t exp erien ces repeated fever-related

A An t iseizu re dr ugs do n ot a ect n eu rom u scu lar t ran sm ission .

seizu res, as in th is case. Diazep am , given rect ally as soon as a febrile illn ess app ears an d m ain tain ed u n t il th e p at ien t is

B−D All of th ese act ion s w ou ld decrease, n ot in crease, th e in h ibitor y act ivit y of th e CNS cells surroun ding th e rap idly ring n euron s.

afebrile for 24 h ou rs, can decrease th e n u m ber of febrile seizu res an d is con sidered th e agen t of ch oice. A, B, D−F Th ese d r ugs are n ot ap p rop r iate for p ed iat r ic febrile seizu res.

Learning objective: Describe the m ain features of the pharm acokinetic of phenytoin.

Learning objective: Outline the therapeutic uses of lam otrigine.

16. C Ph enytoin is on e of th e ver y few drugs th at exh ibit

rst-

20. F Lam ot rigin e is e ect ive in sim ple par t ial seizures, as w ell

order elim in at ion kin et ics at low doses but sw itch to zero-

as in generalized tonic-clonic and absence seizures. It appears

ord er elim in at ion kin et ics at h igh er d oses; t h at is, t h e

to h ave com parable e ect iven ess w ith m ore t radit ion al an t i-

elim in at ion kin et ics of th e dr ug is dose-depen den t . Im port-

convulsan t drugs, such as valproic acid, carbam azepin e, an d

an t con sequ en ces of dose-d ep en den t kin et ics are

p h enytoin . Th e prim ar y m ech an ism of act ion of lam ot rigin e

• Th e clearan ce an d th e h alf-life of th e drug are dose-

m ost likely in clu d es a frequ en cy-d ep en d en t blockad e of voltage-gated Na + ch an n els.

dep en den t . • Th e t im e t aken to reach steady st ate is also dose-d ep en den t an d th erefore can n ot be predicted. • A sligh t in crease in dose can h ave a big e ect on plasm a

ch oice drugs in par t ial seizu res, but th ey are con t rain dicated w h en th ere is a risk of acute in term it ten t porphyria, becau se th ey can t rigger an at t ack. Becau se acu te in term it ten t p or-

levels, leading to toxicit y. A, B, D−F All of th ese drugs follow

C−E Valproic acid, carbam azepin e, an d ph enytoin are rst-

rst-order elim in at ion

kin et ics.

Learning objective: Explain the m ain m olecular m echanism of action of carbamazepine. 17. D Like p h enytoin , carbam azep in e cau ses a volt age- an d frequ en cy-dep en den t blockade of in act ivated Na + ch an n els.

phyria is an au tosom al disorder, it is bet ter to avoid th ese drugs in pat ien t s w h ose p aren t s are kn ow n to su er from th e disease, as in th is case. A, B Diazep am an d eth osu xim ide are n ot e ect ive in sim ple p art ial seizu res.

Answers and Explanations: III-6 Antiseizure Drugs 155 Learning objective: Outline the therapeutic uses of levetiracetam.

Topiram ate also h as been app roved recen tly for m igrain e

21. A Levet iracet am is an an t iseizu re drug ap proved for par t ial,

preven t ion .

ton ic-clon ic, an d m yoclon ic seizures. Th e drug appears to be

A, B Aten olol an d verap am il are u sed for m igrain e p rop hy-

w ell tolerated an d h as n o sign i can t d rug in teract ion s. Sev-

laxis bu t are con t rain dicated in th is pat ien t becau se of at rio-

eral an t iseizu re drugs are e ect ive in p art ial seizu res. How -

ven t ricular block.

ever, in th is pat ien t , oth er drugs are relat ively con t rain dicated

C Am it r ipt ylin e is e ect ive for p reven t ion of bot h m igrain e an d ten sion -t yp e h eadach e bu t is con t rain dicated in

(see an sw er explan at ion s below ).

th is pat ien t becau se of glaucom a.

B Ph enytoin can decrease in su lin secret ion . C Because carbam azepin e is a st rong in ducer of CYP3A4, it could in crease th e m etabolism of several drugs th e pat ien t

D, F Lam ot rigin e an d felbam ate are n ot e ect ive for m igrain e p rop hylaxis.

w as t aking. D Th e risk of valproic acid h epat it is is in creased in pat ien t s w ith liver disease.

Learning objective: Describe the adverse e ects of phenytoin. 26. D Th e sign s an d sym ptom s of th e p at ien t in dicated th at h e

E Topiram ate can cause glaucom a.

w as m ost likely su ering from p eriph eral n eu rop athy an d

F Zon isam ide can cause kidn ey ston es.

lym p h aden op athy, w h ich are adverse e ect s of long-term u se of ph enytoin . Megaloblast ic an em ia is also an adverse

Learning objective: Outline the therapeutic uses of topiram ate.

e ect of ph enytoin becau se th e dr ug in h ibit s th e en zym e

22. B Len n ox−Gast au t syn drom e is a d evast at ing pediat ric epi-

conjugase, located in th e brush border of th e in test in al m u -

lepsy syn drom e (on set 1 to 14 years) ch aracterized by m u l-

cosa. Th is en zym e hyd rolyzes t h e glu t am ate resid u es of

t iple t ypes of seizu res. Topiram ate is a drug w ith a broad

ingested polyglut am ates, th us allow ing th e absorpt ion of

spect ru m of act ion th at in clu des alm ost all t ypes of epilept ic

m on oglu tam ates. Pat ien ts taking ch ron ic h igh doses of p h e-

seizures. Recen tly, it w as app roved by th e U.S. Food an d Drug

nytoin can sh ow m egaloblast ic an em ia, lym p h oid hyp er-

Adm in ist rat ion for Len n ox−Gastau t syn d rom e.

p lasia, an d paresth esias. Kn ee an d an kle ten don re exes are

A, C−G Non e of th ese drugs h ave a broad sp ect ru m of an -

absen t in abou t 18% of th ese pat ien ts, as in th is case. A−C, E, F Non e of t h ese d r ugs sh ow t h e com bin at ion of

t iep ilept ic act ivit y.

adverse e ect s exh ibited by th e p at ien t .

Learning objective: Outline the therapeutic uses of gabapentin. 23. B Gabap en t in is a secon d-gen erat ion an t iseizu re drug th at is u sed for pat ien t s w ith par t ial seizu res w h o h ave failed th e

Learning objective: Describe the m ain features of the pharm acokinetics of phenytoin.

in it ial t reat m en t , as in th is case. In gen eral, if th e in it ial drug

27. D Ph enytoin elim in at ion is d ose-d ep en d en t . At ver y low

d oes n ot con t rol seizures, a t rial w ith an oth er agen t sh ou ld

blood levels, ph enytoin m etabolism follow s a rst-order ki-

be at tem pted before con sidering a m u lt idrug regim en .

n et ics, but as blood level rises w ith in th e th erapeut ic range,

A, C, D Eth osu xim ide, diazep am , an d acet azolam ide are

th e m axim u m cap acit y of th e liver to m etabolize p h enytoin is ap proach ed. Th is m ean s th at th e elim in at ion of ph enytoin

n ot e ect ive in part ial seizures. E, F Carbam azepin e an d ph enytoin are e ect ive in part ial

is d ose-d ep en den t , so t h e clearan ce of t h e d r ug is d ose-

seizu res. bu t th ey are con t rain dicated in th is pat ien t becau se

d epen den t . In th is sit u at ion , even a sm all in crease in dosage

of at rioven t ricular block.

m ay p rodu ce a ver y large in crease in ph enytoin con cen t rat ion , th u s leading to toxic e ect s, as in th is case.

Learning objective: Outline the therapeutic uses of ethosuximide. 24. D Valproic acid is classi ed by th e U.S. Food an d Drug Adm in ist rat ion as p regn an cy categor y D becau se it in creases th e risk of n eu ral t u be defect s (u p to 20-fold) w h en given during pregnan cy. Ethosu xim ide is instead classi ed as pregn ancy category C and is a rst-line drug for absence seizures. A−C, E, F Th ese drugs are n ot e ect ive (an d som e of th em can even be dangerou s) in absen ce seizu res.

25. E Anticonvulsant m edications have em erged as an im portant th erap eu t ic opt ion for th e p reven t ion of m igrain e h eadach e. rst-lin e agen t , as its e

tom s of a hypersen sit ivit y react ion . B Th is w ould h ave cau sed an in creased elim in at ion of th e d rug, m aking toxicit y u n likely. C Th e volum e of dist ribu t ion of a drug is n ot related to d rug elim in at ion . E Th e level of th e steady state, n ot th e t im e to reach th e steady st ate, is directly related to th e toxicit y of th e drug. Moreover, w h en a drug follow s dose-depen den t kin et ics, th e


Valproic acid is con sidered a

A Th e sym ptom s repor ted by th e pat ien t are n ot sym p -

cacy

h as been dem onstrated in several placebo-controlled st udies.

h alf-life of th e drug is dose-depen den t; th erefore, th e t im e to reach steady st ate w ill be dose-depen den t . In fact , w ith low doses, th e steady state of p h enytoin is reach ed in abou t 4 days. With h igh doses it m ay be 4 to 6 w eeks before bloods levels are st able.

156



t h at cat alyzes t h e

28. E Th e p at ien t’s sym ptom s in d icate th at sh e h ad a ton ic-clon ic

carbon dioxide (CO2 ) an d w ater in to carbon ic acid. By in h ib -

seizure concom itant w ith her absence seizure. Because etho-

it ing th is react ion , carbon dioxide ten sion is in creased; th e

su xim ide is n ot act ive again st m ixed seizu re d isorders, th e

gas can di u se freely across n eu ron al cell m em bran es, in -

best strategy is to substitute ethosu xim ide w ith another drug,

h ibit ing n euron al t ran sm ission .

su ch as valproic acid, th at is active on both t ypes of seizures.

rst p ar t of t h e react ion t h at conver t s

A−C, E, F Th ese drugs do n ot a ect th e in t racellular con cen t rat ion of CO2 .


Learning objective: Outline the therapy of infantile spasm s. 29. E Th e boy m ost likely su ered from in fan t ile spasm s (also called West syn drom e or salaam seizu re). Th ey are prim arily

Learning objective: Describe the m ost likely m echanism of action of felbam ate. 32. E Felbam ate is an an t iconvu lsan t d r ug ap p roved by t h e

exion of th e

U.S. Food an d Drug Adm in ist rat ion for par t ial seizu res an d

arm , for w ard exion of th e t ru n k, an d exten sion of th e legs.

Len n ox−Gastau t syn drom e. Th e drug can cau se ap last ic an e-

Seizu res last a few secon ds an d are repeated m any t im es a

m ia an d severe h epat it is at u n exp ectedly h igh rates an d is

day. Th ey occur prim arily in th e

rst 3 years of life an d are

th erefore u sed on ly as a th ird-lin e d rug for refractor y cases.

th en rep laced by oth er t yp es of seizu res. Men tal ret ardat ion

Never th eless, th e drug is frequ en tly u sed in Len n ox−Gastau t

is usually apparen t . Most pat ien t s h ave st ruct u ral brain

syn drom e, as th is t ype of ep ilep sy is often resistan t to sev-

an om alies on n eu roim aging st u dies, as in th is case. Drugs

eral an t iepilept ic drugs. Th e m ech an ism of an t iconvu lsan t

of ch oice for in fan t ile spasm s are adren ocor t icot ropic h or-

action of felbam ate m ost likely involves the ionotropic NMDA

m on e (ACTH) an d cor t icosteroids (predn ison e, dexam eth a-

receptors presen t in th e cen t ral n er vous system . Seizu res

son e, etc.). ACTH seem s m ore e ect ive, bu t th is su bject

can be in it iated an d p ropagated by st im u lat ion of th e NMDA

rem ain s con t roversial. Alter n at ive d r ugs in clu d e ben zod i-

receptors, w h ich results in th e open ing of an ion ch an n el

azepin es (clon azep am ), valproic acid, an d vigabat rin . Th e

th at is n on select ive to cat ion s. Felbam ate p rod u ces a u se-

th erapy of in fan t ile spasm s is able to reduce th e n um ber of

d epen den t block of NMDA receptors, th ereby in creasing th e

at tacks in 40 to 50%of pat ien ts, but it rarely reduces th e pro-

seizu re th resh old an d p reven t ing th e sp read of seizu res.

gen eralized seizu res ch aracterized by su dden

gression of m en tal ret ardat ion . A−D Th ese drugs are n ot e ect ive in in fan t ile spasm s.

A Felbam ate p oten t iates, n ot blocks, GABAA receptor resp on ses. B−D, F Felbam ate does n ot act on th ese receptors.

Learning objective: Outline the therapeutic uses of carbamazepine. 30. E Th e p at ien t ’s sym ptom s suggest t h at h e is a ected by

Learning objective: Outline the therapeutic uses of fosphenytoin.

t r igem in al n euralgia, a n europathy th at usually a ects on ly

33. D Th e p at ien t w as m ost likely su ering from convu lsive st a-

ad u lt s, esp ecially t h e eld erly. Carbam azep in e is a d r ug of

t u s epilept icu s, a life-th reaten ing n eu rologic disorder ch ar-

ch oice in t h is d isease, an d t h e ben e t is often su st ain ed . If

acterized by a p rolonged ton ic-clon ic seizu re or by recu rren t

th e drug is in e ect ive or produ ces toxic react ion s, oth er op -

tonic-clonic seizures w ithout com plete recovery of conscious-

t ion s are p h enytoin , baclofen , an d am it ript ylin e.

n ess bet w een at t acks, as in t h is case. Th e

A, B Th ese an t iconvu lsan ts are n ot e ect ive again st t rigem in al n eu ralgia.

rst -lin e agen t s

for th e in it ial t reat m en t of convu lsive st at u s epilept icu s are lorazepam an d diazepam . Oth er an t iseizure drugs th at can

C, D Trigem in al n eu ralgia is a form of n europath ic pain .

be em p loyed for th e in it ial t reat m en t are fosph enytoin (a

This t ype of pain is usually resistant to opioids and analgesic-

m ore solu ble prodrug of p h enytoin ) an d ph en obarbit al. Th e

an t ipyret ic drugs.

p eak e ect of fosp h enytoin is usually delayed, so th is drug is u sed on ly after th e in it ial t reat m en t w ith diazepam or loraz-

Learning objective: Describe the anticonvulsant e ect of carbonic anhydrase inhibitors. 31. D Th e pat ien t m ost likely received acet azolam ide, th e p rotot ype drug of carbon ic an hydrase in h ibitors. Th ese drugs are rarely u sed today, bu t t h ey can be em p loyed , p r im ar ily as an add-on th erapy, in pat ien ts w ith absen ce seizu res an d

ep am . Ph en obarbital m ay be u sed in p at ien t s w h o can n ot tolerate fosph enytoin or w h en fosph enytoin is n ot e ect ive. A−C, E, F These drugs are not e ective in stat us epilepticus.

Learning objective: Describe the m ost likely m echanism of action of zonisam ide.

m yoclon ic seizures refractor y to th e m ain t reat m en t . Th e

34. D Th e p at ien t w as m ost likely su ering from an allergic reac-

m ech an ism of an t iconvu lsan t act ivit y of carbon ic an hydrase

t ion to lam ot rigin e, a drug th at frequ en tly can cau se an er y-

in h ibitors is n ot fully u n derstood, but it m ay depen d on a

th em atou s skin rash . W h en an an t iepilept ic d rug is e ect ive

d irect in h ibit ion of carbon ic an hydrase in th e cen t ral n er-

bu t cau ses an in tolerable hyp ersen sit ivit y react ion , it is con -

vous system . Carbon ic an hydrase is a ubiquitou s en zym e

ven ien t to subst it ute th e o en ding drug w ith an oth er agen t

Answers and Explanations: III-6 Antiseizure Drugs 157

an ism of act ion . Zon isam ide, like lam ot rigin e, blocks both

Learning objective: Explain the m echanism of action of lam otrigine.

Na + ch an n els an d Ca 2+ ch an n els an d can be u sed ap prop ri-

38. B Lam ot rigin e is a secon d-gen erat ion an t iep ilept ic drug th at

ately in th is case. Oth er an t iepilept ic drugs w h ose m ech a-

likely acts w ith m ult ip le m ech an ism s, in clu ding blockade of

n ism s of act ion m ost likely in clude blockade of both Na +

voltage-gated Na + ch an n els, blockade of voltage-gated Ca 2+

ch an n els an d Ca 2+ ch an n els are topiram ate an d valproic acid.

ch an n els (m ain ly of L, N, an d P t ypes), an d in h ibit ion of glu-

A−C, E, F Non e of th ese drugs can block both Na + ch an n els

t am ate release. Th e drug is com m on ly added to valp roic acid

w ith a di eren t ch em ical st ruct ure but w ith a sim ilar m ech -

an d Ca 2+ ch an n els.

th erapy in p at ien ts resist an t to valp roic acid alon e, as it h as been sh ow n th at th is is th e on ly com bin at ion th at can con -

Learning objective: Describe the adverse e ect s of valproic acid. 35. B Th e sign s an d sym ptom s of th e p at ien t in dicate th at sh e

sisten tly in crease th e e

cacy of th e th erapy.

A, C−F See correct an sw er exp lan at ion .

w as m ost likely su ering from acu te h ep at it is, w h ich is th e m ost seriou s adverse e ect of valproic acid th erapy. Th e dis-

Learning objective: Describe the therapeutic use of valproic acid.

ease is rare w h en valproic acid is given alon e, but it s occur-

39. C All cu rren t an t iepilept ic dr ugs, w ith th e except ion of eth o-

ren ce is about 1/6000 w h en th e drug is given w ith oth er

su xim ide, can be u sed in th e t reat m en t of com p lex par t ial

an t iseizu re drugs, as in th is case. Hep at it is is alw ays seriou s,

seizures. How ever, in this patien t carbam azepine, phenytoin,

often leth al, an d can h ave a fulm inan t cou rse. Th e path ologic

and zonisam ide are contraindicated (see explanations below ).

lesion con sists of a m icrovesicu lar steatosis w ith out any sign

A, B Carbam azep in e an d p h enytoin are con t rain d icated

of in am m at ion . Th e cause of th e disease is un kn ow n but is

in case of at r ioven t r icu lar block becau se t h e d r ug-in d u ced

m ost likely idiosyn crat ic.

blockade of in act ivated Na + ch an n els can slow dow n th e

A, C−F Hepat ic dysfu n ct ion is u n u su al w ith all of th ese d rugs.

h ear t con du ct ion , exacerbat ing th e disease. D See correct an sw er explan at ion . E Zon isam ide is approved for adjun ct ive t reat m en t of par-

Learning objective: Describe the antiseizure use of clonazepam.

t ial seizu res. How ever, it can cau se n ep h rolith iasis in abou t

36. F Myoclon ic seizures con sist of sh ort episodes of bilateral

2.5%of p at ien t s an d is th erefore con t rain dicated in th is case.

jerks of a lim b, several lim bs, or th e t r un k. Con sciou sn ess is n ot lost (un less a gen eralized seizu re occurs). Myoclon ic sei-

Learning objective: Explain the mechanism of action of ezogabine.

zu res u su ally occu r du ring ch ildh ood or adolescen ce (in th is

40. E Ezogabin e (th e d rug is called ret igabin e ou t side th e Un ited

case, th ey are called juven ile m yoclon ic epilepsy, an d th ey

St ates) is th e p rotot ype of a n ew class of an t iseizu re drugs

are u su ally follow ed by gen eralized ton ic-clon ic seizu res).

th at act by op en ing a cer tain fam ily of K+ ch an n els on brain

Treat m en t opt ion s in clude valproic acid, clon azepam , an d

n euron s. Th is act ion hyperpolarizes th e neuron al cell m em -

several secon d-gen eration drugs (lam ot rigin e, levet iracetam ,

bran e, m aking th e n eu ron less excit able. Th is m ech an ism

topiram ate, an d zon isam ide).

of act ion is un ique am ong an t iepilept ic drugs an d m ay h old

A−E Th ese drugs are n ot e ect ive (an d som e of th em can be dangerou s) in m yoclon ic seizu res.

prom ise for th e t reat m en t of oth er n eurologic con dit ion s, in clu ding m igrain e an d n eu ropath ic p ain . A−D, F Th ese drugs h ave n o e ect on K+ ch an n els.

Learning objective: Explain the m echanism of action of perampanel. ANTISEIZURE DRUGS Answ er key

37. D Peram p an el is th e p rotot yp e of a n ew class of an t iseizu re d rugs th at act as n on com p et it ive an tagon ists of AMPA receptors on brain n eu ron s. Th ese are ion ot ropic t ran sm em bran e receptors th at are p ar t of a ligan d-gated ion ch an n el, w h ich is perm eable m ain ly to Na + an d K+. AMPA receptors m ed iate fast , excit ator y n eu rot ran sm ission an d h ave a crit ical role in seizu re developm en t an d spreading. By blocking th ese receptors, p eram p an el can redu ce n eu ron al excit abilit y. Th e d rug h as been ap proved for adjun ct t reat m en t of sim p le p art ial seizu res an d is m ain ly u sed in p oorly con t rolled p art ial seizu res, as in th is case. A−C, E, F Th ese drugs h ave n o e ect on AMPA receptors.

1. 2. 3. 4. 5.

K G I E B

6. 7. 8. 9. 10.

B E G F A

11. 12. 13. 14. 15.

B D D F E

16. 17. 18. 19. 20.

C D C C F

21. 22. 23. 24. 25.

A B B D E

26. 27. 28. 29. 30.

D D E E E

31. 32. 33. 34. 35.

D E D D B

36. 37. 38. 39. 40.

F D B C E

158


Answers and Explanations: III-7 Drugs for Degenerative Disorders of the Central Nervous System Questions 1−5

Learning objective: Describe the adverse e ects of levodopa.

1. B

8. B Th e adverse e ect s rep or ted by th e p at ien t an d th e t im ing

2. E

of th e e ects suggest th at th ey are levodopa-in duced dyski-

3. H

n esias, w h ich occur in up to 80% of pat ien ts receiving th e

4. I

d rug for long p eriods. Th e developm en t of dyskin esias is

5. F

d ose- related, an d dyskin esias are usually associated w ith p eak st riat al dop am in e levels or w h en th e level of th e drug is

Learning objective: Explain the m echanism of action of levodopa in Parkinson disease.

rising or falling. Th e exact m ech an ism of th ese dyskin esias

6. C Dop am in e can n ot cross th e blood−brain barrier an d th ere-

m u ch m ovem en t cau sed by too m u ch st riat al dop am in e re-

fore h as n o th erapeut ic e ect s in parkin son ism if given in to

is n ot kn ow n , bu t sim p list ically it can be th ough t of as too ceptor st im ulat ion .

th e periph eral circulat ion . How ever, levodopa, th e im m ediate

A, C−E Som e of th ese drugs (selegilin e an d en tacap on e)

precu rsor of d op am in e, is readily carried across th e blood−

can cau se dyskin esias, bu t th ey are n ever u sed as th e sole

brain bar r ier by t h e n eu t ral am in o acid t ran sp or ter. In t h e

agen t to t reat Parkin son disease for long p eriods.

brain , levodop a is biot ran sform ed in to dopam in e w ith in th e t u m . Th ese n eu ron s are th erefore able to release m ore dopa-

Learning objective: Describe the m ain drug interactions with levodopa.

m in e, an d th is balan ces th e loss of dopam in ergic n euron s,

9. E Th e sym ptom s rep or ted by t h e p at ien t p oin t ou t a w ors-

presyn apt ic term in als of dopam in ergic n eu ron s in th e st ria-

w h ich con st it utes th e path ologic basis of Parkin son disease.

en ing of h is Parkinson disease. Metoclopram ide, a prokinetic

A Dopam in ergic receptors are upregulated, n ot dow n regu -

drug u sed to t reat diabet ic gast roparesis, can block d op a-

lated , du e to th e decreased availabilit y of d op am in e in th e

m in e D2 receptors in th e brain , th us leading to a decreased

st riat u m .

levodop a e ect that explain s the w orsen ing of parkinsonian

B Su bt h alam ic n eu ron s are m ain ly glu t am atergic, n ot dop am in ergic.

sym ptom s. A−D See correct an sw er explan at ion .

D Th is act ion w ou ld decrease, n ot in crease, th e availabilit y E Th e in h ibit ion of catech ol- O-m et hylt ran sferase (COMT)

Learning objective: Describe the clinical use of benztropine in Parkinson disease.

w ou ld in crease t h e availabilit y of d op am in e, bu t th is is an

10. C Au ton om ic dysfu n ct ion is a p rom in en t feat u re of Parkin -

of dopam in e in basal ganglia.

act ion of COMT in h ibitors, n ot of levodopa.

son disease, an d p ost u ral hypoten sion , u rin ar y urgen cy, an d sialorrh ea are com m on sym ptom s. Sialorrh ea occu rs in u p to

Learning objective: Describe the treatment of parkinsonian tremor resistant to dopaminergic therapy.

55% of p at ien t s an d respon ds to an t ich olin ergic drugs su ch

7. D Parkin son ian t rem or is often less resp on sive to d op am i-

A, B, D, E Th ese an t ip arkin son drugs h ave m in im al e ect s

n ergic th erapy th an oth er sym ptom s. Trem or can be w ors-

as ben zt rop in e. on sialorrh ea.

en ed by perip h eral factors, su ch as catech olam in e release, proves p arkin son ian t rem or in abou t 50%of pat ien ts, so a t rial

Learning objective: Explain the m echanism of action of pram ipexole.

w ith propran olol can be appropriate for th is pat ien t .

11. A Th e sym ptom s of th e pat ien t in dicate th at sh e w as m ost

often in associat ion w ith st ress or an xiet y. Prop ran olol im -

A, B, E All of th ese p rocedu res w ou ld m in im ally a ect th e pat ien t’s t rem or.

likely su ering from Parkin son disease. Dop am in ergic agon ists su ch as pram ipexole are often

rst-lin e agen t s in an t i-

C An t ich olin ergic drugs can im prove t rem or bu t th ey are

p arkin son th erapy, especially in you nger p at ien t s, as th eir

u su ally bet ter avoided in th e elderly because of an in creased

u se seem s associated w ith a low er in ciden ce of respon se

risk of adverse e ect s.

uct uat ion s an d dyskin esias th at can occur w ith long-term levodopa th erapy. B−F Th ese drugs are n ot dopam in ergic agon ist s.

Answers and Explanations: III-7 Drugs for Degenerative Disorders of the Central Nervous System 159 Learning objective: Describe the adverse e ects of bromocriptine. 12. A Brom ocript in e is an ergot-derived dopam in e agon ist .

Learning objective: Explain the mechanism of antiparkinson action of benztropine.

Ergot -d er ived d r ugs m ay cau se con n ect ive t issu e p rolifera-

15. B In Parkin son disease, th e loss of dop am in ergic n eu ron s re-

t ion lead in g to

brosis in d i eren t organ s, in clu d in g p u l-

m on ar y, p leu ral, an d ret rop er iton eal

su lt s in a loss of th e balan ce th at n orm ally exists bet w een

brosis. Th e exact

acet ylch olin e- an d dop am in e-m ediated n eu rot ran sm ission .

m ech an ism of th is adverse e ect is st ill un kn ow n , but bro -

An t im uscarin ic drugs su ch as ben zt ropin e seem to act by

m ocript in e is n o longer used in Parkin son disease due to th is

blocking m u scarin ic receptors in th e st riat u m , th u s d ecreas-

e ect .

ing th e abn orm ally h igh ch olin ergic ton e, w h ich resu lts from

B−F Th ese drugs do n ot cau se pu lm on ar y brosis.

lack of t h e in h ibitor y act ivit y of d op am in e. Th ese d r ugs m ay im p rove t rem or an d rigidit y bu t h ave lit tle e ect on

Learning objective: Outline the therapeutic use of pram ipexole. 13. D Th e pat ien t p resen ted w ith sign s an d sym ptom s t yp ical of

bradykin esia. A, C−E An t im u scarin ic drugs do n ot h ave th ese e ect s.

Parkin son disease (PD). Th e four classic feat ures of PD, th at is, t rem or, rigidit y (t igh t n ess in h is arm s an d legs), brady-

Learning objective: Describe the adverse e ects of benztropine.

kin esia (lack of n orm al ch anges in facial expression ), an d

16. E Th e sym ptom s of th e pat ien t are t ypical adverse e ects of

p ost u ral in st abilit y (fest in at ing gait), are easily recogn ized.

an t im u scarin ic drugs, su ch as ben zt ropin e. Th ese drugs h ad

Pram ipexole is a dopam in e receptor agon ist th at is e ect ive

been u sed exten sively in th e past before th e discover y of

w h en u sed as m on oth erapy for m ild parkin son ism . Dopam i-

levodopa. Because of th eir u n desirable adverse e ect p ro le

n ergic agon ist th erapy of parkin son ism can be in it iated w ith

an d p oor e

a dopam in e agon ist , especially in you nger p at ien t s, as th ese

treatm ent of persisting resting trem or, particularly in younger

d rugs h ave a n um ber of poten t ial advan tages over levodop a,

p at ien ts, as in th is case.

in clu d ing a low er in cid en ce of resp on se

u ct u at ion s an d

dyskin esias.

cacy, today th ey are u su ally reser ved for th e

A−D, F Non e of t h ese d r ugs cau se t h e set of sym ptom s repor ted by th e pat ien t .

A−C Currently, carbidopa, en tacapone, and ben ztropin e are n ot u sed as m on oth erapy, bu t on ly in addit ion to levodop a th erapy.

Learning objective: Outline the pharm acotherapy of restless leg syndrome.

E, F Clon azepam an d propran olol are on ly used adjun c-

17. C Restless leg syn drom e is ch aracterized by abn orm al m o-

t ively to con t rol sym ptom s su ch as t rem or (prop ran olol) an d

t ion an d som et im es sen sat ion s in th e legs th at in terfere w ith

m yoclon u s (clon azepam ) th at , in a par t icu lar pat ien t , are

sleep . Th e disorder can occu r in isolat ion bu t is m ore com -

resistan t to conven t ion al th erapy.

m on d u r in g p regn an cy, ch ron ic ren al or liver failu re, iron d e cien cy an em ia, or diabetes, as in t h is case. Th e cau se

Learning objective: Explain the mechanism of action of selegiline.

of th e disorder is u n clear bu t m ay involve abn orm alit ies in

14. C Tw o isoen zym es of m on oam in e oxidase (MAO) m etabolize

d opam in e n eu rot ran sm ission in th e cen t ral n er vou s system .

m on oam in es. MAO-A m et abolizes p rim arily n orep in ep h -

Num erous drugs h ave been used to t reat th e disorder, bu t

rin e an d seroton in , MAO-B m et abolizes p rim arily dopam in e

on ly dopam in ergic th erapy is speci c an d is th e preferred

an d is p redom in an t in th e st riat u m . Selegilin e is a select ive

t reat m en t for rest less leg syn d rom e. Dop am in e agon ist s

in h ibitor of MAO-B, leading to irreversible in h ibit ion of th e

su ch as pram ipexole h ave rep laced levodopa as a

en zym e, th u s ret arding th e breakdow n of dopam in e in th e

th erapy.

st riat u m . Becau se MAO-B is p rim arily fou n d in th e brain , selegilin e does n ot in h ibit th e p erip h eral m et abolism of do-

rst-lin e

A, B, D−F Th ese drugs are n ot e ect ive in restless leg syn drom e.

p am in e an d can be safely t aken w ith levodopa. D Because ph en elzin e is a n on select ive in h ibitor of MAO, it

Learning objective: Explain the m echanism of action of carbidopa in Parkinson disease.

can redu ce th e m etabolism of dop am in e. How ever, it is n ot

18. D Carbidopa is a dopa decarboxylase in h ibitor th at can n ot

u sed in Parkin son disease because it can lead to hyperten -

cross th e blood −brain barrier. W h en levodopa is given in

sive crises p robably d u e to th e p eriph eral accu m u lat ion of

com bin at ion w ith carbidopa, th e periph eral m et abolism of

n orepin eph rin e.

levodopa is redu ced, p lasm a levels of levodop a are h igh er,

A, B, E See correct an sw er exp lan at ion .

an d m ore levodopa is available to en ter th e brain . Con com it an t adm in ist rat ion of levodop a an d carbidop a m ay red u ce th e daily requ irem en t for levodop a by abou t 75%. A−C, E Carbidopa does n ot cause th ese act ion s.

160


Learning objective: Describe the treatm ent for levodopa-induced hallucinations.

Learning objective: Describe the reduction of the peripheral effects of levodopa by adding carbidopa to the treatm ent.

19. E Th e p at ien t’s sym ptom s are t yp ical m en t al d ist u rban ces

21. B Carbidop a is an in h ibitor of d op a decarboxylase th at can -

cau sed by levodopa an d are m ore com m on in pat ien ts t ak-

n ot cross th e blood−brain barrier. W h en given w ith levodopa,

ing t h e dr ug in com bin at ion w ith carbid op a, p resu m ably

it d im in ish es t h e p er ip h eral m et abolism of levod op a, in -

becau se h igh er levels are reach ed in th e brain . Psych ot ic

creasing it s availabilit y to en ter th e cen t ral n er vou s system .

sym ptom s in clu ding h allu cin at ion s often respon d to n eu ro-

Th erefore, th e n eeded d ose of levodop a can be low ered by

lept ic t reat m en t , bu t classical n eu rolept ics are n ot in dicated

abou t 5-fold, an d th e p erip h eral adverse e ect s of levodop a

becau se th ey m ay cau se m arked w orsen ing of p arkin son ism ,

are con sequ en tly red u ced.

likely th rough th e blockade of D2 receptors in th e st riat um .

A, C−E Th ese are cen t ral adverse e ects of levodop a. Th ey

At ypical n euroleptics such as clozapin e have negligible block-

are n ot red u ced an d m igh t even be in creased , as m ore

ing activit y at D2 receptors, do n ot w orsen parkinsonism , an d

levodopa can en ter th e brain .

are e ect ive in th e t reat m en t of levodop a-in du ced p sych ot ic A Selegilin e h as on ly a m in or t h erap eu t ic e ect on p ar-

Learning objective: Describe the m ain contraindications of pram ipexole.

kin son ism w h en given alon e; th erefore, th e su bst it u t ion of

22. C Dop am in ergic d rugs, su ch as p ram ip exole, levodop a, an d

levodop a w ith selegilin e m ost likely w ould cause a w orsen -

am ph et am in es, etc., are con t rain dicated, or sh ou ld be u sed

ing of Parkin son disease.

w ith caut ion , in pat ien t s w ith a h istor y of psych osis, as th ey

sym ptom s.

B Dopam in ergic agon ist s such as pram ipexole can cause m en tal dist u rban ces ver y sim ilar to th ose cau sed by levodop a, likely because both adverse e ect s h ave th e sam e u n derlying m ech anism .

con sisten tly exacerbate th e sym ptom s of sch izoph ren ic disorders. A, B, D−F Th ese drugs are n ot con t rain dicated in Parkin son p at ien ts w ith a h istor y of psych osis.

C, D Men tal dist urban ces can be exacerbated, n ot alleviated, by con curren t an t ich olin ergic or am an tadin e th erapy.

Learning objective: Describe the adverse e ect s of levodopa.

Learning objective: Explain the mechanism of action of entacapone. 23. B En t acapon e is a periph eral in h ibitor of catech ol-O-m ethylt ran sferase (COMT). Su bst rates of th e en zym e are levodop a

20. C Post u ral hypoten sion is th e m ost com m on cardiovascular

an d catech olam in es. In t h e p resen ce of a d ecarboxylase

adverse e ect of levodopa, especially in th e early st age of

in h ibitor (e.g., carbid op a), COMT becom es t h e m ajor m e-

t reat m en t . Levodopa is a p rodrug, an d all of it s e ects are

t abolizing en zym e for levodop a, w h ich is t ran sform ed in to

d ue to dop am in e. Post ural hypoten sion is m ost likely du e

3-O-m ethyldopa in th e gut an d th e liver. By in h ibit ing th e

both to act ivat ion of D1 receptors in th e ren al an d m esen -

en zym e, en tacapon e cau ses th e follow ing act ion s:

teric vascular bed, w h ich leads to vasodilat ion , an d to act ivat ion of D1 receptors in th e proxim al t u bule, w h ich causes in h ibit ion of t u bu lar sodium reabsorpt ion , th u s in creasing diu resis. Even if periph eral adverse e ect s are reduced w h en carbidop a is given togeth er w ith levod op a, th e risk of p ost u ral hyp oten sion is sign i can t , especially in older p at ien t s, as in th is case. A Dopam in e h as n egligible e ects on accom m odat ion , so blurred vision is un likely. B Dop am in e can act ivate α 1 ad ren oceptors in t h e gast ro -

• More levodop a becom es available for act ive t ran sp or t in to th e cen t ral n er vous system (CNS). • Less 3-O-m ethyldopa can com pete w ith levodopa for act ive t ran sp or t in to th e CNS. A, C−E Th ese drugs do n ot alter th e am ou n t of levodopa in th e pat ien t’s brain .

Learning objective: Describe the m ain contraindications of benztropine.

in test in al system . Act ivat ion of t h ese receptors in t h e gas-

24. B An t ich olin ergic d rugs su ch as ben zt rop in e are som et im es

t roin test in al sm oot h m u scle cau ses hyp er p olar izat ion an d

u sed in Parkin son disease but are con t rain dicated in case

relaxat ion , so d iarrh ea is un likely.

of p rostat ic hyp er t rophy, becau se th ey decrease th e con t rac-

D Dopam in e can act ivate β adren oceptors in th e h ear t , cau sing t achycardia, n ot bradycardia.

t ion of th e det ru sor m u scle, an d in th e case of ch ron ic con st ip at ion , as th ey decrease in test in al p erist alsis. In addit ion ,

E Dopam in e can cause dyskin esias, but bradykin esia is a

th ey are relat ively con t rain dicated in elderly in dividuals (see

classic sym ptom of parkin son ism , w h ich is in fact alleviated,

th e pat ien t’s age) because th e risk of th eir cen t ral adverse

n ot caused, by levodopa.

e ect s in creases w ith age. A, C−F See correct an sw er explan at ion .

Answers and Explanations: III-7 Drugs for Degenerative Disorders of the Central Nervous System 161 Learning objective: Describe the adverse e ect s of am antadine. 25. D Livedo ret icu laris can occu r in u p to 80%of p at ien t s taking

Learning objective: Outline the pharm acotherapy of Alzheim er disease.

am an t adin e an d u su ally clears w ith in 1 m on th after drug

29. C Th e m an w as m ost likely in th e early st ages of Alzh eim er

w ith draw al. Th e disorder is believed to be caused by local

d isease (AD). He disp layed several sym ptom s associated

release of catech olam in es th at can cau se vasocon st rict ion .

w ith dem en t ia, in cluding im paired reason ing (recogn it ion

A−C, E, F Th ese drugs do n ot cau se livedo ret icularis.

d e cits), loss of m em or y, con fu sion , an d disorien tat ion . A m ajor ap p roach to t h e t reat m en t of AD h as involved t h e

Learning objective: Explain the m echanism of levodopa-induced cardiac arrhythmias.

at tem pt to augm en t th e ch olin ergic fu n ct ion in th e brain ,

26. C A variet y of cardiac arrhyth m ias h ave been described in

of th e disease. Don epezil, rivast igm in e, an d galan t am in e are

p at ien ts receiving levodopa. Like all levodopa-in du ced effect s, th ey are due to dopam in e th at can act ivate cardiac β 1 an d β 2 ad ren oceptors. Con com it an t ad m in ist rat ion of

becau se a loss of ch olin ergic n eu ron s is a p rom in en t feat u re ch olin esterase in h ibitors approved for t reat m en t of AD. A, B, D Sedat ive an d n eu rolept ic d rugs are u su ally con t rain dicated in dem en t ias.

carbid op a red u ces t h e likelih ood of t h ese e ect s, bu t ar-

E Physost igm in e is a ch olin esterase in h ibitor th at can

rhyt h m ias are som et im es rep or ted in p at ien t s receiving

en ter th e brain bu t is n ot u sed in dem en t ias becau se of it s

levodopa/ carbidopa, as in th is case.

frequ en t an d often seriou s adverse e ects.

A Th ere are n o d op am in e receptors in t h e h ear t t h at m od u late cardiac rhyth m . B, D, E Dopam in e does n ot cause th ese act ion s.

Learning objective: Outline the treatm ent of the on-o periods of Parkinson disease. 30. D Th e p at ien t is m ost likely su ering from th e on -o

p h e-

Learning objective: Describe the adverse e ect s of donepezil.

n om en on , in w h ich o periods of m arked akin esia altern ate

27. B Th e drugs m ost frequen tly u sed in Alzh eim er disease are

over th e cou rse of a few h ou rs w ith on periods of im p roved

cholinesterase inhibitors, such as donepezil and rivastigm ine.

m obilit y and m arked dyskinesia. These response uctuations

Alth ough th ese drugs preferen t ially in h ibit acet ylch olin es-

can be decreased by adju n ct ive drugs, in clu d ing d op am in e

terase in th e cen t ral n er vous system , th ey can cause m ost of

agon ists su ch as p ram ip exole, catech ol-O-m ethylt ran sferase

th e adverse e ect s sh ared by all ch olin ergic d rugs, w h ich are

(COMT) in h ibitors such as en tacapon e, an d, in som e cases,

due to th e activation of cholinergic receptors. E ects a ecting

selegilin e.

th e gast roin test in al t ract (n au sea, vom it ing, an d diarrh ea) occur in about 15% of pat ien t s taking th e drug.

A−C, E Th ese drugs are n ot usefu l to im prove respon se uct uat ion s.

A, C−E Th ese e ect s are u su ally cau sed by an t im u scarin ic, n ot ch olin ergic, drugs.

Learning objective: Describe the adverse e ects of pram ipexole. 31. C Pram ipexole is a dopam in e D2 receptor agon ist often used

Learning objective: Outline the therapeutic uses of am antadine.

as th e st ar t ing th erapy for Parkin son disease, m ain ly in pa-

28. D Dyskin esias are frequ en t adverse e ect s of lon g-ter m

t ien t s you nger th an 60. All dop am in e D2 receptor agon ist s,

th erapy w ith levodopa or dop am in e agon ist s. Th e e ect s are

as w ell as levodop a, can cau se n au sea an d vom it ing. W h en

d ose- an d t im e-depen den t; dyskin esias occur in m ost pa-

levodop a is given alon e, n au sea an d vom iting occu r in abou t

t ien t s receiving levodopa th erapy for long p eriod s of t im e.

80% of cases. Levodopa p lu s carbidop a, or D2 receptor ago-

Am an t adin e is useful for suppressing levodopa-in duced dys-

n ist s, cause n ausea an d vom it ing in about 15 to 25%of cases.

kin esias, an d its e ect is th ough t to be du e to blockade of

Th e e ect is m ost likely m ed iated by th e act ivat ion of D2 re-

N-m ethyl- d -aspart ate (NMDA) receptors.

ceptors in th e ch em oreceptor t rigger zon e an d n ucleus of

Dyskin esias caused by dopam in ergic drugs are di eren t

th e t ract us solitarius, t w o cen ters located in th e brain stem

from th e m ovem en t disord ers cau sed by Parkin son disease

th at sen d sign als to th e vom it ing cen ter. For t un ately, toler-

w h ere t rem or, bradykin esia, an d akin esia are th e prevalen t

an ce to th e n ausean t e ect s develops in m any pat ien t s.

sym ptom s. How ever, it is w orth n ot ing th at even drugs th at block dopam in e receptors (i.e., n eu rolept ics) can cau se dyskin esias. Because levodopa-in du ced dyskin esias m ay be t riggered w h en th e level of th e drug is rising or falling, th e m ech an ism of th e e ect m ay be related to an un equal dist ribu t ion of striatal dop am in e. A−C, E Th ese d r ugs w ou ld w orsen , n ot d ecrease, dyskin esias.

A, B, D, E Th ese drugs cau se n au sea in less th an 5%of cases.

162

Central Nervous System DRUGS FOR DEGENERATIVE DISORDERS OF THE CENTRAL NERVOUS SYSTEM Answ er key 1. 2. 3. 4. 5.

B E H I F

6. 7. 8. 9. 10.

C D B E C

11. 12. 13. 14. 15.

A A D C B

16. 17. 18. 19. 20.

E C D E C

21. 22. 23. 24. 25.

B C B B D

26. 27. 28. 29. 30. 31.

C B D C D C

Answers and Explanations: III-8 Neuroleptic Drugs Questions 1−3

are usually bet ter con t rolled by t ypical n eu rolept ic drugs

1. C

th an n egat ive sym ptom s (alogia, avolit ion , a ect ive

2. D

ing, social w ith draw al, etc.). It seem s th at at yp ical n eu rolep -

3. A

t ics can con t rol n egat ive sym ptom s bet ter th an t yp ical on es.

at ten -

A−C, E All of t h ese are n egat ive sym ptom s of sch izop h re-

Learning objective: Describe the site of action of neurolepticsinduced tardive dyskinesia. 4. D Th e m any years of an t ipsych ot ic th erapy an d th e sign s an d sym ptom s of th e pat ien t in dicate th at sh e w as m ost likely su ffering from t ardive dyskin esia, an ext rapyram idal syn drom e

n ia an d are less w ell con t rolled by a t ypical n eurolept ic like h aloperidol.

Learning objective: Explain the m echanism of the autonom ic adverse e ects of clozapine.

cau sed by long-term n eu rolept ic t reat m en t . Th e cau se of th e

7. E Som e at yp ical n eu rolept ics su ch as clozapin e h ave sign i -

syn d rom e is u n kn ow n , bu t on e of th e m ost com m on ly ac-

can t blocking act ivit y on m u scarin ic receptors. Th e pat ien t’s

cepted hypoth eses relates th e syn drom e to a sen sit izat ion of

sym ptom s are classic an t im u scarin ic e ect s du e to clozap in e.

dop am in e receptors in th e cau date−p u t am en .

Blockade of ch olin ergic M 3 receptors in th e salivar y glan ds

A−C, E, F All of th ese st ru ct ures can be involved in th e ac-

cau ses dr y m ou th , in th e in test in al system cau ses a decrease

t ion s of n eu rolept ics, bu t th e p rim ar y dysfu n ct ion u n derlying

in peristalsis, an d in th e ciliar y m uscles cau ses a loss of ac-

tardive dyskin esia occu rs in th e st riat u m .

com m odat ion for n ear vision. A−D See correct an sw er explan at ion .

Learning objective: Explain the m echanism of chlorprom azineinduced urinary retention. 5. B Prost at ic hyperplasia is th e m ost com m on cause of di -

Learning objective: Describe the m ental e ects of neuroleptics in normally healthy individuals.

cu lt y in u rin at ion in aged m en . If a drug w ith an t im u scarin ic

8. C In n orm ally h ealthy p eople, n eu rolept ics do n ot cau se eu -

e ect s, su ch as ch lorp rom azin e, is given to a m an w ith p ros-

ph oria, bu t rath er a feeling of u np leasan t n ess an d discom fort ,

tat ic hyp erp lasia, th e m edicat ion can t rigger com p lete u ri-

that is, dysph oria. Neuroleptic-induced dysph oria can explain,

n ar y reten t ion due to relaxat ion of th e det ru sor m uscle of th e

at least in p ar t , w hy t h ese d r ugs h ave n o abu se liabilit y. In

bladder.

ad d it ion to t h eir an t ip sych ot ic e ect s, several n eu rolept ics

A Ch lorprom azin e h as n o e ect on th e urin e form at ion .

h ave pron oun ced sedat ive proper t ies (likely m ediated by th e

C Act ually, captopril can in crease diu resis by in h ibit ing

blockade of H1 an d 5-HT2A receptors), w h ich accoun t for th e

aldosteron e produ ct ion . D, E Th ese prazosin -in duced e ects w ould h ave facilitated, n ot h in dered, th e voiding of th e bladder.

sleep in ess in du ced by th ese drugs. A, B, D Th ese e ect s w ould be cau sed by p sych ost im u lan t d rugs, such as am ph et am in es. E Neurolept ics decrease delu sion s an d perseverat ion s th at

Learning objective: Outline the e cacy of neuroleptics against positive symptom s of schizophrenia 6. D Posit ive sym ptom s of sch izop h ren ia (delu sion s, h allu cin ations, disorganized speech, grossly disorganized behavior, etc.)

are classic psych ot ic sym ptom s.

Answers and Explanations: III-8 Neuroleptic Drugs 163 Learning objective: Describe neuroleptic-induced acute dystonia. 9. A Th e pat ien t’s assault ive beh avior an d persecutor y delu-

Learning objective: Describe the uses of at ypical neuroleptics in acute psychotic disorder.

sion s suggest th at h e w as m ost likely su ering from a sch izo-

12. C Th e beh avior an d th e sym ptom s of th e pat ien t in dicated

p h ren ic disorder, for w h ich h e received a n eurolept ic drug.

th at h e w as m ost likely a ected by an acu te p sych ot ic dis-

Th e n eu rologic sign s of th e p at ien t in d icated th at h e su ered

order. Risperidon e is an at ypical n eurolept ic w ith sedat ive

from acu te dyston ia, an ext rapyram idal sym ptom th at u su -

p ropert ies. Neurolept ics w ith sedat ive p rop er t ies are com -

ally occurs after few days of h igh -dose n eurolept ic th erapy.

m on ly u sed in t raven ou sly to sedate p at ien t s w ith acu te p sy-

Acu te dyston ias p resen t w ith a su dd en on set of brief abn or-

ch osis an d aggressive beh avior. At yp ical n eu rolept ics are

m al post u res, su ch as tongu e p rot ru sion , ocu logyris crisis,

som et im es p refer red over old er n eu rolept ics becau se of

tort icollis, an d un usual posit ion s of th e t run k an d lim bs. Th e

low er in ciden ce of ext rapyram idal adverse e ect s.

ext rapyram idal adverse e ect s of n eu rolept ics occu r m ore often w ith h igh -p oten cy d r ugs, su ch as h alop erid ol an d

A, B, D−F Th ese drugs are n ot u sed for th e acu te sedat ion of an aggressive pat ien t .

uph en azin e. B, D Sedative-hypn ot ic drugs, such as ben zodiazepin es an d eth an ol, h ave a n egligible risk of acute dyston ia. C, E An t idepressan t s, such as

Learning objective: Outline the therapeutic uses of clozapine in resistant schizophrenia.

u oxet in e, an d an xiolyt ics,

13. D Th e poor resp on se to several n eu rolept ic drugs an d th e

su ch as bu sp iron e, are n ot u sed to sedate an aggressive p a-

p revalen ce of n egat ive sym ptom s of sch izoph ren ia in d icate

t ien t an d h ave a n egligible risk of acu te dyston ia.

t h at t h e p at ien t is a can d id ate for clozap in e t h erapy.

F Clozapin e, a n eurolept ic, h as a m uch low er risk of ext ra-

Clozap in e is t h e on ly n eu rolept ic ap p roved by t h e U.S. Food

pyram idal adverse e ects com pared to h aloperidol an d cu r-

an d Dr ug Ad m in ist rat ion for t h e t reat m en t of resist an t

ren tly is n ot used to sedate an aggressive pat ien t .

sch izop h ren ia. A, B Becau se th e resp on se to p reviou s th erapy w as in ade-

Learning objective: Describe the neuroleptic-induced impairm ent of the therm oregulatory function.

qu ate, it is n ot usefu l to t r y oth er n eu rolept ics w ith act ivit y

10. B Th e abilit y of th e body to th erm oregu late is depen den t

or h aloperidol (i.e., u ph en azin e).

u pon an in tact hypoth alam ic th erm oregulator y cen ter. High d oses of n eurolept ics st rongly dim in ish th e th erm oregu la-

spect ra sim ilar to th at of ch lorp rom azin e (i.e., th ioridazin e) C, E Fluoxet in e an d lith iu m are n ot e ect ive in t reat ing sch izop h ren ia.

tor y fun ct ion of th e hypoth alam us. Moreover, clozapin e can m u scarin ic prop er t ies. Th e resu lt is p oikiloth erm ia, in w h ich

Learning objective: Outline the therapeutic uses of haloperidol in Huntington chorea.

th e body can n ot respon d to h eat or cold, an d p at ien t s be-

14. F Hu n t ington disease is a p rogressive n eu rod egen erat ive ge-

com e hypoth erm ic or hyperth erm ic, depen ding on th e sur-

n et ic disorder th at a ect s m uscle coordin at ion an d leads to

roun ding tem perat ure. Th erefore, in an environ m en t of h igh

cogn it ive declin e an d dem en t ia. Th e disease seem s to resu lt

tem perat u re, n eurolept ics can predispose to h eat st roke, es-

from fu n ct ion al overact ivit y in dopam in ergic n igrost riat al

p ecially if th e person is exercising, as in th is case.

p ath w ays, p erh ap s becau se of a de cien cy of a n eu rot ran s-

also in terfere perip h erally w ith sw eat ing becau se of it s an t i-

A, C−F Non e of t h e ot h er listed d r ugs cau se im p air m en t

m it ter (likely gam m a-am in obu t yric acid [GABA]) th at n or-

of th e hyp oth alam ic th erm oregu lator y cen ter at th erapeu t ic

m ally in h ibit s th ose p ath w ays. Th e t reat m en t of th e disease

d oses.

is su ppor t ive. Ch oreic m ovem en ts an d agit at ion can be p art ially su pp ressed by n eu rolept ics su ch as h aloperidol, p rob -

Learning objective: Describe the m ain contraindication of neuroleptics.

ably becau se of th eir an t idopam in ergic act ivit y. A−D Th ese drugs are in e ect ive in Hu n t ington disease.

11. B Th e sym ptom s of th e p at ien t in dicate th at sh e w as m ost

E Alth ough th e developm en t of ch orea seem s related to an

likely su ering from cataton ia related to a psych iat ric dis-

im balan ce of GABA t ran sm ission in th e basal ganglia (GABA

order. The use of traditional neuroleptics such as haloperidol

is m arkedly reduced in basal ganglia of pat ien ts w ith Hun -

is avoided in cataton ia because of th e possible developm en t

t ington disease), t reat m en t to su p p lem en t GABA act ivit y in

of n eu rolept ic m align an t syn drom e.

th e brain h as been in e ect ive.

A, C−F All of t h ese d r ugs h ave been u sed su ccessfu lly in t h e t reat m en t of cat aton ia.

164


Learning objective: Outline the therapy of an acute psychotic state in a patient with concom itant tonic-clonic seizures.

Learning objective: List the brain structure that m ost likely m ediated the therapeutic e ects of neuroleptics.

15. B Neurolept ics are th e preferred drugs for th e con t rol of

19. C Aripiprazole is an at ypical (also called secon d-gen erat ion )

acu te p sych ot ic p at ien t s w h o exh ibit aggressive an d violen t

n eurolept ic drug. Th e fact th at all n eurolept ics block dopa-

beh avior. Neu rolept ics w ith sign i can t sedat ive p rop er t ies,

m in e receptors su p p or ts th e hyp oth esis th at th eir an t ip sy-

su ch as ch lorp rom azin e, are u su ally p referred . Neu rolept ics

ch ot ic e ect m igh t be m ediated by decreased dopam in ergic

low er th e seizu re th resh old, so ep ilept ic pat ien ts are at in -

t ran sm ission in m esolim bic an d m esocort ical p ath w ays, t w o

creased risk of seizu res, as in th is case. For th ese pat ien ts, a

p ath w ays of th e brain dopam in ergic system involved in cog-

p rophylact ic t reat m en t is app rop riate. Becau se th e pat ien t

n it ion , st im u lu s processing, an d m ot ivat ion al beh avior.

h ad ton ic-clon ic seizures, an an t iconvulsan t dr ug e ect ive against grand m al epilepsy (e.g., lam otrigine) is appropriate. A, C−F All of t h e an t iseizu re d r ugs in t h ese d r ug p airs are m in im ally or n ot e ect ive in gen eralized ton ic-clon ic seizu res.

A, D Th ese t w o p ath w ays are dop am in ergic, bu t in terferen ce w ith th ese p ath w ays seem s m ore related to som e of th e adverse e ects, not to the therapeutic e ect of neuroleptics. B, E Dopam in ergic t ran sm ission is scarcely represen ted in th ese st r u ct u res.

Learning objective: Describe the therapeutic uses of uphenazine decanoate.

Learning objective: Explain the mechanism of neuroleptic-induced hyperprolactinemia.

16. C Th e clin ical scen ar io exem p li es a classic case of n on -

20. D Th e am en orrh ea an d galactorrh ea are adverse e ect s of

com p lian ce, w h ich is a p roblem in m any d iseases bu t is

n eurolept ics th at are related to th eir blockade of D2 recep -

esp ecially p rom in en t in p sych iat r ic d isord ers. Th e p at ien t

tors in th e an terior pit uitar y glan d. Dopam in e act s as a pro-

respon ded to n eurolept ic th erapy but relapsed because of

lact in -in h ibit ing factor by act ivat ing th ese receptors in th e

n on com plian ce. Non com plian t psych ot ic pat ien t s are good

pit uit ar y. W h en D2 receptors are blocked, prolact in secre-

can didates for dep ot drug p rep arat ion s adm in istered by IM

t ion in creases. High plasm a levels of p rolact in can resu lt in

inject ion ever y 1 to 2 w eeks. Neurolept ic depot preparat ion s

am en orrh ea, galactorrh ea, an d an ovu lat ion in w om en , an d

are available for u p h en azin e, h aloperidol, an d risperidon e.

azoosp erm ia, im p oten ce, an d gyn ecom ast ia can develop in

Because uph en azin e w as e ect ive an d w ell tolerated, th ere

m en. All t ypical neuroleptics can cause the above-m entioned

is n o n eed to sw itch to an oth er n eurolept ic.

sym ptom s, w h ereas at yp ical n eu rolept ics are m in im ally


associated w ith hyperprolact in em ia. A−C, E See correct an sw er explan at ion .

Learning objective: Outline treatm ent of acute psychosis in a suicidal patient.

Learning objective: Describe neuroleptic-induced akathisia.

17. E Th e sym ptom s of th e p at ien t in dicated th at h e w as m ost

21. D Akath isia, or u n con t rolled m otor restlessn ess, is on e of th e

likely su ering from an acu te p sych ot ic disorder. Clozapin e

dose-depen dent extrapyram idal disorders th at can be caused

is n ot a drug of ch oice for rst-episode pat ien t s, bu t it can be

by n eu rolept ics. Th ese disorders occur m ost frequen tly w ith

a

bu t yrop h en on es an d th e pip erazin e side-ch ain ph en oth i-

rst -lin e d r ug for a p at ien t w it h a h istor y of su icidalit y,

com orbid su bst an ce abu se, an d sign i can t n egat ive p sy-

azin es su ch as

ch ot ic sym ptom s, as in th is case.

su bject ive feelings of restlessn ess an d object ive sign s of pac-


u p h en azin e. Akath isia is ch aracterized by

ing, rocking, an d in abilit y to sit or stan d in on e p lace for exten ded periods of t im e. Th e disorder develops w ith in days to

Learning objective: Explain the m echanism of olanzapine-induced constipation.

w eeks after in it iat ing a n eu rolept ic th erapy.

18. E Neu rolept ics can h ave sign i can t an t im u scarin ic an d an t i-

be cau sed by n eu rolept ics, bu t th e sym ptom s are n ot th ose

seroton ergic p rop er t ies in both th e cen t ral an d au ton om ic n er vou s system s. At ypical n eurolept ics su ch as olan zapin e can cau se a su bst an t ial blockade of m u scarin ic an d seroton ergic receptors in th e gut , w h ich w ould explain th e con st ip at ion cau sed by th is drug. A−D In all of th ese item s, at least on e of th e m en t ion ed receptors is m in im ally involved in gast roin test in al m ot ilit y.

A, C, F Th ese are oth er ext rapyram idal disorders th at can exh ibited by th e pat ien t . B Rarely, n eu rolept ics can cause ton ic-clon ic seizu res bu t n ot com plex par t ial seizu res. E Neurolept ics can relieve cat aton ic sign s of sch izoph ren ic p at ien ts.

Answers and Explanations: III-8 Neuroleptic Drugs 165 Learning objective: Describe haloperidol-induced pseudoparkinsonism .

n ia, if given in overdose or in com bin at ion w ith oth er seroto-

22. B Th e sign s an d sym ptom s of t h e p at ien t in d icate t h at h e

n ergic drugs, th ey could cau se seroton in syn drom e, w h ich

w as m ost likely su ering from n eu rolept ic-in du ced p seu dop arkin son ism . Th e syn d rom e is cau sed by blockade of D2 receptors in th e caudate−p ut am en an d is m ore likely w ith n eurolept ics th at h ave th e h igh est a

n it y for D2 receptors,

su ch as u p h en azin e an d h alop eridol.

D, F Alth ough th ese drugs are n ot u sed to t reat sch izoph re-

h as sign s an d sym ptom s sim ilar to th ose of NMS.

Learning objective: Describe the cardiac adverse e ect s of thioridazine. 25. B Becau se of h er disease, th e w om an w as m ost likely u n der

A, D, E Th ese n eu rolept ics rarely cau se p seudop arkin son ism .

n eurolept ic th erapy. Neuroleptics (m ainly thioridazine and clozapine) can cause

C Metoclopram ide can block D2 receptors but is n ot used to t reat sch izoph ren ia.

ECG ch anges, in cluding prolongat ion of QT in ter val, w h ich can lead to p olym orp h ic ven t ricu lar t achycardia. Th e th ioridazin e e ect on QT in ter val is dose-related an d h as led to a

Learning objective: Outline the use of neuroleptics in case of delirium .

black box w arn ing in th e produ ct labeling ap proved by th e

23. B Th e sym ptom s of th e pat ien t in dicate th at h e w as m ost

A, C, D Trazodon e, am it ript ylin e, an d p aroxet in e can in -

likely su ering from delirium , a severe n europsych iat ric

crease th e risk of p olym orp h ic ven t ricu lar t achycardia u n d er

syn drom e w ith core feat u res of acu te on set an d

cer t ain con dit ion s, but th ey are n ot an t ipsych ot ic drugs an d

u ct u at ing

course, at ten t ion al de cits, an d gen eralized severe disorgan izat ion of beh avior. Neurolept ics are com m on ly used drugs for delirium , alth ough th ey are n ot approved by th e U.S. Food

U.S. Food an d Drug Adm in ist rat ion .

cu rren tly are n ot u sed in sch izop h ren ia. E, F Lith ium an d lorazepam do n ot cause prolongat ion of th e QT in ter val.

an d Dr ug Ad m in ist rat ion for t h is syn d rom e. Th ose w it h for older pat ien t s. Neurolept ics can lessen agit at ion an d psy-

Learning objective: Describe the postural hypotension induced by at ypical neuroleptics.

ch ot ic sym ptom s, bu t t h ey d o n ot cor rect t h e u n d erlyin g

26. B Th e sym ptom s of th e p at ien t in dicate th at sh e w as m ost

p roblem , an d , t h ough rarely, t h ey m ay even exacerbate

likely su ering from p ost ural hypoten sion . At ypical n eu ro-

d elir iu m .

lept ics (w ith th e except ion of clozapin e) h ave becom e rst-

low an t ich olin ergic act ivit y are m ore appropriate, especially

A Clozapin e is n ot a good ch oice because of it s relevan t

lin e agen ts for th e t reat m en t of an acu te p sych ot ic ep isode,

r isk of agran u locytosis an d it s relevan t an t ich olin ergic

m ain ly becau se of few or n o acu tely occu rring ext rapyram i-

p ropert ies.

dal sid e e ect s. Most at yp ical n eu rolept ics h ave sign i can t

C Ben zod iazepin es can m an age agit at ion but can w orsen con fusion an d can cause delirium in older people. Th ey are u sed m ain ly w h en delirium is caused by alcoh ol w ith d raw al. D−F Th ese drugs are n ot e ect ive for delirium .

blocking act ivit y on α 1 receptors, so post u ral hypoten sion is a frequen t adverse e ect , as in th is case. A Haloperidol is used to t reat an acute psych ot ic episode, bu t post u ral hypoten sion is a rare adverse e ect , as it h as m in im al blocking act ivit y on α 1 receptors. C−F Th ese drugs are devoid of an t ipsych ot ic propert ies.

Learning objective: Describe the neuroleptic malignant syndrome. syn drom e (NMS), a rare bu t p oten t ially leth al com p licat ion

Learning objective: Describe the sexual dysfunction caused by thioridazine.

t h at m ay p resen t in a su d d en , u n p red ict able fash ion . Th e

27. D Th ior idazin e is recogn ized as t h e m ost com m on cau se

et iology of NMS is u n kn ow n , bu t a p rop osed m ech an ism

of n eu rolept ic-in du ced sexu al dysfu n ct ion . Sexu al adverse

suggest s th at a n eu rolept ic-in d u ced, excessively rapid block-

e ect s, h ow ever, h ave also been rep or ted w ith oth er t ypical

ade of dop am in ergic receptors in th e d ien cep h alon m ay play

an d at yp ical n eu rolept ics. Th e cau se of n eu rolept ic-in du ced

a role. It is u n cer t ain w h eth er NMS is a sp eci c en t it y or a

sexual dysfunction is related to a num ber of factors, including

varian t of m align an t hyperth erm ia. Th is lat ter disorder is

hyp erprolact in em ia (via dopam in e blockad e), α -adren ergic

m ost com m on ly associated w ith adm in ist rat ion of h aloge-

an d m u scarin ic blockade, an d sedat ive e ect s.

24. C Th e clin ical pict ure is t ypical of n eurolept ic m align an t

n ated in h alat ion al an esth et ics an d depolarizing m uscle re-

A Because h aloperidol caused sym ptom s of pseudopar-

laxan ts. It h as a sh or ter d u rat ion (3−5 days) th an NMS (5−30

kin son ism , th e prescript ion of an oth er n eurolept ic w ith a

days).

h igh poten t ial for ext rapyram idal side e ect s is un likely.

A, B, E Non e of th ese drugs cau se NMS or m align an t hyp er th erm ia.

B, C, E, F All of th ese drugs can cause sexual dysfun ct ion , bu t th ey are devoid of an t ipsych ot ic p rop er t ies an d are n ot u sed to t reat sch izoph ren ia.

166


Learning objective: Describe the adverse e ect s of olanzapine. 28. C Olan zap in e w as m ost likely p rescribed becau se it h as sig-

Learning objective: Describe the hem atological adverse e ect s of clozapine.

n i can t sedat ive e ects. Th e drug, h ow ever, also h as sign i -

30. A Th e low w h ite blood cell coun t an d th e low n eut roph il

can t m u scarin ic-blocking act ivit y an d th erefore can cau se

p ercen tage in dicate th at th e m an w as m ost likely su ering

u rin ar y reten t ion if given to a m an w ith prost at ic hyper-

from drug- in du ced agran u locytosis. Agran u locytosis is th e

p lasia, as in th is case.

m ost fat al adverse drug react ion , accou n t ing for 26% of all

A, B Th ese n eu rolept ics h ave m in im al an t im u scarin ic act ivit y. D−F Th ese drugs h ave m ore or less pron oun ced an t im u scarin ic act ivit y bu t are devoid of an t ip sych ot ic proper t ies.

d rug-related death s. Clozapin e can cau se agran u locytosis in abou t 0.8% of p at ien t s (a rate low er th an th e origin al est im ate of 1 to 2%). Th e on set of th e disorder is variable, as it can occu r a few days after st art ing th e t reat m en t or even several years after a daily ch ron ic t reat m en t . How ever, th e

Learning objective: Describe neuroleptic-induced gynecom astia. 29. C Th e h istor y an d th e sym ptom s of th e pat ien t in dicate th at h e w as m ost likely su ering from gyn ecom ast ia due to a n eurolept ic w ith D2 an t agon ist act ivit y, such as h alop eridol. By blocking D2 receptors, n eurolept ics preven t th e in h ibitor y e ect of dopam in e on prolact in secret ion , th us causing hyperprolactinem ia. High prolactin plasm a levels can in turn

rst 6 m on th s of clozapin e th erapy is th e p eriod of greatest risk. Discon t in u at ion of th e drug u su ally resu lts in correct ion of n eu t rop h il cou n t w ith in 30 days. B, D Ph en oth iazin es can cause agran ulocytosis, but th e risk is on ly 1/10 th at of clozapin e. C, E, F Agran ulocytosis due to th ese drugs can occur, but it is except ion ally rare.

cau se am en orrh ea/galactorrh ea in w om en an d gyn ecom ast ia in m en .

NEUROLEPTIC DRUGS Answ er key

A Clozapin e has low blocking act ivit y on D2 receptors an d th erefore does n ot u su ally cau se hyperp rolactin em ia. B, D−F Th ese dr ugs are n ot u sed to t reat p aran oid sch izop h ren ia.

1. 2. 3. 4. 5.

C D A D B

6. 7. 8. 9. 10.

D E C A B

11. 12. 13. 14. 15.

B C D F B

16. 17. 18. 19. 20.

C E E C D

21. 22. 23. 24. 25.

D B B C B

26. 27. 28. 29. 30.

B D C C A

Answers and Explanations: III-9 Drugs for Depressive and Anxiet y Disorders Questions 1−5

and/or noradrenergic neurotransm ission, as chronic treatm ent

1. A

w ith these drugs increases the availabilit y of central seroton in

2. F

an d /or n orep in ep h r in e. Com p ellin g evid en ce suggest s t h at

3. D

su stain ed sign aling via th ese n eu rot ran sm it ters in creases th e

4. A

expression of speci c dow n st ream gen e produ ct s, part icu -

5. H

larly BDNF. Th is app ears to be th e u lt im ate m ech an ism of act ion of an t id ep ressan t s.

Learning objective: Describe the leading hypothesis about the mechanism of action of antidepressant drugs. 6. C A leading hypoth esis of depression suggest s th at th e disease is associated w ith a loss of n eu rot rop h ic su pp or t in cor t ical areas, such as th e h ippocam pus. Th e n er ve grow th factors, su ch as brain -derived n eu rot rop h ic factor (BDNF), are crit ical for th is n eurot roph ic support , th at is, for th e regulat ion of n eural plast icit y an d n eu rogen esis. All drugs used to t reat depression sh are, at som e level, prim ar y e ect s on seroton ergic

A Mon oam in e oxidase in h ibitors, but n ot oth er an t idepressan t s, in h ibit m on oam in e m et abolism . B Act u ally, d ow n regu lat ion , n ot u p regu lat ion , of cen t ral ad ren oceptors w as an earlier hypoth esis of th e m ech an ism of act ion of an t idepressan t s. D According to th e n eu rot roph ic hypoth esis, an t idepressants should increase, not decrease, hippocam pal neurogenesis. E Act u ally, som e st u dies suggest th at glut am ate an t agon ists, n ot agon ists, could h ave a role as an t idepressan ts.

Answers and Explanations: III-9 Drugs for Depressive and Anxiet y Disorders 167 Learning objective: Describe poisoning with tricyclic antidepressants.

in h ibit t h e seroton in t ran sp or ter h ave been sh ow n to be

7. E Th e h istor y an d sign s of th e pat ien t suggest th at h e took a

able to act w ith this m echanism are SSRIs, serotonin−norepi-

toxic dose of a t ricyclic an t idepressan t . Th ese drugs h ave

n eph rin e reuptake in h ibitors (SNRIs), an d t ricyclic an t ide-

p ron oun ced an t im uscarin ic act ivit y (m ydriasis an d t achy-

pressan t s. SSRIs are cu rren tly con sid ered rst-lin e t reat m en t

cardia) an d an t iadren ergic act ivit y (low blood p ressu re) an d

for obsessive-com pulsive disorders. Tricyclic antidepressants

p rolong th e QT in ter val on ECG by a quin idin e-like act ion .

(m ain ly clom ipram in e) are u sed as secon d-ch oice drugs.

e ect ive in obsessive-com p u lsive disorders. Classes of drugs


A−D, F Poison ing by th ese drugs does n ot cau se all th e sign s exh ibited by th e p at ien t .

Learning objective: Describe the adverse e ect of tricyclic antidepressants.

Learning objective: Outline the appropriate therapy for depression and insom nia associated with a m alignant disease. 11. C Th e p at ien t ’s sym ptom s suggest t h at sh e w as su er in g

8. C Am it ript ylin e is a t ricyclic an t idep ressan t drug. All t ricy-

from d ep ression an d an xiet y, likely becau se of t h e t u m or

clic an t idepressan ts block α 1 -adren oceptors an d th erefore

d iagn osis. Pan creat ic carcin om a is a t ype of can cer m ost fre-

rst

qu en tly associated w ith depressive sym ptom s. Because th e

w eek of t reat m en t . Drow sin ess is an oth er com m on adverse

p at ien t is elderly an d h ad been su ering from an arrhyth -

e ect , m ost likely d u e to cen tral m u scarin ic an d h ist am in ic

m ia, t ricyclic an t idepressan t s are con t rain dicated. Select ive

receptor blockade. At least part ial toleran ce usually develop s

seroton in reu pt ake in h ibitors (SSRIs) su ch as paroxet in e are

to auton om ic e ect s, so th e sym ptom s ten d to dim in ish over

best su ited for d ep ressed pat ien ts of old er age w ith con sid-

t im e.

erable at ten dan t an xiet y, as in th is case. Becau se th e pat ien t

can cau se p ost u ral hyp oten sion , esp ecially du ring th e

A, B, D−F Th ese d rugs ver y rarely cau se p ost u ral hypo-

w as su ering from in it ial in som n ia, a sh ort-act ing hyp n ot ic su ch as zalep lon t aken before bedt im e is ap p rop r iate, as

ten sion .

SSRIs m ay cau se in som n ia. A, B See correct an sw er explan at ion .

Learning objective: Explain the m echanism of action of serotonin− norepinephrine reuptake inhibitors (SNRIs). 9. C Ven lafaxin e is cu rren tly a rst-lin e agen t for an xiet y disord ers. Th e drug blocks both n orepin eph rin e an d seroton in t ran sp or ters. Th e resu lt in g d ecreased reu pt ake of t h ese

D, E Neurolept ics are devoid of an t idepressive proper t ies.

Learning objective: Explain the m echanism of tricyclic-induced postural hypotension.

n eu rot ran sm it ters in creases th eir availabilit y in th e syn apt ic


cleft of cen t ral n er vou s system n eu ron s. Th e relat ion sh ip

su ering from p ost u ral hypoten sion . Tricyclic an t id ep res-

bet w een th is m olecu lar m ech an ism of act ion an d th e th era-

san t s su ch as im ip ram in e can cau se several adverse e ects

peut ic e

cacy of th e drug in an xiet y disorders is still un cer-

d ue to blockade of som e auton om ic receptors. Blockade of α 1

tain, but contem porar y hypotheses im plicate dysregulation of

adrenoceptors can result in substantial postural hypotension. A−C, E, F See correct an sw er explan at ion .

adren ergic an d/or seroton ergic system s in ch ron ic an xiet y. A Tricyclic an t idepressan t s su ch as am it ript ylin e also block m on oam in e t ran sporters, bu t th ey are n ot u sed as an t ian xiet y agen t s. B Cit alopram blocks th e seroton in t ran spor ter bu t n ot th e n orepin eph rin e t ran sporter. D Ben zodiazepin es such as lorazepam do n ot alter m on oam in e reu pt ake. E, F Th ese drugs block on ly n orepin eph rin e t ran sporter

Learning objective: Describe the use of paroxetine in treating social anxiet y disorder. 13. E Th e p at ien t w as m ost likely su ering from a social an xiet y d isorder (SAD). Several t rials h ave p rovided eviden ce of th e e

cacy of p h ar m acot h erapy w it h select ive seroton in re-

u pt ake in h ibitors (SSRIs) or seroton in −n orep in ep h r in e reu pt ake in h ibitors (SNRIs) in SADs. Ap p roxim ately on e

ft h

(bupropion ) or seroton in t ran spor ter (t razodon e) an d are

of patients w ith SAD also su er from an alcohol use disorder,

n ot u sed as an t ian xiet y agen t s.

as in th is case. Paroxet in e sign i can tly redu ces social an xiet y an d decreases th e frequen cy of alcoh ol use in pat ien ts

Learning objective: Explain the m echanism of action of selective serotonin reuptake inhibitors (SSRIs).

w ith both disorders.

10. C Th e pat ien t’s sym ptom s in dicate th at sh e w as m ost likely

as last-lin e agen t s in p at ien t s w ith SAD.

su ering from an obsessive-com p u lsive disorder. Drugs th at

A Ben zodiazepin es such as diazepam sh ould be reser ved B−D, F Th ese drugs are n ot e ect ive in SAD.

168


Learning objective: Describe poisoning with tricyclic antidepressants.

A−C, E, F Th ese drugs are all m in im ally or n ot e ect ive in n europath ic pain .

14. F Tricyclic an t idepressan t poison ing m ay p rodu ce any of th ree m ajor toxic syn drom es: • Antich olinergic syn drom e: sedation, delirium , tachycardia, m ydriasis, dr y m u cou s m em bran es, hyp er th erm ia, con st ip at ion , an d u rin ar y reten t ion

Learning objective: Explain the m echanism of action of am itript yline. 17. A Am it ript ylin e is a t ricyclic an t idepressan t drug. Drugs from th is class are th e m ost p ow erfu l in h ibitors of n orepi-

• Card iovascu lar syn drom e: hypoten sion , sin u s t achycardia

n eph rin e an d seroton in reupt ake in to presyn apt ic term in als.

w ith prolongat ion of QT in ter vals, torsade de poin tes

Th e resu lt in g in creased availabilit y of t h ose n eu rot ran s-

(rare). Bradyarrhyth m ias (various degrees of at rioven t ric-

m it ters in th e syn apt ic cleft m ost likely m ediates th eir an t i-

u lar block) can occur in severe poison ing an d carr y a p oor

d epressan t p rop er t ies. Am it ript ylin e can cau se hypersom n ia

progn osis. Th ey are du e to th e qu in idin e-like act ivit y

in u p to 88% of pat ien ts taking th e dr ug.

com m on to all t ricyclic an t idepressan ts, w h ich can severely im pair cardiac con duct ion . • Convu lsing syn d rom e: seizu res m ay be recu r ren t or persisten t . Depen ding on th e dose, pat ien ts m ay experien ce som e or all of th ese toxic e ect s. Th e pat ien t’s com a in dicates th at th e poison ing w as severe an d m ost likely in clu ded all th ree toxic syn drom es. A−E Tr icyclic an t id ep ressan t s ten d to cau se sym ptom s op p osite to th ose listed .

B Trazodon e can exert a w eak blockade on seroton in reu pt ake bu t h as n o e ect on n orepin eph rin e reuptake. C Bupropion can exer t a w eak blockade on n orepin eph rin e reu ptake bu t h as n o e ect on seroton in reu ptake. D, E Cit alopram an d ser t ralin e are select ive seroton in reu pt ake in h ibitors.

Learning objective: Describe the m ain adverse e ects of selective serotonin reuptake inhibitors/serotonin−norepinephrine reuptake inhibitors (SSRIs/SNRIs). 18. C Most an t id ep ressan t s can cau se sexu al dysfu n ct ion , bu t

Learning objective: Explain the m echanism of paroxetine-induced diarrhea. 15. B By blocking seroton in reu ptake, select ive seroton in reu pt ake in h ibitors (SSRIs) such as paroxet in e in crease seroton in availabilit y at seroton ergic syn apses in both th e cen t ral an d en teric n er vou s system s. Seroton in act ivat ion of seroton in receptors (m ain ly 5-HT2A) is kn ow n to in crease in test in al perist alsis, th us causing diarrh ea, w h ich occurs in up to 20% of p at ien t s t aking SSRIs. A, C−F Paroxet in e does n ot cau se th ese act ion s. Moreover, all of these act ions w ould lead to const ipation, n ot diarrhea.

Learning objective: Describe the therapeutic uses of serotonin− norepinephrine reuptake inhibitors (SNRIs) in neuropathic pain. 16. D Th e pat ien t’s h istor y an d sym ptom s suggest h e w as su ering from ch ron ic ph an tom lim b pain , a pain th at is referred to a lim b th at n o longer exists. Ph an tom lim b pain is a t ype of n europath ic pain , w h ich is caused by dam age to n eural st ru ct u res. Un like n ocicept ive p ain , w h ich is e ect ively alleviated by n on steroidal an t iin am m ator y drugs (NSAIDs) an d op ioids, n eu ropath ic pain often resp on ds p oorly to th ese d rugs bu t is relieved by an t idepressan t s, in cluding t ricyclic an t idep ressan ts an d SNRIs. Ph an tom lim b p ain is som et im es ver y di cu lt to t reat , but ven lafaxin e an d duloxet in e are often e ect ive an d are th e drugs m ost frequen tly used. Th ey are equ ivalen t to t ricyclics bu t h ave th e su bst an t ial advan t age of few er adverse e ect s.

it s in ciden ce seem s th e h igh est w ith SSRIs/SNRIs (m ain ly p aroxet in e an d

u oxet in e) an d th e low est w ith bu p rop ion

an d m ir t azap in e. Sexu al dysfu n ct ion seem s to be p rim arily related to th e in creased act ivit y of th e cen t ral seroton ergic system , as seroton in is m ain ly an in h ibitor y n eu rot ran sm itter in th e cen t ral n er vous system . A, E, F Lith iu m , bu prop ion , an d m irt azap in e rarely cau se sexu al dysfu n ct ion . B Tricyclic antidepressants such as am itript yline frequen tly cau se sexu al dysfu n ct ion bu t are con t rain d icated in th is pat ien t becau se th ey can cau se card iac arrhyth m ias in p at ien t s at risk (p at ien t s w ith a p reviou s episode of ven t ricu lar arrhyth m ia h ave a ver y h igh risk of recu rren t arrhyth m ia). D Ch lorprom azin e is n ot used for depressive disorder an d m ay cau se arrhyth m ias in p at ien t s at risk.

Learning objective: Describe the serotonin syndrom e due to selective serotonin reuptake inhibitors/serotonin−norepinephrine reuptake inhibitor (SSRIs/SNRIs). 19. C Th e h istor y, sign s, an d sym ptom s of th e pat ien t in d icate th at sh e w as m ost likely su ering from seroton in syn d rom e. Th is disorder is a rare bu t poten t ially fat al in teract ion th at can be cau sed by several d rugs eith er alon e or in com bin at ion , w h en given in h igh doses. Th ese in clu d e an t id ep ressan t s, op ioids, p sych ost im u lan ts, t ript an s, psych edelics, an d h erbs (e.g., St . Joh n’s w or t , gin sen g, an d n u t m eg). Th e com bin at ion of t w o drugs th at en h an ce seroton in t ran sm ission (i.e., SSRIs/SNRIs w ith m onoam ine oxidase inhibitors or w ith

Answers and Explanations: III-9 Drugs for Depressive and Anxiet y Disorders 169 t ricyclic an t idep ressan ts) can be par t icu larly dangerou s. Th e

in th is case. Bu prop ion is u n ique am ong all cu rren tly avail-

syn drom e involves m en tal, au ton om ic, an d n eu rologic dis-

able antidepressants, as it has negligible activit y on seroton in

orders of sudden onset less than 24 hours after the beginning

n eurot ran sm ission . It m ost likely acts by en h an cing n orepi-

of t reatm en t or of an overdose. For m ild cases, discon t in ua-

n eph rin e an d dop am in e act ivit y.

t ion of th e o en ding dr ug is th e on ly n eed ed t reat m en t . For m ore serious cases, th erapy in cludes ben zodiazepin es for

B Methylp h en idate blocks th e reu ptake of catech olam in es bu t is n ot act ive as an an t idep ressan t .

agit at ion an d som at ic e ects, seroton in an tagon ists (cyp ro-

C−E Th ese d rugs are som et im es used for an t idepressan t

h ept adin e) or at ypical n eurolept ics w ith seroton in -blocking

augm en t at ion th erapy, but th ey act th rough d i eren t

act ivit y (e.g., olan zap in e), β-blockers for t achycard ia an d

m ech an ism s.

au ton om ic in st abilit y, an d dan t rolen e for hyper th erm ia. A, B, D−F Th ese d isord ers d o n ot cau se t h e sign s an d sym ptom s repor ted by th e pat ien t .

Learning objective: Describe the m ain therapeutic uses of m onoamine oxidase inhibitors. 23. A Ph en elzin e is a n on select ive m on oam in e oxidase in h ibitor

Learning objective: Outline the therapeutic use of selective serotonin reuptake inhibitors (SSRIs) in m ajor depressive disorder.

(MAOI). Th ese drugs are rarely prescribed today because of

20. B W h en given in equ ivalen t doses, all an t idep ressan ts are

an d dr ug−food in teract ion s. How ever, for th e t reat m en t of

abou t equ ally e ect ive in th e gen eral dep ressed pat ien t p op -

at yp ical dep ression , MAOIs are am ong t h e m ost e ect ive

u lat ion , so th e ch oice of th e dr ug in a speci c pat ien t is in u -

agen t s available an d are st ill p rescr ibed for p at ien t s w it h

en ced m ain ly by th e pat ien t’s m edical h istor y, th e p resen t ing

th is depressive su bt yp e, u su ally after failu re of a select ive

sym ptom s, an d con t rain d icat ion s. Select ive seroton in re-

seroton in reupt ake in h ibitor (SSRI) th erapy, as in th is case.

frequ en t adverse e ect s an d th e risk of seriou s dr ug−drug

u pt ake in h ibitors (SSRIs) such as uoxet in e are curren tly th e

B En t acapon e act s by in h ibit ing an en zym e involved in

m ost u sed drugs for d ep ression an d are especially su ited for

n eurot ran sm it ter m etabolism but is an an t iparkin son , n ot

th is p at ien t becau se of th e p resen ce of con com itan t sym p -

an an t id ep ressan t , drug.

tom s of an xiet y. Moreover, in th is p at ien t:

C−F Th ese an t id ep ressan t d r ugs d o n ot act by en zym e

A Tricyclic an t idepressan ts are con t rain dicated because of

in h ibit ion .

th e exert ion al angin a. th ey h ave pron ou n ced sedat ive p rop er t ies, an d th e pat ien t is

Learning objective: Outline the therapeutic uses of selective serotonin reuptake inhibitors (SSRIs) in obsessive-compulsive disorder.

su ering from hyp ersom n ia.

24. C Th e p at ien t’s sym ptom s suggest th at h e is su ering from

C, D Trazodon e an d m ir tazapin e are n ot in dicated because

E, F Lith ium an d h aloperidol are devoid of an t idepressan t act ivit y.

an obsessive-com p u lsive disorder. SSRIs are cu rren tly

rst-

lin e agen t s for obsessive-com p u lsive d isord ers, an d t h eir e ect iven ess gives su p p or t to t h e hyp ot h esis t h at t h ese

Learning objective: Describe the m olecular m echanism of action of m irtazapine. 21. D Mirt azap in e can block p resyn apt ic α 2 receptors, th u s in creasing th e release of both n orep in ep h rin e an d seroton in .

d isorders are due to a dysfun ct ion in cen t ral seroton ergic t ran sm ission . A, B, D−F Th ese drugs h ave m in im al or n o e

cacy in t reat-

ing obsessive-com pu lsive disord ers.

In addit ion , it can also block seroton in (5-HT2A an d 5-HT2C) receptors. All of t h ese act ion s p robably con t r ibu te to t h e an t idep ressan t e ect . Th e dr ug is a secon d-ch oice agen t in dep ressive disorders, bu t som et im es it is h igh ly e ect ive. A−C, E, F See correct an sw er explan at ion .

Learning objective: Describe the m ain adverse e ects of selective serotonin reuptake inhibitors/serotonin−norepinephrine reuptake inhibitors (SSRIs/SNRIs). 25. B Abru pt discon t in u at ion of SSRIs or SNRIs can cau se a variet y of sym ptom s th at can be dist ressing. Th ese in clude dizzi-

Learning objective: Describe the mechanism of action of bupropion.

n ess, nausea an d vom iting, ulike sym ptom s, irritabilit y, and

22. A Becau se th e pat ien t obt ain ed part ial relief from

u oxet in e

an xiet y. Sym ptom s usu ally em erge 1 to 3 days after th e last

th erapy, a reason able n ext step is to add a secon d drug to th e

d ose. Paroxet in e an d sert ralin e are m ost likely to cau se th e

t reat m en t , rath er th an ch anging th e an t idep ressan t . Bu p ro-

d iscon t in uat ion syn drom e, an d th ey sh ou ld be t ap ered over

p ion h as been u sed as augm en tat ion th erapy for m any years,

several w eeks.

an d it s u se is su p p or ted by several t r ials. Pat ien t s t akin g u oxet in e w h o con t in u e to com p lain of fat igu e an d hypersom n ia are good can didates for bu p rop ion augm en t at ion , as

A, C−F Th ese disorders do n ot cau se th e sym ptom s rep orted by th e p at ien t .

170


Learning objective: Describe the m ain drug interactions with selective serotonin reuptake inhibitors (SSRIs).

of sexual dysfun ct ion in m ales in clu de erect ile dysfun ct ion ,

26. D Th e pat ien t’s sym ptom s in dicate th at h e w as su ering

or com plete an orgasm ia.

from an ext rapyram idal adverse e ect . SSRIs are in h ibitors

p riap ism , delayed ejacu lat ion , decreased libido, an d p ar t ial A, C−F SNRIs do n ot cau se th ese sym ptom s.

of th e cytoch rom e P-450 en zym es an d can in crease th e acoxet in e is a p oten t in h ibitor of t h e CYP2D6 isozym e, w h ich

Learning objective: Describe the adverse e ect of tricyclic antidepressants.

is t h e m ain isozym e t h at m et abolizes m etoclop ram id e.

30. D Th e sym ptom s of th e pat ien t in d icate th at h e w as su er-

Th erefore, th e dop am in e-blocking act ion s of m etoclop ra-

ing from obst ru ct ive u ropathy, m ost likely du e to prostat ic

m ide are en h an ced, leading to ext rapyram idal e ect s. More-

hyp erplasia. Drugs w ith an t im u scarin ic p ropert ies, su ch as

over, SSRIs can in directly a ect d op am in ergic t ran sm ission .

am it ript ylin e, can precip itate com p lete an u ria in pat ien ts

In fact , seroton in an d dopam in e appear to h ave an inverse

w it h p rost at ic hyp er p lasia, as t h ese p at ien t s already h ave

relat ion sh ip in cer t ain areas of th e brain , w h ereby st im u -

a u ret h ral obst r u ct ion , an d t h e d r ug in h ibit s blad d er

lat ion of cen t ral seroton in receptors resu lt s in in h ibit ion of

con t ract ion .

t ivit y of oth er drugs given con com it an tly. Speci cally, par-

d op am in ergic t ran sm ission . Th e SSRI−m etoclop ram id e in -

A−C, E None of these drugs have antim uscarinic properties.

teract ion is w ell kn ow n an d occurs rapidly, w ith in h ours of m etoclopram ide adm in ist rat ion , as in th is case. A−C, E, F Th e in teract ion of th ese drugs w ith m etoclopram ide is n egligible.

Learning objective: Describe the latency of e ect of antidepressant m edications. 31. B Th e pat ien t m ost likely st ar ted a th erapy w ith a select ive serotonin reuptake in hibitor (SSRI), such as paroxetine, drugs

Learning objective: Describe the use of selective serotonin reuptake inhibitors (SSRIs) in treating panic disorders.

th at are cu rren tly th e m ost com m on ly u sed an t idepressan t s.

27. E Th e p at ien t’s sym ptom s suggest th at sh e w as m ost likely

tern of th erapeut ic respon se. Typ ically, pat ien t s are in form ed

su ering from a pan ic disorder. Th e disease resp on ds to a

th at app roxim ately 2 to 6 w eeks m u st elap se before th ey w ill

variet y of p sych ot rop ic drugs, in clu ding SSRIs, ben zodiaze-

experien ce any th erapeut ic ben e t . How ever, research ers in

p in es, an d t r icyclic an t idep ressan t s. SSRIs/SNRIs are t h e

th e eld con sider th is a con ser vat ive est im ate, an d m ore rig-

cu r ren t

orou s st udies h ave led to th e con clusion th at pat ien t s can

rst -lin e agen t s for t h e ch ron ic t reat m en t of t h ese

d isorders. A−D, F Th ese drugs are n ot e ect ive in t reat ing pan ic d isorders.

All an t idepressan t m edicat ion s h ave a sim ilar delayed pat-

exh ibit som e im provem en t during th e rst 2 w eeks of t reatm en t an d a m axim u m im provem en t du ring th e fou rth w eek. Despite a variet y of exp lan at ion s for th is delay, th ere is n o con sen sus, an d th e exact reason rem ain s un kn ow n .

Learning objective: Outline the therapeutic e cacy of selective serotonin reuptake inhibitors (SSRIs) in treating bulim ia nervosa.

A Tricyclic an t idepressan t s are absolutely con t rain dicated in p at ien t s w ith at rioven t ricu lar block.

28. A Th e pat ien t’s h istor y an d sym ptom s in dicate th at sh e w as

C Bu p rop ion can cau se ar rhyt h m ias an d can in crease

a ected by bu lim ia n er vosa, a ch ron ic disorder w ith m u l-

blood p ressu re. Th erefore, it sh ou ld be avoided in a pat ien t

t iple ep isodes of relap se an d rem ission th at u su ally occu rs

w ith a recen t m yocardial in farct ion .

in late adolescen ce. If m edicat ion s are required, an t idepres-

D Ph en elzin e is a n on select ive an d irreversible m on o-

san t s are con sidered drugs of ch oice for bu lim ia n er vosa.

am in e oxidase in h ibitor. Th ese drugs sh ou ld be avoided in

Select ive seroton in reu pt ake in h ibitors (SSRIs) are th e p re-

p at ien ts w ith cardiovascu lar diseases.

ferred agen ts because of th eir tolerabilit y an d because th ey h ave been st udied in th e largest n um ber of pat ien ts.

E Ben zod iazep in es, su ch as d iazep am , are n ot u sed as an t idepressan t drugs.

B−F Th ese drugs are n ot e ect ive in t reat ing bu lim ia n er vosa.

Learning objective: Describe the increased risk of suicide that can occur in a young person taking antidepressant drugs.

Learning objective: Describe the m ain adverse e ects of selective serotonin reuptake inhibitors (SSRIs)/serotonin−norepinephrine reuptake inhibitors (SNRIs).

32. E Of th ese drugs, u oxet in e is th ough t to be th e greatest risk

29. B Most an t idepressan ts can cause sexu al dysfun ct ion , but

Adm in ist rat ion (FDA) black box w arn ings, becau se app ar-

its in ciden ce seem s th e h igh est w ith SSRIs/SNRIs. Sym ptom s

ently they increase the risk of suicide during the rst 4 w eeks

for en h an cing su icide poten t ial in pat ien t s such as th e on e d escribed h ere. All an t idep ressan ts h ave U.S. Food an d Drug

of t reat m en t in ch ildren an d at-risk pat ien t s younger th an

Answers and Explanations: III-10 Drugs for Bipolar Disorders 171 age 24, as in th is case. How ever, th e risk of su icide seem s to

DRUGS FOR DEPRESSIVE AND ANXIETY DISORDERS Answ er key

decrease after 12 w eeks of th erapy. It is w orth n ot ing th at , d esp ite t h e FDA’s d ecision , t h e issu e of an t idep ressan t related risk of su icidalit y rem ain s con t roversial, becau se t h is r isk is st ron gly related to sever it y of d ep ression in bot h you t h s an d adu lts, an d long-term an t idepressan t t reat m en t can decrease depression severit y. A Zolp id em is a hyp n ot ic d r ug, m ost likely given to t h e p at ien t becau se in som n ia is a frequ en t adverse e ect of uoxet in e.

1. 2. 3. 4. 5.

A F D A H

6. 7. 8. 9. 10.

C E C C C

11. 12. 13. 14. 15.

C D E F B

16. 17. 18. 19. 20.

D A C C B

21. 22. 23. 24. 25.

D A A C B

26. 27. 28. 29. 30. 31. 32.

D E A B D B E

B−E Th ese drugs are an t ican cer dr ugs u sed to t reat Hodgkin lym ph om a.

Answers and Explanations: III-10 Drugs for Bipolar Disorders Questions 1−4

F Tricyclic an t idepressan t s are used on ly except ion ally in

1. A

bip olar disorders. Moreover, th ey are con t rain dicated in el-

2. G

derly p erson s, as in th is case.

3. G

Learning objective: Explain the mechanism of action of olanzapine.

4. D

7. D An acu te m an ic at t ack often requires t reat m en t w ith a t w o-

Learning objective: Explain the m olecular m echanism s of action of lithium .

or th ree-drug com bin at ion , usually lith ium plus an an t icon -

5. E Lith iu m in h ibit s in ositol m on op h osp h atase, an en zym e in -

likely act by blocking D2 receptors in m esolim bic an d m eso-

volved in th e ph osph at idylin ositol path w ay. Th is leads to de-

cort ical path w ays. In addit ion , th ey block 5-HT2 receptors,

pletion of ph osphatidylinositol 4,5-bisphosph ate (PIP2 ), w hich

an d th is act ion m ay con t ribu te to th eir clin ical e ect s. At yp i-

is th e precursor of both IP3 an d DAG. Th erefore, th e syn th esis of IP3 an d DAG is in h ibited, an d th e act ivit y of m any receptors th at are IP3 /DAG lin ked is depressed. Th is m ay cause an in h ibit ion of overact ive circu its in m an ia.

vulsan t plus an at ypical n eurolept ic. All n eurolept ics m ost

cal n eu rolept ics su ch as olan zap in e seem to h ave a h igh er a

n it y for 5-HT2 receptors th an for D2 receptors. A−C, E, F Non e of th ese drugs block both D2 an d 5-HT2

receptors.

A−D, F Lith ium ten ds to cause act ion s opposite to th ose

Learning objective: Describe the adverse e ects of lithium .

listed.

8. A Lith iu m likely d ecreases thyroid fu n ct ion in m ost p at ien t s,

Learning objective: Outline the use of quetiapine in bipolar disorder.

bu t few of th em sh ow sym ptom s of hyp othyroidism . How -

6. D Th e m an w as m ost likely a ected by a bip olar d isorder re-

thyroidism . Th e e ect is due to in h ibit ion of thyroid h orm on e

sistan t to lith iu m th erapy an d w as su ering from an acu te

syn t h esis. Th e m ech an ism of t h is e ect is likely related to

depressive episode. Because the patient experienced ve m ood

lith iu m -in du ced in h ibit ion of adenylyl cyclase, w h ich in t u rn

sw ings over th e p ast year, h e m eets th e criteria for rap id cy-

in h ibit s thyrot rop in -in d u ced p rod u ct ion of cyclic aden osin e

cling, de n ed as occurren ce of four or m ore m ood sw ings or

m on op h osp h ate (cAMP) in thyroid cells.

ep isodes of m an ia or dep ression in a year. Abou t 70 to 80% of rap id cyclers h ave poor respon se to lith ium . Quet iap in e an d a com bin at ion of olan zapin e an d

uoxet in e are th e drugs ap -

proved by the U.S. Food and Drug Adm inistration for the treatu-

ph en azin e, cou ld be u sed in th e acu te m an ic p h ase of bip olar disorders, bu t n ot in th e depressive p h ase. B, E Th ese drugs are n ot e ect ive in bipolar disorders.

B Lith iu m is n ot m et abolized an d is excreted as su ch by th e kidn ey. C Cim et idin e does n ot cau se th e p at tern of adverse e ect s exh ibited by th e pat ien t . D Cen t ral e ect s of loratadin e are n egligible, as th e dr ug

m en t of acute episodes of depression in bipolar disorder. A, C Typical n eu rolept ics, su ch as h alop eridol an d

ever, in th is case, th e sym ptom s are m ost likely due to hypo-

does n ot cross th e blood−brain barrier. E See correct an sw er explan at ion .

172


Learning objective: Describe the m ain drug interactions with lithium .

su ccessive episod es, th ey ten d to recover less com p letely.

9. B Th e pat ien t’s sym ptom s in dicate th at sh e w as m ost likely

lar disorder, as in th is case, th e person m ay requ ire lith iu m

su ering from adverse e ect s du e to an excessive plasm a con cen t rat ion of lith ium . Th e pat ien t w as t reated w ith hy-

Th erefore, in a case of seriou s an d rep eated episodes of bipofor th e rest of h is or h er life. A−D See correct an sw er explan at ion .

d roch loroth iazide, an d it is kn ow n th at th e clearan ce of lith reabsorbed in th e proxim al t u bule by th e sam e m ech an ism

Learning objective: Describe the use of at ypical antipsychotics for the maintenance therapy of bipolar disorder during pregnancy.

as Na + an d com petes w ith Na + for reabsorpt ion . Th erefore,

13. C Lit h iu m is classi ed by t h e U.S. Food an d Dr ug Adm in is-

lith ium reten t ion can be in creased by Na + loss related to

t rat ion (FDA) in p regn an cy risk categor y D an d th erefore

som e illn esses or to d iu ret ic u se, as in th is case.

m u st be avoided du ring pregn an cy. Som e an t iconvu lsan t s

ium is reduced abou t 25% by th iazides. Lith ium is 80%

A Th iazid es ten d to in d u ce hyp on at rem ia, n ot hyp ern at rem ia.

(valproic acid, lam ot rigin e, an d carbam azepin e) an d som e at ypical antipsych otics (aripiprazole, olan zapine, quetiapin e,

C Th e h epat ic m etabolism of lith iu m is zero.

an d risp eridon e) h ave becom e good altern at ive an d adju n c-

D, E See correct an sw er explan at ion .

t ive t reat m en t s to lith iu m for m ain ten an ce th erapy of bip olar disorder. Am ong at ypical an t ipsych ot ics, quet iap in e

Learning objective: Outline the therapeutic uses of lithium .

h as th e low est rat io of um bilical cord to m atern al plasm a

10. E Th e h istor y an d sym ptom s of th e pat ien t in dicate th at sh e

con cen t rat ion an d does n ot seem to cause sign i can t terato-

w as m ost likely su ering from th e depressive p h ase of a bi-

gen ic risk to th e fet u s. Th erefore, it is a rat ion al ch oice for

p olar disorder. Th e depression is often di cult to con t rol

m ain ten an ce th erapy in a p regn an t w om an w ith bipolar

an d p u t s p at ien t s at sign i can t risk of su icide. Lith iu m (alon e

d isorder.

or in com bin at ion ) rem ain s th e

rst-lin e agen t for m ain te-

n an ce th erapy of bipolar disorder.

A, B Carbam azepine and valproic acid are e ective in m ain ten an ce th erapy of bipolar disorder bu t are con t rain dicated

A An t idepressan t use in bipolar depression is con t rover-

d uring pregn an cy becau se of a su bstan t ial teratogen ic risk

sial, an d cu rren t gu id elin es suggest th at th ey can be u sed

(both are classi ed by FDA in th e pregn an cy risk categor y D).

(togeth er w ith lith ium ) in th e severe acute ph ase of bipolar d ep ression . How ever, t r icyclics are con t rain d icated in p a-

D−F Th ese drugs h ave n o proven e

cacy for m ain ten an ce

th erapy of bip olar disorder.

t ien t s w ith su icidal id eat ion , as in th is case. B, C Lorazepam an d h alop eridol are in dicated in th e acu te

Learning objective: Describe the adverse e ects of lithium .

m an ic ph ase of bipolar disord er, n ot in th e dep ressive p h ase.

14. B Polyu r ia an d p olyd ip sia are com m on adverse e ect s of

D, F An xiolyt ic an d hyp n ot ic d r ugs are n ot in d icated in

lith iu m du e, at least in p ar t , to in h ibit ion of th e vasopres-

bip olar d isord ers.

sin -in du ced in crease of cAMP in th e kidn ey (lith iu m in h ibit s adenylyl cyclase). Circu lat ing levels of vasop ressin are n or-

Learning objective: Describe the adverse e ect s of lithium .

m al or elevated, bu t th ere is a lack of resp on siven ess of th e

11. C Th e sym ptom s of th e pat ien t suggest th at sh e w as likely

collect ing t ubule (i.e., n eph rogen ic diabetes in sipidus).

su ering from adverse e ect s of lith iu m . Trem or is an ad verse e ect of lith ium th at is dose-depen den t an d m ay occur

A Lit h iu m h as n o e ect on ren al reabsor pt ion of sod iu m in th is par t of th e n eph ron .

in up to 60% of pat ien t s receiving h igh doses. W h en t rem or

C Lith ium h as n o e ect on plasm a glucose levels.

is n ot dist u rbing, t reat m en t is n ot n ecessar y. Oth er w ise a

D St im u lat ion of th e th irst cen ter in th e hypoth alam us is

con com itan t t reat m en t w ith a β-blocker can h elp. Polyuria, acn e, an d follicu lit is are oth er adverse e ect s of lith iu m th at u su ally su bside w ith th e discon t in uat ion of th e drug.

th e con sequ en ce, n ot th e cau se, of p olyu ria. E In n eph rogen ic diabetes in sipidus, vasopressin secret ion is n orm al or st im ulated, n ot blocked.

A, B, D−F Th ese drugs do n ot cau se all th e adverse e ect s repor ted by th e pat ien t .

Learning objective: Explain the m olecular m echanism s of action of lithium .

Learning objective: Describe the duration of lithium therapy in recurrent major bipolar disorder.

15. F Th e t w o m ain prop osed m ech an ism s of act ion of lith iu m

12. E The duration of m ainten ance therapy w ith lithium in m ajor

w ays, th at is, in ositol an d glycogen syn th ase kin ase 3 sign al-

bip olar d isord er is at least 9 m on t h s. A p er iod of su ccess-

ing. Th e in h ibit ion of th is en zym e causes su ppression of th e

fu l m ain ten an ce th erapy m ean s th at th e in dividual is con -

expression of proapoptot ic gen es an d in creased expression

t rolled, n ot cu red, as m ost p at ien t s th at stop lith iu m th erapy

of an t iapoptot ic gen es. Th e ult im ate e ect is n europrotec-

even t ually relapse. Fur th erm ore, as in dividu als experien ce

t ion , w h ich m ay u n d erlie th e long-term m ood st abilizat ion .

are related to in h ibit ion of t w o sign al t ran sdu ct ion path -

Answers and Explanations: III-10 Drugs for Bipolar Disorders 173 A−E All of th ese dr ugs h ave been used in augm en tat ion th erapy, but th ey do n ot h ave th e above-m en t ion ed m ech an ism of act ion .

after 40 h ours). A−C, E, F See correct an sw er explan at ion .

Learning objective: Describe the adverse e ect s of lithium . 16. E Edem a is a frequen t adverse e ect of lith ium , especially d uring th e

after on e h alf-life an d 0.75 m Eq/L after t w o h alf-lives (i.e.,

rst 5 to 7 days of th erapy. Edem a is likely due

to in creased Na + in th e ext racellu lar

Learning objective: Explain the m olecular m echanism s of action of lithium . 20. D Main ten an ce th erapy w ith lith iu m redu ces th e frequ en cy

u id, as lith iu m is n ot

an d severit y of ep isodes of both m an ia an d dep ression in p a-

pu m p ed ou t by Na +/K+-ATPase an d th erefore ten ds to accu -

t ien t s w ith bip olar disorder. Th e drug ap p ears to act m ain ly

m ulate in side th e cells, displacing Na +.

by in h ibit ing th e in ositol secon d m essenger system , as it in -

A−D Lith ium ten ds to cause adverse e ect s opposite to th ose listed.

h ibit s in ositol m on oph osph at ase, th e rate-lim it ing en zym e in in ositol recycling. A−C, E, F All of t h ese d r ugs are e ect ively u sed in m ain te-

Learning objective: Outline the therapeutic uses of lithium .

n an ce t h erapy of m an ia, bu t t h ey d o n ot h ave t h e above-

17. E Th e sign s an d sym ptom s of th e pat ien t suggest th at h e

m en t ion ed m ech an ism of act ion .

is su ering from an acute m an ic disorder. Gen eral guidelin es th at in clu des lith iu m , as it red u ces both th e frequ en cy an d

Learning objective: Describe the treatm ent of lithium -induced diabetes insipidus.

th e m agn it u d e of m ood sw ings. How ever, it h as a slow on set

21. C Th e p at ien t’s h istor y an d sym ptom s in dicate th at h e w as

of act ion , t aking as long as 1 to 2 w eeks to fully exer t its

m ost likely su ering from lith iu m -in du ced n eph rogen ic dia-

th erap eu t ic e ect s. Th erefore, an adju n ct ive m edicat ion is

betes in sip idu s, th e m ost com m on com plicat ion of ch ron ic

u sed du ring th e

rst days of th erapy. Ben zodiazep in es are

lit h iu m t h erapy. In t h e collect ing t u bu le, lit h iu m (Li +) is

often given for agit at ion an d in som n ia, but secon d-gen era-

reabsorbed th rough th e Na + ch an n els an d is th erefore con -

t ion n eu rolept ics w ith su bst an t ial sedat ive p rop er t ies, su ch

cen t rated in side th e prin cipal cells. Th is h igh con cen t rat ion

as risp eridon e, are p referred w h en th ere are delu sion s or

blocks th e act ion of vasop ressin , likely by in h ibit ing adenylyl

h allucin at ion s, as in th is case.

cyclase, an d cau ses n eph rogen ic diabetes in sip idu s. Am i-

for acute m an ia suggest a t w o- or th ree-drug com bin at ion

A−D All of th ese com bin at ion s h ave at least on e drug th at is n ot e ect ive in t reat ing m an ic disorders.

lor id e is a K+-sp ar ing d iu ret ic t h at blocks Na + ch an n els in t h e late distal t u bu le an d collect ing du ct , in h ibit ing th e reabsorpt ion of Li+ th rough th ose ch an n els. It is th erefore th e

Learning objective: Describe the use of lithium in augm entation therapy for major depressive disorder.

rst-lin e agen t for th e th erapy of lith iu m -in du ced diabetes in sip idus.

18. D More th an 40% of p at ien t s w ith m ajor dep ressive disorder

A, B Th ese diu ret ics are dangerou s in pat ien ts t aking lith -

d o n ot ach ieve rem ission even after t w o an t idepressan t t ri-

iu m because th ey ten d to cau se Na + deplet ion . Because Na +

als. An accepted st rategy u sed w h en dealing w ith n egligible

an d Li+ go th rough th e sam e ch an n els, Na + d ep let ion p ro-

or poor an t idepressan t respon se is to add an oth er agen t to

m otes a clin ically im por tan t degree of lith iu m reten t ion

th e th erapy (augm en tat ion th erapy). Drugs u sed e ect ively

D Sp iron olacton e can n ot a ect Li+ reabsorpt ion becau se

for augm en tat ion th erapy in clude lith ium , bu propion , bus-

it does n ot block Na + ch an n els in th e late distal t ubule an d

p iron e, lam ot rigin e, an d t riiodothyron in e.

collect ing duct .

A, B Curren tly, an t idepressan ts are n ot used in augm en tat ion th erapy. Moreover, am it ript ylin e an d m ir t azap in e h ave

E Con ivaptan is a vasopressin an t agon ist an d th erefore w ou ld in crease, n ot decrease, th e pat ien t’s polyu ria.

sedat ing act ivit y th at cou ld w orsen th e p at ien t’s sleepin ess. C, E, F Th ese drugs are n ot e ect ive for an t idepressan t

DRUGS FOR BIPOLAR DISORDERS Answ er key

augm en t at ion th erapy.

Learning objective: Calculate the tim e to withhold lithium therapy in case of lithium overdose toxicit y. 19. D By de n it ion , th e plasm a con cen t rat ion of a drug h alves ever y h alf-life. Th erefore, th e plasm a level w ill be 1.5 m Eq/L

1. 2. 3. 4. 5.

A G G D E

6. 7. 8. 9. 10.

D D A B E

11. 12. 13. 14. 15.

C E C B F

16. 17. 18. 19. 20. 21.

E E D D D C

174


Answers and Explanations: III-11 Drugs for Childhood Behavioral Disorders Questions 1−3

Learning objective: Describe the adverse e ects of atom oxetine.

1. D

6. A Atom oxet in e is an an t idep ressan t drug ap proved for th e

2. A

t reat m en t of at ten t ion d e cit hyperact ivit y disorder (ADHD).

3. I

Th e drug select ively in h ibits n orepin eph rin e reupt ake in n oradren ergic term in als; th is m ech an ism m ost likely u n derlies

Learning objective: Identify the neural pathway underlying the therapeutic action of methylphenidate in at tention de cit hyperactivit y disorder.

th e in crease in blood pressu re, w h ich occurs in about 10% of

4. C At ten t ion de cit hyp eract ivit y disorder (ADHD) is associ-

B, C Norep in eph rin e ph enylep h rin e can in crease blood

ated w ith alterat ion s in regu lat ion of m otor beh avior an d atten t ion . Th e prefron t al cor tex (PFC) is im por t an t for sust ain ing at ten t ion over a delay, in h ibit ing dist ract ion s, an d dividing

pat ien ts t reated w ith th e d rug, especially d u ring th e rst days of th erapy. pressu re bu t th ey are n ot u sed to t reat ADHD. D, E Guan facin e an d clon idin e are u sed to t reat ADHD but are also used as an t ihyper ten sive agen t s.

at ten t ion . Th e PFC in th e righ t h em isp h ere is esp ecially im -

n ing, an d locom otor hyperact ivit y. Th e PFC is ver y sen sit ive to

Learning objective: Outline the therapy of at tention de cit hyperactivit y disorder (ADHD) in a patient with a concom itant depressive disorder.

it s n eu roch em ical environ m en t , an d opt im al levels of n orepi-

7. B ADHD an d d ep ression frequ en tly occu r togeth er. W h en th is

n eph rin e an d dopam in e are n eeded for proper PFC con t rol of

is th e case, a com bin ed th erapy w ith t w o d rugs can be appro-

beh avior an d at ten t ion . Recen t elect rop hysiological st u d ies

priate. Methylp h en idate is a com m on ly u sed drug for ADHD,

in an im als suggest t h at n orep in ep h r in e en h an ces “sign als”

an d ser t ralin e is a select ive seroton in reu pt ake in h ibitor an t i-

th rough postsyn apt ic α 2A adren oceptors in th e PFC, w h ereas

dep ressan t drug.

port an t for beh avioral in h ibit ion . Lesion s to th e PFC p rodu ce a pro le of dist ract ibilit y, forgetfuln ess, im pu lsivit y, p oor plan -

dop am in e decreases “n oise” th rough m odest levels of D1 receptor st im ulat ion . St im ulan t m edicat ion s such as m ethyl-

A, C−E Non e of th ese opt ion s h ave a drug th at is app ropriate for use as an an t idepressan t .

ph en idate an d am ph et am in es m ost likely cau se som e of th eir α 2A adren oceptors an d dopam in e D1 receptors in th e PFC, op -

Learning objective: Explain the m olecular m echanism of action of atom oxetine in at tention de cit hyperactivit y disorder (ADHD).

t im izing PFC regu lat ion of beh avior an d at ten t ion .

8. B Alth ough th e precise m ech an ism by w h ich atom oxet in e

th erapeut ic e ect s by in creasing en dogen ou s act ivat ion of


produ ces ben e cial e ect s in ADHD is st ill u n cer tain , it is th ough t th at th e dr ug exer ts it s e ect s th rough select ive in h i-

Learning objective: Describe the adverse e ect s of m ethylphenidate.

bit ion of n orep in ep h rin e reu ptake in n oradren ergic term i-

5. B Th e m oth er’s report in dicated th at th e ch ild w as m ost likely

the know n distribution of norepinephrine-containing neurons.

a ected by a t ic disorder, w h ich is fairly com m on in ch ild-

It is hypoth esized th at th e atom oxet in e-in duced in crease in

h ood. In som e cases th e disorder appears to be cau sed or

n orep in ep h r in e in t h e p refron t al cor tex, a region involved

w orsen ed by p rescript ion m edicat ion s. Th e drugs m ost com -

in at ten t ion an d m em or y, m ediates th e th erapeut ic e ect of

m on ly involved are psych om otor st im ulan ts, such as m ethyl-

atom oxet in e in ADHD.

phenidate and am phetam ines. Because the child was m ost likely u n der m ethylph en idate th erapy, th e drug probably cau sed h is t ic disorder. A Flu p h en azin e can cau se t ics an d dyston ias, bu t t h e d r ug

n als. Th e drug-bin ding sites in th e brain are con sisten t w ith

A, C, E Cocain e, atom oxet in e, an d bu p rop ion are n on select ive in h ibitors of catech olam in e t ran sp or ters. D Dext roam ph et am in e act s by in creasing catech olam in e release from adren ergic term in als.

is not used for attention de cit hyperactivit y disorder (ADHD). C Atom oxet in e is approved for ADHD, bu t th e appearan ce of t ics w ith th is drug is exceedingly rare. D, E Th ese drugs are n ot used in ADHD.

Learning objective: Outline the use of aripiprazole in Touret te syndrome. 9. B Th e pat ien t’s sym ptom s suggest th at th e boy is a ected by Tou ret te syn drom e, a ch ron ic fam ilial disorder ch aracterized by m otor an d ph on ic t ics. Th e syn drom e usually appears at abou t th e age of 5 an d occurs in 1 out of 1000 m ales an d 1 out of 10,000 fem ales. Tics are su dden , involun t ar y m ovem en t s or

Answers and Explanations: III-11 Drugs for Childhood Behavioral Disorders 175 sou n ds th at can be su p pressed volu n t arily w ith di cu lt y

B Im ip ram in e w as used in th e p ast w ith som e su ccess in

an d are often accom p an ied w ith coprolalia (fou l langu age).

n oct urn al en uresis, even th ough it s m ech an ism of act ion in

Progn osis is gen erally good, as th e syn drom e usually disap -

th is disorder rem ain s un kn ow n . How ever, th e drug h as sev-

pears in ad ulth ood, but som e cases can persist later in life.

eral d isadvan t ages (relap se is h igh , overdose toxicit y can be

Expert con sen sus recom m en ds a t rial w ith at ypical n euro-

leth al, etc.) an d is th erefore rarely p rescribed today. More-

lept ics before con sidering h alop eridol, w h ich is ap proved by

over, it is n ot available by n asal sp ray.

th e U.S. Food an d Drug Ad m in ist rat ion , becau se of est ab lish ed e

cacy an d low er risk of ext rapyram idal side e ect s.

Un like ot h er at yp ical n eu rolept ics, ar ip ip razole d oes n ot cau se w eigh t gain . Becau se p oten t ial obesit y is a p roblem

C Som e an t ich olin ergics w ere used in th e past for n oct urn al en uresis, but th ey h ave a vast array of adverse e ect s, an d th eir e

cacy is m in im al.

D−F Th ese drugs are n ot e ect ive in n oct urn al en u resis.

in ch ildren , th e dr ug can be a good ch oice for th is age group. Oth er drugs approved for Touret te syn drom e are clon idin e an d gu an facin e. A, C−F Th ese d r ugs are in e ect ive in t reat in g Tou ret te syn drom e.

Learning objective: Explain the m olecular m echanism of action of dextroamphetam ine. 13. B Th e sym ptom s an d sign s of th e pat ien t suggest th at h e w as a ected by at ten t ion de cit hyp eract ivit y disorder (ADHD). Dysregu lat ion of cen t ral n orad ren ergic an d d op am in ergic

Learning objective: Identify the site of the central anorectic action of amphetam ines.

n et w orks h as long been hyp ot h esized as u n d erlying t h e

10. D Am ph et am in es are th ough t to su pp ress app et ite by in -

from p h arm acological dat a docu m en t ing th at drugs th at

creasing n orep in ep h rin e an d seroton in release in th e lateral

m od u late n oradren ergic an d dopam in ergic fu n ct ion are ef-

hyp oth alam u s. Th is in crease can in terfere w ith several pep -

fect ive in t reat ing ADHD. Am ph et am in es in crease th e avail-

t ides th at in crease food in take by act ivat ing th e feeding cen -

abilit y of catecholam ines in the synaptic cleft m ainly because

ter (n eu ropept ide Y, orexin s A an d B, etc.).

th ey st im u late th e release of catech olam in es from adren er-


p at h op hysiology of ADHD. Th is hyp ot h esis d er ives largely

gic term in als. A, C, E Th ese drugs act by blocking th e reu ptake of cate-

Learning objective: Outline the therapeutic e ect s of bupropion. 11. C Bupropion is an an t idepressan t th at w as also foun d to be

ch olam in es in to adren ergic term in als. D Guan facin e act ivates cen t rally act ing α 2 -adren oceptors.

e ect ive in t reat ing at ten t ion de cit hyp eract ivit y disord er of sm oking cessat ion . Because th e pat ien t h as sym ptom s of

Learning objective: Describe the adverse e ect s of m ethylphenidate.

both depression an d ADHD an d w an ts to qu it sm oking, bu -

14. D Ner vousn ess an d in som n ia are th e m ost com m on adverse

(ADHD) an d is approved as an adjun ct in th e m an agem en t

p ropion can be an ap propriate d rug. A, D Met hylp h en idate an d gu an facin e are e ect ive in ADHD but are n ot an t idepressan t s. B, E Th e an t idepressan t s paroxet in e an d am it ript ylin e are n ot e ect ive in ADHD.

react ion s to m ethylph en idate an d m ay occu r w ith all form ulat ion s. In som n ia occu rs in up to 16% of adult p at ien t s bu t t ypically resolves w ith in a few days of use, provided th e dosage is app ropriate an d doses are n ot adm in istered w ith in 6 h ou rs of bedt im e. In som n ia is m ost likely related to th e d r ug-in d u ced in crease in n orep in ep h r in e an d d op am in e

Learning objective: Outline the use of desm opressin in the treatment of nocturnal enuresis.

availabilit y, w h ich cau ses a st im u lat ion of t h e brain stem

12. A Desm opressin acet ate, a syn th et ic an alogu e of th e n at ural

A Adren ergic drugs act ually cause decreased, n ot in -

h um an an t idiu ret ic h orm on e argin in e vasopressin , is ap -

arou sal system . creased, ap p et ite.

p roved as n asal spray an d oral tablet for th e t reat m en t of

B Methylphenidate-in duced grow th suppression has been

n oct urn al en u resis. Som e st udies h ave sh ow n th at som e pa-

repor ted in ch ildren (even if th e issue is con t roversial) but

t ien t s w ith en u resis d o n ot h ave a n orm al circadian rhyth m

can n ot occu r in an adu lt p at ien t .

of vasop ressin secret ion an d as a resu lt p rod u ce a large

C Methylph en idate h as th e poten t ial to low er th e seizu re

am ou n t of u rin e du ring th e n igh t . Desm op ressin in creases

th resh old m ain ly in p at ien t s w ith a prior h istor y of seizu res.

ren al w ater reabsorpt ion , th us reducing th e volu m e of u rin e

How ever, seizu res are except ion ally rare in n on epilept ic

en tering th e bladder. It is e ect ive in redu cing th e n u m ber of

p at ien ts.

w et n igh t s in 70% of ch ildren .

E Hallu cin at ion s an d d elu sion s can occu r w it h m et hylp h en idate, but th eir frequen cy is low (less th an 0.1%).

176


Learning objective: Describe the use of at ypical neuroleptics in autistic disorder.

E Epin eph rin e is an α 2 -receptor agon ist bu t does n ot cross th e blood−brain barrier an d is n ot u sed to t reat ADHD.

15. B Th ere is n o sp eci c t reat m en t or cu re for au t ism , bu t p h ar m acological t reat m en t , beh avioral th erapy, an d sp ecial

Learning objective: Describe the adverse e ects of guanfacine.

edu cat ion can im prove som e sym ptom s. An t ip sych ot ic m ed -

19. A Gu an facin e is an α 2 select ive agon ist . It is ap p roved for th e

icat ion s h ave been used w idely an d appear to be e ect ive in

th erapy of at ten t ion de cit hyperact ivit y disorder (ADHD)

redu cing stereot ypies, irrit abilit y, an d self-inju rious beh av-

an d hyper ten sion . It s m ech an ism of an t ihyperten sive act ion

ior. At ypical n eurolept ics seem to o er som e advan tage over

is close to th at of clon idin e. Hypoten sion an d palp itat ion s

classical ones, and aripiprazole and risperidone are approved

are th e m ost frequen tly repor ted cardiovascular adverse ef-

by th e U.S. Food an d Drug Adm in ist rat ion for t reat ing irrita-

fect s of th e drug. These ten d to dim in ish or subside w ith

bilit y in au t ist ic ch ildren .

con t in ued th erapy or w ith reduced dosage.

A, C−F All of th ese drugs are u seless or even con t rain dicated in au t ist ic disorder.

B Guan facin e ten ds to cause an orexia. C Dr y m outh , n ot salivat ion , is a frequen t adverse e ect of th e drug.

Learning objective: Describe the m olecular m echanism of action of m ethylphenidate. 16. A Methylp h en idate exert s m any of it s e ect s th rough blockade of dop am in e u pt ake by cen t ral adren ergic n eu ron s. As a

D Aggressive beh avior can occur ver y rarely in som e ch ildren w ith risk factor for bip olar disease. E Sw eat ing, n ot an hidrosis, is a repor ted adverse e ect of th e drug.

result , sym path om im et ic act ivit y in th e cen t ral n er vous system (CNS) is in creased. Th e m ain sites of CNS act ivit y appear to be th e brain stem arousal system an d th e cerebral cortex. B−E Methylph en idate does n ot elicit th ese e ect s.

Learning objective: Outline the use of clonidine in both at tention de cit hyperactivit y disorder (ADHD) and Touret te syndrom e. 20. B Over 90% of ch ildren w ith Tou ret te syn drom e h ave coexisting condition s, such as ADHD (75%), m ood disorders (60%),

Learning objective: Outline the therapy of at tention de cit hyperactivit y disorder (ADHD) in a patient at risk of drug abuse.

obsessive-com pulsive disorder (40%), other anxiet y disorders,

17. E Atom oxetine is a drug approved for the treatm ent of ADHD.

Clon idin e is exten sively u sed an d approved by th e U.S.

Th e dr ug is n ot a p sych ost im u lan t an d lacks abu se p oten t ial.

Food an d Drug Adm in ist rat ion for th e t reat m en t of Tou ret te

It is th erefore suit able for pat ien t s at risk of drug abuse.

syn drom e; it h as been recen tly ap proved for th e t reat m en t

A, C Th ese dr ugs are psych ost im u lan t s w ith a h igh abu se p oten t ial. B, D, F Th ese d rugs are n ot u sed for t reat ing ADHD.

or a com bin at ion of com orbidit ies.

of ADHD. Th e drug is an α 2 -receptor agon ist , an d th is m ech an ism of act ion likely m ediates it s th erapeut ic e

cacy in

both disorders. A, C Th e p sych ost im u lan ts m ethylph en idate an d dext ro-

Learning objective: Explain the m olecular m echanism of action of guanfacine. 18. C Gu an facin e is an oral, cen t rally act ing α 2 -ad ren oceptor agon ist ap p roved for t h e t reat m en t of hyp er ten sion an d at ten t ion de cit hyperact ivit y disorder (ADHD). It h as been th eorized th at ADHD is th e resu lt of dysfu n ction in fron to-

am ph et am in e are curren tly used in ADHD, but th eir use in Tou ret te syn drom e is con troversial, as th ey can exacerbate t ics. D, E Halop er id ol an d r isp er id on e h ave been u sed in To u ret te syn drom e w ith various su ccess, but th ey are in e ect ive in ADHD.

st r iat al p at h w ays, p ossibly related to dysregu lat ion of n eu rot ran sm it ters su ch as catech olam in es. Fron t al n et w orks

DRUGS FOR CHILDHOOD BEHAVIORAL DISORDERS Answ er key

con t rol at ten t ion an d m otor in ten t ion al beh avior. An im al st u d ies h ave d em on st rated t h at gu an facin e im p roves p refron tal cor t ical fu n ct ion th rough p ost syn apt ic α 2 -receptor agon ist e ect s in th e prefron t al cortex. A, B, D Th ese drugs are n ot α 2 -adren oceptor agon ist s.

1. 2. 3. 4. 5.

D A I C B

6. 7. 8. 9. 10.

A B B B D

11. 12. 13. 14. 15.

C A B D B

16. 17. 18. 19. 20.

A E C A B

Answers and Explanations: III-12 Opioid Analgesics and Antagonists 177

Answers and Explanations: III-12 Opioid Analgesics and Antagonists Questions 1−5 1. A

Learning objective: Describe the neurophysiological actions that mediate the analgesic e ects of opioids.

2. F

9. A Op ioids can a ect n ocicept ive in form at ion in t w o w ays:

3. E

• Directly th rough in h ibit ion of ascen d ing t ran sm ission of

4. I

in form at ion by im p airm en t of ascen ding n ocicept ive

5. H

path w ays at variou s levels in th e cen t ral n er vou s system • In directly th rough act ivat ion (likely via µ [m u] receptor−

Learning objective: Identify the anatom ical sites of the analgesic action of opioids.

m ediated in h ibit ion of GABAergic n euron s) of descen ding

6. D Th e an algesic e ect of opioids is m ediated by both spin al

m edulla, locus cer uleus, periaqu educt al gray area, n u-

an d su p rasp in al act ion s. At t h e sp in al level, act ivat ion of

cleu s raph e m agn u s, etc.) th at con t rol th e processing of

op ioid receptors on posterior horn in terneurons and output

pain t ran sm ission in th e spin al cord.

neuron s of th e subst an t ia gelat in osa in h ibits n ocicept ive

B Opioids in h ibit th e release of substan ce P, an excit ator y

t ran sm ission in th e lateral sp in oth alam ic t ract . At th e su p raspin al level, act ivat ion of op ioid receptors occu rs in several brain areas, bu t th e best ch aracterized of th ese areas is th e m esen cep h alic p er iaqu ed u ct al gray m at ter. Microinject ion s of m or p h in e in t h is region block n ocicept ive resp on ses in

am in ergic bulbospin al path w ays (from th e rost ral ven t ral

n eurot ran sm it ter presen t in a eren t sen sor y bers. C Op ioids can in du ce dissociat ive feelings an d dysph oria, bu t th is h as n oth ing to do w ith th e an algesic act ion . D, E Opioids in directly act ivate th ese path w ays (see correct an sw er explan at ion ).

ever y species exam in ed, from roden ts to prim ates. Naloxon e reverses th ese e ects. A−C, E Non e of th ese brain areas are involved in th e an algesic e ect of op ioids, bu t th ey m ay be th e sites for oth er e ects of opioids.

Learning objective: Identify the opioid that is a partial µ (m u) opioid agonist. 10. D Bupren orph in e is a part ial µ agon ist an d a κ (kappa) an t agon ist . It is m uch m ore poten t th an m orph in e (0.3 m g bu-

Learning objective: Identify the m ain site of the spinal analgesic action of morphine. 7. B W h en an op ioid is given by t h e ep id u ral rou te, it p rovid es an except ion ally long an algesic act ion w ith lim ited system ic

p ren orph in e is con sidered equ ian algesic to 10 m g m orph in e), an d its e ect s are n ot readily an t agon ized by n aloxon e, likely becau se bu p ren orp h in e dissociates ver y slow ly from op ioid receptors. A−C, E, F Th ese drugs are n ot part ial opioid agon ists.

e ect s. In th is sit u at ion , th e an algesia is m ain ly sp in al an d m ain ly due to act ivat ion of receptors in th e su bst an t ia gelat in osa, w ith con sequen t in h ibit ion of n ocicept ive t ran sm ission in th e lateral sp in oth alam ic t ract . A, C, F Act ivat ion of op ioid receptors in th ese areas can con t ribu te to th e an algesic e ect of m orp h in e by en h an cing th e descen ding in h ibitor y p ain p ath w ays, bu t th ey are m in im ally involved w hen m orphin e is given locally by th e epidural route. D Th is area is involved in th e grat ifying e ect s of opioids. E Th is area is n ot involved in t h e an algesic act ion of m orph in e.

8. B Op ioid s can cau se n au sea an d vom it ing m ain ly t h rough st im u lat ion of t h e ch em oreceptor t r igger zon e, a grou p of fou rth ven t ricle. A, C−F See correct an sw er explan at ion .

11. D Opioid receptors are m ain ly in h ibitor y receptors coupled to G protein s. The prim ary transduction m ech anism s of th ese receptors are act ivat ion of ph osph olipase C or in h ibit ion of adenylyl cyclase. Tw o w ell-establish ed con sequ en ces of th is t ran sd u ct ion are • At th e p resyn apt ic level, blockade of volt age-gated Ca 2+ ch an n els, w h ich in t urn reduces th e release of a large n um ber of n eurot ran sm it ters (m ost often glut am ate but

Learning objective: Identify the m ain brain site of the em etic action of morphine.

n eu ron s located in t h e area p ost rem a on t h e

Learning objective: Describe the m ain opioid postreceptor m echanism s.

oor of t h e

also acet ylch olin e, n orep in ep h r in e, seroton in , an d su b stan ce P) • At t h e p ost syn apt ic level, op en in g of ligan d -gated K+ ch an n els, w h ich in t urn evokes an in h ibitor y post syn apt ic poten t ial A See correct an sw er explan at ion . B, E Opioids do n ot act on ch loride or Na + ch an n els. C, F Opioids h ave act ion s opposite to th ose listed.

178


Learning objective: Explain the m olecular m echanism s of action of opioids.

Learning objective: Describe the m ain features of the analgesic e ect of opioids.

12. B Th e an algesic act ion of m orph in e (as w ell as th at of m ost

16. F Th e u se of op ioids to t reat ch ron ic n on can cer pain is st ill

opioids) is m ain ly due to direct act ivat ion of µ (m u) recep -

con t roversial because som e clin ician s believe th at th ese sit-

tors in various areas of th e cen t ral n er vou s system .

u at ion s sh ould n ever be t reated w ith opioids. How ever, cur-

A By act ivat ing µ receptors, opioids can cause th e release

ren t gu idelin es recom m en d opioid th erapy as a secon d-lin e

of en dogen ous opioid pept ides. Th is can con t ribute to th e

opt ion for pat ien t s w h o h ave in adequate respon se to oth er

n al an algesic e ect bu t is n ot th e m ain cau se of th is e ect .

th erap ies, as in th is case. Opioids are th e on ly an algesic th at

C Act ivat ion , n ot blockade, of κ (kappa) receptors can con -

can redu ce both th e sen sor y an d th e a ect ive com p on en ts of

t ribu te to th e an algesic e ect of opioids.

th e p ain experien ce. Th e a ect ive com pon en t (i.e., su ering)

D, E Op ioid s d ecrease t h e release of m any n eu rot ran s-

is th e on e m ost e ect ively t argeted . Meth adon e is often th e

m it ters, in clu ding su bst an ce P an d glu tam ate, so th ese listed

p referred op ioid for t w o reason s: it h as excellen t oral bio-

e ect s are u n likely.

availabilit y (abou t 90%), an d it h as a long h alf-life (abou t 25

F Opioids can decrease th e release of n orepin eph rin e, cau sing decreased act ivit y of β adren oceptors, bu t th is act ion is n ot related to th e an algesic act ion of op ioid s.

h ours) th at allow s for a single daily dose. A, B Non steroidal an t iin am m ator y drugs su ch as in dom et h acin an d ketorolac h ave n o sign i can t e ect on t h e em ot ion al aspect of pain .

Learning objective: Describe the m echanism of opioid-induced miosis.

d iazepam , an d ven lafaxin e can red uce th e em ot ion al asp ect

13. C Op ioids can st im u late th e Edinger−West ph al n u cleu s (also

of pain , bu t th ey h ave n egligible an algesic propert ies.

C−E Drugs w ith an xiolyt ic proper t ies such as ser t ralin e,

kn ow n as th e accessor y ocu lom otor n ucleus), w h ich is th e lom otor n er ve supplying th e sph in cter m u scle of th e iris an d

Learning objective: Describe the actions that m ediate the therapeutic e ect of m orphine in pulm onary edem a.

the ciliar y m uscle. Therefore, m iosis is seen w ith virt ually all

17. D Th e th erapeut ic e ect of m orph in e in pulm on ar y edem a

accessor y parasym p ath et ic cran ial n er ve n u cleu s of th e ocu -

opioid agon ists. Toleran ce to th is opioid e ect is n egligible. A, B, D−F See correct an sw er exp lan at ion .

likely involves • Red u ced p ercept ion of sh ort n ess of breath • Red u ced fear an d ap preh en sion (pain an t icipator y an xi-

Learning objective: Describe the e ects of an activation of µ (m u) opioid receptors on the cell m em brane of a nociceptive neuron.

• Red u ced preload du e to p erip h eral ven ou s dilat ion an d

14. E Act ivat ion of post syn apt ic µ opioid receptors on th e cell

afterload due to ar teriolar vasodilat ion , likely du e both to

m em bran e of p ain t ran sm ission n eu ron s in t h e sp in al cord

h istam in e release an d decreased sym path om im et ic act iv-

cau ses op en ing of K+ ch an n els, hyp er p olar izing t h e m em -

it y secon dar y to decreased an xiet y

et y is reduced).

bran e. An in h ibitor y postsyn apt ic p oten t ial en su es; th ere-

How ever, good evid en ce su p port ing a ben e cial h em ody-

fore, th e t ran sm ission of n ocicept ive st im u li is im paired.

n am ic e ect is lacking, an d som e physician s believe th at th e


risks of m orph in e m ay ou t w eigh th e ben e ts. A−C, E Morph in e causes act ion s opposite to th ose listed.

Learning objective: Describe the m echanism of action of pentazocine. 15. A Pen t azocin e is a p ar t ial agon ist at µ (m u ) receptors an d

Learning objective: Describe the m echanism of the constipating action of opioids.

a fu ll agon ist at κ (kap pa) receptors. Becau se of th is m ech a-

18. B Opioids in crease th e ton e of n onvascu lar sm ooth m u scle

n ism of act ion , it is gen erally less e ect ive as an an algesic

(both sph in cteral an d n on sph in cteral) th at in t urn causes a

th an oth er full opioid agon ist s. How ever, th ere is a large in -

con t ract ion of th e colon an d a decrease of its perist alt ic ac-

dividu al variabilit y in op ioid sen sit ivit y th at h as been as-

t ivit y. Opioids also in crease th e in tern al an al sph in cter ton e

cribed to gen et ic diversit y of receptors. For exam p le, som e

an d redu ce th e re ex relaxat ion resp on se to rect al disten -

red-h eaded, pale skin ph en ot ypes h ave a m ore act ive κ opi-

t ion . All of th ese act ion s, com bin ed w ith decreased n orm al

oid system an d are th erefore m ore sen sit ive to th e an algesic

sen sor y st im u li for defecat ion becau se of th e cen t ral n er-

act ion of p en t azocin e. Th is can exp lain t h e ch oice in t h is

vous system depressan t act ion , con t ribute to th e

case.

st ip at ing e ect .


n al con -

Answers and Explanations: III-12 Opioid Analgesics and Antagonists 179 A, C, D Op ioids cau se act ion s op posite to th ose listed.

Learning objective: Describe the adverse e ects of opioids.

E Th e m orph in e-in du ced decrease of in test in al peristalsis

23. D Opioids can h ave addit ive cen t ral n er vous system depres-

delays passage of the fecal m ass and allow s increased absorp -

san t act ion s w h en given to a pat ien t t reated w ith a sedat ive

t ion of w ater. Th erefore, th e feces becom e h arder, n ot softer.

hyp n ot ic drug, su ch as diazep am . In th e m ost seriou s in stan ces, th ese act ion s can lead to st u p or, as in th is case.

Learning objective: Describe the action of opioids on the respiratory system .

A−C, E, F Th ese an algesic drugs do n ot h ave cen t ral n ervous system depressan t proper t ies.

19. D Morp h in e d ep resses all p h ases of respirator y act ivit y (respirator y rate, m in u te volu m e, an d t idal exch anges) m ain ly


becau se th e drug redu ces th e resp on siven ess of th e brain -

24. C Pen t azocin e is an opioid th at can cause dose-depen den t

stem respirator y centers to partial pressure of arterial carbon

dysp h oria an d psych otom im et ic sym ptom s. It is som et im es

d ioxide (Pa CO2 ).

sold illegally w h en h eroin is n ot available. Th e d rug is a p ar-

A Th e cough re ex is depressed, n ot st im ulated, by m or-

t ial agon ist at µ (m u ) receptors an d a fu ll agon ist at κ (kap pa)

p h in e, d u e, at least in p ar t , to dep ression of t h e cough

receptors. Dysph oria an d psych otom im et ic sym ptom s h ave

cen ter.

been ascribed to activation of brain κ receptors. Chronic users

B Morph in e causes bron ch ocon st rict ion , n ot bron ch odilat ion , w h ich is du e, at least in p art , to h istam in e release. C, E See correct an sw er explan at ion .

of can n abis an d h allucin ogen s are m ore sen sit ive to h allucin ogen ic e ects of dr ugs, as in th is case. A, B, D, E With th ese drugs, th e risk of h allu cin ogen ic effect s is n egligible.

Learning objective: List the m orphine e ects that undergo negligible tolerance.


20. B Toleran ce develops to m ost e ects of m orph in e, in cluding

25. B Opioid an algesics h ave st im ulan t e ect s on th e n ucleus

th e leth al e ect . Not able except ion s are th e e ect s on th e

of Edinger−West ph al, th e parasym path et ic por t ion of cran ial

eye (w h ich lead to m iosis) an d th e e ect s on th e en teric

n er ve III. Th e in crease in parasym path et ic ring causes con -

sm ooth m u scle (w h ich lead to con st ip at ion ) for w h ich toler-

st rict ion of th e sp h in cter m u scle of th e iris (m iosis) an d th e

an ce is n egligible.

ciliar y m u scle (cyclosp asm ). Th is im p airs th e accom m oda-


t ion of th e eye for far vision . A Opioids ten d to cau se euph oria in pat ien t s w ith pain ,

Learning objective: Describe the adverse e ect s of opioids.

w h ereas dysph oria is m ore likely to occu r in n orm ally pain -

21. D Codein e is com m on ly used as an an t it ussive w h en a dr y,

free p eop le.

n onproduct ive cough is dist urbing th e pat ien t . Most opioids can cau se con st ipat ion w h en u sed repeatedly, as in th is case. A, B, F Most op ioids can dep ress th e cough re ex, bu t op ioids such as bupren orph in e, fen tanyl, an d m orph in e are n ot

C, D Opioids ten d to cause con st ipat ion , n ot diarrh ea, an d hyp oten sion , n ot hyp er ten sion . E Opioids are given to t reat dr y cough because th ey dep ress th e cough cen ter.

com m on ly u sed as an t it ussives. C, E Albuterol an d th eophyllin e can be used in cases of acute bronchitis because of their bronchodilating properties, bu t th ey u su ally do n ot cau se con st ip at ion .

Learning objective: Describe the adverse e ects of opioids. 26. C Fen tanyl is a µ (m u) receptor agon ist th at can be adm in istered by t ran sderm al patch . Because th e drug is ver y lipid solu ble, it can be absorbed slow ly over abou t 3 days, p rovid-

Learning objective: Describe the adverse e ect s of opioids.

ing a long-last ing an algesic e ect . How ever, fever can in -

22. F An in t ram uscular inject ion of m orph in e can release h ist a-

crease th e drug absorpt ion , leading to an overdose e ect , as

m in e, w h ich can cau se a local react ion (w eal at th e inject ion

in th is case. Occasion al fatalit ies du e to th is act ion of fen -

site an d p ru rit u s).

t anyl are reported in th e literat u re.

A Most opioids can release h ist am in e, but fen t anyl an d congen ers (alfen tan il, rem ifen t an il, an d sulfen t an il) do n ot . B−E Th ese drugs do n ot cau se h ist am in e release.

A, B Pen t azocin e an d codein e are less likely to cau se respirator y depression an d are n ot adm in istered by t ran sderm al p atch . D−F Ibu profen , ketorolac, an d in dom eth acin are n ot adm in istered by t ran sd erm al p atch an d h ave n egligible risk of respirator y depression .

180


Learning objective: Describe the use of laxatives to m anage opioid-induced constipation.

Learning objective: Explain the m ain contraindications of opioids.

27. C Con st ipat ion is on e of th e m ost com m on side e ects of

of Oddi, th ereby in creasing in t rabiliar y pressure. Th e result-

opioids, a ect ing up to 40% of pat ien ts un der ch ron ic t reat-

ing in t radu ct al back p ressure can aggravate p ain sym ptom s.

m en t . Th erefore, all p at ien ts on ch ron ic op ioid s sh ou ld re-

Because th e durat ion of biliar y hyperten sion can outlast th e

ceive concom itant prophylaxis for constipation w ith laxatives

an algesic e ect , it is bet ter to avoid op ioid an algesics in

(bulking laxat ives, e.g., lact ulose an d agar; st im ulan t laxa-

t reat ing biliar y colic.

t ives, e.g., sen n a an d bisacodyl; or soften ing laxat ives, e.g., d ocusate). It sh ou ld be n oted th at , because th e con st ip at ing

30. A Opioids can in du ce sm ooth m u scle spasm in th e sph in cter

B Pat ien t s w ith hypothyroidism m ay h ave prolonged an d exaggerated respon ses to opioids.

e ect does n ot u n dergo toleran ce, con com it an t th erapy w ith

C, D Opioids do n ot h ave th ese e ects.

laxat ives sh ou ld be con t in ued in de n itely.

E Opioids can cause n ausea an d vom it ing, but th ey de-

A Diazepam w ould in crease, n ot coun teract , th e sedat ive e ect of m orp h in e.

crease th e risk of n au sea an d vom it ing w h en th ese sym p tom s are due to visceral pain .

B Select ive seroton in reu ptake in h ibitors are con t rain dicated, or sh ou ld be u sed w ith great cau t ion , in p at ien t s t ak-

Learning objective: Describe the main contraindications of opioids.

ing opioids because of th e risk of seroton in syn drom e.

31. D Pen t azocin e is an op ioid d r ug t h at can cau se a d ose-

D Opioids ten d to cause bradycardia, w h ich w ould be en h an ced, n ot preven ted, by β-blockers. E Opioids ten d to cause hypoten sion , w h ich w ould be en h an ced, n ot preven ted, by calcium ch an n el blockers. F Opioids ten d to decrease gast ric secret ion , w h ich w ould be en h an ced, n ot preven ted , by om eprazole.

d ep en d en t in crease in ar ter ial p ressu re, p u lm on ar y p ressu re, an d h ear t rate. For th is reason , th e d rug is gen erally con t rain dicated in m yocardial in farct ion . A−C Th ese opioids are in dicated, n ot con t rain dicated, in m yocardial in farct ion . E Meth adon e is n ot con t rain dicated in m yocardial in farct ion , bu t it is less su it able t h an m or p h in e or m ep er id in e

Learning objective: Describe the opioid postreceptor mechanisms.

becau se of its slow on set of act ion .

28. B Opioid receptors are m ain ly in h ibitor y receptors cou pled to Gi/G0 protein s. Th e t ran sdu ct ion m ech an ism s t riggered by

Learning objective: Explain the m ain contraindications of opioids.

act ivat ion of th ese receptors in clu de

32. B Morph in e an d oth er µ (m u ) opioid receptor agon ist s are

• In h ibit ion of N- an d P-t yp e Ca 2+ ch an n els in n er ve term i-

universally used for the treatm ent of acute postsurgical pain.

n als, w h ich in t urn reduces th e release of a large n um ber

How ever, th ey h ave an in h ibitor y e ect on gast roin test in al

of n eurot ran sm it ters (m ain ly glut am ate, but also acet yl-

t ract m ot ilit y an d are th erefore absolu tely con t rain d icated

ch olin e, n orepin eph rin e, seroton in , an d su bst an ce P)

in t reat ing ileu s th at can occur m ain ly after abdom in al su r-

• Act ivat ion of K+ ch an n els, w h ich in t u rn leads to hyperpolarizat ion • Act ivat ion of p h osph olipase C, w h ich in t u rn in creases th e

ger y, as in th is case. A, C−E Th ese are an algesic-an t ipyret ic d rugs th at are n ot con t rain dicated for th is pat ien t .

syn th esis of IP3 /DAG • Act ivat ion or in h ibit ion of ad enylyl cyclase, leading to eith er st im u lat ion or in h ibit ion A By in creasing th e act ivit y of ph osph olipase C, opioids in crease th e syn thesis of IP3 /DAG.

Learning objective: Explain the m ain contraindications of opioids. 33. D Th e p at ien t’s vit al sign s suggest th at h ead t rau m a h ad in creased in t racran ial pressu re. W h en th is pressu re is su b stan t ially elevated over a sh ort p eriod, th ere is a st im u lat ion

C Op ioids h ave n egligible e ect on Na + ch an n els.

of the vasom otor area (w hich causes hypertension) and stim -

D, E Opioids h ave act ion s opposite to these.

u lat ion of vagal out ow (w h ich causes bradycardia). Opioid an algesics gen erally are avoided in pat ien ts w ith h ead inju r y

Learning objective: Explain the rationale of the acetam inophen/ codeine com bination to treat pain.

• Op ioids in du ce carbon d ioxide reten t ion , w h ich in t u rn

29. E Acetam in oph en an d op ioid an algesics p rovide p ain relief

cau ses vasodilat ion of th e cerebral arteries an d a con se-

by di eren t m ech an ism s of act ion ; th us, th ey h ave addit ive

qu en t in crease in in t racran ial pressu re, w h ich m igh t be

or syn ergist ic e ect s w h en given con com itan tly.

already elevated because of the head injury, as in this case.

A, B Th e t w o drugs do n ot an t agon ize each oth er’s adverse e ect s. C Toleran ce to th e codein e an algesic e ect does occur w ith ch ron ic use of th e com bin at ion . D Acetam inophen does not a ect codeine biotransform ation.

for th e follow ing reason s:

• Head inju r y p oten t iates th e resp irator y dep ressan t e ects of opioids. A−C, E Non steroidal an t iin am m ator y drugs are n ot con t rain dicated in cases of h ead t rau m a.

Answers and Explanations: III-12 Opioid Analgesics and Antagonists 181 Learning objective: Outline the therapeutic uses of opioids. 34. D Th e pat ien t’s sign s an d sym ptom s in dicate th at h e w as m ost likely receiving an opioid an algesic. Op ioid an algesics su ch as m or p h in e are th e on ly an algesics t h at can redu ce

C Zolpidem is a hyp n ot ic drug used on ly for t reat m en t of in som n ia. E Diazepam could be appropriate, but acet am in oph en is a m ild an algesic an d th erefore n ot usefu l in th is set t ing.

t h e a ect ive aspect of p ain experien ce (“It doesn’t both er m e so m u ch ”). Th e sedat ive e ect of op ioid s can explain th e

Learning objective: Outline the therapeutic uses of tram adol.

p at ien t’s drow sin ess du ring th e day, an d th e opioid -in du ced

37. D Th e pat ien t’s h istor y an d sym ptom s in dicate th at h e w as

in creased ton e of th e in tern al sph in cter of th e bladder can

m ost likely su ering from p osth erpet ic n eu ralgia, a p ain fu l

explain th e di cult y in voiding.

con dit ion th at develops after a case of sh ingles. Sh ingles is a

A Am it ript ylin e can h ave an algesic e ects (m ain ly in n eu-

ver y com m on disease (about on e m illion cases ever y year in

ropath ic pain ) bu t does n ot alter th e a ect ive aspect of pain

th e Un ited St ates), an d a n u m ber of sh ingles cases conver t to

experien ce.

p osth erpet ic n euralgia. Th ree m ajor classes of m ed icat ion s

B, F Acetam in oph en an d ketorolac are less e ect ive th an

are com m on ly u sed in th e t reat m en t of n eu rop ath ic p ain :

opioids as an algesics an d do n ot reduce th e a ect ive aspect

an t idep ressan ts, especially t ricyclics; an t iconvu lsan t s, esp e-

of pain experien ce.

cially gabapen t in an d carbam azep in e; an d sodiu m ch an n el

C, E Haloperidol an d diazepam can alter th e a ect ive as-

blockers, esp ecially m exilet in e. Op ioids are u su ally n ot ver y

p ect of t h e environ m en t , bu t t h ey are d evoid of an algesic

e ect ive, bu t t ram adol is a u n iqu e du al-act ing opioid agen t ,

p ropert ies.

as it is a w eak agon ist at µ (m u ) receptors bu t also in h ibit s th e n eu ron al reu pt ake of seroton in an d n orep in ep h rin e. It

Learning objective: Outline the therapeutic uses of opioids.

h as sh ow n e ect iven ess in a n um ber of n europath ic pain

35. E W h en can cer pain is severe an d n o longer relieved by n on -

states, in clu ding p osth erp et ic n eu ralgia.

steroidal an t iin am m ator y drugs, an opioid an algesic is u sually needed. Methadone is a strong opioid w ith excellent oral bioavailabilit y an d a long h alf-life (abou t 25 h ou rs). Th erefore, its adm inistration is m ost convenient for the patien t, and a single daily dose can provide adequate, continuous coverage. A See correct an sw er explan at ion . B, D Morph in e an d fen t anyl are e ect ive an algesics, bu t th e adm in ist rat ion rou te is m ore di cu lt an d can be p ain fu l

A, F Antipyretics-analgesics are m inim ally e ective against n europath ic pain . B Som e an t iconvulsan ts are e ect ive in n europath ic pain , bu t eth osu xim ide is in e ect ive. C Ben zodiazepin es h ave n o an algesic e ects. E Seroton in an d n orepin eph rin e reuptake in h ibitors su ch as ven lafaxin e an d du loxet in e are e ect ive in n eu ropath ic p ain , bu t select ive seroton in reupt ake in h ibitors are n ot .

in cach ect ic pat ien ts w ith term in al can cer, as in th is case. C Tram ad ol is a m ild an algesic an d is n ot appropriate for st rong pain .

Learning objective: Outline the therapeutic uses of m eperidine. 38. D Postan esth et ic sh ivering is a com m on sym ptom after an esth esia, a ect ing 40 to 60% of pat ien t s w h o receive volat ile

Learning objective: Outline the therapeutic uses of opioids.

an esth et ics. Post an esth et ic sh ivering can be su bdivid ed in to

36. D Con sciou s sedat ion is aim ed at p roviding alleviat ion of

• Therm oregulated sh ivering (w ith vasoconstriction), w h ich

an xiet y an d pain , togeth er w ith a dim in ish ed (bu t n ot abol-

is a n orm al respon se to hyp oth erm ia

ish ed) state of con sciousn ess. Ben zodiazepin es an d opioids

• Nonth erm oregulated shivering (w ithout vasoconstriction).

are u sed m ost often to obt ain con sciou s sedat ion becau se

Th e m ech an ism is un kn ow n bu t seem s related to post-

th is t reat m en t h as th e advan tage of being reversible by spe-

operat ive pain .

ci c receptor an t agon ist s ( u m azen il an d n aloxon e, resp ec-

Becau se m any n euron al system s ap pear to m odu late cen t ral

t ively). Th e u se of op ioids m u st be ver y cau t iou s in cases of

th erm oregulat ion , n um erous drugs can h ave an t ish ivering

h ead t raum a becau se th ese drugs ten d to in crease in t racra-

p rop er t ies, in clu d ing α 2 agon ist s (clon id in e), ch olin ergic

n ial pressure. In th is case, th e fact th at th e pat ien t did n ot

agon ist s (physost igm in e), 5-HT3 an tagon ists (on dan set ron ),

lose con sciou sn ess an d h ad in tact re exes suggests th at in -

an d op iates (m ep eridin e, m orp h in e, fen t anyl, an d t ram adol).

t racran ial inju r y w as u n likely an d th at th e beh avior of th e

Meperidin e is m ore e ect ive th an equ ian algesic con cen t ra-

p at ien t w as m ain ly related to pain .

t ion of oth er opiates an d is cu rren tly u sed for p ostan esth et ic

A Ibuprofen an d codein e are m ild an algesic drugs an d th erefore are n ot u sefu l in th is set t ing. B Buspiron e is an an xiolyt ic drug w ith n egligible hyp n ot ic act ivit y, an d it s an t ian xiet y e ect m ay t ake m ore th an a w eek to becom e est ablish ed. Th erefore, it is n ot u sefu l for acu te t reat m en ts.

sh ivering. Th e m ech an ism is st ill u n cer tain bu t seem s to be related to act ivat ion of κ (kap pa) receptors an d /or to act ivat ion of a su bt yp e of α 2 receptors. A−C, E See correct answ er explan at ion .

182


Learning objective: Outline the therapeutic uses of opioid antagonists.

is m in im ally absorbed, w h ereas bu pren orph in e absorpt ion

39. C Th e sign s of th e pat ien t suggest th at th e m oth er w as

sh ou ld block bu p ren orp h in e’s rew arding e ect s an d even

t reated w ith m orp h in e du ring labor. In th is in st an ce, th e

t h row t h e ad d ict in to p recip it ated w it h d raw al. How ever, it

n ew born baby can presen t sign s of m orph in e overdose (pin -

is w or t h n ot ing t h at t h ese e ect s of t h e com bin at ion can be

p oin t p upil, respirator y an d cen t ral n er vous system [CNS]

ach ieved, at best , on ly p art ially, becau se bu pren orph in e h as

d epression ) becau se th e drug easily crosses th e placen t a.

a h igh er a

Naloxon e, injected in to th e um bilical vein , easily coun teracts

sociates ver y slow ly from op ioid receptors.

th e m orp h in e-in du ced resp irator y an d cen t ral n er vou s system depression . Because n aloxon e act ion s are sh ort , addi-

is good (about 70%). If th e com bin at ion is given IV, n aloxon e

n it y for opioid receptors th an n aloxon e an d dis-

A−C, E Non e of th ese e ects w ill occur, as th e sublingual absorpt ion of n aloxon e is n egligible.

t ion al doses m ay be n eeded to m ain tain m orp h in e reversal. in duced by ben zodiazepin es, but n ot th e on es in duced by

Learning objective: Identify the drug whose analgesic e ect is most likely due to its conversion to morphine.

opioids. Moreover, diazepam is n ot an an algesic drug an d

42. B Non steroidal an t iin am m ator y dr ugs (NSAIDs) are p art ic-

A Flu m azen il can coun teract th e depressive CNS e ects

d oes n ot cause all th e sym ptom s sh ow n by th e baby.

u larly usefu l in th e m an agem en t of can cer-related bon e

B, D Th eop hyllin e an d ca ein e can h ave resp irator y

p ain , but w h en th ey can n ot con t rol it , th e addit ion of an opi-

st im u lan t proper t ies, but th ey are fun ct ion al an t agon ist s of

oid is th e best course of act ion . Because th e pain is m oder-

m orphine-induced respiratory depression and therefore m uch

ate, a m ild op ioid su ch as codein e can be app ropriate. Abou t

less e ect ive th an n aloxon e, w h ich is a ph arm acological

10% of th e adm in istered cod ein e is dem ethylated to m or-

an tagon ist .

p h in e. Because codein e h as an except ion ally low a

n it y for

E, F Albuterol an d iprat ropium are bron ch odilat ing agen t s

opioid receptors, it s an algesic e ect is m ost likely th e result

an d are th erefore u seless in case of dep ression of th e resp ira-

of it s conversion to m orph in e. Th is con clusion is suppor ted

tor y cen ter.

by ph arm acokin et ic dat a. It is kn ow n th at an oral codein e d ose of 120 m g is abou t equie ect ive to th e st an dard in t ra-

Learning objective: Outline the therapeutic uses of codeine/acetaminophen combination.

m u scu lar m orp h in e dose of 10 m g. Th e oral bioavailabilit y

40. C Th e codein e/acetam in op h en com bin at ion is th e on e m ost

abou t 96 m g of th e 120-m g dose can be absorbed , an d 10%of

frequ en tly u sed to t reat m ild or m oderate post su rgical p ain . Th e on set of act ion is rapid, an d it can be t it rated to e ect . A, B, D, E Th ese com bin at ion s are n ot cu rren tly u sed to

of codein e reported in th e literat ure is 70 to 90%. Th erefore, th at dose (i.e., 9.6 m g) is conver ted to m orp h in e. A, C−E Non e of t h ese op ioid s are biot ran sfor m ed to m orp h in e.

t reat m oderate p ost su rgical pain . Moreover, all th ese com bin at ion s in clu de a n on steroidal an t iin am m ator y drug. Th ese

OPIOID ANALGESICS AND ANTAGONISTS Answ er key

agen t s are con t rain dicated in pat ien t s w ith p resen t or past h istor y of pept ic ulcer, as in th is case.

Learning objective: Explain the reason for the use of buprenorphine/ naloxone combination in the treatment of opioid dependence. 41. D Naloxon e is com bin ed w ith bu pren orp h in e in a su blingu al p reparat ion called su boxon e. Th e aim of th e com bin at ion w as to preven t in t raven ou s (IV) bu p ren orp h in e abu se. It is kn ow n th at opioid addict s often dilute an opioid preparat ion and inject it IV. W hen given by the sublingual route, naloxon e

1. 2. 3. 4. 5.

A F E I H

6. 7. 8. 9. 10.

D B B A D

11. 12. 13. 14. 15.

D B C E A

16. 17. 18. 19. 20.

F D B D B

21. 22. 23. 24. 25.

D F D C B

26. 27. 28. 29. 30.

C C B E A

31. 32. 33. 34. 35.

D B D D E

36. 37. 38. 39. 40. 41. 42.

D D D C C D B

Answers and Explanations: III-13 Drugs of Abuse 183

Answers and Explanations: III-13 Drugs of Abuse Questions 1−5

release of glutam ate or gam m a-am inobut yric acid (GABA).

1. N

The physiological role of th ese receptors an d th eir en doge-

2. A

n ous ligan ds is n ot com pletely un derstood, but th ey m ost

3. F

likely h ave im p or tan t fun ct ion s because of th eir w ide loca-

4. B

t ion . For exam p le, in th e h ipp ocam p u s, th ey m ay con t ribu te

5. G

to in duction of synaptic plasticit y during m em ory form ation. B−E Th ese act ion s w ould n ot cause all th e sym ptom s exh ibited by th e pat ien t .

Learning objective: Describe the adverse e ect s of cocaine. 6. C Th e p at ien t’s sign s an d sym ptom s in d icate th at h e m ost likely took a h igh d ose of cocain e. For m icat ion (“Bugs are

Learning objective: Describe the adverse e ects of m arijuana.

craw lin g u n d er m y skin ”), stereot yp ed beh avior, an d p ara-

9. B Th e t w o m ost ch aracterist ic som at ic e ects of can n abi-

n oid delusion s, togeth er w ith sign s of sym path et ic overact iv-

n oids in h um an s are in creased pulse rate an d redden ing of

it y (hyp er ten sion an d t achycardia), are classic sym ptom s of

conjun ct iva, w h ich is related to th e gen eral vasodilat ion in -

cocain e overdose.

d uced by th ese drugs.

A, B, D Th ese drugs do n ot cau se all th e sym ptom s exh ibited

A Can n abin oids can cau se vasod ilat ion , w h ich in t u r n cau ses a dose-related decrease in blood pressu re. Post u ral

by th e pat ien t . E Ph en cyclidin e can cause m any sign s an d sym ptom s sim i-

hyp oten sion , n ot hyp er ten sion , is eviden t .

lar to th ose of cocain e, bu t th e pat ien t is u su ally disorien ted,

C Can n abin oids produ ce ch anges in m ood, but th e m ost

an d nyst agm u s is a prom in en t sign . Both are absen t in th is

com m on psych ic e ect s are euph oria an d disin h ibit ion , n ot

pat ien t .

d epression . D In fact , can n abin oids h ave a w eak but clin ically sign i can t an algesic act ion .

Learning objective: Describe the adverse e ect s of cocaine. 7. D Beh avioral stereot ypy is a p rom in en t sym ptom of ch ron ic u se of h igh doses of psych ost im ulan t s such as cocain e an d am ph et am in es. Stereot yped beh avior is ch aracterized by repet it ive an d p u rposeless m otor act ion s, an d it h as been p ost u lated to resu lt from an abn orm al dopam in e resp on se after long-term u se. A Even after h igh doses of cocain e, th e person usually re-

den ce an d h eigh ten ed creat ivit y, th ey u sually lead to im p airm en t of cogn it ive fu n ct ion s, learn ing, an d m em or y. F Can n abin oids cause gen eralized vasodilat ion , so pale skin is u n likely.

Learning objective: Describe the adverse e ects of LSD. 10. C Th e fact th at th e m an perceived sym ptom s t ypical of LSD

m ain s alert an d orien ted. B, C, E Th ese sym ptom s u su ally occu r w h en cocain e is w ith d raw n , bu t op p osite sym ptom s occu r as long as su

E Alth ough can n abin oids cause subject ive feelings of con -

cien t

cocain e levels are presen t in th e body.

in toxicat ion 2 m on th s after t aking th e o en ding drug poin ts out th at h e w as m ost likely experien cing a ash back, a part icu larly t rou bling aftere ect of LSD an d related drugs. Th e ash back (n ow called h allu cin ogen -persist ing percept ion

Learning objective: Explain the m echanism of action of cannabinoids. 8. A Th e boy’s sign s an d sym ptom s in dicate th at h e w as m ost likely u sing can n abis. Can n abin oid receptors h ave been fou n d in th e h u m an brain , an d en dogen ou s ligan ds (an an dam ide an d 2-arach idonyl glycerol) h ave been iden t i ed th at act as n eurot ran sm it ters. Th ese receptors are w idely dist ributed in th e cerebral cor tex, h ippocam pus, st riat um , an d cerebellum an d are m ain ly located p resyn apt ically, t h u s in h ibit in g t h e

d isorder) is a recurren ce of par t or all of a h allu cin ogen ic d rug exp erien ce, w eeks or m on th s after th e drug w as last taken. Som e users have reported these perceptual sensations even years after th e drug exposure. Precipitat ing con dit ion s in clu de st ress, fat igu e, an xiet y st ates, em ergen ce in to a dark environ m en t , an d n eu rolept ics. A, B, D−F Th ese syn drom es lack th e sym ptom s described by th e pat ien t .

184


Learning objective: Describe the pharm acological therapy of nicotine dependence.

son un der h eroin w ith draw al, but th ey are n ot suit able to

11. B Bupropion is an at ypical an t idepressan t st ruct urally sim i-

ach ieve th e goal of a drug-free pat ien t .

A Ben zodiazep in es are som et im es u sed to sedate a p er-

lar to diethylpropion, an am phetam in e-like appetite suppres-

C Nalt rexon e blocks th e eup h oric e ect of opioids an d is

sant. Th e drug inhibits reuptake of dopam ine, noradren alin e,

th erefore used to preven t relapse an d even t ually to ext in -

an d seroton in in th e cen t ral n er vou s system , is a n on com -

gu ish th e h abit , on ce th e addict h as becom e drug-free, bu t it

p et it ive n icot in e receptor an t agon ist , an d at h igh con cen -

can precip itate w ith draw al if u sed in a p erson st ill p hysically

t rat ion s in h ibits th e

dep en den t on op ioids.

ring of n oradren ergic n eu ron s in th e

locu s ceruleu s. It is n ot clear w h ich of th ese e ect s accoun t s

D−F Th ese drugs are n ot used in opioid detoxi cat ion .

for th e usefuln ess of bupropion during sm oking cessat ion , th ere is a redu ct ion in cen t ral d op am in e an d n orepin ep h rin e

Learning objective: Describer the symptom s and signs of steroid abuse.

levels an d in creased

ring in th e locu s ceruleus. Th e an t i-

14. E Th e pat ien t’s sign s an d sym ptom s, as w ell as h is p erson al

sm oking e ect of bu prop ion does n ot seem to be related to

h istor y (h e is a body bu ild er), suggest th at an an abolic ste-

th e an t idep ressan t e ect , as bu p ropion is equ ally e ect ive

roid is m ost likely t h e cu lp r it d r ug. An abolic steroid s are

as a sm oking cessat ion th erapy in sm okers w ith an d w ith ou t

often abu sed by p eop le en gagin g in com p et it ive sp or t s; by

d epression . Th e dr ug can ach ieve long-term abst in en ce in

body bu ilders, for exam p le. Th e p rim ar y e ects sough t are

abou t 20% of sm okers. Oth er drugs u sed for sm oking cessa-

in creased m u scle m ass an d st rength . Am ong th e m an ifest a-

t ion are clon idin e an d varen iclin e.

t ion s of h eavy u se are in creased irritabilit y an d aggression

bu t all cou ld be im p or tan t . Du ring n icot in e w ith draw al,


(com m on ), ch anges in libido an d sexual fun ct ion s, an d m ood ch anges w ith occasion al psych ot ic feat ures.

Learning objective: Outline the pharm acological therapy of opiate withdrawal.

h avior, an d all can be detected by rout in e drug screen ing.

12. B Th e p at ien t’s sym ptom s in dicate th at h e w as m ost likely

D, F Mifepriston e an d dan azol are n ot abused drugs.

A−C Overdose of th ese drugs rarely causes aggressive be-

experien cing h eroin w ith draw al. Adm in ist rat ion of an opiegy to at ten u ate w ith draw al from opiates. Meth adon e w as

Learning objective: Describe the pharm acological e ect s of marijuana.

th e p referred drug in th e p ast , becau se it h as a long du rat ion

15. B Th e girl’s sign s an d sym ptom s in d icate t h at sh e m ost

of act ion an d can be t apered slow ly to m in im ize abst in en ce

likely sm oked m arijuan a cigaret tes. Tachycardia an d redden -

sym ptom s. More recen tly, bu pren orph in e h as been sh ow n

ing of th e conju n ct iva are th e t w o m ost ch aracterist ic so-

to w ork bet ter th an oth er opioids for t reat ing w ith draw al

m at ic e ect s of can n abin oids in h u m an s. Oth er sym ptom s

from opiates an d is n ow th e drug m ost frequ en tly u sed for

are euphoria, uncontrollable laughter, depersonalization, and

th is p u rp ose.

sh arp en ed vision , as in th is case.

oid drug act ing m ain ly on µ (m u ) receptors is th e best st rat-


A, C−E Th e beh avioral sign s an d sym ptom s cau sed by t h ese d r ugs are d i eren t from t h ose exh ibited by t h is girl.

Learning objective: Outline the use of buprenorphine in the longterm managem ent of opiate dependence.

Moreover, a t yp ical som at ic e ect of LSD an d cocain e is

13. B Detoxi cat ion from opioids follow s th e gen eral p rin ciples

n eith er of w h ich occu rred in th is girl.

m ydriasis, w h ereas h eroin an d ph en cyclidin e cause m iosis,

th at are valid for all drugs of abu se. It is conven ien t to ch ange orally act ive an d ph arm acologically equivalen t opioid, th en

Learning objective: Describe the use of naltrexone in ethanol dependence.

to reduce th e dose of th at opioid gradually. Meth adon e w as

16. D Exp erim en tal st u d ies in an im als suggest th at alcoh ol

exten sively used in th e past , but m ore recen tly th e in t rodu c-

d rin king is in uen ced by op iate receptor act ivit y an d is re-

t ion of bu p ren orp h in e, a p art ial µ (m u ) op ioid agon ist , h as

d uced by opiate an t agon ist act ion . Several clin ical t rials h ave

rep resen ted a m ajor ch ange in t h e t reat m en t of op iate ad -

sh ow n th at n alt rexon e decreases th e rate of relap se to alco-

d ict ion . Th e drug produces m in im al w ith draw al sym ptom s

h ol con sum pt ion an d redu ces alcoh ol craving. Th e drug h as

w h en stopped an d h as low poten t ial for overdose, a long du-

been ap proved by th e U.S. Food an d Drug Adm in ist rat ion for

rat ion of act ion , an d th e abilit y to block h eroin e ect s.

th is p u rpose.

th e p at ien t from an in t raven ou s opioid su ch as h eroin to an

A, B Diazep am an d clon idin e are u sed to t reat eth an ol ab st in en ce syn drom e, bu t th ey do n ot red u ce eth an ol craving in alcoh olics.

Answers and Explanations: III-13 Drugs of Abuse 185 C Disul ram is used to in du ce a con dit ion ed aversion to

• Fat igu e

alcoh ol, bu t th e rat ion ale for its u se is n ot based on a rela-

• Di cult y in con cen t rat ing

t ion sh ip bet w een eth an ol craving an d opioid act ivit y.

• Dysp h oric, an xiou s, or dep ressed m ood

E, F Meth adon e an d bupren orph in e are n ot used to t reat eth an ol depen den ce.

• Cough , dr y th roat , n asal drip • Con st ip at ion , stom ach pain • Decreased h eart rate, hyp oten sion

Learning objective: Describe the signs and symptom s of opiate withdrawal.

• In creased ap p et ite an d w eigh t gain

17. A Th e pat ien t’s sign s an d sym ptom s in dicate th at h eroin w as

listed in th ese opt ion s.

B−E Nicot in e abst in en ce sym ptom s are opp osite to th ose

th e drug from w h ich h e w as exp erien cing w ith draw al. Opi• Prodrom al p h ase, ch aracterized by au ton om ic act ivat ion

Learning objective: Describe the signs and symptom s of benzodiazepine withdrawal.

(rh in orrh ea, lacrim at ion , salivat ion , yaw n ing, an d sw eat-

20. C People w h o h ave been using h igh doses of ben zodiaze-

oid abst in en ce syn drom e in cludes

ing) th at last s 6 to 10 h ou rs

p in es, su ch as alprazolam , for long periods can exp erien ce

• Acu te w it h d raw al syn d rom e, ch aracter ized by a h igh de-

w ith draw al sym ptom s on abrupt term in at ion of th e adm in -

gree of beh avioral, som at ic, an d au ton om ic act ivat ion

ist rat ion . Th e w ith draw al syn drom e m ay in clud e th e follow -

(restlessn ess, sh aking ch ills, piloerect ion , n ausea, abdom -

ing sym ptom s:

in al cram p s, etc.) th at last s abou t 7 to 10 days.

• Follow ing m od erate dose u sage: an xiet y, agit at ion , in -

• Prot racted w ith draw al syn drom e, ch aracterized by su btle sign s an d sym ptom s th at can p ersist for u p to 6 m on th s.

creased sen sit ivit y to ligh t an d sou n d, paresth esias, m yoclon ic jerks, sleep dist urban ces, dizzin ess

Du ring th is period, th e recidivism rate is h igh .

• Follow ing h igh -dose u sage: deliriu m , seizu re

B, C Abst in en ce syn d rom e from th ese dr ugs is p rim arily

Th e abr u pt on set of t h e w ith d raw al syn d rom e, as w ell as

ch aracterized by depressive sym ptom s (depression , sleepi-

it s severit y, is a fu n ct ion of th e h alf-life of th e drug. Ben zodi-

n ess, an d fat igue).

azepin es w ith sh or ter elim in at ion h alf-lives (alprazolam ,

D−F Th ere is n o eviden ce of a clin ically sign i can t w ith draw al syn drom e for th ese drugs in h u m an s.

lorazep am , tem azep am , an d m idazolam ) p rodu ce a rapid ly evolving and severe w ithdraw al syn drom e (sym ptom s w ithin 12 to 24 h ou rs after th e last dose), w h ereas th ose w ith lon -

Learning objective: Describe the signs and symptom s of opiate poisoning.

ger h alf-lives u su ally h ave a bu ilt-in tapering-o act ion th at

18. B Th e t riad of com a, m iosis, an d resp irator y dep ression in di-

du rat ion .

cates th at h eroin w as m ost likely th e drug th e w om an h ad self-injected . Accid en t al overd osage is n ot u n com m on in ad dicts, as th e dose of an illicit drug is n ever accu rate. Th e respirator y rate can be ver y low, or th e pat ien t m ay even be

m akes th e w ith draw al syn drom e less severe but longer in A No w ith draw al syn drom e from a h allucin ogen ic dr ug su ch as LSD h as been obser ved. B, D−F Seizures are except ion ally rare in w ith draw al syn drom es from th ese drugs.

apn eic, an d cyan osis is often p resen t . Th e p u p ils are sym m et rical an d p inpoin t in size, alth ough if hyp oxia is severe,

Learning objective: Explain the mechanism of action of disul ram.

th ey m ay be dilated. Blood p ressu re can be n ear n orm al at

21. B Th e h istor y an d sym ptom s of th e p at ien t p oin t ou t t h at

rst but falls progressively. A, C−F Overdose of th ese drugs is n ot ch aracterized by pin p oin t p up ils.

t h e adm in istered drug w as m ost likely disu l ram , an agen t app roved by th e U.S. Food an d Drug Adm in ist rat ion for th e t reat m en t of alcoh olism . By in h ibit ing ald ehyd e dehyd rogen ase, disu l ram causes an accum ulat ion of acetaldehyde,

Learning objective: Describe the m ain sym ptom s of nicotine abstinence.

th e su bst an ce resp on sible for th e toxic sym ptom s exh ibited

19. A Upon su dden cessat ion of sm oking tobacco, in d ividu als

ram is based on th e p rem ise th at th e p at ien t w ill n ot drin k

w h o sm oke 20 or m ore cigaret tes daily develop an abst i-

eth an ol because of th e unpleasan t e ect th at occurs w h en

n en ce syn drom e, w h ich is usually n ot severe. It s m ain fea-

eth an ol is adm in istered w ith disul ram . Alth ough e ect ive

t u res are

p h arm acologically, th e d rug h as n ot been foun d e ect ive in

• Irritabilit y and restlessness (the m ost com m on sym ptom s)

clin ical t rials because com plian ce w ith th is th erapy is often

• Craving for cigaret tes (u su ally in ten se an d p ersisten t)

ver y low.

• In som n ia

by th e pat ien t . Th e rat ion ale beh in d th e th erapy w ith disul-


186


Learning objective: Describe the adverse e ect s of cannabis.

Learning objective: Describe the adverse e ects of cocaine.

22. E Th e sign s of th e pat ien t (redden ing of th e conjun ct iva w ith

25. E Sm oking freebase cocain e (crack) is a com m on cau se of

n o ch ange in p u p il d iam eter, a fast p u lse, an d a d i u se

d i use alveolar h em orrh age. Oth er causes are Goodpast ure

t rem or) suggest th at th e boy w as sm oking m ariju an a an d

syn drom e, system ic lu p u s er yt h em atosu s, system ic vascu -

w as exp erien cing an acu te pan ic react ion . Th is react ion is

lit is, an d rap idly p rogressing glom er u lon ep h r it is. Bilateral

th e m ost frequ en tly rep or ted adverse e ect of can n abis, an d

alveolar in lt rates are t yp ical of di u se alveolar h em or-

several su r veys in dicate th at abou t on e h alf of can n abis

rh age. Bron ch oscopy is th e m ost u sefu l procedu re in de n -

u sers h ave repor ted at least on e pan ic experien ce.

ing bleeding sites an d determ in ing w h eth er th ey are local or

A, B Am ph et am in e an d cocain e w ou ld h ave cau sed p ron oun ced m ydriasis.

d i use. A−D Non e of t h ese d r ugs cau se d i u se alveolar h em or-

C A p an ic react ion is except ion ally rare w it h gam m a-

rh age.

hydroxybu t yric acid. D Heroin w ould h ave cau sed pron ou n ced m iosis.

Learning objective: Describe the illicit uses of gam m a-hydroxybut yric acid (GHB).

Learning objective: Describe the signs and symptom s of delirium tremens.

26. F Th e girl w as m ost likely raped after a drug w as added to

23. E Delirium t rem en s ch aracterizes st age 4 of eth an ol abst i-

com m ission of a sexu al assault . Drugs used to facilitate rape

n en ce syn drom e. It in cludes terrifying visual (or, less fre-

m ay h ave sedat ive, hyp n ot ic, d issociat ive, or am n esiac ef-

quently, auditor y or tactile) hallucinations, m arked w eakness,

fect s an d can be added to food or drin k w ith out th e vict im ’s

gross disorien t at ion in space an d t im e, con fusion , aggres-

kn ow ledge. Th e th ree m ost com m on ly used date rape drugs

sion , ext rem e psych ic agit at ion , coarse t rem ors of th e h an ds,

are alcoh ol, gam m a-hydroxybu t yric acid (GHB), an d ben zo-

head, an d trunk, m arked ataxia, nystagm us, m uscular cram ps,

d iazepin es (e.g., u n it razep am ). Alcoh ol is m ost frequen tly

an d sign s of auton om ic act ivat ion (sw eat ing, n au sea an d

im plicated in su bst an ce-assisted sexu al assau lt . Both ben zo-

vom it ing, abdom in al pain , hyperten sion , m ydriasis, tachy-

d iazep in es an d GHB can cau se an terograd e am n esia, t h u s

cardia, tachypn ea, an d hyperth erm ia). Th e life-th reaten ing

m aking th e vict im u n able to recall th e sexu al assau lt .

poten t ial of alcoh ol abst in en ce syn drom e is th e h igh est of all

h er drin k. Such “date rape” drugs can be used to assist in th e

A−E Th ese are n ot “date rape” drugs.

su ch syn drom es. W h en deliriu m t rem en s occu rs, th e m oran d is about 35% in un t reated cases. Death usually occurs

Learning objective: Describe the signs and symptom s of m ethanol poisoning.

from resp irator y failu re an d cardiac arrhyth m ias.

27. F Meth an ol (m ethyl alcoh ol) is exten sively u sed in clean ing

talit y ranges from 5 to 15%, despite app ropriate t reat m en t ,

A Mydriasis, n ot m iosis, is a prom in en t sym ptom .

p roducts, fu el for sm all stoves, p ain t st rippers, an d gas lin e

B Hypertension, not hypoten sion, is present in m ost cases.

an t ifreeze. Poison ing som et im es occu rs in h om eless alcoh ol-

C Hyp er t h er m ia, n ot hyp oth er m ia, is a p rom in en t

ics w h o drin k m eth an ol w h en th ey are ou t of m on ey an d

sym ptom .

can n ot p u rch ase th e daily am ou n t of alcoh ol th ey requ ire.

D Mu scu lar cram p s, n ot rela xat ion , is a p rom in en t sym ptom .

Sym ptom s of m eth an ol p oison ing m ay app ear as soon as 12 h ours follow ing ingest ion , bu t th ey usually develop 24 h ours after in gest ion . Th ese m ay resem ble et h an ol in toxicat ion

Learning objective: Describe the sym ptom s of ethanol withdrawal.

an d con sist of drow sin ess, con fu sion , an d at axia, as w ell as

24. C Et h an ol w it h d raw al can occu r w h en an alcoh olic p erson

Meth an ol toxicit y in h u m an s is p rim arily du e to m etabolism

is forced to stop drin king because of som e extern al even t ,

to for m ald ehyd e an d for m ic acid , a react ion cat alyzed by

su ch as th e h osp ital adm ission in th is case. Th e sign s an d

t h e en zym e alcoh ol dehydrogen ase. As m eth an ol m et abo-

sym ptom s of th e p at ien t (agitat ion , t rem u lou sn ess, an d h al-

lism p roceed s, th e accum u lat ion of th ese m etabolites leads

lu cin at ion s) are con sisten t w ith th e

rst ph ase of alcoh ol

to a severe an ion gap m etabolic acidosis. Severe m et abolic

w ith draw al th at t ypically occurs 8 to 48 h ours after th e last

acid osis in conju n ct ion w it h visu al e ect s is t h e h allm ark

eth an ol in t ake.

of m eth an ol poison ing. Pat ien t s u su ally describe blu rred or

A, B, D, E Th ese even t s do n ot cau se th e syn drom e exh ib ited by th e pat ien t .

w eakn ess, h eadach e, n au sea, vom it ing, an d abdom in al pain .

m ist y vision (e.g., being in a sn ow storm ), dou ble vision , or ch anges in color percept ion . Th ere m ay be con st ricted visual

Answers and Explanations: III-13 Drugs of Abuse 187 eld an d , occasion ally, tot al loss of vision . Ch aracter ist ic visu al dysfu n ct ion s in clu d e p u p illar y dilat ion an d loss of

m ovem en t s, bradycardia (about 30% of pat ien ts), an d hypoth erm ia, n ot hyper th erm ia.

p u pillar y re ex. Treat m en t of m eth an ol poison ing in cludes su pp ression of it s m et abolism to toxic produ cts. Becau se

C−F Th e risk of death from overdose by th ese d rugs is n egligible.

eth an ol is m etabolized preferen t ially by alcoh ol dehydroget h e biot ran sfor m at ion of m et h an ol to it s toxic m et abolites.

Learning objective: Explain the m echanism of action of phencyclidine.

A m ore speci c in h ibitor of alcoh ol dehydrogen ase, fom epi-

31. E Th e ver t ical an d h or izon t al nyst agm u s sh ow ed by t h e

zole, h as been ap p roved for t reat m en t of m eth an ol an d eth -

p at ien t suggest s th at sh e sm oked ph en cyclidin e-drugged

ylen e glycol poison ing.

cigaret tes. Nyst agm u s (ver t ical, h orizon tal, or rotator y) is

n ase, it s adm in ist rat ion (orally or in t raven ously) can retard

A−E Th ese syn drom es do n ot cause th e sign s an d sym p tom s exh ibited by th e pat ien t .

con sidered a h allm ark of ph en cyclidin e in toxicat ion , as it is p resen t in u p to 69% of cases. Ph en cyclidin e bin ds w ith h igh a

n it y an d blocks th e N-m ethyl- d -aspar tate (NMDA) sub -

Learning objective: List the m ain risks of cannabis use in people with a history of schizoa ective disorder.

t yp e of glut am ate receptors in th e brain . Th is seem s to be

28. C Th e ordin ar y u se of can n abis p rodu ces lit tle or n o dist u r-

an ism s h ave been proposed, in cluding th e act ivat ion of µ

ban ces of beh avior in people w ith stable person alit y. How -

(m u) opioid receptors, w h ich m ay accoun t for it s an algesic

ever, th ere are n um erous clin ical report s th at can n abis use

propert ies.

can p recip it ate a recu r ren ce in p eop le w it h a h istor y of

th e m ain m ech an ism of act ion of the drug, but oth er m ech -


sch izop h ren ia. A A depressive episode after can n abis use is ext rem ely rare. B, D, E Can n abis use does n ot in crease th e risk of th ese d isorders.

Learning objective: Describe the adverse e ects of LSD. 32. F Th e sym ptom s an d sign s of th e pat ien t in dicate th at sh e h ad taken LSD (lysergic acid diethylam ide) an d w as experien cing a m ild adverse m en t al e ect th at in th e u sers’ jargon is a “bad t rip.” A m ore severe p sych ot ic react ion can rarely

Learning objective: Identify the drug of abuse that does not result in physical or psychological dependence.

occur w ith terrifying h allucin at ion s, pan ic react ion s, loss of

29. C Un like m ost recreat ion al d r ugs, h allu cin ogen ic agen t s

to th is as a “freak-out .”

em ot ion al con t rol, an d cat alept ic beh avior. Th e u sers refer

su ch as LSD in duce n eith er physical n or psych ological de-

A Cocain e can cau se som e of t h e p at ien t ’s sign s an d

p en den ce an d th erefore do n ot lead to add ict ion . A likely

sym ptom s (m ydriasis, tachycardia, in creased blood pressure,

reason for th is is th at th ese drugs prim arily in uen ce cor t i-

sw eat ing, an d t rem or), bu t th e t ype of illu sion sh e exp eri-

cal an d th alam ic circu its an d do n ot act ivate th e m esolim bic

en ced (room fu rn it u re being “alive”) is an ext rem ely rare

d op am in e rew ard system .

e ect of cocain e overd ose.

A, B, D−F All of th ese dr ugs can cau se m ore or less p ron ou n ced physical depen den ce w h en used ch ron ically.

B Op ioid e ect s are m ain ly d ep ressan t in n at u re, an d m iosis, n ot m ydriasis, is a p rom in en t sign . C A ver y large dose of can n abin oids can cause distor t ion of

Learning objective: Describe the syndrom e of cocaine overdose.

visual percept ion an d h allucin at ion s, but th ese are usually

30. G Th e pat ien t’s syn drom e w as m ost likely due to cocain e

accom p an ied by drow sin ess an d leth argy, n ot by excit at ion .

overd ose. Th is syn d rom e is often rapidly fatal becau se of sei-

D Am yl n it rite is a volat ile liqu id th at is som et im es abused

zu res, resp irator y d ep ression , an d ar rhyt h m ias, as in t h is

to en h an ce orgasm . It can on ly produce a t ran sien t feeling of

case.

“ru sh ,” u sh ing, an d dizzin ess.

A Death can occur from h eroin overdose, but the syndrom e

E Ph en cyclidin e causes e ects th at can be sim ilar to th ose

is ch aracterized by com a, sh allow breath ing, an d m iot ic, n ot

of LSD, bu t nyst agm u s is a prom in en t e ect of th e drug an d

m ydriat ic, pu pils.

is absen t in th is pat ien t .

B Death can occur from gam m a-hydroxybu t yric acid overd ose, but th e syn drom e is ch aracterized by com a, m yoclon ic

188


Learning objective: Describe the adverse e ects of phencyclidine.

disturban ces, n ausea, cram ping, an d sweating. The syndrom e

33. C Th e sign s an d sym ptom s of th e pat ien t suggest th at ph en -

is n ever leth al.

cyclidin e w as m ost likely th e self-adm in istered drug. Ph en cyclidin e causes e ect s th at are di eren t from th ose of

C, E Th ere are n o dat a repor ted in th e literat ure of an in creased risk of th ese d iseases w ith th e u se of can n abis.

p sych edelic drugs such as LSD. In low doses, th e drug cau ses im age, an d a m in d−body dissociat ive feeling. Horizon t al nys-

Learning objective: Explain the m echanism of action of m ethylenedioxym ethamphetam ine (MDMA).

t agm u s, vert ical nystagm u s, or both are often p resen t an d

36. B Th e pat ien t’s sign s an d sym ptom s (hyperth erm ia, m en t al

are con sidered h allm arks of ph en cyclidin e in toxicat ion . As

stat u s ch anges, an d m u scle rigidit y) suggest th at h e w as

th e dose of p h en cyclidin e in creases, th e p at ien t m ay m an i-

m ost likely su ering from serotonin syndrom e. MDMA causes

fest agit at ion , h ost ile an d assau lt ive beh avior (un like psy-

th e release of m on oam in es by reversing th e act ion of th eir

ch edelic dr ugs, w h ich ver y rarely cause su ch beh avior). Th e

respect ive t ran spor ters. It h as a preferen t ial a

act ion of th e drug on th e au ton om ic n er vou s system be-

ton in t ran spor ter result ing in in creased syn apt ic levels of

com es m ore prom in en t an d is ch aracterized by a con fusing

seroton in . Th e release of th is n eu rot ran sm it ter is so great

com bin at ion of adren ergic, ch olin ergic, an d dopam in ergic

th at th ere is a m arked in t racellu lar deplet ion for 24 h ou rs

e ect s. A hyp er ten sive resp on se is t yp ically en cou n tered .

after a single d ose

em ot ion al w ith draw al, in ebriat ion , at axia, ch anges in body

Tachycardia, tachyp n ea, hyp er th erm ia, an d m iosis (or, m ore

n it y for sero-


rarely, m ydriasis) m ay also be n oted. Th e agit ated, com bat ive w ith th e an esth et ic e ect of th e drug, can result in serious

Learning objective: Calculate the quantit y of ethanol consum ed by a subject, given su cient data.

injur y becau se th ere is n o pain sen sat ion to stop th e physical

37. B Th e qu an t it y of a d r ug in a p erson’s body can be calcu -

p at ien t often h as feelings of great st rength . Th is, com bin ed

act ivit y. With ver y large doses, cat aton ia an d com a can occu r w ith m uscular rigidit y th at can cause rh abdom yolysis. A, B, D, E All of th ese drugs can cau se som e or m any of th e sym ptom s exh ibited by th e p at ien t , bu t nystagm u s is rare.

lated by Am oun t = Cp × Vd , w h ere Cp is p lasm a con cen t rat ion an d Vd is volu m e of d ist ribu t ion . Th erefore, th e qu an t it y in th e p at ien t’s body on ad -

Learning objective: Describe the use of ethanol in ethylene glycol poisoning. 34. C Poison ing by ethylen e glycol is n ot un com m on in you ng ch ild ren becau se of it s sw eet t aste. Th e ch em ical it self is

m ission w as about 225 g, a quan t it y close to th e leth al dose for 50% of subject s (LD50 ) of eth an ol. A, C−F See correct an sw er exp lan at ion .

relat ively n on toxic, but it is biot ran sform ed in to h ippu ric,

Learning objective: Describe the m echanism of action of LSD.

oxalic, an d glycolic acid s by t h e en zym e alcoh ol d ehyd ro -

38. D LSD (lysergic acid diethylam ide) is a sem isyn th et ic ergot

gen ase. Th ese m et abolites are toxic an d can cau se severe

alkaloid. Exten sive st u dies h ave sh ow n th at th e drug, like

m et abolic acidosis, ren al failu re, an d com a. Met abolism of

m ost ergot d er ivat ives, in teract s w it h several seroton in re-

ethylen e glycol to its toxic products can be blocked by in h ib -

ceptor subt ypes in th e brain (m ain ly 5-HT1A an d 5-HT2 A) as

iting alcohol dehydrogenase. Ethanol is m etabolized preferen-

a fu ll or p ar t ial agon ist . It ap p ears to act as a fu ll agon ist at

tially by alcohol dehydrogenase; therefore, its adm inistration

5-HT1A autoreceptors in raph e n euron s, p rod u cing a m arked

(orally or in t raven ou sly) can retard th e biot ran sform at ion of

slow ing of t h e r ing rate of seroton ergic n eu ron s. Act ion on

ethylen e glycol to its toxic m et abolites.

5-HT2A receptors ap p ears to disru pt th alam ic gat ing, w h ich


in t urn cau ses sen sor y overload of th e brain cortex. A−C, E, F See correct an sw er explan at ion .

Learning objective: List the m ain risks of cannabinoid use. cept ion , th e risk of driving or w ork acciden t s is in creased in

Learning objective: Describe the symptom s of amphetam ine withdrawal.

p eople w h o are using can n abis.

39. D Sign s an d sym ptom s of w ith draw al from an abused drug

35. D Because can n abis alters th e sen se of t im e an d spat ial per-

A Th ere is n o recorded death from paren teral inject ion of

ten d to be opposite to th e origin al e ect s produced by th at

p ure h ash ish oil. Th e th erapeu t ic in dex of can n abin oids is

d r ug. Th erefore, t h e w it h d raw al syn d rom e from p sych o -

exceedingly h igh .

st im u lan t drugs su ch as am ph et am in es an d cocain e is m an ly

B A m ild abst in en ce syn drom e h as been described follow -

depressant in n ature and includes som n olence, headache, de-

ing ch ron ic use of ver y h igh doses. Th e syn drom e in cludes

pression, and lack of m otivation. Because am phetam in e- like

increased restlessness, irritabilit y, confusion, in som n ia, sleep

drugs cause anorexia, a ravenous appetite is also a p rom in en t

Answers and Explanations: III-13 Drugs of Abuse 189 sym ptom of w it h d raw al. Th e w it h d raw al syn d rom e from

such as the brain and the liver. Nearly all in halants have cen -

am ph et am in e-like drugs m ay last for several days.

t ral n er vou s system (CNS) d ep ressan t e ect s, an d evid en ce

A−C, E Th e w ith draw al syn drom e from th ese drugs is m ain ly excit ator y in n at u re.

from an im al st u d ies suggest s t h at t h eir e ect s an d m ech an ism of act ion are sim ilar to t h ose of alcoh ol an d ot h er sedat ive-hyp n ot ics. Th ey produ ce a tem porar y st im u lat ion

Learning objective: Describe the adverse e ects of chronic ethanol use.

an d redu ced in h ibit ion before th e dep ressive CNS e ect s

40. E Ch ron ic u se of h igh doses of eth an ol can dam age several

u sers m ay n ot be exp osed to levels w it h su

occur. In h alan t abu se is t ypically episodic in n at ure; t h u s, cien t frequen cy

organ s, but th e liver, brain , an d h ear t are th e on es m ost fre-

n ecessar y to develop physical depen den ce. How ever, it is a

qu en tly involved. Dilated cardiom yopathy is due to exten -

ver y dangerous h abit because in h aling h igh ly con cen t rated

sive m yocardial brosis w ith di u se loss of m yocytes. Th is

am ou n ts of th e ch em icals can cau se h eart failu re an d d eath

results in th in n ing of h eart w alls, con sequ en t dilat ion of

w ithin m inutes after repeated inhalation (a syndrom e know n

ven t ricu lar ch am bers, an d h eart failure. Pat ien ts w ith ad-

as “su dden sn i ng death ”).

van ced alcoh olic cardiom yopathy an d severe h ear t failu re


h ave a poor progn osis, part icularly if th ey con t in ue to drin k; less th an on e qu ar ter of such p at ien t s su r vive 3 years. A–D, F Th e in creased r isk of t h ese d iseases d u e to alcoh olism is low or n egligible.

Learning objective: Describe the interaction bet ween ethanol and other central nervous system (CNS) depressants. 43. C Th e p at ien t ’s h istor y an d blood exam s suggest t h at h is d eath w as m ost likely due to a com bin at ion of h eroin (w h ich

Learning objective: Describe the polyneuropathy that can occur after chronic administration of nitrous oxide.

is converted to m orph in e) an d alcoh ol. Eth an ol en h an ces th e

41. B Th e p at ien t w as m ost likely su er in g from p olyn eu rop a-

sedat ive-hyp n ot ics, op ioids, several n eu rolept ics, an d som e

t hy du e to ch ron ic adm in ist rat ion of n it rou s oxide. Th is gas

an t ih ist am in es, as w ell as th e e ects of som e p sych ost im u-

can be fou n d easily becau se it is u sed in th e food an d car in -

lan t drugs, in clu ding cocain e an d am ph etam in e. Th e in ter-

d ust ries. Com m on sources are car t ridges u sed to rech arge

act ion bet w een alcoh ol an d sedat ive-hypn ot ics or op ioid s

w h ip p ed cream con t ain ers. Th e br ief eu p h or ia p rodu ced

is p art icu larly prom in en t , an d several st u dies in dicate th at

by n it rou s oxid e m akes it p ron e to abu se. Th e m ech an ism

eth an ol subst an t ially decreases th e m in im u m leth al con cen -

of n it rou s oxid e−in d u ced n eu rop at hy is st ill u n cer t ain bu t

t rat ion of h eroin , as in th is case.

seem s related to a de cien cy of vit am in B12 , becau se th e

sedat ive e ect s of m ost ot h er CNS d ep ressan t s, in clu ding

A, B, D, E Th ese drugs do n ot en h an ce th e CNS depressan t

drug in act ivates th e vit am in by oxidat ion of th e cobalt atom .

e ect s of op ioids. Death du e to a com bin at ion of an op ioid

Th e d e cien cy is m ore likely in p erson s already at r isk of

an d on e of th e listed dr ugs is except ion ally rare.

vitam in B12 de cien cy, as in th is case (see th e long h istor y of alcoh olism ). A Am yl nit rite is som et im es abused but does n ot cause polyn eu ropathy. C−E Th ese are n ot abused drugs.

Learning objective: Di erentiate bet ween cocaine and m etham phetam ine e ect s. 44. D Th e pat ien t’s h istor y an d sym ptom s in dicate th at h e w as m ost likely su ering from a p sych ost im u lan t overdose. Cocaine and am phetam ines have ver y sim ilar physiological and

Learning objective: Describe the pat tern of central e ects caused by inhalants.

p sych ological e ects. Alth ough th e sp eci c m ech an ism s of

42. E In h alan ts are a group of subst an ces w h ose ch em ical va-

lar; th at is, both can in crease th e availabilit y of m on oam in es

p ors can be in h aled to produce pleasan t e ects. W h ereas

in th e syn apt ic cleft of brain n eu ron s. Th is exp lain s w hy

oth er abused substan ces can be in h aled, th e term inhalant s

even exp er ien ced d r ug u sers can n ot d ist in gu ish t h e e ect

is used to describe subst an ces th at are rarely, if ever, t aken in

of th e t w o drugs w h en th ey are injected in t raven ou sly; th e

any oth er w ay. A variet y of produ ct s com m on in th e h om e

orgasm -like sen sat ion is pract ically th e sam e. Th e pat ien t’s

an d w orkp lace con t ain su bst an ces th at can be in h aled. Th ese

h istor y, however, indicates that am phetam ine was m ost likely

in clude volat ile solven t s, su ch as glu es an d st ain rem overs,

th e cu lprit dr ug, as th e e ects of am ph et am in e can last sev-

an d aerosols th at con tain p rop ellan t s an d solven t s, su ch as

eral h ou rs, w h ereas th e e ect s of cocain e gen erally last less

d eodoran t sprays an d w h ipped cream aerosols. Ch ildren an d

th an 1 h ou r.

act ion are d i eren t , th e n al m olecu lar act ion is qu ite sim i-

adolescen ts are p ar t icu larly p ron e to th is form of abu se be-

A See correct an sw er explan at ion .

cau se th e ch em icals can be easily fou n d at h om e. Gases an d

B, C, E, F Th ese drugs do n ot cause th e pat tern of e ect s

vapors are rapidly absorbed w h en in h aled an d ten d to distribute preferen tially in lipid-rich an d highly perfused organs,

sh ow n by th e pat ien t .

190

Central Nervous System DRUGS of ABUSE Answ er key 1. 2. 3. 4. 5.

N A F B G

6. 7. 8. 9. 10.

C D A B C

11. 12. 13. 14. 15.

B B B E B

16. 17. 18. 19. 20.

D A B A C

21. 22. 23. 24. 25.

B E E C E

26. 27. 28. 29. 30.

F F C C G

31. 32. 33. 34. 35.

E F C C D

36. 37. 38. 39. 40. 41. 42. 43. 44.

B B D D E B E C D

IV Cardiovascular and Renal System s Questions: IV-1 Diuretics Directions for questions 1−5


Match each diu ret ic w ith th e ap p rop riate descript ion (each let-

7. A 27-year-old w om an w ith a h istor y of h igh alt it ude sickn ess

tered opt ion can be selected on ce, m ore th an on ce, or n ot at all).

w as p laced on prophylact ic t reat m en t w ith a diu ret ic drug

A. Acetazolam ide

prior to going on a h iking t rip in th e Rocky Mou n tain s. W h ich

B. Am iloride

of th e follow ing urin e elect rolyte pro les is m ost con sisten t

C. Con ivaptan

w ith th is drug t reat m en t?

D. Eth acr yn ic acid

HCO3−

Na+

Ca 2+

K+

P

++

+

0

+

G. Sp iron olacton e

Q

+

++

+

+

H. Triam teren e

R

+

++

−

++

S

+

+++

+

++

T

0

+

−

−

E. In dapam ide F.

Man n itol

Di cult y level: Easy 1. Th is drug in h ibits Na + reabsorpt ion in th e proxim al t ubule.

Note: +, increased; −, decreased; 0, negligible changes.

A. Pro le P


B. Pro le Q

2. Th is drug in h ibits th e syn th esis of n ew Na + ch an n els in th e

C. Pro le R

collect ing duct .

D. Pro le S E. Pro le T

Di cult y level: Easy 3. Th is drug causes an in it ial ext racellular volum e expan sion in n orm al subjects.

Di cult y level: Medium 8. A 69-year-old depressed m an w ith a 10-year h istor y of glau com a w as ad m it ted to t h e em ergen cy d ep ar t m en t after h e

Di cult y level: Easy 4. Th is drug in creases th e ren al reabsorpt ion of Ca 2+.

Di cult y level: Easy 5. Th is d r ug com p et it ively blocks an t id iu ret ic h or m on e receptors.

Di cult y level: Easy 6. A 56-year-old w om an recen t ly d iagn osed w it h congest ive h ear t failure st arted a th erapy th at in cluded fu rosem ide. Acet azolam ide w as added to coun teract th e poten t ial m et abolic

took several t ablet s of on e of h is m ed icat ion s in a su icide at tem pt . Th e pat ien t w as drow sy an d com plain ed of n ausea, paresth esias, an d t iredn ess. Physical exam in at ion revealed eryth em atou s skin eru pt ion s. Lab tests in d icated hyp erch lorem ic m et abolic acidosis. W h ich of th e follow ing m edicat ion s m igh t h ave caused th e pat ien t’s sym ptom s? A. Man n itol B. Latan oprost C. Tim olol D. Acetazolam ide E. Pilocarpin e

alkalosis in du ced by furosem ide. W h ich of th e follow ing m olecu lar act ion s m ost likely m ediated th e th erapeu t ic e ect of acetazolam ide in th is pat ien t? A. In h ibit ion of carbon ic acid dehydrat ion in th e t ubu lar lu m en B. St im u lat ion of bicarbon ate reabsorpt ion in th e p roxim al t u bu le C. In h ibit ion of Na + reabsorpt ion in th e early distal t u bule D. St im ulat ion of H+ reabsorpt ion in th e p roxim al t u bu le E. St im u lat ion of carbon ic acid form at ion in side th e t u bu lar cells 191

192

Cardiovascular and Renal System s



9. A 55-year-old alcoh olic m an w as adm it ted to th e em ergen cy

12. A 67-year-old m an w as foun d to h ave a plasm a calciu m level

d epart m en t because of disorien tat ion , am n esia, con fu sion ,

of 12.2 m g/dL during a follow -up visit . Th e m an h ad a 3-year

an d bizarre beh avior for th e past 24 h ou rs. His w ife reported

h istor y of Hodgkin lym ph om a. He w as recen tly diagn osed

th at th e m an w as being t reated for hyp er ten sion an d for re-

w it h n ep h rolit h iasis for w h ich h e h ad been t reated w it h

cen tly diagn osed glaucom a. Physical exam in at ion revealed a

hyd roch loroth iazide for th e past 3 w eeks. W h ich of th e fol-

cach ect ic m ale in a con fu sed m en t al state. His abdom en ap -

low ing best explain s th e m ost likely m ech an ism of th iazide-

p eared ten se w ith prom in en t vein s an d ascites, an d a m ust y,

in duced hyp ercalcem ia?

p ungen t odor w as n oted in h is breath . Neurologic sign s in -

A. Act ivat ion of th e Na +/Ca 2+ exch anger in th e dist al t ubule

cluded nystagm us, ataxia, and asterixis. W hich of the follow -

B. In creased Ca 2+ reabsorpt ion in th e p roxim al t u bu le

ing drugs m ost likely t riggered th e pat ien t’s syn drom e?

C. Decreased secret ion of parathyroid h orm on e

A. Acetazolam ide

D. Decreased ren al excret ion of vitam in D

B. Nifedipin e

E. Act ivat ion of Na +/K+/2Cl− sym por ter in th e th ick ascen ding loop of Hen le

C. Losar t an D. Tim olol

F.

In creased glom erular ltrat ion of Ca 2+

E. Lovast at in


13. A 67-year-old w om an w as foun d to h ave a plasm a level of

10. A 54-year-old w om an recen tly diagn osed w ith open -angle

p ot assium 2.8 m Eq/L (n orm al 3.5−5.0 m Eq/L) du ring a fol-

glau com a w as p rescribed top ical t im olol. Tw o w eeks later,

low -up visit . Th e w om an h ad been receiving hydroch loro-

in t raocular pressure w as decreased but w as st ill above th e

th iazide for 1 m on th to t reat h er recen tly diagn osed essen t ial

n orm al value. Th e oph th alm ologist decided to add a topical

hyp er ten sion . W h ich of th e follow ing act ion s m ost likely

d r ug t h at act s by d ecreasing aqu eou s h u m or p rodu ct ion .

con t ributed to th e th iazide-in duced in crease in ren al excre-

W h ich of t h e follow ing d r ugs w as m ost likely p rescr ibed as

t ion of p otassiu m ?

th e secon d drug?

A. In creased Na + load in th e lum en of th e collect ing t ubule

A. Pilocarpin e

B. Blockade of Na +/K+/2Cl− cot ran spor ter

B. Carbach ol

C. Th iazide-in du ced d ecrease in ren al secret ion of u ric acid

C. Latan oprost

D. St im u lat ion of Na +/K+ p um p

D. Dorzolam ide

E. Decreased deliver y of bicarbon ate to th e collect ing du ct

E. Man n itol

Di cult y level: Hard Di cult y level: Hard

14. A 52-year-old alcoholic m an su ering from liver cirrhosis w as

11. A 15-year-old boy aw oke w ith w eakn ess an d 1 h our later re-

adm it ted to the em ergency departm ent because of a 2-w eek

alized th at h e cou ld n ot m ove h is legs. Th e at tack lasted

h istor y of n ausea, vom it ing, an d low er abdom in al cram ps.

abou t 2 h ou rs bu t th en d isap peared w ith ou t residu al sym p -

Physical exam in at ion sh ow ed a ten se abdom en w ith prom i-

tom s. Th e boy w as referred to a n eurologic clin ic, w h ere th e

n en t vein s, an d 3+ ascites w as n oted by sh ift ing dulln ess an d

d iagn osis of fam ilial hypokalem ic periodic paralysis w as

a u id w ave. A diagn osis of ascites w as m ade, an d an ap p ro-

m ade. He w as prescribed p ot assiu m ch lorid e an d a diu ret ic

p riate th erapy w as star ted . W h ich of th e follow ing diuret ics

th at is able to p reven t th e at tacks in m any cases. W h ich of


th e follow ing drugs w as m ost likely p rescribed?

A. Eth acr yn ic acid

A. Man n itol

B. Sp iron olacton e

B. Hydroch loroth iazide

C. Acetazolam ide

C. Eth acr yn ic acid

D. Fu rosem id e

D. Triam teren e

E. Triam teren e

E. Acetazolam ide

Questions: IV-1 Diuretics 193 Di cult y level: Hard


15. A 76-year-old w om an from a n u rsing h om e presen ted to th e

17. A 63-year-old m an w ith a long h istor y of h ear t failure w as

em ergen cy dep ar t m en t w ith a ch ange in h er m en t al state

adm it ted to th e em ergen cy depart m en t becau se of severe

over th e past few h ours. She had a m edical history of coron ary

dysp n ea an d ed em a in h is legs, th igh s, an d low er abdom in al

arter y disease an d hyp er ten sion . Her m edicat ion s in clu d ed

w all. Pert in en t lab resu lt s on adm ission in clu ded a glom eru -

aspirin , captop ril, lovast at in , an d a diu ret ic. On p hysical ex-

lar lt rat ion rate of 20 m L/m in . A diu ret ic w ith w h ich of th e

am in at ion sh e sh ow ed d ecreased skin t u rgor, or t h ost at ic

follow ing m ech an ism of act ion w ould be appropriate to re-

hyp oten sion , an d disorien tat ion to t im e, p lace, an d person

lieve th e edem a in th is pat ien t?

w ith out focal n eurologic de cit s. Per t in en t blood test results

A. Blockade of Na + reabsorpt ion in th e p roxim al t u bu le

on ad m ission w ere Na + 125 m Eq/L, creat in in e 2.7 m g/d L.

B. Blockade of Na + ch an n els in th e collect ing t u bu le

W h ich of the follow ing drugs m ost likely caused the patien t’s

C. Blockade of Na +/K+/2Cl− sym port in th e loop of Hen le

syn drom e?

D. In hibition of aldosterone actions in th e collecting t ubule

A. Captopril

E. Blockade of Na +/Cl− sym port in th e early distal t ubu le

B. Sp iron olacton e C. Lovast at in


D. Triam teren e

18. A 42-year-old obese w om an w as h ospitalized because of hy-

E. Acetazolam ide

p okalem ia d esp ite daily adm in ist rat ion of a potassiu m su p -

F.

p lem en t . Laborator y tests on adm ission revealed m etabolic

In dapam ide

alkalosis. Th e pat ien t adm it ted taking fu rosem id e tablet s in


an e or t to lose w eigh t . W h ich of th e follow ing act ion s m ost

16. A 47-year-old w om an su ering from m etastat ic breast can -

likely con t ribu ted to fu rosem ide-in du ced m et abolic alkalo-

cer w as adm it ted to th e em ergen cy depar t m en t because of

sis in th is pat ien t?

p ersisten t th irst an d p olyuria. Pert in en t seru m valu es on ad-

A. In creased reabsorpt ion of uric acid

m ission w ere seru m

K+

2.8 m Eq/L (n orm al 3.5−5.0 m Eq/L);

B. In creased deliver y of Na + to th e dist al t ubule

Ca 16.2 m g/dL (norm al 8.5−10.5 m g/dL); Na + 155 m Eq/L (nor-

C. Mild in h ibit ion of carbon ic an hydrase

m al 136−145 m Eq/L). Urin alysis: sp eci c gravit y 1.001; os-

D. Decreased reabsorpt ion of Ca 2+ in th e loop of Hen le

m olalit y 80 m Osm /L (range 50−1440 m Osm /L); ch em ist r y

E. In h ibit ion of ren in secret ion

an d sedim en t n egat ive. Th e pat ien t w as given a w ater dep rivat ion test: all u ids w ere w ith h eld u n t il seru m osm olalit y in creased in to th e hyperosm olar range (> 310), th en 5 u n its of vasopressin w ere given subcutaneously. Results are show n in th e follow ing t able.

Di cult y level: Hard 19. A 78-year-old m an from a n ursing h om e w as adm it ted to th e em ergen cy dep ar t m en t becau se of a ch ange in h is m en tal state over th e past few h ou rs. He h ad a m edical h istor y of angin a an d hyp er ten sion presen tly t reated w ith isosorbide

Urine Osmolality (mOsm/ L)

Serum Osmolality (mOsm/ L)

Onset of test

80

292

am in at ion sh ow ed a p erson w ith decreased skin t u rgor an d

Water deprivation

82

312

d isorien tat ion to t im e an d place w ith out focal n eurologic

After vasopressin

84

310

d e cits. Blood pressure w as 110/65 m m Hg on st an ding an d

m on on it rate, losart an , an d hydroch loroth iazide. Physical ex-

140/88 m m Hg on lying. Pert in en t blood test s on adm ission W h ich of th ese drugs w ould be m ost appropriate to t reat th e

w ere Na + 116 m Eq/L (n orm al 136−145 m Eq/L); K+ 3.1 m Eq/L

p at ien t’s con dit ion ?

(norm al 3.5−5.0 m Eq/L); uric acid 10.2 m g/dL (norm al 3.0−

A. Desm opressin B. Hydroch loroth iazide C. Dem eclocyclin e D. Am iloride E. Fu rosem id e

8.2 m g/dL); creatinine 3.1 m g/dL (norm al 0.6−1.2 m g/dL). The physician th ough t th at th e syn drom e w as du e to d iu ret ic therapy. W hich of the follow ing drug-induced adverse e ects m ost likely caused th e pat ien t’s sign s an d sym ptom s? A. Kidn ey in su

cien cy

B. Hyp okalem ia C. Hyp ovolem ic hyp on at rem ia D. Hyp eru ricem ia E. Hyp er volem ic hypon at rem ia

194



Bow el m ovem ent s w ere frequen t an d w ater y. Th e p at ien t’s

20. A 66-year-old w om an su ering from systolic cardiac failu re

ow n rep or t w as vagu e, bu t n otes in th e ch ar t from oth er h os-

w as brough t to th e em ergen cy d ep art m en t becau se of a su d-

pit als revealed th at sh e h ad a ver y long h istor y of laxat ive

d en on set of ext rem e dysp n ea. Sh e presen ted w ith cyan osis,

abuse. Blood test result s on adm ission sh ow ed pron oun ced

t achypn ea, hyp erpn ea, restlessn ess, an xiet y, an d a sen se of

hyp okalem ia (K+ 2.8 m Eq/L). An appropriate th erapy w as

su ocation. Cough w as prom inent and produced pin k-tinged,

st ar ted t h at in clu d ed t h e ad m in ist rat ion of t r iam teren e.

frothy sp u t u m . Pu lse w as th ready an d fast (120 bp m ), blood

W hich of the follow ing actions best explains the potassium -

p ressure 80/45 m m Hg, an d rales w ere audible at th e lu ng

sparing e ect of th is drug?

bases. W h ich of th e follow ing drugs w as m ost likely in clu ded

A. En h an cem ent of K+ reabsorpt ion in th e proxim al t ubule

in th e im m ediate m edical t reat m en t of th is pat ien t?

B. Blockade of Na + ch an n els in th e collect ing d u ct

A. Hydroch loroth iazide

C. En h an cem en t of K+ reabsorpt ion in th e loop of Hen le

B. Am iloride

D. Blockade of aldosteron e receptors in th e collect ing du ct

C. Man n itol

E. Blockade of Na + reabsorpt ion in th e p roxim al t u bu le

D. Epin eph rin e E. Fu rosem id e


F.

24. A 60-year-old m an w as adm it ted to th e h ospital because

Metop rolol

of sym ptom s of episodic w eakn ess, polydipsia, an d polyuria


over th e past 2 w eeks. Vital sign s on adm ission w ere blood


p ressu re 136/95 m m Hg; h ear t rate 80 bp m ; resp irat ion s

p ar t m en t becau se sh e h ad becom e m ore leth argic an d u n re-

13/m in . Sign i can t ser u m resu lt s on ad m ission w ere K+

spon sive over th e p ast several days. Her p ast m edical h istor y

3.1 m Eq/L (n orm al 3.5−5.0 m Eq/L); aldosteron e 45 ng/dL

w as signi cant for bone m etastases from breast cancer. Phys-

(n orm al 7−30 ng/dL). A com puted tom ography scan sh ow ed

ical exam in at ion revealed a dehydrated, cach ect ic fem ale

bilateral adren al hyp erp lasia. W h ich of th e follow ing dr ugs

respon sive on ly to pain fu l st im uli. Per t in en t serum values

w as m ost likely in clu d ed in th e th erap eu t ic regim en of th is

w ere Na + 148 m Eq/L (136−145 m Eq/L); Ca 19.2 m g/dL (8.5−

pat ien t?

10.5 m g/dL). An in t raven ou s salin e in fu sion w as star ted , an d


a diu ret ic w as given con cu rren tly. W h ich of th e follow ing

B. Man n itol

diu ret ics w as m ost likely adm in istered ?

C. Fu rosem id e

A. Acetazolam ide

D. Fen old opam


E. Nit rop ru sside

C. Fu rosem id e

F.

Sp iron olacton e

D. Am iloride E. Sp iron olacton e

Di cult y level: Medium 25. A 54-year-old alcoh olic m an w as adm it ted to th e em ergen cy


d epart m en t w ith a 2-w eek h istor y of n au sea, vom it ing, an d

22. A 64-year-old w om an su er ing from st age C h ear t failu re

low er abd om in al cram ps. Physical exam in at ion revealed an

h ad h er d iu ret ic m ed icat ion ch an ged becau se of a ser iou s

afebrile, jau n diced, an d cach ect ic m ale in m oderate dist ress.

allergic react ion to fu rosem ide. W h ich of th e follow ing di-

The abdom en appeared very tense w ith prom inent veins, and

u ret ics w as m ost likely prescribed?

2+ ascites w as n oted by sh ift ing du lln ess an d a

A. Sp iron olacton e B. Acetazolam ide C. Man n itol D. Eth acr yn ic acid E. Triam teren e F.

In dapam ide

Per t in en t serum values on adm ission w ere Na + 144 m Eq/L (norm al 136−145 m Eq/L); K+ 2.9 m Eq/L (norm al 3.5−5.0 m Eq/L); bicarbon ate 34 m Eq/L (n orm al 22−28 m Eq/L); albu m in 2.3 g/dL (n orm al 3.3−4.8 m Eq/L). W h ich of th e follow ing diu ret ics w ou ld be th e drug of ch oice for th is p at ien t? A. In dapam ide B. Man n itol

Di cult y level: Easy 23. A 49-year-old w om an w as adm it ted to th e h ospital because of gen eralized w eakn ess, con t in uous n ausea, an d diarrh ea.

u id w ave.

C. Sp iron olacton e D. Fu rosem id e E. Triam teren e

Questions: IV-1 Diuretics 195 Di cult y level: Easy


26. A 65-year-old pat ien t w as sch edu led for surger y to rem ove

29. A 69-year-old m an w as recen tly diagn osed w ith severe car-

a gliom a located on h is left p ariet al lobe. W h ich of th e fol-

d iac failu re, an d t h e p hysician st ar ted t reat m en t w it h p ro-

low ing drugs w ou ld be m ost app ropriately given before an d

p ran olol, captop r il, an d d igoxin . Diu ret ic t h erapy w as also

after su rger y to preven t in creased in t racran ial pressu re?

in clu d ed . W h ich of t h e follow ing p airs of d iu ret ics w ou ld

A. Man n itol

h ave been m ost appropriate for th is pat ien t?


A. Hydroch loroth iazide an d acet azolam ide

C. Triam teren e

B. Fu rosem id e an d sp iron olacton e

D. Verapam il

C. Triam teren e an d acet azolam ide

E. Propran olol

D. Hydroch loroth iazide an d m an n itol E. Fu rosem id e an d m an n itol

Di cult y level: Easy 27. A 57-year-old Black w om an, recently diagnosed w ith closed-


angle glaucom a, w as sch edu led for iridotom y. W h ich of th e


follow ing agen ts w as m ost likely given in t raven ously before

m en t becau se of a 12-h ou r h istor y of dysp n ea an d brady-

an d after su rger y to redu ce in t raocu lar p ressu re?

cardia. He w as t aking propran olol, captopril, furosem ide,

A. Fu rosem id e

an d am iloride becau se of a previou s m yocardial in farct ion ,

B. Triam teren e

as w ell as ibu p rofen for osteoar th rit is. Physical exam in at ion

C. Man n itol

sh ow ed th e pat ien t w as in respirator y dist ress w ith th e fol-

D. Hydroch loroth iazide

low ing vit al sign s: blood pressu re 150/86 m m Hg; h ear t rate

E. Hom at ropin e

40 bpm ; resp irat ion s 20/m in . A lab an alysis w as ordered.

F.

W h ich of th e follow ing subst an ces w as m ost likely in creased

Ph enylep h rin e

in th e p at ien t’s seru m ?


A. Sodiu m

28. A 52-year-old w om an w as adm it ted to th e h ospit al w ith a

B. Calcium

1-w eek h istor y of m u scle cram p s, let h argy, an d con fu sion .

C. Glucose

Past h istor y of t h e p at ien t w as sign i can t for d ep ression

D. Potassium

t reated w it h am it r ipt ylin e. Vit al sign s on ad m ission w ere

E. Urea n it rogen

blood p ressu re 134/82 m m Hg (w ith n o sign i can t ch anges

F.

Triglycerid es

u p on st an d in g); h ear t rate 85 bp m ; resp irat ion s 14/m in . Physical exam in at ion w as u n rem arkable. Per t in en t lab test


results on adm ission w ere serum Na + 118 m Eq/L (n orm al

31. A 32-year-old w om an su er ing from id iop at h ic hyp ercal-

136−145 m Eq/L); seru m osm olalit y 220 m Osm /kg (n orm al

ciu ria w as d iagn osed w ith a large u rin ar y ston e in th e righ t

275−295 m Osm /kg); u rin e osm olalit y 950 m Osm /kg (n or-

ren al pelvis. Sh e w as sch eduled for surgical rem oval of th e

m al 50−1400 m Osm /kg). A d iagn osis w as m ad e, an d an

calcu lu s. W h ich of th e follow ing drugs w ou ld be ap p rop riate

ap propriate th erapy w as prescribed. W h ich of th e follow ing

for th is pat ien t to preven t n ew ston e product ion after th e

drugs w as m ost likely in cluded in th e pat ien t’s t reat m en t?

operat ion ?

A. Man n itol

A. Acetazolam ide

B. Triam teren e


C. Con ivaptan

C. Fu rosem id e

D. Acetazolam ide

D. Triam teren e

E. Hydroch loroth iazide

E. Sp iron olacton e

F.

Fu rosem id e

196



W h ich of the follow ing drugs m ost likely produced the great-

32. In a ph ase 1 clin ical t rial, th e sam e dose of four n ew diuret ics

est in crease in diuresis in th e subject?

(P, Q, R, an d S) w as given in t raven ously to a h ealthy volun -

A. Drug P

teer on four separate occasion s. Lab st udies h ad sh ow n th at

B. Drug Q

all drugs w ere acidic m olecu les th at w ere able to block th e

C. Drug R

Na +/Cl− cotransporter in the early distal tubule w ith the sam e

D. Drug S

a

n it y. Th ey h ad about th e sam e plasm a protein bin ding

levels an d w ere n ot m et abolized in th e body. Th e acid dissociat ion con st an t (p Ka ) levels of th e drugs w ere P = 3.5 Q = 7.2 R = 5.1 S = 10.1

Questions: IV-2 Drugs for Ischem ic Heart Disease Directions for questions 1−4


Match each an t ian gin al d r ug w it h t h e ap p rop r iate d escr ipt ion

5. A 55-year-old w om an recen tly diagn osed w ith varian t angin a


star ted t reat m en t w ith isosorbide m on on it rate an d dilt iazem .

at all).

W h ich of th e follow ing act ion s m ost likely m ediated th e th er-

A. Am yl n it rite

apeut ic e ect of n it rates in th e pat ien t’s disease?

B. Dilt iazem

A. In creased left ven t ricular en d-diastolic volum e

C. Isosorbide m on on it rate

B. In creased blood ow in large epicardial vessels

D. Metop rolol

C. In creased h ear t rate

E. Nifedipin e

D. Decreased diastolic perfusion t im e

F.

E. In creased cardiac con t ract ilit y

Nicardip in e

G. Nit roglycerin


H. Verapam il

6. A 59-year-old m an recen tly diagn osed w ith exer t ion al angin a


star ted t reat m en t w ith verapam il, on e t ablet daily. W h ich of

1. Th is drug is som et im es used to t reat cyan ide toxicit y.

th e follow ing cardiac an d sm ooth m u scle Ca 2+ ch an n els is m ost likely th e m ain site of act ion of th is drug?


A. Ligan d-gated ch an n els in cell m em bran es

2. Th is drug h as n o th erapeut ic e ect on varian t angin a.

B. Store-operated ch an n els in m itoch on dria C. Volt age-gated ch an n els in th e sarcoplasm ic ret iculum


D. Volt age-gated ch an n els in cell m em bran es

3. Th is drug h as a good t ran sderm al bioavailabilit y.

E. Ligan d-gated ch an n els in th e sarcoplasm ic reticu lu m


Di cult y level: Easy 4. Th is drug h as h igh a vessels.

n it y for calcium ch an n els of cerebral

7. A 57-year-old m an com plain ed of dizzin ess an d palpitat ion s sh ortly after t aking a tablet of h is prescribed m edicat ion . Th e m an w as recen tly diagn osed w ith varian t angin a for w h ich h e had started an appropriate therapy 4 days earlier. W hich of the follow ing action s m ost likely cau sed th e patient’s sym ptom s? A. Coron ar y vasodilat ion B. Decreased tot al periph eral resist an ce C. In creased ven ous ret urn to th e h eart D. Decreased m yocardial con t ract ilit y E. Coron ar y steal ph en om en on

Questions: IV-2 Drugs for Ischem ic Heart Disease 197 Di cult y level: Medium


8. A 47-year-old m an recently diagnosed w ith exertional angina


star ted t reat m en t w ith su blingu al n it roglycerin , as n eeded,

m en t becau se of severe ch est p ain t h at h ad been on goin g

an d oral isosorbide m on on it rate. W h ich of th e follow ing is

for over 3 h ou rs. Th e m an h ad been su ering from ch ron ic

a poten t ial det rim en t al e ect of n it rates in th e p rophylact ic

stable exer t ion al angin a for 1 year an d from d u oden al u lcer

t reat m en t of exert ion al angin a?

for 3 m on t h s. His cu r ren t m ed icat ion in clu d ed isosorbid e

A. Decreased eject ion t im e

m on on it rate an d verap am il for an gin a an d fam ot id in e for

B. In creased cardiac rate

d u od en al u lcer. On e w eek earlier, t h e p at ien t stop p ed t h e

C. In creased capacit an ce of system ic vein s

an t iangin al m edicat ion s becau se h e h ad n ot h ad angin al at-

D. Decreased ar terial pressure

t acks du ring th e p ast m on th . W h ich of th e follow ing even t s

E. In creased ven t ricular en d-diastolic volum e

m ost likely t riggered th e pat ien t’s p resen t ch est p ain ? A. Ch ron ic progression of isch em ia un covered by discon -

Di cult y level: Medium 9. A 58-year-old m an com plain ed to h is physician of severe

t in u ing th erapy B. Fam ot idine-induced inhibit ion of verapam il m etabolism

ch est pain w h en h e w alked rapidly despite th e th erapy h e

C. Abrupt w ith draw al from n it rate th erapy

h ad carefully follow ed for 3 w eeks. Th e m an w as recen tly

D. Fam otidine-induced inhibition of isosorbide m ononitrate m etabolism

d iagn osed w ith exert ion al angin a an d h ad star ted t reat m en t w ith t ran sderm al n it roglycerin an d aten olol. Th e physician

E. Re ex tachycardia due to n it rate th erapy

decided to add a drug and prescribed diltiazem . W hich of the follow ing e ects w as m ost likely com m on to all th e dr ugs


th e p at ien t w as taking?

12. A 48-year-old w om an presen ted to th e clin ic because of

A. Decreased cardiac rate

ch est pain on exert ion for th e past 2 days. Physical exam in a-

B. In creased cardiac con t ract ilit y

t ion sh ow ed a w om an in n o app aren t dist ress. Physical sign s

C. Decreased ar terial pressure

w ere blood p ressu re 105/60 m m Hg, p u lse 85 bpm , resp ira-

D. Decreased left ven t ricular en d-diastolic volum e

t ion s 15 breath s/m in . Cardiac au scu ltat ion revealed a regu -

E. In creased eject ion t im e

lar rhyth m w ith n o abn orm al cardiac soun ds or m u rm u rs. An elect rocardiogram after exercise st ress test ing con rm ed

Di cult y level: Hard 10. A 51-year-old m an w as adm it ted to t h e h osp it al in acu te d ist ress w ith ext rem e dyspn ea, restlessn ess, an d an xiet y. Th e pat ien t h ad been su ering from ch ron ic h eart failu re

th e diagn osis of exer t ion al angin a, an d th erapy w ith su blin gu al n it roglycerin an d isosorbide m on on it rate w as st ar ted. W h ich of th e follow ing adverse e ects w ould be m ost likely to occur in th is pat ien t?

for 3 years. Vital sign s w ere blood pressu re 115/90 m m Hg,

A. Cough an d w h eezing

p ulse 120 bpm , respirat ion s 22/m in . A ch est x-ray don e im -

B. Post ural hypoten sion

m ediately sh ow ed m arked in terst it ial edem a. An ap p rop ri-

C. Re ex bradycardia

ate therapy w as started th at included an intravenous infusion

D. Meth em oglobin em ia

of n it roglycerin . W h ich of th e follow ing act ion s m ost likely

E. Diarrh ea

m ediated th e th erap eu t ic e ect of th e drug in th e p at ien t’s

F.

Ven ou s th rom bosis

d isorder? A. Decreased ven t ricular en d diastolic volum e B. Re ex in crease in h ear t rate C. Re ex in crease in cardiac con t ract ilit y D. Decreased ven t ricular eject ion t im e

Di cult y level: Medium 13. A 46-year-old m an com plain ed to h is physician of in som n ia, n igh t m ares, fat igue, dim in ish ed libido, an d blan ch ing of th e ngers w h en exp osed to cold. Th e m an , recen tly diagn osed

E. Decreased afterload

w ith exert ion al angin a, h ad been t aking an an t iangin al drug

F.

for 1 m on th . W h ich of th e follow ing drugs m ost likely caused

Decreased platelet aggregat ion

th e p at ien t’s sym ptom s? A. Propran olol B. Isosorbide m on on it rate C. Nit roglycerin D. Nifedipin e E. Verapam il

198



ago, she becam e nauseous and vom ited, and she stopped t ak-

14. A 47-year-old m an com plain ed to h is physician th at h e ex-

ing all h er m edicat ion s. Th e abrupt w ith draw al from w h ich

p erien ced m ild angin a at tacks during exer t ion . Th e pat ien t ,

of th e follow ing drugs m ost likely t riggered th e recen t MI?

recen t ly d iagn osed w it h exer t ion al angin a, h ad st ar ted a

A. Aspirin

therapy w ith a transderm al nitroglycerin preparation 2 w eeks

B. Propran olol

p reviously. He carefully applied a n ew patch ever y m orn ing

C. Lovast at in

im m ediately after rem oving th e old on e. Angin al at tacks h ad

D. Captopril

d isap peared com pletely during th e rst w eek of th erapy bu t


w ere back th ereafter. W h ich of th e follow ing best exp lain s th e reason for h is angin al ep isodes?


A. Vasospast ic angin a com plicat ing th e exert ion al angin a


B. Cellu lar toleran ce to n it roglycerin

m en t w ith an acu te m yocardial in farct ion (MI). Th e m an reg-

C. In creased m etabolism of n it roglycerin

u larly used silden a l in preparat ion for sexual in tercourse

D. In su

cien t origin al n it roglycerin dosage

becau se of an erect ile dysfu n ct ion . He h ad recen tly been di-

E. Decreased absorpt ion of n it roglycerin from th e skin

agn osed w ith exer t ion al angin a, an d h e h ad been taking an appropriate prescribed th erapy. W h ich of th e follow ing drugs


m ost likely cau sed th e p at ien t’s MI?

15. A 54-year-old m an h ad been diagn osed recen tly w ith vari-

A. Propran olol

an t angin a. Th e p at ien t h ad been su ering from a cerebellar

B. Nit rop ru sside

ast rocytom a for 2 years an d from a secon d-degree at rioven -

C. Nit roglycerin

t ricu lar block for 1 year. W h ich of th e follow ing an t iangin al

D. Nifedipin e

d rugs w ou ld be app ropriate for th is p at ien t?

E. Verapam il

A. Isosorbide m on on it rate B. Dilt iazem


C. Verapam il

19. A 54-year-old m an com plain ed to h is physician of palpita-

D. Nifedipin e

t ion s, facial u sh ing, an d vert igo. Th e m an h ad been su er-

E. Propran olol

ing from gast roesop h ageal re u x d isease for 3 years. Tw o w eek earlier, h e w as diagn osed w ith exert ion al angin a an d


star ted th e prescribed th erapy. W h ich of th e follow ing drugs

16. A 55-year-old w om an com plain ed to h er physician of palpi-

m ost likely cau sed th e p at ien t’s sym ptom s?

t at ion s, u sh ing of th e face, an d ver t igo. Th e w om an , su er-

A. Propran olol

ing from diabetes m ellit us, w as giving h erself th ree daily

B. Verapam il

d oses of in su lin . Sh e h ad been recen tly diagn osed w ith exer-

C. Dilt iazem

t ion al angin a for w h ich n it rate th erapy w as st arted w ith

D. Nit roglycerin

t ran sd erm al n it roglycerin an d oral isosorbide m on on it rate.

E. Nifedipin e

After 3 w eeks of t h erapy, h er angin al at t acks w ere less frequ en t bu t n ot com p letely p reven ted . W h ich of t h e follow -


ing w ou ld be an ap p rop r iate n ext t h erap eu t ic step for t h is

20. A 50-year-old w om an w as adm it ted to th e h ospital w ith a

p at ien t?

3-w eek h istor y of early m orn ing ch est p ain th at cau sed h er

A. Red u ce th e dosage of both n it rates

to aw aken from sleep. Th e pain lasted 10 to 15 m in utes an d

B. Add prop ran olol

frequ en tly radiated to h er left arm . An exercise toleran ce test

C. Add n ifedipin e

failed to elicit precordial pain . A diagn osis of angin a w as

D. Stop isosorbide m on on it rate

m ade, an d sh e w as disch arged from th e h osp it al w ith a p re-

E. Add dilt iazem

script ion for n ifed ipin e. W h ich of th e follow ing act ion s m ost likely m ediated th e th erapeu t ic e ect of th e drug in th e pa-


t ien t’s disease?

17. A 77-year-old w om an w as brought to the em ergency depart-

A. Decreased preload

m en t w ith an acu te m yocardial in farct ion (MI). Six m on th s

B. Decreased afterload

ago, sh e su ered from an MI an d began taking p rop ran olol,

C. In creased m yocardial con t ract ilit y

aspirin, and lovastatin. Her current m edications also included


captopril and hydrochloroth iazide for hyperten sion. Tw o days

E. Decreased coron ar y vascular ton e

Questions: IV-2 Drugs for Ischem ic Heart Disease 199 Di cult y level: Hard


21. A 53-year-old m an w as t aken to th e em ergen cy depar t m en t

24. A 59-year-old m an w as recen tly diagn osed w ith exer t ion al

becau se of dizzin ess an d ch est discom for t th at app aren tly

angin a. Th e p at ien t , w h o w as a h eavy sm oker, h ad been su f-

h ad been ongoing for over 5 h ou rs. His vit al sign s w ere blood

fering from ch ron ic obst ruct ive pulm on ar y disease for 15

p ressure 165/100 m m Hg, h ear t rate 50 bpm , respirat ion s

years an d from gast roesop h ageal re u x disease for 3 years.

22/m in . Physical exam in at ion revealed sign s of severe p u l-

W h ich of th e follow ing drugs w ould be appropriate to pre-

m onary congestion, and an electrocardiogram w as consistent

ven t angin al at tacks in th is pat ien t?

w ith an an terior acute m yocardial in farct ion . An appropriate

A. Propran olol

th erapy w as in st it u ted th at in clu ded an in t raven ou s in fu sion

B. Verapam il

of w h ich of th e follow ing drugs?

C. Dilt iazem

A. Epin eph rin e

D. Isosorbide m on on it rate

B. Metop rolol

E. Nifedipin e

C. Nit roglycerin D. Verapam il


E. Nifedipin e

25. A 47-year-old m an recen tly diagn osed w ith exert ion al an gin a st arted t reat m en t w ith t ran sderm al n it roglycerin an d


oral propran olol. W h ich of th e follow ing w as m ost likely a

22. A 65-year-old m an su dden ly collap sed in th e din ing room

p urpose for th e com bin at ion th erapy in th is case?

of h is h om e. Upon arrival by am bu lan ce at th e em ergen cy

A. To en h an ce n it rate-in d u ced coron ar y vasod ilat ion

d epart m en t , h e regain ed con sciousn ess an d com p lain ed of a

B. To p reven t n it rate-in du ced tachycardia

severe h eadach e. Physical exam in at ion w as sign i can t for a

C. To p reven t n it rate-in du ced decrease in ar terial p ressu re

st i n eck an d m ild m en tal con fu sion . A com p u ted tom ogra-

D. To en h an ce p rop ran olol-in du ced decrease in cardiac rate

p hy scan revealed blood in th e subarach n oid sp ace. W h ich of

E. To en h an ce p rop ran olol-in d u ced d ecrease in card iac

th e follow ing drugs w ou ld be app ropriate to p reven t delayed

con t ract ilit y

cerebral isch em ia in th is pat ien t? A. Verapam il


B. Isosorbide m on on it rate

26. A 50-year-old m an w as disch arged from th e h ospital after

C. Propran olol

recover y from an acute m yocardial in farct ion . His postdis-

D. Dobutam in e

ch arge m edicat ion s in clu ded propran olol. How long sh ould

E. Nicardip in e

th e p at ien t con t in u e to t ake th is drug?

F.

Clon idin e

A. Th ree m on th s B. Six m on th s


C. On e year

23. A 53-year-old m an diagn osed w ith exer t ion al angin a w as p rescribed in h aled n it roglycerin an d oral isosorbide m on o-

D. Tw o years E. In de n itely

n it rate. W h ich of th e follow ing m olecular act ion s m ost likely m ediated th e th erap eu t ic e

cacy of th ese drugs in th e pa-


Di cult y level: Medium 27. A 46-year-old m an com p lain ed to h is fam ily p hysician of

A. Conversion of n it rite ion s in to n it rou s oxide (N2 O)

t h robbin g h eadach es an d severe con st ip at ion . Th e m an ,

B. In creased in t racellular Ca 2+ con cen t rat ion

recen t ly d iagn osed w ith exer t ion al an gin a, h ad st ar ted an

C. Deph osph or ylat ion of th e m yosin ligh t ch ain

an t iangin al t reat m en t 2 w eeks ago. W h ich of th e follow ing

D. Decreased syn th esis of gu anylyl cyclase

p airs of drugs w as h e m ost likely t aking?

E. Ph osp h or ylat ion of m yosin ligh t ch ain kin ase

A. Verapam il an d isosorbide m on on it rate B. Nit roglycerin an d isosorbide m on on it rate C. Nit roglycerin an d prop ran olol D. Propran olol an d isosorbide m on on it rate E. Propran olol an d verapam il

200



cold w ater, an d t ingling w as felt in th e h an d. W h ich of th e

28. A 24-year-old m an com p lain ed to h is fam ily p hysician of

follow ing dr ugs w ould be appropriate to t reat th e pat ien t’s

ep isodes of precordial p ain p recip it ated by exer t ion an d re-

disorder?

lieved by rest . Th e m an h ad been recen tly diagn osed w ith

A. Nit rop ru sside

hyper t roph ic card iom yopathy. W h ich of th e follow ing pairs

B. Albuterol

of drugs w ould be appropriate for th is pat ien t?

C. Nifedipin e

A. Isosorbide m on on it rate an d n ifedipin e

D. Clon idin e

B. Nit roglycerin an d captopril

E. Labet alol

C. Nit roglycerin an d verapam il

F.

Fen old op am

D. Verapam il an d m etoprolol E. Nifedipin e an d captop ril


F.

30. A 43-year old m an w as adm it ted to th e h ospital w ith a m yo-

Isosorbide m on on it rate an d m etoprolol

cardial in farct ion (MI) an d w as st ar ted on a th erapy th at in -


cluded aten olol. W h ich of th e follow ing act ion s m ost likely

29. A 48-year-old m an presen ted to th e h ospital w ith a 5-day

con t r ibu te to m or t alit y red u ct ion obt ain ed by β-blockers

h istor y of burn ing pain in h is righ t h an d an d arm . Th e pain

in MI?

occurred m ain ly w h en h e w as using h is h an ds at w ork an d

A. In creased m yocardial oxygen supply

w as accom p an ied by th e m iddle

B. Decreased at rioven t ricular con du ct ion

ngers of h is righ t h an d

t u rn ing cold an d som ew h at blu e. Th e m an w as a con st ru c-

C. Decreased m yocardial rem odeling

t ion w orker an d frequ en tly used vibrat ing m ach in er y. Sev-

D. In creased system ic vascular resist an ce

eral w h ite sp lotch es ap p eared w h en th e h an d w as placed in

E. In creased left ven t ricular en d-diastolic pressure

Questions: IV-3 Drugs for Cardiac Failure Directions for questions 1−5


Match each dr ug u sed in cardiac failu re w ith th e ap prop riate de-

4. Th is drug can cause periph eral vasodilat ion by in creasing th e


syn th esis of cyclic gu an osin e m on op h osp h ate (cGMP).

on ce, or n ot at all). A. Captopril


B. Digoxin

5. Th is drug can in crease cen t ral parasym path et ic ring.

C. Dobutam in e D. Fu rosem id e


E. Losar t an

6. A 68-year-old m an recen tly diagn osed w ith st age C h ear t fail-

F.

Milrin on e

ure started a treatm en t w ith m etoprolol, losartan , furosem ide,

G. Nesirit ide

an d digoxin . W h ich of th e follow ing m olecular act ion s m ost

H. Propran olol

likely m ediated th e posit ive in ot rop ic act ion of d igoxin ?

I.

Sp iron olacton e

Di cult y level: Easy 1. Th is dr ug can cause periph eral vasodilat ion by blocking ph osph odiesterase t yp e 3.

A. Closing of calcium ch an n els in cardiac cell m em bran es B. In creased release of Ca 2+ from th e sarcoplasm ic ret icu lu m du ring systole C. Act ivat ion of Na +/K+ ATPase D. Act ivat ion of t h e Ca 2+/Na + exch an ger in card iac cell m em bran es

Di cult y level: Easy 2. Th is drug can in crease th e syn th esis of cyclic aden osin e m on oph osph ate (cAMP) in th e h ear t .

Di cult y level: Easy 3. Th e ch ron ic use of th is aldosteron e an t agon ist can reduce m or t alit y in pat ien t s w ith severe h eart failure.

E. Open ing of K+ ch an n els in cardiac cell m em bran es

Questions: IV-3 Drugs for Cardiac Failure 201 Di cult y level: Medium 7. A 57-year-old m an su ering from persisten t at rial

Di cult y level: Medium brilla-

11. A 68-year-old w om an recen tly diagn osed w ith stage C h ear t

tion started a treatm ent w ith digoxin , on e tablet daily. W h ich

failure st arted a t reat m en t w ith digoxin . Kn ow ing th at di-

of th e follow ing t ypes of receptors m ost likely m ediated th e

goxin h as a clearan ce of abou t 7 L/h an d an oral bioavailabil-

th erap eu t ic e ect of th e drug in th is p at ien t?

it y of abou t 70%, w h ich of th e follow ing doses (in m illigram s)

A. Beta-2 adren ergic

w as m ost likely given to ach ieve a m ean steady-st ate plasm a

B. M 2 ch olin ergic

con cen t rat ion of 1 µg/L?


A. 1.4

D. Seroton in ergic

B. 0.125

E. Nm ch olin ergic

C. 0.24 D. 2.0

Di cult y level: Easy 8. A 57-year-old w om an su ering from persisten t at rial ut ter

E. 0.5 F.

2.4

star ted a t reat m en t w ith digoxin . W h ich of th e follow ing cardiac act ion s m ost likely occu rred du ring th e th erapy? A. In creased en d-systolic volum e B. Decreased abn orm al cardiac au tom at icit y C. Decreased diastolic t im e D. In creased at rial refractorin ess E. Decreased h eart rate

Di cult y level: Easy 9. A 61-year-old m an recen tly diagn osed w ith st age C h ear t failure w as adm it ted to th e h ospital for evaluat ion . It w as fou n d th at h e h ad an eject ion fract ion of 30% at rest . A t reatm en t th at in clu ded digoxin w as st arted. W h ich of th e follow ing cardiovascu lar p aram eters did digoxin m ost likely in crease in th is pat ien t? A. St roke volu m e B. Tot al p eriph eral resist an ce C. Oxygen con sum pt ion of th e h ear t D. En d-diastolic volum e E. Hear t rate

Di cult y level: Medium 10. A 42-year-old m an w as adm it ted to th e em ergen cy depar tm en t in acu te dist ress w ith breath lessn ess, m arkedly disten ded n eck vein s, an d at rial brillat ion . His blood pressure w as 100/90 m m Hg, p u lse 120 bp m . An ech ocardiogram revealed an eject ion fract ion of 35%. Treat m en t w as started w ith furosem ide, captopril, an d digoxin . In th is pat ien t , digoxin m ost likely decreased w h ich of th e follow ing card iovascu lar param eters? A. St roke volu m e B. En d-systolic volum e C. En d-diastolic volum e D. Systolic p ressu re E. Pu lse pressure

Di cult y level: Easy 12. A 63-year-old m an com plain ed to h is physician of n au sea, vom iting, and a visual sensation of green-yellow halos around bright objects. The m an, recently diagnosed w ith cardiac failu re an d at rial brillat ion , h ad st arted an appropriate t reat m en t 2 w eeks earlier. W h ich of th e follow ing drugs m ost likely cau sed th e p at ien t’s sym ptom s? A. Verapam il B. Propran olol C. Digoxin D. Lidocain e E. Fu rosem id e F.

Captopril

Di cult y level: Hard 13. A 63-year-old w om an w as fou n d to h ave a t h ird -d egree at r ioven t r icu lar block. Th e w om an , w h o h ad been su ering from stage C h eart failure, h ad been receiving captopril, fu rosem ide, an d digoxin for 2 m on th s, an d th e disease w as w ell con t rolled. Th e p hysician believed th at th e block w as d ue to digoxin th erapy. W h ich of th e follow ing w ou ld be an app ropriate th erap eu t ic adju st m en t for th is pat ien t? A. Discon t in ue digoxin an d star t m ilrin on e B. Add physost igm in e an d d ecrease th e digoxin dose C. Add at rop in e an d d ecrease th e digoxin dose D. Discon t in ue digoxin an d star t m etoprolol E. Add dobu t am in e an d decrease th e digoxin dose F.

Discon t in ue digoxin an d star t losart an

202



A. Captopril

14. A 54-year-old w om an presen ted to th e clin ic com plain ing of

B. Digoxin

p alpitat ion s. On e m on th earlier, th e w om an w as diagn osed

C. Iprat ropium

w ith st age C h ear t failu re an d started t reat m en t w ith m etop -

D. Metop rolol

rolol, digoxin , an d captopril. Her m edicat ion s also in cluded

E. Eth acr yn ic acid

est rogen an d a calciu m su p p lem en t for p ost m en op au sal

F.

Albuterol

osteop orosis. Th e p at ien t ’s vit al sign s w ere blood p ressu re 145/90, p u lse 130 bpm . An elect rocardiogram sh ow ed ven -


t ricu lar tachycardia. Sign i can t p lasm a levels on adm ission

17. A 65-year-old w om an presen ted to th e h ospital w ith a ch ief

w ere K+ 5.8 m Eq/L, Ca 2+ 12.2 m Eq/L, creat in in e 3.5 m g/dL.

com plain t of palpitat ion s. Th e w om an w as su ering from

W h ich of th e follow ing even t s m ost likely t riggered th e pa-

stage C h ear t failu re an d h ad been receiving digoxin , fu rose-

t ien t’s arrhyth m ia?

m ide, an d losart an for 6 m on th s. Laborator y dat a on adm is-

A. Metop rolol-in du ced decrease in cardiac con t ract ilit y

sion in clu ded p ot assiu m 3.9 m Eq/L (n orm al 3.5−5.0 m Eq/L),

B. In creased seru m K+ level

calciu m 9.2 m g/dL (n orm al 8.5−10.5 m g/dL), m agn esiu m 2.5

C. Captopril-in duced vasodilat ion

m Eq/L (n orm al 1.5−2.0 m Eq/L), tot al thyroxin e (T4 ) 42 ng/m L

D. In creased seru m Ca 2+ level

(n orm al 50−110 ng/m L), thyroid-st im u lat ing h orm on e (TSH)

E. Est rogen -in duced hyperten sion

15 m IU/m L (n orm al 0.5−5.5 m IU/m L). An elect rocardiogram sh ow ed ju n ct ion al tachycardia, w h ich , according to h er phy-

Di cult y level: Medium 15. A 61-year-old alcoh olic m an w as adm it ted to th e h ospital w ith a 2-day h istor y of epigast ric pain associated w ith n au -

sician , w as m ost likely d u e to digoxin t reat m en t . W h ich of th e follow ing path ologic con dit ion s m ost likely in creased th e risk of digoxin toxicit y in th is pat ien t?

sea an d vom it ing. Th e m an h ad been su ering from systolic

A. Hyp erm agn esem ia

h ear t failure for 1 year, an d h is disease w as w ell con t rolled

B. Hyp eraldosteron ism

w ith captopril, fu rosem ide, an d digoxin . Per t in en t serum

C. Hyp erparathyroidism

data on adm ission w ere K+ 2.8 m Eq/L, creat in in e 3.2 m g/dL.

D. Con com itan t fu rosem ide t reat m en t

An elect rocardiogram sh ow ed a h ear t rate of 65 bpm w ith

E. Hyp othyroidism

occasion al p rem at u re ven t ricu lar con t ract ion s an d r u n s of bigem iny. W h ich of t h e follow in g w ou ld be an ap p rop r iate


th erapeut ic adju st m en t for th is pat ien t?


A. Add p ot assiu m su p p lem en t at ion an d red u ce t h e d igoxin d ose

m en t in acu te dist ress. He w as agit ated, in coh eren t , disorien ted in t im e an d sp ace, an d seem ed to be h allu cin at ing. Th e

B. Add at rop in e an d redu ce th e digoxin dose

p at ien t h ad been su ering from severe ch ron ic cardiac fail-

C. In crease t h e fu rosem ide d ose an d red u ce t h e d igoxin

u re for 2 years, an d h is w ife repor ted th at sh e h ad fou n d an

dose

em pt y bot tle of digoxin t ablets n ear h er h u sban d’s bed . Vit al

D. Discon t in ue digoxin an d star t losart an

signs w ere blood pressure 100/50 m m Hg, heart rate 45 bpm .

E. Discon t in ue digoxin an d star t m ilrin on e

An em ergen cy t reat m en t w as in st it u ted, an d a d r ug w as given in t raven ou sly. W h ich of th e follow ing drugs w as m ost


likely adm in istered?


A. Lidocain e

an u ria. Th e m an h ad a long h istor y of severe systolic cardiac

B. At ropin e

failure an d ch ron ic obst r uct ive pu lm on ar y disease. Sh or tly

C. Ph enytoin

after adm ission , th e p at ien t st arted vom it ing, th en becam e

D. Potassium ch loride

agit ated, verbally abusive, an d disorien ted in space an d t im e.

E. Digoxin an t ibodies

He w as telling th e n u rse th at h e h eard lou d voices cu rsing

F.

h im . An elect rocardiogram sh ow ed at rial t achycardia w ith at rioven t ricular block. W h ich of th e follow ing drugs m ost likely caused th e p at ien t’s sym ptom s?

Am iodaron e

Questions: IV-3 Drugs for Cardiac Failure 203 Di cult y level: Medium


19. A 73-year-old m an com plain ed to h is physician of in creasing

22. A 52-year-old m an com plain ed to h is physician of diarrh ea,

fatigue and shortness of breath that w as often w orse at night,

p alpitat ion s, an d blu rred vision . Five days earlier, th e m an

forcing h im to “sit bolt uprigh t .” He also n ot iced th at h is feet

w as diagn osed w ith st age C systolic h ear t failu re an d st ar ted

w ere get t ing sw ollen . Past h istor y w as u n rem arkable. Vit al

a t reat m en t w ith captop ril, aten olol, an d a stan dard d ose of

sign s w ere blood p ressu re 150/90, resp irat ion s 17/m in . On

d igoxin . Past h istor y w as sign i can t for h eredit ar y n eph ro-

exam in at ion , m ild pit t ing edem a w as seen on th e legs. An

gen ic diabetes in sipidu s, presen tly con t rolled by hydroch lo-

elect rocardiogram disclosed a secon d-degree at rioven t ricu -

rot h iazid e (100 m g daily). W h ich of t h e follow in g con d i-

lar block. His physician diagn osed in it ial cardiac failu re an d

t ion s cou ld h ave facilitated th e app earan ce of th e p at ien t’s

p rescribed an approp riate th erapy. W h ich of th e follow ing

sym ptom s?

d rugs w ou ld be con t rain dicated for th is pat ien t?

A. Advan ced age

A. Captopril

B. Th iazide t reat m en t


C. Hyp ern at rem ia du e to w ater deplet ion

C. Digoxin

D. Decreased clearan ce of digoxin

D. Losar t an

E. Worsen ing of th e h ear t failu re

E. Fu rosem id e F.

Sp iron olacton e

Di cult y level: Easy 23. A 61-year-old m an recen t ly d iagn osed w it h st age C h ear t


failu re st ar ted a t reat m en t t h at in clu d ed d igoxin . W h ich of

20. A 62-year-old w om an w as adm it ted to the hospital com plain -

t h e follow in g card iovascu lar p aram eters w as m ost likely

ing of n au sea, m en t al con fu sion , dizzin ess, an d p alp itat ion s.

in creased after few days of th erapy?

The w om an, su ering from hypertension and recurrent atrial

A. Cardiac reser ve

brillat ion , h ad been receiving hydroch loroth iazide, capto-

B. Coron ar y vasocon st rict ion

pril, an d digoxin for several m onths. One week ago, she started

C. Oxygen con sum pt ion

er yth rom ycin an d ibu p rofen for an acu te u p per respirator y

D. En d-diastolic volum e

t ract in fect ion . W h ich of th e follow ing even t s m ost likely

E. Hear t rate

cau sed th e p at ien t’s sym ptom s? A. Hydroch lorot iazide-in d u ced hyp okalem ia


B. Er yt h rom ycin -in d u ced in crease in d igoxin oral bio-

24. A 66-year-old m an w ith a long h istor y of h ear t failure w as

availabilit y

adm it ted to th e h osp ital becau se of a h ear t failu re exacer-

C. Hydroch lorot iazide-in d u ced hyp ocalcem ia

bat ion . His cu rren t m edicat ion s in clu ded fu rosem ide, cap -

D. Captopril-in duced decrease in digoxin clearan ce

topril, an d car vedilol. On adm ission , th e pat ien t sh ow ed th e

E. Ibuprofen -in duced decrease in digoxin clearan ce

follow ing h em odyn am ic pro le: blood pressu re 100/60 m m Hg, p u lse 118/m in , cardiac ou t p u t 2.6 L/m in . Physical exam -


in at ion con rm ed th e diagn osis of acu te h eart failu re, an d

21. A 62-year-old m an w as seen at a clin ic because of n ausea,

an in t raven ou s in fu sion of m ilrin on e w as st arted. W h ich of

vom it ing, diarrh ea, dizzin ess, an d con fusion for 8 h ours. Th e

th e follow ing m olecu lar even ts m ost likely m ediated th e

m an , su ering from systolic h ear t failu re, h ad been receiving

p osit ive in ot ropic act ion of th e drug?

captop ril, digoxin , an d fu rosem ide for 8 m on th s. A few days

A. cAMP-m ediated in crease in cardiac in t racellu lar Ca 2+

earlier, h is physician added am iodaron e to th e th erapy becau se of th e ap pearan ce of m u lt ifocal p rem at u re ven t ricu lar beat s. W h ich of th e follow ing w ou ld be th e m ost p lau sible

levels B. cGMP-m ediated deph osp h or ylat ion of th e m yosin ligh t ch ain

explan at ion of th e pat ien t’s sym ptom s?

C. Open ing of K+ ch an n els in cardiac cell m em bran es

A. Captopril-in duced hyperkalem ia

D. In creased bin ding of Ca 2+ to calm odulin

B. Am iodaron e-in duced in crease in digoxin plasm a levels

E. Act ivat ion of th e 1Ca 2+/3Na + an t iport

C. Am iodaron e-in d u ced d ecrease in at r ioven t r icu lar con du ct ion D. Fu rosem id e-in du ced in crease in diu resis E. Fu rosem id e-in du ced hyp eru ricem ia

204



A. Digoxin

25. A 61-year-old m an p resen ted to t h e h osp it al w it h sh or t -


n ess of breath , decreased exercise capacit y, an d disten ded

C. Lidocain e

n eck vein s. Th e m an h ad a h istor y of severe hyp er ten sion

D. Nesirit ide

cu r ren t ly t reated w it h hyd roch lorot h iazid e an d captop r il.

E. Verapam il

Despite th e t reat m en t , h is blood pressure w as st ill 170/110.

F.

Losar t an

After physical exam in at ion an d laborator y tests, a diagn osis of diastolic cardiac failure w as m ade. W h ich of th e follow ing


w ou ld be a u sefu l drug to add to th e p at ien t’s th erap eu t ic

28. A 67-year-old m an w as adm it ted to th e coron ar y un it w ith

regim en ?

an acu te in ferior m yocardial in farct ion . Despite th e in it ial

A. Metop rolol

t h erapy, h is con d it ion d eter iorated , an d 2 h ou rs after ad -

B. Digoxin

m ission , h e h ad th e follow ing h em odyn am ic p ro le: blood

C. Dobutam in e

p ressu re 94/50, card iac ou t p u t 2.9 L/m in , card iac in d ex 1.5

D. Milrin on e

L/m in /m 2 (n orm al 2.6−4.2 L/m in /m 2 ). An in t raven ous in fu-


sion of dobu tam in e w as star ted . W h ich of th e follow ing ac-

F.

t ion s m ost likely m ed iated th e p ositive in ot rop ic act ion of

Man n itol

dobu tam in e?


A. In h ibit ion of ph osph odiesterase

26. A 22-year-old previously h ealthy w om an w as brough t to th e

B. Protein kin ase−m ediated in crease in cytoplasm ic Ca 2+

em ergen cy room becau se sh e h ad collapsed w h ile jogging. Sh e den ied orth opn ea, paroxysm al n oct u rn al dyspn ea, ch est p ain , or edem a. Her you nger broth er w as kn ow n to h ave h ad

availabilit y C. In h ibit ion of t h e Ca 2+/Na + exch anger in cardiac cell m em bran e

t w o ep isod es of syn cop e after exer t ion . An elect rocard io -

D. Act ivat ion of ph osph olipase A2

gram in dicated left ven tricular hypertrophy, and an echocar-

E. In h ibit ion of Na +/K+ ATPase in cardiac cell m em bran es

d iogram sh ow ed a n orm al eject ion fract ion an d asym m et ric sept al hypert rophy. W h ich of th e follow ing drugs w ou ld be


m ost app ropriate for th is pat ien t?

29. A 68-year-old m an w as diagn osed w ith systolic h eart failure

A. Prazosin

w ith n orm al eject ion fract ion an d n orm al sin us rhyth m at

B. Aten olol

rest . A t reat m en t w ith captopril w as st ar ted. W h ich of th e

C. Digoxin

follow ing actions m ost likely m ediated the therapeutic e ect

D. Nit roglycerin

of captopril in th is pat ien t?

E. Fu rosem id e

A. In creased cardiac con t ract ilit y B. Red u ct ion of angioten sin -m ediated vasocon st rict ion in

Di cult y level: Hard 27. A 60-year-old m an w as adm it ted to th e cardiac un it becau se of progressive, debilitat ing sym ptom s of cardiac failure th at h ad con n ed h im to bed for th e past m on th . Th e m an h ad a 2-year h istor y of ch ron ic cardiac failu re th at w as sym p -

th e kidn ey C. Red u ct ion of p reload an d afterload D. St im u lat ion of ep in ep h r in e release from ad ren ergic n er ves E. St im ulat ion of bradykin in m etabolism

tom atic despite treatm en t w ith m axim al doses of furosem ide, en alap r il, m etop rolol, an d d igoxin . Physical exam in at ion


sh ow ed sign i can t jugu lar ven ou s disten t ion , w arm an d w et

30. A 52-year-old w om an w as discharged from the hospital after

skin , bilateral rales, an d h epatom egaly. Th e h em odyn am ic

recover y from an acute MI. Her post disch arge m edicat ion s

p ro le w as blood p ressu re 100/66 m m Hg, h ear t rate 105

in clu ded captopril. W h ich of th e follow ing act ion s m ost

bp m , cen t ral ven ou s p ressu re 23 m m Hg, card iac ou t p u t

likely con t ribu tes to m or talit y redu ct ion obt ain ed by th e u se

3.9. L/m in . Fu rosem ide an d dop am in e w ere given in t rave-

of angioten sin -convert ing en zym e (ACE) in h ibitors in MI?

n ou sly, but 15 m in utes later, th e cen t ral ven ou s p ressu re

A. Decreased cardiac con t ract ilit y

w as st ill 20 m m Hg. An oth er drug w as given in t raven ou sly.

B. In creased preload


C. Coron ar y vasodilat ion

th e pat ien t at th is t im e?

D. Decreased ven t ricular au tom at icit y E. Red u ct ion of m yocard ial rem odeling

Questions: IV-3 Drugs for Cardiac Failure 205 Di cult y level: Medium


31. A 58-year-old m an presen ted to a clin ic w ith th e ch ief com -

34. A 53-year-old m an w ith st age C h eart failure con t in u ed to

p lain t of in creasing sh or t n ess of breath an d a 10-lb w eigh t

experien ce sym ptom s of periph eral edem a an d dyspn ea on

gain over th e past 2 w eeks. Physical exam in at ion revealed a

exer t ion despite t reat m en t w ith m axim al doses of captopril,

dysp n eic an d cyan ot ic m ale w ith th e follow ing vit al sign s:

m etop rolol, fu rosem id e, an d d igoxin . His card iologist d e-

blood p ressu re 135/100 m m Hg, pu lse 125 bp m , respirat ion s

cid ed to ad d a d r ug to t h e p at ien t ’s t h erapy. W h ich of t h e

22/m in . His liver w as en larged, an d p it t ing edem a w as seen


on th e legs. A Doppler ech ocardiogram sh ow ed an eject ion

t im e?

fract ion of 35%. An ap prop riate drug th erapy w as star ted

A. Losar t an

t h at in clu d ed m etop rolol. W h ich of t h e follow in g act ion s

B. Triam teren e

m ost likely con t ribu te to th e th erapeu t ic e ect of m etop ro-

C. Sp iron olacton e

lol in th is p at ien t?

D. In dapam ide

A. In creased ren in secret ion

E. Milrin on e

B. Decreased preload

F.

Nesirit ide

C. Preven t ion of ch ron ic sym path et ic overact ivit y D. In creased m yocardial rem odeling


E. Dow n regulat ion of cardiac β receptors

35. A 63-year-old w om an recen tly diagn osed w ith systolic h ear t failure star ted a t reat m en t w ith fu rosem ide an d captopril.


Plasm a levels of w h ich of th e follow ing pairs of com pou n ds

32. A 58-year-old African -Am erican m an diagn osed w ith st age

w ere m ost likely in creased after t h e ad m in ist rat ion of

B systolic h ear t failure st arted a t reat m en t th at in cluded a

captop ril?

hydralazin e/isosorbide din it rate com bin at ion . W h ich of th e

A. Vasopressin an d sodium

follow ing act ion s m ost likely m ediated th e th erapeut ic ef-

B. Norep in ep h rin e an d angioten sin II

fect of th e drug in th e pat ien t’s disease?

C. Bradykin in an d angioten sin I

A. In creased cardiac con t ract ilit y

D. At rial n at riu ret ic pept id e an d seroton in

B. Red u ct ion of angioten sin II secret ion

E. Angioten sin III an d prostaglan din s

C. Red u ct ion of p reload an d afterload D. In h ibit ion of sym path et ic act ivit y


E. Decreased h eart rate

36. A 65-year-old w om an com plain ed to h er physician of dysp n ea of exer t ion despite ongoing th erapy an d of a frequ en t


d r y, n onprod uct ive cough . Th e p at ien t h ad been diagn osed

33. A 64-year-old w om an com plained to her physician of fat igue,

w ith stage C systolic h ear t failure for w h ich sh e h ad been

in creasing sh or t n ess of breath , an d an kle edem a. Th e pa-

t akin g captop r il an d fu rosem id e for t h e p ast m on t h . Th e

t ien t’s vit al sign s w ere blood p ressu re 145/85 m m Hg, pu lse

p hysician told th e p at ien t th at th e cough w as m ost likely du e

78 bpm , resp irat ion s 18/m in . After fu r th er exam s, a diagn o-

to captop r il an d su bst it u ted an ot h er d r ug t h at h e believed

sis of st age C systolic h eart failu re w as m ade. An ap prop riate

to be m ore e ect ive, as it is able to an t agon ize t h e act ion s

m u lt idrug th erapy w as prescribed th at in clu ded fu rosem ide.

of n on -angioten sin -conver t ing en zym e (ACE)−gen erated an -

W h ich of th e follow ing is a prim ar y reason for th e use of

gioten sin II. W h ich of th e follow ing drugs w as m ost likely

loop diu ret ics in ch ron ic systolic h ear t failure?

p rescribed?

A. Th ey in h ibit angioten sin II syn th esis.

A. En alapril

B. Th ey in crease ven ous ret urn to th e h ear t .

B. Fen old op am

C. Th ey in h ibit ren al prost aglan din biosyn th esis.

C. Dilt iazem

D. They act even w hen the glom erular ltration rate is very

D. Sp iron olacton e

low. E. Th ey in crease th e con t ract ilit y of th e failing h eart .

E. Losar t an F.

Nit rop ru sside

206




37. A 59-year-old w om an recen t ly d iagn osed w it h st age C

39. A 61-year-old m an recen tly diagn osed w ith stage C systolic

h ear t failure started a th erapy th at in cluded spiron olacton e.

h ear t failure star ted a th erapy w ith captopril an d car vedilol.


W h ich of th e follow ing set s of e ect s on diuresis, arteriolar

ated th e th erap eu t ic e ect of spiron olacton e in th e p at ien t’s

ton e an d m yocardial oxygen con sum pt ion m ost likely oc-

d isease?

cu rred after 1 w eek of th erapy?

A. In h ibit ion of potassium excret ion in th e collect ing du ct

Diuresis

Arteriolar Tone

Myocardial Oxygen Consumption

A

Increased

Decreased

Decreased

B

Increased

Unchanged

Increased

C

Decreased

Decreased

Unchanged

D

Unchanged

Decreased

Unchanged

E

Decreased

Increased

Decreased

B. Blockade of th e Na +/H+ an tiporter in th e proxim al tubule C. Decreased Na + con ductan ce in aldosteron e-con t rolled Na +

ch an n els

D. In h ibit ion of ren in secret ion by th e m acula den sa E. Blockade of th e Na +/Cl− sym p or ter in th e early d istal t u bu le

Di cult y level: Easy 38. A 57-year-old w om an recen tly diagn osed w ith systolic h ear t


failure st ar ted a t reat m en t w ith captopril an d car vedilol.

40. A 54-year-old m an com plain ed to h is physician of an abn or-

W h ich of th e follow ing laborator y results w as m ost likely to

m al in crease in th e size of h is breast s. Th e m an h ad been


su ering from systolic h ear t failu re for 3 years. Tw o m on th s

A. Hyp ercalcem ia

earlier, th e cardiologist h ad added a drug to th e pat ien t’s

B. Hyp erkalem ia

th erap eu t ic regim en . W h ich of th e follow ing d rugs m ost

C. Hyp er volem ia

likely cau sed th e p at ien t’s sym ptom ?

D. Hyp ern at rem ia

A. Fu rosem id e

E. Hyp erglycem ia

B. Losar t an C. Car vedilol D. Sp iron olacton e E. In dapam ide

Questions: IV-4 Antihypertensive Drugs Directions for questions 1−5

K. Methyld op a

Match each an t ihyperten sive drug w ith its app ropriate m ech a-

L.

n ism of act ion (each let tered opt ion can be selected on ce, m ore

M. Nit rop ru sside

th an on ce, or n ot at all).

N. Prazosin

A. Aliskiren B. Clon idin e C. Diazoxide D. En alapril E. Fen old op am F.

Fu rosem id e

Nifedipin e

O. Propran olol P.

Sp iron olacton e

Q. Verapam il

Di cult y level: Easy 1. Nit ric oxide is th e act ive m et abolite.

G. Hydralazin e H. Hydroch loroth iazide


I.

Labet alol

2. Act ivat ion of dop am in e D1 receptors

J.

Losar t an

Questions: IV-4 Antihypertensive Drugs 207 Di cult y level: Easy 3. Blockade of angioten sin AT1 receptors

Di cult y level: Hard 9. A 52-year-old w om an su ering from hyperten sion st ill h ad a blood p ressu re of 156/92 m m Hg after 3 m on th s of th erapy


w it h hyd roch lorot h iazid e an d losar t an . Her p hysician d e-

4. Potassium ch an n el open ing in sm ooth m uscle cells

cided to add a th ird drug th at act s by decreasing cen t ral sym path et ic ou t ow. W h ich of th e follow ing adverse e ect s

Di cult y level: Easy 5. Com p et it ive in h ibit ion of ren in

w as m ost likely to occu r after a few days of th erapy w ith th e n ew drug? A. Severe p ost u ral hyp oten sion

Di cult y level: Medium 6. A 63-year-old m an recen tly diagn osed w ith st age 1 essen t ial hyp er ten sion started a t reat m en t w ith hyd roch loroth iazide. After several w eeks of t reat m en t , th e an t ihyperten sive act ion of th e drug w as m ost likely associated w ith w h ich of th e follow ing e ect s? A. Rem arkable p ost u ral hyp oten sion B. Decreased cardiac out put C. Decreased periph eral vascular resistan ce D. In creased in terst it ial u id volum e E. Decreased ren al blood ow

Di cult y level: Medium 7. A 52-year-old m an com plain ed to h is physician of acute pain at th e base of h is righ t big toe. Th e m an , w h o h ad been w orking as a p ain ter for 15 years, w as recen t ly d iagn osed w it h essen t ial hyperten sion an d st ar ted an an t ihyper ten sive th erapy 1 m on th ago. A lab test sh ow ed a plasm a uric acid level of 17 m g/dL. W h ich of th e follow ing drugs is m ost likely to h ave cau sed th e sign s an d sym ptom s of th is p at ien t? A. Captopril B. Hydroch loroth iazide C. Methyld op a D. Fu rosem id e E. Prazosin F.

Min oxidil

Di cult y level: Medium 8. Du ring a rou t in e physical, a 65-year-old w om an w as foun d to h ave a blood pressure of 165/90 m m Hg. Past m edical h istor y w as sign i can t for a secon d-degree h eart block an d for osteo porosis. On e year ago, sh e h ad su ered from a severe ep isode of angioedem a. W hich of the follow ing antihypertensive drugs w ou ld be m ost app ropriate for th is p at ien t? A. Captopril B. Propran olol C. Verapam il D. Hydroch loroth iazide E. Min oxidil

B. Megaloblast ic an em ia C. Palpitat ion s D. Pron ou n ced sedat ion E. Sialorrh ea

Di cult y level: Medium 10. A 65-year-old m an w as adm it ted to th e em ergen cy depar tm en t becau se of restlessn ess, ap p reh en sion , t rem or, sw eating, an d tachycardia. Vit al sign s on adm ission w ere blood p ressure 190/100 m m Hg, pu lse 110 bp m , respirat ion s 18/ m in . Histor y revealed t h at t h e p at ien t h ad been t akin g a t h iazide diu ret ic an d losar tan for 3 m on th s for st age 2 hyp erten sion . How ever, h is blood pressu re w as st ill n ot w ell con t rolled, an d recen tly h is physician h ad added a th ird drug to th e th erapeu t ic regim en . Becau se th e pat ien t w as experien cing dayt im e som n olen ce an d dr y m ou th , h e decided to d iscon t in ue th e n ew ly prescribed m edicat ion th e day before adm ission . W h ich of th e follow ing drugs w as m ost likely th e n ew drug th at th e pat ien t decided to stop t aking? A. Captopril B. Min oxidil C. Nifedipin e D. Hydralazin e E. Clon idin e F.

Fen old op am

Di cult y level: Easy 11. A 35-year-old w om an in h er 29th w eek of gestat ion w as fou n d to h ave a posit ive direct Coom bs test du ring a rout in e p ren at al visit . Tw o m on th s after sh e becam e pregn an t , sh e w as d iagn osed w it h st age 1 hyp er ten sion an d st ar ted an an t ihyperten sive th erapy. W h ich of th e follow ing drugs w as sh e m ost likely t aking? A. Captopril B. Propran olol C. Nifedipin e D. Methyld op a E. Prazosin F.

Losar t an

208




12. A 47-year-old m an w ith a h istor y of hyper ten sion h ad been

15. A 50-year-old w om an cam e to h er p hysician com p lain in g

t aking hydroch loroth iazide for 1 m on th , bu t h is blood p res-

of dizzin ess an d ver t igo for th e past 3 days. Th e w om an w as

su re w as n ot con trolled despite adh eren ce to m edicat ion an d

recen t ly d iagn osed w it h hyp er ten sion an d d iastolic dys-

n onph arm acologic m easures. Th e pat ien t w as also t r ying to

fu n ct ion an d h ad started a hyperten sive th erapy 1 w eek ear-

qu it sm oking w ith ou t su ccess. Th e physician decided to add

lier. Physical exam in at ion sh ow ed sup in e blood pressu re of

a secon d drug to th e th erap eu t ic regim en th at cou ld h elp th e

166/94 m m Hg an d st an ding blood p ressu re of 140/83 m m

p at ien t as an adjun ct to a sm oking cessat ion p rogram . W h ich

Hg. W h ich of th e follow ing an t ihyperten sive dr ugs w as th e

of th e follow ing drugs w as m ost likely prescribed?

p at ien t m ost likely t aking?

A. Min oxidil

A. Propran olol

B. Propran olol

B. Clon idin e

C. Nifedipin e

C. Captopril

D. Clon idin e

D. Hydroch loroth iazide

E. Hydralazin e

E. Labet alol



13. A 60-year-old m an repor ted to h is physician th at for th e past

16. A 38-year-old m an w as diagnosed w ith hypertension (156/95

2 days h e felt ver y dizzy an d fain t w h en h e stood up rapidly.

m m Hg) d u ring a rou t in e physical exam . Su bsequ en t exam s

Th e m an h ad a h istor y of essen t ial hyp erten sion th at w as

in dicated h e w as a ected by hyp er t roph ic cardiom yop athy.

p oorly con t rolled w ith losart an an d hydroch loroth iazide.

W h ich of t h e follow ing an t ihyp er ten sive d r ugs w ou ld be

On e w eek earlier, h e w as d iagn osed w it h p rost at ic hyp er-

m ost app rop riate for th is p at ien t?

p lasia, an d th e physician added a n ew drug to th e th erapy.

A. Min oxidil

W h ich of th e follow ing drugs m ost likely caused th is adverse

B. Hydralazin e

e ect?

C. Clon idin e

A. Propran olol

D. Prazosin

B. Min oxidil

E. Propran olol

C. Hydralazin e

F.

Captopril

D. Prazosin E. Methyld op a


F.

17. A 64-year-old m an w ith a long h istor y of hyper ten sion w as

Fen old op am

adm it ted to th e em ergen cy d ep art m en t becau se of th e su d -


d en on set of severe, sh arp, di u se ch est pain th at radiated to

14. A 61-year-old m an su ering from hyper ten sion h ad been

h is back. Physical exam in at ion revealed a pulse of 110 bpm

t aking hyd roch loroth iazide an d p rop ran olol for 2 m on th s,

an d blood p ressu re of 230/120 m m Hg. A com p u ted tom og-

bu t th e th erapy failed to com pletely con t rol h is blood p res-

raphy scan sh ow ed a dissect ion of th e arch of th e aor ta. An

su re. Th e m an w as recen tly diagn osed w ith ben ign p rostat ic

em ergen cy in t raven ou s t reat m en t w as star ted . W h ich of th e

hyp erplasia an d experien ced frequ en t n oct u ria. His p hysi-

follow ing pairs of drugs w ere m ost likely adm in istered?

cian decided to add a th ird drug th at cou ld also h elp w ith th e

A. Labet alol an d p razosin

p at ien t’s di cult y in urin at ing. A dr ug from w h ich of th e

B. Diazoxide an d hydralazin e

follow ing drug classes w as m ost likely prescribed?

C. Clon idin e an d captopril

A. Alph a-1 blockers

D. Nit rop ru sside an d esm olol

B. Ca 2+ ch an n el blockers

E. Min oxidil an d n ifedip in e

C. Angioten sin -conver t ing en zym e (ACE) in h ibitors D. Dopam in e D1 blockers E. Alph a-2 agonists F.

Beta-blockers

Questions: IV-4 Antihypertensive Drugs 209 Di cult y level: Medium

bu t disorien ted fem ale w ith a blood pressu re of 240/130

18. A 56-year-old w om an recen t ly d iagn osed w it h hyp er ten -

m m Hg an d a pulse of 95 bpm . A prelim in ar y diagn osis of

sion an d at rial brillat ion st ar ted a t reat m en t w ith aten olol.

hyp er ten sive en ceph alop athy w as m ade, an d an in t raven ou s

W h ich of th e follow ing sets of physiologic ch anges w as m ost

infusion of diazoxide w as started. W h ich of the follow ing m o-

likely after th e adm in ist rat ion of th e drug?

lecular actions m ost likely m ediated the therapeutic e ect of th is drug?

Cardiac Output

Venous Tone

Postural Hypotension

A

Decreased

Unchanged

Negligible

B

Increased

Unchanged

Negligible

C

Decreased

Decreased

Marked

D

Unchanged

Decreased

Marked

E

Decreased

Increased

Slight

A. In creased syn th esis of cyclic guan osin e m on oph osph ate (cGMP) B. Act ivat ion of dop am in e D1 receptors C. Open ing of K+ ch an n els D. In creased syn th esis of cyclic aden osin e m on oph osph ate (cAMP) E. Increased synthesis of inositol triphosphate/diacylglycerol (IP3 /DAG)

Di cult y level: Medium 19. A 56-year-old m an com plain ed to h is physician th at for th e p ast 2 days h e h ad experien ced palpit at ion s, sw eat ing, an d ush ing. Histor y revealed th at th e m an h ad been diagn osed w ith hypertension 3 m onths earlier. He had started a therapy w ith hydroch loroth iazide an d captopril, bu t h is blood pressu re w as st ill 170/100 m m Hg. On e w eek ago, h is p hysician d ecided to add a th ird an t ihyperten sive agen t to th e t reatm en t . W h ich of th e follow ing drugs w as m ost likely added to th e p at ien t’s th erapy resu lt ing in h is p resen t com p lain t? A. Hydralazin e B. Propran olol C. Verapam il D. Clon idin e E. Nit rop ru sside

Di cult y level: Easy 20. A 61-year-old m an w h o h ad been su ering from stage 2 hyp erten sion for m any years h ad recen tly added m in oxidil to h is an t ihyper ten sive th erapy. W h ich of th e follow ing act ion s best exp lain s th e an t ihyp er ten sive e ect of th is drug? A. Decreased cardiac out put B. Decreased cen t ral adren ergic ton e C. Decreased ext racellu lar uid volum e D. Decreased syn th esis of angioten sin II E. Decreased tot al periph eral resist an ce

Di cult y level: Easy 21. A 45-year-old w om an w as adm it ted to th e h ospit al w ith a 2-day h istor y of n au sea, blu rred vision , con fu sion , an d in t ract able h eadach e. Physical exam in at ion revealed an alert

F.

Blockade of Ca 2+ ch an n els

Di cult y level: Medium 22. A 47-year-old Black m an presen ted to h is physician com p lain ing of a pou n ding m orn ing h eadach e. Th e pat ien t h ad been su ering from ch ron ic obst ru ct ive p u lm on ar y d isease for 3 years an d h ad h is righ t kidn ey rem oved after a car accid en t 5 years ago. His blood p ressure w as 170/115 m m Hg, an d p hysical exam in at ion revealed a systolic-diastolic bru it on th e epigast rium . Th e diagn osis of ren ovascular hyper ten sion du e to ar teriosclerot ic sten osis of th e ren al arter y w as con r m ed later by ar ter iograp hy. W h ich of t h e follow in g w ou ld be a su it able drug t reat m en t for th is p at ien t? A. Hydroch loroth iazide an d captop ril B. Fu rosem id e an d captop ril C. Fu rosem id e an d p rop ran olol D. Propran olol an d n ifedipin e E. Hydroch loroth iazide an d n ifedip in e

Di cult y level: Hard 23. A 45-year-old African -Am er ican w om an w ith kn ow n hyp er ten sion h as been receiving hydroch loroth iazide an d prop ran olol for several m on th s. Now sh e h as been diagn osed w ith varian t angin a, an d h er physician w an t s to revise h er th erapy. W h ich of th e follow ing w ou ld be th e m ost app rop riate th erap eu t ic ch ange to m ake at th is t im e? A. Su bst it u te n ifedip in e for th e prop ran olol, B. Add n it roglycerin to th e th erap eu t ic regim en , C. Su bst it u te captopril for th e propran olol, D. Su bst it u te n ifedip in e for th e hydroch loroth iazide, E. Add captop ril to th e th erap eu t ic regim en ,

210



A. Clopidogrel

24. A 63-year-old hyper ten sive w om an h ad been receiving an

B. Isosorbide m on on it rate

an t ihyp er ten sive d r ug for 15 days. Th e follow in g ser u m

C. Aten olol

valu es w ere obt ain ed from th e pat ien t before an d after drug

D. Captopril

th erapy:

E. Lovast at in

Plasma Levels Aldosterone Pot assium (m Eq/L) Renin Angiotensin II


Before

After

High

Low


3.5

4.3

m en t becau se h e h ad n ot u rin ated for th e p ast 12 h ou rs. He

Norm al

High

h ad recen tly been diagn osed w ith m oderate hyper ten sion

High

Low

an d h ad star ted t aking t w o an t ihyp er ten sive drugs 10 days ago. After a Foley cath eter w as in ser ted, on ly 30 m L of u rin e

W hich of th e follow ing drugs w as m ost likely adm inistered?

w as obt ain ed . A Dop pler u lt rason ograp hy revealed bilateral


ren al arter y sten osis. W h ich of th e follow ing pairs of drugs

B. Propran olol

w as th e pat ien t m ost likely t aking?

C. Captopril

A. Nifedipin e an d fu rosem ide

D. Hydralazin e

B. Hydralazin e an d p rop ran olol

E. Sp iron olacton e

C. Captopril an d hydroch loroth iazide D. Prazosin an d m ethyldopa


E. Clon idin e an d verapam il

25. A 33-year-old w om an w it h kn ow n hyp er ten sion is n ow 2 w eeks’ p regn an t . W h ich of t h e follow in g an t ihyp er ten sive


d rug classes is absolutely con t rain dicated in th is w om an ?

29. A 60-year-old w om an w as fou n d to h ave a blood pressure of

A. Potassium ch an n el open ers

155/95 m m Hg du ring a rou t in e doctor’s visit . Th e pat ien t

B. Angioten sin -conver t ing en zym e (ACE) in h ibitors

h ad been su ering from t ype 1 diabetes for 12 years an d

C. Ca 2+ ch an n el blockers

from gou t y ar t h r it is for 5 years. Ur in alysis sh ow ed m icro -

D. Alpha-1 blockers

h em at u r ia. Fu r th er blood p ressu re ch ecks su p p or ted t h e

E. Cen t ral sym path olyt ics

d iagn osis of stage 1 essen t ial hyperten sion . W h ich of th e follow ing w ou ld be th e m ost ap p rop riate an t ihyper ten sive


d rug for th is p at ien t?

26. A 67-year-old m an com p lain ed to h is p hysician of a d r y,


d ist u rbing cough . In ad d it ion , h e n oted t h at food seem ed

B. Propran olol

to h ave lost it s avor. Th e m an w as recen tly diagn osed w ith

C. Captopril

stage 2 essen t ial hyp er ten sion an d h ad star ted a m u lt idr ug

D. Clon idin e

t reat m en t 1 w eek earlier. W h ich of th e follow ing d rugs m ost

E. Nit rop ru sside

likely caused th e p at ien t’s sign s an d sym ptom s?

F.

A. Nifedipin e B. Clon idin e C. Propran olol

Aliskiren

Di cult y level: Hard 30. A 52-year-old m an w as recen tly diagn osed w ith stage 1 hy-

D. Min oxidil

p erten sion an d st age 1 systolic h ear t failu re. W h ich of th e

E. Captopril

follow ing w ould be an appropriate an t ihyperten sive t reatm en t for th is p at ien t?


A. Hydroch loroth iazide an d verap am il

27. A 59-year-old Black m an presen ted to th e clin ic com plain ing

B. Hydroch loroth iazide an d m in oxid il

of prurit ic sw elling of th e eyelids, n ose, lips, h an ds, feet , an d

C. Fu rosem id e an d hydralazin e

gen italia. Th e m an h ad recen tly been d isch arged from th e

D. Hydroch loroth iazide an d captop ril

h ospital after an acute m yocardial in farct ion . He h ad been

E. Fu rosem id e an d m ethyldop a

p rescr ibed an ap p rop r iate m u lt id r ug t reat m en t . He n oted t h at t h e sw ellin g ap p eared a few h ou rs after st ar t in g t h e th erapy. W h ich of th e follow ing dr ugs m ost likely cau sed th e p at ien t’s presen t ing sym ptom s?

Questions: IV-4 Antihypertensive Drugs 211 Di cult y level: Easy

valu es on ad m ission w ere ser u m creat in in e 1.6 m g/d L, p o -

31. A 65-year-old Black w om an recen tly diagn osed w ith stage 1

t assiu m 5.1 m Eq/L. W h ich of t h e follow in g w ou ld be t h e

essen t ial hyp er ten sion st ar ted a t reat m en t w it h a t h iazid e

m ost appropriate ch ange in th e pat ien t’s an t ihyperten sive

d iu ret ic. W h ich of t h e follow ing m olecu lar m ech an ism s is

regim en ?

m ost likely to m ediate th e long-term an t ihyp er ten sive e ect

A. Add fu rosem ide.

of th e th iazide drug in th is pat ien t?

B. Ch ange captopril to losart an .

A. Increased nitric oxide release from vascular endoth elium

C. Add hydroch loroth iazide.

B. Decreased pot assiu m in th e ext racellu lar uid

D. Ch ange verapam il to n ifedipin e.

C. Decreased sodium in sm ooth m u scle cells

E. Add m in oxidil.

D. In creased calcium in th e ext racellular uid E. In creased cyclic guan osin e m on oph osph ate (cGMP) in sm ooth m u scle cells

Di cult y level: Easy 35. A 38-year old w om an in w eek 16 of gestat ion w as diagn osed w ith st age 1 ch ron ic hyper ten sion an d star ted a t reat m en t


w ith m ethyldopa. W h ich of th e follow ing m olecular act ion s

32. A 55-year-old African -Am erican w om an w as fou n d to h ave

m ost likely m ediated the antihypertensive e ect of this drug?

a blood p ressu re of 165/100 m m Hg d u ring a rou t in e visit .

A. Open ing K+ ch an n els in vascular sm ooth m uscle cells

Fu r t h er an alyses sh ow ed sim ilar blood p ressu re valu es on

B. Blockade of β 1 adren oceptors in ju xt aglom eru lar cells

m u lt ip le read in gs, a n or m al elect rocard iogram , n or m al lab

C. Act ivat ion of α 2 adren oceptors in th e vasom otor cen ter

valu es, an d n o evid en ce of left ven t r icu lar hyp er t rop hy or

D. Act ivat ion of dop am in e D1 receptors in ren al vessels

ret in opathy. W h ich of th e follow ing an t ihyperten sive d rugs

E. Blockade of α 1 receptors in vascu lar sm ooth m u scle cells

w ou ld be m ost app ropriate for th is pat ien t? A. Captopril


B. Fu rosem id e

36. A 55-year-old w om an w ith a long h istor y of poorly con -

C. Nit rop ru sside

trolled essen tial hypertension had recen tly added atenolol to

D. Fen old op am

h er th erapeut ic regim en . W h ich of th e follow ing w as m ost


likely a prim ar y m ech an ism th at m ediated th e an t ihyp er-

F.

ten sive e ect of aten olol in th is pat ien t?

Aten olol

A. Dilat ion of large vein s


B. In h ibit ion of ep in ep h r in e release from t h e ad ren al m ed u lla

33. A 66-year-old m an recen tly diagn osed w ith st age 2 essen t ial hyp er ten sion st arted a t reat m en t w ith hydroch loroth iazide

C. Blockade of β 2 receptors of th e vascu lar w all

an d losar t an . W h ich of th e follow ing st atem en ts best ex-

D. Decreased sym path et ic out ow from vasom otor area

p lain s th e rat ion ale for th e associat ion of th ese t w o dr ugs?

E. Decreased cardiac out put

A. Thiazides enhance the antihypertensive e ect of losartan.

F.

Decreased tot al blood volum e

B. Losar t an coun teracts th iazide-in du ced hypercalcem ia. C. Thiazides inhibit the appearance of tolerance to losartan.


D. Person s over age 65 rarely respon d to a th erapy w ith lo-

37. A 46-year-old m an un der w en t surger y to rem ove a gliom a

sar tan alon e. E. Losar t an in h ibits th iazide-in duced hypovolem ia.

of th e left brain lobe. An in t raven ous in fusion of a drug w as star ted to in du ce con t rolled hyp oten sion to m in im ize blood loss du ring surger y. W h ich of th e follow ing d rugs w ou ld be


m ost app ropriate for th is pu rp ose?

34. A 70-year-old m an w it h a recen t h istor y of st age 2 hyper-

A. Labet alol

ten sion cam e to th e clin ic for a ch ecku p. He sm oked on e

B. Hydralazin e

p ack of cigaret tes daily an d con su m ed th ree to ve eth an ol-

C. Nifedipin e

con t ain ing d rin ks w eekly. His presen t m edicat ion s in clu ded

D. Nit rop ru sside

captop ril an d verap am il. Th e p at ien t’s vit al sign s w ere blood

E. En alaprilat

p ressu re 166/96 m m Hg, h ear t rate 68 bp m . Per t in en t lab

F.

Diazoxide

212



clon idin e, an d propran olol. His physician decided to add a


fou rth drug to th e pat ien t’s regim en . W h ich of th e follow ing

p ar t m en t w it h a 1-day h istor y of n au sea, blu r red vision ,

drugs w ou ld be app ropriate at th is t im e?

con fu sion , an d in t ract able h eadach e. Her h istor y sh ow ed

A. Nifedipin e

th at sh e w as a h eavy sm oker an d h ad been su ering from

B. Diazoxide

toxic tobacco am blyopia for 2 years. Physical exam in at ion

C. Methyld op a

revealed an aler t but disorien ted w om an w ith a blood pres-

D. En alaprilat

su re of 220/140 m m Hg an d a p u lse of 90 bp m . An elect ro-

E. Min oxidil

cardiogram sh ow ed a secon d-degree at rioven t ricu lar block.

F.

Fen old op am

A prelim inary diagnosis of hypertensive encephalopathy w as m ade, an d an in t raven ou s in fu sion of a drug w as st ar ted.



40. A 31-year-old w om an com plain ed to h er physician of poun d-

th is p at ien t?

ing h eadach e an d occasion al palpit at ion s. Th e w om an w as

A. Verapam il

recen tly m arried, an d th e couple w an ted to h ave ch ildren .

B. Diazoxide

Sh e h ad been su ering from m oderate asth m a for 5 years,

C. Labet alol

p resen tly t reated w ith in h aled albu terol. Sh e w as fou n d to

D. Clon idin e

h ave a h igh blood pressure (160/92 m m Hg), an d subsequen t

E. Captopril

exam s con rm ed th e diagn osis of essen t ial hyperten sion

F.

an d at rial t achycardia. W h ich of th e follow ing drugs w ou ld

Nit rop ru sside

be an appropriate antihypertensive therapy for this patient?


A. Fu rosem id e

39. A 55-year-old m an at a rout in e ch ecku p w as foun d to h ave

B. Captopril

a blood p ressu re of 175/105 m m Hg. He h ad a long h istor y of

C. Prazosin

hypertension and had previously experienced adverse e ects

D. Propran olol

w ith verapam il (severe con st ipat ion ) an d captopril (an n oy-

E. Dilt iazem

ing cough ). He w as presen tly t aking hydroch loroth iazide,

F.

Fen old op am

Questions: IV-5 Antiarrhythm ic Drugs Directions for questions 1−6


Match each an t iarrhyth m ic drug w ith th e app ropriate descrip -

1. Th is drug is an an t iconvulsan t frequen tly u sed to t reat gen er-

t ion (each let tered opt ion can be selected on ce, m ore th an on ce,

alized ton ic-clon ic seizures.

or n ot at all). A. Aden osin e


B. Am iodaron e

2. Th is drug acts on acet ylch olin e-sen sit ive K+ ch an n els.

C. Dilt iazem D. Esm olol


E. Flecain ide

3. Th is drug is th e m ost e ect ive an t iarrhyth m ic agen t for both

F.

Ibut ilide

su p raven t ricu lar an d ven t ricu lar arrhyth m ias.

G. Lidocain e H. Magn esiu m su lfate I.

Metop rolol

J.

Mexilet in e

K. Ph enytoin L.

Procain am ide

M. Qu in idin e N. Sotalol

Di cult y level: Easy 4. Th is drug blocks in act ivated (but n ot act ivated) Na + ch an n els.

Di cult y level: Easy 5. Th is drug blocks both β receptors an d K+ ch an n els.

Di cult y level: Easy 6. Th is drug m ay be used for t reat ing m alaria.

Questions: IV-5 Antiarrhythm ic Drugs 213 Di cult y level: Medium 7. A 51-year-old w om an at a rout in e o

A. Digoxin ce visit w as foun d to

B. Verapam il

h ave a h eart rate of 110 bpm . Th e w om an h ad a h istor y of

C. Propran olol

at rial ut ter for w h ich sh e h ad been receiving qu in idin e for

D. Procain am ide

th e past 2 w eeks follow ing a su ccessfu l elect rical cardiover-

E. Nifedipin e

sion . Th e p hysician th ough t th at h er tachycardia w as cau sed by quin idin e. W h ich of th e follow ing act ion s best explain s


th e m ech an ism of th is adverse e ect of qu in idin e?

11. A 47-year-old w om an su ering from sust ain ed ven t ricu lar

A. Blockade of m u scarin ic receptors

t achycard ia h ad been receivin g m exilet in e for 1 m on t h . In

B. Act ivat ion of α 1 receptors

th is pat ien t’s abn orm al pacem aker cells, th e d rug m ost likely

C. St im u lat ion of ar terial baroreceptors

d ecreased w h ich of th e follow ing elect rophysiological pa-

D. Act ivat ion of calciu m ch an n els

ram eters of th e h ear t?

E. Act ivat ion of pot assiu m ch an n els

A. Refractorin ess B. Slope of ph ase 4


C. Act ion p oten t ial du rat ion

8. A Purkinje ber w as isolated from an anim al heart and placed

D. Length of p h ase 2

in a recording ch am ber. Act ion poten t ials w ere recorded be-

E. Diastolic in ter val

fore an d after a low dose of quin idin e w as added to th e perfu sate. W h ich of th e follow ing elect rop hysiological respon ses


w ou ld qu in idin e m ost likely p rodu ce in th is p rep arat ion ?

12. A 47-year-old m an developed in creasing ectopic beats fol-

A. Decreased act ion poten t ial du rat ion

low ed by su stain ed tachycardia after being adm it ted to th e

B. In creased slope of ph ase 3

coron ar y un it follow ing a m yocardial in farct ion . An elect ro-

C. Decreased slope of ph ase 0

cardiogram sh ow ed a frequ en cy of 175 bp m , w ide QRS com -

D. Decreased e ect ive refractor y period

p lexes, an d at rioven t ricu lar dissociat ion . He w as given an

E. In creased slope of ph ase 4

in t raven ou s in fu sion of an an t iarrhyth m ic drug th at restored th e n orm al sin u s rhyth m , bu t 1 h ou r later th e p at ien t sh ow ed

Di cult y level: Easy 9. A 63-year-old m an w as adm it ted to th e h ospital because of fever, ch ills, an d profu se epist axis. Th e m an , su ering from

in creased agitat ion , loss of coordin at ion , con fusion , slu rred speech , nyst agm u s, t rem bling, an d m u scle t w itch ing. W h ich of th e follow ing drugs w as m ost likely adm in istered?

a reen t ran t su praven t ricu lar arrhyth m ia, h ad st arted a n ew

A. Lidocain e

an t iarrhyth m ic drug th e day before. Lab resu lt s on adm is-

B. Ph enytoin

sion disclosed a platelet cou n t of 50,000/m m 3 . W h ich of th e

C. Sotalol

follow ing drugs m ost likely caused th e pat ien t’s disorder?

D. Mexilet in e

A. Lidocain e B. Verapam il C. Qu in idin e D. Aden osin e E. Sotalol F.

Dilt iazem

E. Verapam il F.

Digoxin

Di cult y level: Easy 13. A 65-year-old w om an adm it ted to th e em ergen cy depar tm en t w ith a m yocardial in farct ion develop ed su st ain ed ven t ricu lar t achycardia. Neith er am iodaron e n or lidocain e w as

Di cult y: Hard 10. A 24-year-old m an presen ted to th e em ergen cy depart m en t w ith a ch ief com plain t of palpit at ion s for th e past 3 h ours. He h ad experien ced n o p rior sym ptom s an d h ad n o sign i -

e ect ive, an d t h e card iologist d ecid ed to t r y an ot h er d r ug t h at act s m ain ly by blockin g act ivated Na + ch an n els an d K+ ch an n els. W h ich of th e follow ing drugs w as m ost likely adm in istered ?

can t p ast m ed ical h istor y. Vit al sign s w ere blood p ressu re

A. Mexilet in e

100/60 m m Hg, p u lse 190 bp m , resp irat ion s 14/m in . An

B. Aden osin e

electrocardiogram showed a picture com patible w ith Wol −

C. Sotalol

Parkin son −W h ite syn drom e. An appropriate th erapy w as

D. Verapam il

instituted th at included in travenous adm in istration of a drug.

E. Procain am ide

W h ich of th e follow ing drugs w as m ost likely given ?

214



Parkin son −W h ite syn drom e, h ad been receiving an an t i-

14. A 54-year-old w om an com plain ed to h er physician of pal-

arrhyth m ic d rug for 1 m on th . Discon t in u at ion of th e drug

p it at ion s, in som n ia, diarrh ea, an d in creased sw eat ing for

cau sed th e sym ptom s to abate. W h ich of th e follow ing d rugs

th e p ast 3 w eeks. Physical exam in at ion revealed a p at ien t


in m oderate dist ress w ith m ild h an d t rem ors an d exoph th al-

A. Qu in idin e

m os. Vit al sign s w ere blood pressure 146/62 m m Hg, pulse

B. Lidocain e

122 bp m , respirat ion s 18/m in . An elect rocardiogram sh ow ed

C. Am iodaron e

at rial tachycardia. W h ich of th e follow ing drugs w ou ld be

D. Aden osin e

m ost appropriate to t reat th e pat ien t’s arrhyth m ia?

E. Procain am ide

A. Qu in idin e

F.

Ibut ilide

B. Am iodaron e C. Verapam il


D. Propran olol

18. A 56-year-old w om an w as adm it ted to th e in ten sive care

E. Digoxin

u n it because sh e h ad been experien cing ch est palpitat ion s for th e past 3 h ours. Vit al sign s on adm ission w ere blood


p ressure 96/70 m m Hg, h ear t rate 210 bpm , resp irat ion 15


breath s/m in . An elect rocardiogram in d icated at rial brilla-

m en t w ith severe dyspn ea an d ch est p ain . Fam ily h istor y

t ion w ith w ide QRS. A diagn osis w as m ade, an d am iodaron e

revealed th at h is fath er died sudden ly from a h ear t at tack

w as given in t raven ou sly (IV). Fifteen m in u tes later, th e h ear t

th at w as app aren tly related to a gen e defect . Au scu ltat ion

rate w as st ill 180 bp m . An ot h er ap p rop r iate d r ug w as ad -

of th e h ear t sh ow ed an eject ion -t ype m urm ur, an d ch est

m in istered IV. W h ich of t h e follow in g w as m ost likely t h e

x-ray disclosed m assive cardiom egaly. The electrocardiogram

secon d drug ad m in istered?

sh ow ed at rial brillat ion . An ap prop riate th erapy w as pre-

A. Lidocain e

scribed. W h ich of th e follow ing drugs w as m ost likely given ?

B. Mexilet in e

A. Procain am ide

C. Ph enytoin

B. Qu in idin e

D. Nifedipin e

C. Flecain ide

E. Nit roglycerin

D. Aten olol

F.

Procain am ide

E. Nit roglycerin

Di cult y level: Hard Di cult y level: Easy

19. A 53-year-old w om an w ith a h istor y of m ajor depression

16. A 78-year-old m an w as adm it ted to th e h ospit al because

w as brough t to th e clin ic by h er h u sban d becau se sh e w as

of dyspn ea, a n onproduct ive cough , an d fever. Th e m an h ad

exp erien cing ongoing leth argy. Her m edicat ion s in clu ded

been receiving an an t iarrhyth m ic drug for 2 m on th s to t reat

am it ript ylin e, an d th e h u sban d said th at h e fou n d an em pt y

refractor y supraventricular tachycardia. A chest x-ray sh ow ed

bot t le of t h e m ed icat ion in h er room . Physical exam in at ion

di use bilateral in ltrates. Bacterial, fungal, and viral cult ures

sh ow ed a let h argic, or ien ted p at ien t w it h blood p ressu re

w ere n egat ive. W h ich of th e follow ing dr ugs m ost likely

113/64, p u lse 135 bp m , resp irat ion s 22/m in . An elect ro-

cau sed th e p at ien t’s pu lm on ar y disorder?

cardiogram sh ow ed a ven t ricu lar arrhyth m ia w ith w iden ed

A. Flecain ide B. Mexilet in e C. Am iodaron e D. Sotalol E. Procain am ide

QRS com plexes. An ap propriate th erapy w as in st it u ted, an d an an t iar rhyt h m ic d r ug w as p rescr ibed . W h ich of t h e follow in g an t iar rhyt h m ic d r ugs w ou ld be absolu tely con t rain dicated for th is pat ien t? A. Mexilet in e B. Lidocain e

Di cult y level: Easy 17. A 44-year-old m an com p lain ed to h is p hysician of join t p ain s in h is elbow s an d kn ees an d of an un usual m asklike rash over h is face. Th e m an , w h o w as su ering from Wol −

C. Qu in idin e D. Ph enytoin E. Propran olol

Questions: IV-5 Antiarrhythm ic Drugs 215 Di cult y level: Medium



23. A 59-year-old w om an p resen ted w it h an abr u pt on set of

of an episode of dizzin ess an d n ear-syn cope. Her m edical

p alpitat ion s accom pan ied by a vague com p lain t of “feeling

h istor y w as sign i can t for u rin ar y t ract in fect ion , presen tly

ill.” Su bsequen t Holter m on itoring revealed at rial brillat ion

t reated w ith cip ro oxacin . A few days earlier, sh e w as diag-

w ith a ven t ricular respon se u p to 152 bpm . Th e pat ien t’s

n osed w ith at rial

brillat ion an d star ted a t reat m en t w ith

p ast h istor y in cluded p rim ar y hyperparathyroidism an d in -

sotalol. An electrocardiogram strip recorded by a Holter m on -

term it tent claudication for 3 years, apparently due to periph-

itor d u r in g an ot h er ep isod e of n ear-syn cop e clar i ed t h e

eral occlu sive ar teriosclerosis. W h ich of th e follow ing drugs

d iagn osis. From w h ich of t h e follow ing d isorders d id t h e

w ou ld be app ropriate for th e ch ron ic con t rol of th e pat ien t’s

p at ien t m ost likely su er?

arrhyth m ia?

A. Prem at ure ven t ricular con t ract ion s

A. Digoxin

B. At rial brillat ion

B. Propran olol

C. Secon d -d egree at rioven t ricu lar block

C. Verapam il

D. Polym orph ic ven t ricular tachycardia

D. Lidocain e

E. At rial t achycardia

E. Ph enytoin

F.

F.

Ven t ricular brillat ion

Aden osin e



21. A 55-year-old w om an w h o h ad been su ering from at rial

24. A 44-year-old m an presen ted to th e em ergen cy depart m en t

ut ter for 3 m on th s w as adm it ted to th e h ospital for cardio-

com plain ing of fat igue an d palpit at ion s of 3-h our durat ion .

version . Sh e received an in t raven ous in fusion of a drug for

Vital sign s w ere h ear t rate 160 bpm , blood pressure 100/60

10 m in u tes, an d a few m in u tes later th e h eart rever ted to

m m Hg, resp irat ion s 15/m in . Physical exam in at ion w as u n -

a n orm al sin u s rhyth m . W h ich of th e follow ing drugs w as

rem arkable. An elect rocardiogram con rm ed th e diagn osis

m ost likely adm in istered?

of n arrow com plex supraven t ricular t achycardia. An in t rave-

A. Mexilet in e

n ous inject ion of aden osin e w as given , an d 10 m in utes later

B. Lidocain e

th e h eart rate w en t back to n orm al. W h ich of th e follow ing

C. Aden osin e

m olecu lar act ion s m ost likely m ediated th e th erapeu t ic e

D. Am iodaron e

cacy of th e drug in th e p at ien t’s disease?

E. Ibut ilide

A. Blockade of Na + ch an n els

F.

B. Open ing of Ca 2+ ch an n els

Ph enytoin

-

C. Act ivat ion of M 2 receptors


D. Blockade of β 1 receptors

22. A 50-year-old w om an w as brough t to t h e em ergen cy d e-

E. Open ing of K+ ch an n els

p ar t m en t by h er brot h er, w h o st ated sh e con su m ed a fu ll bot t le of on e of h er m ed icat ion s in a su icid e at tem pt . Th e


w om an h ad a long h istor y of dep ression , ch ron ic obst ru ct ive

25. 45-year-old m an w as adm it ted to th e coron ar y u n it becau se

p ulm on ar y disease (t reated by iprat ropium ), an d recurren t

of a m yocardial in farct ion in th e posterior w all. Tw o h ours

su p raven t ricu lar tachycardia. Th e p at ien t w as con fu sed an d

after adm ission , h is h ear t rate st ar ted decreasing (40 bp m ),

d row sy. Vit al sign s w ere blood pressure 85/45 m m Hg, p u lse

and an electrocardiogram indicated sinus bradycardia. W hich

45 bp m , resp irat ion s 23/m in . W h ich of th e follow ing drugs

of th e follow ing drugs w ou ld be m ost appropriate for th is


p at ien t?

A. Iprat ropium

A. Isoproteren ol

B. Aden osin e

B. Epin eph rin e

C. Propran olol

C. Dobutam in e

D. Lidocain e

D. Dopam in e

E. Verapam il

E. At ropin e

216



A. Dilt iazem

26. A 46-year-old w om an com plain ed to h er physician of sleep -

B. Mexilet in e

in ess, fat igu e, cold in toleran ce, w eigh t gain , an d con st ip a-

C. Am iodaron e

t ion . Th e w om an , w h o h ad been su er in g from ven t r icu lar

D. Lidocain e

t achycard ia, h ad been receiving an an t iarrhyth m ic drug for

E. Propran olol

2 m on th s. A blood test revealed a h igh level of thyrot rop in . W hich of the follow ing drugs m ost likely caused the patient’s



30. A 33-year-old w om an presen ted to th e em ergen cy depar t-

A. Mexilet in e

m en t com p lain ing of fat igu e an d p alp it at ion s for th e p ast

B. Sotalol

3 h ou rs. Physical exam in at ion revealed a fem ale in n o app ar-

C. Flecain ide

en t dist ress w ith th e follow ing vital sign s: blood pressu re

D. Lidocain e

100/60 m m Hg, h ear t rate 172 bp m , resp irat ion s 12/m in . An

E. Procain am ide

elect rocardiogram sh ow ed a regu lar rhyth m w ith h ear t rate

F.

168 bpm . A Valsalva m an euver an d a carot id sin u s m assage

Am iodaron e

w ere at tem pted w ith n o su ccess. An in t raven ou s inject ion

Di cult y level: Easy 27. A 56-year-old alcoh olic m an presen ted to th e em ergen cy de-

of a drug w as given . W h ich of th e follow ing drugs w ould be app ropriate for th is p at ien t?

p ar t m en t w ith a ch ief com plain t of ch est palpit at ion s for th e

A. Lidocain e

p ast 3 h ours. Vit al sign s w ere blood pressure 170/90, pu lse

B. Mexilet in e

170 beats/m in . An elect rocardiogram con rm ed at rial bril-

C. Aden osin e

lat ion , an d th e physician w as con sidering prescribing on e of

D. Ph enytoin

th e follow ing drugs: aten olol, verap am il, or digoxin . W h ich

E. Verapam il

of th e follow ing act ion s best explain s th e th erapeut ic e ec-

F.

Dilt iazem

t iven ess of all of th ese d rugs in t reat ing at rial brillat ion ? A. Decreased at rioven t ricular con du ct ion B. In creased in t ra-at rial con duct ion

Di cult y level: Medium 31. A 24-year-old m an com plain ed to h is physician of frequ en t

C. In creased ven t ricular refractorin ess

bu rst s of palp itat ion s for th e p ast w eek. Fu rth er exam s led to

D. In creased m yocardial con t ract ilit y

the diagnosis of idiopathic left ventricular tachycardia. W hich

E. Decreased cardiac preload

of th e follow ing drugs w ou ld be appropriate for th e ch ron ic con t rol of th e pat ien t’s arrhyth m ia?


A. Lidocain e

28. A 52-year-old m an w ith a long h istor y of ch ron ic obst ruct ive

B. Digoxin

p ulm on ar y disease w as recen tly diagn osed w ith at rial bril-

C. Qu in idin e

lat ion . W h ich of t h e follow ing dr ugs w ou ld be ap p rop r iate

D. Flecain ide

for th e ch ron ic con t rol of th e pat ien t’s arrhyth m ia?

E. Aden osin e

A. Am iodaron e B. Verapam il C. Nifedipin e

Di cult y level: Hard 32. A 57-year-old m an adm it ted to th e coron ar y un it after coro-

D. Lidocain e

n ar y bypass surger y developed in creasing ectopic beat s fol-

E. Mexilet in e

lowed by sustained tachycardia. An electrocardiogram showed

F.

a frequ en cy of 170 bp m , w ide QRS com plexes, an d at rioven -

Sotalol

t ricu lar dissociat ion . An in t raven ou s (IV) loading d ose of an

Di cult y level: Hard 29. A 63-year-old m an w h o h ad been su ering from hyperten sion an d m ild card iac failu re for 3 years w as recen tly d iag-

app ropriate drug w as given , th en an IV in fu sion of th e sam e d rug w as st ar ted. W h ich of th e follow ing d rugs w as m ost likely adm in istered?

n osed w ith sust ain ed at rial brillat ion . Th e arrhyth m ia w as

A. Ph enytoin

refractor y to th erapy w ith verapam il an d w as on ly par t ially

B. Verapam il

con t rolled by sot alol. W h ich of th e follow ing drugs w ould be

C. Qu in idin e

app ropriate to p rescribe to th e p at ien t at th is t im e?

D. Mexilet in e E. Lidocain e

Questions: IV-5 Antiarrhythm ic Drugs 217 Di cult y level: Easy 33. A 62-year-old m an su er ing from at r ial

am iodaron e. W h ich of th e follow ing w ould be an appropriu t ter w as elec-

ate adju st m en t of th e ongoing th erapy of th is pat ien t?

t r ically card iover ted an d d isch arged from t h e h osp it al w it h

A. Decrease th e w arfarin dose on ly.

a p ostd isch arge t h erapy for rhyt h m con t rol. Th e p rescr ibed

B. Decrease th e digoxin dose on ly.

d rug prim arily blocks act ivated Na + ch an n els an d h as n egli-

C. Decrease both w arfarin an d digoxin doses.

gible e ect s on act ion p oten t ial du rat ion . W h ich of th e fol-

D. In crease th e digoxin dose before st art ing am iodaron e.

low ing drugs w as m ost likely given ?

E. Discon t in ue w arfarin as soon as sin us rhyth m is restored .

A. Am iodaron e B. Flecain ide C. Lidocain e


D. Aden osin e

37. A 67-year-old w om an com plain ed to h er physician of frequent palpitations for the past 2 w eeks. The w om an had been

E. Dilt iazem

su ering from severe asth m a for 5 years an d from exer t ion al


angin a for 2 years. An elect rocardiogram sh ow ed absen ce

34. A 35-year-old m an w ith a long h istor y of h eroin abuse w as

of P w aves an d an “irregularly irregular” ven t ricular rate.

adm it ted to th e em ergen cy depar t m en t becau se of n au sea

W h ich of th e follow ing an t iarrhyth m ic drugs w ould be ap -

an d vom it ing, blu rred vision , d izzin ess, ringing in th e ears,


an d h eadach e. Th e m an said h e h ad in t raven ou sly (IV) self-

A. Sotalol

injected a dose of h eroin bought from a new ven dor. One hour

B. Flecain ide

after th e adm ission , h e w as foun d u n respon sive by th e n urs-

C. Mexilet in e

ing sta . An elect rocardiogram sh ow ed torsade de poin tes.

D. Lidocain e

Cardiopulm on ar y life su ppor t w as in it iated, an d a dr ug w as

E. Labet alol

given IV. W h ich of th e follow ing drugs w ou ld be ap prop riate

F.

for th e pat ien t at th is t im e?

G. Dilt iazem

Aden osin e

A. Ibut ilide B. Am iodaron e


C. Procain am ide

38. A 55-year-old m an , adm it ted to th e coron ar y un it w ith a

D. Sotalol

m yocardial in farct ion developed ven t ricu lar

E. Magn esiu m su lfate

w as su ccessfu lly cardioverted. To p reven t fu rth er brillator y

F.

ep isodes, h e w as given an in t raven ou s an t iarrhyth m ic drug

Verapam il

brillat ion an d

t h at is e ect ive in bot h su p raven t r icu lar an d ven t r icu lar

G. Lidocain e

ar rhyth m ias an d h as a h alf-life of abou t 1 m on th . W h ich of


th e follow ing drugs w as m ost likely ad m in istered?

35. A 58-year-old-w om an adm it ted to th e coron ar y un it w ith a

A. Mexilet in e

m yocardial in farct ion developed ven t ricular t achycardia an d

B. Sotalol

w as given an in t raven ou s inject ion of am iodaron e. Th e th er-

C. Qu in idin e

apeu t ic e ect of th e drug w as m ost likely m ediated by an

D. Am iodaron e

in crease in w h ich of th e follow ing elect rophysiological

E. Procain am ide

p aram eters?

F.

Lidocain e

A. Slope of ph ase 4 B. Slope of ph ase 0


C. Act ion p oten t ial du rat ion

39. A Pu rkinje

ber w as isolated from an an im al h ear t an d

D. Length of ph ase 2

p laced in a recording ch am ber. Act ion p oten t ials w ere re-

E. Maxim u m diastolic p oten t ial

corded before an d after a low dose of ibut ilide w as added to th e perfu sate. W h ich of th e follow ing w as th e m ost likely

Di cult y level: Medium 36. A 53-year-old w om an is in h er cardiologist’s o

elect rophysiological act ion of th e drug on th is p reparat ion ? ce for a rou-

A. Decreased act ion poten t ial du rat ion

t in e visit . Th e w om an h as been su ering from p aroxysm al

B. Decreased slope of ph ase 0

at rial brillat ion for 4 m on th s. Her cu rren t m edicat ion s are

C. In creased act ion poten t ial durat ion

d igoxin an d w ar far in . Now t h e cardiologist w ou ld like to

D. Decreased e ect ive refractor y period

at tem pt to restore an d m ain t ain sin u s rhyt h m w it h oral

E. In creased slope of ph ase 4

218


Questions: IV-6 Antihyperlipidem ic Drugs Directions for questions 1−4


Match each an t ihyperlip idem ic d rug w ith th e app ropriate de-

7. A 54-year-old obese m an h ad plasm a low -den sit y lipoprotein


(LDL) ch olesterol of 270 m g/dL despite 4 m on th s of th erapy


w ith lovast at in . Th e physician decided to add ch olest yr-

A. Ch olest yram in e

am ine to th e patien t’s regim en. Recently, th e pat ient h ad been

B. Ezet im ibe

fou n d to h ave st age 1 hyper ten sion for w h ich h e w as cu r-

C. Gem brozil

ren t ly t aking p rop ran olol an d hyd roch loroth iazid e. W h ich of

D. Niacin

th e follow in g ch anges in th e p h arm acokin et ics of th ese t w o

E. Lovast at in

d rugs w as m ost likely to occu r w h en th e pat ien t began to t ake ch olest yram in e?


A. Clearan ce of p ropran olol in creased.

1. Th is drug can som et im es cause hyper t riglyceridem ia.

B. Clearan ce of hydroch loroth iazide decreased. C. Oral bioavailabilit y of propran olol in creased. D. Oral bioavailabilit y of hydroch loroth iazide decreased.

Di cult y level: Easy 2. Facial ushing is the m ost com m on adverse e ect of this drug.

Di cult y level: Easy 3. High d oses of th is d rug can cau se m et abolic acidosis.

F.

Volum e of dist ribu t ion of hydroch loroth iazide decreased.

Di cult y level: Hard 8. A 52-year-old m an w as fou n d to h ave tot al ch olesterol of 380 m g/d L an d t r iglycer id es of 230 m g/d L d esp ite 3 m on t h s

Di cult y level: Easy 4. Th is drug act ivates a n uclear t ran script ion receptor.

of a d iet low in sat u rated fat . Th e m an h ad been su er in g from h em op h ilia sin ce bir th an d from extern al h em orrh oids for 2 years. An an t ihyperlipidem ic th erapy w as prescribed.


W h ich of th e follow ing drugs w ould be con t rain dicated in th is

5. A 21-year-old w om an recen tly diagn osed w ith fam ilial com bin ed hyp erlip id em ia st ar ted a t reat m en t w it h lovast at in . W hich of the follow ing m olecular actions m ost likely m ediated th e th erapeu t ic e

E. Volum e of dist ribu t ion of propran olol in creased.

cacy of th e drug in th e pat ien t’s disease?

A. Dow n regulat ion of h epat ic low -den sit y lipoprotein (LDL) receptors

pat ien t? A. Lovast at in B. Ch olest yram in e C. Ezet im ibe D. Niacin E. Gem brozil

B. In creased syn th esis of lipoprotein lipase C. Decreased syn th esis of m evalon ic acid


D. Decreased storage of LDL in h epat ic en dosom es

9. A 24-year-old w om an su er ing from fam ilial hyp er t r igly-

E. In creased plasm a levels of h epat ic am in ot ran sferases F.

In creased plasm a levels of creat in e ph osph okin ase


cer id em ia w as screen ed w it h a blood lip id p ro le d u r in g a rou t in e visit . Relevan t laborator y test resu lt s w ere uric acid 15 m g/dL (n orm al 4.0−8.5 m g/dL), total ch olesterol 170 m g/dL (n or m al < 200 m g/d L), t r iglycer id es 1230 m g/d L (n or m al

6. A 28-year-old w om an recen t ly d iagn osed w it h fam ilial com -

< 200 m g/dL). A lip id-low ering drug w as prescribed. W h ich of

bin ed hyp erlip id em ia st ar ted a t reat m en t w it h a low -fat

th e follow ing w as m ost likely th e m ech an ism of act ion of th at

d iet an d ch olest yram in e. Th is t h erapy m ost likely cau sed t h e

drug?

greatest redu ct ion in p lasm a levels of w h ich of th e follow ing

A. In crease of lipid syn th esis by adipose t issue

com poun ds? A. Ver y-low -den sit y lipoprotein (VLDL) B. High -den sit y lip op rotein (HDL) C. Low -den sit y lipoprotein (LDL)

B. Dow n regulat ion of low -den sit y lipoprotein (LDL) recep tors in th e liver C. In h ibit ion HMG- CoA (3-hydroxy-3-m ethylglut ar yl−coen zym e A) redu ctase act ivit y in th e liver

D. Chylom icron s

D. St im u lat ion of lip op rotein lipase syn th esis

E. Triglycerid es

E. Decreased absorpt ion of exogen ous ch olesterol

Questions: IV-6 Antihyperlipidem ic Drugs 219 Di cult y level: Easy


10. A 55-year-old obese w om an w as foun d to h ave a tot al ch o-

13. A 49-year-old m an w as brough t by am bulan ce to th e em er-

lesterol level of 360 m g/dL (n orm al < 200 m g/dL), despite

gen cy d ep ar t m en t w it h t h e ad m it t in g d iagn osis of m yo -

m any m on th s of lovastat in t reat m en t . Th e physician d ecid ed

card ial in farct ion . Em ergen cy t h erapy w as st ar ted , w h ich

to add ezet im ibe to th e th erapeut ic regim en . W h ich of th e

in clu d ed altep lase, asp ir in , h ep ar in , an d m etop rolol. Th e

follow ing cells represents the m ain site of action of the added

n ext day lovastat in an d ezet im ibe w ere added to th e th era-

d rug?

p eut ic regim en . W h ich of th e drugs received by th e pat ien t

A. Adip ocytes

act s prim arily in th e cytop lasm ic com p ar t m en t of liver cells?

B. Capillar y en doth elial cells

A. Alteplase

C. Platelet s

B. Aspirin

D. Hepatocytes

C. Lovast at in

E. In test in al epith elial cells

D. Heparin E. Ezet im ibe


F.

Metop rolol

11. A 57-year-old m an w as foun d to h ave low -den sit y lipoprotein (LDL) ch olesterol of 360 m g/dL (n orm al < 130 m g/dL)


d espite 5 m on th s of t reat m en t w ith lovastat in . Th e p hysi-

14. A 52-year-old obese m an su ering from gou t an d hyper ten -

cian decided to add ezet im ibe to th e th erap eu t ic regim en .

sion w as fou n d to h ave low -den sit y lipoprotein (LDL) ch oles-

W h ich of th e follow ing st atem en t s best explain s th e rat io-

terol of 360 m g/dL (n orm al < 130 m g/dL) an d a serum u ric

n ale of adding ezet im ibe to lovast at in th erapy?

acid of 15.5 m g/dL (n orm al 4.0−8.5 m g/dL). Oth er laborator y

A. The com bination decreases the risk of lovastatin-induced

valu es w ere w ith in n orm al lim its. A lipid-low ering th erapy w as p rescribed. W h ich of th e follow ing an t ihyp erlip idem ic

m yop athy. B. Th e com bin at ion resu lt s in syn ergist ic ch olesterollow ering e ect s.

d rugs w ou ld be relat ively con t rain dicated in th is p at ien t? A. Ch olest yram in e

C. Ezet im ibe slow s dow n th e m etabolism of lovast at in .

B. Niacin

D. Ezetim ibe increases the intestinal absorption of lovastatin.

C. Ezet im ibe

E. Th e com bin at ion st rongly in creases h igh -den sit y lipo-

D. Lovast at in

protein (HDL) plasm a levels.

E. Gem brozil



12. A 46-year-old m an su ering from fam ilial hyperch olesterol-

15. A 56-year-old w om an su ering from fam ilial hyperch oles-

em ia w as fou n d to h ave tot al ch olesterol of 430 m g/dL de-

terolem ia w as foun d to h ave total ch olesterol of 470 m g/dL

spite m any m on th s of t reat m en t w ith lovastat in . Triglyceride

(n orm al < 200 m g/dL) despite m any m on th s of t reat m en t

levels w ere n orm al. His p hysician decided to add n iacin to

w ith lovast at in . Triglyceride levels w ere n orm al. Th e physi-

th e th erap eu t ic regim en . W h ich of th e follow ing m olecu lar

cian decided to add n iacin to th e th erap eu t ic regim en . W h ich

act ion s m ost likely m ediated th e th erap eu t ic e

of th e follow ing drugs sh ould be given during th e

cacy of n ia-

cin in th e p at ien t’s disease?

of th erapy to avoid n iacin -in duced ush es?

A. In h ibit ion of ver y-low -den sit y lipoprotein (VLDL) pro-

A. Warfarin

du ct ion by th e h epatocyte B. In h ibit ion of h igh -den sit y lipoprotein (HDL) syn th esis by th e liver C. In crease of circulat ing brin ogen D. St im u lat ion of lip olysis in ad ipose t issu e E. Decreased absorpt ion of exogen ous ch olesterol

B. At ropin e C. Aspirin D. Prazosin E. Gem brozil

rst days

220



w eigh ed 295 lb (134 kg) an d w as a h eavy cigaret te sm oker.

16. A 40-year-old obese m an su er ing from t yp e I d iabetes

W h ich of th e follow ing an t ihyperlipidem ic drugs w ould be

m ellit u s an d hyp erlip idem ia w as adm it ted to th e h osp ital

m ost appropriate for th is pat ien t?

becau se of vom it in g an d circu lator y collap se. Th e p at ien t

A. Gem brozil

h ad st ar ted an an t ihyp erlip id em ic t h erapy 1 m on t h ago.

B. Lovast at in

Per t in en t plasm a data on adm ission w ere pH 7.32, HCO3− 12

C. Ch olest yram in e

m Eq/L (n orm al 22−26 m Eq/L), par t ial pressure of arterial

D. Niacin

carbon dioxide (Pa CO2 ) 16 m m Hg (n orm al 25−45 m m Hg),

E. Ezet im ibe

Cl− 125 m Eq/L (n or m al 90−105 m Eq/L). W h ich of t h e follow ing drugs could h ave con t ributed to th e syn drom e th e


patien t w as su ering from ?

20. A 26-year-old obese w om an w h o w as foun d to h ave a low -

A. Lovast at in

d en sit y lip op rotein (LDL) ch olesterol level of 270 m g/m L

B. In sulin

(n or m al <130 m g/m L) d esp ite 4 m on t h s of d iet , st ar ted a

C. Niacin

lipid-low ering th erapy w ith ch olest yram in e. W h ich of th e

D. Gem brozil

follow ing is th e prim ar y site of act ion of th is drug?

E. Ch olest yram in e

A. Liver B. Sm all in test in e


C. Colon

17. A 57-year-old w om an w as found to have triglyceride levels of

D. Plasm a

630 m g/dL (n orm al < 200 m g/dL). Th erapy w ith gem brozil

E. Adip ose t issu e

w as p rescribed. W h ich of th e follow ing cellu lar st ru ct u res

F.

Gall bladd er

m ost likely represen ts th e site of act ion of th is drug? A. Sm ooth en dop lasm ic ret icu lu m


B. Nucleu s

21. A n ew an t ihyperlipidem ic drug w as tested on pat ien t s w ith

C. Cell m em bran e

h igh ch olesterol levels during a ph ase 3 clin ical t rial. W h ich

D. Cytoplasm

of th e follow ing populat ion s w ou ld be best suited to sh ow

E. Rough en doplasm ic ret icu lu m

th e poten t ial p rotect ive e ect of th e d rug again st coron ar y

F.

arter y d isease?

Mitoch on dria

A. Wom en ages 40 to 50


B. Men ages 50 to 60

18. A 45-year-old m an com plain ed to h is physician of m uscle

C. Obese ch ildren

ach es, soren ess, an d w eakn ess. Th e p at ien t h ad been su er-

D. Wom en over age 75

ing from du oden al ulcer for 2 years, from fam ilial hyperch o-

E. Men over age 75

lesterolem ia for 5 years, an d from op en -angle glaucom a for 1 year. Cu rren t th erapy in clu ded fam ot idin e an d su cralfate


for ulcer, lovastat in for hyperlipidem ia, an d t im olol an d lata-

22. A 53-year-old w om an w as brough t to th e h ospital because

n oprost for glaucom a. A u rin alysis sh ow ed m yoglobin uria.

of su d d en u n ilateral blin d n ess an d in abilit y to m ove t h e

W hich of the follow ing drugs m ost likely caused this nding?

ext rem it ies of th e con t ralateral body side. All sym ptom s d is-

A. Latan oprost

app eared a h alf h ou r later. An angiogram revealed a 55%ste-

B. Fam ot idin e

n osis of th e righ t carot id ar ter y. An app ropriate th erapy w as

C. Tim olol

p rescribed. W h ich of th e follow ing drugs given ch ron ically

D. Su cralfate

w ou ld be m ost likely to con t ribu te to a decreased risk of fu r-

E. Lovast at in

th er st roke in th is p at ien t? A. Isosorbide m on on it rate


B. Fu rosem id e

19. A 49-year-old m an at a rout in e ch ecku p w as foun d to h ave

C. Lovast at in

th e follow ing lipid pro le: low -den sit y lip op rotein (LDL)

D. Esm olol

ch olesterol 180 m g/dL (n orm al < 200 m g/dL), h igh -den sit y

E. Alteplase

lipoprotein (HDL) ch olesterol 14 m g/dL (n orm al > 35 m g/dL),

F.

t riglycerides 150 m g/dL (n orm al < 200 m g/dL). Th e m an

Gem brozil

Questions: IV-6 Antihyperlipidem ic Drugs 221 Di cult y level: Medium

m on th s earlier an d w as on an appropriate postdisch arge

23. A 35-year-old m an w ith fam ilial com bin ed hyperlipidem ia

th erapy. W h ich of th e follow ing drugs m ost likely cau sed th e

w as fou n d to h ave a tot al ch olesterol level of 380 m g/m L

lab resu lt s?

(n orm al < 200 m g/m L) an d a t riglyceride level of 720 m g/m L

A. Aten olol

(n orm al < 150 m g/m L). His fam ily doctor decided to star t

B. Lovast at in

th erapy w ith lovastat in an d gem brozil. Th e p hysician w as

C. Warfarin

aw are th at w ith th is th erapy th e p at ien t w as at in creased

D. Clopidogrel

risk of m yopathy. To preven t th is disorder, w h ich of th e fol-

E. Captopril

low ing en zym es sh ou ld be m easured ever y 2 w eeks? A. HMG- CoA (3-hyd roxy-3-m et hylglu t ar yl−coen zym e A) reductase

Di cult y level: Hard 27. A 51-year-old m an su ering from hyperlipidem ia w as

B. Am in ot ran sferase

screen ed w ith a lip op rotein pro le d u ring a follow -u p m ed-

C. Alkalin e ph osph atase

ical evalu at ion . He w as fou n d to h ave a low -den sit y lipopro-

D. Cyclooxygen ase

tein (LDL) ch olesterol level of 440 m g/dL (n orm al <130 m g/

E. Creat in e kin ase

d L) despite m any m on th s of lovastat in th erapy. Triglyceride levels w ere 120 m g/dL. Th e pat ien t h ad been su ering from


t ype I diabetes for 15 years. Because a su bst an t ial reduct ion

24. A 57-year-old obese w om an h ad low -d en sit y lip op rotein

of LDL ch olesterol w as n eeded, a com bin at ion of t w o an t i-

(LDL) ch olesterol of 350 m g/dL (n orm al < 130 m g/dL) despite

hyp erlipid em ic drugs w as con sidered . W h ich of th e follow -

3 m on th s of th erapy w ith lovast at in . Th e p hysician decided

ing w ould be th e m ost app ropriate dr ug com bin at ion for th is

to add to th e pat ien t’s regim en a drug th at act s by in creasing

p at ien t?

th e elim in at ion of bile acids. W h ich of th e follow ing drugs

A. Lovast at in an d ch olest yram in e

w as m ost likely p rescribed?

B. Lovast at in an d n iacin

A. Ch olest yram in e

C. Ch olest yram in e an d n iacin

B. Gem brozil

D. Gem brozil an d ezet im ibe

C. Ator vast at in

E. Gem brozil an d ch olest yram in e

D. Niacin E. Ezet im ibe

Di cult y level: Hard 28. Each of th e follow ing pat ien ts (1 to 5) w as fou n d to h ave an


abn orm al lip id p ro le an d w as p laced on a lipid -low ering

25. A 53-year-old m an con t in ued to h ave a low -den sit y lipopro-

d iet for 4 m on th s. Non e h ad any h istor y of isch em ic h ear t

tein (LDL) ch olesterol level of 270 m g/dL (n orm al < 130 m g/

d isease. Th e results of th e pat ien t s’ fast ing lip id p ro le after

d L) after a 6-m on t h t r ial of d iet t h erapy. His t r iglycer id e

4 m on th s of diet are given in th e follow ing t able.

levels w ere in th e n orm al range. Th e pat ien t h ad been su f-

Triglycerides (m g/dL)

fering from t ype II diabetes m ellit us for 2 years an d pept ic u lcer for 4 m on th s. Curren t th erapy in cluded glyburide an d m et for m in for d iabetes an d om ep razole for p ept ic u lcer. W h ich of th e follow ing drugs w ould be m ost appropriate to t reat th is pat ien t’s hyp erlip idem ia? A. Niacin B. Ch olest yram in e C. Lovast at in D. Nicot in am ide E. Gem brozil

Di cult y level: Medium 26. Du ring a rout in e follow -up visit , a 52-year-old m an w as fou n d to h ave th e follow ing lab result s: alan in e am in ot ran sferase 120 U/L (n orm al 8−20 U/L), aspar tate am in ot ran sferase 108 U/L (n orm al 8−20 U/L). Th e m an h ad been disch arged from t h e h osp it al after an acu te m yocard ial in farct ion 2

LDL (m g/dL)

HDL (m g/dL)

1

300

120

20

2

190

130

25

3

300

210

20

4

230

180

65

5

180

120

45

< 200

< 130

> 35

Norm al values

Abbreviations: HDL, high-densit y lipoprotein; LDL, low-densit y lipoprotein.

For w h ich on e of th e follow ing pat ien t s w ou ld it be m ost im port an t to recom m en d an an t ihyp erlip idem ic drug at th is t im e? A. Pat ien t 1 B. Pat ien t 2 C. Pat ien t 3 D. Pat ien t 4 E. Pat ien t 5

222




29. A 63-year-old obese m an presen ted to th e h ospital w ith th e

30. A 54-year-old m an su ering from fam ilial hyperch olesterol-

adm it t ing diagn osis of acu te ren al failu re. He reported th at

em ia st arted t reat m en t w ith lovastat in an d ch olest yram in e.

2 days earlier, h e realized h is u rin e w as clear an d red . On e

W h ich of t h e follow in g act ion s m ost likely m ed iated t h e

m on th earlier, th e m an w as fou n d to h ave plasm a ch oles-

th erap eu t ic e ect of both drugs in th e pat ien t’s disease?

terol of 310 m g/dL (n orm al < 200 m g/dL) an d t riglycerides of

A. Decreased in test in al reabsorpt ion of bile acids

950 m g/dL (n orm al < 150 m g/dL). He st ar ted an app ropriate

B. Decreased conversion of ch olesterol to bile acids

lipid-low ering th erapy at th at t im e. W h ich of th e follow ing

C. Decreased syn th esis of ch olesterol by th e liver

p h arm acoth erapies m ost likely caused th e pat ien t’s ren al

D. Up regu lat ion of h epat ic low -den sit y lip op rotein (LDL)

failure? A. Ch olest yram in e alon e

receptors E. Decreased syn th esis of t riglycerides by th e liver

B. Ch olest yram in e an d n iacin C. Lovast at in an d gem brozil D. Lovast at in alon e E. Niacin alon e

Questions: IV-7 Drugs A ecting Hem ostasis Directions for questions 1−4


Match each drug a ect ing h em ost asis w ith th e ap prop riate de-

5. A 54-year-old w om an su ering from asth m a w as brough t to


th e em ergen cy depar t m en t because of a sudden on set of left-


sid e p aralysis. Im aging st u d ies con r m ed t h e d iagn osis of

A. Abcixim ab

th rom boem bolic st roke, an d th e pat ien t st arted a t reat m en t

B. Alteplase

th at in cluded a drug th at act s by blocking platelet aden osin e

C. Am in ocaproic acid

diph osp h ate (ADP) receptors. W h ich of th e follow ing drugs

D. Aspirin

h as th is m ech an ism of act ion ?

E. Clop idogrel

A. Warfarin

F.

B. Am in ocaproic acid

Desm opressin

G. En oxaparin

C. Alteplase

H. Factor VIII

D. Clop idogrel

I.

Heparin

E. Heparin

J.

Protam in e sulfate

F.

Aspirin

K. Vitam in K L.

Warfarin

Di cult y level: Easy 6. A 34-year-old m an adm it ted to th e em ergen cy depart m en t


w ith a presum pt ive diagn osis of pulm on ar y th rom boem bo-

1. Th is drug bin ds n on com pet it ively to glycoprotein IIb/IIIa re-

lism st ar ted a t reat m en t th at in clu ded a drug th at act s by ac-

ceptor com plex.

celerat ing th e bin ding bet w een an t ith rom bin III an d clot t ing factor proteases. W h ich of th e follow ing drugs h as th is m ech -


an ism of act ion ?

2. Th is drug in creases th e act ivit y of factor VIII.

A. Warfarin B. Am in ocaproic acid


C. Alteplase

3. Th is drug blocks th e conversion of plasm in ogen to plasm in .

D. Clop idogrel E. Heparin

Di cult y level: Easy 4. Th is drug catalyzes th e conversion of plasm in ogen in to act ive plasm in .

F.

Aspirin

Questions: IV-7 Drugs A ecting Hem ostasis 223 Di cult y level: Medium

su rger y, th e p at ien t received a subcu tan eou s inject ion of

7. A 30-year-old w om an p resen ted to h er fam ily p hysician

desm opressin , a dr ug th at w as e ect ive for h im in th e p ast .

com p lain ing of black, t arr y stools. Th e w om an h ad h ad a

W h ich of th e follow ing statem en t s best explain s w hy des-

p rosth et ic valve rep lacem en t 4 m on th s earlier for severe

m opressin w as an appropriate th erapy for th e pat ien t?

aor t ic sten osis secon dar y to rh eu m at ic disease an d h ad been

A. It in creases th e plasm a levels of factor VIII.

receiving daily oral an t icoagulan t th erapy sin ce th en . Physi-

B. It in creases th e in test in al absorpt ion of vitam in K.

cal exam in at ion revealed su bconju n ct ival h em orrh age an d

C. It h as a p ron oun ced an t i brin olyt ic act ivit y.

bru ises on h er arm s an d legs. W h ich of th e follow ing dr ugs

D. It in h ibits th e act ivit y of an t ith rom bin III.


E. It in h ibits th e act ivit y of protein s C an d S.

A. St reptokin ase B. Aspirin


C. Heparin

11. A 72-year-old m an recen tly diagn osed w ith at rial brillat ion

D. Warfarin

star ted a t reat m en t th at in clu ded dabigat ran . Th e in h ibit ion

E. Am in ocaproic acid

of w h ich of th e follow ing m olecular act ion s m ost likely m e-

F.

d iated th e th erapeu t ic e ect of th e drug in th is pat ien t?

Bivaliru din

A. Proth rom bin syn th esis

Di cult y level: Hard 8. A 42-year-old w om an su ering from system ic lupu s er yth e-

B. Th rom boxan e A2 act ivit y C. Th rom bin act ivit y

m atosu s p resen ted to th e clin ic w ith su bstern al, n on radiat-

D. Plasm in ogen synth esis

ing pain th at aw aken ed h er from sleep. Physical exam in at ion

E. An t ith rom bin III act ivit y

sh ow ed a pat ien t in m oderate dist ress, com p lain ing of ch est p ain t h at w as w orsen ed by t h oracic m ot ion . Vit al sign s in -


clu d ed tem p erat u re 103°F (39.4°C), p u lse 90 bp m , blood

12. A 62-year-old w om an com plain ed to h er physician of n ose

p ressure 150/90 m m Hg, respirat ion s 18/m in . Au scu lt at ion

bleed s an d red eyes. Th e w om an h ad been receivin g w ar-

revealed a precordial systolic an d diastolic friction rub. W h ich

far in for 1 m on th becau se of d eep ven ou s th rom bosis. Fou r

of th e follow ing drug classes w ou ld be absolutely con t rain -

days earlier, sh e h ad st arted t reat m en t w ith er yth rom ycin

d icated for th is pat ien t?

for acute ph ar yngit is. W h ich of th e follow ing drug-in duced

A. Non steroidal an t iin am m ator y d rugs

ch an ges w as m ost likely resp on sible for t h e p at ien t ’s

B. Fibrin olyt ic drugs

sym ptom s?

C. Glucocor t icoids

A. Er yt h rom ycin -in d u ced in h ibit ion of clot t in g factors

D. Opioids E. An t ibiot ics

syn th esis B. Erythromycin-induced inhibition of warfarin m etabolism C. Warfarin -in du ced th rom bosis of th e n asal m u cosal

Di cult y level: Medium 9. A 55-year-old m an com plain ed to h is physician of red blood

m icrovascu lat u re D. Er yth rom ycin -in duced decrease of in test in al absorpt ion

in h is stools an d pin k u rin e. Tw o w eeks earlier, th e m an h ad star ted a t reat m en t w ith w arfarin for recu rren t deep vein

of vitam in K E. Warfarin -in du ced decreased of vit am in K produ ct ion by

th rom bosis. On physical exam in at ion , th e p at ien t app eared

in test in al ora

p ale an d diaph oret ic. Vital sign s w ere blood pressure 85/55 m m Hg, h ear t rate 105 bpm , resp irat ion s 20/m in . An ap p ro-


p r iate t h erapy w as st ar ted . W h ich of t h e follow ing d r ugs

13. A 56-year-old m an adm it ted to th e h ospital w ith a m yocar-

w as m ost likely adm in istered in t raven ou sly to th e pat ien t?

d ial in farct ion un der w en t a p ercut an eous coron ar y angio-

A. Vitam in K

p last y for th e revascu larizat ion of h is left coron ar y. W h ich

B. Am in ocaproic acid

of th e follow ing drugs w as m ost likely given in t raven ously

C. Protam in e sulfate

d uring th e procedure?

D. Alteplase

A. Warfarin

E. Fresh frozen p lasm a

B. Clopidogrel C. Protam in e


D. Am in ocaproic acid

10. A 32-year-old m an su ering from h em oph ilia A w as at h is

E. Recom bin an t factor VIIa

dentist’s o ce for a tooth extraction . In preparation for m in or

F.

Abcixim ab

224






m en t w ith th e p resu m pt ive d iagn osis of pu lm on ar y em bo-

m en t by am bu lan ce for m an agem en t of severe, u n relen t ing

lism . He w as st arted on an appropriate em ergen cy th erapy.

ch est p ain for t h e p ast h ou r. Th e m an h ad been su er in g

Th ree days later, h is

n gers becam e d iscolored , an d labo -

from exer t ion al an gin a for 5 years. Physical exam in at ion

rator y tests sh ow ed th e follow ing: w h ite blood cell cou n t

revealed a m id d le-aged m an in obviou s d ist ress w it h t h e

(W BC) 10.2 × 10 3 /m m 3 (n orm al 4.3−10.8 × 10 3 /m m 3 ), red

follow ing vital sign s: blood p ressu re 165/100 m m Hg, h eart

blood cell cou n t (RBC) 4.8 × 10 6 /m m 3 (n orm al 3.5−5.0 × 10 6 /

rate 110 bpm , respirat ion s 22/m in . An elect rocardiogram

m m 3 ), platelets 75 × 10 3 /m m 3 (n orm al 140−440 × 10 3 /m m 3 ).

sh ow ed ST-segm en t dep ression in m u lt ip le lead s. W h ich of


th e follow ing p airs of d rugs sh ou ld be in clu ded in th e im m e-


d iate t reat m en t of th is pat ien t?

A. Vitam in K

A. Clopidogrel an d am in ocaproic acid

B. Aspirin

B. Alteplase an d w arfarin

C. Heparin

C. Heparin an d asp irin

D. Warfarin

D. Abcixim ab an d w arfarin

E. Alteplase

E. Am in ocaproic acid an d abcixim ab

F.

F.

Am in ocaproic acid

Aspirin an d desm op ressin



15. A 63-year-old m an told h is p hysician t h at in t h e m or n ing

18. A 67-year-old w om an presen ted to th e clin ic because of pro-

h e discovered h is urin e w as cloudy an d red. Th e m an w as

gressive sw elling an d soren ess of th e left calf. After physical

su ering from p ersisten t at rial brillat ion an d h ad been sta-

exam in at ion an d lab exam s, a d iagn osis of d eep ven ou s

bilized on w arfarin therapy for 1 m onth. Three days earlier, he

th rom bosis w as m ade, an d a t reat m en t w ith en oxap arin w as

h ad star ted t aking an over-th e-coun ter preparat ion con tain -

star ted. W h ich of th e follow ing is th e m ain advan t age of th is

ing cim et idin e for h eartburn . W h ich of th e follow ing st ate-

d rug over th e st an dard u n fract ion ated h eparin ?

m en ts best exp lain s th e cau se of th e p at ien t’s sym ptom s?

A. Com p lete absen ce of bleed ing com p licat ion s

A. Decreased ren al clearan ce of w arfarin

B. Good oral bioavailabilit y

B. Decreased in test in al absorpt ion of vit am in K

C. Low er in ciden ce of dr ug-in du ced th rom bocytopen ia

C. In h ibit ion of h epat ic m et abolism of w arfarin

D. Pron ou n ced an t iplatelet act ivit y

D. An t icoagulan t e ect of cim et idin e

E. In h ibit ion s of a larger n um ber of coagulat ion factors

E. Warfarin disp lacem en t from plasm a p rotein −bin ding sites

Di cult y level: Hard 19. A 65-year-old m an developed sudden dyspnea and chest pain


2 days after su rger y to rem ove a gast ric carcin om a. Physical

16. A 71-year-old w om an w h o un der w en t h ip replacem en t w as

exam in at ion revealed an an xious m an in severe respirator y

d isch arged from th e h ospit al w ith an app ropriate postdis-

d ist ress w ith th e follow ing vit al sign s: tem p erat u re 99.5°F

ch arge th erapy th at in cluded daily su bcut an eous inject ion

(37.5°C), pulse 120 bpm , blood pressu re 90/50 m m Hg, res-

of regu lar h eparin . W h ich of th e follow ing lab exam s sh ould

p irat ion s 28 breath s/m in . A com p uted tom ography scan

be p erform ed frequ en tly d u ring th e h ep arin t reat m en t?

sh ow ed com p lete obst ru ct ion of a bran ch of th e left pu lm o-

A. Red blood cell cou n t (RBC)

n ar y ar ter y. W h ich of th e follow ing drugs sh ou ld be in clu ded

B. Platelet cou n t

in th e acu te paren teral t reat m en t of th is p at ien t?

C. Plasm a K+ level

A. Nit roglycerin

D. Plasm a Na + level

B. Aspirin

E. Bleeding t im e

C. Alteplase

F.

D. Warfarin

Fibrin olysis t im e

E. Heparin F.

Clopidogrel

Questions: IV-7 Drugs A ecting Hem ostasis 225 Di cult y level: Medium


20. A 48-year-old w om an w h o h ad been su ering from breast

23. A 50-year-old w om an adm it ted to th e coron ar y un it because

can cer for 2 years w as adm it ted to th e h ospit al w ith a d iag-

of a m yocardial in farct ion received an appropriate m ult idrug

n osis of deep ven ous th rom bosis. An in t raven ous (IV) load-

th erapy. Th e n ext day sh e com p lain ed of an abr u pt h ead -

ing dose of h eparin w as adm in istered, follow ed by an IV

ache, follow ed shortly by vom iting and loss of consciousness.

in fu sion . After 6 h ours of h eparin th erapy, th e pat ien t’s act i-

A com puted tom ography scan of th e brain con rm ed th e di-

vated par t ial th rom boplast in t im e (aPTT) h ad n ot in creased

agn osis of st roke due to cerebral h em orrh age. W h ich of th e

relat ive to h er h ep ar in p ret reat m en t levels. W h ich of t h e

follow ing dr ugs m ost likely con t ributed to th e appearan ce of

follow ing st atem en ts best exp lain s th is n ding?

th e p at ien t’s stoke?

A. Th e pat ien t h ad h igh plasm a levels of h eparin -bin ding

A. Aspirin

protein s.

B. Propran olol

B. Th e pat ien t’s th erapy in cluded a vitam in K supplem en t .

C. Nit roglycerin

C. Heparin h as a ver y sh or t h alf-life (2 to 4 m in u tes).

D. Alteplase

D. Heparin e ects are delayed at least 12 h ou rs after ad-

E. Warfarin

m in ist rat ion . E. Th e pat ien t h ad h igh plasm a levels of an t ith rom bin III.

Di cult y level: Medium 24. A 55-year-old w om an recen tly diagn osed w ith at rial ut ter


st ar ted a t reat m en t t h at in clu d ed w ar far in . Th e t im e of

21. A 63-year-old m an su d d en ly collap sed at h om e an d w as

on set of t h e an t icoagu lan t e ect of t h is d r ug m ain ly d e-

brough t u n con sciou s to t h e em ergen cy d ep ar t m en t . Physi-

p en d s on t h e h alf-life of w h ich of t h e follow ing en d ogen ou s

cal exam in at ion sh ow ed a com atose p at ien t w it h

com poun ds?

accid

paralysis on both left extrem ities. Vital signs were blood pres-

A. Already-form ed factor VII

su re 132/70 m m Hg, p u lse 90 bpm , resp irat ion s 8 breath s/

B. Circulat ing an t ith rom bin

m in . A d i u sion m agn et ic reson an ce im agin g (MRI) scan

C. Already form ed factor II

d isclosed com plete occlusion of th e righ t in tern al carot id ar-

D. Vitam in K

ter y. Em ergen cy th erapy w as ordered. W h ich of th e follow -

E. Circulat ing brin ogen

ing drugs w as m ost likely in cluded in th e em ergen cy t reat m en t of th is p at ien t?


A. Am in ocaproic acid

25. A 68-year-old m an w ith n o past m edical h istor y w as adm it-

B. Desm opressin

ted to th e em ergen cy depar t m en t because of severe subster-

C. Alteplase

n al cru sh ing ch est pain w ith radiat ion to th e left arm for th e

D. Dabigat ran

p ast 2 h ou rs. An elect rocardiogram con rm ed th e diagn osis

E. Bivaliru din

of acute an terior m yocardial in farct ion . W h ich of th e follow -

F.

ing pairs of drugs w ere m ost likely im m ediately given in t ra-

Warfarin

ven ously to th e pat ien t?

Di cult y level: Medium 22. A 69-year-old obese m an presen ted to th e clin ic becau se of

A. Alteplase an d h eparin B. Alteplase an d w arfarin

left calf sw elling an d pain of 1-day durat ion . He stated th at a

C. Dobutam in e an d m ilrin on e

few days before th e on set of sym ptom s, h e h ad arrived h om e

D. Dobutam in e an d aspirin

after a 14-h ou r igh t from In dia. Du plex scan n ing w as per-

E. Clopidogrel an d h eparin

form ed an d revealed clot form at ion in th e pat ien t’s left calf.

F.

Th e pat ien t did n ot exh ibit sign s of p u lm on ar y em bolism . W h ich of th e follow ing pairs of drugs w ere m ost likely prescribed to th e p at ien t? A. Heparin an d abcixim ab B. Warfarin an d abcixim ab C. Heparin an d w arfarin D. Alteplase an d w arfarin E. Alteplase an d h eparin F.

Alteplase an d abcixim ab

Aspirin an d w arfarin

226



a diagn osis of at rial brillat ion w as m ad e, an d cardioversion

26. A 64-year-old w om an w as diagn osed w ith hypothyroidism

w as p lan n ed for t h is p at ien t in 6 w eeks. W h ich of t h e fol-

an d started on levothyroxin e replacem en t th erapy. For th e

low ing drugs did th e pat ien t m ost likely receive during th e

p reviou s 8 m on th s, sh e h ad been receiving w arfarin th erapy

6 w eeks before cardioversion ?

for th e t reat m en t of recurren t deep ven ous th rom bosis. Her

A. Heparin

w arfarin d ose w as adju sted to m ain tain h er in tern at ion al

B. St reptokin ase

n orm alized rat io (INR) bet w een 2 an d 3. W h en sh e st arted

C. High -dose asp irin

thyroxin e rep lacem en t th erapy, h er physician redu ced th e

D. Warfarin

d osage of w ar far in by 50% an d advised h er t h at h er INR

E. Abcixim ab

w ou ld n eed to be m on itored on a w eekly basis u n t il a n ew app ropriate dose of w arfarin w as determ in ed. W h ich of th e


follow ing st atem en t s best explain s w hy th e w arfarin dose


w as redu ced?

m en t becau se of u n relen t ing ch est pain for th e p ast 3 h ou rs.

A. Warfarin decreases the ren al clearan ce of levothyroxine.

After physical exam ination and lab tests, a diagnosis of unsta-

B. Warfarin decreases the hepatic clearance of levothyroxine.

ble angina w as m ade, and the patient received an em ergency

C. Levot hyroxin e d ecreases t h e h ep at ic clearan ce of

th erapy th at in clu ded abcixim ab. W h ich of th e follow ing

w ar far in .

step s of th rom bu s form at ion w as m ost likely in h ibited by

D. Levot hyroxin e in creases t h e cat abolism of clot t in g factors.

th is drug? A. Bin ding of brin ogen to platelet surface

E. Levot hyroxin e in creases t h e in test in al absor pt ion of w ar far in .

B. Act ivat ion of factor X C. Syn th esis of th rom boxan e A2 D. Syn th esis of factor II


E. Bin ding of aden osin e diph osph ate (ADP) to it s platelet receptor

27. A 67-year-old m an recen tly diagn osed w ith at rial brillat ion star ted a t reat m en t th at in clu ded w arfarin . W h ich of th e follow ing m olecular act ion s m ost likely m ediated th e e

F.

Act ivat ion of factor IX

cacy

of th e drug in th e pat ien t’s disease?


A. Poten t iat ion of th e act ivit y of an t ith rom bin III in th e

30. A 65-year-old m an leaving th e h ospit al after a m yocardial

blood

infarction received an appropriate postdisch arge therapy that

B. Blockade of th e redu ct ion of vitam in K epoxide

in clu ded asp irin , on e low -dose tablet daily. W h ich of th e fol-

C. St im u lat ion of th e m etabolism of factors II, VII, IX, an d X

low ing act ion s m ost likely m ediated th e th erapeu t ic e ect of

in th e liver D. Act ivat ion of en dogen ou s an t icoagu lan t p rotein s in th e liver E. Blockade of th e syn th esis of vitam in K in th e liver

th e drug in th e p at ien t’s disease? A. Com p et it ive in h ibit ion of cyclooxygen ase B. Com p et it ive in h ibit ion of lip oxygen ase C. Irreversible blockade of aden osin e diph osph ate (ADP) receptors


D. Act ivat ion of th e glycoprotein IIb/IIIa receptor com p lex

28. A 65-year-old m an w ith congestive heart failure presented to

E. Irreversible acet ylat ion of cyclooxygen ase

the clinic com plaining of several days of fatigue and fast heart rate. On physical exam ination , h is pulse w as irregular, and his h ear t rate w as 130 bp m . After d oing an elect rocard iogram ,

F.

Blockade of th e syn th esis of prostaglan din I2 (PGI2 , prost acyclin )

Answers and Explanations: IV-1 Diuretics 227

Answers and Explanations: IV-1 Diuretics Questions 1−5

D Th is urin e pro le w ould be caused by loop diu ret ics.

1. A

E Th is u r in e p ro le w ou ld be cau sed by K+-sp ar in g diu ret ics.

2. G 3. F

Learning objective: Describe the m ain adverse e ects of carbonic anhydrase inhibitors.

4. E 5. C

8. D Th e sym ptom s of th e pat ien t are classic for acetazolam ide

Learning objective: Explain the m olecular m echanism of diuretic action of carbonic anhydrase inhibitors.

overd ose. Th e d r ug is u sed to t reat glau com a, becau se it

6. A Acet azolam ide is a carbon ic an hydrase in h ibitor. Carbon ic

bicarbon ate. High doses of carbon ic an hydrase in h ibitors

an hydrase is an en zym e located in th e brush border an d cyto-

su ch as acet azolam ide can cau se m etabolic acid osis as th ey

plasm of ren al proxim al convolu ted t u bu le ep ith elial cells. In

p rofou n dly in crease th e u rin ar y excret ion of bicarbon ate.

th e proxim al t ubule, a large am ou n t of H+ is secreted in to th e

Because th e plasm a loss of bicarbon ate is coun terbalan ced

lu m en via t h e Na +/H + exch anger. Most of t h is H + com bin es

by an in crease of ext racellular Cl−, m ost in ciden t s of m et a-

w it h bicarbon ate ion in t h e t u bu lar

bolic acidosis are hyperch lorem ic.

u id to for m carbon ic

acid, w h ich is rapidly dehydrated to CO2 an d w ater (th is react ion is catalyzed by carbon ic an hyd rase). Th e CO2 di u ses in to

d ecreases th e produ ct ion of aqueou s h um or, a

u id rich in

A−C, E All of th ese dr ugs are used for glaucom a, but th ey do n ot cau se hyp erch lorem ic m etabolic acidosis.

th e p roxim al t u bu lar cells, w h ere th e opp osite react ion t akes

eral side an d is reabsorbed as bicarbon ate. Hydrogen ion is

Learning objectives: Outline comorbidit y contraindications for the use of carbonic anhydrase inhibitors; describe the main adverse e ects of carbonic anhydrase inhibitors.

secreted in to th e lu m en via th e Na +/H+ exch anger. By blocking

9. A Th e h istor y, sym ptom s, an d sign s of th e p at ien t suggest

carbon ic an hydrase, acet azolam ide blocks th e reabsorpt ion of

th at h e w as su ering from p or tal-system ic en cep h alopathy,

bicarbon ate an d Na +, resu lt ing in in creased diu resis.

a syn drom e th at can occu r w h en exten sive p or t al-system ic

p lace to form H+ an d HCO3− (th is react ion is also catalyzed by carbon ic an hydrase). Th e HCO3− exit s th e cell on th e basolat-

B Acet azolam ide causes an in h ibit ion , rath er th an a st im u -

collaterals h ave developed as a result of por tal hyper ten sion . Liver cir rh osis is on e of t h e m ost com m on cau ses of p or-

lat ion , of bicarbon ate reabsorpt ion . C Th is is th e m echan ism of act ion of th iazide diuret ics.

t al-system ic en cep h alop at hy, an d t h is w as m ost likely t h e

D Hydrogen is n ot reabsorbed by th e kidn ey. By in h ibit ing

cau se in th is case. Carbon ic an hydrase in h ibitors cau se u rin e

carbon ic an hydrase, acet azolam id e in h ibit s th e form at ion of

alkalin izat ion , w h ich in t u rn redu ces u rin ar y excret ion of

carbon ic acid in side th e t u bu lar cells, w h ich in t u rn in h ibit s

am m on ia. Th e resu lt ing hyp eram m on em ia is an im port an t

th e secret ion of hydrogen in to th e lu m en .

cau se of p or t al-system ic en cep h alop at hy, as NH 4 + cau ses

E Acet azolam ide causes in h ibit ion , n ot st im ulat ion , of carbon ic acid form at ion in side th e t u bu lar cells.

brain toxicit y. Most likely, th e oph th alm ologist overlooked th e possibilit y th at th e pat ien t h ad liver cirrh osis an d prescribed acetazolam id e for glau com a.

Learning objectives: Outline the use of carbonic anhydrase inhibitors in the prophylaxis of altitude sickness; describe the urine prole of a patient treated with carbonic anhydrase inhibitors.

B−E Th ese d r ugs d o n ot t r igger liver en cep h alop at hy in p at ien t s at risk for liver cirrh osis.

diu ret ic u sed to p reven t m ou n t ain sickn ess in p eople w h o are

Learning objective: Describe the m ain therapeutic uses of carbonic anhydrase inhibitors.

at risk for th is disord er an d h ave to go to a h igh alt it u de. Th e

10. D Dorzolam id e is a carbon ic an hydrase in h ibitor. Th e rat io-

m ech an ism of t h is act ion is n ot clear, bu t it m ay be related

n ale for t h e u se of carbon ic an hyd rase in h ibitors in op en -

to th e in duct ion of m et abolic acidosis. Carbon ic an hydrase

an gle glau com a is based on t h e fact t h at aqu eou s h u m or is

in h ibitors p rodu ce u rin e th at is ver y rich in bicarbon ate. Uri-

rich in bicarbon ate. By in h ibit ing bicarbon ate syn th esis, th e

n ar y sodium is on ly sligh tly in creased (th e e

p roduct ion of aqueous h um or is decreased .

7. A Acet azolam ide, a carbon ic an hydrase in h ibitor, is th e on ly

cacy of th e di-

u ret ic is low ). Urin ar y K+ excret ion is also in creased (all

A−C, E All of th ese drugs are used to t reat glaucom a, but

d iuret ics except p otassiu m -sparing diu ret ics in crease urin ar y

th ey act by in creasing th e ou t ow of aqu eou s h u m or, n ot by

K+ excret ion ).

d ecreasing it s p rod uct ion .

B Th is u rin e pro le w ould be caused by osm ot ic d iuret ics. C Th is u rin e p ro le w ould be cau sed by th iazide diu ret ics.

228


Learning objective: Describe the therapeutic uses of carbonic anhydrase inhibitors.

h as n oth ing to do w ith th e th iazide-in duced in crease in K+

11. E Fam ilial hypokalem ic periodic paralysis is a rare autoso-

excret ion .

C Th iazides can decrease th e secret ion of u ric acid, but th is

m al con dit ion ch aracterized by ep isodes of accid p aralysis

D Th iazides do n ot st im ulate th e Na +/K+ p u m p .

w ith loss of deep ten don re ex. Potassium

ow s from th e

E Th iazides are w eak carbon ic an hydrase in h ibitors an d

bloodst ream in to m u scle cells du ring at t acks. Acetazolam ide

th erefore ten d to in crease, n ot decrease, th e deliver y of bi-

m ay h elp to p reven t th e at tacks; th e m ech an ism of act ion is

carbon ate to th e collect ing du ct .

st ill u n cer tain , bu t it cou ld be related to th e p rodu ct ion of ATPase, th u s low ering th e en t r y of p ot assiu m in to m u scle

Learning objective: Explain the m ain contraindications to carbonic anhydrase inhibitors.

cells.

14. C Dr ugs t h at can cau se alkalin e u r in e are u su ally con t rain -

m etabolic acidosis, w h ich decreases th e act ivit y of Na +/K+

A−C Th ese diuret ics can cause hypokalem ia an d are th erefore con t rain dicated in th is disease.

d icated in seriou s h epat ic disease for th e follow ing reason : am m on ia (NH 3 ) is secreted by t h e p roxim al t u bu le by a

D Potassium -sparing diuret ics are som et im es u sed in hy-

cou n ter t ran sp or t m ech an ism in exch an ge for Na +, w h ich

pokalem ic periodic paralysis, but th ey are n ot n eeded in th is

is reabsorbed . If t h e u r in e is acid ic, it accept s a p roton an d

case, as a pot assiu m su p plem en t at ion w as prescribed.

exist s alm ost en t irely as NH4 +, w h ich is t rap ped th ere. If th e u rin e is alkalin e, few er protons are available, an d am m on ia

Learning objective: Explain the m echanism of thiazide-induced hypercalcem ia.

can ret u rn to th e system ic circu lat ion . In p at ien t s w ith seri-

12. A In th e kidn ey, th e dist al convolu te t ubu le reabsorbs abou t

an d can cause hyperam m on em ia, w h ich in t urn can t rigger

8%of th e ltered Ca 2+ load. Th is reabsorpt ion occu rs th rough ep ith elial Ca 2+ ch an n els. In th e steady state, h ow ever, th e cell m u st ext r u d e all t h e en tered Ca 2+; t h is occu rs t h rough a p lasm a m em bran e Ca 2+-ATPase (t h e Ca 2+ p u m p ) an d also th rough th e Na +/Ca 2+ exch anger located on th e basolateral

ous h epat ic disease, am m on ia can n ot be conver ted in to urea a h epat ic com a. B Sp iron olacton e is t h e p refer red d iu ret ic in ascites d u e to h epat ic cirrh osis A, D, E All of th ese diu ret ics can be u sed in ascites du e to h epat ic cirrh osis.

su r face of cells of th e d ist al t u bu le. Th iazid es in h ibit t h e decreasing th e in t racellular con cen t rat ion of Na. Th is likely

Learning objectives: Outline the signs of hyponatremia; identify the diuretics that can cause hyponatrem ia.

en h an ces th e act ivit y of th e Na +/Ca 2+ exch anger, w h ich in

15. F In dap am ide is a su lfon am ide com pou n d categorized as a

t u rn creates a greater d riving force for reabsorpt ion of Ca 2+

“th iazide-like” d iu ret ic. Th e pat ien t’s sign s an d sym ptom s

t h rough t h e ep it h elial Ca 2+ ch an n els. Th e

n al e ect is an

suggest th e diagn osis of dilu t ion al hypon at rem ia, w h ich is a

in creased reabsor pt ion of Ca 2+ t h at can cau se hyp ercalce-

rare bu t som et im es fatal adverse e ect of th iazide an d th ia-

m ia or, m ore often , can u n m ask hyp ercalcem ia du e to oth er

zid e-like diu ret ics. Th ese d rugs a ect th e dilu t ing abilit y of

cau ses, as in th is case (m align an cy is a com m on cau se of

th e kidn ey w h ile in creasing Na + excret ion . On ce volum e de-

hyp ercalcem ia).

plet ion occu rs, th e release of an t idiuret ic h orm on e (ADH)

Na +/Cl− sym porter in th e early dist al convolu ted t u bu le, th u s

B−F Th iazides do n ot cau se these e ect s.

cau ses w ater reten t ion an d w orsen s th e hyp on at rem ia. In con t rast , loop diuret ics (n ot in clu ded in th e quest ion ) also

Learning objective: Explain the m echanism of thiazide-induced increase in renal excretion of potassium .

a ect th e con cen t rat ing abilit y of th e kidn ey, th u s lim it ing

13. A Potassium secret ion by th e dist al t ubule is a passive pro-

last 1 to 2 w eeks after cessat ion of th e th erapy. Elderly pa-

cess th at depen ds on th e elect roch em ical gradien t bet w een

t ien t s are especially p ron e to th iazide-in du ced hyp on at re-

t h e d ist al t u bu lar cells an d t h e t u bu lar lu m en . Th e h igh er

m ia, par t icu larly if a p reexist ing ren al in su

th e Na + load in th e distal t ubule, th e h igh er th e Na+ reab -

in th is case (see th e h igh creat inin e level).

sorpt ion . Th is creates a lu m en -n egat ive p oten t ial th at favors K+ excret ion . B Th iazides do n ot in h ibit th e Na +/K+/2Cl– cot ran spor ter.

ADH-m ediated w ater reten t ion . Th e e ect of th iazides m ay

cien cy exist s, as

A−E Th e risk of dilut ion al hypon at rem ia w ith th ese drugs is n egligible.

Answers and Explanations: IV-1 Diuretics 229 Learning objective: Describe the therapeutic use of thiazides in diabetes insipidus.

Learning objective: Explain the m olecular m echanism of furosemide-induced metabolic alkalosis.

16. B Polyuria w ith low urin e osm olalit y suggest s th e diagn osis

18. B Th ere are th ree m ain cau ses of alkalosis in du ced by loop

of diabetes in sipidus. To determ in e th e cause of th is syn -

d iu ret ics. Th e m ost im p or tan t is in creased deliver y of Na +

d rom e, vasopressin is used. Because n eph rogen ic diabetes

to th e distal t ubu le. Th e con sequen t in creased reabsorpt ion

in sipidus is vasopressin -resistan t , urin e osm olalit y w ould

of Na + creates a lu m en -n egat ive poten t ial th at favors both

n ot ch ange sign i can tly after vasopressin , as in th is case. A

H+ an d K+ excret ion . Th e secon d cau se is th e st im ulat ion of

com m on cause of n eph rogen ic diabetes in sipidus is hyper-

aldosterone release due to volum e con t ract ion an d in creased

calcem ia, w h ich is com m on in bon e m etastases of variou s

ren in secret ion . Th e th ird cau se occurs on ly w h en hypokale-

t u m ors. Th iazide diu ret ics can redu ce p olyu ria an d p olydip -

m ia is severe. In th is case, K+ ten ds to leave th e cell, an d H+

sia in diabetes in sip idu s. Th e m ech an ism of th is p aradoxical

en ters to m ain tain elect ron eu t ralit y, w ith th e n al resu lt of

e ect is likely related to th e ext racellu lar volu m e redu ct ion ,

ext racellular alkalosis an d in t racellular acidosis.

w h ich in t u rn causes an act ivat ion of th e ren in −angioten sin system . Angioten sin en h an ces th e reabsorpt ion of Na + an d w ater in th e p roxim al t u bu le by st im u lat ing th e Na +/H+ ex-

A, C, D All of th ese are act ion s of loop diu ret ics, bu t th ey do n ot lead to m et abolic alkalosis. E Loop diuret ics act ually in crease ren in secret ion .

ch anger. Th is in t urn causes a decreased deliver y of u id to th e distal t u bu le. Th u s, th ere is a decrease in th e m axim u m volum e of dilute urin e th at can be produced.

Learning objective: Explain the m echanism of thiazide-induced extracellular volum e depletion.

A Desm opressin is e ect ive in n eu rogen ic diabetes in sipi-

19. C Th e p at ien t’s sign s an d sym ptom s suggest th e diagn osis of

du s, but it is in e ect ive in n eph rogen ic diabetes in sipidu s.

hyp ovolem ic hyp on at rem ia, w h ich is a rare bu t som et im es

Neu rogen ic diabetes in sip idu s is u n likely in th is case, be-

fat al adverse e ect of th iazide diuret ics. Th ese drugs a ect

cau se it is vasopressin -sen sit ive; th erefore, u rin e osm olalit y

th e dilu t ing abilit y of th e kidn ey w h ile in creasing Na + excre-

w ou ld h ave been in creased sign i can tly after vasop ressin .

tion. Once volum e depletion occurs, the release of antidiuretic

C Dem eclocyclin e is ap p rop r iate for t h e t reat m en t of

h or m on e cau ses w ater reten t ion an d w orsen s hyp on at re-

syn drom e of in ap p rop r iate an t id iu ret ic h or m on e secret ion

m ia. Th is e ect of th iazides m ay last 1 to 2 w eeks after ces-

(SIADH). Th is syn drom e leads to hypon at rem ia (n ot hyper-

sat ion of th e th erapy. Elderly pat ien t s are especially p ron e to

natrem ia, as in diabetes insipidus) and low serum osm olalit y.

th iazide-in duced hypon at rem ia, par t icularly if preexist ing

D Am iloride is used e ect ively in case of lith ium -in duced n eph rogen ic diabetes in sipidus because th e drug blocks lith ium t ran spor t in to th e cells of th e collect ing t ubu le. How ever, it is n ot e ect ive in oth er form s of diabetes in sipidus.

ren al in su

cien cy exists, as in th is case (see th e h igh creat i-

n in e level). A, B, D Th ese disorders do n ot cau se th e sign s an d sym p tom s sh ow n by th e pat ien t .

E Furosem ide is n ot e ect ive in n eph rogen ic diabetes in -

E Th e pat ien t is hypon at rem ic, but th e post u ral hypoten -

sip idu s. It can be u sed in case of ch ron ic ren al failu re, bu t

sion an d th e diu ret ic th erapy in dicate th at hypon at rem ia is

th is diagn osis is u n likely in th is case becau se u rin e osm olal-

hyp ovolem ic, n ot hyper volem ic.

it y is low er th an serum osm olalit y (in ch ron ic ren al failure, u rin e osm olalit y is usually xed close to th at of serum ).

Learning objective: Describe the m ain therapeutic uses of loop diuretics.

Learning objective: Explain the m olecular m echanism of action of loop diuretics. 17. C W h en th e glom eru lar

lt rat ion rate (GFR) is less th an 30

20. E Th e pat ien t exh ibit s th e classic sym ptom s of pulm on ar y ed em a. Fu rosem id e is t h e d iu ret ic of

con dit ion becau se it is able to qu ickly red u ce p reload (an d

m L/m in (as can occu r in severe h ear t failu re), th e on ly d i-

t h erefore t h e left ven t r icu lar

u ret ics th at are st ill act ive are loop diuret ics. Th is is likely

follow ing act ion s:

related, at least in part , to th e fact th at by in h ibit ing Na + an d Cl− t ran sp or t in to th e m acu la den sa, th e m acu la den sa is n o longer able to sen se salt con cen t rat ion in th e t u bu lar

u id

an d th erefore in creases ren in secret ion , leading to an in crease in angioten sin II. Becau se angioten sin II p referen t ially const ricts th e e eren t ar teriole, GFR is en h an ced. A, B, D, E See correct an sw er explan at ion .

rst ch oice for t h is

llin g p ressu re) t h rough t h e

• Rapid in crease in ven ou s capacit an ce, likely m ediated by prost aglan d in release (th e in it ial ben e cial e ect m ay resu lt m ore from th is act ion th an from diu resis) • Brisk an d abu n dan t n at riu resis A, B Hyd roch lorot h iazid e an d am ilor id e are less e ect ive t h an loop d iu ret ics an d d o n ot h ave acu te vasod ilat in g p rop er t ies. C, D, F Man n itol, epin eph rin e, an d m etoprolol are con t rain dicated in pu lm on ar y edem a.

230


Learning objective: Describe the m ain therapeutic uses of loop diuretics.

Learning objective: Explain the m olecular m echanism of action of potassium -sparing diuretics.

21. C Lab valu es of t h is p at ien t in d icate ver y h igh Ca 2+ levels,

23. B Pot assiu m -sparing diu ret ics are adm in istered in cases of

an d h er sym ptom s an d h istor y are in accordan ce w ith th e

hyp okalem ia, w h ich m ay occu r in laxat ive abu sers, as in th is

diagn osis of profoun d hypercalcem ia. Malign an cy an d hy-

case. Epith elial cells in th e late distal t u bu le an d collect ing

perp arathyroidism are th e m ost com m on cau ses of hyper-

d uct h ave lu m in al m em bran e Na + ch an n els th at p rovide a

calcem ia. The rst-line em ergency treatm ent for th is disorder

con duct ive path w ay for th e en t r y of Na + in to th e cells dow n

is hydrat ion an d volu m e expan sion , as such pat ien ts are vol-

an electrochem ical gradient created by the basolateral Na +/K+

u m e depleted due to th e accom pany polyuria, n ausea, an d

pu m p . Th is en t r y creates a lu m en -n egat ive p oten t ial th at

vom it ing.

su p p lies a driving force for th e secret ion of K+ in to th e lu m en

Fu rosem ide is adm in istered becau se it can in crease u ri-

th rough K+ ch an n els located in th e lum in al m em bran e. Tri-

n ar y Ca 2+ excret ion . Ca 2+ an d Mg 2+ are reabsorbed in th e

am teren e an d am iloride block Na + ch an n els in th e late distal

th ick ascen ding lim b of th e loop of Hen le, becau se th e act ion

t u bu le an d collect ing du ct . Becau se K+ secret ion is cou p led

of th e Na +/K+/2Cl− cot ran spor ter in th at por t ion of th e n eph -

w ith Na + en t r y in th ese segm en t s, th e blockade of Na + ch an -

ron leads to excess K+ accu m u lat ion w ith in th e t u bu lar cells.

n els cau ses a K+-sparing e ect .

Th is resu lt s in back-d i u sion of K+ in to t h e t u bu lar lu m en


an d d evelop m en t of a lu m en -p osit ive elect r ical p oten t ial. of Ca 2+ an d Mg 2+ via t h e p aracellu lar p at h w ay. By blocking

Learning objective: Describe the therapeutic uses of spironolactone.

t h e Na +/K+/2Cl− cot ran sp or ter, fu rosem ide d ecreases th e re-

24. F Th e sign s of th e pat ien t an d lab resu lts in dicated th at h e

Th is p oten t ial p rovid es t h e d r ivin g force for reabsor pt ion

absorpt ion of these ion s. A Acetazolam ide h as n o sign i can t e ect on urin ar y Ca 2+ excret ion . B, D, E Th ese d iu ret ics act u ally d ecrease u r in ar y Ca 2+ excret ion .

w as m ost likely su er in g from p r im ar y hyp erald osteron ism d u e to ad ren al hyp er p lasia, w h ich is m ore com m on in eld erly m en . Un like adren al ad en om a, su rger y is n ot recom m en ded for bilateral ad ren al hyperp lasia; th e hyperald osteron ism u su ally can be con t rolled by spiron olacton e, an ald osteron e receptor an tagon ist . How ever, abou t 50%of su ch

Learning objective: Determ ine the choice of a loop diuretic in a patient with a serious allergic reaction to sulfa drugs.

p at ien ts n eed addit ion al an t ihyper ten sive t reat m en t .

22. D Th e on ly loop diuret ic th at is n ot a sulfon am ide is eth ac-

w orsen th e hypokalem ia an d th e m etabolic alkalosis.

A−C Th ese diuret ics are con t rain dicated, as th ey can

r yn ic acid. Th erefore, eth acr yn ic acid rep resen t s a su it able

D, E Pat ien ts w ith prim ar y hyperaldosteron ism usually

altern at ive to th e u se of fu rosem ide w h en fu rosem ide is

n eed antihypertensive treatm ent, but fenoldopam and nitro-

con t rain dicated because of seriou s adverse e ects, as in th is

p ru sside are used on ly in hyperten sive em ergen cies.

case. d rug, bu t it can n ot subst it u te for a loop diuret ic in a p at ien t

Learning objective: Describe the therapeutic uses of spironolactone.

w ith st age C h ear t failure.

25. C Th e h istor y an d sym ptom s of th e pat ien t suggest th at h e

A Spiron olacton e is used in h ear t failure as an adjun ct

B, E Acetazolam ide an d t riam teren e are n ot used in h ear t

h as been su ering from liver cirrh osis. Moreover, th e low K+

failu re becau se t h ey are m u ch less e ect ive t h an loop

an d h igh bicarbon ate levels suggest th at h igh levels of aldo-

d iu ret ics.

steron e are p resen t . Secon dar y hyp eraldosteron ism is com -

C Man n itol is absolutely con t rain dicated in pat ien ts w ith h ear t failure. F All th iazides an d th iazide-like drugs are sulfon am ides an d are th erefore relat ively con t rain dicated in a pat ien t w h o experienced a serious allergic reaction to a sulfonam ide drug even th ough th e risk of an allergic react ion after adm in ist rat ion of a th iazid e diu ret ic in a pat ien t w ith su lfon am ide hyp ersen sit ivit y appears to be ver y low. Moreover, th e p at ien t h ad stage C h eart failure, an d loop diu ret ics are usually n ecessar y to restore an d m ain t ain euvolem ia.

m on in advan ced liver cirrh osis for th e follow ing reason s: • Ascites-in du ced hyp ovolem ia act ivates th e ren in −angioten sin −aldosteron e system . • Liver m et abolism of aldosteron e is redu ced becau se of liver im pairm en t . • Hyp oalbu m in em ia is a kn ow n con sequ en ce of liver cirrh osis. Becau se aldosteron e is h igh ly bou n d to albu m in , cirrh ot ic p at ien t s h ave a h igh er free, act ive con cen t rat ion of aldosteron e. Sp iron olacton e is an aldosteron e receptor an tagon ist an d th erefore is a rat ion al diuret ic ch oice.

Answers and Explanations: IV-1 Diuretics 231 A, B, D All of th ese diu ret ics w ou ld cau se hyp okalem ia,

are asym ptom at ic. How ever, w h en plasm a Na + is m ore th an

w h ich w ould w orsen th e disease. A th iazide or furosem ide

120 m Eq/L, and sym ptom s super vene, as in this case, therapy

can be added to sp iron olacton e if diu resis rem ain s in su

-

sh ou ld be in it iated. Becau se th e syn drom e is du e to exces-

cien t after 4 or m ore days of in creasingly large doses of

sive ADH secretion, th e use of an ADH an tagonist, conivaptan ,

spiron olacton e.

is a rat ion al ch oice. Pat ien t s w ith ver y h igh u rin e osm olalit y

E Triam teren e is a pot assium -sparing diuret ic, like spiron olacton e, but is n ot an aldosteron e an t agon ist .

(like th is p at ien t) ben e t m ost from ADH an tagon ists. A, B, D−F Th ese d r ug are u seless or even dan gerou s in SIADH.

Learning objective: Describe the therapeutic uses of osm otic diuretics. 26. A Osm ot ic diu ret ics are often given to pat ien ts w ith a brain

Learning objective: Describe the therapeutic uses of loop and potassium -sparing diuretics.

t u m or before an d after n eu rosu rger y to redu ce cerebrosp i-

29. B Th e m ajorit y of pat ien ts w ith cardiac failu re w ill requ ire

n al uid volu m e an d th erefore in t racran ial pressure. Th ese

t h e ch ron ic ad m in ist rat ion of a loop d iu ret ic to m ain t ain

d r ugs can n ot cross t h e blood −brain bar r ier, an d t h ey en -

eu volem ia. How ever, th ese d rugs cau se hyp okalem ia, w h ich

h an ce th e di usion of w ater back in to th e plasm a by elevat-

in creases th e risk of adverse e ect s w ith cardiac glycosides.

ing plasm a osm olalit y.

In fact , a decrease in serum K+ con cen t rat ion in creases th e

B, C Oth er diu ret ics are useless in decreasing in t racran ial p ressure. D, E In creased in t racran ial pressu re often causes hyperten sion an d bradycardia. Drugs th at decrease th e h ear t rate are th erefore con t rain dicated.

bin d in g of card iac glycosid es to Na +/K+ ATPase. Th e con cu rren t adm in ist rat ion of p otassiu m -sp aring diu ret ics su ch as spiron olacton e w ill p reven t fu rosem ide-in du ced hyp okalem ia. A Th is com bin at ion w ou ld preven t th e th iazide-in du ced m etabolic alkalosis (as acetazolam id e ten ds to cau se acido-

Learning objective: Describe the therapeutic uses of osm otic diuretics.

sis) bu t does n ot preven t hyp okalem ia.

27. C Hyperosm ot ic agen t s such as m an n itol can low er in t ra-

an d th erefore are n ot su itable for t reat ing a pat ien t w ith car-

ocular pressure by creat ing an osm ot ic gradien t bet w een th e

C Pot assium -sparing diuret ics h ave low diuret ic e

cacy

diac failure.

ocular uid an d plasm a. Th ey are used to decrease in t raoc-

D, E Man n itol is absolu tely con t rain dicated in h ear t failure

u lar pressure before an d after iridotom y an d, togeth er w ith

becau se th e resu lt ing ext racellu lar volum e exp an sion can

oth er drugs th at low er in t raocular pressure, in acute at t acks

cau se a dangerou s circu lator y overload .

of glaucom a. A, B, D Fu rosem ide, t riam teren e, an d hyd roch loroth iazide d o n ot reduce in t raocular pressure.

Learning objective: Identify the drugs that can cause hyperkalem ia.

E, F Hom at rop in e an d p h enylep h r in e are act u ally con -

30. D Th e h istor y an d th e sign s of th e pat ien t (ext rem e brady-

t rain dicated in glau com a, as th ey can in crease in t raocu lar

cardia) suggest th at h e w as m ost likely su ering from hy-

p ressure.

p erkalem ia du e to several cau ses. He received am iloride, a p ot assium -sparing diu ret ic, an d captopril, w h ich in directly

Learning objective: Describe the therapeutic uses of antidiuretic hormone antagonists.

d ecreases aldosteron e form at ion , th u s h in dering th e body’s

28. C Th e sign s an d lab valu es of t h is p at ien t suggest t h e d iag-

in crease in K+ con cen t rat ion w ill in crease ald osteron e se-

n osis of syn d rom e of in ap p rop r iate an t id iu ret ic h or m on e

cret ion several fold). Th e p at ien t w as also t reated w it h

secret ion (SIADH), w h ich is u su ally ch aracter ized by hy-

propran olol and ibup rofen . Beta-blockers can cau se hyp er-

p er volem ic (or som et im es n orm ovolem ic) hypon at rem ia,

kalem ia by suppressing ren in release an d by decreasing K+

low seru m osm olalit y, an d urin e osm olalit y h igh er th an

uptake by skeletal m uscle, an d nonsteroidal antiin am m ator y

serum osm olalit y. Th e syn drom e is associated w ith m yriad

drugs can cau se hyp erkalem ia by redu cing ren al K+ excre-

d isord ers, in clu d in g ch ron ic t reat m en t w it h t r icyclic an t i-

t ion . Th e pat ien t w as also t aking fu rosem ide, bu t th e hypo-

d epressan ts, as in th is case. Th e m ajorit y of pat ien t s w ith

kalem ic act ion of th e furosem ide m ost likely w as n ot en ough

SIADH do n ot requ ire th erapy becau se p lasm a Na + usually

to coun teract all th e hyperkalem ic act ion s m en t ion ed above.

stabilizes in th e range of 125 to 130 m Eq/L; th ese pat ien ts

abilit y to cou n teract t h e hyp erkalem ia (n or m ally, a sm all


232


Learning objective: Describe the use of thiazides to prevent kidney stone production.

related to th e lipid solubilit y in th e u rin e. An acidic drug is

31. B Th iazide diuret ics decrease urin ar y Ca 2+ excret ion an d

(pKa ) is less th an th e pH of th e m edium . Becau se th e pH

th erefore are often used in cases of kidn ey ston es an d idio-

range of th e urin e is from 4.0 to 8.5, drug P w ill be th e on e

path ic hyp ercalciu ria.

w ith th e low est lipid solubilit y an d be th e least reabsorbed

A Carbon ic an hydrase in h ibitors su ch as acet azolam ide h ave n egligible e ect s on th e urin ar y excret ion of Ca 2+. C Loop d iu ret ics su ch as fu rosem id e in crease u r in ar y

m ain ly w ater solu ble w h en its acid dissociat ion con st an t

by the proxim al t ubule. Th is m ean s th at it s con cen t rat ion in th e late dist al t u bu le w ill be th e h igh est . Th e fou r diu ret ics h ave equ al a

n it y for t h e Na +/Cl − t ran sp or ter, so t h eir d i-

u ret ic e ect w ill be p rop or t ion al to t h eir con cen t rat ion at

Ca 2+ excret ion . D, E Pot assium -sparing diuret ics su ch as t riam teren e an d sp iron olacton e decrease Ca 2+ excret ion , but th eir act ion is

th e site of act ion . B−D See correct an sw er exp lan ation .

w eak, an d th ey are n ot u sed for idiopath ic hyp ercalciu ria.

Learning objective: Explain the relationship bet ween the pharm acokinetics of diuretics and their concentration at the site of action. 32. A In order to act , all diuret ics m ust reach a cer tain con cen t rat ion in th e t u bu lar lu m en , as th e t u bu lar cells in di eren t p ar t s of t h e n ep h ron are t h e m olecu lar t arget s of t h ese agen t s. Th e diu ret ics un der st udy are given at th e sam e dose an d h ave th e sam e p lasm a p rotein bin ding, w h ich in dicates th at th e sam e am ou n t w as

ltered by th e glom eru lu s. Th e

DIURETICS Answ er key 1. 2. 3. 4. 5.

A G F E C

6. 7. 8. 9. 10.

A A D A D

11. 12. 13. 14. 15.

E A A C F

16. 17. 18. 19. 20.

B C B C E

21. 22. 23. 24. 25.

C D B F C

26. 27. 28. 29. 30. 31. 32.

A C C B D B A

reabsor pt ion of t h e d r ug by t h e p roxim al t u bu le w ill be

Answers and Explanations: IV-2 Drugs for Ischem ic Heart Disease Questions 1−4

Learning objective: Identify the site of action of verapam il.

1. A

6. D Calciu m ch an n el blockers w ith h ear t act ivit y, su ch as ver-

2. D

apam il and diltiazem , act on voltage-gated channels in cardiac

3. G

and sm ooth m uscle cell m em branes. The blockade of channels

4. F

in cardiac m uscle leads to a redu ct ion in cardiac con t ract ilit y an d rate, w h ereas th e blockade in vascular sm ooth m uscle

Learning objective: Outline the actions leading to the therapeutic e ect of nitrates in variant angina.

cau ses vasod ilat ion , w h ich in t u r n red u ces t h e afterload of

5. B Nit rates dilate large epicardial vessels, th us in creasing epi-

of th ese d rugs in exert ion al angin a.

cardial blood

ow. Th is act ion is th e m ost im p or t an t for th e

th erapeut ic e ect of th ese drugs in varian t angin a, w h ich is ch aracterized by coron ar y spasm . A By causing ven ous dilat ion , n it rates can cau se a decrease, n ot an in crease, of left ven t ricular en d-diastolic volu m e. C, E Nit rates can cause re ex t achycardia an d re ex in crease in cardiac con t ract ilit y, bu t th ese are det rim en tal, n ot th erapeu t ic, e ect s in pat ien ts w ith angin a. D Nit rates can decrease diastolic perfusion t im e (as a con sequence of re ex tachycardia), but this is a detrim ental e ect in p at ien t s w ith angin a.

t h e h ear t . Both act ion s are u sefu l for t h e t h erap eu t ic e ect A Th ese ch an n els are n ot blocked by calciu m ch an n el blockers. B Calciu m is exch anged bet w een cytosol an d m itoch on d ria, w h ich are storage sites for calcium , th rough speci c m itoch on drial store-operated calcium ch an n els, but th ese ch an n els are n ot blocked by calcium ch an n el blockers. C, E Calcium ch an n els in th e sarcoplasm ic ret iculum are open ed by depolarizat ion an d blocked by r yan odin e. Calcium ch an n el blockers a ect t h ese ch an n els on ly at ver y h igh con cen t rat ion .

Answers and Explanations: IV-2 Drugs for Ischemic Heart Disease 233 Learning objective: Describe the peripheral vascular actions of antianginal drugs.

d ecrease cardiac rate. On th e con t rar y, n it rates an d dihydro-

7. B Th e prescribed drug w as m ost likely n ifedipin e, a drug of

pyridin es h ave n o d irect e ect on h eart rate bu t can cau se

ch oice in varian t angin a. Th e sym ptom s w ere m ost likely due to a decrease in tot al periph eral resistan ce th at in t u rn can

A Cardiac-act ive calcium ch an n el blockers an d β-blockers

re ex t achycardia becau se of drug-in du ced vasodilat ion . B Cardiac-act ive calcium ch an n el blockers an d β-blockers

ow ) an d

d ecrease cardiac con t ract ilit y. Nit rates an d dihydropyridin es

palp itat ion s (d u e to re ex t achycardia). Th ese are t w o com -

h ave no direct e ect on h eart contractilit y, but th ey can cause

m on adverse e ect s of n ifedipin e.

re ex in crease in con t ract ilit y becau se of d r ug-in du ced

in du ce dizzin ess (du e to decreased cerebral blood

A Coron ar y vasodilat ion is a n ifedipin e e ect but does n ot cau se th e sym ptom s reported by th e p at ien t . C A decrease in tot al periph eral resist an ce causes a decrease, n ot an in crease, of ven ou s ret u rn to th e h ear t . D A d ecrease in card iac con t ract ilit y can n ot exp lain t h e p alpitat ion s reported by th e pat ien t .

vasodilat ion . D Left ven t r icu lar en d -d iastolic volu m e is d ecreased by n it rates (because of th e predom in an t ven ous vasodilat ion ), but calcium channel blockers w ith heart activit y and β-blockers ten d to in crease it because of th e in creased durat ion of d iastole.

E Coron ar y steal is a ph en om en on w h ere an alterat ion of

E Eject ion t im e is in creased by calcium ch an n el blockers

circu lat ion p at tern s leads to a redu ct ion in th e blood d irected

w it h h ear t act ivit y an d β-blockers d u e to t h e d ecrease

to th e coron ar y circulat ion . It is caused w h en th ere is n arrow -

in card iac con t ract ilit y, bu t it can be decreased by n it rates

ing of th e coron ar y arteries (as in exert ion al angin a), an d an

an d d ihydropyridin es du e to re ex in crease in cardiac con -

arteriolar vasodilator is used. Th is h appen s becau se th e coro-

t ract ilit y.

n ar y arteries dow n st ream of th e n arrow ing are m axim ally ply. Th u s, dilat ing th e resist an ce vessels u pst ream of th e n ar-

Learning objective: Outline the actions leading to the therapeutic e ect of nitrates in pulmonary edema.

row ing causes blood to be sh un ted (stolen ) aw ay from th e

10. A Th e sign s an d sym ptom s of t h e p at ien t in d icate th at h e

coron ar y vessels supplying th e isch em ic zon es, creat ing m ore

is su ering from pulm on ar y edem a. By in creasing cyclic

isch em ia. Th e coron ar y steal p h en om en on can n ot occu r in

gu an osin e m on op h osp h ate p rod u ct ion , n it rates cau se relax-

varian t angin a, w h ere th ere is n o an atom ical n arrow ing but

ation of both resistance and capacitan ce vessels, but relax-

on ly an arterial spasm , an d can n ot explain th e sym ptom s re-

at ion of th e lat ter (especially large vein s) is m ore p ron ou n ced ,

ported by th e p at ien t .

w ith stan dard th erapeut ic doses, probably because th e en -

dilated to com p en sate for th e decreased u pst ream blood su p -

zym e th at conver ts n it rates to n it ric oxide is m ore abu n dan t

Learning objective: Describe the m ain potential detrim ental effects of nitrates in exertional angina.

in vein s th an in ar teries. Th is ven odilat ion redu ces p reload

8. B By cau sing p erip h eral vasodilat ion , h igh doses of n it rates

in g ven t ricu lar en d-diastolic volu m e. In th is w ay, p ulm on ar y

can in du ce re ex t achycardia, w h ich in t u rn in creases oxygen con sum pt ion . Th is det rim en tal e ect can be preven ted by th e con com itan t u se of a β-blocker. A, C, D Th ese are all u sefu l e ects of n it rates in exert ion al

to t h e h ear t by p ooling blood in t h e p er ip h er y, t h u s red u ccongest ion is reduced, an d pulm on ar y edem a is relieved. B−D Th e n it rate-in duced periph eral vasodilat ion ten ds to cau se re ex t achycard ia an d re ex in crease in card iac con t ract ilit y w h en h igh d oses are given , bu t t h is w ou ld ad versely a ect pulm onary edem a by increasing the pulm onar y

angin a. E Nit rates ten d to d ecrease, n ot in crease, ven t r icu lar en d-

p ressure. A decreased ven t ricu lar eject ion t im e is u su ally th e con sequ en ce of t achycardia, so it w ou ld adversely a ect

diastolic volu m e.

p ulm on ar y ed em a.

Learning objective: Describe the cardiovascular e ects of antianginal drugs. 9. C Ar terial pressure (AP) is equal to st roke volum e (SV) by h ear t rate (HR) by periph eral vascular resist an ce (PVR): AP = SV × HR × PVR . Nit rates m ain ly d ecrease SV (by d ilat in g t h e large vein s), calciu m ch an n el blockers m ain ly decrease HR an d PVR, an d β-blockers m ain ly decrease HR an d SV (by decreasing h ear t con t ract ilit y). Th erefore, all can low er th e blood pressure.

E By causing ar teriolar vasodilat ion , n it rates also decrease afterload, bu t th is act ion is less p ron ou n ced th an th e ven ou s vasodilat ion . Th u s, th e decreased afterload is n ot th e m ain reason for th e th erapeut ic e

cacy of n it rates in pulm on ar y

edem a. F Nit rates decrease platelet aggregat ion , bu t th is is n ot th e reason th at th ey are e ect ive in t reat ing pulm on ar y edem a.

234


Learning objective: Discuss the risk of abrupt withdrawal from nitrate therapy.

Learning objective: Discuss the problem of tolerance development to nitrates.

11. C Lon g-ter m n it rate t h erapy sh ou ld be d iscon t in u ed grad u -

14. B Toleran ce to n it rates does occur. Becau se it appears rapidly

ally, as t h ere is clin ical evid en ce t h at severe m yocard ial

(24 h ours) an d disappears rapidly (6 to 10 h ours), brief peri-

isch em ia m ay occur in person s w ith draw ing sudden ly from

ods of n o th erapy (overn igh t) can be su

long-term organ ic n it rate exp osu re.

cover y, but th is pat ien t w as con t in u ou sly receiving th e dr ug.

A Un like u n st able an gin a, st able exer t ion al angin a ver y rarely p rogresses to m yocard ial in farct ion . Moreover, t h e fact th at th e pat ien t h ad n o at t acks during th e past m on th in dicates th at th e th erapy w as appropriate. B, D Un like cim et idin e, fam ot idin e h as n o in h ibitor y effect s on drug m etabolism .

cien t to perm it re-

A Vasospast ic angin a com plicat ing exert ion al angin a is an u n likely p ossibilit y. C Nit roglycerin does n ot in duce th e cytoch rom e P-450 system . D Angin al at tacks disappeared com pletely du ring th e rst w eek of th erapy, so th e dosage w as m ost likely appropriate.

E A too-h igh dose of n it rates m ay cause re ex tachycardia by redu cing th e blood pressu re, bu t th is is un likely in th is

E Tran sderm al bioavailabilit y of n it roglycerin is 50 to 90% an d does n ot ch ange over t im e.

p at ien t because h e w as receiving verapam il, w h ich act u ally

Learning objective: Choose the appropriate antianginal therapy for a patient with concomitant diseases.

d ecreases th e h ear t rate.

Learning objective: Describe nitrate-induced postural hypotension.

15. D Calcium ch an n el blockers are con sidered drugs of

12. B Nit rates can cau se p ost u ral hyp oten sion becau se ven od i-

ch oice in varian t angin a. Moreover, in th e presen t case:

lat ion decreases preload. In fact , in su

cien t left ven t ricular

en d-diastolic volu m e (du e to decreased ven ou s ret u rn , hy-

rst

A A brain tum or is likely to increase the intracranial pressu re, so n it rates are con t rain dicated .

p ovolem ia, etc.) is t h e m ost com m on cau se of p ost u ral hy-

B, C Th e at rioven t ricu lar (AV) block also con t rain dicates

p oten sion . Post ural hypoten sion is even m ore likely in th is

d rugs th at ten d to decrease at rioven t ricular con duct ion ,

p at ien t because h er blood p ressure is low.

su ch as verapam il an d dilt iazem .

A Nit rates ten d to cause bron ch odilat ion , so cough an d w h eezing are un likely.

E Bet a-blockers such as propran olol are n ot e ect ive in varian t angin a, an d th ey m ay be dangerou s by cau sing coro-

C Nitrates tend to cause re ex tachycardia, not bradycardia.

n ar y vasocon st r ict ion . Moreover, t h ey are con t rain dicated

D Nit rates ver y rarely cause m eth em oglobin em ia w h en

in th is case because of th e AV block.

given at th erap eu t ic doses. To get th is e ect , th e doses given m u st be h uge. How ever, th erap eu t ic doses of n it rites can cau se m eth em oglobin em ia. E Nit rates ten d to cause relaxat ion of th e gut sm ooth m uscle, so diarrh ea is un likely. F Nit rates decrease platelet aggregat ion , so ven ou s th rom bosis is u n likely.

Learning objective: Explain the m ain approaches to com bination therapy for angina. 16. E Th e p at ien t ’s cu r ren t sym ptom s are m ost likely d u e to n it rate t h erapy. Th e add it ion of a card iac-act ive calciu m ch an n el blocker su ch as dilt iazem can at ten u ate th e n it ratein d u ced re ex t achycard ia an d re ex in crease in card iac con t ract ilit y. Moreover, in th is pat ien t:

Learning objective: Describe the main adverse e ects of β-blockers.

A, D Becau se angin al at t acks are n ot com p letely p reven ted ,

13. A All th e sym ptom s reported by th e p at ien t are classic ad -

it is u seless to redu ce n it rate dosage, w h ich w ou ld decrease

verse e ects of β-blockers. Th ese drugs block β 2 -m ediated

adverse e ects bu t also decrease th erapeu t ic e ects.

vasodilat ion an d cause a re ex vasocon st rict ion because of

B Beta-blockers such as propran olol are relat ively con t ra-

th e decreased cardiac out put . Th ese act ion s can accoun t for

in dicated in p at ien t s receiving in su lin t reat m en t , becau se

th e blan ch ing of th e ngers w h en exposed to cold. Fat igue is

th ey can m ask som e sym ptom s of hyp oglycem ia an d in h ibit

likely d u e to d ecreased cardiac ou t p u t . Th e oth er e ects are

glu con eogen esis, th u s im p airing th e body’s cap acit y to re-

cen t rally m ediated, but th e m ech an ism s are st ill un cer tain .

cover from hypoglycem ia.

B−E Th e oth er listed drugs do n ot cause all th e e ects reported by th e p at ien t .

C Nifed ip in e cou ld in crease p alp it at ion s becau se it can cau se re ex tachycardia.

Answers and Explanations: IV-2 Drugs for Ischemic Heart Disease 235 Learning objective: Discuss the risk of abrupt withdrawal from β-blocker therapy.

vasod ilat ion by blockin g L-t yp e calciu m ch an n els in sm oot h

17. B Abru pt discon t in uat ion of β-blockers su ch as propran olol

ch an n el blockers an d n it rates in varian t angin a is m ain ly due

can precip itate m yocard ial in farct ion an d can in crease th e

to coron ar y vasod ilat ion , w h ich in t u r n in creases oxygen

r isk of su d d en d eat h in card iac p at ien t s. Th e u n d erlyin g

su p p ly to t h e h ear t . Today, calciu m ch an n el blockers are

m ech an ism is u n clear, bu t it is w ell establish ed th at th ere is

con sidered th e d rug of ch oice to p reven t at t acks of varian t

en h an ced sen sit ivit y to β-ad ren oceptor agon ists in p at ien ts

angin a th at are ch aracterized by coron ar y sp asm s. Dihydro -

w h o h ave un dergon e long-term t reat m en t w ith β-blockers,

pyridin es, verap am il an d d ilt iazem , are con sid ered equ ally

likely due to u pregu lat ion of β receptors. Abrupt w ith draw al

e

from th e β-blocker allow s an in creased n u m ber of receptors to be exposed to n orepin eph rin e. Th is supersen sit ivit y can be at ten u ated by tap ering th e dose of th e β-blocker for several w eeks before discon t in u at ion . A, C−E All of th e oth er listed dr ugs do n ot cau se abru pt w ith draw al sym ptom s.

m u scle m em bran es. Th e an t ian gin al e ect of bot h calciu m

caciou s in th is disease. A Because dihydropyridin es are m ain ly arteriolar vasodi-

lators, th ey m in im ally a ect preload. B Dihydropyridin es decrease afterload, but th is is n ot th e m ain m ech an ism of an t iangin al act ion in varian t angin a. In fact , by decreasing eith er preload or afterload, th e oxygen d em an d of th e h eart is decreased, w h ich is good in case of exer t ion al angin a. By con t rast , an in crease in oxygen supply

Learning objective: Describe the interaction bet ween nitrates and sildena l. 18. C Erect ion requires relaxat ion of th e n onvascular sm ooth m u scle of th e corp ora cavern osa. Silden a l is u sed in erect ile dysfu n ct ion becau se it in h ibits isoform 5 of ph osp h odiesterase, w h ich is fou n d in h igh con cen t rat ion in sm ooth m u scle cells of th e corpora cavern osa. Th is in creases th e con cen t rat ion of cyclic gu an osin e m on oph osp h ate (cGMP), w h ich in t u rn st im u lates th e dep h osph or ylat ion of th e m yosin ligh t

is n eeded in varian t angin a, an d th is can be accom p lish ed on ly by coron ar y vasodilat ion . C, D In th erapeut ic doses, dihydropyridin es h ave n o direct e ect on t h e h ear t . Large d oses can cau se a re ex in crease in cardiac con t ract ilit y an d rate, bu t th ese are n ot useful act ion s in a pat ien t w ith angin a.

Learning objective: Describe the use of nitroglycerin in myocardial infarction.

ch ain. Because of th is m ech an ism of act ion , silden a l poten -

21. C Recen t st u dies h ave reinvest igated th e u se of n it rate th er-

t iates th e act ion of n it rates (w h ich also cau se an in crease in

apy in m yocardial in farct ion (MI) in th e set t ing of con com i-

cGMP), an d severe hypoten sion an d a few m yocardial in farc-

t an t th rom bolyt ic th erapy an d aspirin ad m in ist rat ion . Th e

t ion s h ave been reported in m en u sing both drugs.

p ooled e ect s from several st u dies h ave sh ow n a sm all bu t

B Nit rop r u ssid e can cau se an in crease in cGMP, an d it s

stat ist ically sign i can t d ecrease in m ort alit y in pat ien ts re-

act ion s are p oten t iated by sild en a l, bu t th e d rug is n ot u sed

ceiving n it rates. Th erefore, in t raven ous n it roglycerin is cu r-

to t reat angin a.

ren tly recom m en ded for rout in e u se during th e rst 24 to 48

A, D, E Non e of th ese drugs h ave act ion s p oten t iated by silden a l.

h ou rs in m ost p at ien t s w it h MI, p ar t icu larly if t h ey h ave sign s of acu te h ear t failu re (im p en d ing p u lm on ar y ed em a) an d are hyperten sive, as in th is case.

Learning objective: Describe the m ain adverse e ect s of nitrates. 19. D Th e dose of n it roglycerin given to th is p at ien t w as likely too h igh , as th e sym ptom s th e pat ien t is referring to are classic for n it rate toxicit y. A−C Bet a-blockers su ch as p rop ran olol, verap am il, an d d ilt iazem ten d to decrease h ear t rate, so p alp it at ion s are u n likely. E Nifedipin e can cause all th e adverse e ect s repor ted by th e p at ien t . How ever, all calciu m ch an n el blockers are con t rain dicated in gast roesoph ageal re u x disease becau se th ey ten d to relax th e low er esoph ageal sph in cter.

Learning objective: Outline the actions leading to the therapeutic e ect of nifedipine in variant angina. 20. E Th e sign s an d sym ptom s of th e pat ien t in dicate th at sh e w as m ost likely su er in g from var ian t an gin a. Nifed ip in e is a d ihyd ropyr id in e calciu m ch an n el blocker t h at cau ses

A Ep in ep h r in e is con t rain d icated in MI becau se it in creases card iac w ork an d oxygen dem an d . B In t raven ous β-blockers such as m etoprolol given w ith in the

rst few h ou rs after on set of MI im p rove p rogn osis by

red u cing in farct size an d in ciden ce of ven t r icu lar

br illa-

t ion . In th is case, h ow ever, th ey are con t rain dicated becau se of bradycardia an d th e im pen ding pulm on ar y edem a (th ese p at ien ts are dep en d en t on sym p ath et ic act ivat ion to in crease th e h ear t rate an d to m ain t ain blood p ressu re to vit al organ s). D Verapam il an d dilt iazem h ave been sh ow n to reduce th e rate of rein farct ion an d death in pat ien t s w ith preser ved left ven t ricu lar fun ct ion , but th ey are con t rain dicated in th is case becau se of bradycardia an d sign s of cardiac failu re. E Dihydropyridines such as nefedipine have been uniform ly u n successful in reducing eith er m or talit y or rein farct ion in p at ien ts w ith MI.

236


Learning objective: Choose the appropriate drug therapy for a patient with subarachnoid hem orrhage.

adverse e ects. Som etim es β-blockers are adm inistered w ith

22. E Su barach n oid h em orrh age sh ou ld alw ays be con sid ered in

• Beta-blockers can o set th e n it rate-in d uced in crease in

p at ien ts w h o p resen t w ith h eadach e an d syn cope. Th e diagn ost ic test of ch oice for th is disease is com puted tom ography

n it rates in th e th erapy of exert ion al angin a because cardiac con t ract ilit y an d rate. • Nit rates can p reven t th e β-blocker-in du ced in crease in

scan , w h ich h as a sen sit ivit y greater th an 90%. Delayed isch -

en d-diastolic volu m e an d eject ion t im e.

em ic de cit du e to vasosp asm is th e m ost com m on cau se

A Bet a-blockers cause vasocon st rict ion of coron ar y ves-

of m orbidit y an d m or t alit y follow ing su barach n oid h em orrh age. Nicardip in e is a calciu m ch an n el blocker w ith som e a

n it y for cerebral blood vessels an d is used by in t raven ous

in fusion to preven t cerebral vasosp asm associated w ith su b arach n oid h em orrh age or st roke. A All of th e oth er calcium ch an n el blockers, in cluding ver-

sels, m ain ly as a con sequ en ce of th e redu ced h eart rate. C Bet a-blockers d o n ot p reven t t h e n it rate-in d u ced d ecrease in ar ter ial p ressu re. Moreover, t h is is a u sefu l e ect of n it rates, an d it w ou ld be irrat ion al to p reven t it . D, E Nit rates coun teract , n ot en h an ce, th e e ect of propran olol on cardiac rate an d con t ract ilit y.

apam il, lack select ivit y for cerebral blood vessels an d th erefore are n ot in dicated in subarach n oid h em orrh age. B−D, F All of th ese drugs are useless or dangerou s in sub arach n oid h em orrh age.

Learning objective: Explain the molecular mechanism of the antianginal action of nitrates. 23. C Nit rates release free n it r ite ion s, w h ich in t u r n are con -

Learning objective: Describe the use of β-blockers in the postdischarge therapy of myocardial infarction. 26. E Beta-blocker th erapy after a m yocardial in farct ion sh ou ld be con t in u ed in de n itely (u n less th ere are con t rain dicat ion s or adverse e ects super ven e) because of proven long-term m orbidit y an d m ort alit y ben e t s. A−D See correct an sw er explan at ion .

ver ted to n it r ic oxid e. Nit r ic oxid e cau ses t h e act ivat ion of gu anylyl-cyclase, t h ereby cau sin g an in crease in cyclic gu an osin e m on op h osp h ate. Th is secon d m essenger cau ses d ep h osp h or ylat ion of th e m yosin ligh t ch ain . Myosin is n o longer able to in teract w ith act in , an d vascular sm ooth m uscle relaxes. A Nit rite ion s are converted to n it ric oxide, n ot to N2 O. B In t racellular Ca 2+ con cen t rat ion is act u ally redu ced by n it rates. C Th e syn th esis of guanylyl cyclase is act u ally in creased, n ot decreased, by n it rates. E Ph osph or ylat ion of m yosin ligh t ch ain kin ase w ou ld in crease, n ot decrease, sm ooth m u scle con t ract ion .

Learning objective: Choose the appropriate antianginal therapy for a patient with concomitant diseases. 24. D A long-act ing n it rate, a β-blocker, or a calciu m ch an n el blocker can all be u sed for exer t ion al an gin a p rop hyla xis. How ever, in th is p at ien t A Propran olol is con t rain dicated because of th e ch ron ic obst ruct ive pulm on ar y disease. B, C, E Calcium ch an n el blockers relax th e low er esoph ageal sp h in cter an d th erefore sh ou ld be avoided in th e p resen ce of gast roesoph ageal re u x disease.

Learning objective: Explain the m ain reasons for com bination therapy of angina. 25. B Becau se th e th ree classes of an t iangin al drugs use di eren t

Learning objective: Describe the adverse e ects of calcium channel blockers and nitrates. 27. A Calciu m ch an n el blockers som et im es are ad d ed to n it rates to at ten u ate th e n it rate-in du ced t achycardia. Th rob bin g h eadach e is a t yp ical adverse e ect of n it rates, an d severe con st ip at ion is a t yp ical adverse e ect of verap am il. B−D Nit rates an d β-blockers d o n ot cau se severe con st ip at ion . E Bet a-blockers an d verap am il do n ot cau se t h robbing headach e (in fact, both are used in th e therapy of headache).

Learning objective: Choose the appropriate antianginal therapy for a patient with hypertrophic cardiomyopathy. 28. D Calcium channel blockers acting on the heart and β-blockers (alon e or in com bin at ion ) are th e t reat m en t of ch oice in an gin a associated w ith hyp er t roph ic cardiom yop athy. In th is d isease, th ere is a m arked hyper t rop hy an d th icken ing of th e upper in terventricular septum below the aortic valve. During systole, th e sept u m th icken s, an d th e an terior lea et of th e m it ral valve is su cked tow ard th e sept u m , produ cing ou t ow t ract obst ru ct ion . Th e m ajor con sequ en ce of hyp er t rop hy is th at th e st i , n on com plian t ven t ricle resist s diastolic lling. Beta-blockers an d calcium ch an n el blockers decrease m yocardial con t ract ilit y. Th is act ion in creases ven t ricu lar com pliance and decreases out ow obstruction. Beta-blockers and calciu m ch an n el blockers act ing on th e h ear t also slow th e h ear t rate, w h ich allow s a m ore com plete diastolic lling.

m ech an ism s of act ion s, a com bin at ion of t w o of th ese agen ts

A−C Nit rates, as w ell as oth er drugs th at reduce preload

m ay in crease th e e ect iven ess an d redu ce th e in ciden ce of

(diuret ics, angioten sin -convert ing en zym e [ACE] in h ibitors,

Answers and Explanations: IV-3 Drugs for Cardiac Failure 237 etc.), are con t rain dicated in th is disease because th ey de-

decrease m yocard ial oxygen dem an d (by decreasing h ear t

crease the already de cient ventricular end-diastolic volum e.

con t ract ilit y an d rate) an d th e risk of ven t ricular brillat ion

E Dihydropyridin es are devoid of cardiac act ivit y an d

(by decreasing h eart con duct ion an d autom at icit y), an d th ey

th erefore are n ot u sefu l in hypert roph ic cardiom yopathy.

lim it th e in farct size, th u s decreasing th e risk of m yocardial

ACE in h ibitors are relat ively con t rain dicated in th is disease

ru pt u re.

becau se th ey can redu ce p reload .

A By decreasing h ear t con t ract ilit y an d rate, β-blockers decrease, n ot in crease, m yocardial oxygen su pp ly.

Learning objective: Describe the use of calcium channels blockers in Raynaud phenom enon.

th is is n ot a m ajor factor con t ribut ing to reduced m or talit y.

29. C Th e sign s an d sym ptom s of t h e p at ien t suggest t h e d iag-

D Bet a-blockers can in crease system ic vascular resist an ce

n osis of Rayn aud ph en om en on , a vasospasm of part of th e

(by blocking β 2 receptors in th e vascular sm ooth m u scle),

h an d in resp on se to cold , em ot ion al st ress, or vibrat ion

but th is w ould in crease m or talit y.

B Beta-blockers decrease at rioven t ricular con du ct ion , bu t

(w h ich is likely a causal factor in th is case). Th e disorder can

E Beta-blockers can in crease left ven t ricu lar en d-diastolic

be p rim ar y or secon dar y to several p ath ological con dit ion s

pressure (if given in too h igh doses, du e to th e in creased dia-

(m ostly con n ect ive t issue disorders). Nifedipin e h as becom e

stolic t im e), bu t th is w ou ld in crease m or talit y.

th e arteriolar vasod ilator of ch oice in p at ien t s w ith Rayn au d p h en om en on n ot con t rolled by con ser vat ive m easu res.

DRUGS FOR ISCHEMIC HEART DISEASE Answ er key

A, B, D−F Th ese drugs are n ot u sed for th e th erapy of Rayn aud ph en om en on .

Learning objective: Explain why β-blockers can decrease m ortalit y in myocardial infarction. 30. C Several st u dies h ave sh ow n th at β-blockers decrease in farct-associated m ort alit y (by abou t 25% w h en given in th e rst 2 days an d by abou t 13%w h en given later). Th ey redu ce m yocardial rem odeling (an in crease in m yocardial m ass th at

1. 2. 3. 4. 5.

A D G F B

6. D 7. B 8. B 9. C 10. A

11. C 12. B 13. A 14. B 15. D

16. E 17. B 18. C 19. D 20. E

21. C 22. E 23. C 24. D 25. B

26. 27. 28. 29. 30.

E A D C C

is en h an ced by catech olam in es an d angioten sin II). Th ey also

Answers and Explanations: IV-3 Drugs for Cardiac Failure Questions 1−5

C, D See correct an sw er explan at ion .

1. F

E Digitalis glycosides h ave n o direct e ect on pot assium ch an n els.

2. C 3. I

Learning objective: Identify the m ain receptors involved in the therapeutic e ect of digoxin in atrial brillation.

4. G 5. B

7. B Digoxin is st ill used in persisten t at rial brillat ion (alth ough

Learning objective: Explain the m olecular m echanism of action of digoxin.

it is n o longer a rst-lin e th erapy) because it can decrease th e

6. B At th e m olecular level, all cardiac glycosides in h ibit Na +/K+

ular rate. Th is is accom plished by a stim ulation of vagal activit y

at rioven t ricu lar con du ct ion , th u s decreasing th e h igh ven t ric-

ATPase, th e m em bran e-bou n d t ran sp or ter called th e sodiu m

du e to

p u m p . Th e in creased am ou n t of sod iu m in side t h e cell in -

• St im u lat ion of vagal n u clei in th e brain stem

h ibit s t h e Ca 2+/Na + exch an ger, an an t ip or ter t h at u ses t h e

• Sen sit izat ion of carot id sin u s baroreceptors

elect roch em ical p oten t ial for Na + to d r ive Ca 2+ ext r u sion . Th e

• Facilit at ion of m u scarin ic t ran sm ission at th e cardiac m u s-

con sequen ce of th is in h ibit ion is th at less Ca 2+ is rem oved

cle cells.

from t h e cell. Th e in creased in t racellu lar calciu m is stored

Th e receptors involved in vagal act ivit y on t h e h ear t are

in t h e sarcop lasm ic ret icu lu m d u r ing d iastole, so a greater

m ain ly m uscarin ic.

am ou n t of Ca 2+ is released from th e sarcoplasm ic ret iculum du ring systole. A Digit alis glycosides at h igh con cen t rat ion can open , n ot close, cardiac calcium ch an n els.


238


Learning objective: Describe the cardiac actions of digoxin. 8. E Digoxin decreases h eart rate both in th e n orm al an d th e failing h ear t (un less toxic e ect s of th e drug super ven e) due

D Digoxin in creases, n ot decreases, th e systolic blood pressu re in p at ien t s in cardiac failu re becau se of th e in crease in cardiac ou t p u t .

to decreased at rioven t ricu lar (AV) con duct ion , w h ich is a

E Pulse pressure m ay be sh arply decreased in pat ien ts

con sequen ce of a direct act ion an d of a parasym path om i-

w it h card iac failu re becau se of t h e d ecrease in st roke vol-

m et ic act ion on th e AV n od e.

u m e, t h e m ain d eter m in an t of p u lse p ressu re. Moreover,

A By in creasing con t ract ilit y, digoxin decreases, n ot in creases, th e en d-systolic volu m e.

diastolic p ressu re is n or m al or in creased becau se of sym p at h et ic act ivat ion . By in creasing cardiac con t ract ilit y, digoxin

B Digoxin dose-depen den tly in creases abn orm al cardiac

in creases t h e st roke volu m e an d o set s t h e react ive, sym -

au tom at icit y, as in dicated by th e m any variet ies of arrhyth -

p ath et ically m ediated vasocon st rict ion . Th erefore, th e pulse

m ia cau sed by th e drug.

pressu re is in creased, n ot decreased .

C By cau sing bradycardia, digoxin in creases, n ot decreases, th e diastolic t im e. D At rial refractorin ess is decreased, n ot in creased, by digoxin , du e to both a direct act ion an d a p arasym p ath om i-

Learning objective: Calculate the m aintenance dose of digoxin, given su cient data. 11. C A m ain ten an ce dose of a dr ug is given by

m et ic act ion of th e drug.

Learning objective: Describe the hem odynam ic actions of digoxin in the failing heart. 9. A Th e in crease in st roke volu m e is a direct con sequ en ce of th e p osit ive in ot ropic act ion of digit alis glycosides. B Digoxin can cau se periph eral vasocon st rict ion in th e n orm al subject , but in pat ien t s w ith cardiac failure, digoxin

D = (Css × CL)/F, w h ere D is dose, Css is con cen t rat ion at steady st ate, CL is clearan ce, an d F is oral bioavailabilit y. Th erefore: Dose = (1 µg/L × 7L/h )/0.7 = 10 µg/h = 0.24 m g daily A, B, D−F See correct an sw er explan at ion .

cau ses periph eral vasodilat ion becau se th e in creased cardiac

Learning objective: Describe the m ain adverse e ect s of digoxin.

out put o set s th e react ive vasocon st rict ion .

12. C Th e m ost solid in dicat ion for digoxin is st ill th e com bin a-

C Digoxin act ually d ecreases oxygen con sum pt ion in th e

t ion of ch ron ic cardiac failu re w ith at rial brillat ion . Becau se

failing h ear t because

of its direct at rioven t ricular (AV) blocking e ect s an d vago-

• In creased con t ract ilit y redu ces th e left ven t ricu lar en d-

m im et ic p rop er t ies, digoxin redu ces th e n u m ber of im p u lses

diastolic volu m e an d th e associated st retch of th e cardiac bers (oxygen con sum pt ion of th e h ear t is directly pro port ion al to th e st retch of th e cardiac bers). • In creased cardiac out pu t o set s th e t achycardia in duced by th e sym path et ic act ivat ion . D, E See explan at ion C.

Learning objective: Describe the hem odynam ic actions of cardiac glycosides in the failing heart. 10. B An in ot rop ic drug in creases th e force of h ear t con t ract ion ;

con ducted th rough th e AV n ode an d th erefore con t rols th e ven t ricu lar respon se rate in pat ien t s w ith at rial brillat ion . Most likely, digoxin w as in cluded in th e pat ien t’s m an agem en t , an d th e sym ptom s of th e p at ien t are classic sym ptom s of digitalis toxicit y. A, B Verap am il an d p rop ran olol can con t rol t h e ven t r icu lar resp on se rate in p at ien t s w it h at r ial

br illat ion by

d ecreasing AV con du ct ion . How ever, th ey do n ot cau se th e p at ien t’s sym ptom s. D, E Lid ocain e an d fu rosem id e d o n ot d ecrease AV con d u ct ion an d are of n o value in at rial brillat ion .

th erefore, a h igh er fract ion of th e en d-diastolic volu m e is ejected during systole. Con sequen tly, th e en d-systolic volu m e (i.e., th e volu m e of blood rem ain ing in th e ven t ricle at th e en d of th e systole) is decreased. A All in ot rop ic dr ugs in crease, n ot decrease, t h e st roke volum e. C Th e en d-diastolic volu m e is th e sum of th e en d-systolic volu m e p lu s t h e st roke volu m e. Becau se t h e st roke volu m e is in creased an d t h e en d -systolic volu m e is d ecreased by in ot ropic drugs, th e en d-diastolic volu m e is n ot sign i can tly ch anged.

Learning objective: Outline the therapy for digoxin-induced atrioventricular block. 13. C Digoxin -in du ced at rioven t ricular (AV) block is m ost likely d ue, at least in par t , to th e p arasym path om im et ic act ion of d igoxin . Th erefore, t reat m en t w ith at rop in e an d a reduct ion of th e digoxin dose is a rat ion al th erapeut ic approach . A Milrin on e is used on ly for sh or t-term in t raven ous t reatm en t of p at ien t s w ith en d-st age h eart failu re. B Becau se physost igm in e is a ch olin ergic drug, it w ould w orsen th e AV block.

Answers and Explanations: IV-3 Drugs for Cardiac Failure 239 D To discon t in ue digoxin w ould be irrat ion al because th e

im prove th e sym ptom s of th e disease. W h en a dr ug is e ec-

ongoing th erapy w as e ect ive. Moreover, m etoprolol is con -

t ive bu t cau ses adverse e ect s, as in th is case, th e rst th ing

t rain dicated in th e presen ce of AV block.

to do is to adjust th e dosage.

E Beta-adren ergic agon ists are u sed on ly for sh ort-term in t raven ou s t reat m en t of pat ien ts w ith acute cardiac failu re.

Learning objective: Describe digoxin-induced arrhythm ias.

Addit ion ally, even if a β-adren ergic agon ist can in crease th e

16. B A pat ien t w ith severe systolic dysfun ct ion w as m ost likely

ven t ricular rate in pat ien t s w ith AV block due to in creased

receiving cardiac th erapy th at in cluded digoxin . Th e pat ien t

vagal act ivit y, it w ou ld be act ing as a physiological an t ago-

p robably develop ed acu te ren al failure (as in dicated by th e

n ist of th e acet ylch olin e-m ediated e ect . In th is case, at ro-

su d d en an u r ia) t h at su bst an t ially in creased t h e toxicit y of

pin e is a m u ch bet ter ch oice, as a ph arm acological an tagon ist

d igoxin . In fact , t h e p at ien t ’s sym ptom s are t yp ical of so-

is sup erior to a physiological an t agon ist in m ost cases.

called digit alis deliriu m .

F See an sw er explan at ion D.

A, C−E Th ese drugs do n ot cross th e blood−brain barrier, so cen t ral e ect s are u n likely.

Learning objective: Describe the factors that enhance the risk of digoxin toxicit y.

feelings of appreh en sion an d an xiet y but n ot th e sym ptom s

14. D Ven t ricular t achycardia is a serious adverse e ect of di-

exh ibited by th e pat ien t .

F Albuterol crosses th e blood−brain barrier an d m ay cause

goxin . Th e pat ien t’s redu ced ren al fu n ct ion (see th e creat iof digoxin , th us in creasing th e risk of adverse e ect s. Di-

Learning objective: Describe the factors that enhance the risk of digoxin toxicit y.

goxin toxicit y is en h an ced by m any factors, in clu d ing hyper-

17. E Th e p at ien t is su ering from hyp othyroid ism , as in d icated

calcem ia, w h ich accelerates th e overloading of in t racellu lar

by th e low thyroxin e (T4 ) an d h igh thyroid-st im ulat ing h or-

n in e serum level) m ost likely decreased th e ren al excret ion

calciu m stores. In creased in t racellu lar calciu m ap p ears to be respon sible for an in creased abn orm al autom at icit y. A−C, E See correct an sw er explan at ion .

m on e (TSH) levels. Hypothyroidism in creases th e risk of digoxin toxicit y becau se elim in at ion of digoxin is decreased, an d th e h ear t is m ore sensit ive to digoxin . A Hypom agn esem ia, not hyperm agn esem ia, can in crease

Learning objective: Describe the therapy of digoxin toxicit y. 15. A Th e p at ien t’s sym ptom s (n au sea an d vom it ing), as w ell as th e arrhyth m ia sh ow n by th e elect rocardiogram , are classic sign s of digoxin toxicit y. Furosem ide t reat m en t m ost likely cau sed hyp okalem ia, w h ich is a w ell-recogn ized p red ispos-

digoxin toxicit y. B Hyperald osteron ism is un likely, as p ot assiu m levels are n orm al. C Hyperparathyroidism is u n likely, as calciu m levels are n orm al.

ing factor to digoxin toxicit y. In fact , in pat ien t s w ith serum

D Concom itant furosem ide treat m ent can increase digoxin

K+ of 3 m Eq/L, th e dose of digoxin n eeded to produce toxicit y

toxicit y m ain ly by causing hypokalem ia, but th is is u n likely

is about on e h alf of th at n eeded in p at ien t s w ith seru m K+ of

in th is case, as th e p at ien t h as been receiving furosem ide

5 m Eq/L. Moreover, th e pat ien t h ad redu ced ren al fu n ct ion

an d digoxin for several m on th s w ith ou t adverse e ect s, an d

(see th e creat in in e serum level), w h ich m ost likely decreased

pot assiu m levels are n orm al.

th e ren al excret ion of digoxin . Pot assiu m su p p lem en tat ion is th e rat ion al th erapy for hypokalem ia. Th e dose of digoxin

Learning objective: Describe the treatment for digoxin poisoning.

m ust also be reduced because of th e ren al in su

18. E Th e p at ien t ’s h istor y an d sym ptom s in d icated t h at t h e

cien cy.

B Th is st rategy w ould be used w h en digoxin toxicit y is du e

p at ien t at tem pted suicide by ingest ing several digoxin t ab -

to excessive parasym pathom im etic activit y of the drug, w hich

let s. Th e best w ay to t reat digoxin p oison ing is to adm in ister

is usually suggested by th e presen ce of severe bradycardia or

d igoxin an t ibodies (digoxin im m u n e Fab) th at bin d digoxin

by an at rioven t ricular block.

w it h ver y h igh a

C Th is opt ion is irrat ion al; a reduced digoxin dose w ould, of cou rse, red uce toxicit y, but an in creased furosem ide dose w ou ld w orsen th e hyp okalem ia.

n it y, t h u s rem ovin g t h e d r ug from it s

t issue-bin d ing sites. Th is approach is ext rem ely e ect ive in reversing digoxin in toxicat ion . A−D, F All of th ese drugs m ay be used in digoxin toxicit y to

D Digoxin w as e ect ive for 1 year, w h ich in dicates th at th e

t reat speci c digoxin -in du ced cardiac sym ptom s (e.g., lido-

heart failure w as serious enough to require an inotropic drug.

cain e in case of ven t ricu lar t achycardia an d at rop in e in case

Th erefore, it w ou ld be irrat ion al to w ith draw an in ot ropic

of at rioven t ricular block). How ever, w h en poison ing is se-

m edicat ion .

vere an d m any body fun ct ion s are seriously a ected (see th e

E Milrin on e is an e ect ive in ot ropic drug, but because of its toxicit y, it is u sed on ly w h en oth er drugs are n ot able to

p sych ic sym ptom s of th e p at ien t), digoxin an t ibod ies m ust be adm in istered rst .

240


Learning objective: Describe the main contraindication of digoxin.

digoxin is required to produce toxicit y in patients w ith serum

19. C Digoxin is relatively contraindicated in patients w ith signif-

K+ of 5 m Eq/L as in th ose w ith a serum K+ of 3 m Eq/L.

ican t at rioven t ricu lar (AV) block becau se th e drug decreases

A Advan ced age can in crease th e risk of digit alis toxicit y,

AV con du ct ion via both parasym p ath om im et ic act ion s an d

bu t t h is p at ien t is n ot old (an old p erson is d e n ed as 65

a direct depressive e ect on th e AV n ode. Moreover, digoxin

years of age or m ore).

is n ot in dicated for m ild cardiac failure. Because th e pat ien t is hyperten sive, all th e oth er listed drugs are appropriate for in it ial h ear t failu re or for hyperten sion .

C Hypern at rem ia is n ot a pred isp osing factor for digit alis toxicit y. D, E Th ere is n o eviden ce to support th ese opt ion s.


Learning objective: Describe a digoxin−drug interaction of clinical importance.

Learning objective: Describe the hem odynam ic actions of digoxin in the failing heart. 23. A By d e n it ion , card iac reser ve is t h e cap acit y of t h e h ear t

20. B Broad-spect ru m an t ibiot ics such as er yth rom ycin can in -

to fun ct ion w ell beyon d it s basal level. In cardiac failure, th e

crease th e oral bioavailabilit y of digoxin becau se th ey kill

h ear t is u n able to in crease it s force of con t ract ion w h en

bacteria p resen t in n orm al in test in al ora (m ain ly Eubacte-

t h e dem an d for w ork is in creased. Th erefore, card iac ou t pu t

rium lent um ) th at are able to m et abolize digoxin . Th is is a

m igh t be adequ ate u n der rest ing con dit ion s, bu t be in su

m ajor and clinically im portant drug interaction w ith digoxin.

cien t w h en th e body is exercising. Th is w ou ld exp lain w hy

A Alth ough hypokalem ia can in crease digoxin toxicit y, it is

dysp n ea of exert ion is on e of th e m ost com m on sym ptom s

u n likely in th is case because th e pat ien t h as been receiving

of cardiac failu re. By in creasing h ear t con t ract ilit y, digoxin

hydroch loroth iazid e an d d igoxin for several m on th s w ith ou t

can in crease th e st roke volu m e u n der exercise; th at is, it in -

adverse e ects.

creases card iac reser ve.

C Hydroch loroth iazide can cause hypercalcem ia, n ot hyp ocalcem ia. D Captopril rarely decreases digoxin ren al excret ion , but it is un likely in th is case for th e reason s explain ed above. E Alth ough ibuprofen rarely decreases digoxin ren al excret ion , th e e ect is t ran sien t an d clin ically u n im p or t an t .

-

B An in crease in cardiac con t ract ilit y w ould cause coron ar y vasodilat ion , n ot vasocon st rict ion . C Oxygen con sum pt ion is decreased, n ot in creased, in a failing h ear t un der digoxin t reat m en t because th e in creased con t ract ilit y dim in ish es th e st retch of cardiac bers, w h ich is th e m ajor determ in an t of oxygen con sum pt ion . D, E Th ese cardiovascular param eters are decreased, n ot

Learning objective: Describe a digoxin−drug interaction of clinical importance. 21. B Th e pat ien t’s sym ptom s suggest digoxin overdose. Som e an t iarrhyth m ic drugs (e.g., qu in idin e, am iodaron e, an d ver-

in creased, by digoxin .

Learning objective: Explain the m olecular m echanism of the positive inotropic action of milrinone.

apam il) can su bst an t ially in crease th e p lasm a con cen t rat ion

24. A A p at ien t w ith acu te decom p en sated h ear t failu re u su ally

of d igoxin , lead in g to adverse e ect s. In fact , t h e p lasm a

n eed s p osit ive in ot rop ic agen t s. Becau se t h e p at ien t w as

levels of digoxin can be dou bled by con com itan t t reat m en t

u sing β-blockers, ph osph odiesterase in h ibitors are preferred

w ith am iodaron e. Th e m ech an ism of th e in teract ion is un -

over dobu t am in e. Ph osp h odiesterase in h ibitors in h ibit th e

kn ow n an d probably m ult ifactorial.

cyclic aden osin e m on oph osph ate (cAMP) ph osph odiester-

A Captopril-in duced hyperkalem ia is usually m ild. A m ild

ase 3 isozym e w ith a resu lt ing in crease in cAMP levels. Th e

hyp erkalem ia act u ally cou n teract s m ost adverse e ect s of

cascade of even t s th at follow s th is in crease is equ al to th at

d igoxin .

triggered by other inotropic drugs (β 1 agonists, glucagon, etc.),

C Am iodaron e can decrease at rioven t ricular con du ct ion , bu t th is can n ot explain th e p at ien t’s sym ptom s. D, E Th ese e ect s of furosem ide do n ot in crease digoxin toxicit y.

w h ich also in crease (alth ough by a di eren t m ech an ism ) cAMP levels. It involves op en ing of voltage-gated Ca 2+ ch an n els, w h ich in t urn in creases in t racellular Ca 2+ levels. B Ph osph odiesterase in h ibitors do n ot in h ibit th e cyclic gu an osin e m on op h osp h ate (cGMP) p h osph odiesterase iso-

Learning objective: Identify a digoxin−drug interaction of clinical importance. 22. B Th e pat ien t’s sym ptom s are classic sign s of digit alis toxicit y. Th e fairly h igh dose of th iazide m ost likely cau sed hypokalem ia an d hypercalcem ia, w h ich are t w o w ell-recogn ized p red isp osing factors to d igit alis toxicit y. Tw ice as m u ch

zym e. Also, th e deph osp h or ylat ion of th e m yosin ligh t ch ain w ou ld lead to relaxat ion , n ot con t ract ion , of m u scle cells. C Th e in creased cAMP level does n ot t rigger th e open ing of K+ ch an n els. Addit ion ally, th is op en ing w ou ld cau se hyperpolarization of th e cell m em bran e, w hich w ould adversely a ect m yocyte con t ract ilit y.

Answers and Explanations: IV-3 Drugs for Cardiac Failure 241 Learning objective: Explain the use of β-blockers in diastolic cardiac failure.

h igh , a ven ou s vasodilator such as n it roglycerin or n esirit ide

25. A Bet a-blockers are drugs of ch oice in diastolic h ear t failu re

n at riuret ic pept ide) h as th e advan tage of h aving both n at ri-

becau se • Th ey slow t h e h ear t rate, t h u s allow ing m ore t im e for com plete ven t ricular lling. • Th ey in crease h ear t relaxat ion , th u s cou n teract ing th e st i n ess of th e ven t ricu lar w all. • Th ey redu ce m yocardial oxygen dem an d . B−D In ot ropic drugs are usually con t rain dicated in diastolic h ear t failu re becau se th ey do n ot relieve th e h igh en ddiastolic p ressu re an d m ay in du ce arrhyth m ias. E Ph enylep h r in e is a p u re α agon ist an d w ou ld fu r t h er in crease th e blood pressure. F Man n itol is an osm ot ic diuret ic, w h ich can be dangerous in pat ien t s w ith h eart failure.

Learning objective: Explain the use of β-blockers in hypertrophic obstructive cardiomyopathy. 26. B Th e h istor y an d exam resu lt s in dicate t h at t h e p at ien t w as m ost likely su ering from hyp ert rop h ic obst ru ct ive card iom yopathy, a disorder usually in h erited in an autosom al d om in an t p at ter n . In t h is d isease, t h e asym m et r ic hyp ert rop hy of th e ven t ricu lar sept u m leads to left ven t ricu lar out ow obst ruct ion . Syn cope usually occurs after exercise, p robably becau se th e in creased ep in eph rin e causes an in creased con t ract ile fu n ct ion th at w orsen s th e obst ru ct ion an d a decreased diastolic t im e th at red u ces diastolic ven t ricu lar lling. Oth er classic sym ptom s of th e disease are angin a (a lim ited coron ar y blood ow reser ve is presen t in hyper t roph ied states) an d diastolic h eart failu re (du e to th e redu ced com pliance of the hypertroph ied left ven tricle). Beta-blockers an d calciu m ch an n el blockers th at act on th e h ear t (verap am il an d d ilt iazem ) are drugs of ch oice in th is disease, becau se they decrease cardiac contractilit y and increase diastolic vent ricu lar lling. A, C−E All of t h e ot h er listed d r ugs are con t rain d icated in hyper t roph ic obst ruct ive cardiom yopathy becau se eith er th ey decrease ven ou s ret u rn (p razosin , n it rates, or diu ret ics) or in crease con t ract ile fun ct ion (in ot ropic agen ts).

Learning objective: Outline the use of nesiritide in stage D heart failure. 27. D Th e pat ien t w as m ost likely su ering from stage D cardiac failure despite m axim al doses of th e stan dard recom m en ded th erapy. On adm ission , th e pat ien t w as in acute h ear t failu re, as in dicated by th e h igh cen t ral ven ou s p ressu re an d p oor cardiac ou t p u t . Becau se th e cen t ral ven ou s p ressu re is ver y

is in dicated to reduce preload. Nesirit id e (recom bin an t at rial uretic and vasodilator y properties and can add to th e diuretic e ect of fu rosem ide in refractor y pat ien ts. A Th e pat ien t h as been receiving m axim al doses of digoxin w it h ou t e ect , an d t h e long h alf-life of t h e d r ug suggest s t h at a steady-st ate p lasm a level of d igoxin h as already been at tain ed in th e p at ien t . To add digoxin w ou ld m ost likely be w ith out th erapeut ic e ect an d w ould subst an t ially in crease th e risk of toxicit y. B, C, E, F Th ese drugs are w ith ou t e ect an d cou ld be dan gerou s in a p at ien t in acu te cardiac failu re.

Learning objective: Explain the m olecular m echanism of the positive inotropic action of dobutamine. 28. B Dobu t am in e act ivates m ain ly β 1 ad ren oceptors. Th e su b sequ en t act ivat ion of cyclic ad en osin e m on op h osp h ate (cAMP)−depen den t protein kin ase A in creases th e open ing of m em bran e volt age-gated calcium ch an n els (causing an in creased sp eed an d st rength of m yocyte con t ract ion ), as w ell as th e op en ing of sarcop lasm ic calciu m ch an n els (cau sing an in creased reu ptake of Ca 2+ by th e sarcoplasm ic ret iculum ). Th erefore, both th e sp eed of con t ract ion an d th e speed of relaxat ion of m yocytes are in creased. A Th is is th e m ech an ism of action of m ilrin on e. C, E Th ese m olecular act ion s are t riggered by digoxin , n ot dobu tam in e. D Th e in crease of t h is en zym e is t r iggered by act ivat ion of α receptors, n ot β receptors.

Learning objective: Explain the reasons for the bene cial e ect of angiotensin-converting enzyme (ACE) inhibitors in heart failure. 29. C Captop ril is an ACE in h ibitor, an d m ost e ect s of th e d rug are th e con sequ en ce of decreased p lasm a angioten sin levels. Th is d ecrease in t u r n red u ces p er ip h eral resist an ce, bot h d irectly an d th rough a reduct ion in sym path et ic act ivit y (th us decreasing afterload), an d reduces aldosteron e secretion (th us decreasing preload). These e ects relieve th e w orkload of th e h ear t an d resu lt in im p roved systolic con t ract ile fu n ct ion . B Alth ough th is act ion is ben e cial, th is is n ot at all th e m ain reason w hy captop ril is u sefu l in h ear t failu re. A, D By in h ibit ing angioten sin II form at ion , captop ril act u ally w ou ld in h ibit all angioten sin -m ediated e ect s, in clu ding in creased cardiac con t ract ilit y an d epin ep h rin e release from adren ergic n er ves. E By in h ibit in g ACE, captop r il in h ibit s, n ot st im u lates, bradykin in m et abolism .

242


Learning objective: Explain angiotensin-converting enzym e inhibitor (ACE)−induced m ortalit y reduction in myocardial infarction. 30. E ACE in h ibitors block th e vasocon st rict ing act ivit y of angioten sin II, th us reducing both preload an d afterload, w h ich in t u rn redu ces th e w orkload of th e h ear t . In addit ion , th ey re-

• Up regu lat ion of β 1 receptors (in h eart failu re, β 1 receptors are dow n regulated due to th e ch ron ic act ivat ion of th e sym path et ic n er vou s system ) A, B, D, E Bet a-blockers elicit act ion s op p osite to t h ose listed.

duce the grow th e ects of angioten sin II on cardiac m yocytes

Th e in it ial rem odeling p h ase after a m yocard ial in farct ion

Learning objective: Explain the m echanism of the therapeutic effect of the hydralazine/isosorbide dinitrate combination in Black patient s with heart failure.

(repair of th e n ecrot ic area an d m yocardial scarring) m ay be

32. C It h as been sh ow n th at th e hydralazin e/isosorbide din i-

con sidered ben e cial, but over t im e rem odeling causes an

trate com bination can be e ective prim arily in Black patien ts

in crease of ven t ricular m ass an d volum e th at adversely af-

w ith systolic h ear t failure. Because of th is, th e U.S. Food an d

fect s cardiac fun ct ion . By redu cing cardiac rem odeling, ACE

Drug Adm in ist rat ion h as approved th e com bin at ion product

in h ibitors im prove eject ion fract ion an d decrease m ort alit y.

for th e t reat m en t of h eart failure as an adjun ct to stan dard

A ACE in h ibitors d o n ot ap p reciably a ect card iac con -

h ear t failu re t h erapy in Black p at ien t s. Th e m ech an ism of

an d at ten u ate th e cardiac brosis in du ced by angioten sin II. Th ese act ion s lead to redu ct ion of m yocardial rem od eling.

t ract ilit y.

th e th erap eu t ic e ect of th e com bin at ion is m ost likely re-

B By blocking aldosteron e form at ion , ACE in h ibitors decrease, n ot in crease, p reload .

lated to th e n it rate-m ed iated redu ct ion of preload an d th e hydralazin e-m ediated red u ct ion of afterload.

C By decreasing th e w orkload of th e h eart , ACE in h ibitors act u ally can in d irectly cau se coron ar y vasocon st rict ion .

A Both hydralazin e an d n it rates can cause re ex in crease in cardiac con t ract ilit y, bu t th is act ion is n ot th e m ain reason

D ACE in h ibitors h ave n egligible e ect s on ven t ricu lar au tom at icit y.

th at th e com bin at ion is u sefu l in h ear t failu re. B By cau sing th e re ex act ivat ion of th e sym path et ic system , both drugs can increase, not decrease, the angiotensin II

Learning objective: Explain the role of β-blockers in the therapy of systolic heart failure.

form at ion .

31. C Th e patient’s sym ptom s indicate that he w as su ering from

system .

stage C h eart failu re. His decreased eject ion fract ion p oin t s out th at h is h eart failure w as systolic. Th e left ven t ricular

D Bot h d r ugs can act ivate, n ot in h ibit , t h e sym p at h et ic E By cau sing th e re ex act ivat ion of th e sym path et ic system , both drugs can in crease, n ot decrease, th e h ear t rate.

ejection fraction is the best w ay to di eren tiate bet w een syslin e agen t s for both systolic an d diastolic h eart failure, bu t

Learning objective: Describe the role of loop diuretics in the therapy of chronic systolic heart failure.

th e clin ical u se is di eren t:

33. D Diu ret ics are in d icated in systolic h ear t failu re becau se

tolic an d diastolic h ear t failure. Today, β-blockers are

rst-

• For systolic h ear t failu re, gu id elin es suggest early u se, low

th ey d ecrease p reload. Th erefore, th ey are u sed p rim arily in

dose, gradu al t it rat ion , an d selected agen t s. Th ere is fairly

p at ien ts w ith pu lm on ar y congest ion an d p erip h eral edem a,

st rong eviden ce th at th e ben e t s of β-blockers in systolic

as in th is case.

h ear t failure are n ot a class e ect . Metoprolol, bisoprolol,

In m ost pat ien t s in h eart failure, loop diuret ics are pre-

an d car vedilol are th e β-blockers sh ow n to redu ce m or-

ferred for t w o m ain reason s:

talit y in large h ear t failu re t rials.

• Th ey are th e m ost e ect ive diuret ics presen tly available.

• For d iastolic h ear t failu re, h igh er d oses are u sed , t h ere

• Th ey are th e on ly diu ret ics th at ret ain th eir act ivit y even

is less n eed to t it rate, an d a w id er range of d r ugs is

w h en th e glom erular

acceptable.

u ret ics lose th eir e ect iven ess w h en creat in in e clearan ce

lt rat ion rate is ver y low. Most di-

Bene cial e ects of β-blockers in systolic heart failure include

is less th an 30 m L/m in . Loop diuret ics ret ain th eir e ec-

• Preven t ion of ch ron ic overact ivit y of t h e sym p at h et ic

t iven ess u n t il creat in in e clearan ce is less th an 5 m L/m in .

n er vou s system , w h ich leads to decreased h eart rate an d

In systolic h ear t failu re, th e glom erular lt rat ion rate is often

reduced m yocardial rem od eling th rough in h ibit ion of th e

qu ite low because of th e decreased cardiac out put; th is ex-

m itogen ic act ivit y of catech olam in es

plain s w hy all d iu ret ics, except loop d iu ret ics, are m in im ally

• In h ibit ion of ren in secret ion by blocking β 1 receptors in ju xt aglom erular cells

e ect ive in stage C h ear t failu re.

Answers and Explanations: IV-3 Drugs for Cardiac Failure 243 A Loop diuret ics st im u late, n ot in h ibit , angioten sin II syn th esis by decreasing m acu la den sa sen sit ivit y. B Loop diu ret ics decrease, n ot in crease, ven ous ret u rn to

d egradat ion of bradykin in . By blocking t h e en zym e, ACE in h ibitors w ill in crease th e plasm a levels of angioten sin I an d bradykin in . Both act ion s con t ribu te to th e vasodilat ing

th e h eart by in creasing ven ous capacit an ce vessels (w h ich

act ivit y of th ese d rugs (even if th e

seem s m ain ly related to t h e in creased syn t h esis of p rost a-

im port an t), as angioten sin II is a p ow erfu l vasocon st rict ing

glan din s).

agen t , an d bradykin in is a vasodilator. Th e result an t decrease

C Loop diu ret ics st im ulate, n ot in h ibit , prost aglan din biosyn th esis.

rst is by far th e m ost

in afterload is a prim ar y m ech an ism of th e th erapeu t ic effect of ACE in h ibitors in systolic h ear t failure.

E By decreasing preload, loop diuret ics in crease th e st roke

A It is kn ow n t h at angioten sin II p rom otes t h e secret ion

volum e, but th is is n ot because th ey in crease h ear t con t rac-

of vasop ressin from th e p oster ior p it u it ar y. By in h ibit in g

t ilit y. By de n it ion , con t ract ilit y is th e ch ange in th e peak

an gioten sin II form at ion , vasopressin plasm a levels are, if

isom et ric force of th e cardiac ber at any given in it ial ber

anyth ing, decreased, n ot in creased . By blocking aldosteron e

lengt h . Diu ret ics in crease con t ract ion , n ot con t ract ilit y, of

syn th esis, p lasm a sodiu m levels are exp ected to decrease,

t h e h ear t by d ecreasin g p reload , t h at is, by d ecreasin g t h e

n ot in crease.

cardiac ber length .

B Angioten sin II st im u lates n orepin eph rin e release from sym p at h et ic n er ve ter m in als. By in h ibit in g angioten sin II

Learning objective: Describe the use of spironolactone in heart failure.

for m at ion , ACE in h ibitors d ecrease, n ot in crease, p lasm a

34. C It h as been sh ow n th at spiron olacton e sign i can tly re-

D ACE in h ibitors h ave n egligible e ect s on th ese en doge-

d uces (about 30%) m or talit y an d h ospitalizat ion for h ear t failure du e to left ven t ricular systolic dysfun ct ion . Th e protect ive e ect of t h e d r ug is m ost likely related to it s an t ag-

levels of n orepin eph rin e. n ous com poun ds. E Prost aglan d in p lasm a levels can be in creased by ACE in h ibitors, but angioten sin III levels w ould be decreased.

on ist ic act ivit y at ald osteron e receptors rat h er t h an to it s and because other direct-acting potassium -sparing diuretics,

Learning objective: Describe the m ain advantages of angiotensin antagonists over angiotensin-converting enzyme (ACE) inhibitors.

su ch as t riam teren e an d am iloride, are com p letely devoid of

36. E Th e p rescribed drug w as m ost likely losar tan , an angio-

p rotect ive e ect s in systolic h eart failure. Curren t guidelin es

ten sin II receptor blocker. Angioten sin II is syn th esized from

recom m en d in it iat ing aldosteron e an t agon ist s in pat ien t s

ren in an d cat alyzed by ACE. How ever, som e t issues con tain

w ith severe h ear t failure, as in th is case.

n on ren in an gioten sin ogen -p rocessin g en zym es t h at cat a-

d iu ret ic e ect , becau se sp iron olacton e is a m ild d iu ret ic

A Losar t an is an angioten sin receptor an t agon ist . Even if

lyze th e syn th esis of angioten sin II w ith ou t th e n eed for ACE.

th e act ion s of angioten sin -convert ing en zym e (ACE) in h ibi-

ACE in h ibitors redu ce th e biosyn th esis of angioten sin II pro-

tors an d angioten sin an t agon ist s are n ot exactly th e sam e, it

d uced by th e act ion of ACE, bu t th ey do n ot in h ibit altern a-

is un likely th at losar tan can be e ect ive in a pat ien t n ot re-

t ive n on -ACE angioten sin II−gen erat ing p ath w ays. Becau se

spon ding to captopril.

angioten sin II an t agon ist s block t ype 1 angioten sin II recep -


tors, th e act ion s of angioten sin II are blocked regardless of

D In dapam ide is a th iazide diuret ic. It is m in im ally e ec-

th e bioch em ical p ath w ays leading to angioten sin syn th esis.

t ive in severe h ear t failu re. Moreover, th e p at ien t already

W h eth er th e ph arm acological di eren ces bet w een angio-

received furosem ide w ith out eviden t im provem en t .

ten sin blockers an d ACE in h ibitors result in sign i can t dif-

E, F Milrin on e an d n esirit ide are used on ly for acute h eart failure w h en oth er drugs are n ot e ect ive.

feren ces in t h erap eu t ic ou tcom e is st ill an op en qu est ion . It is com m on to su bst it u te an ACE in h ibitor w it h an angioten sin blocker w h en t h e rst is n ot e ect ive an d can cau se ad -

Learning objective: Describe the pharm acological actions of angiotensin-converting enzym e (ACE) inhibitors. 35. C Captop r il is an ACE in h ibitor. ACE cat alyzes t h e syn t h esis of angioten sin II from an gioten sin I an d p rom otes t h e

verse e ects, as in th is case. A−D, F See correct an sw er explan at ion .

244


Learning objective: Explain the m ost likely m olecular m echanism of the therapeutic e ect of spironolactone in systolic heart failure. 37. C Sp iron olacton e is a com pet it ive aldosteron e receptor an -

Learning objective: Describe the e ect s of angiotensin-converting enzym e (ACE) inhibitors and β-blockers in a patient with stage C systolic heart failure.

tagonist that signi cantly reduces m orbidit y and m ortalit y in

39. A A pat ien t su ering from stage C systolic h ear t failu re m ost

advan ced systolic h ear t failu re. Th is redu ct ion is ach ieved

likely sh ow s decreased diu resis (becau se of th e decreased

in th e absen ce of dem on st rable diuret ic e ect , len ding sup -

cardiac ou t p u t), in creased arteriolar ton e (becau se of angio-

port to th e hyp oth esis th at th e th erap eu t ic e ect of th e d rug

tensin II actions and sym pathetic overactivit y), and increased

is related to it s blocking act ivit y at aldosteron e receptors.

m yocardial oxygen con su m pt ion (becau se th e h igh p reload

Th e m ajor act ion of aldosteron e is to st im ulate th e kidn ey

in creased th e st retch of th e cardiac bers, w h ich is a m ajor

to reabsorb Na + an d w ater. How ever, aldosteron e h as sim ilar

d eterm in an t of oxygen con su m pt ion ).

act ion s on salt an d w ater t ran sp or t in t h e colon , salivar y

By decreasing preload an d afterload, ACE in h ibitors in -

glan d s, an d sw eat glan d s. Moreover, ald osteron e receptors

crease cardiac ou t p u t ,w h ich in t u rn can

are presen t in several oth er t issu es, in cluding m yocardium ,

• Im p rove kid n ey blood

and it is likely that the drug increases

Na +

conductan ce across

m ost cell m em bran es. Morph ologic st udies in dicate th at ch ron ic excess of aldosteron e (plus salt loading), as occurs in h ear t failure, can in duce a path ologic rem odeling, causing brosis in th e h ear t , kidn ey, an d oth er organ s in an im als an d h um an s. Th e m ech an ism of th is e ect is st ill un cer tain , but it cou ld be related to th e in creased Na + con du ct an ce in aldosteron e-con t rolled Na + ch an n els in several t issu es, in clu ding the m yocardium . By blocking aldosterone receptors, spironolactone can decrease aldosterone-controlled Na + conductance. A Spiron olacton e can h ave a potassium -sparing e ect by

ow , lead ing to an in creased

d iu resis • O set th e sym path et ic overact ivit y, leading to decreased arteriolar ton e • Decrease th e diastolic st retch of cardiac bers, leading to a decrease in m yocardial oxygen con sum pt ion Car vedilol is an α -/β-blocker th at can • Decrease ar teriolar ton e • Decrease h ear t rate, leading to a decrease in m yocardial oxygen con su m pt ion B−E See correct an sw er explan at ion .

in h ibit ing p ot assiu m excret ion in t h e collect ing d u ct , bu t th is is n ot th e reason for it s e

cacy in ch ron ic h ear t failu re.

B Th is w ould be th e m ech an ism of act ion of carbon ic an hydrase in h ibitors.

Learning objective: Describe the main adverse e ects of spironolactone. 40. D Th e pat ien t w as su ering from gyn ecom ast ia, a w ell-

D Sp iron olacton e h as n o d irect e ect on ren in secret ion by th e m acu la den sa.

d escribed adverse e ect of sp iron olacton e th at is related to d ose an d durat ion of t reat m en t . High doses h ave been asso-

E Th is w ould be th e m ech an ism of act ion of th iazide diu ret ics.

ciated w ith u p to a 50% p revalen ce of th is adverse e ect . Ow ing to it s a

n it y for oth er steroid receptors, sp iron olac-

ton e can in duce gyn ecom ast ia m ost likely by displacing an -

Learning objective: Describe the m ain adverse e ect s of angiotensin-converting enzyme (ACE) inhibitors.

drogen s from an drogen receptors. Generally, discontinuation

38. B ACE in h ibitors decrease aldosteron e syn th esis. Low er al-

A−C, E Th e r isk of gyn ecom ast ia w it h t h ese dr ugs is

d osteron e levels ten d to decrease K+ excret ion . Car ved ilol is

of t reat m en t result s in resolut ion of gyn ecom ast ia. n egligible.

a n on select ive β-blocker an d a select ive α 1 -blocker. Blockade of β 2 receptors in th e skelet al m uscle ten ds to decrease K+

DRUGS FOR CARDIAC FAILURE Answ er key

u ptake. Hyperkalem ia is un com m on if on e of th e t w o drugs is given singly, bu t th e risk of hyp erkalem ia is substan t ially in creased w h en th ey are given con com itan tly. A ACE in h ibitors an d β-blockers h ave a n egligible e ect on calciu m p lasm a levels. C, D Blockade of aldosteron e product ion is expected to decrease, n ot in crease, ext racellu lar

u id volu m e an d sodiu m

plasm a levels. E ACE in h ibitors h ave a n egligible e ect on glucose m et abolism . Beta-blockers can decrease, n ot in crease, th e glu cose level by blocking β 2 −m ediated glu con eogen esis an d glycogen olysis in th e liver.

1. 2. 3. 4. 5.

F C I G B

6. 7. 8. 9. 10.

B B E A B

11. 12. 13. 14. 15.

C C C D A

16. 17. 18. 19. 20.

B E E C B

21. 22. 23. 24. 25.

B B A A A

26. 27. 28. 29. 30.

B D B C E

31. 32. 33. 34. 35.

C C D C C

36. 37. 38. 39. 40.

E C B A D

Answers and Explanations: IV-4 Antihypertensive Drugs 245

Answers and Explanations: IV-4 Antihypertensive Drugs Questions 1−5 1. M

Learning objective: Identify the m ost appropriate antihypertensive drug in a patient with concom itant diseases.

2. E

8. D Th e p at ien t h as stage 2 essen t ial hyp er ten sion ; th erefore,

3. J

an antihypertensive m edication is recom m ended in addition

4. C

to lifest yle m odi cat ion . Th e pat ien t is a good can didate for

5. A

a th iazide d iu ret ic for several reason s. First , th ese dr ugs are u su ally th e m ost appropriate in it ial th erapy for un com pli-

Learning objective: Describe the m ain action leading to the antihypertensive e ect of thiazides.

cated hyp er ten sion becau se th ey d ecrease m orbid it y an d

6. C Th e in it ial hypoten sive e ects of diuret ics are associated

an d th iazides can cau se reten t ion of calciu m , a p oten t ially

w ith a reduct ion in plasm a volu m e an d cardiac out pu t . Perip h eral vascu lar resist an ce is u su ally u n a ected (or som et im es in creased). After 4 to 8 w eeks of con t in u ous th erapy, blood volu m e an d cardiac ou t p u t ret u rn to n orm al, an d perip h eral vascu lar resistan ce decreases. Mech an ism s u n d erlying th is decrease are probably related to a dep let ion of body

m ortalit y. Second, the w om an is su ering from osteoporosis, ben e cial e ect . Moreover, in th is p at ien t: A Angiotensin-converting enzym e (ACE) inhibitors are contrain dicated becau se of th e p ast ep isod e of angioed em a. B, C Bet a-blockers an d verapam il are con t rain dicated becau se of th e h ear t block. E Min oxidil is n ever a drug of rst ch oice for an t ihyperten sive th erapy.

Na + stores. A Diu ret ics cau se n egligible post ural hypoten sion , because th e baroreceptor re ex is n ot a ected. B See correct an sw er exp lan at ion . D Th iazides ten d to decrease, n ot in crease, in terst it ial uid volum e. E Blood

Learning objective: Describe the m ain adverse e ects of central sympathoplegic antihypertensive drugs. 9. D Sedat ion is a frequen t , an d som et im es pron oun ced, adverse e ect of central sym pathoplegic antihypertensive drugs

ow in any organ is related to perfusion pressure

an d vessel resist an ce. Perfusion pressure in t urn is m ain ly re-

(m ethyldopa an d clon idin e), probably due to decreased adren ergic t ran sm ission in th e cen t ral n er vou s system .

lated to cardiac ou t pu t . After several w eeks of t reat m en t w ith

A Postural hypotension is an uncom m on and usually m inor

diu ret ics, cardiac ou t p u t is n orm al; th erefore, ren al blood

adverse e ect of m ethyldopa an d clon idin e, becau se basal

ow is eith er n orm al or in creased, n ot decreased.

cen t ral adren ergic ton e is redu ced, but th e baroreceptor reex is st ill operat ive.

Learning objective: Describe the main adverse e ects of thiazides. 7. B Th e pat ien t’s sym ptom s an d th e lab results in dicate th at h e w as m ost likely su ering from gou t y arth rit is. Ch ron ic t reatm ent w ith thiazides m ay cause hyperuricem ia and precipitate

B Hem olyt ic, n ot m egaloblast ic, an em ia occasion ally occu rs w ith m ethyldop a. C Methyldopa an d clon idin e ten d to decrease th e h ear t rate, so palp itat ion s are u n likely.

at tacks of gou t in at-risk p at ien t s. Hyperu ricem ia is likely du e

E Methyldopa an d clon idin e frequen tly cause xerostom ia,

to both a hypovolem ia-in duced in crease in uric acid reabsorp -

n ot sialorrhea. The m echanism of the e ect is still un certain.

t ion an d com pet it ion w ith u rates for th e organ ic acid t ran sBeing a pain ter, th e pat ien t w as already at risk for gou t be-

Learning objective: Describe the symptom s of clonidine withdrawal.

cau se a st rong associat ion exists bet w een th e risk of gou t an d

10. E Th e pat ien t’s sym ptom s are m ost likely due to sudden

lead exposure through diet or occupation (painters, plum bers,

clon idin e w ith draw al. Reboun d hyperten sion can occur (to

etc.).

levels above th ose presen t prior to t reat m en t), but th e syn -

port system in th e proxim al t u bu le.

A, C, E, F Th ese drugs do n ot cau se hyp er u ricem ia.

d rom e can appear in th e absen ce of an oversh oot in blood

D Furosem ide can cau se hyperu ricem ia, but th e drug is

p ressure. Th e sign s an d sym ptom s of th e syn drom e are asso-

rarely used as an an t ihyper ten sive.

ciated w ith in creased sym p ath et ic disch arge (p lasm a levels of catech olam in es are in creased). Th e exact m ech an ism underlying the clon idine w ith drawal syndrom e is not know n , bu t t h e rebou n d hyp er ten sion seem s to be d u e to an u p regulat ion of α 1 receptors. A−D, F With draw al of n on e of th e oth er listed drugs precip itates th e described syn drom e.

246


Learning objective: Identify the antihypertensive drug that can most likely cause a positive Coom bs reaction.

cause signi cant postural hypotension because they decrease

11. D Methyldopa is th e m ost com m on ly used drug for ch ron ic

th e basal adren ergic ton e, but th e sym path et ic n er vou s sys-

t reat m en t of hyper ten sion during pregn an cy, prim arily becau se th ere h as been th e m ost exp erien ce w ith th is d rug

E Cen t rally act ing an t iadren ergic agen ts usually do n ot

tem can st ill be act ivated by proper st im uli. F Fen oldopam is used on ly for hyper ten sive em ergen cies.

d uring pregn an cy. Posit ive Coom bs react ion occu rs in u p to 30% of pat ien ts t reated for m ore th an 6 m on th s, bu t h em o-

Learning objective: Describe the therapeutic uses of α 1 -blockers.

lyt ic an em ia occu rs in on ly 1 to 5% of cases. Th is is a t yp e II

14. A Alp h a-1 blockers (e.g., p razosin an d terazosin ) are u sed

allergic drug react ion . Apparen tly, th e drug is able to alter

as an t ihyp erten sive d rugs p rim arily in m en w ith p rostat ic

th e red blood cell surface ch em ically, th ereby un covering an

hyp erplasia becau se th ey relax th e in tern al sp h in cter of th e

an t igen th at in d uces an d th en reacts w ith an an t ibody, th us

bladder an d th e prost ate cap su le.

cau sing cell lysis.

B−F Non e of th ese drugs h ave relaxan t proper t ies on th e

A−C, E, F Non e of th ese drugs produ ce a posit ive Coom bs

in tern al sp h in cter of th e bladder an d prost ate cap su le.

test or h em olyt ic an em ia.

Learning objective: Describe the therapeutic uses of clonidine.

Learning objective: Identify the antihypertensive drug that is most likely to cause postural hypotension.

12. D Clon idin e is th e on ly an t ihyp er ten sive th at is also u sed in

15. E By blocking α 1 receptors, labet alol a ect s t h e barorecep -

sm oking cessat ion program s because it redu ces an xiet y, irri-

tor re ex th at is respon sible for rapid, m om en t-to-m om en t

t abilit y, an d craving du ring tobacco w ith draw al (it dou bles

adju st m en t in blood pressure, su ch as in t ran sit ion from a

th e n u m ber of p at ien t s w h o rem ain abst in en t for 6 m on th s

reclin ing to an up righ t post u re. Th e in creased sym p ath et ic

or m ore). Th e m ech an ism of th is act ion is un cer tain , but it

out ow can n ot in du ce n orm al vasocon st rict ion becau se α 1

seem s to be related to th e d rug-in du ced decrease in cen t ral

receptors are blocked, so post u ral hyp oten sion resu lt s.

sym p ath et ic ou t ow, w h ich m ay m it igate m any of th e sign s

A In gen eral, β-blockers su ch as p rop ran olol cau se n egli-

of sym path et ic overact ivit y th at are presen t du ring tobacco

gible post u ral hypoten sion because th e baroreceptor re ex

w ith draw al.

is n ot a ected .

A−C, E Th ese drugs do n ot a ect tobacco w ith draw al.

B Clon idin e act s cen t rally to reduce sym path et ic out ow. How ever, th e baroreceptor re ex is on ly m argin ally a ected,

Learning objective: Describe the main adverse e ects of prazosin.

an d post u ral hypoten sion is sligh t .

13. D Th e drug t aken by th e pat ien t w as m ost likely prazosin , an

C Angioten sin -conver t ing en zym e (ACE) in h ibitors such

an t ihyp er ten sive agen t som et im es given to p at ien t s w ith re-

as captopril rarely cau se post u ral hypoten sion . Th e reason is

sistan t hyperten sion an d con com itan t p rost at ic hyp erp lasia,

u n cert ain bu t could be due to dow nw ard reset t ing of baro-

becau se it can also facilit ate u rin at ion by relaxing th e blad -

receptors.

d er in tern al sp h in cter. Prazosin can cause m arked post u ral hyp oten sion an d syn cop e w ith th e

rst dose (th e so-called

rst-dose p h en om en on ). Th is is p robably du e to th e blockade of α 1 receptors both in th e ar terioles (w h ich im pairs th e

D In general, thiazide diuretics such as hydrochlorothiazide cau se n egligible p ost u ral hyp oten sion becau se th e baroreceptor re ex is n ot a ected.

venous ret urn). The orthostatic e ect declines over t im e. Th e

Learning objective: Choose the appropriate antihypertensive drug for a patient su ering from hypertrophic cardiomyopathy.

m ech an ism respon sible for th e developm en t of such toler-

16. E Beta-blockers su ch as prop ran olol are

re ex vasocon st rict ion ) an d in th e vein s (w h ich decreases

rst-lin e agen t s in

ance is not clear. Other ant ihypertensive drugs th at can cause

hyp er t roph ic cardiom yop athy becau se th ey in crease th e du -

syn cop e are labet alol, angioten sin -convert ing en zym e (ACE)

rat ion of diastole an d decrease left ven t ricular con t ract ilit y

in h ibitors, losar t an , an d n it ropru sside.

an d m yocardial w all st ress du ring systole. In th is case, th ey

A Bet a-blockers do n ot cau se post u ral hyp oten sion an d syn cop e becau se th ey do n ot sign i can tly a ect th e baroreceptor re ex or ven ous ret u rn . B, C Unlike drugs th at dilate capacit an ce vessels, ar teriolar vasodilators do n ot cau se sign i can t p ost u ral hyp oten sion , so th e risk of fain t ing w ith th ese d rugs is n egligible.

sh ou ld also redu ce th e h igh blood p ressu re an d are th erefore th e m ost ap prop riate drugs for th is p at ien t . A−D Th ese drugs w ill n ot im prove an d m ay even exacerbate th e hyp er t roph ic cardiom yop athy an d th erefore are n ot su ited for th is p at ien t . F Th e use of angioten sin -convert ing en zym e (ACE) in h ibitors in hyper t roph ic cardiom yopathy is con t roversial. Som e clin ician s th in k th ey h ave n o role in th e disease, w h ereas oth ers believe th ey are ben e cial by lim it ing hyp er t rophy.

Answers and Explanations: IV-4 Antihypertensive Drugs 247 Learning objective: Describe the use of antihypertensive drugs in aortic dissection.

th et ic n er vous system , w h ich resu lt s in e ects opposite to

17. D Aor t ic dissect ion is a h igh ly leth al disorder. Because m or-

th ose listed.

t alit y is h igh est in t h e early h ou rs after d issect ion begin s, d rug th erapy to low er th e ar terial pressure sh ou ld be star ted as soon as p ossible. Nit rop r u ssid e is given as a con st an t in t raven ou s drip w ith th e object ive of reducing th e blood

A, B Min oxidil cau ses a re ex act ivat ion of th e sym pa-

C Min oxidil can som et im es in crease, n ot decrease, th e ext racellu lar u id volu m e, leading to ed em a. D By decreasing blood pressure, m inoxidil can activate, not in h ibit , th e ren in angioten sin system .

p ressure to th e low est level com pat ible w ith adequ ate cereu sed alon e can cause re ex t achycardia, a β-blocker such as

Learning objective: Explain the m olecular m echanism of action of diazoxide.

esm olol is usually used con com itan tly. Both drugs h ave ver y

21. C Diazoxide is an ar teriolar vasodilator som et im es used for

sh ort h alf-lives th at allow blood p ressu re resp on se t it rat ion

hyp er ten sive em ergen cies (bu t n ot for n on em ergen cy t reat-

from m in u te to m in u te. Su rgical rep air on an em ergen cy

m en t of hyp er ten sion ). It op en s p ot assiu m ch an n els in

basis u su ally follow s th e m edical th erapy.

sm ooth m u scle cell m em bran es, th u s st abilizing th e m em -

bral, coron ar y, an d ren al perfusion . Becau se n it roprusside

A Labetalol is used for acute aort ic dissect ion , bu t th e add it ion of prazosin is irrat ion al, as labetalol itself is also an α 1 -blocker.

bran e poten t ial at th e rest ing level. In th is w ay, it cou n teract s sm ooth m u scle con t ract ion . A, B, D−F See correct an sw er exp lan at ion .

B Diazoxid e is u sed in case of hyp er ten sive em ergen cy, bu t th e addit ion of hydralazin e is irrat ion al, as th e dr ug can cause re ex tachycardia. C, E None of these drugs are suitable for hyperten sive em ergen cies becau se th eir on set of act ion is too slow.

Learning objective: Describe the antihypertensive uses of calcium channel blockers. 22. E Th e p at ien t is su ering from st age 2 hyp er ten sion , so a com bin at ion th erapy is advisable. A diu ret ic (hydroch loroth iazide) an d a Ca 2+ ch an n el blocker (n ifedipin e) w ou ld be a

Learning objective: Describe the hemodynamic e ects of atenolol.

rat ion al ch oice becau se Blacks often h ave low -ren in hyper-

18. A Aten olol is a select ive β 1 -blocker. Cardiac ou t put is de-

ten sion an d m ay respon d best to diu ret ics an d Ca 2+ ch an n el

creased becau se of th e decrease in cardiac con t ract ilit y an d rate; ven ou s ton e is u n ch anged becau se t h ere are n o β 1 receptors on t h e vessels; an d p ost u ral hyp oten sion is n egligible because th e drug does n ot cause hypovolem ia, an d th e baroreceptor re ex is u n a ected .

blockers. Moreover, in th is p at ien t A, B Captopril is con t rain dicated becau se of th e ren al arter y sten osis in a solitar y kidn ey. C, D Prop ran olol is con t rain d icated becau se of ch ron ic obst ru ct ive pu lm on ar y disease.


Learning objective: Describe the m ain adverse e ect s of hydralazine.

Learning objective: Explain the antihypertensive use of nifedipine in a patient with concom itant disease. 23. A Beta-blockers are useless in varian t angin a an d can even be

19. A Hydralazin e is an ar teriolar vasodilator th at causes re ex

dangerou s by cau sing coron ar y vasocon st rict ion . Nifedip in e

t achycard ia, w h ich explain s th e su bject ive feeling of p alp it a-

is a drug of ch oice in varian t angin a, as it causes a gen eral-

t ion s. Skin vasodilat ion cau ses sw eat ing an d u sh ing.

ized vasodilation that in cludes the coronar y arteries. Because

B−D All of t h ese d r ugs ten d to cau se bradycard ia, so p alp itat ion s are un likely.

th e d rug is also e ect ive in hyp er ten sion , th e su bst it u t ion of p ropran olol w ith n ifedipin e is a rat ion al th erap eu t ic ch oice.

E Nit roprusside can cause t achycardia an d u sh ing. How -

B Nit roglycerin is e ect ive in varian t angin a (but less ef-

ever, it is used on ly in hyper ten sive em ergen cies, as it s h alf-

fect ive th an calcium ch an n el blockers). In th is case, h ow ever,

life is ver y sh or t .

p ropran olol m u st be w ith draw n , so th e sim p le addit ion of an oth er d rug is n ot a w ise ch oice.

Learning objective: Describe the actions leading to the therapeutic e ect of m inoxidil. 20. E Min oxidil act s by open ing pot assium ch an n els in sm ooth m u scle cell m em bran es, w h ich lead s to m em bran e st abilizat ion , t h u s m aking con t ract ion less likely. Vasod ilat ion is lim ited to t h e ar ter ioles (t h e e ect on cap acit an ce vessels is n egligible) an d cau ses t h e red u ct ion of tot al p er ip h eral resistan ce.

C Captopril is a good th erapy for hyperten sion but can n ot cu re th e varian t angin a. D, E See explan at ion B.

248


Learning objective: Describe the pharm acological e ects of angiotensin-converting enzym e (ACE) inhibitors.

pat ien ts w ith ch ron ic ren al failu re. On th e oth er h an d, th ey

24. C Captopril is an ACE in h ibitor th at reduces th e syn th esis

arter y sten osis (or sten osis of th e ren al ar ter y of a solit ar y

of angioten sin II. Th is in t urn w ill reduce th e plasm a level of

kidn ey), severe aor t ic sten osis, an d even severe in t raren al

ald osteron e, w h ereas ren in w ill in crease (sh or t-loop n ega-

m icrovascular disease. In fact , in th ese diseases, angioten -

t ive feedback), as w ill p otassiu m .

sin II is th e m ain determ in an t of a su

can produce acute renal failure in patients w ith bilateral renal

cien t glom eru lar l-

A, B, D Th ese drugs do n ot cau se th is pat tern of e ect s.

t rat ion rate (GFR). Factors th at predisp ose a pat ien t to acu te

E Spironolactone causes hyperkalem ia but does not change

ren al failu re from ACE in h ibit ion in clu de con com itan t u se

th e p lasm a levels of aldosteron e, ren in , an d angioten sin II.

of diuret ics (sodium -volum e deplet ion caused by diuret ics m akes p at ien t s m ore sen sit ive to ACE in h ibitors) an d of n on -

Learning objective: List the m ain contraindications for angiotensin-converting enzym e (ACE) inhibitors. 25. B ACE in h ibitors are kn ow n to cause various m alform at ion s, grow th ret ardat ion , an d even fetal death , prim arily w h en given du ring th e secon d an d th ird t rim ester of pregn an cy. Th ey are categor y D (p osit ive eviden ce of h u m an risk) in th e

steroidal an t iin am m ator y drugs, w h ich p reven t th e vasodilat ing act ion of ren al prost aglan din s. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Choose the appropriate antihypertensive drug for a patient with concomitant diseases. 29. C Angioten sin -conver t ing en zym e (ACE) in h ibitors appear

classi cat ion by th e U.S. Food an d Drug Adm in ist rat ion . A, C−E Non e of th e oth er listed drug classes are absolu tely

to be ideal agen t s to t reat hyper ten sion in diabet ics because t h ey d o n ot h ave bioch em ical adverse e ect s on glu cose

con t rain dicated in p regn an cy.

regu lat ion , like oth er agen t s m ay. In addit ion , th ey are drugs

Learning objective: Describe the m ain adverse e ect s of angiotensin-converting enzyme (ACE) inhibitors. 26. E A dr y, dist u rbing cough is a t ypical adverse e ect of ACE in h ibitors th at occurs in up to 20% of pat ien t s an d is m ost likely due to th e in creased plasm a levels of bradykin in . Th e loss of t aste (dysgeu sia) repor ted by th e pat ien t is an oth er t ypical e ect of ACE in h ibitors (th e reason is un kn ow n ). A−D None of th e other listed an tihypertensive drugs cause th ese adverse e ect s.

slow dow n th e progression of th e disease. Th e pat ien t sh ow s sign s of ren al im p airm en t (m icroh em at u ria), so captopril represen t s a rat ion al ch oice. Moreover, in th is pat ien t A Th iazide diu ret ics are con t rain dicated because of gout y arth rit is. B Bet a-blockers are relat ively con t rain dicated in in sulin d epen den t diabet ics becau se th ey can m ask sign s an d sym p tom s of hypoglycem ia. D, F Clon idin e an d aliskiren are n ot

Learning objective: Describe the m ain adverse e ect s of angiotensin-converting enzyme (ACE) inhibitors. 27. D Th e sign s an d sym ptom s of th e pat ien t st rongly suggest th e diagn osis of angioedem a. ACE in h ibitors are kn ow n to cau se angioedem a in 0.1 to 0.3%of p at ien t s. Th is e ect is n ot d ose-related an d n early alw ays develop s w ith in th e

of ch oice in ch ron ic diabet ic glom erulopathy becau se th ey

rst

w eek of th erapy. Air w ay obst ruct ion m ay lead to death . Th e m ech an ism u n derlying th e disorder seem s to be related to accu m u lat ion of bradykin in produ ced by th ese drugs. An gioed em a is ver y rare in p at ien t s t aking t ype 1 angioten sin II receptor an t agon ist s. A−C, E Non e of th e oth er listed dr ugs cause angion eurot ic edem a.

Learning objective: Describe the m ain adverse e ect s of angiotensin-converting enzyme (ACE) inhibitors. 28. C ACE in h ibitors are kn ow n to slow th e progression of ren al im pairm en t in hyper ten sive diabet ics an d in hyper ten sive

rst-ch oice drugs in

an t ihyp er ten sive th erapy. E Nit ropr u sside is used in hyp er ten sive em ergen cy on ly.

Learning objective: Choose the appropriate therapy for a patient su ering from hypertension and heart failure. 30. D Diu ret ics an d angioten sin -conver t ing en zym e (ACE) in h ibitors are t h e dr ugs of rst ch oice in all st ages of cardiac failure. The sam e drugs are also rst-choice agen ts for hyperten sion . Th erefore, th e com bin at ion of hydroch loroth iazide an d captop ril is a rat ion al ch oice for th is pat ien t . A, B Verap am il an d m in oxidil are n ot u sefu l (an d can be dangerou s) in h eart failu re. C, E Many pat ien ts w ith cardiac failure w ill require th e ch ron ic adm in ist rat ion of a loop diu ret ic to m ain t ain euvolem ia, bu t hydralazin e an d m ethyldop a are n ot drugs of ch oice to t reat st age 1 cardiac failure.

Answers and Explanations: IV-4 Antihypertensive Drugs 249 Learning objective: Explain the m olecular m echanism of antihypertensive action of thiazides.

of th is, th e associat ion of hydroch loroth iazide an d losar tan

31. C Th iazide diu ret ics are drugs of ch oice for m ild hyp er ten -

t ion regim en s. Th e com bin at ion th erapy w ith losar tan an d

sion , an d t h ey are esp ecially e ect ive in t h e eld erly an d

hydroch loroth iazide can ach ieve a greater redu ct ion in blood

Black p op u lat ion s. Th ey can low er systolic blood p ressu re

pressu re th an th e com bin ed e ects of eith er of th ese d rugs

(BP) by 15 to 20 m m Hg an d diastolic BP by 8 to 15 m m Hg.

alon e an d is th erefore a t rue syn ergist ic e ect .

Th e m ain an d long-term BP low ering e ect resu lts from a

is today on e of th e m ost com m on an t ihyperten sive m edica-


d ecrease in periph eral vascu lar resist an ce. Th e m ech an ism to a d ep let ion of body Na + stores, w h ich lead s to a fall in

Learning objective: Explain the reasons for a change in antihypertensive therapy.

sm oot h m uscle in t racellu lar Na + con cen t rat ion . Th is in t u rn

34. C Th e pat ien t’s blood p ressure is st ill h igh despite th e th er-

decreases in t racellu lar Ca 2+ con cen t rat ion by act ivat ing th e

apy. Moreover, seru m p otassium is close to th e u p per lim it of

1Ca 2+/3Na + exch anger. Because less calcium is available, re-

th e n orm al range. In th is sit u at ion , a th ird an t ihyp er ten sive

laxat ion occu rs.

d rug sh ou ld be added . Hydroch loroth iazide is th e best ch oice

of th is d ecrease is st ill u n cer t ain , bu t it is p robably related

A Blood volu m e deplet ion can in it ially con t ribute to th e

becau se it is a rst-ch oice an t ihyperten sive drug, it en h an ces

an t ihyper ten sive e ect of th iazides, bu t th is is n ot th e m ain

th e act ion of angioten sin -conver t ing en zym e (ACE) in h ibi-

long-term m ech an ism , becau se after 6 to 8 w eeks of con t in -

tors, an d it can low er plasm a potassium levels.

uous th erapy, in t ravascular volu m e an d cardiac ou t pu t ret u rn to n orm al, bu t th e an t ihyp er ten sive e ect p ersists.

A Loop diuret ics are less e ect ive th an th iazide diuret ics as an t ihyp er ten sives, an d th ey are n ot in dicated u n less th ere

B, D Hypokalem ia an d hypercalcem ia are adverse e ect s

is a con com it an t d isord er, su ch as severe ch ron ic kid n ey

of th iazides. If th ey are severe, th ey can cau se several sign s

d isease (glom erular lt rat ion rate less th an 30 m L/m in ), left

an d sym ptom s, in clu d in g hyp oten sion , bu t t h ese are n ot

ven t ricu lar dysfun ct ion , or severe edem a.

m ech an ism s of th e an t ihyp er ten sive e ect of th iazides.

B, D In dicat ion s for ch anging a drug in an t ihyper ten sive

E An in crease in t h e cyclic gu an osin e m on op h osp h ate

th erapy are m ain ly related to dr ug-in du ced adverse e ect s

(cGMP) level can cau se vasod ilat ion , bu t t h iazid es d o n ot

(w h en a drug is n ot e ect ive, an oth er drug is added w ith out

a ect th is secon d m essenger.

ch anging th e rst drug). Th ere is n o eviden ce of adverse effect s due to th e drugs th e pat ien t w as t aking.

Learning objective: Describe the antihypertensive use of thiazides. 32. E Th e p at ien t w as m ost likely su er in g from essen t ial hy-

E Min oxidil h as several adverse e ects an d is reser ved for ver y di cult-to-con t rol hyperten sion .

perten sion . African -Am erican s ten d to h ave h igh er an d m ore d i eren ces in elect rolyte h om eost asis, glom erular lt rat ion

Learning objective: Describe the m olecular m echanism of the antihypertensive action of methyldopa.

rate, an d sodiu m excret ion . Th ese di eren ces likely con t rib -

35. C Hyperten sion is th e m ost com m on m edical problem en -

u te to th e h igh er an t ihyperten sive e ect iven ess of th iazide

cou n tered du ring p regn an cy, com plicat ing 2 to 3% of p reg-

d iu ret ics in African -Am erican s.

n an cies, an d is a m ajor cause of perin at al m orbidit y an d

severe hyperten sion th an other population s, likely because of

A, F Captop ril is an angioten sin -conver t ing en zym e (ACE)

m or t alit y. Methyld op a is th e drug m ost com m on ly u sed to

in h ibitor, an d aten olol is a β-blocker. It ap pears th at ACE

t reat ch ron ic hyperten sion in p regn an cy in th e Un ited St ates.

in h ibitors, angioten sin an tagon ist s, an d β-blockers are less

Th e an t ihyp er ten sive e ect of m ethyldopa is m ost likely m e-

e ect ive in Blacks th an th iazide diu ret ics or calciu m ch an n el

d iated by an act ion on th e cen t ral n er vou s system . Th e dr ug

blockers.

is taken up by th e adren ergic n eu ron s, w h ere it is t ran s-

B Loop diuret ics such as fu rosem ide are by far less e ec-

form ed in to m ethyln orepin eph rin e, an α 2 receptor agon ist .

t ive th an th iazide diu ret ics for th e long-term m an agem en t

Methyln orep in ep h rin e act ivates α 2 receptors located in th e

of hyper ten sion .

n ucleus of th e t ract us solitariu s an d in th e rost ral ven t rolat-

C, D Th ese dr ugs are used on ly in cases of hyperten sive em ergen cies.

eral m edu lla. Th is act ivat ion decreases th e

ring from th e

ret icu lospin al t ract , leading to a decreased cen t ral adren ergic ton e.

Learning objective: Explain the reasons for the association of thiazides and angiotensin II antagonist s.

A Th is is th e m ech an ism of act ion of m in oxidil.

33. A It h as been sh ow n th at th iazides can en h an ce th e act ion of

D Th is is th e m ech an ism of act ion of fen oldopam .

m ost an t ihyp er ten sive drugs given con com itan tly. Because

B Th is is th e m ech an ism of act ion β–blockers. E Th is is th e m ech an ism of act ion of prazosin .

250


Learning objective: Explain the m echanism of antihypertensive action of β-blockers.

Learning objective: Explain the choice of a fourth antihypertensive drug in a patient under antihypertensive therapy.

36. E Several m ech an ism s of th e an t ihyp er ten sive act ion of

39. E Min oxidil is a ver y e ect ive an t ihyper ten sive drug but

β-blockers h ave been p ost u lated, bu t th e t w o m ain m ech a-

is u su ally con sidered a th ird- or fou r th -lin e agen t becau se of

n ism s are m ost likely th e follow ing:

it s toxicit y. Becau se th e cu rren t t reat m en t is n ot e ect ive for

• Red u ct ion of cardiac ou t p u t du e to th e decrease in cardiac

th is p at ien t , th e rat ion ale is to add a fou rth drug w ith a differen t m ech an ism of act ion . Min oxid il, an ar ter iolar vaso -

con t ract ilit y an d rate • In h ibit ion of th e ren in −angioten sin system due to in h ibit ion of ren in secret ion A Bet a-blockers h ave n egligible e ect on large vein s, bu t blockad e of β 2 receptors sh ou ld con st r ict , n ot d ilate, t h e vessels. B Bet a-blockers h ave n egligible e ect on th e release of ep in ep h rin e from th e adren al m edu lla. C Blockade of β 2 receptors sh ou ld in crease, n ot d ecrease, blood pressu re. In fact , th is act ion of β-blockers is w eak u n der rest ing con dit ion s an d is overridden by th e e ect on cardiac ou t p u t . D Th is is a post ulated m ech an ism of an t ihyper ten sive act ion of β-blockers bu t is by n o m ean s th e m ain on e. In fact , even β-blockers that do n ot cross th e blood−brain barrier, su ch as aten olol, do h ave an t ihyperten sive e ect . F Beta-blockers have n egligible e ect on blood volum e.

Learning objective: Describe the therapeutic uses of nitroprusside. 37. D Nit ropru sside is th e drug m ost frequen tly used to in du ce con t rolled hyp oten sion du ring surger y. Th e drug h as h igh e

cacy an d can in du ce a decrease of blood p ressu re to th e

d esired level. Moreover, th e drug h as a ver y sh or t h alf-life (about 2 m in utes), so blood pressure w ill quickly ret urn to p reop erat ive values w h en th e drug is discon t in ued. A−C, E, F All th ese drugs h ave h alf-lives of h ours, so th ey are n ot su ited for a con t rolled hypoten sion du ring su rger y.

Learning objective: Describe the therapeutic use of diazoxide in a patient with concom itant diseases. 38. B Hyper ten sive en ceph alopathy is a m edical em ergen cy, an d th e p at ien t’s blood pressu re sh ou ld be low ered at on ce w ith p aren teral m edicat ion s th at h ave a rapid on set of act ion . Diazoxide is used for hyper ten sive em ergen cies on ly. It is u sually given by slow in t raven ou s in fu sion , an d it s m axim u m

d ilator th at act s by open ing potassium ch an n els in sm ooth m u scle cell m em bran es, is m ore e ect ive th an oth er ar teriolar vasodilators (n ifedipin e, hydralazin e, etc.) in refractor y hyp er ten sion . Min oxidil-in d u ced ar teriolar vasod ilat ion resu lt s in re ex act ivat ion of th e sym p ath et ic n er vou s system , w h ich in t urn cau ses t achycardia, in creased cardiac out put , an d u id reten t ion (du e to in creased p lasm a ren in act ivit y). Th erefore, con com it an t β-blocker an d d iu ret ic th erapy is alm ost alw ays requ ired w ith m in oxidil t reat m en t , as in th is case. A Nifedipin e w ould be con t rain dicated in th is pat ien t becau se h e h as exp erien ced con st ip at ion w ith an oth er calciu m ch an n el blocker. B, F Th ese dr ugs are u sed on ly in case of hyp er ten sive em ergen cies. C Th e m ech an ism of an t ihyperten sive act ion of m ethyld opa is ver y close to th at of clon idin e, so it s addit ion w ou ld n ot be rat ion al. D En alap r ilat w ou ld be con t rain d icated in t h is p at ien t becau se h e h as experien ced cough w ith an oth er angioten sin conver t ing en zym e (ACE) in h ibitor.

Learning objective: Choose the right antihypertensive drug in a patient with concom itant disease. 40. E Th e p at ien t w as su ering from hyperten sion an d at rial t achycard ia. Dilt iazem h as both an t ihyperten sive an d an t iarrhyth m ic act ion s an d is th erefore an ap p rop riate drug. Moreover, in th is p at ien t A, C Fu rosem ide an d prazosin are n ot rst-ch oice d rugs for hyp er ten sion . B Captopril is con t rain dicated in w om en w h o w an t to get p regn an t . D Propran olol is con t rain dicated because of asth m a. F Fen oldop am is used in hyper ten sive em ergen cies on ly.

e ect occu rs w ith in 2 to 3 m in u tes. A, C Verap am il an d labetalol can be u sed to t reat hyp er-

ANTIHYPERTENSIVE DRUGS Answ er key

ten sive em ergen cies bu t are con t rain d icated in t h is case becau se of th e at rioven t ricu lar block. D, E Clon idin e an d captopril are given by oral route on ly an d are n ot su ited to t reat hyp er ten sive em ergen cies. F Nit roprusside is a

rst-lin e drug for hyper ten sive crisis

bu t is con t rain dicated in th is p at ien t becau se of toxic tobacco am blyopia. This rare condition is likely associated w ith d efect ive or absen t rh odan ese, t h e m itoch on d r ial en zym e th at detoxi es cyan ide by convert ing it to th iocyan ate.

1. 2. 3. 4. 5.

M E J C A

6. 7. 8. 9. 10.

C B D D E

11. 12. 13. 14. 15.

D D D A E

16. 17. 18. 19. 20.

E D A A E

21. 22. 23. 24. 25.

C E A C B

26. 27. 28. 29. 30.

E D C C D

31. 32. 33. 34. 35.

C E A C C

36. 37. 38. 39. 40.

E D B E E

Answers and Explanations: IV-5 Antiarrhythm ic Drugs 251

Answers and Explanations: IV-5 Antiarrhythmic Drugs Questions 1−6

associat ion w ith th is disorder. Qu in idin e-in du ced th rom bo-

1. K

cytop en ia ap pears to be im m u n ologically m ediated an d u su -

2. A

ally develop s w ith in 12 to 24 h ou rs after ingest ion of th e

3. B

d rug by a sen sit ized in d ividu al. A, B, D−F The risk of drug-induced throm bocytopenia w ith

4. B

these drugs is quite low.

5. N 6. M

Learning objective: Describe the therapeutic uses of procainamide. Learning objective: Describe the m echanism of quinidine-induced paradoxical tachycardia.

10. D Wol −Parkin son −W h ite (W PW) is a p reexcit at ion syn -

7. A Quin idin e is st ill som et im es u sed to m ain tain th e n orm al

as a Ken t bu n dle) con n ect ing th e at riu m to th e ven t ricle. An

sin u s rhyth m after cardioversion , bu t it can cau se paradoxical

im pulse can t ravel dow n th is p ath w ay an d excite th e ven t ri-

t achycard ia, d u e to it s an t im u scar in ic act ion on t h e h ear t ,

cle before th e expected regular im pulse th rough th e at rio-

w h ich in creases at rioven t ricular con du ct ion .

ven t ricu lar (AV) n ode; h en ce th e term preexcitat ion. W PW

B Quin idin e blocks, n ot act ivates, α 1 receptors, th u s cau sing p eriph eral vasod ilat ion . C By causing vasodilat ion , quin idin e act ually decreases th e st im u lat ion of arterial baroreceptors. D, E Qu in id in e can block, n ot act ivate, bot h calciu m an d p otassium ch an n els.

d rom e in w h ich t h ere is an accessor y byp ass t ract (kn ow n

syn drom e can occu r in ch ildren an d ad u lts w ith ou t over t card iac d isease. Th e t r u e in cid en ce is u n kn ow n bu t var ies in di eren t report s from 0.1 to 3.0 per 1000 elect rocardiogram s. Abou t 20 to 30% of all supraven t ricular t achycardias are associated w it h W PW syn d rom e. A d irect cu r ren t card ioversion represen t s th e t reat m en t of ch oice for W PW syn d rom e (for long-term ablat ion of th e accessor y path w ay).

Learning objective: Describe the electrophysiological actions of quinidine. 8. C Blockade of act ivated sodiu m ch an n els is t h e dist in ct ive feat ure of class Ia an t iarrhyth m ic drugs. Th e slope of ph ase 0 of th e cardiac act ion poten t ial in n orm al at rial, Purkinje, an d ven t ricu lar cells is depen den t on sodium curren t . Th e h igh er th e n um ber of sodium ch an n els th at are in th e open state, th e higher the sodium current an d th e steeper th e slope of phase 0. By blocking activated sodium ch ann els (the num ber of ch an n els th at are blocked is dose-depen den t), th e sodium curren t w ill be less in ten se, an d th e slope of ph ase 0 decreases. A, B, D By blocking p otassiu m ch an n els, qu in idin e slow s dow n repolarizat ion . Th erefore, act ion p oten t ial du rat ion is in creased, th e slop e of p h ase 3 is decreased, an d th e e ect ive refractor y p eriod is in creased . E Th e slope of ph ase 4 is related to autom at icit y (th e steeper th e slope, th e h igh er th e au tom at icit y). Most an t iarrhyth m ic drugs d ecrease th e slop e of p h ase 4, u n less toxic doses are given .

Med ical t h erapy m u st be u sed cau t iou sly becau se it m ay u n expectedly in crease th e ven t ricular rate. Of th e drugs ap p roved by th e U.S. Food an d Drug Adm in ist rat ion , p rocain am ide, w h ich prolongs th e refractor y period of th e accessor y p ath w ays, in addit ion to blocking sodiu m ch an n els an d dep ressing p h ase 0, is con sidered by m any th e d rug of ch oice. A−C Digoxin, calcium channel blockers, and β-blockers m ay be dangerou s becau se th ey can block th e AV n ode an d m ay redirect im pulses dow n th e bypass t ract . E Nifed ip in e h as n o d irect act ion on t h e h ear t , an d t h e re ex tachycardia it in duces m ay w orsen th e arrhyth m ia.

Learning objective: Describe the electrophysiological actions of mexiletine. 11. B Th e t ypical act ion of m ost an t iarrhyth m ic drugs is th e decreased slope of p h ase 4 in p acem aker cells, w h ich m ean s a d ecrease in au tom at icit y. A, C Mexilet in e is a class Ib drug. Th ese agen t s can decrease act ion poten t ial du rat ion (an d th u s refractorin ess) in n orm al cardiac cells, bu t th ey in crease act ion poten t ial dura-

Learning objective: Describe the main adverse e ects of quinidine. 9. C Qu in idin e is rarely used today as an an t iarrhyth m ic dr ug becau se of its n u m erou s adverse e ects, bu t it is st ill occasion ally prescribed w h en oth er an t iarrhyth m ic drugs are eith er n ot tolerated or in e ect ive. More th an 100 drugs h ave been im plicated in cau sing th rom bocytop en ia, bu t qu in idin e an d h ep arin are th e t w o drugs th at h ave th e st rongest

t ion in abn orm al cells. D Phase 2 is due to m ovem ent of calcium across cardiac cell m em brane. Class Ib drugs do not a ect calcium m ovem ent. E Because an t iarrhyth m ic drugs ten d to decrease cardiac rate, t h e in ter val bet w een t w o act ion p oten t ials (i.e., t h e d iastolic in ter val) is in creased, n ot decreased.

252


Learning objective: Describe the main adverse e ects of lidocaine.

ch an n el blockers th at act on th e h ear t , e.g., verapam il an d

12. A Lidocain e is a drug of ch oice for ven t ricu lar arrhyth m ias

dilt iazem ) are drugs of ch oice in th is disease becau se th ey

associated w it h m yocard ial in farct ion , an d t h e p at ien t ’s

decrease cardiac con t ract ilit y an d in crease diastolic ven t ric-

t achycard ia w as m ost likely ven t ricu lar in n at u re, as at rio-

ular

ven t ricu lar dissociat ion w as n oted. Th e pat ien t’s sign s an d

in dicated in at rial

sym ptom s are t ypical cen t ral n er vou s system e ect s of a

t ricu lar rate (“rate con t rol”), even if th ey can n ot rein state

h igh dose of lidocain e.

n orm al sin us rhyth m (“rhyth m con t rol”). In th is case, th ey

B, C High doses of ph enytoin or sot alol do n ot cause th e p at tern of sign s an d sym ptom s exh ibited by th e pat ien t . D Mexilet in e is a lidocain e-like drug th at is on ly used orally to preven t recurren ce of ven t ricu lar tachycardia. E, F Verapam il an d digoxin are n ot used an d m ay even be con t rain dicated in ven t ricular t achycardia.

lling (by cau sing bradycardia). Beta-blockers are also brillat ion , as th ey can con t rol th e ven -

are useful for both con dit ion s. A−C All of th e listed drugs can be u sed, albeit rarely, in at rial

brillat ion , bu t in th is case, β-blockers are de n itely

preferred (see correct an sw er explan at ion ). E Nit rates are con t rain dicated in hypert roph ic cardiom yopathy because th ey reduce preload, w h ich is already low becau se of th e redu ced volu m e an d com p lian ce of th e left

Learning objective: Describe the molecular mechanism of action of procainam ide. 13. E Procain am id e is a class Ia an t iarrhyth m ic drugs. All drugs of th is class block act ivated sodiu m an d potassium ch an n els.

ven t ricle.

Learning objective: Describe the m ain adverse e ect s of am iodarone.

Am iodaron e an d lidocain e are drugs of ch oice for t reat m en t

16. C Th e p at ien t’s sign s an d sym ptom s in dicate a p u lm on ar y

of ven t r icu lar ar rhyt h m ias in t h e p er i-in farct ion p er iod .

d isord er. Microbial in fect ion is u n likely, an d di u se bilat -

Procain am id e is an alter n at ive agen t w h en t h e above-

eral lu n g in lt rates are con sisten t w it h p u lm on ar y brosis.

m en t ion ed drugs are eith er n ot tolerated or in e ect ive. Th e

Am iodaron e-in duced pulm on ar y brosis is th e m ost serious

drug blocks activated Na + channels, and recover y from block-

adverse e ect of th e drug. It s in ciden ce is variable (1 to 7%of

ad e is abou t 1.8 secon d s (t h e fastest of class Ia d r ugs), so

th e popu lat ion ), an d m or t alit y is also qu ite variable (0.1 to

it exert s greater e ect in depolarized an d/or rapidly driven

10.0% of th ose a ected). Am iodaron e toxicit y is cu m u lat ive

cardiac m yocytes.

an d is m ore com m on in eld erly p at ien t s, as in th is case.


A, B, D, E All of th e oth er listed drugs m ay be u sed for prophylaxis of sustained ventricular tachycardia, but they do not

Learning objective: Describe the uses of propranolol in hyperthyroidism. 14. D Th e pat ien t presen t s w ith classic sym ptom s of hyperthyroidism . W h en a tachyarrhyth m ia is associated w ith hyper-

cau se p u lm on ar y brosis.

Learning objective: Describe the lupoid syndrom e caused by procainam ide.

thyroidism , β-blockers rem ain th e drugs of ch oice, as m any

17. E Th e pat ien t’s sign s an d sym ptom s are con sisten t w ith

sym ptom s of th is d isease are associated w ith sym p ath et ic

d rug-in duced lu pu s (also called lu poid syn drom e), an au to-

act ivat ion .

im m u n e disorder th at is sim ilar to idiopath ic system ic lu pus

A−C, E All of th e oth er listed drugs can be used to t reat

er ythem atosus. The agents m ost com m only reported to cause

su p raven t r icu lar ar rhyt h m ias, bu t in t h is case, a β-blocker

th e disorder are p rocain am ide (abou t on e th ird of th e pa-

is preferred (see correct an sw er explan at ion ).

t ien t s taking th e drug over a 1-year p eriod) an d hydralazin e. Oth er drugs th at can cause drug-in duced lupus are ch lor-

Learning objective: Describe the use of β-blockers for atrial brillation associated with congenital hypertrophic cardiomyopathy. 15. D Th e p at ien t ’s h istor y, sym ptom s, an d sign s in d icate t h at h e w as m ost likely a ected by congen ital hypert roph ic card iom yopathy, a disorder usually in h erited in an autosom al d om in an t p at tern . Classic sym ptom s of th e disease are an gin a (a lim ited coron ar y blood

ow reser ve is p resen t in

hyp ert rop h ied states) an d diastolic h ear t failure (due to th e red u ced com p lian ce of t h e hyp er t rop h ied left ven t r icle). Bet a-blockers w ith ou t par t ial agon ist act ivit y (an d calcium

p rom azin e, ison iazid, m ethyld opa, qu in idin e, su lfon am id es, and penicillam ine. Onset of the drug-induced lupus syndrom e can occu r as soon as 1 m on th after th erapy begin s, as in th is case. Un like idiopath ic lu pu s, drug-in du ced lu p u s t ypically im proves rap idly after th e discon t in u at ion of th e drug. A Quinidine can cause lupus but is not used to treat Wol − Parkin son −W h ite syn drom e. B−D, F Th e risk of drug-in duced lupu s w ith th ese drugs is qu ite low.

Answers and Explanations: IV-5 Antiarrhythm ic Drugs 253 Learning objective: Choose the appropriate antiarrhythm ic drug for a patient with atrioventricular nodal tachycardia resistant to amiodarone.

toxicit y an d is n ot con t rain dicated in ven t ricular arrhyth -

18. F Th e pat ien t w as d iagn osed w ith a reen t ran t su praven t ric-

E Bet a-blockers such as propran olol m igh t be e ect ive in

u lar tachycardia. Th e t w o com m on t ypes of reen t ran t tachy-

treating tricyclic-induced arrhythm ias, but they are not drugs

cardias are

of ch oice because th ey can cau se bradycardia an d w orsen

• At r ioven t r icu lar n odal reen t ran t t achycard ia (AVNRT), w h ich is due to a fu n ct ion al division of th e at rioven t ricu lar (AV) n ode in to t w o p ath w ays w ith di eren t con du c-

D Ph enytoin is in dicated in arrhyth m ias due to digit alis m ias, alth ough its e

cacy rem ain s con t roversial.

t ricyclic-in du ced hypoten sion .

Learning objective: Describe the m ain adverse e ect s of sotalol.

t ion ch aracterist ics. On e is a fast con du ct ing p ath w ay, an d

20. D Th e elect rocardiograph ic h allm ark of polym orph ic ven -

th e oth er is a slow er con duct ing path w ay. Becau se th e

t ricu lar t achycardia is a long Q-T in ter val. Prolongat ion of

electrical signal travels th rough th e AV node, th e QRS com -

Q-T in ter val in dicates prolongat ion of act ion p oten t ial du ra-

plex of th is t achycardia is n arrow. Th e tachycardia is u su -

t ion , w h ich is related to a d ecreased ou t w ard p ot assiu m cu r-

ally respon sive to vagal m an euvers or aden osin e acu tely,

ren t during ph ase 3 of th e act ion poten t ial. Long Q-T in ter val

or to calcium channel blockers, β-blockers, or (historically)

is p resen t prior to th e on set of tachycardia an d is du e to h e-

digoxin ch ron ically.

redit ar y or acquired pot assium ch an n el defects. Hereditar y

• At rioven t ricu lar recip rocat ing t achycardia (AVRT) is du e

Q-T syn drom es are du e to rare m u tat ion s of th e gen es en -

to an ext ra, abn orm al elect rical con n ect ion in th e h eart

coding pot assium ch an n els. How ever, th e im por tan ce of th e

(often called an accessor y path w ay) th at join s on e of th e

d isorder in ever yday pract ice is related to its p rovocat ion by

at ria w ith on e of th e ven t ricles. Becau se th e elect rical sig-

d iseases or drugs th at p rolong Q-T in ter val. Diseases in clu de

n al t ravels th rough both th e AV n ode an d th e accessor y

hyp othyroidism , su barach n oid h em orrh age, m yocardit is, hy-

path w ay, th e QRS com plex of th is t achycardia is usu ally

p okalem ia, an d hypom agn esem ia. Drugs in clu de class Ia an d

w ide. In this form of tachycardia, adenosine, calcium chan-

III an t iarrhyth m ic drugs, t ricyclic an t idepressan t s, n eurolep -

nel blockers, β-blockers, an d digoxin are u su ally con t ra-

t ics, som e an t ih istam in es, m acrolide an t ibiot ics, an d qu in o-

in dicated becau se th ey decrease th e con du ct ion th rough

lon es. All of th ese drugs are able to in crease act ion poten t ial

th e AV n ode, facilitat ing th e con duct ion th rough th e ac-

d urat ion by blocking or m odifying p ot assiu m ch an n els. High

cessor y path w ay.

d oses of th ese drugs can t rigger polym orph ic ven t ricu lar

Th e elect rocardiogram of th e pat ien t in dicates th at sh e w as m ost likely su ering from an AVRT. Drugs th at prim arily decrease conduction across the accessor y pathw ay include som e class I drugs (procainam ide, propafenone, and ecainide) and class III drugs (am iodaron e an d sot alol), an d th ey are u sed un t il th e accessor y path w ay can be rem oved by ablat ion . It is com m on to ch ange drug class w h en th e rst drug w as n ot e ect ive, as in th is case. A−C Lidocain e, m exilet in e, an d ph enytoin are m in im ally e ect ive in su p raven t ricu lar arrhyth m ias. D, E Nifedipin e an d n it roglycerin are act ually con t rain dicated in AVRT (see correct an sw er exp lan at ion ).

t achycard ia in p at ien t s at risk. Sotalol is th e on ly β-blocker th at can block p ot assiu m ch an n els (a p ropert y n ot related to β-receptor blockade), an d it can cau se polym orph ic ven t ricu lar tachycardia. Moreover, th e pat ien t w as t aking a quin olon e an d so w as already at risk of develop ing th e disorder. A−C, E, F See correct an sw er explan at ion .

Learning objective: Describe the use of ibutilide in pharm acological cardioversion. 21. E Ibu t ilide, a class III an t iarrhyth m ic drug w ith p ot assiu m ch an n el−blockin g an d sod iu m ch an n el−en h an cin g e ect s, w as the rst drug approved by the U.S. Food and Drug Adm in ist rat ion for th e term in at ion of at rial

Learning objective: Identify the m ain contraindications of quinidine. 19. C Class Ia an d Ic an t iarrhyth m ic drugs are absolu tely con t rain dicated in case of poison ing w ith t ricyclic an t idepressan t s as they share cardiotoxic and anticholinergic side e ects w ith th ese drugs. Moreover, an t iarrhyth m ic drugs th at in crease act ion p oten t ial du rat ion are gen erally con t rain dicated in p at ien ts w ith w iden ed QRS com plexes. A, B Mexilet in e an d lidocain e are in dicated, n ot con t rain dicated, for t reat m en t of ven t ricular arrhyth m ias.

u t ter or

brillat ion .

Th e conversion rate w ith th is dr ug is low er th an th e conversion rate w ith d irect cu rren t bu t is gen erally at tem pted rst , as elect rical cardioversion requ ires gen eral an esth esia. Oth er drugs that have been used for pharm acological cardioversion are qu in idin e, p rocain am id e, an d

ecain ide, bu t th ey are

u su ally less e ect ive th an ibut ilide w ith m ore frequen t adverse e ects. A−D Non e of th ese drugs are used for ph arm acological cardioversion .

254


Learning objective: Describe the main adverse e ects of verapamil.

agen t of choice for the acute conversion of paroxysm al supra-

22. E W it h in creasing p rescr ipt ion u sage, p oison ing w it h cal-

ven t ricular t achycardia. Vagoton ic m an euvers (carot id sin us

ciu m ch an n el blockers h as in creased dram at ically. Clin ical

m assage, Valsalva m an euver, etc.), p ar t icu larly if u sed early,

m an ifest at ion s of verap am il overdosage in clu de decreased

m ay term in ate th e arrhyth m ia. If th ese m an euvers are in ef-

con sciousn ess, hypoten sion , an d various bradyarrhyth m ias

fect ive, aden osin e is u sed. Blocking con duct ion th rough th e

(bradycardia, at rioven t ricular block, asystole).

AV n ode for on e beat in terru pt s th e reen t ran t cycle. On th e

A Ipratropium is given only by th e in halation route. Moreover, system ic absorpt ion of th e drug is m in im al. B Ad en osin e is used for th e acute t reat m en t of paroxysm al ven t ricu lar tachycardia but is n ot a dr ug for ch ron ic t reat-

oth er h an d, aden osin e is con t rain dicated in w ide com plex su praven t ricu lar t achycardias becau se it can in crease con du ct ion th rough th e accessor y path w ay. A−D See correct an sw er explan at ion .

m en t . Moreover, it is given by th e in t raven ou s rou te, so p oiC Propran olol is used to t reat sup raven t ricular arrhyth -

Learning objective: Choose the appropriate drug for a patient with sinus bradycardia.

m ias bu t is con t rain dicated in th is case becau se of ch ron ic

25. E Sin us bradycardia com plicat ing a m yocardial in farct ion is

son ing by th is drug is u n likely in th is case.

obst ruct ive pulm on ar y disease. D Mexilet in e is n ot u sed to t reat su p raven t r icu lar arrhyth m ias.

m ost likely du e to in creased vagal act ivit y. In th is case, at rop in e is th e drug of ch oice. A−D All of th e oth er listed drugs can in crease th e h eart rate, but th ey are physiological an tagon ists of acet ylch olin e.

Learning objective: Choose the appropriate antiarrhythm ic drug for a patient with concomitant diseases. 23. C Th e

A ph arm acological an t agon ist is bet ter th an a physiological an tagon ist in m ost cases.

rst t reat m en t goal in at rial brillat ion is to slow th e

em pt y m ore e ect ively. Digoxin , β-blockers, an d calciu m

Learning objective: Describe the m ain adverse e ect s of am iodarone.

ch an n el blockers all can be u sed e ect ively becau se t h ey

26. F Th e p at ien t’s sign s an d sym ptom s are con sisten t w ith hy-

can cau se an in com plete at rioven t ricular block, th u s allow -

p othyroidism . Am iodaron e can cause eith er hyp erthyroid-

ing few er at rial im pulses to pass in to th e ven t ricle. How ever,

ism or hyp othyroidism , alth ough hyp othyroidism is m ore

in th is pat ien t

com m on . Th ese com plicat ion s are a con sequ en ce of th e h igh

ven t ricu lar rate, th us allow ing th e ven t ricles to con t ract an d

A Digoxin is con t rain dicated because of hyperparathyroid-

iodin e con ten t in am iodaron e. W h en am iodaron e is m et ab -

ism , because hypercalcem ia st rongly in creases digit alis sen -

olized in t h e liver, iod in e m olecu les are released an d can

sit ivit y. Prim ar y hyperp arathyroidism is th e m ost com m on

exer t ph arm acological e ect s.

cau se of hypercalcem ia; its in ciden ce is h igh er in post m en op au sal w om en . B Non select ive β-blockers are con t rain dicated becau se of p erip h eral occlusive ar teriosclerosis. D, E Class Ib an t iarrhyth m ic drugs are n ot e ect ive in su -

A−C, E All of th ese drugs m ay be used for su stain ed ven t ricu lar t achycardia p rophylaxis, bu t th ey do n ot cau se thyroid disorders. D Lidocain e is n ot used for sust ain ed ven t ricular tachycard ia prophylaxis.

p raven t ricular arrhyth m ias. F Aden osin e is on ly used for th e acu te t reat m en t of supraven t ricu lar arrhyth m ias.

Learning objective: Identify the electrophysiological propert y common to β-blockers, Ca 2+ channel blockers, and digoxin. 27. A Th e rst t reat m en t goal in at rial brillat ion is to slow th e

Learning objective: Explain the m olecular m echanism of action of adenosine.


24. E Aden osin e act ivates speci c A1 aden osin e receptors in th e

ch an n el blockers can all be u sed e ect ively becau se t h ey

h ear t , w h ich in t u rn open acet ylch olin e-sen sit ive K+ ch an -

can cau se an in com plete at rioven t ricular block, th u s allow -

n els, th at is, ch an n els n orm ally driven by parasym path et ic

ing few er at rial im pu lses to p ass in to th e ven t ricle.

act ivit y. Th is lead s to hyp er p olar izat ion of t h e sin oat r ial an d at rioven t ricu lar (AV) n odes. Aden osin e is con sidered th e

em pt y m ore e ect ively. Digoxin , β-blockers, an d calciu m


Answers and Explanations: IV-5 Antiarrhythm ic Drugs 255 Learning objective: Choose the appropriate antiarrhythm ic drug for a patient with a concomitant disease.

Learning objective: Describe the use of ecainide to treat certain forms of ventricular tachycardia

28. B Th e rst t reat m en t goal in at rial brillat ion is to slow th e

31. D Idiopath ic left ven t ricular t achycardia is a ven t ricular ar-


rhyth m ia th at u su ally presen t s in pat ien ts bet w een 15 an d

em pt y m ore e ect ively. Calciu m ch an n el blockers su ch as

40 years of age w ith st ru ct u rally n orm al h ear ts. Th e arrhyth -

verapam il w ith cardiac act ivit y can decrease cardiac rate by

m ia resp on d s w ell to class Ic an t iar rhyt h m ic d r ugs an d to

cau sing an in com p lete at rioven t ricu lar block, so th at few er

verap am il for acu te ter m in at ion , as w ell as for lon g-ter m

at rial im pu lses can pass in to th e ven t ricle.

con t rol.

A Am iodaron e is used to m ain t ain rhyth m con t rol in at rial

A, E Th ese drugs are given in t raven ou sly an d h ave a sh ort

brillat ion bu t is con t rain d icated in th is case becau se of th e

h alf-life. Th ey can n ot be used for th e ch ron ic con t rol of ven -

ch ron ic obst ruct ive pulm on ar y disease. C Nifedipin e is useless in th is case becau se it h as n o an t iarrhyth m ic act ivit y.

t ricu lar t achycardia. B, C Th ese d r ugs are u seless in id iop at h ic ven t r icu lar t achycardia.

D, E Class Ib an t iarrhyth m ic drugs such as lidocain e an d F Beta-blockers such as sot alol can be u sed e ect ively in

Learning objective: Describe the use of lidocaine in the acute treatment of ventricular arrhythmias.

at rial brillat ion bu t are con t rain dicated in th is case becau se

32. E Making t h e d ist in ct ion bet w een su p raven t r icu lar t achy-

m exilet ine are not e ective in supraventricular arrhythm ias.

of th e ch ron ic obst ruct ive pulm on ar y disease.

card ia an d ven t r icu lar t achycard ia (VT) is im p or t an t becau se th is dist in ct ion in u en ces subsequ en t m an agem en t .

Learning objective: Outline the use of am iodarone in a patient with concomitant disease.

Th e h allm ark of VT is at rioven t ricu lar dissociat ion , as in th is

29. C Am iodaron e is con sidered a secon d-ch oice dr ug in any

sh ip to th e at ria, u n less ret rograd e at rial con d u ct ion occu rs.

in stan ce of at rial brillat ion , bu t it m ay be a rst-ch oice drug

Su st ain ed VT is a m edical em ergen cy becau se it can develop

in pat ien t s w ith con com itan t hyper ten sion an d left ven t ric-

in to ven t ricular brillat ion if u n t reated . Lid ocain e an d am io-

u lar dysfu n ct ion . It is th erefore an appropriate dr ug to be

daron e are rst-lin e agen t s in th is set t ing. Procain am ide is a

t ried in th is case, Moreover, in th is p at ien t

backu p drug for VT.

A Verapam il w as n ot e ect ive, so it seem s unw ise to t r y

case. Th e im p u lse arises from th e ven t ricle w ith ou t relat ion -

A Ph enytoin is m ain ly e ect ive in VT resu lt in g from

an ot h er d r ug (d ilt iazem ) w it h t h e sam e m ech an ism of

d igit alis excess. It s e

act ion .

qu est ion able.

B, D Mexilet in e an d lidocain e are n ot e ect ive in sup raven t ricu lar arrhyth m ias. E Becau se sot alol w as on ly p ar t ially e ect ive, it is n ot ap p ropriate to t r y an oth er β-blocker.

cacy in VT d u e to ot h er cau ses is

B, C Calciu m ch an n el blockers su ch as verapam il an d quin idin e are usually n ot e ect ive in VT. D Mexilet in e is a lidocain e-like drug th at is used to preven t recu rren ce of VT. How ever, it is given orally an d is n ot a d rug for an em ergen cy t reat m en t .

Learning objective: Describe the use of adenosine for the acute treatment of supraventricular arrhythmias. 30. C Th e elect rocardiogram record an d th e th erap eu t ic m an eu -

Learning objective: Describe the use of ecainide for the chronic control of supraventricular arrhythm ias.

vers st rongly suggest th at th e pat ien t is su ering from par-

33. B Dr ugs u sed to m ain t ain sin u s rhyt h m after card ioversion

oxysm al su p raven t ricu lar tachycardia. Aden osin e is th e drug

in clu d e class Ia, Ic, an d III an t iar rhyt h m ics, bu t in a p a-

of ch oice for th e acu te conversion of paroxysm al su praven -

t ien t w it h n o st r u ct u ral h ear t d isease, ecain id e is u su ally

t ricu lar t achycardia. Th e d rug act ivates A1 aden osin e recep -

p refer red .

tors, w h ich in t urn open acet ylch olin e-sensit ive K+ ch an n els.

A Am iodaron e could be u sed in th e presen t case but it

Th is leads to hyperpolarizat ion of sin oat rial (SA) an d at rio-

blocks th e in act ivated Na + ch an n els on ly an d st rongly in -

ven t ricular (AV) n odes, th us decreasing SA n ode rhyth m an d

creases th e act ion p oten t ial du rat ion .

AV con du ct ion . A, B, D Class Ib d r ugs h ave n o e ect on m ost su p raven t r icu lar arrhyth m ias. E, F Class IV drugs w ith cardiac act ivit y m ay be at tem pted to slow con duct ion in th e AV n ode, but aden osine is t ried rst in m ost cases.

C−E Th ese dr ugs are n ot u sed for rhyth m con t rol of at rial ut ter an d brillat ion after cardioversion .

256


Learning objective: Describe the antiarrhythm ic use of m agnesium sulfate.

Learning objective: Choose the appropriate antiarrhythm ic drug for a patient with concomitant diseases.

34. E Th e pat ien t’s h istor y an d sym ptom s suggest th at h e w as

37. G Th e elect rocardiogram is diagn ost ic for at rial

brillat ion

m ost likely su ering from an adverse e ect of qu in idin e, a

(absen ce of P w aves an d th e “irregularly irregular” ven t ricu-

d rug cu rren tly u sed to cut h eroin an d cocain e. Th e elect ro-

lar rate).Th e aim of th erapy of at rial brillat ion is to reduce

card iogram in d icated t h at t h e p at ien t ’s ar rhyt h m ia w as

th e h igh ven t ricu lar rate to avoid th e risks related to t achy-

torsades de poin tes (TdP). TdP occurs in conjun ct ion w ith

cardia. Th is can be ach ieved by

a long Q-T in ter val th at w as p resen t p rior to th e on set of

• Givin g d r ugs t h at dep ress con d u ct ion an d in crease re-

t achycard ia. A vast array of drugs can cau se TdP, especially

fractorin ess in th e at rioven t ricu lar n ode, so th at few er

w h en given at h igh doses. An except ion is quin idin e, because

im pu lses can reach th e ven t ricle (called “rate con t rol”)

it can cause th e disorder even at th erapeu t ic plasm a con cen -

• Restor ing t h e n or m al sin u s rhyt h m (called “rhyt h m

t rat ion s. Magn esiu m is con sidered a

rst-lin e agen t to re-

store an d m ain t ain n orm al sin u s rhyth m in TdP. A load ing d ose is u su ally given in t raven ou sly (IV) follow ed by IV in fu sion . Th e exact m ech an ism of act ion of m agn esiu m is u n kn ow n . A−D All of th ese drugs are in fact con t rain dicated, as th ey can t rigger TdP in pat ien ts at risk. F, G Verap am il an d lid ocain e are n ot e ect ive in TdP.

Learning objective: Describe the electrophysiological actions of amiodarone. 35. C Th e in crease in act ion p oten t ial du rat ion is th e h allm ark of class III drugs. Th is in crease prim arily result s from blockade of potassium ch an n els. A Th e slope of ph ase 4 is act ually decreased by m ost an t iarrhyth m ic drugs. B Slope of ph ase 0 is u n a ected by am iodaron e because it blocks th e in act ivated potassiu m ch an n el on ly. D Th e length of ph ase 2 depen ds on calcium ch an n els. Am iodaron e h as lit tle e ect on calcium ch an n els un less h igh d oses are given . E A con dit ion th at in creases (i.e., m akes less n egat ive) th e m axim u m diastolic p oten t ial w ou ld in crease th e au tom at icit y of pacem aker cells; am iodaron e does th e reverse.

Learning objective: Describe the main drug−drug interactions with of am iodarone. 36. C Am iodaron e is a poten t in h ibitor of th e cytoch rom e P-450 en zym e system . Tw o of t h e m ost sign i can t in teract ion s associated w ith am iodaron e are w ith w arfarin an d d igoxin . Th e t im e cou rse of t h ese in teract ion s is p rolon ged d u e to t h e long h alf-life of am iodaron e. Usu ally dosages of w arfarin are redu ced by 30 to 50% after am iodaron e is in st it u ted. Am iodaron e can in crease d igoxin ser u m levels, w it h m ost st u dies rep or t ing an ap proxim ate dou bling of th ese levels. Th e exact m ech an ism of th is in teract ion is u n kn ow n an d is p robably m u lt ifactorial. A, B, D See correct an sw er exp lan at ion . E Warfarin sh ould be con t in ued for at least 3 w eeks after ret urn to sin us rhyth m .

con t rol”) Usually th e con t rol of ven t ricular rate is in st it uted

rst , as

th is con t rol m ay cause a dram at ic dim in u t ion of th e pat ien t’s sym ptom s. Ap prop riate drugs are digoxin , β-blockers, and calcium channel blockers. The choice am ong these agents dep en ds on th e con com it an t disease. Restorat ion of th e sin u s rhyth m can be at tem pted w ith • Electrical cardioversion, w h ich is accom plished w ith a single st rong elect ric sh ock th at th row s th e en t ire h ear t in to refractorin ess for a few secon ds; a n orm al sin u s rhyth m u su ally follow s. • Pharm acological cardioversion, w h ich can be accom plished w ith m any an t iarrhyth m ic drugs, in cluding

ecain ide,

β-blockers, sot alol, an d am iodaron e Today ibu t ilide seem s th e th erapy of ch oice. Both elect rical an d p h arm acological cardioversion can be com plicated by system ic em bolism . Th erefore, th erapeu t ic an t icoagu lat ion sh ou ld be given for at least 3 w eeks p r ior to card ioversion an d con t in u ed for 4 w eeks after card ioversion . It is im port an t to n ote th at restorat ion to n orm al sin us rhyth m can be ach ieved easily (in over 90% of pat ien t s after cardioversion ) bu t is di cu lt to m ain tain (sin u s rhyth m rem ain s for 12 m on th s in on ly 30 to 50%), an d u sing rhyth m con t rol rath er th an rate con t rol in pat ien t s w ith at rial brillat ion does n ot im prove ou tcom es an d in creases th e risk of torsad es d e p oin tes. Th is exp lain s w hy m any p at ien t s can sim ply be m an aged w ith rate con t rol, as in th is case. Th e ch oice of a calcium ch an n el blocker for th is pat ien t is approp riate becau se A, E Beta-blockers are contraindicated because the patient is su ering from severe asth m a. B Flecain ide can be used for rate con t rol in pat ien ts w ith at rial

brillat ion , bu t it can provoke or exacerbate p oten -

t ially leth al arrhyth m ias p rim arily w h en th e pat ien t h as coron ar y arter y disease, as in th is case. C, D Mexilet in e an d lidocain e are usually n ot e ect ive in su p raven t ricu lar arrhyth m ias. F Aden osin e h as a ver y sh or t h alf-life an d is used to o set at tacks of p aroxysm al su praven t ricular t achycardia.

Answers and Explanations: IV-6 Antihyperlipidem ic Drugs 257 Learning objective: Identify the antiarrhythm ic drug with a halflife of about 1 m onth.

izat ion ; th erefore, act ion p oten t ial du rat ion is in creased, n ot

38. D Am iodaron e is th e t reat m en t of ch oice w h en an t iarrhyth -

decreased.

A By blocking K+ ch an n els, ibu t ilide slow s d ow n rep olar-

m ic th erapy is ch osen to preven t recu rren ce of ven t ricu lar

B Ibu t ilide h as lit tle e ect on Na + ch an n els (if anyth ing, it

t achycard ia or w h en th e t achycardia is accom pan ied by h e-

seem s to act ivate som e Na + ch an n els); th erefore, th e slope of

m odyn am ic in stabilit y, as in th is case. Am iodaron e’s h alf-life

ph ase 0, w h ich depen ds on th e act ivat ion of th ose ch an n els,

is ext rem ely long (14 to 53 days) because th e drug is ver y

is n ot decreased.

lipid soluble an d th erefore h as a h uge volu m e of dist ribu t ion (about 4500 L). This very long half-life has t wo consequences: • Adverse e ects p ersist long (4 to 6 w eeks) after th e discon t in uat ion of th e drug. • Loading doses are u sed to accelerate th e on set of d rug e ect .

D Th e e ect ive refractor y period depen ds on th e act ion poten t ial du rat ion ; it is th erefore in creased, n ot decreased . E Th e slop e of p h ase 4 is related to au tom at icit y (t h e steeper th e slop e, th e h igh er th e au tom at icit y). Most an t iarrhyth m ic drugs decrease th e slope of ph ase 4, u n less toxic doses are given .

A−C, E, F Th e h alf-life of th ese drugs does n ot exceed 24 h ours.

ANTIARRHYTHMIC DRUGS Answ er key

Learning objective: Describe the electrophysiological actions of ibutilide. 39. C Blockade of act ivated K+ ch an n els is th e dist in ct ive feat ure of class III an t iarrhyth m ic drugs. Th e slope of ph ase 3 of th e cardiac act ion p oten t ial is m ain ly dep en d en t on K+ curren t . Th e h igh er th e n u m ber of K+ ch an n els th at are in th e op en state, th e h igh er th e K+ cu rren t an d th e faster th e repolariza-

1. 2. 3. 4. 5.

K A B B N

6. 7. 8. 9. 10.

M A C C D

11. 12. 13. 14. 15.

B A E D D

16. 17. 18. 19. 20.

C E F C D

21. 22. 23. 24. 25.

E E C E E

26. 27. 28. 29. 30.

F A B C C

31. 32. 33. 34. 35.

D E B E C

36. 37. 38. 39.

C G D C

t ion p h ase. By blocking K+ ch an n els, th e K+ curren t w ill be less in ten se, an d th e repolarizat ion p h ase w ill be p rolonged , in creasing th e act ion poten t ial durat ion .

Answers and Explanations: IV-6 Antihyperlipidemic Drugs Questions 1−4

D Th e LDLs rem oved from th e blood fuse togeth er in th e

1. A

liver, form ing larger vesicles called en dosom es. Becau se re-

2. D

m oval of ch olesterol from blood is in creased by st at in s, stor-

3. A

age of LDL in h epat ic en dosom es w ill also be in creased, n ot

4. C

decreased. E, F St at in s can in crease th e plasm a levels of h epat ic am in o-

Learning objective: Describe the m echanism of action of HMG-CoA (3-hydroxy-3-methylglutaryl−coenzyme A) reductase inhibitors. 5. C HMG-CoA redu ct ase in h ibitors in h ibit 3-hyd roxy-3-m eth ylglu tar yl−CoA redu ct ase, w h ich is th e en zym e th at cat alyzes

t ran sferase an d creat in e p h osp h okin ase, bu t th is is a sign of poten t ial toxicit y, n ot of th erapeu t ic e

cacy of th ese drugs.

Learning objective: Describe the antihyperlipidem ic e ect s of cholest yramine.

th e syn th esis of m evalon ic acid from 3-hydroxy-3-m ethylglu -

6. C Typ e II hyp erlip op rotein em ia is ch aracterized by an eleva-

taryl−CoA. The form ation of m evalonic acid is the rate-lim iting

t ion of low -den sit y lip op rotein (LDL), w h ich m ay be prim ar y

step in ch olesterol biosyn th esis.

or secon dar y. St at in s are cu rren tly used in th is disease, but

A Th e stat in -in duced in h ibit ion of ch olesterol syn th esis in

th e physician avoided th em in th is case becau se th e pat ien t is

th e liver result s in an upregu lat ion , n ot dow n regulat ion , of

a w om an of reproduct ive age. Bile acid−bin ding resin s in -

h epat ic h igh -a

n it y low -den sit y lipoprotein (LDL) receptors,

crease th e in test in al elim in at ion of bile acids. Th is in creased

w h ich in t urn causes an in creased rem oval of LDL from th e

elim in at ion cau ses an u p regu lat ion of h ep at ic LDL receptors,

blood.

w h ich in t urn reduces th e plasm a level of LDL.

B St at in s h ave n o e ect on lipop rotein lipase.

A, B, D, E Th ese com p ou n d s are n ot con sisten tly a ected by bile acid−bin ding resin s.

258


Learning objective: Describe the m ain drug interactions with cholest yramine.

Learning objective: Describe the m ain drug interactions with ezetim ibe.

7. D Ch olest yram in e is an an ion exch ange resin th at bin ds bile

11. B Ezet im ibe low ers t h e ser u m ch olesterol con cen t rat ion

acids in th e in test in al lu m en , th u s preven t ing th eir reab -

by select ively in h ibit ing t h e absor pt ion of ch olesterol from

sorpt ion . In fact , th e excret ion of bile acid is in creased u p to

t h e sm all in test in e. It h as a m od est ch olesterol-low er in g

10-fold w h en th e resin is given . Th is in t u rn cau ses an en -

e ect w h en u sed alon e, bu t t h e com bin at ion w it h HMG

h an ced conversion of ch olesterol to bile acids in th e liver, an

(3-hyd roxy-3-m et hylglu t ar yl) red u ct ase in h ibitors can re-

in creased u ptake of low -den sit y lipoprotein (LDL) an d in ter-

d u ce low -d en sit y lip op rotein (LDL) ch olesterol levels u p to

m ediate-den sit y lipoprotein from p lasm a, an d an u p regu la-

70%.

t ion of h igh -a

n it y LDL receptors on cell m em bran es. Resin s

A Th e risk of st at in -in du ced m yopathy is n ot a ected by

can bin d m any drugs (in clu d ing β-blockers an d th iazides),

t h e con com it an t ad m in ist rat ion of ezet im ibe (t h e r isk is,

reducing th eir in test in al absorpt ion .

in stead, in creased by th e con com itan t adm in ist rat ion of -

A, B, E, F Ch olest yram in e does n ot a ect th e d ist ribu t ion or th e elim in at ion of drugs given con com itan tly. C Intestin al absorption of propranolol is act ually decreased; therefore, the oral bioavailabilit y is decreased, not increased.

brates or n iacin ). C, D Ezet im ibe d oes n ot a ect t h e p h ar m acokin et ics of lovastat in . E Ezetim ibe does not appreciably increase the high-densit y lipop rotein (HDL)−raising e ect of lovast at in .

Learning objective: Describe the m ain contraindications of cholest yram ine.

Learning objective: Explain the m echanism of action of niacin.

8. B Ch olest yram in e can cau se severe con st ip at ion an d is

12. A Niacin in h ibit s ver y-low -den sit y lipoprotein (VLDL) pro-

t h erefore con t rain d icated in p at ien t s w it h h em or rh oid s. In

d uct ion by h epatocytes, w h ich in t urn decreases produ ct ion

ad d it ion , t h e d r ug is con t rain d icated in p at ien t s w it h any

of low -d en sit y lip op rotein (LDL). Th e m ech an ism of t h is

coagu lat ion defect becau se it decreases th e in test in al ab -

act ion is st ill u n cer t ain bu t seem s to involve

sorpt ion of vitam in K.

• A decreased syn th esis of t riglycerides by th e liver


• An in h ibit ion of lip olysis in ad ipose t issu e, w h ich in t u rn cau ses a decreased deliver y of free fat t y acids to th e liver

Learning objective: Explain the m echanism of action of gem brozil. 9. D Th e prescribed drug w as m ost likely a

brate. In fact , -

• A stim ulation of lipoprotein lipase activit y, w hich enh ances hydrolysis of VLDL an d deliver y of t riglycerides to adip ose t issu e

brates are th e drugs of rst ch oice w h en th ere is a big, iso-

B Niacin act u ally in creases th e syn th esis of h igh -den sit y

lated in crease in t riglyceride level. Moreover, in th is pat ien t ,

lip op rotein (HDL) by th e liver. It also can cau se hyp eru rice-

n iacin is con t rain dicated becau se of hyperuricem ia, resin s

m ia in about 20% of pat ien t s by an un kn ow n m ech an ism .

can cau se an in crease in t riglycerid e level, an d st at in s sh ou ld

C Niacin cau ses a su bst an t ial red u ct ion of

br in ogen

be avoided in a w om an of rep rodu ct ive age. Th e m ech an ism

levels, w h ich can be of value in case of ath erosclerosis or

of act ion of brates is st ill un cert ain but m ost likely involves

th rom bosis.

a gen e- m ed iated in crease in lip op rotein lipase syn th esis. A Fibrates cau se lip olysis, n ot an in crease of lip id syn th esis.

D Niacin act ually in h ibits lipolysis of t riglycerides by h orm on e-sen sit ive lip ase in adipose t issu e. E Niacin h as n egligible e ects on exogen ous ch olesterol

B Th e an t ihyp erlipidem ic agen ts ten d to cause an u pregu la-

absorpt ion .

t ion , n ot a dow n regu lat ion , of low -den sit y lip op rotein (LDL) receptors. C St at in s, n ot

brates, in h ibit HMG- CoA (3-hydroxy-3-

m ethylglutar yl−coen zym e A) redu ct ase act ivit y in th e liver. E Fibrates h ave n o e ect on absor pt ion of exogen ou s ch olesterol.

Learning objective: Explain the mechanism of action of ezetimibe. 10. E Ezet im ibe in h ibit s th e absorpt ion of ch olesterol by th e

Learning objective: Describe the site of action of HMG-CoA (3-hydroxy-3-m ethylglutaryl−coenzym e A) reductase inhibitors. 13. C HMG- CoA redu ct ase is located in t h e liver en d op lasm ic ret iculum , so all HMG- CoA reduct ase in h ibitors such as lovast at in act in th e cytop lasm ic com p ar t m en t of liver cells, w h ere th e en doplasm ic ret iculum is located A, D Alteplase an d h ep arin act on p lasm a en zym es. B Aspirin in h ibits th rom boxan e syn th esis in platelet s.

sm all in testine, apparently by blocking a speci c sterol trans-

E Ezetim ibe acts on intestinal cell brush border m em branes.

p or ter, Niem an n −Pick C1−like 1 (NPC1L1), located in t h e

F Metoprolol acts on receptors located in cell m em bran es.

ep ith elial cells of in test in al m u cosa. A−D See correct an sw er explan at ion .

Answers and Explanations: IV-6 Antihyperlipidem ic Drugs 259 Learning objective: Describe the main contraindications of niacin.

Learning objective: Describe the site of action of gem brozil.

14. B Niacin is relat ively con t rain dicated in pat ien t s su ering

17. B Fibrates bind to and activate a nuclear receptor (the peroxi-

from gou t an d hyp eru ricem ia becau se it ten ds to in crease

som e p roliferator-act ivated receptor alph a) in h ep atocytes,

u ric acid levels.

skelet al m u scle, an d th e h ear t . Act ivat ion of th is receptor in

A Ch olest yram in e could be appropriate in th is pat ien t be-

t u rn act ivates t ran script ion of gen es th at m odu late p rotein

cau se h e h as an isolated in crease of low -d en sit y lip op rotein

expression . Th e m ain con sequen ce is th e in creased expres-

(LDL).

sion of lipoprotein lip ase.

C, D St at in s are e ect ive in all disorders involving elevated


levels of LDL. E Fibrates are u seless (red u ct ion of LDL is u su ally n egligible) bu t n ot con t rain dicated in th is pat ien t .

Learning objective: Describe the adverse e ect s of HMG-CoA (3-hydroxy-3-m ethylglutaryl−coenzym e A) reductase inhibitors. 18. E Th e pat ien t w as m ost likely a ected by m yopathy, a rare

Learning objective: Describe the clinically relevant drug interactions with niacin.

bu t seriou s adverse e ect of st at in s. Th e disord er occu rs in

15. C Th e cu t an eou s vasodilat ion an d u n com fort able u sh es are

it can occur m ore often w h en th ey are given togeth er w ith

less t h an 0.1% of p at ien t s w h en st at in s are given alon e, bu t

adverse e ect s th at m ost p eople exp erien ce after each dose

n iacin or

of niacin. They seem to be prim arily prostaglandin-m ediated,

Myop athy can cau se rh abdom yolysis w ith m yoglobin u ria, as

and therefore an aspirin (or another nonsteroidal antiin am -

in th is case.

m atory drug) can alleviate the ushing in m any patients. Be-

brates (up to 5% w h en given w ith gem brozil).

A−D Th ese drugs do n ot cau se m yopathy.

cause these e ects undergo rapid tolerance, aspirin is n eeded A Th ere is n o rat ion ale for th e use of w arfarin . In fact , n ia-

Learning objective: Describe the antihyperlipidem ic e ect s of niacin.

cin can cau se a su bstan t ial redu ct ion of circu lat ing brin o-

19. D Low h igh -den sit y lip op rotein (HDL) level is a predictor of

on ly during th e rst days of th erapy.

gen levels, w h ich act u ally redu ces th e risk of th rom bosis.

in creased coron ar y ar ter y disease (CAD), in depen den t of all

B Th ere is n o rat ion ale for th e use of at ropin e. Moreover,

oth er risk factors. Th erefore, it is im port an t to raise HDL,

t h e d r ug w ou ld w orsen t h e ch olest yram in e-in d u ced con -

even if th e oth er lipid fract ion s are n orm al, especially if th e

st ip at ion .

p at ien t h as oth er risk factors for CAD, as in th is case. Th e

D Prazosin would increase the niacin-induced vasodilation.

m ain factors th at are correlated w ith low HDL are cigaret te

E Gem brozil is used on ly in case of hyper t riglyceridem ia.

sm oking, obesit y, an drogen ic or related steroid s, hyper t ri-

In th is pat ien t , t riglyceride levels are n orm al.

glyceridem ia, an d gen et ic factors. Som e lip id-low ering drugs can raise HDL even if oth er lipid param eters are in th e n or-

Learning objective: Describe the adverse e ects of cholestyramine.

m al range, as in th is case. Niacin (by an un kn ow n m ech a-

16. E Th e sign s an d sym ptom s of th e p at ien t in d icate th at h e is

n ism ) h as th e greatest abilit y to raise HDL, up to 30%, an d is

su ering from m etabolic acidosis m ost likely du e to ch ole-

th erefore th e drug of ch oice in disorders associated w ith ex-

st yram in e overd ose. A ver y h igh d ose of ch olest yram in e

t rem ely low seru m levels of HDL (th ese p at ien ts ten d to h ave

can cau se m et abolic acidosis m ain ly in pat ien t s at risk, as in

p rem at u re ath erosclerosis, an d th e low HDL level m ay be th e

th is p at ien t , w h o is p ron e to m etabolic acidosis becau se of

on ly iden t i ed risk factor). A Gem brozil can raise HDL up to 10%.

d iabetes. Ch olest yram in e is an an ion exch ange resin th at bin ds n egat ively ch arged bile acids. Ch loride is released from bin ding

B St at in s can raise HDL up to 10% C, E Resin s an d ezet im ibe h ave lit tle e ect on HDL.

sites in exch ange for bile acid s, so ch loride an ion s can be ab in plasm a, HCO3− m u st decrease in order to m ain tain elec-

Learning objective: Describe the m ain site of action of cholest yram ine.

t ron eut ralit y. A reduced plasm a bicarbon ate con cen t rat ion

20. B Ch olest yram in e is an acid-bin ding resin . Th ese drugs act

is de n ed as acidosis. Becau se in th is case th e acid osis is du e

by bin ding bile acids an d sim ilar steroids in th e sm all in tes-

to an in crease in ch loride an ion , it is called hyperch lorem ic.

t in e, th u s preven t ing reabsorpt ion of bile acids secreted by

B In sulin protect s diabet ic p at ien t s from ketoacid osis, so

th e liver. In th is w ay, th ey in crease th e n eed of ch olesterol

sorbed. W h en an an ion oth er th an bicarbon ate is in creased

in t h is case on e can su sp ect t h at an in su

cien t in su lin

d osage an d an in app rop riate diet w ere un likely con t ribut ing factors. A, C, D Th ese drugs do n ot cau se or t rigger m et abolic acidosis.

by th e liver, w h ich in t urn in du ces an upregu lat ion of liver low -den sit y lip oprotein (LDL) receptors. A, C−E See correct an sw er explan at ion .

260


Learning objective: Identify the patient population that can benet most from antihyperlipidemic drugs.

exch ange w ith Cl−. Becau se of th eir large size, resin s are n ot

21. B It is w ell kn ow n th at th ere is a direct relat ion sh ip bet w een

In t h is w ay, en teroh ep at ic circu lat ion of bile acid s is p re-

th e tot al an d low -den sit y lip oprotein (LDL) ch olesterol in

ven ted (n or m ally, m ore t h an 95% of bile acid s are reab -

blood an d th e risk of coron ar y h ear t disease (CHD). It is also

sorbed; th eir excret ion is in creased u p to 10-fold w h en th e

w ell kn ow n th at th e risk of CHD in creases w ith age an d th at

resin s are given ).

w om en h ave a ver y low risk of CHD du ring p rem en op au sal

absorbed, an d th e boun d bile acids are excreted in th e stool.

B−E Non e of th ese drugs a ect bile acid elim in at ion .

years, bu t th at after m en op au se, th e rate of developing CHD th eir 50s an d 60s, w h ereas w om en ten d develop it in th eir

Learning objective: Choose the appropriate antihyperlipidem ic drug for a patient with concom itant disease.

60s an d 70s. Th is explain s w hy th e an t ihyp erlipidem ic drugs

25. C Cu rren tly, stat in s rep resen t th e m ost e ect ive an d best tol-

are m ostly ben e cial for m id dle-aged m en an d least ben e -

erated agen t s for t reat ing dyslip idem ia. Th ey are e ect ive in

cial for w om en d u ring p rem en opau sal years.

all t ypes of dyslipidem ia, an d w h en given as a single agen t ,

p arallels th at of m en . Th erefore, m en ten d to develop CHD in


th ey m ay decrease low -den sit y lipoprotein (LDL) ch olesterol u p to 60%an d total ch olesterol u p to 45%. Th erefore, th ey are

Learning objective: Outline the therapeutic uses of HMG-CoA (3-hydroxy-3-m ethylglutaryl−coenzym e A) reductase inhibitors.

th e drugs of rst ch oice for t reat m en t of elevated LDL ch oles-

22. C Th e sign s an d sym ptom s of th e pat ien t in dicate th at sh e

35%. Moreover, in th is p at ien t

w as m ost likely su ering from a t ran sien t isch em ic at t ack, a brief episode of n eu rologic dist u rban ce cau sed by a redu ced

terol. High er doses can also reduce t riglyceride levels up to A Niacin sh ould be avoided because of diabetes an d pept ic u lcer.

blood su p p ly to an area of th e brain . Asp irin is th e drug m ost

B Ch olest yram in e is relat ively con t rain d icated becau se

frequ en tly u sed to d ecrease th e risk of st roke in th ese p a-

it could im p air th e absorpt ion of th e oth er cu rren tly u sed

t ien t s, bu t it h as been con sisten tly sh ow n th at stat in s can

d rugs. D Un like n iacin , n icot in am ide is devoid of an t ihyperlipid -

also redu ce th is risk. E Fibrin olyt ic drugs are rst-lin e agen ts for th e acu te th erapy of stroke but not for the chronic prophylactic treatm ent. A, B, D, F See correct an sw er explan at ion .

em ic p ropert ies. E Fibrates such as gem brozil are th e drugs of ch oice for treating t ype III hyperlipidem ia (fam ilial dysbetalipoprotein em ia), as w ell as h igh t riglycerid e levels. Th ey do n ot sign i -

Learning objective: Describe the adverse e ect s of HMG-CoA (3-hydroxy-3-m ethylglutaryl−coenzym e A) reductase inhibitors. 23. E Creat in e kin ase is an en zym e fou n d in h igh con cen t rat ion in h ear t an d skelet al m uscle. Because th is en zym e exists in

can tly decrease LDL.

Learning objective: Describe the adverse e ect s of HMG-CoA (3-hydroxy-3-m ethylglutaryl−coenzym e A) reductase inhibitors.

relat ively few organ s, its serum con cen t rat ion is used as a

26. B St at in s are often p rescribed after a m yocardial in farct ion

speci c in d ex of inju r y of m yocard iu m or skelet al m u scle. In

to p reven t rein farct ion . St at in s cau se an in crease in liver

fact , creat in e kin ase levels can prove h elpful in recogn izing

en zym es in abou t 2% of p at ien t s. Abn orm al en zym e valu es

m u scu lar dyst rophy before clin ical sign s ap pear.

u su ally resolve w it h cessat ion of t reat m en t , bu t t h e d r ug

A Th is en zym e m ed iates t h e

rst step in ch olesterol

biosyn th esis. B Am in ot ran sferase (alan in e an d aspar t ate am in ot ran sferase) levels are m easu red p rim arily to diagn ose liver disease. C Alkalin e ph osph at ase is an en zym e origin at ing m ain ly in

sh ou ld be discon t in u ed w h en th e am in ot ran sferase act ivit y is p ersisten t ly elevated to m ore t h an 3 t im es t h e n or m al lim it s becau se of th e risk of h epatotoxicit y. A, C−E Th ese drugs do n ot cau se an in crease in liver en zym es.

th e bon e an d liver, w ith som e act ivit y in th e kidn ey an d in test in e. Th e en zym e is m easu red prim arily as an in dex of bon e or liver d isease. D Th is en zym e m ediates th e syn th esis of eicosan oids.

Learning objective: Outline the therapeutic uses of antihyperlipidemic drug combinations. 27. A Th e ve m ajor classes of an t ihyperlip idem ic drugs can be given in com bin at ion w h en

Learning objective: Explain the m echanism of action of cholest yram ine.

• Low -den sit y lip op rotein (LDL) an d ver y-low -den sit y lip o-

24. A Ch olest yram in e is a bile acid−bin ding resin . Drugs of th is

• LDL or VLDL is n ot n orm alized w ith a single agen t .

class are h igh ly posit ively ch arged (ch olest yram in e is a quater n ar y am in e) an d bin d n egat ively ch arged bile acid s in

protein (VLDL) are both elevated . • Pron ou n ced h igh -d en sit y lip op rotein (HDL) d e cien cy coexist s w ith oth er hyperlipidem ias.

Answers and Explanations: IV-7 Drugs A ecting Hem ostasis 261 St at in s w ork w ith resin s in a h igh ly syn ergist ic m an n er, de-

w ith lovastat in an d gem brozil, as both ch olesterol an d t ri-

creasing total ch olesterol by u p to 65%. Moreover, in th is

glycerides w ere elevated .

pat ien t B, C Niacin sh ould be avoided becau se it can cau se hyp erglycem ia in diabet ics by in creasing in su lin resist an ce. D, E Fibrates cau se on ly a m od est red u ct ion in tot al ch olesterol, an d t h e com bin at ion s w it h ot h er an t ihyp er-

A, B Ch olest yram in e d oes n ot in crease th e risk of rh abdom yolysis w h en t aken w ith oth er an t ihyp erlip idem ic drugs. D As st ated above, st at in s alon e h ave a low r isk of m yopathy. E Niacin alon e does n ot cau se m yopathy.

lip id em ic d r ugs are u sed on ly in p at ien t s w it h com bin ed hyp erlip id em ia.

Learning objective: Describe the m echanism of action of antihyperlipidem ic drugs.

Learning objective: Outline the therapeutic uses of antihyperlipidemic drugs.

30. D The increased bile acid excretion caused by an ion exchange

28. C All of t h e p at ien t s except p at ien t 5 sh ou ld st ar t a lip id -

protein (LDL) receptors, w hich in t urn increases th e extraction

low ering dr ug th erapy, as th ey st ill h ave an abn orm al lip id

of ch olesterol from p lasm a. In th e sam e w ay, th e in h ibit ion

p ro le after 4 m on th s of diet . Pat ien t 3, h ow ever, is th e on e

of ch olesterol syn th esis by stat in s causes an upregu lat ion of

w h o n eeds th e drug th erapy th e m ost , because h e h as th ree

h epat ic LDL receptors.

risk factors: h igh t riglycerides, h igh low -den sit y lip op rotein (LDL), an d low h igh -den sit y lipoprotein (HDL) levels. A Pat ien t 1 h as h igh t riglycerides, n orm al LDL ch olesterol levels, an d low HDL ch olesterol levels (t w o risk factors). B Patient 2 has norm al triglycerides an d norm al LDL cholesterol levels bu t low HDL ch olesterol levels (on e risk factor). D Pat ien t 4 h as m argin ally h igh t riglycerides an d h igh LDL ch olesterol levels but ver y h igh HDL ch olesterol levels (an HDL > 60 m g/d L rep resen ts a n egat ive risk factor).

resin s leads to an upregu lat ion of h epat ic low -den sit y lipo-

A Th e in test in al reabsorpt ion of bile acids is decreased by ch olest yram in e, but stat in s can cause a com pen sator y in crease in ch olesterol absorpt ion . B Th e conversion of ch olesterol to bile acid s is act u ally in creased by ch olest yram in e. C Th e syn th esis of en dogen ous ch olesterol by th e liver is d ecreased by st at in s, bu t ch olest yram in e can cau se a com p en sator y in crease of ch olesterol syn th esis. E St at in s decrease t riglyceride product ion , but th e resin induced increase in bile acid production can be accom panied

Learning objective: Outline the therapeutic uses of antihyperlipidemic drug combinations.

by an in crease in h epat ic t riglyceride syn th esis.

29. C Th e pat ien t’s acute ren al failure w as m ost likely du e to

ANTIHYPERLIPIDEMIC DRUGS Answ er key

rh abdom yolysis, w h ich is a con sequen ce of m yopathy, a rare bu t seriou s adverse e ect of st at in s. Th e excessive release of m yoglobin from th e dam aged m u scle can explain th e red an d clear u rin e an d th e acu te ren al failu re, m ost likely du e to p recipitat ion of m yoglobin in to ren al t ubu les w ith secon dar y t u bu lar obst ru ct ion . Th e in ciden ce of m yop athy is low (< 0.1%) w h en a st at in is given alon e but is m uch in creased (u p to 5%) in pat ien t s w h o con com itan tly receive brates. In this case, the patient m ost likely received a com bined therapy

1. 2. 3. 4. 5.

A D A C C

6. 7. 8. 9. 10.

C D B D E

11. 12. 13. 14. 15.

B A C B C

16. 17. 18. 19. 20.

E B E D B

21. 22. 23. 24. 25.

B C E A C

26. 27. 28. 29. 30.

B A C C D

Answers and Explanations: IV-7 Drugs A ecting Hem ostasis Questions 1−4 1. A

Learning objective: Explain the m echanism of actions of clopidogrel.

2. F

5. D Clop id ogrel is an an t ip latelet d r ug t h at cau ses an ir re-

3. C

versible in h ibit ion of aden osin e dip h osph ate (ADP) receptors,

4. B

th ereby in h ibit ing ADP-m ediated platelet aggregat ion . Th e drug is u sed to p reven t recu rren ce of isch em ic st roke m ain ly in peop le w h o are at risk of aspirin hyp ersen sit ivit y, su ch as th e asth m at ic pat ien t in th is case. A−C, E, F Non e of th ese dr ugs block platelet ADP receptors.

262


Learning objective: Explain the m olecular m echanism of action of heparin.

Learning objective: Choose the appropriate therapy for a patient su ering from severe warfarin overdose.

6. E Th e act ivit y of an t ith rom bin III in h ibit s clot t ing factor p ro-

9. E Th e sym ptom s of th e p at ien t st rongly suggest a h em or-

teases by for m ing equ im olar st able com p lexes w it h t h em .

rh agic com plicat ion of w arfarin th erapy. Th e stan dard t reat-

Heparin st rongly accelerates th is react ion , w h ich is th e basis

m en t of w arfarin overdose w ou ld be vit am in K, bu t th e

of it s an t icoagu lan t act ivit y.

patient is diaph oretic an d hypoten sive, suggesting that bleed-

A−D Th ese drugs do n ot a ect th e bin ding bet w een an t ith rom bin III an d clot t ing factor proteases.

ing is life- th reaten ing. In th is case, th e act ion of vit am in K is too slow to be usefu l (on set is delayed for 6 h ou rs an d is com plete by 24 h ours). Fresh frozen plasm a (w h ich con t ain s

Learning objective: Describe the main adverse e ects of warfarin.

p roth rom bin an d factors VII, IX, an d X) or act ivated clot t ing

7. D Th e p r im ar y ap p roach to p reven t valvu lar t h rom bosis

factors sh ould be adm in istered in case of severe acute bleed-

an d system ic th rom boem bolism associated w ith m ech an ical

ing du e to an t icoagu lan t th erapy.

prosth et ic valve replacem en t is long-term an t icoagu lat ion


w ith w arfarin . Most likely, th e dose of w arfarin w as too h igh ,

B−D Th ese drug are eith er u seless or dangerous in bleed-

so bleeding occu rred , as p oin ted ou t by th e sign s an d sym p -

ing disorders.

tom s of th e pat ien t . A Fibrin olyt ic drugs such as st reptokin ase are n ot in dicated for long-term preven t ion of th rom bosis.

Learning objective: Explain the m echanism of coagulant action of desm opressin.

B Aspirin is som etim es used togeth er w ith w arfarin in treat-

10. A Vasop ressin an d desm op ressin in crease plasm a levels of

ing pat ien ts w ith prosth et ic valves, m ain ly w h en eviden ce of

factor VIII an d von Willebran d factor, presum ably by V2 re-

th rom boem bolism exist s despite adequate an t icoagulat ion .

ceptor-m ediated release from storage sites in vascular endo-

How ever, it is n ot e ect ive for p reven t ion w h en given alon e.

th elium . Because of th is, desm opressin is som et im es used

C, F Th e qu est ion speci es oral an t icoagu lan t th erapy. Hep -

after m in or t rau m a or before elect ive d en t al su rger y in

arin an d bivalirudin m u st be given paren terally an d th erefore

p at ien t s w it h m ild h em op h ilia A w h o h ave d em on st rated

are n ot suited for long-term an t icoagulat ion .

respon siven ess.

E Am in ocaproic acid is an an t iplasm in drug an d th erefore

B−E Desm opressin does n ot h ave th ese e ect s.

w ou ld be con t rain dicated in th is set t ing.

Learning objective: Explain the mechanism of action of dabigatran. Learning objective: Describe the m ain contraindications for brinolytic drugs.

11. C Dabigat ran is a n ew oral an t icoagu lan t th at act s by bin ding

8. B Th e p at ien t ’s sign s an d sym ptom s suggest t h at sh e w as

like w arfarin , th is direct th rom bin in h ibitor h as a rap id on set

m ost likely su er in g from acu te p er icard it is. In th e cu r ren t

of act ion , does n ot in teract w ith P-450-in teract ing drugs,

era of t h rom bolyt ic t h erapy for acu te coron ar y occlu sion ,

an d gives a p redictable an t icoagu lan t resp on se, m aking rou -

t h e d ist in ct ion bet w een m yocardial in farct ion (MI) an d acu te

t in e an t icoagulan t m on itoring u n n ecessar y.

pericardit is is cru cial. If p ericardit is is m isdiagn osed as MI,


reversibly to th rom bin , th us blocking th rom bin act ivit y. Un -

th rom bolyt ic dr ugs m ay cause pericardial h em orrh age an d gu ish ed from isch em ic coron ar y p ain becau se t h e lat ter is

Learning objective: Describe the clinically important drug interactions of warfarin.

n ot aggravated by ch est m ot ion . W h en presen t , a precordial

12. B Macrolid e an t ibiot ics can in h ibit w arfarin m et abolism , re-

frict ion r u b is diagn ost ic, as in th is case. Pericardit is m ay be

su lt ing in in creased p lasm a levels of th e drug. Th is in ter-

cau sed by in am m at ion , t rau m a, or n eop lasm . Som et im es it

act ion is w ell est ablish ed, an d p rolongat ion of p roth rom bin

accom pan ies system ic diseases, as in th is case. Most often ,

t im e m ay occu r even w ith sm all doses of er yth rom ycin .

cardiac tam p on ade. Usu ally p ericardial p ain can be dist in-

h ow ever, th e et iology of acute pericardit is can n ot be iden t ied an d is referred to as idiopath ic. A, C An t iin am m ator y drugs are u sed to relieve in am m at ion an d p ain of acu te p ericardit is. D If pain does n ot subside w ith an t iin am m ator y drugs, opioids can be used. E An t ibiot ics are em p loyed w h en p er icard it is is d u e to bacterial in fect ion (m ost com m on ly t u bercu losis).

A Er yth rom ycin does n ot in h ibit th e syn th esis of clot t ing factors. C Warfarin can cau se local th rom bosis th at seem s related to th e in h ibit ion of an t icoagu lan t protein C, bu t th is adverse e ect is rare an d u su ally occu rs d u r in g t h e

rst day of

w ar farin th erapy w h en th e an t icoagulan t e ect is n ot yet operat ive.

Answers and Explanations: IV-7 Drugs A ecting Hem ostasis 263 D Er yth rom ycin h as n o e ect on th e in test in al absorpt ion of vit am in k.

A, C, D Th ese exam s are n ot n eeded du ring h eparin t reat m en t .

E Warfarin does n ot a ect product ion of vit am in K by in test in al ora.

E Bleeding t im e is n orm al in th e presen ce of coagulat ion disorders oth er th an th rom bocytop en ia or von Willebran d disease. It can be in creased in case of HIT, bu t th e p latelet

Learning objective: Describe the therapeutic uses of abcixim ab. 13. F Variou s an t icoagu lat ion regim en s are alw ays perform ed before, du ring, an d after angiop last y to redu ce th e in ciden ce

coun t is a m uch m ore reliable test . F This test evaluates brinolytic activit y. Heparin does not alter brin olysis.

of th rom bosis. Heparin (n ot listed) an d abcixim ab are th e A, B Warfarin an d clopidogrel are n ot given in t raven ou sly.

Learning objective: Describe the therapeutic uses of aspirin and heparin in unstable angina.

Th ey are u su ally st ar ted som e t im e before th e in ter ven t ion

17. C Th e pat ien t w as m ost likely su ering from un st able angin a

t w o drugs given in t raven ously for th is pu rpose.

an d con t in u ed for m on th s after it .

(see th e sym ptom s an d th e elect rocardiogram ). Un stable

C−E Th e use of protam in e, am in ocaproic acid, an d recom -

angin a is a m edical em ergen cy to be t reated in a cardiac care

bin an t factor VIIa d u r in g coron ar y an giop last y w ou ld be

u n it . Th e im m ediate ch allenge is relief of pain an d con t rol

irrat ion al.

of all isch em ic episodes. Pain relief is usually accom plish ed w it h in t raven ou s in fu sion of n it roglycer in , w h ich h as t h e

Learning objective: Describe the m ain adverse e ect s of heparin.

advan t age of fast on set of act ion an d rap id reversibilit y.

14. C Th e lab result s in dicate th at th e pat ien t w as m ost likely

Op ioid s sh ou ld be u sed to con t rol p ain on ly w h en it is n ot

su er ing h ep ar in -in d u ced t h rom bocytop en ia (HIT). Th e

adequately relieved by an t i-isch em ic m edicat ion . To reduce

d isord er can be asym ptom at ic (t yp e I) or associated w it h

in t racoron ar y clot t ing, oral aspirin an d in t raven ou s h eparin

p eriph eral vascular occlusion , w h ich can cau se st roke, m yo-

sh ou ld be in st it u ted im m ed iately (t h ese d r ugs h ave been

cardial in farct ion , t issu e gangren e, or even death (t ype II). In

sh ow n to red u ce t h e in cid en ce of su bsequ en t m yocardial

fact , th e m or talit y rate of t ype II HIT can be as h igh as 40%.

in farct ion ).

HIT occu rs in abou t 1 to 5% of p at ien t s receiving u n fract ion -

A, D, E, F Each of th ese com bin at ion s h as at least on e d rug

ated h eparin . Th e path ogen esis of HIT is st ill un cer tain , bu t

th at is useless (w arfarin an d desm opressin ) or con t rain di-

it appears th at h eparin -depen den t im m un oglobu lin G (IgG)

cated (am in ocap roic acid).

an t ibodies act ivate platelets th at aggregate in t ravascularly.

B Alteplase is a brin olyt ic drug. Th ese drugs can be used

Con sequ en tly, platelet- brin th rom bi m ay form , leading to

to break dow n th rom bi but n ot to preven t th rom bus form a-

vascu lar occlu sion .

t ion . Th erefore, th ey are n ot u sefu l (an d m ay be h arm fu l) in

A, B, D, E Th e risk of th rom bocytop en ia w ith all of th e

u n st able angin a. Warfarin is n ot used for em ergen cy an t icoagulat ion because of it s delayed on set of act ion .

oth er listed drugs is eith er low (aspirin ) or n egligible.


Learning objective: Describe the m ain advantages of lowmolecular-weight heparins (LMWHs) over standard heparin.

15. C Cim et idin e is a p oten t in h ibitor of th e cytoch rom e P-450

18. C High -m olecular-w eigh t h eparin (HMW H) causes t ran sien t

system an d can th ereby in crease th e p lasm a level of several

th rom bocytop en ia in u p to 15% of p at ien t s an d severe

d rugs, in clu ding w arfarin . Blood in u rin e is often th e

th rom bocytop en ia (w h ich is an t ibody-m ed iated) in u p to

rst

sign of bleeding from an t icoagulan t th erapy. A Warfarin is alm ost com pletely m etabolized by th e liver, so it s ren al clearan ce is n egligible.

5% of p at ien t s. En oxap arin is low -m olecu lar-w eigh t h ep arin (LMW H). LMW H-in duced th rom bocytopen ia is seen in less th an 1% of p at ien ts.

B, D, E Cim et idin e h as n o e ect on th e in test in al absorp -

A LMW Hs cause a low er in ciden ce of bleeding com plica-

t ion of vit am in K, on blood coagu lat ion , or on bin ding of

t ion s, w h ich cou ld be related to th e fact th at th ese agen t s

w arfarin to p lasm a protein s.

p referen t ially in h ibit factor Xa m ore poten tly th an th ey in h ibit throm bin (throm bin inhibition requires a larger heparin

Learning objective: List the exam s that should be done frequently during heparin treatm ent. 16. B Becau se h ep arin -in du ced th rom bocytopen ia (HIT) is a seriou s adverse e ect of h ep arin , a platelet coun t sh ou ld be p erform ed w eekly during h ep arin t reat m en t . Any th rom bocytop en ia app earing during t reat m en t sh ou ld be con sidered su spiciou s for HIT.

m olecu le). Never th eless, bleeding com p licat ion s do occu r even w ith LMW H. B Th e oral bioavailabilit y of both HMW an d LMW h eparin s is zero. D, E LMW Hs d o n ot h ave an t ip latelet act ivit y, an d t h ey act u ally in h ibit few er coagu lat ion factors t h an st an d ard h eparin .

264


Learning objective: Describe the therapeutic uses of heparin.

w ith in 3 h ours of on set , can reduce th e ult im ate disabilit y

19. E Th e sudden dyspn ea, hypoten sion , an d pleuritic ch est pain ,

cau sed by th e isch em ic st roke.

p ar t icu larly in a h igh -risk set t ing (gast ric can cer), w ou ld

A, B Th ese drugs can in crease blood coagu labilit y (desm o-

suggest th e diagn osis of m assive pu lm on ar y em bolism ,

pressin ) or in h ibit

w h ich is con rm ed by th e com puted tom ography scan . Hep -

th erefore con t rain dicated in isch em ic st roke.

arin is a dr ug of ch oice to p reven t fu rth er th rom bu s form a-

brin olysis (am in ocaproic acid) an d are

D, E, F No st udies h ave clearly dem on st rated th at em ergen cy t reat m en t w ith an t icoagu lan t s is u sefu l in m it igat ing

t ion an d em bolizat ion . A Nit roglycerin is used on ly if ch est pain is due to coron ar y

th e n eurologic e ect s of a st roke. How ever, th e use of a full

d isease; m oreover, it is con t rain dicated in th is case because

dose of u n fract ion ated h eparin rem ain s con t roversial de-

of hypoten sion .

spite years of debate an d lack of eviden ce su pp ort ing it s u se.

B, F Aspirin an d clopidogrel h ave been t ried to p reven t sive or fran kly n egat ive. Moreover, t h ey are n ot given

Learning objective: Choose the appropriate drugs for a patient with deep venous thrombosis.

p aren terally.

22. C Th e st an d ard t h erapy for u n com p licated d eep ven ou s

(n ot to t reat ) t h rom boem bolism , bu t resu lt s are in con clu -

C Th e system ic hypoten sion an d ext rem e hypoxem ia w ar-

th rom bosis (DVT) is an in t raven ou s inject ion of u n fract ion -

ran t con siderat ion of th rom bolyt ic th erapy. How ever, recen t

ated h ep arin follow ed by a sh ort cou rse (4 or 5 days) of su b -

su rger y (as in t h is case) is a m ajor con t rain d icat ion for

cu tan eou s h eparin . Warfarin is st arted th e

-

br in olyt ic drugs. D Warfarin is n ot used for th e acute t reat m en t of pulm on ar y em bolism because of it s slow on set of act ion .

rst or secon d

day of h ep arin th erapy an d con t in u ed for m on th s. A, B Abcixim ab is n ot u sed for th rom bosis p rop hylaxis. D−F Th e use of alteplase in an un com plicated DVT is n ot recom m en ded because of th e poten t ial adverse e ect s of -

Learning objective: Explain the main reasons for heparin resistance.

brin olyt ic drugs (i.e., th e in du ct ion of a lyt ic st ate). Alth ough

20. A Th e lack of act ion of h eparin in th is case w as m ost likely

som e st u d ies h ave suggested t h at

br in olyt ic t h erapy is

d ue to h eparin resist an ce. Heparin can bin d to di eren t

m ore e ect ive t h an an t icoagu lan t t h erapy in DVT, br in o-

p lasm a p rotein s, in clu ding p latelet factor 4, br in ogen , an d

lyt ic th erapy is u su ally con sidered on ly w h en th rom bosis is

factor VIII. As m any h ep ar in -bin d in g p rotein s are acu te-

m assive an d/or com p licated by hypoten sion or sh ock.

p h ase react an t s, t h e p h en om en on of h ep ar in resist an ce is often en coun tered in acutely ill pat ien ts or in pat ien ts w ith m align an cy, as in th is case. B Vitam in K does n ot a ect th e an t icoagulan t act ion of h eparin . C Th e h alf-life of h eparin is dose-depen den t an d is 30 to 150 m in u tes at th erapeu t ic doses. D Hep ar in is e ect ive im m ed iately after in t raven ou s in ject ion or delayed 20 to 60 m in u tes after su bcu t an eou s inject ion . E Heparin resistan ce can occu r w ith ver y low, n ot h igh , levels of an t ith rom bin III. Th is de cien cy is a rare h ered itar y disorder th at gen erally com es to ligh t w h en th e pat ien t su ffers recurren t ven ou s th rom bosis.

Learning objective: Describe the m ost serious adverse e ect of alteplase. 23. D Th e st an dard th erapy of m yocardial in farct ion (MI) in cludes an intravenous throm bolytic drug (alteplase, reteplase, etc.), w hich is m ost e ective in th e rst few hours after onset. Bleeding (m ost com m on in cerebral vessels) is th e m ost frequ en t adverse e ect of th ese drugs. A Aspirin , if n ot con t rain dicated, is given at presen tat ion an d daily in de n itely th ereafter. Its an t ip latelet e ect red uces sh ort- an d long-term m or talit y. Bleeding, h ow ever, is n ot as com m on as w ith th rom bolyt ic drugs. B Beta-blockers, if n ot con t rain dicated, are given w ith in th e

rst few h ou rs after on set becau se th ey redu ce recu r-

ren ce rate an d m ort alit y. Bleeding is n ot an adverse e ect of

Learning objective: Describe the therapeutic uses of alteplase in ischem ic stroke.

th is drug class.

21. C Th e sign s an d sym ptom s of t h e p at ien t suggest t h at h e

h ours in pat ien ts w ith MI an d h ear t failure or hyperten sion .

C Nit roglycerin is recom m en ded for th e

is m ost likely su ering from an isch em ic st roke due to th e

Bleeding is n ot an adverse e ect of n it rates.

occlusion of a cerebral ar ter y. Th e guidelin es of th e Am eri-

E Warfarin is n ot curren tly used in MI.

can St roke Associat ion in dicate th at altep lase, adm in istered

rst 24 to 48

Answers and Explanations: IV-7 Drugs A ecting Hem ostasis 265 Learning objective: Explain why the onset of anticoagulant e ect of warfarin is delayed.

h er t hyroid level w as raised to n orm al, th e w arfarin dose

24. C Warfarin h as n o e ect on th e act ivit y of already form ed

rate of clot t ing factors th at w ould occur in th e p resen ce of

clot t ing factors II, VII, IX, an d X in th e circulat ion . Because

h igh er thyroxin e levels. Mon itoring m ust be carried out to

w arfarin in h ibits th e syn th esis of n ew clot t ing factors bu t

reest ablish th e ap propriate n ew, low er dose of w arfarin .

n ot th e m et abolism of t h e already for m ed clot t ing factors, it s e ect depen ds on th e t im e taken for th e degradat ion of these factors, or their half-lives. Additionally, because throm bin (i.e., factor II) h as th e longest h alf-life (abou t 60 h ou rs),

n eeded to be adju sted to adapt to t h e in creased cat abolic

A, B Warfarin h as n o e ect on th e ph arm acokin et ics of thyroid h orm on es. C, E Thyroid h orm on es h ave n egligible e ect s on th e absorpt ion or m etabolism of w arfarin .

its h alf-life is th e m ain determ in an t of th e on set of act ion of

Learning objective: Explain the m olecular m echanism of action of warfarin.

w arfarin . A, B, D, E Th ese opt ion s are un likely.

27. B Vitam in K is an essen t ial cofactor for conver t ing p recu rsor

Learning objective: Describe the therapeutic uses of anticoagulant and brinolytic drugs in myocardial infarction.

p rotein s in to th e act ive coagu lat ion factors in th e liver. Vit a-

25. A All pat ien ts w ith m yocardial in farct ion (MI) w h o seek

to vit am in K epoxide is coupled w ith act ivat ion of coagula-

m in K qu in on e is th e act ive form . Oxidat ion of th is qu in on e

rst 12 h ou rs after sym ptom on set

tion factors II, VII, IX, and X, as w ell as the anticoagulant fac-

sh ou ld be con sidered for u rgen t rep erfu sion of th e in farct-

tors protein s C an d S. Epoxide is th en reconverted to quin on e,

related ar ter y, but th e earlier th erapy is begun , th e greater

an d w arfarin blocks th is redu ct ive conversion .

m edical care w ith in th e

-

A Th is is act ually th e m ech an ism of act ion of h eparin .

br in olysis or p ercu t an eou s coron ar y in ter ven t ion (PCI). Th e

C Warfarin does n ot a ect clot t ing factor m etabolism .

t h e ben e t . Th e d e n it ive t h erap ies for rep er fu sion are

brin olyt ic dr ugs m ost often u sed are t issu e plasm in ogen act ivators (e.g., altep lase), as it h as been sh ow n th at th ey are “ brin -speci c”; th at is, th ey preferen t ially act ivate plasm inogen bound to

brin. Tissue plasm inogen act ivators clearly

D Warfarin act ually blocks th e act ivat ion of an t icoagulan t factors protein s C an d S. E Vit am in K is n ot syn th esized in th e liver bu t is stored th ere in it ially, after in test in al absorpt ion .

open coron ar y ar teries m ore rapidly th an n on speci c act iacu te MI, u n less a con t rain d icat ion exist s. Hep ar in given

Learning objective: Choose the appropriate anticoagulant for a patient with atrial brillation.

w it h altep lase im p roves t h e rap id it y w it h w h ich p aten cy is

28. D Ch ron ic an t icoagu lan t th erapy is alw ays given before car-

in d u ced an d is essen t ial for m ain t ain ing t h e p aten cy, t h u s

d ioversion in order to p reven t th rom boem bolism . In fact ,

avoiding reocclu sion , w h ich is a p roblem w ith

on e of th e m ost feared con sequen ces of at rial brillat ion is

vators. Heparin sh ou ld be adm in istered to all p at ien t s w ith

brin olyt ic

th erapy. B War far in is n ot an em ergen cy an t icoagu lan t becau se it s on set of act ion is slow. C In ot rop ic d rugs are adm in istered on ly w h en cardiogen ic sh ock is presen t . E Clopidogrel can be adm in istered as an adju n ct ive th erapy, but it is n ot given in t raven ou sly. D, F See correct an sw er explan at ion .

t h e d evelop m en t of at r ial t h rom bi, w it h su bsequ en t em bolizat ion . Th is is m ost likely to occu r on ce th e n orm al sin us rhyth m is restored, du e to th e m ore e ect ive con t ract ion of th e at ria. A Heparin is n ot appropriate for long-term th erapies, as it m u st be given paren terally. B St reptokin ase is a th rom bolyt ic drug an d th erefore n ot u sed to preven t th rom bus form at ion . C Alth ough aspirin is som et im es used as an altern at ive


to w arfarin in th is set t ing, st udies to determ in e its e

26. D Thyroid h orm on es in crease th e catabolism of m any en -

d ose sh ould be a low dose, n ot a h igh dose.

cacy

h ave yielded in con sisten t result s. Moreover, th e an t iplatelet

d ogen ous com pou n ds, in cluding clot t ing factors. Th is act ion

E Abcixim ab is a m on oclon al an t ibody th at bin ds n on com -

results in a decreased coagulabilit y of blood, so th e e ects of

p et it ively to glycop rotein IIb/IIIa receptor com plex, w h ich

an t icoagu lan t s are en h an ced . In th is case, th e w om an’s in i-

regulates th e n al step in platelet aggregat ion . Its th erapeu -

t ial w arfarin dose w as ap prop riate to provide a safe level of

t ic u ses are lim ited to p ercu t an eou s coron ar y in ter ven t ion

an t icoagu lat ion th erapy for h er hyp othyroid st ate, bu t w h en

an d u n stable angin a.

266


Learning objective: Explain the m olecular m echanism of action of abciximab.

w ith doses of 160 to 300 m g per day. High er doses do n ot

29. A Abcixim ab is a h um an ized m on oclon al an t ibody directed

follow ing reason : cyclooxygen ase blockad e redu ces both th e

again st th e IIb/IIIa receptor com plex. Th is com plex fu n ct ion s

p latelet-m ediated produ ct ion of TXA2 , w h ich prom otes ag-

as a receptor m ain ly for

brin ogen bu t also for von Wille-

gregat ion , an d th e en doth elial cell−m ediated produ ct ion of

bran d factor an d can be act ivated (directly or in directly) by

p rost aglan d in I2 , or p rost acyclin (PGI2 ), w h ich in h ibit s ag-

m ost of the other m entioned m olecules, including adenosine

gregat ion . How ever, en d ot h elial cells p rod u ce n ew cyclo-

d iph osp h ate (ADP), th rom bin , collagen , an d th rom boxan e

oxygen ase in a m at ter of h ou rs, w h ereas platelets can n ot

A2 . Th e bin ding of brin ogen to th e IIb/IIIa receptor resu lt s

m an u fact u re th e en zym e. With low doses, th en , on ly p ro-

im p rove e

cacy an d are p oten t ially less e ect ive for t h e

n al com m on

longed in h ibit ion of TXA2 syn t h esis occu rs. If t h e d ose of

p at h w ay in p latelet aggregat ion . By blocking t h e p latelet

asp irin is in creased, prost acyclin syn th esis can be in h ibited

glycoprotein IIb/IIIa receptor com plex, th ese drugs preven t

for a longer t im e, th us counteract ing th e e ect s of TXA2 syn -

platelet aggregat ion in du ced by any aggregat ing su bstan ce.

th esis in h ibit ion .

in cross-lin king bet w een platelets an d is th e

B, F Th ese step s are in h ibited by h eparin .

A F See correct an sw er explan at ion .

C Th is step is in h ibited by asp irin .

B Asp irin does n ot in h ibit th e lipoxygen ase p ath w ay.

D Th is step is in h ibited by w arfarin .

C Th is is th e m ech an ism of act ion of clopidogrel.

E Th is step is in h ibited by clopidogrel.

D Th is w ould cause, n ot in h ibit , platelet aggregat ion .

Learning objective: Explain the m echanism of antithrom botic action of aspirin. 30. E Aspirin in h ibit s th e syn th esis of th rom boxan e A2 (TXA2 ) th rough th e irreversible acet ylat ion of cyclooxygen ase I. TXA2 is a p oten t p latelet aggregator an d is released from platelet s du ring aggregat ion . Becau se platelet s do n ot syn th esize n ew p rotein s, th e act ion of aspirin on p latelet cyclooxygen ase is p erm an en t , last ing for th e life of th e platelet (4 to 10 days). Com plete in act ivat ion of th e en zym e is ach ieved

DRUGS AFFECTING HEMOSTASIS Answ er key 1. 2. 3. 4. 5.

A F C B D

6. 7. 8. 9. 10.

E D B E A

11. 12. 13. 14. 15.

C B F C C

16. 17. 18. 19. 20.

B C C E A

21. 22. 23. 24. 25.

C C D C A

26. 27. 28. 29. 30.

D B D A E

V Endocrine System Questions: V-1 Drugs for Hypothalam ic and Pituitary Disorders Directions for questions 1−6


Match each endocrine drug w ith th e appropriate description (each

8. A 37-year-old m an recen t ly d iagn osed w it h acrom egaly

lettered option can be selected on ce, m ore than once, or not at all).

star ted a t reat m en t w ith oct reot ide. W h ich of th e follow ing

A. Cabergolin e

cells m ost likely represen t th e m ain site of act ion of th e drug

B. Ch orion ic gon adot ropin

in th is pat ien t?

C. Cosyn t ropin

A. Su p raopt ic n eu ron s

D. Desm opressin

B. Pit u it ar y som atot rop h s

E. Degarelix

C. Pit u it ar y thyrot rop h s

F.

D. Paraven t ricu lar n euron s

Follit ropin alfa

G. Leuprolide

E. Ven t rom edial n euron s

H. Oct reot ide I.

Oxytocin

J.

Pegvisom an t

Di cult y level: Medium 9. A 33-year-old w om an w h o h ad been u n able to con ceive a

K. Som at rop in

baby for 3 years star ted a con t rolled ovarian hyp erst im u lat ion t reat m en t for in vit ro fer t ilizat ion . W h ich of th e follow -


ing drugs w as m ost likely adm in istered daily to sup p ress th e

1. An adren ocort icot ropic h orm on e (ACTH) an alogu e

lu tein izing h orm on e su rge th at cou ld p rem at u rely t rigger ovu lat ion ?


A. Testosteron e

2. A recom bin an t follicle-st im ulat ing h orm on e (FSH) an alogue

B. Oct reot ide C. Leu p rolide


D. Cosyn t ropin

3. A som at ropin receptor an tagon ist

E. Som at rop in



4. A som atost at in an alogue

10. A 34-year-old w om an com p lain ed to h er gyn ecologist of severe pelvic pain during both m en st rual an d n on m en st r ual d ays. Th e w om an , d iagn osed w it h en d om et r iosis 1 year

Di cult y level: Easy 5. A gon adot ropin -releasing h orm on e (Gn RH) an alogue

m et riot ic lesions, but her sym ptom s h ad ret urned. Her gynecologist prescribed a cycle of therapy w ith leuprolide. W h ich

Di cult y level: Easy 6. A drug w ith lutein izing h orm on e (LH) act ivit y

of th e follow ing adverse e ects w ould be expected to occu r d uring th e th erapy? A. Galactorrh ea

Di cult y level: Easy 7. A 27-year-old prim ipara w om an w as adm it ted to th e obstetrical un it for labor in duct ion becau se of a postdate p regn an cy. An in t raven ous in fusion of oxytocin w as st arted. Act ivat ion of w h ich of th e follow ing sign aling path w ays m ost likely m ediates th e th erap eu t ic e

earlier, h ad good p ain relief after su rgical ablat ion of en do-

B. Vagin al in fect ion s C. Men orrh agia D. Hot u sh es E. Ven ou s th rom bosis

cacy of th is drug?

A. Cyclic aden osin e m on oph osph ate (cAMP) syn th esis B. Ph osp h oin osit ide hydrolysis C. Cyclic gu an osin e m on op h osph ate (cGMP) syn th esis D. Tyrosin e residu e p h osp h or ylat ion E. Gen e t ran script ion 267

268

Endocrine System


w eek. Vit al sign s w ere blood p ressu re 100/55 m m Hg, pu lse

11. A 54-year-old w om an com p lain ed to h er p hysician of an

95 bp m , resp irat ion s 16/m in . Physical exam in at ion revealed

u n com fort able ush ing for th e past few days. Fu rth er exam s

increased pigm entation , especially on skinfolds and extensor

led to th e diagn osis of carcin oid syn drom e due to prim ar y

su rfaces. Blu ish black discolorat ion of th e areolae an d m u -

carcin oid t u m or of th e lu ng, an d th e p at ien t w as sch edu led

cous m em bran es w as also n oted. Sign i can t serum levels on

for su rger y. W h ich of th e follow ing drugs w ould be ap pro-

adm ission w ere Na + 122 m Eq/L (n orm al 136−145 m Eq/L), K+

p r iate to con t rol t h e p at ien t ’s sym ptom s an d to p reven t a

6.2 m Eq/L (n orm al 3.5−5.5 m Eq/L), fast ing glu cose 58 m g/dL

su rger y-in du ced carcin oid crisis?

(norm al 70−110 m g/dL), blood urea nitrogen (BUN) 34 m g/dL (n or m al 7−18 m g/d L). Th e ser u m level of a h or m on e w as

A. Som at rop in

m easu red before an d after th e in t raven ou s inject ion of a test

B. Leuprolide

drug to con rm th e diagn osis. W h ich of th e follow ing test

C. Desm opressin

drugs w as m ost likely adm in istered?

D. Oct reot ide

A. Som at rop in

E. Prolact in

B. Mecaserm in C. Adren ocor t icot rop ic h orm on e (ACTH)

Di cult y level: Easy 12. A 64-year-old w om an w as foun d to h ave h igh serum levels of in sulin -like grow th factor 1 (IGF-1) during a regular clin ic visit . Her m edical h istor y w as sign i can t for at rial

brilla-

t ion p resen tly con t rolled w ith a pacem aker an d for a pit u itar y aden om a diagn osed 8 m on th s ago. Because radiat ion

D. Oct reot ide E. Leu p rolide F.

Som atostat in


th erapy w as con t rain dicated, th e pat ien t h ad been receiving


oct reot ide sin ce th en . W h ich of th e follow ing drugs w ou ld

t w o episodes of h em atoch ezia an d h em atem esis of dark red

be ap prop riate to add to th e p at ien t’s th erapy at th is t im e?

blood over a 7-h ou r period. Past h istor y of th e p at ien t w as

A. Cosyn t ropin B. Mecaserm in C. Leuprolide D. Cabergolin e E. Degarelix

Di cult y level: Medium 13. A 52-year-old w om an p resen ted to t h e h osp it al w it h a 3-w eek h istor y of fat igu e, cold in toleran ce, an d con st ip at ion . Physical exam in at ion sh ow ed a pat ien t w ith coarse, dr y, scaly skin , eyelid drop , a p u y face, an d a large tongu e. Pert in en t seru m valu es on adm ission w ere free thyroxin e (FT4 ) 0.2 ng/dL (n orm al 0.4−2 ng/dL), thyroid-st im u lat ing h orm on e (TSH) 0.3 µIU/m L (n orm al 0.5−4.7). An in t raven ous

sign i can t for alcoh olism for 12 years. Physical exam in at ion show ed a som n olen t but easily arousable m an w ith subicteric skin . Th e abd om en w as m ildly disten ded w ith a 10-cm liver span . Sm all uid w aves w ere present. An esoph agoscopy w as ordered, an d a drug w as given by con t in uous in fusion after an in t raven ou s loading dose. W h ich of th e follow ing drugs w as m ost likely adm in istered? A. Adren alin e B. Albuterol C. Nifedipin e D. Prazosin E. Vasopressin


inject ion of thyrot rop in -releasing h orm on e (TRH) w as given

16. A 37-year-old w om an recen tly diagn osed w ith pit u itar y ad-

to bet ter clarify th e diagn osis. Serum TSH levels m easured

en om a u n der w en t ablat ive radiat ion th erapy, bu t th e t reat-

soon after th e inject ion sh ow ed a sign i can t in crease in TSH.

m en t failed to con t rol th e p at ien t’s sym ptom s. Lab tests st ill

W h ich of th e follow ing w as m ost likely th e cause of th e pa-

sh ow ed a h igh level of in su lin -like grow th factor 1. A ph ar-

t ien t’s syn d rom e?

m acoth erapy w ith oct reot ide w as p rescribed. W h ich of th e

A. Hash im oto thyroidit is B. Hyp oth alam ic dysfu n ct ion

follow ing actions m ost likely m ediated the therapeutic e ect of th e drug in th e pat ien t’s disorder?

C. Pap illar y thyroid carcin om a

A. St im ulat ion of grow th h orm on e m et abolism

D. Graves disease

B. In h ibit ion of grow th h orm on e release

E. Pit uit ar y dysfu n ct ion

C. In h ibit ion of in sulin release D. Blockade of grow th h orm on e receptors

Di cult y level: Hard 14. A 45-year-old w om an w as seen at th e clin ic because of episodic w eakn ess, p aresth esias, an d con st ip at ion for th e past

E. Blockade of thyroid-stim ulating horm one (TSH) receptors

Questions: V-1 Drugs for Hypothalam ic and Pituitary Disorders 269 Di cult y level: Easy


17. A 41-year-old m an w as foun d to h ave grow th h orm on e de -

21. A 6-year-old girl presen ted to h er pediat rician w ith pubic

cien cy after irrad iat ion of th e hyp op hysis to t reat a p arasel-

h air, breast d evelop m en t , an d regu lar m en st r u at ion . After

lar t um or. Th erapy w ith som at rop in w as star ted. W h ich of

clin ical an d laborator y evalu at ion s, a d iagn osis of t r u e p re-

th e follow ing adverse e ect s is m ost likely to occu r in th is

cociou s p u ber t y w as m ad e. W h ich of t h e follow in g d r ugs

p at ien t?

w ou ld be app ropriate for th is girl?

A. Arth ralgias

A. Som at rop in

B. Hyp oglycem ia

B. Est radiol

C. Weigh loss

C. Testosteron e

D. Osteoporosis

D. Brom ocript in e

E. Dehydrat ion

E. Men ot ropin s F.

Leu p rolide

Di cult y level: Medium 18. A 26-year-old m an w ish ing to st art a fam ily w as diagn osed


w ith in fert ilit y due to oligosperm ia. He st arted a t reat m en t

22. A 71-year-old m an su ering from sym ptom at ic advan ced

th at in clu ded in t ram u scu lar inject ion of h u m an ch orion ic

p rost ate can cer star ted a t reat m en t w ith a dr ug th at fu n c-

gon adot ropin th ree t im es w eekly. W h ich of th e follow ing

t ion s as com p et it ive an t agon ist at gon ad ot rop in -releasin g

m olecu lar act ion s is th e in ten ded target for th is th erapy?

h or m on e (Gn RH) receptors. W h ich of t h e follow ing d r ugs

A. St im u lat ion of Leydig cell testosteron e produ ct ion


B. Activation of testosterone receptors in the hypoth alam us

A. Degarelix

C. In h ibit ion of grow t h h or m on e−releasing h or m on e

B. Leu p rolide

(Gn RH) secret ion from th e hypoth alam u s

C. Cabergolin e

D. St im u lat ion of secret ion of p rostat ic u id

D. Pegvisom an t

E. St im u lat ion of m itot ic act ivit y of Ser toli cells

E. Mecaserm in



19. A 62-year-old m an diagn osed w ith m etastasized prostate

23. An 8-year-old h ealthy girl w as referred to a pediat ric en do-

can cer star ted a t reat m en t th at in clu ded a dep ot p rep arat ion

crinologist for short stature. Physical exam ination and kar yo-

of goserelin . W h ich of t h e follow in g act ion s m ost likely

t ype an alysis led to th e diagn osis of Turn er syn drom e. W h ich

m ediated th e th erapeu t ic e ect of th e drug in th e p at ien t’s

of th e follow ing drugs w ould be m ost appropriate to t reat

d isease?


A. In h ibit ion of arom at ase en zym e

A. Oxan drolon e

B. In h ibit ion of follicle-st im u lat ing h or m on e (FSH) an d

B. Som at rop in

lu tein izing h orm on e (LH) release

C. Som atostat in

C. Blockade of prost ate testosteron e receptors

D. Testosteron e

D. In h ibit ion of topoisom erase I

E. Oct reot ide

E. Blockade of gon adot ropin receptors

F.

Cabergolin e



20. A 56-year-old m an recen tly diagn osed w ith carcin oid t u m or

24. An 8-year-old boy w as referred to a pediatric endocrinologist

of th e lung started a t reat m en t th at in cluded oct reot ide Th e

becau se of grow th retardat ion . Lab tests sh ow ed in creased

p at ien t w as m ost likely at in creased risk of w h ich of th e fol-

seru m grow th h orm on e levels bu t ver y low seru m levels of

low ing adverse e ects as a resu lt of th is th erapy?

in su lin -like grow th factor 1 (IGF-1). Fu r th er exam s led to th e

A. Gallston es

d iagn osis of Laron dw ar sm . W h ich of th e follow ing drugs

B. Drow sin ess

w ou ld be m ost app ropriate for th is boy?

C. Hyp oglycem ia

A. Som at rop in

D. Heat in toleran ce

B. Oct reot ide

E. Flush ing

C. Mecaserm in D. Oxan drolon e E. Cabergolin e

270

Endocrine System



25. A 70-year-old m an , recen tly diagn osed w ith a sm all-cell car-

28. A 36-year-old w om an com plain ed to h er physician of am en -

cin om a, w as adm it ted to th e h ospit al for su rgical resect ion

orrh ea for th e past 2 m on th s an d of a w h ite disch arge from

of the lung. On adm ission , the patient appeared lethargic and

h er breast s during th e past m on th . A com puted tom ography

con fused. Per t in en t lab resu lt s on adm ission w ere

scan sh ow ed a p it u it ar y aden om a. A drug w ith w h ich of th e

Seru m :

follow ing m ech an ism of act ion w ould be m ost appropriate

Na+ 120 m Eq/L (n orm al 136−145 m Eq/L)

for th is pat ien t?

K+ 4.8 m Eq/L (n orm al 4.5−5.0 m Eq/L)

A. St im ulat ion of dopam in e syn th esis

Osm olalit y 250 m Osm /L (n orm al 275−300 m Osm /L) Urin e:

B. St im ulat ion of grow th h orm on e (GH) m etabolism C. Blockade of GH receptors D. Blockade of D2 receptors

Na + 50 m Eq/L (n orm al 40−220 m Eq/L)

E. In h ibit ion of GH release

Osm olalit y 400 m Osm /L (n orm al 50−1200 m Osm /L)

F.

A dr ug from w h ich of th e follow ing classes w ould be usefu l in correct ing th e pat ien t’s elect rolyte im balan ce? A. Loop diuret ics B. Th iazide diuret ics C. Ant idiuret ic h orm on e (ADH) agon ists D. Glucocor t icoids E. ADH an t agon ists

Di cult y level: Medium 26. A 34-year-old m an presen ted to th e h ospit al w ith a h istor y of join t pain , h eadach e, excessive sw eat ing, an d deepen ing of th e voice. Physical exam in at ion revealed hyperten sion , en largem en t of th e h an d s, a doughy ap pearan ce of th e skin , an d a barrel ch est . A com pu ted tom ography scan disclosed a pit u it ar y ad en om a, an d th e p at ien t u n der w en t rad ioth erapy. W h ich of th e follow ing drugs w ould be appropriate for th is pat ien t w h ile w ait ing for radioth erapy to w ork? A. Leuprolide B. Cosyn t ropin C. Som at rop in D. Oct reot ide E. Degarelix

Di cult y level: Easy 27. A 36-year-old m an w as fou n d to h ave h igh serum levels of in su lin -like grow th factor 1 (IGF-1) du ring a regular clin ic visit . Ten m on th s earlier, th e m an w as diagn osed w ith acrom egaly an d un der w en t radiat ion th erapy, bu t th e t reat m en t w as on ly p ar t ially e ect ive, an d th e m an h ad been receiving oct reot ide sin ce th en . Addit ion of w h ich of th e follow ing d rugs w ou ld be app ropriate for th e pat ien t at th is t im e? A. Pegvisom an t B. Degarelix C. Leuprolide D. Cosyn t ropin E. Meth im azole

Act ivat ion of D2 receptors

Di cult y level: Medium 29. A 35-year-old w om an presen ted to h er gyn ecologist w ith con cern th at sh e an d h er h usban d h ad n ot con ceived despite u np rotected in tercou rse for t h e p ast 15 m on t h s. Fu r t h er exam s led to th e diagn osis of un explain ed in fert ilit y, an d th e w om an st arted a “step -u p ” p rotocol of ovu lat ion in d u ct ion th at in clu ded in it ial daily inject ion s of follit rop in alfa. Th e d rug can act ivate speci c receptors located in gran u losa cells of th e ovar y to produce w h ich of th e follow ing en zym es? A. Tran sglycosylase B. Topoisom erase II C. Dehydrogen ase D. Desm olase E. Arom atase

Di cult y level: Hard 30. A 34-year-old m an w as adm it ted to th e h ospit al because of prolonged, m assive w ater y diarrh ea for th e past 2 days. Physical an d lab exam s in dicated a pan creat ic t um or, an d radioim m u n oassay con rm ed th e diagn osis of vip om a. Th e p at ien t w as given in t raven ou s u ids for hydrat ion an d w as sch ed u led for su rger y. W h ich of th e follow ing drugs w ou ld be ap prop riate to con t rol th e p at ien t’s diarrh ea? A. Som atot ropin B. Hydroch loroth iazide C. Adren ocor t icot rop ic h orm on e (ACTH) D. Oct reot ide E. Cabergolin e F.

Leu p rolide

Di cult y level: Medium 31. A 35-year-old w om an presen ted to th e clin ic com plain ing of con t in uous th irst an d polyuria. Sh e reported th at sh e often aw oke at n igh t becau se of th irst an d th e n eed to u rin ate. Histor y sh ow ed t h at 6 m on t h s p reviou sly, sh e h ad su st ain ed

Questions: V-2 Drugs for Thyroid Disorders 271 a basal sku ll fract u re d u r in g a car accid en t from w h ich sh e

A. Fat t issu e

recovered com pletely. Lab test s sh ow ed a urin e osm olalit y of

B. Plasm a

20 m Osm /kg (n orm al 50−1200 m Osm /kg) an d u n detect able

C. Ext racellular uids

seru m an t idiu ret ic h orm on e (ADH) levels. W h ich of th e fol-

D. Cell cytosol

low ing drugs w ould be m ost ap prop riate for th is p at ien t?

E. Tot al body w ater

A. Hydroch loroth iazide B. Am iloride


C. Desm opressin

33. A 55-year-old w om an w as adm it ted to the em ergency de-

D. Carbam azepin e

partm ent w ith the diagnosis of septic sh ock. Despite

uid

E. Ch lorpropam ide

therapy and norepinephrine, she w as still hypotensive (80/50 m m Hg) an d t achycardic (120 bpm ), an d th e cardiologist de-


cided to star t an in t raven ou s in fu sion of an oth er drug. A few

32. A 7-year-old boy recen tly diagn osed w ith idiopath ic hypop -

m in u tes later, h er blood p ressu re w as 106/75 m m Hg, an d

it uit arism st arted a t reat m en t w ith som at ropin , a recom bi-

h er pulse w as 88 bpm . W h ich of th e follow ing w as m ost

n an t grow th h orm on e w ith a m olecular w eigh t of about

likely th e drug given to th e p at ien t?

22,000 D. W h ich of th e follow ing w as m ost likely th e m ain

A. Epin eph rin e

site of dist ribu t ion of th is drug?

B. Desm opressin C. Ph enyleph rin e D. Dobutam in e E. Vasopressin

Questions: V-2 Drugs for Thyroid Disorders Directions for questions 1−3

2 days. W h ich of th e follow ing w ere m ost likely th e p at ien t’s

Match each drug u sed in thyroid diseases w ith th e ap prop riate

seru m levels of free thyroxin e (FT4 ) an d thyroid-st im ulat ing

descript ion (each let tered opt ion can be selected on ly on ce, m ore

h orm on e (TSH, thyrot ropin ) after 2 days of th erapy?

th an on ce, or n ot at all):

A. FT4 low, TSH h igh

A. Levothyroxin e

B. FT4 h igh , TSH low

B. Liothyron in e

C. FT4 h igh , TSH h igh

C. Meth im azole

D. FT4 low, TSH low

D. Potassium iodide E. Propylth iouracil


F.


Radioact ive iodin e

because of fever, irritabilit y, in creased leth argy, an d m u lt ip le


ep isodes of diarrh ea. Th e m oth er rep or ted th at sh e fou n d h er

1. Th is drug is a t arget for thyroid deiodin ase.

levothyroxin e bot tle em pt y a few h ou rs earlier. Vit al sign s of th e boy w ere blood pressure 130/80 m m Hg, h ear t rate 180

Di cult y level: Easy 2. Th is drug causes thyroid cell n ecrosis.

Di cult y level: Easy 3. Th is drug acts m ain ly by in h ibit ing h orm on e release from th e thyroid glan d.

Di cult y level: Medium 4. A 64-year-old w om an w as adm it ted to th e em ergen cy depar t m en t w ith th e ad m it t ing diagn osis of m yxedem a com a. An em ergen cy t reat m en t w as st ar ted th at in cluded an in t raven ou s inject ion of t r iiod ot hyron in e (T3 ) ever y 6 h ou rs for

bp m , resp irat ion s 26/m in . Laborator y test resu lt s on adm ission sh ow ed a total t riiodothyron in e level of 472 ng/dL (n orm al: 40−130 ng/dL). An appropriate em ergen cy th erapy w as p lan n ed . W h ich of t h e follow ing d r ugs sh ou ld be ad m in istered

rst to con t rol h or m on e-related e ect s t h at cou ld be

rap idly leth al in th is pat ien t? A. Betam eth ason e B. Propran olol C. Potassium iodide D. Propylth iouracil E. Radioact ive iodin e

272

Endocrine System


w ou ld be ap p rop riate for th is p at ien t du ring th e rst t rim es-

6. A 50-year-old w om an w h o un der w en t thyroid ablat ion w ith

ter of pregn an cy?

radioact ive iodin e h ad been t aking levothyroxin e as rep lace-

A. Radioact ive iodin e

m en t th erapy. W h ich of th e follow ing best represen t s th e per-

B. Oct reot ide

cen t age of drug boun d to plasm a protein s in th is pat ien t?

C. Potassium iodide

A. 10.5%

D. Methyld op a

B. 30.57%

E. Propylth iouracil

C. 50.72%

F.

Esm olol

D. 75.0% E. 99.96 %

Di cult y level: Easy 10. A 53-year-old w om an su ering from thyrotoxicosis un der-


w en t thyroid ablat ion w ith radioact ive iodin e. Th ree w eeks

7. A few days after a n orm al deliver y, a n ew born baby boy be-

later, sh e st ar ted a th erapy w ith levothyroxin e. W h ich of th e

cam e leth argic, h ad respirator y di cult ies an d a h oarse cr y,

follow ing best describes th e m olecular m ech an ism of act ion

an d su cked p oorly. Physical exam in at ion revealed large fon t a-

of th is drug?

n elles, m acroglossia, a disten ded abdom en , cyan ot ic skin , hy-

A. Agonist at thyroid-stim ulating horm one (TSH) receptors

poton ia, slow re exes, an d rect al tem p erat u re of 95°F (35°C).

B. An tagon ist at TSH receptors


C. Agon ist at thyroid h orm on e (TH) receptors

baby?

D. An tagon ist at TH receptors

A. Meth im azole

E. Agonist at thyrotropin-releasing horm one (TRH) receptors

B. Som at rem

F.

An tagon ist at TRH receptors

C. Levothyroxin e D. Th eophyllin e


E. Potassium iodide

11. A 50-year-old w om an w h o u n d er w en t t hyroid ablat ion

F.

Predn ison e

w ith radioactive iodine started treatm ent w ith levothyroxine. W h ich of th e follow ing cell elem en t s represen t th e m ain site


of th erapeut ic act ion of th e drug?

8. A 51-year-old w om an su er ing from ch ron ic ast h m a w as

A. Cell m em bran e

ad m it ted to th e h ospit al w ith n au sea an d vom it ing, ext rem e

B. Mitoch on dria

restlessn ess, in som n ia, t rem or, m en t al con fu sion , an d fever

C. Sm ooth en dop lasm ic ret icu lu m

(103.1°F, 39.5°C). After h er sister died a few days ago, sh e ex-

D. Cell n u cleu s

perienced increased hunger, dyspn ea on exertion , palpitations,

E. Golgi apparat us

an d diarrh ea. Laborator y data on adm ission in cluded a free

F.

Lysosom es

thyroxin e (FT4 ) level of 11 ng/dL (n orm al 0.9−2.0 ng/dL) an d undetectable thyroid-stim ulating horm on e (TSH, thyrotropin)


levels. W h ich of th e follow ing drugs sh ou ld be in cluded in th e

12. A 53-year-old w om an recently diagnosed w ith hyperthyroid-

em ergen cy t reat m en t of th e p at ien t?

ism st arted an ap prop riate t reat m en t . On e m on th later, th e

A. Dilt iazem

follow ing laborator y valu es w ere obtain ed:

B. Radioact ive iodin e C. Triiodothyron in e D. Dan azol E. Propran olol F.

Aspirin

Red blood cell cou n t (RBC): 4.6 × 10 6 /m m 3 (n or m al 4.0−5.5 × 10 6 /m m 3 ) W h ite blood cell cou n t (W BC): 0.6 × 10 3 /m m 3 (n or m al 3.2−9.8 × 10 6 /m m 3 ) Platelet s 180 × 10 3 /m m 3 (n orm al 140−400 × 10 6 /m m 3 )


Which of the follow ing drugs m ost likely caused these results?

9. A 30-year-old w om an w h o w as 1 m on th pregn an t com plain ed

A. Radioact ive iodin e

to h er physician of sw elling of th e eyelids an d in creasing lid

B. Potassium iodide

apert ure. Su bsequen t blood test s gave th e follow ing resu lt s:

C. Meth im azole

free thyroxin e (FT4 ) 3.3 ng/dL (n orm al 0.9−2.0 ng/dL), thyroid-

D. Propran olol

st im u lat ing h orm on e (TSH, thyrot ropin ) < 0.01 m U/L (n orm al

E. Levothyroxin e

0.5−5.0 m U/L). Treat m en t w ith w h ich of th e follow ing drugs

Questions: V-2 Drugs for Thyroid Disorders 273 Di cult y level: Medium



16. A 67-year-old w om an com plain ed to h er physician th at for

of an orexia, m alaise, jau n d ice, an d r igh t u p p er qu ad ran t

th e p ast few days sh e h ad experien ced restlessn ess an d fre-

abd om in al pain for th e p ast 2 days. Th e w om an , w h o w as

quent runs of tachycardia. The w om an had undergone thyroid

2 m on th s’ p regn an t , w as diagn osed w ith hyp er thyroidism

ablat ion 7 m on th s earlier an d st ar ted rep lacem en t th erapy

1 m on th ago an d star ted an ap prop riate th erapy. Pert in en t

w ith levothyroxine. Further exam s led to the diagnosis of hy-

lab result s on adm ission in cluded alan in e am in ot ran sferase

p er t hyroid ism , m ost p robably d u e to excessive self-d osage

of 410 U/L (n orm al 20−40 U/L). W h ich of th e follow ing drugs

of t h e d r ug. W h ich of t h e follow in g d isord ers m ost likely

m ost likely cau sed th e p at ien t’s disorder?

cau sed th e p at ien t’s tachycard ia?

A. Meth im azole

A. Hyp er t rop h ic card iom yop athy

B. Radioact ive iodin e

B. At rial brillat ion

C. Propylth iouracil

C. Mit ral regu rgitat ion

D. Propran olol

D. Mit ral sten osis

E. Potassium iodide

E. Con st rict ive p ericardit is



14. A 40-year-old m an com plain ed to h is physician of in creased

17. A 44-year-old w om an recen tly diagn osed w ith Graves dis-

app et ite, p alp it at ion s, an d d iarrh ea. Laborator y resu lts con -

ease started a therapy w ith m ethim azole. Inhibition of w hich

rm ed th e diagn osis of m ild hyp erthyroidism , an d a t reat-

of th e follow ing en zym es m ost likely m ediated th e th era-

m en t w ith m eth im azole w as st arted. W h ich of th e follow ing

p eut ic e ect of th e drug in th e pat ien t’s disease?

act ion s m ost likely con t ribu ted to th e th erapeu t ic e

A. Thyroid p rotease

cacy

of th e drug in th is pat ien t?

B. Topoisom erase I

A. Proteolysis of thyroglobu lin

C. Thyroid m on odeiodin ase

B. St im u lat ion of thyroid p eroxidase

D. Thyroid p eroxidase

C. Blockade of iodin e uptake by th e thyroid glan d

E. Thyroid aldolase

D. Accu m u lat ion of iod in e in to thyroglobu lin E. In h ibit ion of iodin at ion of t yrosin e residues

Di cult y level: Medium 18. A 60-year-old alcoh olic w om an w as brough t to th e em er-


gen cy dep art m en t after a car acciden t . Medical h istor y of


th e p at ien t w as sign i can t for h ep at ic cirrh osis an d hyp o-

som n ia. Th e w om an h ad u n dergon e rad ioiodin e t reat m en t

thyroidism . Although she had been advised repeatedly to take

for thyroid ablat ion 6 m on th s earlier an d st arted replace-

h er thyroxin e regu larly, sh e con t in u ed to t ake it sp oradically.

m en t th erapy w ith levothyroxin e. Fu rth er qu est ion ing re-

Physical exam in at ion sh ow ed a dist ressed pat ien t com plain -

vealed th at sh e h ad recen tly in creased h er daily drug dose

ing of severe p ain in bot h legs. An in t ram u scu lar inject ion

becau se sh e felt fat igu ed an d sad . A lab test sh ow ed thyroid-

of m or p h in e su lp h ate w as given to allay p ain . Soon after

st im u lat ing h orm on e (TSH) 0.1 m U/L (n orm al 0.5−5.0 m U/L)

t h e inject ion , th e pat ien t sh ow ed disorien t at ion , leth argy,

an d free thyroxin e (FT4 ) 2.4 ng/dL (n orm al 0.8−2.7 ng/dL).

an d sh allow breath ing, follow ed by u n con sciou sn ess. Her

W h ich of th e follow ing sign s an d sym ptom s m ost likely oc-

tem perat u re w as 93°F (30°C). W h ich of th e follow ing d rugs

cu rred in th is p at ien t after th e in ap p rop riate in crease of th e

should be included in the em ergen cy therapy of this patient?

drug dose?

A. In t raven ous (IV) potassium iodide

A. Decreased h eart rate

B. Oral m eth im azole

B. Fluid reten t ion

C. Oral levothyroxin e

C. Decreased diastolic pressure

D. IV t riiodothyron in e

D. Decreased body tem perat ure

E. Oral propylth iouracil

E. An orexia F.

Con st ip at ion

274

Endocrine System


A. Dilt iazem an d m eth im azole

19. A 45-year-old w om an com plained to her physician of cold in-

B. Aspirin an d aten olol

toleran ce and m enstrual irregularities over the past 3 w eeks.

C. Radioact ive iodin e an d dexam eth ason e

Th e w om an , recen tly diagn osed w ith Graves disease, h ad

D. Esm olol an d verapam il

star ted a t reat m en t w ith m eth im azole 2 m on th s earlier. Th e

E. Propylth iouracil an d pot assiu m iodide

p hysician told th e pat ien t th at h er sym ptom s w ere m ost likely d ue to an excessive dose of m eth im azole. W h ich of th e


follow ing e ects could also occur as a result of an excessive

23. A 48-year-old m an com plain ed to h is physician of a feeling

d ose of th at drug?

of fu lln ess in h is n eck. Physical exam in at ion sh ow ed d i u se

A. Palp itat ion s

en largem en t of t h e t hyroid glan d w it h ou t any ap p aren t

B. Sw eat ing

m asses. Further exam s led to the diagnosis of nontoxic goiter,

C. In som n ia

m ost likely en d em ic becau se t h e m an lived in an iod in e-

D. Trem or

d e cien t cou n t r y. Iod ide su p p lem en t at ion w as p rescr ibed

E. Con st ip at ion

to provide su

cien t iodide ion s to th e thyroid. Th ese ion s

cross thyroid cell m em bran es by act ive t ran sp or t . W h ich of

Di cult y level: Easy 20. A 46-year-old m an w as t aking levothyroxin e as replacem en t

th e follow ing is th e p rim ar y t ran sporter carr ying iodide ion s th rough th e ap ical m em bran e of thyroid follicu lar cells?

th erapy follow ing radioact ive iodin e-in du ced thyroid abla-

A. Na +/iodin e sym por ter

t ion . W h ich of th e follow ing m olecu lar act ion s m ost likely

B. Su lfate exch anger

m ediated th e m ajorit y of th erapeu t ic e ect s of th e d rug in

C. Cl−/iodide exch anger

th is p at ien t?

D. Na +/K+ exch anger

A. Alterat ion of t ran script ion of speci c gen es B. Decreased Na +/K+ ATPase act ivit y C. In h ibit ion of RNA act ivit y D. In h ibit ion of m itoch on drial oxidat ive ph osph or ylat ion E. In creased plasm a catech olam in e levels

E. Na +/Cl− sym p or ter

Di cult y level: Medium 24. A 64-year-old m an com plain ed to h is physician of con st ipat ion , cold in toleran ce, an d abn orm al sen sat ion s in h is h an ds an d feet . A blood test sh ow ed th e follow ing resu lt s:

Di cult y level: Easy 21. A 29-year-old w om an com plain ed to h er physician of fa-

Free t r iiod ot hyron in e (FT3 ) 0.02 n g/d L (n or m al 0.23− 0.42 ng/d l)

t igu e, con st ip at ion , an d m en st ru al irregu larit ies for th e p ast

Free thyroxin e (FT4 ) 0.2 ng/dL (n orm al 0.8−2.7 ng/dL)

2 m on t h s. Physical exam in at ion sh ow ed d elayed d eep ten -

Thyroid-st im u lat ing h orm on e (TSH) 0.1 m U/L (n orm al

d on re exes, m ild bradycard ia, an d a n on ten d er, n od u lar thyroid goiter. A blood an alysis sh ow ed thyroid p eroxidase an t ibodies of 120 IU/L (n orm al < 0.8 IU/L). W h ich of th e follow ing drugs w ould be m ost ap prop riate for th is pat ien t? A. Meth im azole B. Potassium iodide C. Levothyroxin e D. Eth inyl est radiol E. Radioact ive iodin e

Di cult y level: Hard 22. A 50-year-old w om an su ering from hyperthyroidism w as adm it ted to th e em ergen cy depar t m en t w ith th e adm it t ing d iagn osis of thyroid storm . Fur th er exam s con rm ed th e diagnosis, an d an em ergency therapy w as started that included propranolol an d hydrocortisone. W hich of the follow ing pairs of drugs sh ould also be added to th e em ergen cy t reat m en t of th is p at ien t?

0.5−5.0 m U/L) A com puted tom ography scan con rm ed th e diagn osis, an d an appropriate th erapy w as plan n ed. W h ich of th e follow ing w as m ost likely th e p at ien t’s disease? A. Hash im oto thyroidit is B. Graves disease C. Myxed em a D. Pit u it ar y t u m or E. Thyroid can cer

Di cult y level: Easy 25. A 24-year-old w om an w it h Hash im oto t hyroid it is w as 6 w eeks’ p regn an t . Th e on ly m edicat ion sh e w as taking w as levothyroxin e. Laborator y test resu lt s sh ow ed free thyroxin e (FT4 ) 0.6 n g/d L (n or m al 0.7−1.9 n g/d L) an d t hyroid -st im u lat ing h orm on e (TSH) 4.8 m U/L (n orm al 0.5−5.0 m U/L). Th e p hysician d ecid ed to in crease h er daily d ose of levot hyroxin e by abou t 30%. W h ich of th e follow ing best explain s th e

Questions: V-2 Drugs for Thyroid Disorders 275 prim ary reason for careful adjustm en t of the levothyroxin e

A. Longer h alf-life

dose du ring p regn an cy?

B. Less frequ en t adverse e ects

A. To avoid m atern al p reeclam p sia

C. High er a

B. To con t rol m atern al w eigh t gain

D. Bet ter gast roin test in al absorpt ion

C. To avoid m atern al m yxed em a com a

E. High er volu m e of dist ribu t ion

n it y for thyroid receptors

D. To m ain tain n orm al fetal brain develop m en t E. To cou n teract t h e TSH act ivit y of h u m an ch or ion ic gon adot rop in

Di cult y level: Medium 29. A 50-year-old w om an com plain ed to h er physician of sleep in ess, fat igu e, cold in toleran ce, w eigh gain , an d con st ip at ion .


Medical h istor y w as sign i can t for a reen t ran t su p raven t ric-

26. A 43-year-old m an w as un dergoing surger y to rem ove a ver y

u lar t achycard ia p resen t ly t reated w it h am iodaron e an d for

large n on toxic goiter, apparen tly due to iodide d e cien cy.

t yp e 2 d iabetes p resen t ly t reated w it h m et for m in . Fu r t h er

A sh ort course of pot assium iodide w as adm in istered before

exam s led to t h e d iagn osis of m ild hyp ot hyroid ism , an d an

su rger y. W h ich of th e follow ing st atem en t s best exp lain s

ad equ ate t reat m en t w as p lan n ed . W h ich of th e follow in g

w hy th is drug w as given to th e pat ien t?

w ou ld be th e m ost ap p rop riate in it ial th erap eu t ic step for

A. To st im u late thyroid h orm on e syn th esis before su rger y

th is p at ien t?

B. To overcom e iodin e de cien cy after su rger y

A. St art oral levothyroxin e.

C. To redu ce th e size an d vascu larit y of th e thyroid glan d

B. St art oral pot assiu m iodide.

D. To decrease th e risk of hypothyroidism after su rger y

C. St art oral liothyron in e.

E. To in h ibit th e excessive secret ion of thyroid-st im u lat ing

D. With d raw m etform in .

h orm on e (TSH, T4 ) from th e pit uit ar y

E. With d raw am iodaron e.



27. A 57-year-old w om an w as adm it ted to th e h ospit al w ith

30. A 75-year-old w om an com p lain ed to h er p hysician of ver y

restlessn ess, in som n ia, t rem or, an d pron oun ced exoph th al-

d r y skin an d con st ip at ion , w h ich sh e t reated w it h m ilk of

m os. Th e w om an , w h o h ad been su ering from Graves dis-

m agn esia. Sh e h ad n o ot h er m ed ical p roblem s an d took

ease for 3 m on th s, h ad been t reated w ith propylth iouracil,

n o ot h er m edicat ion s. A blood an alysis gave t h e follow ing

bu t th e drug h ad been discon t in u ed a few days earlier be-

resu lt s:

cau se of th e app earan ce of n eu t rop en ia. W h ich of th e fol-

Free t r iiod ot hyron in e (FT3 ): 0.3 n g/d L (n or m al 0.23−

low ing agen t s w ou ld be m ost appropriate for th e longterm

0.42 ng/d L)

m an agem en t of th e pat ien t at th is t im e?

Free thyroxin e (FT4 ): 0.9 ng/dL (n orm al 0.8−2.7 ng/dL)

A. Meth im azole

Thyroid-stim ulating horm one (TSH, thyrotropin): 15 m U/L

B. Radioact ive iodin e

(n orm al 0.5−5.0 ng/dL)

C. Propran olol D. Predn ison e E. Potassium iodide

Thyroperoxidase ant ibodies: 28 IU/L (n orm al < 0.8 IU/L) W h ich of th e follow ing drugs w ould be appropriate for th is pat ien t?


A. Potassium iodide

28. A 53-year-old w om an w h o h ad un dergon e tot al thyroidec-

B. Propran olol

tom y started replacem en t therapy w ith levothyroxine. W hich

C. Meth im azole

of th e follow ing ph arm acological proper t ies best explain s

D. Lop eram id e

w hy th e levo isom er of th e h orm on e is curren tly used in -

E. Levothyroxin e

stead of a racem ic m ixt u re for replacem en t th erapy in thy-

F.

roid disorders?

Dilt iazem

276

Endocrine System

Questions: V-3 Corticosteroids and Antagonists Directions for questions 1−5


Match each cor t icosteroid or an t agon ist w it h t h e ap p rop r iate descript ion (each let tered opt ion can be selected on ly on ce).

7. A 57-year-old m an su ering from severe derm atom yosit is h ad been receiving h igh -d ose p red n ison e for 6 m on t h s.

A. Am in ogluteth im ide

W h ich of t h e follow ing laborator y resu lt s w ou ld be m ost

B. Aldosteron e

likely to occu r in th is p at ien t?

C. Desoxycor t icosteron e

A. Hyp on at rem ia

D. Dexam eth ason e

B. Hyp ocalcem ia

E. Fludrocort ison e

C. Hyp erkalem ia

F.

D. Hyp oglycem ia

Hydrocor t ison e

G. Ketocon azole

E. Hyp erch lorem ia

H. Mifep riston e I.

Predn ison e

L.

Sp iron olacton e

Di cult y level: Easy 8. A 74-year-old w om an w ith a long h istor y of rh eu m atoid arth rit is h as been receiving p redn ison e for th e past 3 m on th s.


Sh e also h as been receiving captopril to t reat h er hyperten -

1. A glucocort icoid devoid of salt-retain ing act ivit y

sion . W h ich of th e follow ing laborator y resu lts w ou ld be m ost likely to occu r in th is p at ien t?


A. Hyp on at rem ia

2. A m in eralocort icoid an tagon ist

B. Hyp ercalcem ia C. Hyp okalem ia

Di cult y level: Easy 3. A m in eralocort icoid used to t reat adren al in su

D. Hyp erglycem ia cien cy

Di cult y level: Easy 4. This drug blocks the conversion of cholesterol to pregnenolone.

E. Hyp och olesterolem ia

Di cult y level: Easy 9. A 42-year-old w om an, recently diagnosed w ith lupus erythem atosus, started a therapy w ith high-dose dexam ethasone.

Di cult y level: Easy 5. Th is drug blocks th e cytoplasm ic glucocort icoid receptors.

Di cult y level: Easy 6. A 66-year-old m an com plain ed to h is physician of h ear tburn an d a w eigh t gain of 15 lb (6.8 kg). Th e pat ien t , w h o w as su ffering from m yasth en ia gravis, h ad been receiving a m u lt iple drug t reat m en t for 3 m on th s. Lab resu lts sh ow ed seru m calciu m of 7.4 m g/dL (n orm al 8.5−10.5 m g/dL) an d fast ing blood glu cose of 160 m g/dL (n orm al 70−110 m g/dL). W h ich of th e follow in g d r ugs m ost likely cau sed t h e p at ien t ’s sign s an d sym ptom s? A. Fludrocort ison e B. Edroph on ium C. Azath iop rin e D. Neost igm in e

W h ich of th e follow ing best explain s w hy syn th et ic glucocor t icoids are usually preferred over cort isol in th e th erapy of n on en docrin e disorders? A. Lack of u lcerogen ic act ivit y B. Less p ron e to in du ce salt an d w ater reten t ion C. Less p ron e to in du ce m yop athy D. Less p ron e to in du ce opp ort u n ist ic in fect ion s E. Lack of d iabetogen ic e ect s

Di cult y level: Medium 10. A 45-year-old m an com plain ed to h is physician of severe sh ou lder pain . Fu r th er exam s led to th e diagn osis of acu te bu rsit is, an d in t ra-art icu lar inject ion s of dexam eth ason e w ere p rescribed . W h ich of th e follow ing act ion s m ost likely con t r ibu ted to t h e t h erap eu t ic e

cacy of t h e d r ug in t h e

p at ien t’s disease?

E. Testosteron e

A. Inhibition of adrenocorticotropic horm one (ACTH) release

F.

B. In creased cat abolism of prostaglan din s

Dexam eth ason e

C. In creased postcapillar y perm eabilit y D. In creased release of in terleukin -1 E. In du ct ion of lipocor t in syn th esis

Questions: V-3 Corticosteroids and Antagonist s 277 Di cult y level: Easy



14. A 65-year-old m an com plain ed to h is physician of epigast ric

of in creasing m u scle w eakn ess, an xiet y, an d loss of em o-

d ist ress, m u scle w eakn ess, hyp er ten sion , an d w h ite plaqu es

t ion al con t rol. Th e pat ien t w as diagn osed w ith p olym yosit is

in h is m ou t h . Th e p at ien t , diagn osed w it h p olyar ter it is

5 m on th s ago an d h ad been receiving an app ropriate th erapy

n odosa 8 m on th s ago, h ad been receiving an app ropriate

sin ce th en . Physical exam in at ion sh ow ed a p at ien t w ith face

th erapy sin ce th en . Laborator y valu es sh ow ed fast ing blood

an d t r u n k obesit y an d t h in an d easily br u ised skin . Vit al

glucose of 135 m g/dL (norm al 70−110 m g/dL) and blood urea

sign s w ere blood p ressu re 168/98 m m Hg, p u lse 84 bp m ,

n it rogen (BUN) of 40 m g/dL (n orm al 7−18 m g/dL). W h ich of

respirat ion s 18/m in . A bon e x-ray revealed di use osteopo-

th e follow ing drugs m ost likely cau sed th e pat ien t’s sign s

rosis. W h ich of th e follow ing drugs m ost likely caused th e

an d sym ptom s?

p at ien t’s sign s an d sym ptom s?

A. In dom eth acin

A. Meth ot rexate

B. Ketocon azole

B. Azath iop rin e

C. Flu d rocort ison e

C. Fludrocort ison e


D. Cycloph osph am ide

E. Predn ison e

E. Dexam eth ason e

F.

F.

Ibuprofen

Mifep riston e

Di cult y level: Medium Di cult y level: Hard

15. A 57-year-old w om an com plain ed to h er physician of m u s-

12. A 46-year-old obese w om an w as brough t un con scious to th e

cle w eakn ess, recurren t epigast ric dist ress, an d dull, ach ing

em ergency departm ent. The w om an had been su ering from

back p ain . Th e w om an , recen tly diagn osed w ith severe u l-

asth m a u su ally con t rolled w ith in h aled albu terol. Oral pred-

cerat ive colit is, h ad been taking an appropriate th erapy for

n ison e w as added to th e th erapeut ic regim en 3 w eeks ago

5 m on th s. Laborator y valu es sh ow ed a decreased n u m ber of

becau se of an exacerbat ion of h er d isease. Vit al sign s on ad-

lym phocytes and an increased num ber of neutrophils. W hich

m ission w ere blood p ressu re 130/85 m m Hg, h eart rate 120

of th e follow ing drugs m ost likely caused th e pat ien t’s sign s

bpm , respirations 22/m in. Physical exam ination showed a pa-

an d sym ptom s?

t ien t u n resp on sive to verbal st im u li, w ith draw n to p ain , an d

A. Predn ison e

w ith pupils equ al an d react ive. Per t in en t laborator y n dings

B. Mesalam in e

on ad m ission w ere fast in g blood glu cose 900 m g/d L (n or-

C. Lop eram id e

m al 70−110 m g/dL), seru m osm olalit y 500 m Osm /L (n orm al

D. Azath iop rin e

< 350 m Osm /L). Urin alysis: speci c gravit y 1.030, glucose

E. In ixim ab

4+, n o protein s, n o keton es. W h ich of th e follow ing disorders

F.

Met ron idazole

m ost likely cau sed th e p at ien t’s sign s an d sym ptom s? A. Predn ison e-precipitated hyperosm olar com a


B. Albuterol-precipitated diabet ic ketoacidosis

16. A 33-year-old w om an su ering from lu pus er yth em atosus

C. Predn ison e-in du ced diabet ic ketoacidosis

w as ad m it ted to t h e h osp it al becau se of fever (101.1°F,

D. Albuterol-in duced ven t ricular t achycardia

38.5°C), cough , dysp n ea, an d t h oracic p ain aggravated by

E. Albuterol-in duced cerebral edem a

breath ing. Sh e h ad been receiving h igh doses of oral p red n ison e for 3 m on t h s to t reat a

are-u p of t h e d isease. Ch est


x-rays con r m ed t h e d iagn osis of p leu ral e u sion , an d a

13. A 42-year-old m an com plain ed to h is physician of progres-

sputum test showed acid-fast rods. The patien t did not sm oke,

sive loss of vision . Th e m an , diagn osed w ith rh eu m atoid ar-

an d past h istor y for p u lm on ar y disease w as u n rem arkable.

th rit is 6 m on th s ago, h ad been receiving a h igh d ose of a

W h ich of t h e follow ing d isord ers m ost likely cau sed t h e

d rug sin ce th en . An oph th alm ic exam in at ion revealed early


cataract form at ion . W h ich of th e follow ing drugs m ost likely

A. Pn eum ococcal pn eum on ia

cau sed th e p at ien t’s sign s an d sym ptom s?

B. Ch ron ic obst ruct ive pulm on ar y disease

A. Mifep riston e

C. Pu lm on ar y t ubercu losis

B. Predn ison e

D. Mycop lasm al p n eu m on ia

C. Fludrocort ison e

E. Pu lm on ar y brosis

D. Meth ot rexate

F.

E. Azath iop rin e F.

Cycloph osph am ide

Acu te p ericardit is

278

Endocrine System


A. Min oxidil

17. A 49-year-old w om an un der w en t a blood test during a rou -

B. Fu rosem id e

t in e clin ic visit . Th e w om an , recen tly diagn osed w ith lu pu s

C. Predn ison e

er yt h em atosu s, h ad been receivin g h igh -d ose p red n ison e


for 3 w eeks. W h ich of th e follow ing ch anges in th e pat ien t’s

E. Flu d rocort ison e

blood cell con cen t rat ion m ost likely occu rred as a resu lt of

F.

Testosteron e

h er th erapy? A. Decreased n eut roph ils B. Decreased er yth rocytes

Di cult y level: Medium 21. A 57-year-old w om an h ad been receiving h igh -dose beta-

C. In creased basoph ils

m eth ason e for 6 m on th s to t reat severe relapsing polych on -

D. Decreased lym ph ocytes

d rit is. Becau se of th e ongoing th erapy, th e pat ien t w as m ost

E. In creased eosin oph ils

likely at in creased risk of w h ich of th e follow ing disorders? A. Exert ion al angin a


B. Osteoporosis

18. A 12-year-old boy, recen tly diagn osed w ith acute lym ph o-

C. Rh eu m atoid ar th rit is

blast ic leu kem ia, received a m u lt idrug t reat m en t th at in -

D. Agran u locytosis

cluded prednisone. The therapeutic e ect of the drug is m ost

E. Ulcerat ive colit is

likely m ediated by th e drug−receptor com plex bin ding to w h ich of th e follow ing m olecular target s?


A. Fin al sequ en ce on p ept idyl RNA

22. A 41-year-old w om an w as p rep ar ing to u n dergo su rger y

B. Sp eci c n u cleot ide sequ en ces on DNA

to rem ove a biliar y calcu lu s. Th e w om an h ad su ered from

C. Fin al sequ en ce on ribosom al RNA

T-cell lym p h om a t reated su ccessfu lly w it h a fou r-d r ug

D. Ph osp h olip ase A2

com bin at ion th at in clu ded p redn ison e. Th e th erapy en ded

E. In terleukin -6

6 m on th s previou sly. Th e p hysician p rescribed a cou rse of

F.

p redn ison e t reat m en t before th e u pcom ing su rger y. W h ich

Cyclooxygen ase-2

of th e follow ing w as m ost likely th e prim ar y goal for restar t-


ing predn ison e t reat m en t in th is pat ien t?

19. A 72-year-old m an com plain ed to h is physician of large pur-

A. To avoid adren al in su

cien cy after su rger y

p le blotch es on h is arm s th at did n ot seem to disap pear in

B. To sp eed u p su rgical w ou n d h ealing

a reason able am ou n t of t im e. Th e m an , recen tly d iagn osed

C. To avoid op port u n ist ic in fect ion s after su rger y

w it h d er m atom yosit is, h ad st ar ted an ap p rop r iate t h erapy

D. To p rom ote gallbladd er relaxat ion before su rger y

3 w eeks earlier. W h ich of t h e follow in g d r ugs m ost likely

E. To decrease adren ocorticotropic horm one (ACTH) release before su rger y

cau sed th e adverse e ect reported by th e p at ien t? A. Warfarin B. Predn ison e C. Heparin

Di cult y level: Easy 23. A 46-year-old w om an su ering from polyar terit is n odosa,

D. Meth ot rexate

an au toim m u n e disease, h ad been receiving h igh -dose dexa-

E. Azath iop rin e

m eth ason e. W h ich of th e follow ing act ion s m ost likely con -

F.

t ribu ted to th e th erapeu t ic e ect of th e drug in th e p at ien t’s

Cyclosporin e

d isease?


A. In h ibit ion of cat abolism of prost aglan din s


B. In h ibit ion of liver protein syn th esis

a 1-m on th h istor y of hyp er ten sion , h ear tbu rn , paresth esias,

C. In creased proliferat ion of B cells

an d t ran sien t paralysis. Seru m valu es on adm ission w ere Na +

D. In creased act ivat ion of com plem en t system

150 m Eq/L (n orm al 136−145 m Eq/L), K+ 2.4 m Eq/L (n orm al

E. In h ibit ion of cat abolism of in terleukin -1

3.5−5.0 m Eq/L), pH 7.5, an d decreased plasm a ren in act ivit y.

F.

In h ibit ion of syn th esis of t um or n ecrosis factor (TNF)

A com puted tom ography scan sh ow ed hyper t rophy of both adren al glan ds. W h ich of th e follow ing drugs w ou ld be ap -


propriate to t reat th e pat ien t’s disease?

24. A 40-year-old w om an w as adm it ted to the hospital com plaining of nausea and vom iting, weigh t loss, fatigue, and weakn ess. Sh e also repor ted a persisten t feeling of fain t n ess on

Questions: V-3 Corticosteroids and Antagonist s 279 stan ding an d decreased toleran ce to cold. Physical exam in a-


t ion sh ow ed a p at ien t in m oderate d ist ress w ith in creased

27. A 63-year-old m an w ith kn ow n m et ast at ic prost ate can cer

pigm en tat ion arou n d th e n ip ples, absen ce of axillar y an d

w as adm it ted to th e h osp it al becau se of su d den on set of low

pubic hair, and di use tanning of exposed portions of the body.

back p ain th at p rogressed over 24 h ou rs. He also n oted th at

Sign i can t seru m levels on adm ission w ere Na + 130 m Eq/L

h is legs w ere w eaker th an usual. Neurologic exam on adm is-

(norm al 136−145 m Eq/L), K+ 6.2 m Eq/L (norm al 3.5−5.0 m Eq/L),

sion sh ow ed hyperre exia, an d m agn et ic reson an ce im aging

fast ing blood glu cose 42 m g/dL (n orm al 70−110 m g/dL).

(MRI) dem on st rated spin al cord com pression at th e T12 ver-

W h ich of th e follow ing pairs of drugs w ould be appropriate

tebra. A dr ug w as adm in istered to reduce spin al cord edem a.


Th e follow ing day, both th e back pain an d th e hyp erre exia

A. Mifep riston e an d p redn ison e

w ere su bst an t ially decreased. W h ich of th e follow ing d rugs

B. Dan azol an d cor t isol

w as m ost likely given ?

C. Fludrocort ison e an d spiron olacton e

A. Flu d rocort ison e

D. Cort isol an d p redn ison e

B. Ibuprofen

E. Fludrocort ison e an d cort isol

C. Predn ison e D. Ketorolac


E. Fu rosem id e

25. A 43-year-old m an w as adm it ted un con scious to th e em er-

F.

Sp iron olacton e

gen cy depar t m en t . Th e m an h ad been su ering from bron ch ogen ic carcin om a for 8 m on th s. Vital sign s on adm ission


w ere blood p ressu re 90/50 m m Hg, p u lse 95 bp m , resp i-

28. A 54-year-old m an , recen t ly d iagn osed w it h im m u n ologic

rat ion s 10/m in . Physical exam in at ion revealed sign s of in -

t h rom bocytop en ic p u r p u ra, st ar ted t reat m en t w it h a large

creased in t racran ial p ressu re, an d a com pu ted tom ography

d ose of an app ropriate drug. Th e m olecular m ech an ism of

scan d isclosed d i u se cerebral ed em a d u e to brain m et as-

act ion of th at drug involved bin d ing to a receptor−h eat sh ock

t ases. Th e ap prop riate em ergen cy t reat m en t of th is p at ien t

p rotein com p lex in th e cytop lasm . W h ich of th e follow ing

sh ou ld in clu de w h ich of th e follow ing drugs?

d rugs w as m ost likely p rescribed?

A. Epin eph rin e


B. Albuterol

B. Azath iop rin e

C. Dexam eth ason e

C. Noreth in dron e

D. Nit roglycerin

D. Predn ison e

E. Dilt iazem

E. Calcit riol

F.

F.

Nifedipin e

Eth inyl est radiol




29. A 43-year-old m an presen ted to th e h ospital com plain ing of

of fever (102.7°F, 39.2°C), ch ills, an d w orsen ing dyspn ea th at

w eigh t gain , m ild bu t con t in u ing facial acn e, an d decreased

required in t ubat ion an d m ech an ical ven t ilat ion just after

m u scle st rength . On p hysical exam in at ion , th e pat ien t w as

ad m ission . A ch est rad iograp h sh ow ed bilateral p atchy al-

fou n d to be pleth oric, red-faced w ith violaceous pigm en ted

veolar in lt rates. Th e pat ien t w as given er yth rom ycin an d

st riae on a p rot u beran t abdom en , an d w ith relat ively th in

cefepim e for presum ed bacterial pn eum on ia, but 24 h ours

ext rem it ies. On adm ission , serum K+ levels w ere 4.5 m Eq/L

later a repeat ch est radiograph sh ow ed p rogression of th e

(n orm al 3.5−5.0 m Eq/L). A com puted tom ography scan dis-

in lt rates. A bron ch oscopy w ith bron ch oalveolar lavage w as

closed an adren al aden om a in th e left adren al glan d, an d th e

p erform ed, an d a di eren t ial cell coun t of a lavage specim en

pat ien t w as sch eduled for su rger y. W h ich of th e follow ing

show ed 33%eosinophils. W hich of th e follow ing drugs w ould

drugs w ou ld be app ropriate to give to th is p at ien t during

be ap prop riate for th is pat ien t?

an d after surger y?

A. Van com ycin


B. Acyclovir

B. Sp iron olacton e

C. Predn ison e

C. Cort isol

D. Ketocon azole

D. Am in ogluteth im ide

E. Piperacillin

E. Mifep riston e

F.

F.

Gen t am icin

Ketocon azole

280

Endocrine System


A. In dom eth acin

30. A 53-year-old w om an com plain ed to h er physician of w eigh t

B. Er yth rom ycin

gain , m ild bu t con t in u ing facial acn e, an d p igm en ted st riae

C. Dan azol

on h er abdom en . Furth er exam s led to th e diagn osis of Cush -

D. Oct reot ide

ing syn drom e, an d a pharm acotherapy w as prescribed. W h ich

E. Betam eth ason e

of th e follow ing drugs w ould be m ost appropriate to t reat

F.

Mifep riston e



A. Predn ison e

34. A 22-year-old m an w as ad m it ted to t h e em ergen cy d e-

B. Fludrocort ison e C. Ketocon azole

p ar t m en t becau se of dysp n ea, p r u r it u s, an d er yt h em a t h at


d evelop ed soon after receiving an am p icillin inject ion . On

E. Meth im azole

adm ission , the m an w as w heezing and had prom in ent sw ell-

F.

ing of th e face, eyelids, lip s, an d tongu e. A diagn osis of drug

Triam teren e

an aphylaxis w as m ade, an d an inject ion of ep in ep h rin e w as given . W h ich of th e follow ing drugs sh ou ld also be adm in is-

Di cult y level: Easy 31. A 24-year-old w om an com plain ed to h er physician th at sh e

tered to th e pat ien t?

h ad to go to th e bath room several t im es at n igh t . Tw o w eeks

A. Aspirin

earlier, t h e w om an h ad st ar ted a t reat m en t w it h sp iron o -

B. Predn ison e

lacton e for excessive h air on h er face an d arm s. W h ich of th e

C. Ph enyleph rin e

follow ing m olecular act ion s m ost likely m ediated th e pa-

D. Acetam in op h en

t ien t’s n oct u ria?

E. Aten olol

A. Com p et it ive blockade of α 1 receptors of th e bladder in tern al sph in cter B. Act ivat ion of M 3 receptors on th e det r usor m uscle C. Osm ot ic act ion on th e th in descen ding loop of Hen le D. Com p et it ive blockade of aldosteron e receptors E. Blockade of Na +/Cl− sym port in th e early d istal t u bu le

F.

Dopam in e

Di cult y level: Medium 35. A 45-year-old w om an su ering from Croh n disease h ad been receiving h igh doses of oral p redn ison e to t reat a severe are-up. W h ich of th e follow ing act ion s w as m ost likely to con t ribute to th e th erapeut ic e ect of th e drug in th e pa-



32. A 52-year-old m an w ith Addison disease presen ted to th e

A. In creased cat abolism of prostaglan din s

h ospital com plaining of episodic weakness, paresthesias, and

B. Decreased n um ber of circu lat ing n eut roph ils

con st ipat ion . He h ad been t aking cor t isol an d

C. In creased proliferat ion of T cells

udrocort i-

son e for several m on th s. On adm ission , h is blood p ressu re

D. In creased act ivat ion of com plem en t system

w as 160/98 m m Hg, an d an elect rocardiogram sh ow ed p ro-

E. In h ibit ion of lym ph ocyte-m ediated product ion of in terleukin -2

longat ion of th e Q-T in ter val. Lab result s revealed a K+ serum level of 2.5 m Eq/L (norm al 3.5−5.0 m Eq/L). W h ich of the follow ing even t s best explain s th e pat ien t’s syn drom e?


A. Cort isol-in du ced hyp erglycem ia

36. A 44-year-old w om an com plain ed to h er physician of h azy vision, black oating spots, an d severe pain in both eyes. After

B. Fludrocort ison e excess C. In adequate th erapy of adren al in su

cien cy

an op h th alm oscop ic evalu at ion , a diagn osis of acu te iridocy-

D. Cort isol-in du ced m yop athy

clit is w as m ade, an d a local dr ug t reat m en t w as prescribed.

E. Essen t ial hyperten sion

W h ich of th e follow ing dr ugs w ould be appropriate for th e pat ien t’s disease?


A. In dom eth acin

33. A 45-year-old m an com p lain ed to h is p hysician of in creas-

B. Apraclon idin e

ing an orexia an d m alaise. Th e m an also n oted th at h is u rin e

C. Tim olol

w as frothy. Medical h istor y an d physical exam in at ion of th e

D. Dexam eth ason e

p at ien t w ere u n rem arkable. Urin alysis of a 24-h ou r u rin e

E. Latan oprost

collect ion sh ow ed 3.8 g of protein . W h ich of th e follow ing

F.

d rugs w ou ld be app ropriate to t reat th e pat ien t’s d isease?

Pilocarp in e

Questions: V-3 Corticosteroids and Antagonist s 281 Di cult y level: Medium


37. A 61-year-old m an su ering from n on -Hodgkin lym ph om a

40. A 32-year-old w om an su ering from ulcerat ive colit is h ad

w as h osp it alized for h is

rst cycle of ch em ot h erapy. A

been receiving an ap p rop riate t reat m en t th at in clu ded oral

p h ar m acoth erapy w as prescribed to preven t ch em oth erapy-

p redn ison e for 3 m on th s. W h ich of th e follow ing reason s

in duced n ausea an d vom it ing. Th e drug regim en m ost likely

best exp lain s w hy th is drug w as u sed in th e t reat m en t of th e

in cluded on dan set ron , aprepitan t , an d w h ich of th e follow -


ing drugs?

A. To in d u ce a gen eral d ep ressive e ect on in test in al

A. Dexam eth ason e B. Scop olam in e C. Diph en hydram in e D. Loperam ide E. Diazepam F.

Om eprazole

fu n ct ion s B. To elicit an t iin am m ator y an d im m u n osu p p ressive e ect s C. To con t rol n au sea an d vom it ing, w h ich are p rom in en t in th is disease D. To in du ce an an algesic e ect th at can abolish abd om in al p ain


E. To p reven t th e risk of colorect al can cer

38. A 45-year-old m an , HIV posit ive, w as adm it ted to th e em ergen cy depar t m en t becau se of p ersisten t epistaxis. Physical


exam in at ion revealed fever (103.2°F, 39.6°C) an d altered

41. An 8-year-old boy w ith m ild persisten t asth m a w as in th e

m ental status. Laboratory results on adm ission showed renal

ch est clin ic for follow -up of h is disease. He h ad been on ly

failure, h em olyt ic an em ia, an d severe con sum pt ive th rom -

m od erately w ell con t rolled on in h aled albu terol “as n eeded.”

bocytop en ia. A diagn osis of th rom bot ic th rom bocytopen ic

Physical exam in at ion sh ow ed di u se expirator y w h eezes,

p u r p u ra w as m ad e, an d a t h erapy w it h rep eated p lasm a-

an d p u lm on ar y fu n ct ion test ing revealed a p eak exp irator y

p h eresis w as st ar ted . W h ich of t h e follow ing d r ugs w ou ld

ow rate 60% of predicted. Th e physician decided to add in -

be ap prop riate to add to th e ongoing t reat m en t?

h aled beclom eth ason e to th e th erapy, but th e boy’s m oth er

A. Fludrocort ison e

w as con cern ed abou t th e adverse e ect s of glu cocor t icoids.

B. Alteplase

Th e p hysician told th e m oth er th at system ic adverse e ect s

C. Aspirin

of in h aled beclom eth ason e are ext rem ely rare. W h ich of th e

D. Iron dext ran

follow ing st atem en t s best explain s th e reason for th is low

E. Predn ison e

toxicit y?

F.

A. Th e d rug is com pletely m etabolized by th e lu ng.

Sargram ost im

B. Th e d rug is quickly elim in ated by th e kidn ey.


C. Th e dose reach ing th e system ic circu lat ion is ver y sm all.

39. A 33-year-old w om an , 29 w eeks’ pregn an t , w as adm it ted to

D. Th e d rug is com pletely elim in ated w ith th e exh aled air.

th e obstet rical u n it w ith ru pt u red m em bran es. Th e p at ien t

E. Beclom eth asone is the least toxic of glucocorticoid drugs.

w as t reated w ith n ifed ipin e to delay p rem at u re labor an d w ith an oth er drug to accelerate m at urat ion of th e fet al lu ngs,


th u s decreasing th e in ciden ce of n eon atal resp irator y d is-

42. A 63-year-old w om an com plained to her physician of a recent

tress syndrom e. W h ich of th e follow ing drugs w as m ost likely

progressive loss of vision . Th e patien t had been su ering from

adm in istered ?

m yasth en ia gravis for 6 m on th s an d w as being t reated w ith

A. In dom eth acin

p redn ison e, azath iop rin e, an d n eost igm in e. Oth er m edica-


t ion s t aken by th e pat ien t in clu ded om eprazole for gast ro-

C. Dexam eth ason e

esoph ageal re u x disease an d lovast at in for hyperlipidem ia.

D. Ergon ovin e

Fu r th er exam s of th e eye led to th e diagn osis of glau com a.

E. Din oproston e

W h ich of th e drugs t aken by th e pat ien t w ould be relat ively

F.

con t rain dicated at th is t im e?

On dan set ron

A. Azath iop rin e B. Om eprazole C. Predn ison e D. Neost igm in e E. Lovast at in

282

Endocrine System



43. A 40-year-old m an com p lain ed to h is p hysician t h at t h e


d r ug h e w as taking caused an abn orm al in crease in th e size

m en t becau se of a 1-w eek h istor y of n au sea, vom it ing, an d

of h is breast s. Medical h istor y of th e pat ien t w as n egat ive for

low er abdom in al cram ps. Th e m an h ad recen tly been diag-

p ast diseases or u se of alcoh ol or drugs. Tw o w eeks earlier,

n osed w ith Cush ing syn drom e an d h ad st ar ted an appropri-

th e m an w as diagn osed w ith bilateral adren al hyp erplasia

ate th erapy 3 w eeks earlier. Physical exam in at ion revealed

an d h ad star ted an ap prop riate t reat m en t . W h ich of th e fol-

an afebrile, jau n diced, an d cach ect ic pat ien t w ith clou ded

low ing drugs m ost likely cau sed th e adverse e ect in th is

m en tat ion . Per t in en t lab exam resu lts on adm ission w ere

p at ien t?

aspart ate am in ot ran sferase 510 U/L, alan in e am in ot ran sfer-

A. Ketocon azole

ase 392 U/L (norm al 8−20 U/L), alkaline phosphatase 660 U/L

B. Cim et id in e

(n or m al 25−100 U/L), tot al bilir u bin 3 m g/d L (n or m al 0.1−

C. Eth inyl est radiol

1.0 m g/dL). W h ich of th e follow ing drugs m ost likely cau sed


th e p at ien t’s disorder?

E. Oxan drolon e

A. Met yrap on e

F.


Om eprazole

C. Ketocon azole D. In dom eth acin E. Valproic acid F.

Lovast at in

Questions: V-4 Drugs for Gonadal Disorders Directions for questions 1−5


Match each drug u sed in gon adal disord ers w ith th e app rop riate

4. A drug able to block est rogen receptors in all target t issues

descript ion (each let tered opt ion can be selected on ly on ce, m ore th an on ce, or n ot at all). A. An ast rozole

Di cult y level: Easy 5. A com pet it ive an t agon ist at an drogen receptors

B. Clom iph en e C. Dan azol


D. Dihydrotestosteron e

6. A 56-year-old w om an com plain ed to h er gyn ecologist of per-

E. Fin asteride

sisten t vagin al bu rn ing an d vagin al p ain du ring in tercou rse.

F.

One year earlier, the w om an had undergone total hysterectom y

Flut am ide

G. Fu lvest ran t

becau se of a large leiom yom a. Physical exam in at ion sh ow ed

H. Mifep riston e

dr yn ess an d at rop hy of th e vagin a. A vagin al cream w as pre-

I.

Norgest rel

scr ibed . W h ich of t h e follow in g d r ugs w ou ld be ap p rop r iate

J.

Oxan drolon e

for local th erapy in th is pat ien t?

K. Tam oxifen

Di cult y level: Easy 1. An in h ibitor of th e en zym e th at cat alyzes th e conversion of an drogen s to est rogen s

A. Eth inyl est radiol B. Norgest rel C. An ast rozole D. Tam oxifen E. Fin asteride



2. A select ive est rogen receptor m odulator

7. A 61-year-old w om an com plain ed to h er physician of in creasing t iredn ess, a dr y cough , an d a lu m p in h er righ t breast . Th e


w om an h ad a h istor y of a h orm on e-p osit ive carcin om a of h er

3. An in h ibitor of th e en zym e th at cat alyzes th e conversion of

left breast 15 m on th s earlier, for w h ich sh e h ad a m astectom y

testosteron e to dihydrotestosteron e

and 3 m onths of chem otherapy. She had been taking tam oxifen

Questions: V-4 Drugs for Gonadal Disorders 283 daily sin ce en d ing t h e ch em ot h erapy. Magn et ic reson an ce

appropriate th erapy w as prescribed. W h ich of th e follow ing

im aging revealed m ult iple pulm on ar y an d liver m et ast ases.

drugs w ou ld be m ost app ropriate for th is pat ien t?

W h ich of th e follow ing drugs w ould be appropriate to t reat

A. Diethylst ilbest rol

th e m et ast at ic can cer of th is p at ien t?

B. Oxan drolon e

A. An ast rozole

C. An ast rozole

B. Flut am ide

D. Mifep riston e

C. Mifep riston e

E. Dan azol

D. Noreth in dron e

F.

Eth inyl est radiol

E. Eth inyl est radiol F.

Fin asteride

Di cult y level: Easy 11. A 40-year-old w om an com p lain ed to h er gyn ecologist of

Di cult y level: Easy 8. A 63-year-old w om an w as adm it ted to th e h ospital because

h eavy an d p ain fu l m en st r u at ion over t h e p ast 3 m on t h s. Fu r th er exam s led to th e diagn osis of u terin e

broids, an d

of severe th oracic pain after a fall at h om e. Medical h istor y

th e p at ien t w as sch edu led for surger y. W h ich of th e follow -

w as sign i can t for m astectom y for breast can cer 8 years

ing drugs w ou ld be app ropriate to decrease th e pat ien t’s

ago. An x-ray sh ow ed fract ure of th ree ribs an d di use an d

sym ptom s before su rger y?

advan ced osteop orosis. An ap prop riate th erapy w as st arted

A. Eth inyl est radiol

th at in clu ded a drug th at cou ld lead to an in crease in th e

B. Flu t am ide

bon e m ass in dex an d cou ld also decrease th e risk of breast

C. Fin asteride

can cer react ivat ion . W h ich of th e follow ing drugs w as m ost

D. Mifep riston e


E. Medroxyp rogesteron e

A. An ast rozole B. Alen dron ate


C. Raloxifen e

12. A 23-year-old w om an asked h er physician for a postcoit al

D. Testosteron e

contraceptive 2 days follow ing unprotected intercourse. Which

E. Norgest rel

of th e follow ing drugs w ou ld be m ost appropriate for th is p urpose?

Di cult y level: Easy 9. Du ring h er an n ual ch eckup, a 32-year-old w om an w as foun d

A. Clom iph en e B. Leu p rolide

to h ave m ild hyper ten sion (160/90 m m Hg). Th e w om an ,

C. Levon orgest rel

oth er w ise h ealthy, h ad st ar ted an oral con t racept ive (eth inyl

D. Fu lvest ran t

est radiol an d n orgest rel) 2 m on th s earlier. Th e physician de-

E. Tam oxifen

cided to ch ange h er con t racept ive pill an d p rescribed eth inyl

F.

Dan azol

est radiol an d drospiren on e. An in creased excret ion of w h ich of t h e follow in g ion s m ost likely occu r red in t h is p at ien t after a few days of th erapy?

Di cult y level: Medium 13. A 34-year-old w om an com plain ed to h er physician of sw ell-

A. Potassium

ing an d p ain in h er left an kle. Th e w om an w as oth er w ise

B. Sodiu m

h ealthy, an d th e on ly m edicat ion sh e h ad been t aking w as a

C. Magn esiu m

com bin ed oral con t racept ive. Fur th er exam s con rm ed th e

D. Calcium

d iagn osis of ven ou s th rom bosis th at th e physician believed

E. Bicarbon ate

to be caused by th e con t racept ive pill. W h ich of th e follow ing act ion s m ost likely con t ribu ted to th e adverse e ect of


th e drug in th is p at ien t?

10. A 16-year-old girl w as seen by h er physician because of pri-

A. In creased an t ith rom bin III syn th esis

m ar y am en orrh ea. Physical exam in at ion sh ow ed a sh or t girl

B. Decreased platelet aggregat ion

(h eigh t 135 cm , 53.15 in .) w ith a broad ch est , poor breast

C. In creased syn th esis of protein C

d evelop m en t , an d n or m al exter n al gen it alia. Su bsequ en t

D. In creased syn th esis of clot t ing factors

exam s revealed ru dim en tar y ovaries, an d cytogen et ic an aly-

E. Decreased plasm in ogen syn th esis

sis sh ow ed a 45,X kar yot yp e. A diagn osis w as m ad e, an d an

284

Endocrine System



14. A 26-year-old w om an asked h er fam ily physician for a h or-

17. A 20-year-old w om an st ar ted using a h orm on al con t racep -

m on al con t racept ive. Sh e refu sed oth er m eth ods of con t ra-

t ive w ith a m on oph asic com bin at ion of eth inyl est radiol an d

cept ion . Past h istor y of th e w om an in dicated dissem in ated

n oreth in dron e. Th e prim ar y con t racept ive m ech an ism of

in t ravascu lar coagu lat ion t h at follow ed an abor t ion du e to

act ion of th is con traceptive preparation m ost likely includes

p lacen t al abr u pt io. W h ich of t h e follow ing w ou ld be t h e

decreased secret ion of a h orm on e from w h ich of th e follow -

m ost ap p rop r iate h or m on al con t racept ive p rep arat ion for

ing organ s or t issu es?

th is w om an ?

A. Ovar y

A. Diethylst ilbest rol

B. Adren als

B. Eth inyl est radiol an d n oreth in d ron e

C. Posterior pit uit ar y

C. Mest ran ol an d n oreth in dron e

D. En dom et rium

D. Mifep riston e

E. Hyp oth alam u s

E. Eth inyl est radiol an d levon orgest rel F.

Levon orgest rel

Di cult y level: Medium 18. A 43-year-old w om an recen tly diagn osed w ith en dom et rio-


sis star ted a t reat m en t w ith m edroxyp rogesteron e, on e tab -

15. A 39-year-old obese w om an w as adm it ted to th e h ospital

let daily. W h ich of th e follow ing e ect s m ost likely occu rred

becau se of a severe p ain in h er righ t calf. Medical h istor y

after a few days of th erapy?

in cluded ch ron ic bron ch ial asth m a, curren tly t reated w ith

A. Decreased body tem perat ure

in h aled albuterol, an d m ild t ype II diabetes, curren tly t reated

B. In creased est rogen secret ion by th e ovar y

w ith ch lorpropam ide an d m etform in . Sh e h ad been t aking

C. In creased ven t ilator y respon se to carbon dioxide

com bin ed oral con t racept ives for 2 years. Physical exam in a-

D. Decreased kidn ey excret ion of sodium an d w ater

t ion sh ow ed a red, sw ollen , an d ten d er righ t calf. A du plex

E. In creased circulat ing levels of am in o acids

u lt rason ograp hy con r m ed t h e d iagn osis of d eep ven ou s th rom bosis. W h ich of th e follow ing drugs m ost likely cau sed th e p at ien t’s disorder?

Di cult y level: Easy 19. A 21-year-old w om an st ar ted u sing a com bin ed oral con -

A. Noreth in dron e

t racept ive p ill (eth inyl est radiol an d n oreth in dron e). W h ich

B. Albuterol

of th e follow ing cell st ruct ures is th e prim ar y site of act ion

C. Eth inyl est radiol

of both drugs?

D. Ch lorpropam ide E. Metform in F.

Diethylst ilbest rol


A. Nucleu s B. Mem bran e C. Mitoch on dria D. Ribosom es E. Golgi apparat us

16. A 68-year-old m an w ith a long h istor y of ch ron ic cardiac failure presen ted to h is physician com plain ing of u rin ar y h esit an cy an d frequ en t n eed to u r in ate d u r in g t h e n igh t . An exam in at ion revealed an en larged prostate, an d fur th er exam s con rm ed the diagnosis of benign prostatic hyperplasia. Finasteride w as included as part of h is therapeutic regim en. W h ich of th e follow ing act ion s m ost likely m ediated th e th erap eu t ic e ect of th e drug in th e p at ien t’s disease? A. In h ibit ion of follicle-st im u lat ing h or m on e (FSH) an d lu tein izing h orm on e (LH) release B. In h ibit ion of gon adot ropin -releasing h orm on e (Gn RH) release C. In h ibit ion of 5α -reductase en zym e D. Blockade of progesteron e receptors E. Blockade of testosteron e receptors

Di cult y level: Easy 20. A 45-year-old w om an com plain ed to h er physician th at for th e p ast m on th sh e h ad frequ en t ep isodes of develop ing a su d den feeling of w arm th over h er ch est accom p an ied by a p atchy u sh ing of h er skin . Sh e stated th at th ese sym ptom s w ere ext rem ely dist u rbing. Sh e h ad been h aving irregu lar m en st ru al p eriods for th e p ast year, often skip ping t w o or th ree p eriods at a t im e. W h ich of th e follow ing p rep arat ion s w ould be m ost appropriate for short-term horm onal replacem en t th erapy in th is w om an ? A. Oral eth inyl est radiol B. Tran sderm al est radiol C. Oral n oreth in dron e D. Su bcu tan eou s im plan t of levon orgest rel E. Oral eth inyl est radiol−n orgest rel com bin at ion F.

Paren teral m edroxyprogesteron e

Questions: V-4 Drugs for Gonadal Disorders 285 Di cult y level: Medium

an d a th erapy w ith a com pet it ive est rogen receptor an tago-

21. A 26-year-old w om an cam e to h er physician com plain ing

n ist w as in it iated. W h ich of th e follow ing drugs w as m ost

of hyp er p igm en t at ion of h er face. Physical exam in at ion re-

likely given ?

vealed a p oorly d e n ed , blotchy, m asklike zon e of facial

A. An ast rozole

p igm en t at ion w it h alm ost equ al involvem en t of h er ch eeks,

B. Dan azol

tem ples, an d foreh ead. Skin biopsy sh ow ed in creased m ela-

C. Leu p rolide

n in pigm en t in basal layers. Th e w om an h ad been taking a

D. Fu lvest ran t

h orm on al con t racept ive for 6 years. Sh e w as a long-dist an ce

E. Mifep riston e

ru n n er an d adm it ted th e u se of oxan d rolon e, er yth ropoiet in , an d m eth am p h etam in e w h ile t rain ing. W h ich of th e fol-


low ing drugs m ost likely cau sed th e hyp erpigm en tat ion in


th is w om an ?

ing of h ot u sh es an d n igh t sw eat s th at dist u rbed h er sleep.


Her last m en st ru al period w as 6 m on th s ago. Th e physician

B. Oxan drolon e

prescribed a horm one replacem en t therapy w ith a com bined

C. Er yth ropoiet in

contraceptive pill (ethinyl estradiol and norethindrone). This

D. Noreth in dron e

th erapy m igh t carr y a sm all in crease in th e risk of w h ich of

E. Meth am p h etam in e

th e follow ing diseases? A. Osteoporosis


B. Breast can cer

22. A 59-year-old w om an d iagn osed w it h m et ast at ic breast

C. Colon can cer

can cer st arted a t reat m en t th at in cluded an ast rozole. W h ich

D. Ovarian can cer

of th e follow ing m olecular act ion s m ost likely m ediated th e

E. En dom et rial can cer

th erap eu t ic e ect of th e drug in th e p at ien t’s disease? A. Act ivat ion of est rogen cat abolism


B. Com p et it ive blockade of est rogen receptors

26. A 27-year-old w om an w h o w as h aving t rou ble t r ying to

C. Com p et it ive blockade of p rogesteron e receptors

con ceive star ted a cycle of th erapy w ith clom ip h en e. Eigh t

D. In h ibit ion of conversion of an drogen s to est rogen s

w eeks later, sh e h ad a p osit ive p regn an cy test . W h ich of

E. In h ibit ion of conversion of progesteron e to an drogen s

t h e follow ing w as m ost likely th e p rim ar y site of act ion of th e drug th at led to th e w om an’s su ccessfu lly becom ing


p regn an t?

23. A 32-year-old w om an h ad been t aking a com bin ed oral con -

A. Corp u s lu teu m

t racept ive p ill for th e past 5 years. How ever, sh e recen tly de-

B. Hyp oth alam u s

veloped a disorder th at prom pted h er physician to w ith draw

C. Uterin e t ube

t h e p ill an d to recom m en d ot h er for m s of con t racept ion .

D. Posterior pit uit ar y

W h ich of th e follow ing disorders m ost likely occurred to th is

E. Ovar y

p at ien t?

F.

En dom et rium

A. Rh eum atoid ar th rit is B. Vein th rom bosis


C. Vagin al in fect ion

27. A 22-year-old w om an st arted using a com bin at ion h orm on al

D. Acn e

con t racept ive (et h inyl est rad iol an d n oret h in d ron e). Syn -

E. An orexia

t h et ic est rogen s an d p rogest in s are cu r ren t ly u sed in m ost con t racept ive for m u lat ion s in stead of n at u ral h or m on es


m ain ly becau se of w h ich of t h e follow in g p h ar m acological


advan t ages?

of in creasin g sh or t n ess of breat h . Five years earlier, t h e

A. Mu ch low er in ciden ce of adverse e ect s

w om an h ad been diagn osed w ith h orm on e-p osit ive breast

B. Greater oral bioavailabilit y

can cer an d u n der w en t radical m astectom y an d six cycles

C. High er h orm on al e

of ch em oth erapy. Sh e h ad been receiving h orm on al th erapy

D. High er in h ibit ion of gon adot ropin secret ion

w it h t am oxifen sin ce t h en . A com p u ted tom ograp hy scan

E. Low er teratogen ic act ivit y

sh ow ed m u lt ip le lu ng m etastases. Tam oxifen w as stopp ed,

cacy

286

Endocrine System


C. In creased viscosit y of th e cer vical m ucus

28. A 24-year-old m an com plain ed to h is physician of erect ile

D. Increased frequency of gonadotropin -releasing horm one (Gn RH) pulse gen erator

dysfu n ct ion . Fu r th er exam s led to th e diagn osis of adu ltonset hypogonadism , and a therapy w ith a testosterone patch

E. St im ulat ion of con t ract ion of th e m yom et rium

w as star ted. W h ich of th e follow ing e ect s m ost likely occu rred after a few days of th erapy?


A. En h an ced lutein izing h orm on e (LH) secret ion

32. A 54-year-old w om an had been receiving tam oxifen for 1 year

B. Decreased syn th esis of clot t ing factors

follow ing surger y for breast can cer. W h ich of th e follow ing

C. Decreased grow th of bon e m arrow stem cells

d rug classes best de n es th is drug?

D. En h an ced er yth ropoiet in syn th esis

A. Est rogen receptor an t agon ist

E. In creased h igh -den sit y lipoprotein (HDL) levels

B. Progest in receptor agon ist C. Progest in receptor an t agon ist


D. Select ive est rogen receptor m od u lator

29. A 30-year old m an , w h o w as a long-dist an ce run n er, h ad

E. Arom atase syn th esis in h ibitor

been u sing large d oses of an abolic steroids for m ore th an 10

F.

An drogen receptor agon ist

years to in crease h is at h let ic p er for m an ce. Th e m an w as m ost likely at in creased r isk of d evelop in g w h ich of t h e fol-


low ing diseases?

33. A 15-year-old boy w as adm it ted to th e h ospital because of a

A. Osteoporosis

su d den sw elling in h is arm s, legs, abdom en , lips, tongu e, an d

B. Angion eurot ic edem a

th roat . Past h istor y of th e p at ien t in d icated th at h is fath er

C. Hem olyt ic an em ia

h ad h ad a sim ilar episode in h is youth . An em ergen cy th er-

D. Hepat ic t u m ors

apy w as st arted, an d fu rth er exam s in dicated ver y low levels

E. Kidn ey failure

of C1 esterase in h ibitor. A few days later, th e pat ien t w as dis-

F.

ch arged w it h a su it able t h erapy. W h ich of t h e follow ing

Gast ric u lcer

drugs w ou ld be app ropriate to p reven t fu rth er at t acks in th is


pat ien t?

30. A 16-year-old girl com plain ed to h er physician th at h er peri-

A. Flut am ide

ods w ere ver y irregular, w ith in ter vals bet w een 22 days an d

B. Oct reot ide

4 m on th s. Sh e also n ot iced in creased h air grow th on h er

C. Clom iph en e

face, ext rem it ies, abd om en , an d breast s. Fu r t h er exam s led

D. Medroxyp rogesteron e

to t h e d iagn osis of p olycyst ic ovar y syn drom e, an d an ap -

E. Dan azol

p ropriate t reat m en t w as prescribed. W h ich of th e follow ing

F.

Mifep riston e

p airs of drugs w ould be appropriate for th is pat ien t? A. Eth inyl est radiol an d m ifep riston e B. Dan azol an d n orgest rel

Di cult y level: Medium 34. A 63-year-old m an cam e to h is physician com plain ing of a

C. Eth inyl est radiol an d dan azol

p ersisten t backach e. Rect al exam in at ion revealed a single,

D. Dan azol an d m ifep riston e

h ard, irregular nodule w ith in his prostate. Subsequent exam s

E. Mifep riston e an d n orgest rel

found his prostate-speci c antigen (PSA) level to be 100 ng/m L

F.

(n orm al < 3.0 ng/m L), an d a com puted tom ography scan

Eth inyl est radiol an d n orgest rel

sh ow ed several en larged p elvic lym p h n odes an d m u lt iple

Di cult y level: Easy 31. A 23-year-old w om an asked h er physician for a con t racep -

sclerot ic lesion s in h is sp in e. W h ich of th e follow ing p airs of drugs w ould be m ost appropriate for th e patient at th is tim e?

t ive p ill. Becau se th e w om an h ad su ered in th e p ast from

A. Paclitaxel an d cisplat in

d eep ven ou s th rom bosis, th e physician prescribed a p roges-

B. Vin crist in e an d predn ison e

t in -on ly oral con t racept ive (th e m in i p ill). W h ich of th e fol-

C. Leu p rolide an d u t am ide

low ing act ion s m ost likely con t ributed to th e con t racept ive

D. Tam oxifen an d an ast rozole

e ect of th e prescribed drug?

E. Vin crist in e an d act in om ycin

A. Act ivat ion of progest in receptors in th e corpu s lu teu m B. Stim ulation of follicle-stim ulating h orm one (FSH) release from th e p it u itar y

Di cult y level: Easy 35. A 19-year-old w om an started using daily norethindrone pills as a h orm on al con t racept ive. W h ich of th e follow ing adverse

Questions: V-4 Drugs for Gonadal Disorders 287 e ect s w ou ld be m ost likely associated w ith th is m eth od of


con t racept ion ?

39. A 37-year-old w om an com plained of severe pelvic pain during

A. In creased skin pigm en tat ion

m en st ru at ion an d m ild to m od erate p ain on som e n on m en -

B. Megaloblast ic an em ia

st r u al days. Physical exam in at ion of t h e p at ien t revealed

C. Ret in al th rom bosis

d i use uterin e an d adn exal ten dern ess an d m ult iple n odes

D. Breakth rough bleeding

palpated along the uterosacral ligam ent. Laparoscopic exam -

E. Galactorrh ea

ination sh ow ed endom etriotic lesion s. W hich of th e follow ing drug th erapies w ould be m ost appropriate for th is patien t?


A. An ast rozole

36. A 21-year-old w om an com p lain ed to h er p hysician of re-

B. Hu m an ch orion ic gon adot ropin

cu r ren t n au sea last ing m ost of t h e day. Th e w om an h ad

C. Lu t rop in alfa

been su ering from a u rin ar y t ract in fect ion p resen tly being

D. Tam oxifen

t reated w ith cip ro oxacin an d from gast roesop h ageal re u x

E. Com bin ed oral con t racept ives

d isease presen tly being t reated w ith om eprazole. Sh e also

F.

Urofollit rop in

rout in ely took ibuprofen du ring h er m en st ru al period. On e w eek ago, sh e star ted taking a con t racept ive p ill (eth inyl es-


t radiol an d n orgest rel). W h ich of th e follow ing drugs m ost


likely caused th e p at ien t’s n ausea?

p ar t m en t becau se of excruciat ing abdom in al p ain over th e


p ast 4 h ours. Th e w om an h ad been su ering from asth m a,

B. Cipro oxacin

p resen tly t reated w ith albuterol an d iprat rop iu m , an d from

C. Norgest rel

recu r ren t u r in ar y t ract in fect ion , p resen t ly t reated w it h ci-

D. Om eprazole

p ro oxacin an d azith rom ycin . A few days earlier, sh e h ad

E. Ibuprofen

started using a com bined oral contraceptive for the rst tim e. Physical exam in at ion sh ow ed a pat ien t in obvious dist ress


w ith pron oun ced m u scle w eakn ess. Bladder cath eterizat ion

37. A young couple presen ted to th e physician com plain ing th at

sh ow ed clear red u rin e. Fu rth er exam s con rm ed th e diag-

th ey h ave been t r ying for 2 years to con ceive a secon d ch ild

n osis of an acute porphyric at tack. W h ich of th e follow ing

bu t h ave n ot been su ccessfu l. Th eir rst ch ild w as a h ealthy

d rugs m ost likely t riggered th e pat ien t‘s disord er?

4-year-old girl. Lab test s revealed th at th e h u sban d w as se-

A. Albuterol

verely oligosperm ic. On questioning, he adm it ted he had been

B. Noreth in dron e

t aking som e drugs to aid h is ath let ic p erform an ce. W h ich of

C. Iprat ropium

th e follow ing d rugs m ost likely con t ribu ted to th e oligosp er-

D. Cipro oxacin

m ia of th is m an ?

E. Azith rom ycin

A. Vitam in B12 B. Dan azol


C. Ferrou s su lph ate

41. A 10-year-old boy w as brough t to th e em ergen cy depart-

D. Medroxyp rogesteron e

m en t w ith th e adm it t ing diagn osis of bacterial m en ingit is.

E. Er yth ropoiet in

Fu r th er exam s con rm ed th e diagn osis of m en ingococcal

F.

m en ingit is, an d a drug w as given p rophylact ically to all th e

Oxan drolon e

h eath personn el assisting th e boy. The fem ale personn el w ere


in st ru cted th at h orm on al con t racept ives w ere n ot e ect ive

38. A 38-year-old w om an un der w en t a hysterectom y an d bilat-

w h en t aken w ith th e given drug, as th at drug w as able to

eral oop h orectom y becau se of acu te pelvic p eriton it is. On e

sign i can tly redu ce p lasm a con cen t rat ion of est rogen s an d

m on th later, a h orm on al t reat m en t w as st arted. W h ich of

p rogest in s. W h ich of th e follow ing w as m ost likely th e drug


u sed to preven t th e in fect ion in close con tact s of th is boy?

A. Leuprolide

A. Ceft riaxon e

B. Est radiol

B. Cipro oxacin

C. Tam oxifen

C. Er yth rom ycin

D. Hu m an ch orion ic gon adot ropin

D. Ketocon azole

E. Norgest rel

E. Rifam pin

F.

An ast rozole

288

Endocrine System

Questions: V-5 Drugs for Bone Hom eostasis Directions for questions 1−5 Match each dr ug a ect ing bon e h om eost asis w ith th e app ropriate descript ion (each opt ion can be selected m ore th an on ce).

Di cult y level: Easy 7. A 76-year-old m an com plain ed to h is physician of m uscle ach es. Fu rth er exam s led to th e diagn osis of vitam in D de -

A. Alen dron ate

cien cy du e to in adequ ate in t ake. A vitam in D su p p lem en -

B. Calcipot rien e

t at ion w as p rescribed. W h ich of th e follow ing w ou ld be th e

C. Calciton in

m ost app ropriate p h arm acoth erapy for th is p at ien t?

D. Calcit riol

A. Ch olecalciferol

E. Calcium

B. Calcit riol

F.

C. Terip arat id e

Ch olecalciferol

G. Cin acalcet

D. Cin acalcet

H. Den osu m ab

E. Calciton in

I.

Fluoride

J.

Paricalcitol

K. Terip arat id e L.

Sevelam er

Di cult y level: Easy 8. A 49-year-old m an su ering from ch ron ic ren al failu re w as adm it ted to th e h ospit al becau se of a h ip fract u re. Fu r th er exam s revealed a di use dem in eralizat ion of bon e. An ap -


p ropriate th erapy w as star ted th at in cluded calcit riol. W h ich

1. Th is drug can in duce osteoclast apoptosis.

of th e follow ing act ion s m ost likely m ediated th e th erapeut ic e

cacy of th e drug in th is pat ien t?


A. St im ulat ion of liver hydroxylat ion of ch olecalciferol

2. Th is d r ug is a recom bin an t h u m an p arat hyroid h or m on e

B. St im ulat ion of ren al α 1 hydroxylase

(1-34).

C. Decreased in test in al phosph ate absorpt ion D. In creased in test in al calcium absorpt ion


E. Decreased ren al ph osphate reabsorpt ion

3. Th is dr ug act ivates a calcium -sen sing receptor on th e parathyroid glan ds.

Di cult y level: Easy 9. A 66-year-old w om an su ering from osteoporosis an d hy-


p erten sion h as been t reated for th e past year w ith raloxifen e

4. Th is drug can in h ibit th e gen e expression of parathyroid

an d calciu m carbon ate for osteoporosis an d w ith hydroch lo-

h orm on e.

rot h iazid e for hyp er ten sion . Desp ite t h e t h erapy, a recen t bon e m in eral den sit y test sh ow ed a sign i can t decrease in

Di cult y level: Easy 5. Th is h or m on e is secreted by t h e p arafollicu lar cells of t h e t hyroid glan d.

bon e m ass. W h ich of th e follow ing w ou ld be an app ropriate ch ange in th e t reat m en t plan of th is pat ien t? A. Su bst it u te hyd roch loroth iazide w ith prop ran olol. B. Su bst it u te raloxifen e w ith eth inyl est radiol.

Di cult y level: Easy 6. A 61-year-old w om an , su er ing from severe osteop orosis, su stain ed a t ibial fract u re, an d h er p hysician decided to add teriparat ide to th e curren t th erapy. W h ich of th e follow ing act ion s m ost likely m ediated th e th erapeut ic e ect of teriparat ide in th is p at ien t? A. St im u lat ion of osteoblast act ivit y B. In h ibit ion of osteoclast act ivit y C. In h ibit ion of ren al ph osph ate excret ion D. St im u lat ion of bon e collagen syn th esis E. In h ibit ion of ren al syn th esis of calcit riol

C. Add calciton in to th e cu rren t regim en . D. In crease th e daily dose of calciu m carbon ate. E. Add predn ison e to th e cu rren t regim en . F.

Add alen dron ate to th e cu rren t regim en .

Di cult y level: Easy 10. A 50-year-old wom an recently hospitalized because of w orsen ing of h er d isease star ted a t reat m en t th at in clu ded sevelam er. W h ich of th e follow ing w as m ost likely th e clin ical con dit ion for w h ich th e drug w as prescribed?

Questions: V-5 Drugs for Bone Hom eostasis 289 A. Liver cirrh osis

Th e physician suspen ded alen dron ate an d prescribed in t ra-

B. Lu p u s er yth em atosu s

ven ou s ad m in ist rat ion of zoled ron ate, exp lain in g to t h e

C. Croh n disease

p at ien t t h at a single inject ion w ou ld be e ect ive for at least

D. Ch ron ic h ear t failure

5 to 6 m on th s. Zoledron ate h as a h alf-life of abou t 7 days.

E. En d-st age ren al disease

W h ich of th e follow ing best explain s th e reason for th e except ion ally long e

cacy of th e drug?


A. Alterat ion of gen e expression of bon e osteoblasts

11. A 7-year-old Black boy w as brough t to th e em ergen cy de-

B. In corporat ion in to bon e hydroxyapat ite cr ystals

p ar t m en t after h e fell w h ile playing in th e yard. Physical ex-

C. Rep eated en teroh ep at ic cycling of th e drug

am in at ion revealed on ly m in or skin scratch es, bu t an x-ray

D. Ver y slow biot ran sform at ion to act ive in term ediates

sh ow ed t w o rib fract u res, clearly dem in eralized bon e, an d

E. Irreversible bin ding to plasm a protein s

w id en in g an d cu p p in g of m et ap hyses w it h exaggerated n orm al concavit y and irregular calci cat ion . Pertinent serum


valu es on adm ission w ere calciu m 8.3 m g/dL (n orm al 8.5−


10.5 m g/dL), p h osp h ate 2.2 m g/dL (n orm al 3.0−4.5 m g/dL),

altered m en tal stat u s an d dehydrat ion . Six m on th s earlier,

an d a t w o-fold in crease in alkalin e ph osp h at ase. W h ich of

th e p at ien t h ad u n dergon e radical p rostatectom y for p ros-

th e follow ing drugs w ou ld be m ost app rop riate for th is boy?

t ate can cer. Physical exam in at ion sh ow ed a dehydrated m an

A. Ch olecalciferol

w ith uct uat ing con sciousn ess level an d disorien ted to t im e

B. Calciton in

an d p lace. Pert in en t seru m valu es on adm ission w ere cal-

C. Calcit riol

ciu m 16.5 m g/L (n orm al 8.5−10.5 m g/L), alkalin e p h osph a-

D. Terip arat id e

t ase 304 U/L (n or m al 20−90 U/L). W h ich of t h e follow in g

E. Alen dron ate

d rugs sh ou ld be in clud ed in th e th erapeut ic m an agem en t of

F.

th is p at ien t?

Cin acalcet

A. Sodiu m p h osph ate



12. A 4-year-old boy recen tly diagn osed w ith rickets st arted a

C. Pam idron ate

t reat m en t w ith ch olecalciferol. W h ich of th e follow ing m o-

D. Man n itol

lecu lar act ion s m ost likely m ed iated t h e t h erap eu t ic e ect

E. Flu d rocort ison e

of th e d rug in th e pat ien t’s disease?

F.

Cin acalcet

A. Ch olecalciferol-act ivated vit am in D receptor com p lex bin d s to RNA. B. Ch olecalciferol-act ivated vit am in D receptor com p lex bin d s to DNA. C. Calcit r iol-act ivated vit am in D receptor com p lex bin d s to RNA. D. Calcit r iol-act ivated vit am in D receptor com p lex bin d s to DNA. E. Ergocalciferol-act ivated vit am in D receptor com p lex F.

Di cult y level: Medium 15. A 46-year-old m an com plain ed to h is physician of m uscle w eakn ess, fat igu e, con st ip at ion , n au sea, an d p olyu r ia. Past m ed ical h istor y w as u n rem arkable. Su bsequ en t lab exam s sh ow ed th e follow ing serum values: calcium 14.5 m g/dL (n or m al 8.5−10.5 m g/d L), p h osp h ate 2.1 m g/d L (n or m al 3.0−4.5 m g/dL), an d im m u n oreact ive p arathyroid h orm on e 142 pg/m L (n orm al 11−54 pg/m L). W h ich of th e follow ing

bin d s to RNA.

d rugs w ou ld be app rop riate to in clude in th e th erapeut ic

Ergocalciferol-act ivated vit am in D receptor com p lex

m an agem en t of th is p at ien t?

bin d s to DNA.

A. Calcit riol B. Hydroch loroth iazide


C. Sodiu m

13. A 52-year-old w om an com plain ed to h er physician of a per-

D. Triam teren e

sisten t gast ric pain ever y t im e sh e took a p rescribed dr ug.

E. Terip arat id e

Th e w om an , recen tly diagn osed w ith severe osteoporosis,

F.

h ad st ar ted a th erapy w ith oral alen dron ate 1 w eek earlier.

u oride

Calciton in

290

Endocrine System


disclosed di u se dem in eralizat ion of bon es. An app ropriate

16. A 51-year-old w om an, recently diagnosed w ith Paget disease

th erapy w as ordered. W h ich of th e follow ing drugs sh ould

of bon e, h ad been receiving alen dron ate for 1 w eek, bu t th e

be in clu ded in th e th erap eu t ic m an agem en t of th is p at ien t?

d r ug h ad to be su sp en d ed becau se of a p ersisten t abd om i-

A. Terip arat id e

n al p ain . Th e p hysician d ecid ed to rep lace t h e alen d ron ate

B. Ch olecalciferol

w it h calciton in . W h ich of th e follow ing act ion s m ost likely

C. Alen dron ate

m ediated th e th erapeu t ic e ect of calciton in in th e p at ien t’s

D. Calcit riol

d isease?

E. Calcipot rien e

A. In h ibit ion of osteoclast act ivit y B. St im u lat ion of osteoblast act ivit y


C. St im u lat ion of ren al calciu m reabsorpt ion

20. A 64-year-old w om an com plain ed to h er physician of per-

D. St im u lat ion of ren al p h osp h ate reabsorpt ion

sisten t back pain for th e past 3 days. Du al-en ergy x-ray ab -

E. In h ibit ion of in test in al calcium absorpt ion

sor pt iom et r y sh ow ed d i u se osteop orosis of t h e sp in e an d h ip s. Th e p hysician p rescr ibed calciu m an d vit am in D su p -


p lem en t at ion an d alen d ron ate, on e t ablet daily. W h ich of

17. A 43-year-old m an w ith a 25-year h istor y of t ype 1 diabetes

th e follow ing act ion s m ost likely m ed iated th e th erapeu t ic

w as evalu ated at a regu lar clin ic visit . Per t in en t seru m val-

e ect of alen dron ate in th e p at ien t’s disease?

u es determ in ed w ere glucose 190 m g/dL, calcium 7.3 m g/dL

A. St im ulat ion of osteoblast act ivit y

(n orm al 8.5−10.5 m g/dL), ph osph ate 5.1 m g/dL (n orm al 3.0−

B. St im ulat ion of in test in al calcium absorpt ion

4.5 m g/d L), creat in in e 3.9 m g/dL. An x-ray exam revealed

C. In h ibit ion of ren al calcium excret ion

d en sit y ch anges in th e bon es th at w ere con sisten t w ith ren al

D. In h ibit ion of osteoclast act ivit y

osteodyst rop hy. W h ich of t h e follow in g d r ugs sh ou ld be

E. In h ibit ion of ren al syn th esis of calcit riol

in clu ded in th e t reat m en t plan for th is pat ien t? A. Alen dron ate


B. Calciton in

21. A 61-year-old w om an su ering from osteoporosis h ad been

C. Calcit riol

receiving alen dron ate an d vit am in D su pplem en t at ion for

D. Terip arat id e

2 years. Recen t du al-en ergy x-ray absorpt iom et r y sh ow ed a

E. Cin acalcet

big decrease in bon e den sit y. Th e pat ien t’s h istor y w as sign i can t for a fem ur fract ure 2 m on th s earlier an d a rib frac-


t u re 1 m on th earlier. W h ich of th e follow ing drugs is m ost

18. A 59-year-old w om an w ith a long h istor y of ch ron ic kidn ey

likely to in crease bon e den sit y in th is p at ien t?

d isease w as recen tly diagn osed w ith secon dar y hyperp ara-

A. Terip arat id e

thyroidism an d star ted a t reat m en t th at in clu ded cin acalcet .

B. Ethyn il est radiol


C. Pam idron ate

ated the therapeutic e ect of the drug in the patient’s disease?

D. Calciton in

A. Act ivat ion of parathyroid h orm on e (PTH) receptors

E. Paricalcitol

B. Blockade of PTH receptors C. Act ivat ion of calciu m -sen sing receptors


D. Blockade of calciu m -sen sing receptors

22. A 56-year-old w om an com p lain ed to h er p hysician of fre-

E. Act ivat ion of calcit riol receptors

qu en t h ear t bu r n an d p ain in t h e su bster n al region . Th e

F.

w om an h ad star ted an app rop riate th erapy for osteop orosis

Blockade of calcit riol receptors

2 w eeks earlier. W h ich of th e follow ing drugs m ost likely


cau sed th e p at ien t’s sym ptom s?

19. A 54-year-old h om eless m an w ith a 15-year h istor y of alco-

A. Predn ison e

h olism w as brough t to th e h ospital by th e police, w h o h ad

B. Calciton in

fou n d h im lying on th e st reet . Physical exam in at ion sh ow ed

C. Raloxifen e

a dish eveled, con fu sed, an d cach ect ic m an w ith p rom in en t

D. Terip arat id e

vein s on a ver y ten se abd om en . Per t in en t ser u m valu es

E. Ch olecalciferol

on ad m ission w ere calciu m 5.5 m g/L (n or m al 8.5−10.5) an d

F.

alan in e am in ot ran sferase 300 U/L (n or m al 8−35). An x-ray

Alen dron ate

Questions: V-5 Drugs for Bone Hom eostasis 291 Di cult y level: Hard

daily. W h ich of th e follow ing act ion s m ost likely occurred

23. A 57-year-old m an com plain ed to h is physician of occasion al

after th e adm in ist rat ion of th is drug?

bon e p ain , w h ich w as accen t u ated at n igh t , an d decreasing

A. In creased ren al ph osph ate reabsorpt ion

au d itor y acu it y. Th e p at ien t h ad a lon g h istor y of gast ro -

B. In creased ren al calcium reabsorpt ion

esophageal re u x disease currently treated w ith om eprazole.

C. Decreased ren al calcit riol produ ct ion

Physical exam in at ion revealed skull en largem en t , a h obbling

D. In creased bon e resorpt ion

gait , an d an terolateral bow ing of th e legs w ith w arm th an d

E. In creased parathyroid h orm on e secret ion

p eriosteal ten d ern ess. Plain x-rays sh ow ed in creased bon e d en sit y, cor t ical th icken ing, an d bony en largem en t . Labora-


tor y result s sh ow ed alkalin e ph osph atase of 230 IU/L (n or-

27. A 58-year-old w om an su ering from in creasingly w orsen ing

m al 20−90 IU/L). W h ich of th e follow ing drugs w ou ld be

osteoporosis recen tly h ad den osum ab added to h er ph arm a-


coth erapeut ic regim en . W h ich of th e follow ing act ion s m ost

A. Paren teral calciton in

likely m ediated th e th erapeu t ic e ect of th e drug in th e pa-

B. Oral alen dron ate


C. Paren teral terip arat ide

A. En h an cem en t of osteoblast apoptosis

D. Oral cin acalcet

B. In h ibit ion of parathyroid h orm on e biosyn th esis

E. Oral raloxifen e

C. In h ibit ion of osteoclast form at ion

F.

D. En h an cem en t of in test in al absorpt ion of vitam in D

Paren teral calcit riol

E. En h an cem en t of calciton in biosyn th esis

Di cult y level: Easy 24. A 49-year-old w om an w as adm it ted to th e h ospital because of tet an ic m uscle spasm s an d paresth esias follow ing a recen t

Di cult y level: Easy 28. A 42-year-old m an su ering from advan ced ren al in su

-

thyroidectom y. W h ich of th e follow ing drugs given in t rave-

cien cy w as sch ed u led for kid n ey t ran sp lan t . A recen t labo -

n ously cou ld rapidly reverse th e pat ien t’s sym ptom s?

rator y test sh ow ed t h e follow ing ser u m valu es: calciu m

A. Vitam in D

6.9 m g/d L (n or m al 8.5−10.5 m g/d L), p h osp h ate 6.1 m g/d L

B. Calciton in

(n or m al 3.0−4.5 m g/dL). W h ich of th e follow ing dr ugs w ou ld

C. Sodiu m p h osph ate

be app ropriate to in clu de in th e cu rren t p h arm acoth erapy

D. Calcium glucon ate

of th is pat ien t?

E. Hydrocor t ison e

A. Alen dron ate

F.

B. Sevelam er

Alen dron ate

C. Calciton in


D. Fu rosem id e


E. Ch olecalciferol

p ar t m en t w ith p rom in en t skeletal m u scle w eakn ess, drow sin ess, em ot ion al labilit y, con fusion , d izzin ess, n au sea, an d


con st ip at ion . Th e p at ien t ’s m ed icat ion s on ad m ission in -

29. A 49-year-old m an presen ted to h is physician com plain ing

clu d ed losar tan an d fu rosem ide for ch ron ic h ear t failu re,

of recurring skin lesion s m ost prom in en t over th e scalp, ex-

teriparat ide for osteoporosis, an d t im olol an d dorzolam ide

ten sor surfaces of th e elbow s an d kn ees, bu t tocks, an d pen is.

for glau com a. Lab test s revealed a seru m calcium level of 14

Th e m an also com p lain ed of in creasing p ain in h is left h an d

m g/dL (n orm al 8.5−10.5 m g/dL). W h ich of th e drugs t aken

and left hip. Physical exam ination show ed oval er ythem atous

by th e pat ien t s m ost likely cau sed h er hypercalcem ia?

p laques covered w ith th ick, silver y, sh iny scales. Th e dist al

A. Losar t an

in terph alangeal join t s of d igit s 2 an d 3 of th e left h an d w ere

B. Fu rosem id e

sw ollen and ten der. A diagnosis w as m ade, an d a topical drug

C. Tim olol

t reat m en t w as p rescr ibed . W h ich of t h e follow in g d r ugs

D. Terip arat id e


E. Dorzolam ide

A. Flu d rocort ison e B. Calciton in


C. Calcipot rien e

26. A 62-year-old w om an su er ing from severe osteop orosis

D. Er yth rom ycin

started a th erapy w ith teriparatide, a subcutan eous injection

E. Alen dron ate F.

Cin acalcet

Endocrine System

292


th at in cluded cin acalcet . W h ich of th e follow ing w as m ost

30. A 63-year-old m an w it h a long h istor y of ch ron ic kid n ey

likely th e m ain site of act ion of th is drug for t reat ing th e p a-

d isease w as adm it ted to th e h ospital because of in creasing

t ien t’s con dit ion ?

an orexia, n au sea an d vom it ing, an d w eigh t loss. Per t in en t

A. Lu ng

seru m valu es on adm ission w ere creat in in e 3.4 m g/dL, cal-

B. Kidn ey

ciu m 8.6 m g/dL (n orm al 8.5−10.5 m g/dL), p h osph ate 4.9 m g/

C. Parathyroid glan ds

d L (n orm al 3.0−4.5 m g/dL). A diagn osis of severe ren al in su f-

D. Sm all in test in e

cien cy w as m ade, an d an ap p rop riate th erapy w as st arted

E. Bon e

Questions: V-6 Drugs for Diabetes Mellitus Directions for questions 1−7


Match each an t idiabet ic drug w ith th e ap p ropriate descript ion

6. A d r ug u sed to t reat bot h d iabetes m ellit u s an d d iabetes


in sip idu s

at all). A. Ch lorpropam ide


B. Exen at ide

7. In sulin preparat ion w ith n o peak e ect

C. In sulin glargin e D. Glybu ride


E. In sulin lispro

8. A 44-year-old m an w ith t ype 1 diabetes st arted an in ten sive

F.

Metform in

th erapy to ach ieve a t igh t con t rol of h is diabetes. W h ich of th e

G. Miglitol

follow ing com plicat ion s w ill th e m an be at greatest in creased

H. NPH in su lin

risk of experien cing?

I.

Regu lar in su lin

L.

Rep aglin ide

M. Pioglitazon e N. Sitaglipt in


A. Loss of vision B. Hyp er ten sion C. Nep h rop athy D. Hyp oglycem ia E. Weigh loss F.

Allergic react ion s

1. An in sulin preparat ion w ith a ver y fast on set of act ion

Di cult y level: Easy Di cult y level: Easy 2. In su lin p rep arat ion t h at can be u sed for in t raven ou s ad m in ist rat ion

9. A 22-year-old w om an w ith t ype 1 diabetes w as brough t un con scious to th e em ergen cy depar t m en t . Her blood glucose level w as 395 m g/dL (n orm al 70−110 m g/dL). An in t raven ou s in fusion of in sulin w as st ar ted, an d 6 h ou rs later th e p at ien t’s


blood glu cose decreased to a n orm al level. W h ich of th e fol-

3. A dipept idyl pept idase in h ibitor

low ing m olecu lar act ion s m ost likely con t ribu ted to th e th erapeut ic e ect of th e dr ug in th e pat ien t’s disorder?

Di cult y level: Easy 4. An in h ibitor of an en zym e located on th e brush border of th e in test in al ep ith eliu m

A. In h ibit ion of glu cose t ran sp or ters in p an creas cell m em bran es B. Ph osp h or ylat ion of a t yrosin e kin ase−lin ked receptor C. Act ivat ion of aden osin e t riph osp h ate (ATP)−sen sit ive K+

Di cult y level: Easy 5. This noninsulin drug regulates transcription of several insulinresp on sive gen es.

ch an n els in t arget cells D. St im u lat ion of h orm on e-sen sit ive lip ase E. In h ibit ion of liver glucokin ase

Questions: V-6 Drugs for Diabetes Mellitus 293 Di cult y level: Hard


10. A 17-year-old girl w as adm it ted to th e em ergen cy depar t-


m en t follow ing a m otor veh icle acciden t . Sh e w as obt u n ded

by h is paren ts because of n ausea, vom it ing, an d persisten t

an d respon ded on ly to p ain . Medical h istor y obtain ed from

abdom in al pain secon dar y to th e u . Med ical h istor y of th e

h er m oth er w as unrem arkable. Physical exam ination sh ow ed

patient was unrem arkable. Pertin ent serum values on adm is-

a p at ien t w it h con t u sion s on h er face an d ar m s bu t n o

sion w ere fast ing blood glu cose 300 m g/dL (70−110 m g/dL),

sign s of cran ial t raum a. Vit al sign s w ere tem perat ure 97°F

glycosu ria 3+. W h ich of th e follow ing drugs w ou ld be ap p ro-

(36.1°C), blood pressu re 105/70 m m Hg, pulse 112 bpm , res-

p riate for th is p at ien t?

p irat ion s 22/m in . Per t in en t seru m values w ere bicarbon ate

A. Regu lar in su lin

6 m Eq/L (n orm al 22−28 m Eq/L), glu cose 847 m g/dL (n orm al

B. Metform in

70−110 m g/dL), creatinine 1.1 m g/dL (norm al 0.6−1.2 m g/dL).

C. Pioglitazon e

Urin alysis sh ow ed th e follow ing: speci c gravit y 1.036, glu-

D. Rep aglin ide

cose 4+, keton es 4+. W h ich of th e follow ing correctly pairs

E. Miglitol

th e m ost likely pat ien t disorder w ith th e app ropriate em er-

F.

Glyburide

gen cy t reat m en t? A. Diabet ic hyperosm olar com a/in t raven ou s (IV) regular in su lin

Di cult y level: Medium. 14. An 11-year-old boy recen tly diagn osed w ith t ype 1 diabetes

B. Acu te ren al failu re/fu rosem id e

star ted in sulin th erapy. W h ich of th e follow ing in sulin regi-

C. Post t raum at ic liver failure/IV acet ylcystein e

m en s (from A to E) w ou ld be app ropriate for th e ch ron ic

D. Resp irator y acidosis/IV bicarbon ate in fu sion

th erapy of th is boy?

E. Diabet ic ketoacidosis/IV regular in sulin Before . . . . .


Regimen

11. A 24-year-old obese w om an in h er 26th w eek of pregn an cy

Breakfast

Lunch

Supper

Bedtime

A

Lispro

Lispro

Lispro

Glargine

w as diagn osed w ith gestat ion al diabetes m ellit u s after a

B

Regular

−

−

Lispro

p osit ive glucose toleran ce test . Sh e w as oth er w ise h ealthy,

C

NPH

Lispro

NPH

Lispro

an d h er p ast m ed ical h istor y w as u n rem arkable. Diet ar y

D

Lispro

Regular

−

Regular

m an agem en t failed to con t rol th e blood glu cose, an d h er

E

Glargine

−

−

−

p hysician decided to prescribe an t idiabet ic th erapy. W h ich of t h e follow in g d r ugs w ou ld be m ost ap p rop r iate for t h e p at ien t at th is t im e?


A. Glyburide

15. A 42-year-old w om an recen t ly d iagn osed w it h lu p u s er y-

B. Metform in

t h em atosu s st ar ted a t reat m en t w it h a h igh daily d ose of

C. Rep aglin ide

p red n ison e. Th e w om an h ad a h istor y of t yp e 1 d iabetes

D. In sulin

cu r ren tly con t rolled w ith t w o daily adm in ist rat ion s of p re-

E. Sitaglipt in

m ixed insulin. W hich of the follow ing changes in the patient’s an t idiabet ic regim en sh ou ld be m ade at th is t im e?

Di cult y level: Easy 12. A 60-year-old w om an w ith a long h istor y of severe t ype 2 d iabetes h ad been t aking m ult iple daily inject ion s of in sulin , in cluding an in sulin glargin e preparat ion . W h ich of th e follow ing sets of p ropert ies (from A to E) best describes th e t im e cou rse of e ect s of th is p rep arat ion ? Set

Abbreviation: NPH, neutral protam ine Hagedorn, or isophane insulin.

Onset of Ef ect (h)

Peak Ef ect (h)

Duration of Ef ect (h)

A

1−2

6−10

12

B

0.25

2−3

3−5

C

0.25

No peak

3−5

D

1−4

6−10

12

E

1−4

No peak

24

A. Decrease th e daily in sulin dosage. B. In crease th e daily in sulin dosage. C. Add glybu ride to th e an t idiabet ic regim en . D. Add exen at ide to th e an t idiabet ic regim en . E. Add sit aglipt in to th e an t idiabet ic regim en .

294

Endocrine System


A. Acarbose

16. A 16-year-old boy su ering from t ype 1 diabetes w as adm it-

B. In sulin

ted to th e em ergen cy depart m en t w ith th e ch ief com plain t

C. Glyburide

of severe right-sided chest pain. Tw o hours earlier, he felt fe-

D. Metform in

verish and experienced a teeth-chat tering chill. The patient’s

E. Exen at ide

diabetes w as w ell controlled on t w o daily adm inistrations of

F.

Pioglitazon e

p rem ixed in su lin . Th e pat ien t w as also ver y com plian t w ith h is p rescr ibed diet . After p hysical exam in at ion an d labo-


rator y test s, a diagn osis of at ypical pn eum on ia w as m ade.

20. A 78-year-old m an w as brough t to th e em ergen cy room ex-

W h ich of th e follow ing ch anges in th e pat ien t’s t reat m en t

h ibit ing bizarre beh avior an d paran oid ideat ion . He com -

sh ou ld be app ropriate at th is t im e?

p lain ed of h eadach e, m en tal con fu sion , w eakn ess, dizzin ess,

A. In crease th e daily in sulin dosage.

an d blu rred vision . Th e m an w as su ering from t yp e 2 dia-

B. St art a cou rse of am picillin th erapy.

betes, w h ich w as bein g t reated w it h an oral an t id iabet ic

C. Add a daily adm in ist rat ion of ch lorpropam ide.

d rug. Per t in en t seru m values on adm ission w ere creat in in e

D. St art a cou rse of van com ycin th erapy.

1.8 m g/d L (n orm al 0.6−1.2 m g/dL), glu cose 50 m g/dL (n or-

E. Add a daily adm in ist rat ion of m etform in .

m al 70−110 m g/dL). W hich of the follow ing drugs m ost likely cau sed th e p at ien t’s sign s an d sym ptom s?


A. Metform in

17. A 55-year-old w om an su ering from t ype 2 diabetes h ad

B. Pioglitazon e

star ted t reat m en t w ith m etform in , bu t th e drug w as poorly

C. Glyburide

tolerated, an d h er physician decided to sh ift to repaglin ide.

D. Acarbose

W hich of the follow ing actions m ost likely m ediated the ther-

E. Exen at ide

apeu t ic e ect of repaglin ide in th e pat ien t’s disease? A. Decreased glu cose absorpt ion from th e gast roin test in al t ract

Di cult y level: Easy 21. A 52-year-old alcoh olic m an w as brough t u n con sciou s to

B. Blockade of glu cagon receptors

t h e em ergen cy d ep art m en t . On adm ission , th e p at ien t w as

C. Blockade of β 2 receptors in th e liver

sw eat ing, h is body tem perat u re w as 94.5°F (34.7°C), an d h is

D. Blockade of som atostat in receptors in th e pan creas

cardiac pu lse w as 135 bpm . Sh ortly after adm ission , th e p a-

E. St im u lat ion of in su lin release

t ien t d evelop ed a ton ic-clon ic seizu re. His w ife rep or ted th e

F.

Regu lat ion of tran script ion of gen es involved in glu cose

m an w as a diabet ic on in su lin th erapy. W h ich of th e follow -

u t ilizat ion

ing disorders m ost likely caused th e p at ien t’s syn drom e? A. Hyp erglycem ia du e to in su lin resistan ce


B. Hyp oglycem ia du e to alcoh ol con su m pt ion

18. An 8-year-old girl diagnosed w ith t ype 1 diabetes began treat-

C. Ketoacidosis du e to in su

cien t in su lin th erapy

m en t w ith in su lin . W h ich of th e follow ing act ion s on lip id

D. Hyp erglycem ia du e to alcoh ol w ith draw al

m etabolism m ost likely occu rred in th is pat ien t after star t-

E. An aphylact ic react ion to in su lin

ing th e th erapy?

F.

A. In creased lipid breakdow n by th e liver B. Decreased t riglyceride storage in fat t issue C. In creased t riglyceride syn th esis

Hyp erosm olar com a du e to alcoh ol overdose

Di cult y level: Easy 22. A 12-year-old boy diagn osed w ith t ype 1 diabetes star ted a

D. Decreased syn th esis of lipoprotein lipase

t reat m en t w ith in su lin . W h ich of th e follow ing set s of e ects

E. In creased act ivit y of h orm on e-sen sit ive lipase

on th e liver m ost likely con t ributed to th e th erapeut ic e ect of th e drug in th e pat ien t’s disease?

Di cult y level: Easy 19. A 59-year-old m an su ering from t ype 2 diabetes h ad been receiving an oral an t idiabet ic th erapy th at in cluded a drug th at closes ad en osin e t riph osp h ate (ATP)−sen sit ive K+ ch an n els on pan creat ic β-cell m em bran es. W h ich of th e follow ing drugs m ost likely u ses th is m ech an ism of act ion ?

Set

Glycolysis

Gluconeogenesis

Glycogenolysis

A

↑-

0

↓

B

↑-

↓

↓

C

↓

0

0

D

0

↑-

↑-

E

↑-

↑-

↓

Note: ↑ , increased; ↓ , decreased; 0, no change.

Questions: V-6 Drugs for Diabetes Mellitus 295 Di cult y level: Easy


23. A 56-year-old m an w as foun d to h ave th e follow ing serum

26. A 78-year-old w om an w ith t ype 2 diabetes w as brough t un -

valu es d u r in g a rou t in e clin ic visit: fast in g blood glu cose

conscious to the em ergency departm ent. Her husband stated

146 m g/d L (n or m al 70−110 m g/d L), glycated h em oglobin

th at th e w om an took several p ills of h er an t id iabet ic m edi-

(HbA1c) 7.4% (n orm al 6%), total ch olesterol 160 m g/dL (n or-

cat ion in a su icide at tem pt . On adm ission , vit al sign s w ere

m al < 200 m g/dL). Th e pat ien t h ad been su ering from t yp e

blood pressu re 134/90, p u lse 80 bp m , respirat ion s 22/m in .

2 d iabetes for 6 years, an d h is disease w as w ell con t rolled

Laborator y data sh ow ed an an ion gap of 24 m m ol/L (n orm al

w ith diet an d m etform in u n t il th e m ost recen t visit . Th e pa-

< 12 m m ol/L), plasm a lactate of 6 m m ol/L (n orm al 0.5−1.5

t ien t w as oth er w ise h ealthy, an d physical exam in at ion w as

m m ol/L), creat in in e 3.2 m g/dL (n orm al 0.6−1.2.0 m g/dL),

u n rem arkable. All tests w ere con rm ed in a secon d exam .

an d ar terial blood p H 7.24 (n orm al 7.35−7.45). W h ich of th e

W h ich of th e follow ing w ould be th e m ost appropriate n ext

follow in g d r ugs m ost likely cau sed t h e p at ien t ’s sign s an d

step in th e m an agem en t of th e p at ien t’s d isease?

sym ptom s?

A. Add glybu ride to th e cu rren t regim en .

A. Glucagon

B. Su bst it u te m etform in w ith p ioglitazon e.

B. Metform in

C. Su bst it u te m etform in w ith repaglin ide.

C. Rep aglin ide

D. Su bst it u te m etform in w ith in su lin .

D. In sulin

E. Add lovast at in to th e cu rren t regim en .

E. Glyburide F.

Pioglitazon e

Di cult y level: Easy 24. A 59-year-old w om an recen tly diagn osed w ith t ype 2 diabe-


tes star ted a th erapy w ith diet an d m etform in . W h ich of th e

27. A 57-year-old obese m an w as d iagn osed w it h t yp e 2 d ia-

follow ing actions m ost likely m ediated the therapeutic e ect

betes m ellit u s. Th e p at ien t h ad been su ering from ch ron ic

of th e drug in th e pat ien t’s disease?

obst r u ct ive p u lm on ar y d isease for 5 years an d from hyp er-

A. Blockade of aden osin e t riph osph ate (ATP)−sen sit ive K+

ten sion for 3 years. His cu r ren t t h erapy in clu d ed ip rat ro-

ch an n els

pium and captopril. W hich of the follow ing antidiabetic drugs

B. Blockade of glucagon receptors

w ou ld be relat ively con t rain dicated in th is p at ien t?

C. Act ivat ion of glu cagon -like p olyp ept id e-1 (GLP-1) re-

A. Acarbose

ceptors D. Activation of adenosine m onophosph ate (AMP)−activated protein kin ase E. In h ibit ion of m et abolism of in cret in h orm on es

B. Metform in C. Sitaglipt in D. Rep aglin ide E. Glyburide



25. A 56-year-old w om an w as recen tly diagn osed w ith t ype 2

28. A 51-year-old m an w ith a long h istor y of severe t ype 2 dia-

d iabetes. Her m edical h istor y w as sign i can t for a seriou s

betes h ad been on a p h ar m acot h erapy t h at involved t w o

allergic react ion to su lfam et h oxazole an d for recu r ren t u r i-

d i eren t in sulin form ulat ion s. Several available in sulin for-

n ar y t ract in fect ion s p resen t ly t reated w it h cip ro oxacin .

m ulations di er from one another prim arily because of w hich

An appropriate th erapy w as prescribed th at in clu ded a st rict

of th e follow ing ph arm acokin et ic proper t ies?

d iet an d an oral an t idiabet ic drug. W h ich of th e follow ing

A. Rate of absorpt ion

d rugs w ou ld be con t rain dicated for th is pat ien t?

B. Elim in at ion h alf-lives

A. Glyburide

C. Tot al clearan ce

B. Metform in

D. Volum e of dist ribu t ion

C. Rep aglin ide

E. Oral bioavailabilit y

D. Acarbose E. Pioglitazon e

296

Endocrine System


A. Lact ic acid osis

29. A 66-year-old m an su ering from t ype 2 diabetes h ad been

B. Hyp oglycem ic react ion

receiving a com bin at ion th erapy w ith m etform in an d glybu -

C. Un stable angin a

ride, bu t 2 m on th s later lab exam s in dicated th at th e con t rol

D. Diabet ic ketoacidosis

of h is diabetes w as in adequate. His physician decided to add

E. In sulin resistan ce

p ioglit azon e to th e t reat m en t regim en . W h ich of th e follow ing m olecular act ion s m ost likely m ediated th e th erapeut ic


e ect of th e added drug in th e p at ien t’s disease?


A. Slow ing glucose absorption from the gastrointestinal tract

an orexia, n au sea an d vom it ing, an d an u npleasan t taste in

B. Blockade of K+ ch an n els in pan creat ic β-cell m em bran es

h is m outh for th e past 12 h ou rs. Th e m an h ad been su ering

C. In h ibit ion of incret in h orm on e m etabolism

from t ype 2 diabetes for 10 years an d w as being t reated w ith

D. Act ivat ion of glu cagon -like p olyp ept id e-1 (GLP-1) re-

m etform in an d sitaglipt in . He also h ad a long h istor y of hyp erten sion an d hyp erch olesterolem ia, cu rren tly con t rolled

ceptors E. Activation of adenosine m onophosph ate (AMP)−activated F.

w ith losart an , n ifedipin e, an d lovast at in . Pert in en t labora-

protein kin ase

tor y serum levels on adm ission w ere fast ing blood glucose

Regu lat ion of t ran script ion of gen es related to glu cose

115 m g/d L (n orm al 70−110), creat in in e 3.4 m g/dL (n orm al

u t ilizat ion

0.6−1.2 m g/d L), blood u rea n it rogen (BUN) 42 m g/dL (n orm al 7−18 m g/dL), h igh -den sit y lipoprotein (HDL) ch olesterol 85 m g/d L (n or m al < 100 m g/d L). Takin g in to accou n t t h e

Di cult y level: Easy 30. A 54-year-old m an com plain ed to h is physician of an an n oying dr y cough over th e past few days an d an u n expected

patient’s history an d sym ptom s, w hich of the follow ing drugs sh ou ld be rem oved from h is cu rren t th erap eu t ic regim en ?

w eigh t gain over th e p ast few w eeks. Th e p at ien t h ad been

A. Losar t an

su er ing from t ype 2 diabetes for 3 years, presen tly con -

B. Nifedipin e

t rolled w ith a com bin at ion of oral an t id iabet ic agen t s. Phys-

C. Lovast at in

ical exam in at ion sh ow ed eviden t p erip h eral edem a, m ild

D. Sitaglipt in

jugu lar ven ou s disten t ion , an d rales on bot h lu ngs. W h ich

E. Metform in

of th e follow ing drugs m ost likely cau sed th e p at ien t’s sign s an d sym ptom s?


A. Acarbose

33. A 47-year-old obese w om an w as fou n d to h ave t h e follow -

B. Metform in

ing serum levels during a rout in e clin ic visit: fast ing blood

C. Glyburide

glu cose 122 m g/dL (n orm al 70−110 m g/d L), t riglycerid es

D. Pioglitazon e

390 m g/dL (n orm al < 150 m g/dL), total ch olesterol 220 m g/

E. Exen at ide

d L (n orm al < 200 m g/dL), glycated h em oglobin (HbA1c) 6.1% (n orm al < 6%). Past h istor y of th e pat ien t w as un rem arkable, an d th e w om an h ad n o sign i can t sym ptom s. W h ich of th e

Di cult y level: Easy 31. A 65-year-old obese m an w as in h is physician’s o

ce for a

rou t in e visit . Th e p at ien t h ad been su er ing from t yp e 2

follow ing w ould be th e m ost appropriate ph arm acoth erapy for th is pat ien t?

d iabetes for 1 year, an d t h e d isease w as reason ably w ell

A. In sulin

con t rolled w ith diet an d m etform in . Physical exam in at ion

B. Metform in

sh ow ed th at body m ass in dex w as in creased abou t 40%from

C. Miglitol

th e last visit , an d abdom in al obesit y w as eviden t . Vit al sign s

D. Glyburide

of th e pat ien t w ere blood pressu re 150/90 m m Hg, pulse 85

E. Exen at ide

bp m , respirat ion s 14/m in . Fu r th er laborator y tests sh ow ed th e follow ing seru m valu es: fast ing glu cose 155 m g/dL (n or-


m al 70−110 m g/dL), fast ing in su lin 60 IU/m L (n orm al 5−20

34. A 7-year-old boy diagn osed w ith t ype 1 diabetes star ted a

IU/m L), tot al ch olesterol 340 m g/dL (n orm al > 200 m g/dL).

t reat m en t w ith in su lin . W h ich of th e follow ing act ion s on

Th e p at ien t w as m ost likely su ering from w h ich of th e fol-

glu cose m et abolism m ost likely occu rred in th is p at ien t after

low ing path ologic con dit ion s?

star t ing th e th erapy?

Questions: V-6 Drugs for Diabetes Mellitus 297 A. In creased liver glucose u ptake


B. In creased glycogen syn th ase act ivit y

38. A 63-year-old obese m an com p lain ed to h is p hysician of

C. Decreased glu cose-6-ph osph ate syn th esis

at u len ce, belch ing, diarrh ea, an d abd om in al p ain soon after

D. Decreased glu cokin ase act ivit y

star t ing an app rop riate oral th erapy for t yp e 2 d iabetes. Th e

E. Decreased glycerol syn th esis

d isease w as diagn osed after th e m an w as fou n d to h ave a fast in g blood glu cose level of 170 m g/d L, an d su bsequ en t


lab exam s revealed decreased glucose toleran ce an d fast ing

35. A 62-year-old w om an recen t ly d iagn osed w it h t yp e 2 d ia-

hyp erglycem ia. W h ich of th e follow ing drugs m ost likely

betes st ar ted a t h erapy t h at in clu d ed acarbose. In h ibit ion


of w h ich of th e follow ing en zym es m ost likely m ediated th e

A. Regu lar in su lin

th erap eu t ic e ect of th e drug in th e p at ien t’s disease?

B. Glyburide

A. Pyruvate carboxylase

C. Miglitol

B. Alph a-glucosidase

D. Metform in

C. Glucokin ase

E. Rep aglin ide

D. Horm on e-sen sit ive lip ase

F.

Pioglitazon e

E. Acylt ran sferase


39. A 48-year-old obese m an com plain ed of frequen t th irst an d

36. A 50-year-old obese w om an w ith t ype 2 diabetes w as foun d

p olyu ria. His p ast h istor y in cluded seriou s angioed em a ap -

to h ave in adequate con t rol of h er disease 2 m on th s after

p aren tly d ue to an allergic react ion to sulfon am ide th erapy.

star t ing th erapy w ith m etform in an d glybu ride. Th e p hysi-

In th e past h e t ried m any t im es to con t rol h is diet w ith out

cian d ecid ed to add exen at ide to th e t reat m en t regim en .

su ccess. A fast ing plasm a glu cose level w as fou n d to be 180


m g/dL (norm al 70−110 m g/dL). W hich of the follow ing w ould

ated th e th erapeut ic e ect of th e added drug in th e p at ien t’s

be an ap p ropriate t reat m en t for th is p at ien t?

d isease?

A. St rict d iet ar y con t rol

A. In h ibit ion of dipept idyl pept idase-4

B. Ch lorpropam ide

B. In h ibit ion of α -glucosidase

C. Metform in

C. Activation of adenosine m onophosph ate (AMP)−activated

D. NPH (n eu t ral p rot am in e Hagedorn ) in su lin

protein kin ase

E. In sulin lispro

D. Act ivat ion of glu cagon -like p olyp ept id e-1 (GLP-1) receptors E. Act ivat ion of aden osin e t rip h osp h ate (ATP)−sen sit ive K+ F.

Di cult y level: Easy 40. A 6-year-old girl diagn osed w ith t ype 1 diabetes star ted a

ch an n els

t reat m en t w ith in su lin . W h ich of th e follow ing act ion s on

Ph osp h or ylat ion of t yrosin e kin ase receptor

p rotein m etabolism m ost likely occurred in th is pat ien t after star t ing th e th erapy?


A. St im ulat ion of protein syn th esis in th e liver

37. A 13-year-old boy w ith t ype 1 diabetes received h is m orn ing

B. St im ulat ion of protein cat abolism in th e liver

inject ion of a m ixt u re of in sulin lispro an d glargin e. A few

C. In h ibit ion of protein syn th esis in m uscle cells

h ours later, h e w as foun d un con scious in h is room . His h ear t

D. In creased conversion of keto acids in to am in o acids

rate w as 120 bpm an d body tem perat u re 94.7°F (34.8°C),

E. Decreased am in o acid t ran spor t in to cells

an d tet an ic con t ract ion s of skeletal m u scles w ere p resen t . W h ich of th e follow ing w ould be th e im m ediate appropriate t reat m en t for th is p at ien t? A. Regu lar in su lin in t raven ou s B. Oral glu cose C. Glucagon in t ram uscular (IM) D. Oral m etform in E. Exen at ide IM F.

Epin eph rin e IM

298

Endocrine System

Answers and Explanations: V-1 Drugs for Hypothalam ic and Pituitary Disorders Questions 1−6

a follicle-st im u lat ing h orm on e (FSH) p reparat ion is adm in -

1. C

istered for 7 to 12 days, st ar t ing th e th ird day after m en st ru -

2. F

at ion . Sp on t an eou s ovu lat ion d u r ing t h e cycle is t yp ically

3. J

p reven ted by daily su bcut an eou s inject ion of leu prolide or

4. H

daily n asal ap plicat ion of n afarelin . A, B, D, E See correct an sw er exp lan at ion .

5. G 6. B

Learning objective: Describe the adverse e ects of leuprolide. Learning objective: Explain the m olecular m echanism of action of oxytocin.

10. D Ph ar m acologic t h erapy an d su rger y are bot h e ect ive in

7. B Oxytocin cau ses sust ain ed con t ract ion of uterin e sm ooth

cept ives or n on steroidal an t iin am m ator y drugs are recom -

relieving m ost sym ptom s of en d om et r iosis. Oral con t ra-

m uscle. Because calcium is n eeded to con t ract m uscle cells,

m en ded as

th e act ivated sign aling path w ay m ust lead to in creased in t ra-

h orm on e (Gn RH) agon ist s can be em ployed in w om en for

cellular calcium . Th is is brough t about by a receptor-m ediated

w h om th e

act ivat ion of ph osph olipase C th at split s by hydrolysis th e

erelin , an d n afarelin are Gn RH agon ists ap p roved by th e U.S.

ph osph at idylin ositol 4,5-bip h osph ate in to t w o secon d m es-

Food an d Drug Adm in ist rat ion for th is pu rp ose. Con t in u ous

sengers, in ositol t rip h osp h ate (IP3 ) an d diacylglycerol (DAG).

adm in ist rat ion of th ese drugs in h ibits th e release of follicle-

IP3 t r iggers t h e release of calciu m from storage vesicles,

rst-lin e th erapy, bu t gon adot rop in -releasing rst-lin e agen t s are in adequate. Leuprolide, gos-

st im u lat ing h orm on e (FSH) an d lu tein izing h orm on e (LH)

w h ereas DAG act ivates p rotein kin ase C, an en zym e w it h a

from th e p it uit ar y, resu lt ing in a hypoest rogen ic state. Ad -

vast array of p hysiological e ect s, in clu ding sm ooth m u scle

verse e ect s of th e Gn RH th erapy are sim ilar to th ose of

cont ract ion .

m en op au se, an d h ot

A, C−E Alth ough th e act ivat ion of th ese sign aling p ath w ays can in som e cases cau se in creased in t racellu lar calciu m , th e activat ion of th e p h osph oin osit ide path w ay rem ain s th e m ost

u sh es are ver y com m on (m ore th an

80% w ith leu p rolide). A−C, E Th ese are all adverse e ect s of est rogen s. Th erefore, th ey are u n likely in a hyp oest rogen ic p at ien t .

im port an t t rigger for in t racellular calciu m in crease in sm ooth m uscle cells.

Learning objective: Identify the site of action of octreotide.

Learning objective: Identify the drug used to control ushing in carcinoid syndrome. 11. D Carcin oid syn drom e develop s in som e peop le w ith en do-

8. B Oct reot ide is a som atost at in an alogue th at acts by act ivat-

crinologically active m alignant tum ors that develop from en-

ing receptors located in several organ s, in clu ding th e p it u -

terochrom a n cells located m ostly in the ileum , and (rarely)

it ar y, pan creas, an d gast roin test in al t ract , an d som e t ypes of

in oth er organ s. Carcin oid syn drom e is ch aracterized by cu -

t u m ors. In th is p at ien t , oct reot ide act ivates receptors located

t an eou s u sh ing, abd om in al cram p s, an d diarrh ea. Flu sh ing

on som atotroph cells of the pit uitary. This activation decreases

is t h e m ost com m on an d often t h e earliest sign , occu r r ing

th e release of grow th h orm on e, th us im proving th e pat ien t’s

in m ore th an 90%of pat ien ts. Th e syn drom e result s from va-

sign s an d sym ptom s.

soact ive su bst an ces, in clu ding seroton in , bradykin in , h ist a-

A, D, E See correct an sw er exp lan at ion .

m in e, an d p rostaglan din s, secreted by th e t u m or. Resect ion

C Som atost at in receptors are also located on th ese cells, an d

of prim ar y lung carcin oid is often cu rat ive. Som atost at in can

th eir act ivat ion can in h ibit th e secret ion of thyrot ropin , but

reduce sym ptom s caused by a variet y of h orm on e-secret ing

th is in h ibit ion is n ot th e reason for th e th erapeut ic e ect of

t um ors, and octreotide, a long-acting som atostatin analogue,

th e drug in th is pat ien t .

is a rst-lin e agen t to con t rol u sh ing in carcin oid syn drom e. Oct reot ide given before surger y is also th e best drug to avoid

Learning objective: Identify the drugs used for controlled ovarian hyperstimulation. 9. C Con t rolled ovarian hyp erst im u lat ion is u sed to st im u late th e developm en t of m u lt iple ovarian follicles du ring a single cycle, resu lt ing in th e release of a larger th an n orm al n u m ber of eggs th at can be used for in vit ro fer t ilizat ion . In m ost cases,

carcin oid crisis, a dangerou s con dit ion th at can occu r du ring surger y, likely due to m an ip ulat ion of th e t um or. It is ch aracterized by a profoun d drop in blood pressure, causing sh ock, som etim es accom pan ied by prolonged severe ushing, bron ch ospasm , an d h em odyn am ic in st abilit y. A−C, E See correct an sw er explan at ion .

Answers and Explanations: V-1 Drugs for Hypothalam ic and Pituitary Disorders 299 Learning objective: Outline the therapeutic use of cabergoline in acromegaly.

Learning objective: Outline the therapeutic uses of vasopressin. 15. E Th e pat ien t w as likely su ering from liver cirrh osis, w h ich

12. D Th e w om an w as m ost likely su ering from acrom egaly, as

cau sed an acu te variceal h em orrh age secon dar y to port al

h igh seru m levels of in sulin -like grow th factor 1 (IGF-1) are

hyp er ten sion . Esop h ageal varices represen t a con sequ en ce

h igh ly sp eci c for acrom egaly an d cor relate w it h clin ical

of collaterals th at develop in cirrh osis to sh un t blood from

in d exes of d isease act ivit y. Rad iat ion t h erapy w as con t ra-

th e p or t al system (w h ich is obst r u cted, u su ally at th e level

in dicated in th is pat ien t because m odern pacem akers using

of sin usoids) in to th e system ic circu lat ion . A con sequen ce of

m etal oxid e con du ctors are sen sit ive to rad iat ion . Dop am in e

th is is th at th e perfu sion p ressu re of th e h epat ic ar ter y is

D2 agon ist s such as cabergolin e h ave been sh ow n to reduce

p ar tly t ran sm it ted in to th e por tal vein , th u s in creasing th e

IGF-1 an d grow th h orm on e levels in about 50% of pat ien t s

p ort al p ressu re. En doscop ic scleroth erapy is th e procedure

w ith acrom egaly, w h en given alon e, even in pat ien t s w ith

of ch oice to con t rol acute bleeding. Ph arm acologic agen t s

n orm al prolact in levels. Moreover, th ey en h an ce th e act ion

can also be adm in istered to decrease port al p ressu re. Most

of som atostatin analogues such as octreotide. Therefore, they

experien ce h as been w ith vasopressin , a n on select ive, ver y

are often added w h en oct reot ide alon e is n ot fu lly e ect ive,

p ow erfu l vasocon st rictor th at directly con st rict s m esen teric

as in th is case (see h igh levels of IGF-1). Th e reason for th e

arterioles an d decreases por tal ven ou s in ow, th ereby re-

e ect iven ess of D2 agon ist s in acrom egaly is st ill u n cer t ain ,

du cing portal pressu re. Oth er drugs u sed for th e sam e pu r-

bu t it is n otable th at dopam in e app ears to in h ibit grow th

pose are n on select ive β-blockers an d oct reot ide.

h orm on e−releasing h orm on e (GH-RH) release, an d also th at

A, B Adren alin e an d albu terol are β 2 st im u lan ts. Th e β 2 re-

of th e an terior pit uit ar y h orm on es, grow th h orm on e is m ost

ceptor−m ediated vasodilat ion w ould in crease, n ot decrease,

sim ilar to prolact in .

h epat ic blood ow.


C, D Nifedipin e an d prazosin can reduce th e system ic blood pressu re bu t w ou ld h ave u np redict able e ect s on th e

Learning objective: Outline the diagnostic uses of thyrotropinreleasing hormone.

perfu sion pressu re of liver ar terial vessels.

13. B Th e sign s an d sym ptom s of th e pat ien t suggest sh e w as

Learning objective: Explain the mechanism of action of octreotide.

a ected by hyp othyroid ism , w h ich is con rm ed by th e low

16. B Th e diagn osis of p it u it ar y aden om a an d th e h igh level of

free t hyroxin e (FT4 ) ser u m levels. Th e fact t h at t hyroid -

in su lin -like grow th factor 1 in d icate th at th e pat ien t w as

st im u lat ing h orm on e (TSH) w as low suggest s th at hyp othy-

m ost likely su ering from acrom egaly. Oct reot id e is a som a-

roidism w as n ot prim ar y (i.e., due to failure of th e thyroid

tostat in an alogue th at e ect ively in h ibit s th e secret ion of

itself) but secon dar y (i.e., due to pit uit ar y failure) or tert iar y

grow t h h or m on e an d rep resen t s a com m on t reat m en t of

(i.e., d u e to hyp ot h alam ic failu re). A t hyrot rop in -releasin g

acrom egaly w h en radiat ion th erapy is con t rain dicated or

h or m on e (TRH) test can be u sefu l to clar ify t h e d iagn osis,

n ot e ect ive, as in th is case.

alth ough it is n ot often don e. After TRH ch allenge, TSH w ill

A, D, E Som atost at in d oes n ot h ave th ese e ect s

be in creased if th e sou rce is hypoth alam ic failu re, w h ereas it

C Som atostatin can inhibit insulin release, but this is not the

w ill n ot be in creased in pit uit ar y failure.

cause of th e th erapeut ic e ect of th e drug in acrom egaly.

A, C Th ese diseases w ou ld cau se p rim ar y hypothyroidism , as th e thyroid it self can n ot syn th esize thyroid h orm on es. D Graves d isease cau ses hyp er t hyroid ism , n ot hyp o t hyroid ism . E See correct an sw er explan at ion .

Learning objective: Describe the adverse e ects of som atropin. 17. A Ar t h ralgias are t h e m ost com m on adverse e ect s of so m at rop in th erapy in adu lt s, being presen t in u p to 23% of pat ien ts. Th ey are likely related to th e st im u lat ion of ch on drogen esis an d skelet al grow th th at is m ediated by in su -

Learning objective: Outline the diagnostic uses of adrenocorticotropic hormone (ACTH).

lin -like grow th factor 1.

14. C Th e sign s an d sym ptom s of th e pat ien t suggest th e diagn o-

th ose listed.

sis of Ad d ison d isease, w h ich in t h e Un ited St ates is m ain ly d u e to id iop at h ic at rop hy of t h e ad ren al cor tex, p robably cau sed by au toim m u n e p rocesses. ACTH is cu rren tly u sed to est ablish th e diagn osis by dem on st rat ing failu re to in crease seru m cor t isol levels u p on adm in ist rat ion of th e h orm on e. A, B, D−F See correct an sw er exp lan at ion .

B−E Grow th h orm on e ten ds to cau se act ion s opp osite to

300

Endocrine System

Learning objective: Explain the m echanism of action of chorionic gonadotropin when used to treat oligosperm ia.

Learning objective: Identify the drug to be used to treat precocious pubert y.

18. A Hu m an ch or ion ic gon ad ot rop in (h CG) is p rod u ced by

21. F Tru e p recociou s pu ber t y is th e m ost frequ en t en docrin e

h u m an placen t a an d ext racted from th e urin e of pregn an t

sym ptom of hypoth alam ic disease. Th e p ath ophysiology of

w om en . Th e st ru ct u re an d act ion s of h CG are p ract ically

th e disorder is related to an act ivat ion of th e hyp oth alam -

iden t ical to th ose of lutein izing h orm on e, th e h orm on e th at

ic-pit u itar y-gon adal axis. Th e th erapy is to su pp ress pit u -

in m en st im ulates th e Leydig cell secret ion of testosteron e,

it ar y gon ad ot rop in secret ion u n t il an app ropriate age for

w h ich is n eeded for n orm al grow th an d division of germ in al

n orm al pu bert y to begin . Con t in u ous adm in ist rat ion of a

cells in form ing sperm .

gon adot rop in -releasing h orm on e (Gn RH) an alogu e su ch as

B Th e drug is n ot a testosteron e agon ist .

leup rolide (in t raven ou s in fu sion or depot form u lat ion ) in -

C Th e hypoth alam ic secret ion of gon adot ropin -releasing

h ibit s follicle-st im ulat ing h orm on e an d lutein izing h orm on e

h orm on e is in h ibited by testosteron e. D Th e product ion of prost at ic

uid is st im ulated by di-

hydrotestosteron e.

secret ion (du e to receptor desen sit izat ion or d ow n regu lat ion ) an d w ill sh u t dow n th e st im u lat ion of ovarian fu n ct ion . Th e t reat m en t is fu lly reversible, an d n orm al fu n ct ion w ill

E Th e m itot ic act ivit y of Ser toli cells is st im u lated by follicle-st im ulat ing h orm on e.

Learning objective: Outline the therapeutic uses of goserelin.

resum e w h en th erapy is stopped. A−E See correct an sw er explan at ion .

19. B Goserelin is a syn th et ic an alogue of n at urally occurring

Learning objective: Identify the drug that acts as a gonadotropinreleasing hormone (GnRH) antagonist.

gon adot rop in -releasing h orm on e (Gn RH). Th e h orm on e is

22. A Degarelix is a syn t h et ic d ecap ept id e t h at fu n ct ion s as

p hysiologically released in pulses th at var y in frequ en cy in

com pet it ive an tagon ist at Gn RH receptors. It reduces con -

d i eren t p h ases of th e m en st r ual cycle an d con t rol th e syn -

cen t rat ion s of gon adot ropin s an d an drogen s m ore rapidly

th esis an d release of follicle-st im u lat ing h orm on e (FSH) an d

th an Gn RH agon ists an d avoid s th e in it ial testosteron e su rge

lu tein izing h orm on e (LH) in both w om en an d m en . Becau se

seen w ith th ose dr ugs. Degarelix is ap p roved for th e t reat-

th e release of Gn RH is p u lsat ile, th e secret ion of FSH an d LH

m en t of sym ptom at ic advan ced p rost ate can cer.

is also pulsat ile, w h ich is essen t ial for th e m ain ten an ce of


n orm al ovu lator y m en st ru al cycles an d th e n orm al producd epot preparat ion ), Gn RH in h ibits th e release of FSH an d LH

Learning objective: Identify the drug used to treat Turner syndrom e.

in both m en an d w om en . Th is in h ibit ion cau ses suppression

23. B Treat m en t w ith grow th h orm on e (som at ropin ) h as been

t ion of sp erm . How ever, w h en given con t in u ou sly (or as a

of ovu lat ion in w om en an d cessat ion of test icular an drogen

sh ow n to h ave a st rong ben e cial e ect on

syn th esis in m en . Th e syn th et ic an alogu es of Gn RH are cu r-

girls w ith Tu rn er syn drom e, th e m ost com m on sex ch rom o-

ren tly used alon e or in com bin at ion w ith an an t ian drogen

som e an om aly in fem ales. Con t in u ou s ch ron ic t reat m en t of

in th e ph arm acoth erapy of advan ced prostate can cer.

th ese girls can in crease th e m ean stat u re by 10 to 12 cm .


n al h eigh t in

A Oxan drolon e can in crease th e grow th rate in girls w ith Tu rn er syn drom e, bu t th e in crease is lim ited (5 cm ), an d th e

Learning objective: Outline the adverse e ects of octreotide. 20. A A m ajor u n d esirable e ect t h at can occu r as a resu lt of oct reot ide th erapy is redu ct ion of bile produ ct ion an d gall-

d rug is n ot curren tly used to t reat Tu rn er syn d rom e. C−F All of th ese drugs are u seless, or even dangerou s, in Tu rn er syn drom e.

bladder con t ract ilit y, w h ich leads to in creased viscosit y of bile an d in creased in ciden ce of gallston es. Th is can occu r in

Learning objective: Outline the therapeutic uses of m ecaserm in.

u p to 30% of pat ien t s after 6 m on th s of t reat m en t .

24. C Laron syn drom e (also called Laron dw ar sm ) is an au to-

B The drug does not e

cien tly cross th e blood−brain bar-

rier, so drow sin ess is un likely. C Because th e drug can in h ibit in sulin secret ion , hyp oglycem ia is rare.

som al recessive disorder ch aracterized by grow th h orm on e in sen sit ivit y (also referred to as p rim ar y in sulin -like grow th factor 1 [IGF-1] de cien cy) caused by a varian t of grow th h orm on e receptor. Because of th is, grow th h orm on e serum

D Th e drug can in h ibit thyrot ropin secret ion , w h ich can

levels are n orm al or in creased, bu t th e h orm on e is in e ec-

lead to hyp ot hyroid ism . Th is in t u r n can lead to cold , n ot

t ive. A m ajor con sequ en ce of th is in sen sit ivit y is ext rem ely

h eat , in toleran ce.

low ser u m levels of IGF-1, leading to severe im p air m en t

E In pat ien t s w ith carcin oid t um or, th e drug can e ect ively redu ce, n ot cau se, u sh ing.

of grow th . Recen tly, recom bin an t IGF-1 (m ecaserm in ) w as

Answers and Explanations: V-1 Drugs for Hypothalam ic and Pituitary Disorders 301 ap p roved by t h e U.S. Food an d Dr ug Ad m in ist rat ion for

Learning objective: Outline the therapeutic uses of pegvisom ant.

dw ar sm d u e to grow t h h or m on e in sen sit ivit y. Alt h ough

27. A Th e h igh ser u m levels of in su lin -like grow th factor 1 (IGF-

t h e n u m ber of ch ildren t reated w ith th e d rug is low (th e d is-

1) are h igh ly speci c for acrom egaly an d correlate w ith clin -

ease is ver y rare), all dat a sh ow a good in crem en t of grow th

ical in dices of disease act ivit y. Th ey are th e sim p lest w ay to

rate w ith m ecaserm in during th e rst year of t reat m en t .

m on itor th e respon se to th erapy, as th ey do n ot u ct uate like


grow t h h or m on e levels d o. Th e fact t h at IGF-1 levels are st ill elevated in th is p at ien t in dicates th at th e th erapy w ith

Learning objective: Outline the therapeutic uses of antidiuretic hormone (ADH) antagonists.

oct reot ide w as n ot com pletely e ect ive. Pegvisom an t is a

25. E Th e p at ien t w as m ost likely su er in g from syn d rom e of

larly u seful in p at ien t s resistan t to som atostat in an alogues

in ap p rop r iate an t id iu ret ic h or m on e secret ion (SIADH), a

becau se it h as been sh ow n th at it can n orm alize th e h igh

d isorder ch aracterized by low seru m osm olalit y, h igh u rin e

seru m levels of IGF-1 in th ese pat ien ts.

osm olalit y w it h resp ect to ser u m , an d hyp er volem ic (or


grow th h orm on e receptor an t agon ist . Th e drug is part icu-

som et im es n orm ovolem ic) hypon at rem ia. SIADH is cau sed by an in creased secret ion of ADH, w h ich is associated w ith a

Learning objective: Identify the drug used to treat prolactinom a.

m yriad of disorders, in cluding m align an cy, in t racran ial pa-

28. F Th e sign s an d sym ptom s of th e pat ien t in dicate th at sh e is

thology (encephalitis, m eningitis, subarachnoid hem orrhage,

m ost likely a ected by p rolact in om a, th e m ost com m on se-

etc.), h or m on al d e cien cy st ates (ad ren al an d t hyroid in -

cretor y t um or in th e pit u itar y. Dopam in e agon ists su ch as

su

cien cy), an d m et abolic d iseases (acu te in ter m it ten t

cabergolin e an d brom ocript in e are w idely u sed as rst-lin e

p or phyria). Th e exact m ech an ism w h ereby th ese disorders

agen t s. By act ivat ing D2 receptors in th e p it u it ar y, th ese

p rovoke an in crease in con cen t rat ion of ADH is u n cer t ain ,

drugs m im ic th e e ect of dopam in e to in h ibit th e secret ion

bu t th is p at ien t w as su ering from sm all-cell lu ng can cer,

of prolact in . Th ey can restore abn orm al m en st rual fun ct ion

w h ich is kn ow n to syn th esize ADH de n ovo. Treat m en t m o-

in up to 90% of w om en , sh rin k prolact in om as, an d im prove

dalit ies of SIADH dep en d on th e u n derlying cau se. In cases

galactorrh ea an d t u m or-associated h eadach e.

w h ere th is cause is un t reat able, w ater rest rict ion an d ADH


an tagon ist s (con ivapt an an d tolvapt an ) are th e t reat m en t of ch oice. Th ese drugs block vasopressin receptors, causing reversible n eph rogen ic diabetes in sipidu s. A, B Th ese diu ret ics ten d to cau se hypon at rem ia an d are th erefore con t rain dicated in SIADH. C ADH agon ist s (vasopressin an d desm opressin ) are con t rain dicated, as th e syn drom e is cau sed by an excessive ADH secret ion . D Glucocorticoids are useless, as SIADH secretion is not due to adren al in su

cien cy (see th e n orm al serum levels of

K+

).

Learning objective: Describe the therapeutic use of octreotide in acromegaly. 26. D Th e p at ien t ’s sign s an d sym ptom s in d icate t h at h e w as a ected by acrom egaly d u e to p it u itar y aden om a, w h ich is th e cau se of th e disease in vir t u ally all p at ien t s a ected by acrom egaly. Som atostat in can redu ce grow th h orm on e (GH) levels an d sym ptom s in acrom egaly, an d oct reot ide (a som atostat in an alogu e) is frequen tly used for th is purpose. Th e d rug is 40 t im es m ore poten t th an som atost at in in blocking GH secret ion bu t on ly t w ice as p oten t in blocking in su lin secret ion , an d is th erefore m ore su it able th an th e n at u ral h orm on e to t reat acrom egaly. A−C, E See correct an sw er explan at ion .

Learning objective: Identify the enzym e whose synthesis is promoted by follicle-stimulating hormone (FSH). 29. E Follitropin alfa is recom binant follicle-stim ulating horm one (FSH). It act ivates speci c receptors th at act via th e adenylyl cyclase p ath w ay to st im u late th e gran u losa cells of th e ovar y to produce arom at ase. Th is en zym e (also called est rogen syn th ase) is a key step in biosyn th esis of est rogen s. It con vert s an drosten edion e to est ron e an d testosteron e to est rad iol. A “step -u p” p rotocol of ovu lat ion in du ct ion m im ics th e n at ural m en st rual cycle. In creasing doses of FSH are given d uring th e rst h alf of th e cycle to prom ote follicular developm ent. Then an injection of hum an chorionic gonadotropin is adm in istered to sim ulate th e lu tein izing h orm on e surge th at n at u rally occu rs in m idcycle an d t riggers ovu lat ion . A−D See correct an sw er explan at ion .

302

Endocrine System

Learning objective: Describe the therapeutic use of octreotide in vipoma tumor.

m em bran es. Th erefore, it dist ributes prim arily in th e ext ra-

30. D Oct reot id e is a som atost at in an alogu e. W h en given in

bu t ion of th e drug th at is abou t 12 L.

ph arm acological am ounts, som atostatin inhibits virt ually all

cellular

uid. Th is is also in dicated by th e volu m e of dist ri-


exocrin e an d en docrin e secret ion s of th e pan creas (in sulin , intestin e (secretin, m otilin, vasoactive intestin al polypeptide

Learning objective: Describe the use of vasopressin in the treatment of vasodilatory shock.

[VIP], gast ric in h ibitor y polyp ept ide [GIP], an d seroton in ), as

33. E Th e pat ien t’s poor respon se to n orepin eph rin e suggests

w ell as secret ion of grow th h orm on e, thyroid-st im u lat ing

t h at sh e w as m ost likely su er in g from sept ic sh ock t h at

h orm on e, parathyroid h orm on e, calciton in , an d adren ocor-

w as catech olam in e-resist an t . Sept ic sh ock is a vasod ilator y

t icot ropic h orm on e. Becau se of th is, oct reot ide is u sed to

sh ock, an d sep sis is a com m on cau se of th e disord er. Vasodi-

reduce sym ptom s caused by a variet y of h orm on e-secret ing

lator y sh ock is ch aracterized by low ar terial blood pressu re

t u m ors. Vip om a is a rare VIP-secret ing t u m or of n on -β p an -

d ue to decreased system ic vascular resist an ce. Catech ol-

creat ic islet cells, cau sing a syn drom e of prolonged, m assive

am in es are

w ater y d iar rh ea, hyp okalem ia, an d ach lorhyd r ia (W DHA

sh ock, bu t loss of adren ergic sen sit ivit y can occu r du e to

syn drom e). Oct reot ide e ect ively con t rols th e diarrh ea in

m u lt ip le m ech an ism s, in clu d ing dow n regu lat ion of adren o-

m ost pat ien ts, bu t large doses m ay be n eeded.

ceptors, im pairm en t of post receptor sign al path w ays, an d


excessive p rod u ct ion of n it r ic oxid e an d ot h er in am m a-

glu cagon , an d pan creat ic en zym es), stom ach (gast rin ), an d

rst-lin e agen ts for th e th erapy of vasodilator y

tor y m ed iators. Mor t alit y rates of vasod ilator y sh ock are

Learning objective: Outline the therapeutic uses of desmopressin.

excessively h igh , an d if th e sh ock becom es catech olam in e-

31. C Polyu ria an d n oct uria, w ith low urin e osm olalit y, suggest

resistant, m ortalit y can be n ear 100%. Recently, several inves-

th e diagn osis of d iabetes in sipid u s (DI). Th e p reviou s basal

t igators h ave dem on st rated th at vasop ressin can su ccessfu lly

sku ll fract u re in dicates th at th e DI is m ost likely related to

stabilize hem odynam ics even in advanced vasodilator y shock,

a t rau m a of th e pit u it ar y stalk, an d th e u n detectable seru m

an d cu rren t gu idelin es suggest th at vasopressin sh ou ld be

an t idiu ret ic h orm on e (ADH) levels con rm s th at th e DI is

reser ved for pat ien ts in w h om adequate h em odyn am ic sta-

n eurogen ic in n at ure. Desm opressin is th e agen t of ch oice in

bilizat ion can n ot be ach ieved w ith conven t ion al th erapy, as

th is disease. Un like vasopressin , it s vasocon st rict ing act ivit y

in th is case.

is n egligible, as it act ivates on ly V2 receptors. A Th iazide diuret ics paradoxically reduce polyuria both in cen t ral an d n eph rogen ic DI (likely because of volu m e con t ract ion , leading to en h an ced p roxim al reabsorpt ion ), bu t th ey are n ot u sed in cen t ral DI, w h ere a m u ch bet ter th era-

A, C, D Becau se th e sh ock is catech olam in e-resist an t , th e u se of th ese drugs m ay be dangerous by causing sign i can t catech olam in e toxicit y. B Desm opressin h as n egligible vasocon st rict ing act ivit y becau se it act ivates on ly V2 receptors.

peut ic ch oice exist s. B Am iloride is e ect ive on ly in lith iu m -in duced DI. D, E Carbam azepin e an d ch lorpropam ide are ADH-releasing dr ugs u sed on ly w h en ADH secret ion is n ot com p letely abolish ed (par t ial n eu rogen ic DI) or w h en th e p at ien t can n ot tolerate exogen ous ADH.

Learning objective: Identify the m ain site of distribution of som atropin. 32. C Som at rop in is a p ept id e h or m on e t h at is u su ally ad m in istered su bcu t an eou sly. It s m olecu lar w eigh t in d icates t h at it is su

cien t ly sm all to be absorbed from t h e inject ion

site by bulk

ow t ran sport an d to leave th e blood by th e

sam e t ran sport system . How ever, it is too big to cross cell

DRUGS FOR HYPOTHALAMIC AND PITUITARY DISORDERS Answ er key 1. 2. 3. 4. 5.

C F J H G

6. 7. 8. 9. 10.

B B B C D

11. 12. 13. 14. 15.

D D B C E

16. 17. 18. 19. 20.

B A A B A

21. 22. 23. 24. 25.

F A B C E

26. 27. 28. 29. 30. 31. 32. 33.

D A F E D C C E

Answers and Explanations: V-2 Drugs for Thyroid Disorders 303

Answers and Explanations: V-2 Drugs for Thyroid Disorders Questions 1−3 1. A

Learning objective: Identify the correct percent age of levothyroxine (T4 ) bound to plasma proteins.

2. F

6. E Most circulat ing T3 an d T4 are boun d to plasm a protein s

3. D

(about 75%to thyroxin e-bin ding globulin , th e rest to prealbu m in an d albu m in ). On ly 0.4% T3 an d 0.04% T4 are free. Th ere-

Learning objective: Identify the serum level of free thyroxine (FT4 ) and thyroid-stimulating hormone (TSH, thyrotropin) in a patient without functional thyroid after a few days of triiodothyronine treatment.

fore, th e boun d h orm on es represen t a h uge reser voir, w h ich

4. D Myxed em a com a is a rare bu t ser iou s con sequ en ce of

radioact ive iod in e disru pts h orm on e syn th esis in a few days.

long-st an d in g u n cor rected hyp ot hyroid ism . Desp ite aggres-

exp lain s w hy, in a p erson w it h t h e t hyroid glan d d est royed by rad ioact ive iodin e, it t akes 3 m on t h s to 1 year after rad ioact ive t reat m en t before hyp ot hyroid ism occu rs, even t h ough A−D See correct an sw er explan at ion .

sive th erapy w ith large doses of thyroid h orm on es, m or talit y rates of 60 to 70% are com m on . W h eth er levothyroxin e or t riiodothyron in e (T3 ) is th e drug of ch oice in m yxedem a com a

Learning objective: Identify the drug used in a newborn baby with neonatal hypothyroidism .

is con troversial. Although triiodothyronine is poten tially m ore

7. C Th e sign s an d sym ptom s of th e baby suggest th at h e is su f-

cardiotoxic, it is som et im es p referred becau se its m ore rapid

fering from n eon at al hypothyroidism , w h ich occurs in abou t

on set can reverse com a faster an d because deiodin ase act ivit y

1/4000 live bir th s. Th e m ost frequ en t cau se is congen ital ab -

is m arked ly redu ced in m yxed em a, t h u s im p air ing conver-

sen ce of th e thyroid glan d, w h ich requ ires lifelong th erapy.

sion of T4 to T3 . In th is p at ien t , after a few days of t riiod othy-

Treat m en t w ith levothyroxin e m u st be st ar ted im m ediately

ron in e th erapy, seru m T4 levels are low becau se of th e disease,

an d closely m on itored.

an d thyrot ropin (TSH) levels are low becau se of t riiodothy-


ron in e n egat ive feedback. A−C See correct an sw er explan at ion .

Learning objective: Identify the drug used in thyroid storm in an asthmatic patient.

Learning objective: Identify the drug used rst to treat levothyroxine poisoning.

8. A Th e sign s an d sym ptom s of th e pat ien t an d th e lab exam s

5. B Th e pat ien t’s sym ptom s an d th e lab resu lt s in d icated th at

en in g syn d rom e ch aracter ized by t h e abr u pt on set of t h e

in dicate th at sh e is su ering from thyroid storm , a life-th reat-

h e w as su ering from drug-in duced severe hyper thyroidism .

m ore

A leading cause of death in thyroid h orm on e excess is related

t reat m en t is m an dator y an d u su ally in clu des prop ran olol to

to th e cardiovascular e ect s th at can cause arrhyth m ias an d

con t rol hyper ten sion an d t achycardia. W h en propran olol is

acute m yocardial isch em ia due m ain ly to thyroid h orm on e−

con t rain dicated, as in th is case, calcium ch an n el blockers w ith

in du ced in creased sen sit ivit y of th e sym p ath et ic n er vou s sys-

cardiac act ivit y (dilt iazem or verap am il) can be u sed .

tem . Adm in ist rat ion of a β-blocker can prom ptly coun teract cardiovascu lar sym ptom s an d m ay be lifesaving. A, C, D All of these drugs are used in severe thyroid horm one excess from any cause, but th e adm in ist rat ion of a β-blocker m ust be don e rst . E Radioact ive iodin e is n ot an em ergen cy th erapy.

or id sym ptom s of hyp er t hyroid ism . An em ergen cy

B Radioact ive iod in e can be u sed for t h e lon g-ter m m an agem en t of th e disease bu t is n ot a drug for th e em ergen cy t reat m en t of thyroid storm . C−F See correct an sw er explan at ion .

304

Endocrine System

Learning objective: Describe the treatm ent of thyrotoxicosis during pregnancy.

Learning objective: Identify the drug that can cause agranulocytosis in a patient with hyperthyroidism .

9. E Th e pat ien t’s FT4 (free thyroxin e) an d TSH (thyrot rop in )

12. C Th e pat ien t’s ver y low w h ite blood cell coun t in dicates th at

levels in dicate th at sh e w as su ering from thyrotoxicosis.

sh e w as su ering from agran u locytosis, a p oten t ially leth al

Eith er surger y or thioam ide is th e t reat m en t of ch oice for

adverse e ect of th ioam ide an t ithyroid d rugs, su ch as m eth i-

hyp er thyroidism in a p regn an t p at ien t . W h en an t ithyroid

m azole an d p ropylth iou racil. Agran u locytosis occu rs in 0.3

drug th erapy m ust be used du ring pregn an cy, propylth -

to 0.6% of pat ien t s t reated w ith th ese drugs, bu t th e risk is

iouracil is th e preferred th ioam id e during th e rst t rim ester

in creased in older p at ien t s. Th e m ech an ism of agran u locy-

becau se it crosses th e placen t a m u ch less th an m eth im azole

tosis is st ill un kn ow n , an d both allergic an d toxic-t ype reac-

does, an d becau se a rare em br yopathy w as associated w ith

t ion s h ave been suggested. Th e disease is u su ally rapid ly

m et h im azole. Su bsequ en t ly, m et h im azole sh ou ld be p re-

reversible if th e drug is prom ptly discon t in u ed, an d colony-

scribed to avoid th e rare bu t seriou s p oten t ial h ep at ic dam -

st im u lat in g factors m ay h asten t h e recover y of gran u -

age associated w ith propylth iouracil.

locytes.

A Radioact ive iodin e is con t rain dicated during pregn an cy. B Oct reot id e is a som atost at in an alogu e. It is u sed on ly

A, B, D, E Th ese d r ugs h ave a n egligible r isk of agran u locytosis.

in rare cases of hyperthyroidism du e to a pit uitar y aden om a secret ing TSH (thyrot ropin om a). Th is is n ot th e case in th is

Learning objective: Identify the drug that causes toxic hepatitis.

pat ien t , as TSH w as ver y low.

13. C Th e pat ien t’s h istor y, sign s, an d sym ptom s suggest th at sh e

C Iod in e com p ou n ds are n ot u sed for rou t in e t reat m en t

w as m ost likely su ering from propylth iou racil-in du ced

of hyp er thyroidism . Low doses of iodin e h ave been u sed in

toxic h epat it is. More th an 900 drugs h ave been im plicated

pregn an cy, but on ly w h en all oth er ap proach es are con t ra-

in cau sing liver inju r y, bu t p ropylth iou racil, ison iazid, h alo-

in dicated.

th an e, valproate, an d cer t ain an t ipyret ics (acet am in oph en ,

D Methyldopa is used during pregn an cy on ly in hyper ten sive p at ien t s.

diclofen ac, an d in d om eth acin ) are am ong th e drugs m ost frequ en tly involved in acu te h ep atocellular toxicit y. Prop -

F Beta-blockers are used in hyper thyroidism , but esm olol

ylth iou racil-in du ced toxic h epat it is occu rs in abou t 1% of

h as a ver y sh or t h alf-life an d t h erefore is n ot su ited for

t reated p at ien t s, is alw ays severe, an d can be leth al. Th e U.S.

ch ron ic use.

Food an d Drug Adm in ist rat ion h as add ed a black box w arn ing to th e label of propylth iouracil.

Learning objective: Explain the m echanism of action of levo thyroxine.

addit ion , propylth iouracil is preferred over m eth im azole in

10. C Levothyroxin e (T4 ) can act ivate a speci c thyroid h orm on e

th e

(TH) receptor th at is located in th e n u cleus of m ost body cells. Th is act ion in t urn leads to act ivat ion or repression of

A Meth im azole-in duced liver injur y is ext rem ely rare. In rst t rim ester of pregn an cy becau se it crosses th e pla-

cen t a m uch less th an m eth im azole. B, D, E Liver inju r y w ith th ese drugs is n egligible.

t ran scr ipt ion of sp eci c gen es, w h ich u lt im ately m ed iate A, E By d e n it ion , an agon ist is a d r ug t h at bin d s to a

Learning objective: Explain the m echanism of action of thioam ide antithyroid drugs.

receptor an d act ivates it . Levot hyroxin e d oes n ot act ivate

14. E Meth im azole an d propylth iou racil are th ioam ides used as

thyroid-st im ulating horm one (TSH) or thyrotropin -releasing

an t ithyroid agen ts. Th ese drugs in h ibit thyroid p eroxidase,

(TRH) receptors.

th e en zym e th at cat alyzes th e follow ing th ree step s in thy-

excitator y or in h ibitor y resp on ses.

B, D, F By de n it ion , a receptor an tagon ist is a d rug th at bin ds to a receptor an d blocks receptor act ion s. Levothyroxin e does n ot block TH, TSH, or TRH receptors.

Learning objective: Identify the cell target of thyroid horm ones. 11. D Thyroid h orm on es are t ran spor ted in to th e t arget cells by a sp eci c t ran sp or t system . With in th e cytoplasm , levothyroxin e (T4 ) is converted to T3 an d m oves in to th e n u cleu s, w h ere it bin ds to th e thyroid receptor. Th e bin ding displaces a bou n d corep ressor an d bin ds a coact ivator to th e receptor com plex. Th e receptor−coact ivator com plex m odulates gen e t ran script ion . A−C, E, F See correct an sw er explan at ion .

roid h orm on e biosyn th esis: • Oxidat ion of iodide to iodin e • Iodin at ion of t yrosin e residu es w ith in thyroglobu lin (iodide organ i cat ion ) • Com bin at ion of t w o diiodot yrosin es (DITs), leading to T4 , an d com bin at ion of m on oiodot yrosin e (MIT) an d DIT, w h ich leads to T3 . By blocking th e en zym e, th e syn th esis of thyroid h orm on es is blocked. In addit ion , propylth iouracil an d, to a lesser exten t , m eth im azole in h ibit th e periph eral deiodin at ion of T4 an d T3 . A−D See correct an sw er explan at ion .

Answers and Explanations: V-2 Drugs for Thyroid Disorders 305 Learning objective: Identify the signs and sym ptom s of hyperthyroidism.

Learning objective: Identify the drug and adm inistration route used to treat myxedema coma.

15. C Th e p at ien t’s h istor y an d th e low thyroid-st im u lat ing h or-

18. D Th e sign s an d sym ptom s of th e pat ien t suggest sh e is af-

m on e (TSH) valu e in dicate th at th e p at ien t w as su ering

fected by m yxedem a com a, a life-th reaten ing com plicat ion

from su bclin ical hyperthyroidism , w h ich is de n ed as a low

of long-st an ding hypothyroidism . Factors th at can precipi-

level of TSH in conjun ct ion w ith n orm al thyroid h orm on e

t ate th e d isorder are exp osu re to cold, illn ess, t rau m a, an d

levels. Th e disorder can occu r in m any pat ien ts t aking levo-

d r ugs t h at are cen t ral n er vou s system dep ressan t s, as in

thyroxin e becau se of in ap p rop riate adju st m en t of th e daily

t h is case. Em ergen cy t reat m en t is im perat ive, as th e con di-

h orm on e dose. Pat ien t s w ith subclin ical hyper thyroidism

t ion is rap idly fat al. A large dose of T4 (levothyroxin e) or T3

are u su ally asym ptom at ic or p resen t on ly a few sp eci c

(t riiodothyron in e) sh ou ld be given in t raven ou sly.

sym ptom s (i.e., in som n ia), as in th is case. An excess of thyroid h or m on es can cau se sign i can t alterat ion in card io vascu lar fu n ct ion . At rest , p erip h eral vascu lar resist an ce is

A, B, E Th ese d r ugs are absolu tely con t rain d icated in hyp othyroidism . C T4 can be given , bu t th e in t raven ous rou te is m an dator y.

d ecreased, w h ich exp lain s th e decreased diastolic pressure, w h ereas systolic pressure is in creased due to in creased h eart rate an d cardiac out put . A, B, D−F Levothyroxin e excess ten d s to cau se e ect s op p osite to th ose listed.

Learning objective: Describe the m ain symptom s of drug-induced hypothyroidism. 19. E Th ioam ide an t ithyroid drugs such as m eth im azole are curren tly used to t reat hyper thyroidism , bu t excessive doses of th ese drugs can sh ift a hyperthyroid pat ien t to a hyp othy-

Learning objective: Describe the adverse e ects of excessive doses of levothyroxine. 16. B At rial

brillat ion is th e m ost com m on cardiac com plica-

t ion of hyp er thyroidism , a ect ing 10 to 25%of hyp er thyroid

roid on e, as in th is case. Con st ipat ion is a com m on sym ptom of hypothyroidism . A−D All of th ese are sym ptom s of hyper thyroidism an d th erefore u n likely after an excessive dose of m eth im azole.

p at ien ts. Th e disorder seem s to be du e, at least in par t , to n om ic n er vous system . Both sym path et ic an d parasym pa-

Learning objective: Explain the m echanism of action of thyroid hormones.

th et ic im pu lses can in crease au tom at icit y an d con du ct ion in

20. A Most of th e e ect s of thyroid h orm on es ap pear to be m e-

hyp er thyroidism -in d u ced in creased sen sit ivit y of th e au to-

at rial m yocytes, th u s t riggering at rial

brillat ion . Becau se

d iated by act ivat ion of n u clear receptors th at lead to act iva-

it is kn ow n th at cardiac brosis (w h ich in creases w ith age) is

t ion or rep ression of t ran script ion of speci c gen es. Large

th e m ost com m on cau se of at rial brillat ion , th e disorder is

n um bers of thyroid h orm on e receptors are foun d in m ost

seen m ore frequ en tly in elderly hyperthyroid pat ien ts, as in

t issu es. Alth ough gen om ic act ion s of thyroid h orm on es pre-

th is case.

d om in ate, n ongen om ic act ion s of thyroid h orm on es h ave

A, C−E All of th ese disorders can cau se t achyarrhyth m ias, bu t th ey are ver y rarely associated w ith hyp erthyroidism .

also been obser ved, in clu ding en h an cem en t of m itoch on d rial oxidat ive ph osph or ylat ion , as w ell as act ion s on ion ch an n els, secon d m essengers, an d protein kin ases.

Learning objective: Identify the enzym e that is inhibited by thioamides such as methimazole.

B−D Thyroid h or m on es h ave act ion s op p osite to t h ose listed.

17. D Th ioam ides such as m eth im azole in h ibit thyroid peroxi-

E Plasm a catech olam in e levels are n ot ch anged by thyroid

dase, th e en zym e th at oxidizes iodid e to a react ive in term e-

h orm on es, bu t th ese h orm on es raise th e sen sit ivit y of t is-

d iate th at couples w ith t yrosin e in th e in it ial step of thyroid

su es to th e act ion of catech olam in es.

h orm on e syn th esis (iodide organ i cat ion ). Th e en zym e also catalyzes m on oiodot yrosin e an d diiodot yrosin e cou p ling to form T3 an d T4.

Learning objective: Identify the drug used in treating hypothyroidism.

A Th is en zym e cat alyzes th e proteolysis of thyroglobulin .

21. C Th e pat ien t’s sign s an d sym ptom s in dicate th at sh e w as

B Th is en zym es catalyzes th e relaxat ion of su percoiled

m ost likely su ering from hyp othyroidism , an d lab resu lts

RNA. C Th is en zym e convert s som e T4 in to T3 in th e follicular cell. E Th is en zym e is a glycolyt ic en zym e found m ain ly in thyroid t um ors.

con rm ed th at th e disorder w as due to Hash im oto thyroidit is. In m ost cases, h igh levels of an t ibod ies to thyroid p eroxidase are diagn ost ic for th is disease. Hash im oto thyroidit is is likely th e m ost com m on cau se of hypothyroidism in Nor th Am erica. Th e t reat m en t usually requ ires lifelong replacem en t th erapy w ith thyroid h orm on es. A, B, D, E See correct an sw er exp lan at ion .

306

Endocrine System

Learning objective: Outline the em ergency pharm acotherapy of thyroid storm.

su ch as Hash im oto thyroidit is, m yxedem a, or p apillar y thy-

22. E Thyroid storm (also called thyrotoxic crisis) is a life-

roid can cer, TSH levels are usually h igh , n ot low.

th reaten ing syn drom e du e to a su dden in crease in all of th e sym ptom s of hyp er thyroidism . Th e m an agem en t of thyroid

A, C, E In hypothyroidism du e to diseases of th e thyroid,

B In Graves disease, thyroid h orm on e levels are h igh , n ot low.

storm m u st be aggressive an d fast . Treat m en t in clu d es fou r d rugs: p ropylth iouracil (w h ich blocks h orm on e syn th esis an d th e perip h eral conversion of T4 to T3 ), potassium iodide

Learning objective: Explain why it is essential to m aintain m aternal euthyroidism during pregnancy.

(w h ich blocks h orm on e syn th esis an d in hibits th e release of

25. D Congen it al hypothyroidism , abn orm al fetal developm en t ,

h orm on es from th e thyroid glan d), hydrocor t ison e (w h ich

an d im paired cogn it ive developm en t in th e n ew born h ave

protect s th e pat ien t again st sh ock an d inh ibit s th e periph -

been at t ribu ted to m atern al hyp othyroidism . A delay in both

eral conversion of T4 to T3 ), an d p rop ran olol (w h ich an -

m en tal an d m otor develop m en t w as obser ved in ch ildren

t agon izes t h e severe card iovascu lar m an ifest at ion s of t h e

w h o w ere born to m oth ers w ith low circu lat ing thyroid h or-

syn d rom e). Th e t reat m en t can restore th e n orm al con cen -

m on e levels bu t n orm al thyroid-st im u lat ing h orm on e (TSH,

t rat ion of t riiodothyron in e in 24 to 48 h ou rs.

thyrot ropin ) levels du ring th e

rst t rim ester of p regn an cy.

A, D Methim azole can be used (although propylthiouracil is

Th is is becau se early d evelop m en t of th e fetal brain d ep en ds

a bet ter choice, because m ethim azole does not block the con-

on m ater n al levot hyroxin e. Most w om en w it h p r im ar y hy-

version of T4 to T3 ), but diltiazem , atenolol, esm olol, and ver-

p ot hyroid ism w ill requ ire abou t 30 to 50% in crem en t in

apam il are useless, as the patient w as receiving propranolol.

h orm one dosage to m aintain euthyroidism during pregnan cy.

B Becau se fever is alm ost alw ays presen t in thyroid storm ,

Exp lan at ion s for t h is in crem en t in clu d e t h e p regn an cy-

an t ipyret ics are indicated, but salicylates sh ould be avoided

in d u ced in crease in t hyroid -bin d ing p rotein s an d an in -

becau se th ey com pete w ith T3 an d T4 for bin ding to thyrox-

creased volu m e of dist ribut ion during pregn an cy.

in e-bin ding globu lin , th u s in creasing free h orm on e levels.

A−C Matern al hypothyroidism can be associated w ith ex-

C Rad ioact ive iodin e is con t rain dicated because it can in -

cessive w eigh t gain , preeclam psia, or even m yxedem a com a,

crease thyroid h orm on e release from d egen erat ing follicles

bu t t h ese are ver y rare even t s, an d to avoid t h ese d isord ers

in th e

is n ot th e m ain reason for th e in creased dosage of thyroid

rst days after t reat m en t . Dexam eth ason e is u seless,

as th e pat ien t w as receiving a glu cocor t icoid.

h orm on e du ring p regn an cy. E Hum an ch orion ic gon adot ropin h as sign i can t TSH ac-

Learning objective: Identify the transporter that carries iodide ions through the apical m em brane of thyroid follicular cells.

t ivit y, bu t th is h as n oth ing to do w ith th e reason for th e in creased dosage of thyroid h orm on e du ring p regn an cy.

23. C Iodide ion s are carried th rough th e apical m em bran e of porter called p en drin th at exch anges on e iodide ion w ith a

Learning objective: Outline the therapeutic uses of potassium iodide.

ch lorin e ion .

26. C Potassiu m iodid e is often u sed for th e preop erat ive p rep a-

thyroid follicu lar cells by a secon dar y act ive Cl−/iodide an t i-


rat ion of pat ien ts un dergoing thyroidectom y because it decreases th e vascu larit y an d fragilit y of a hyp erp last ic glan d .

Learning objective: Identify the m ost likely disease in a patient with low thyroid-stim ulating horm one (TSH) and low thyroid horm ones.

n eeds to go to th e thyroid to m ain tain product ion of thy-

24. D Th e low levels of both thyroid horm on es and TSH indicate

th is, th e blood ow to th e glan d m u st be in creased, an d th e

th at th e pat ien t w as su ering from secon dar y hyp othyroid -

thyroid cells m ust increase in num ber. These actions are pro-

ism , w h ich occurs w h en th e pit u itar y produces in su

cien t

m oted by TSH, w h ose p rodu ct ion is in creased, m aking th e

cien t thyrot ropin -

gland hyperplastic. W hen iodine supply is restored, th e feed-

cien cy is som et im es

back m ech an ism is n o longer n eeded, an d vascu larit y an d

term ed ter t iar y hypothyroidism ).Th e fact th at a com puted

fragilit y of th e glan d decrease. Th ere is convin cing eviden ce

tom ography scan con rm ed th e diagn osis in dicates th at th e

of decreased thyroid blood ow from iodine treatm ent. How -

p at ien t’s hyp othyroidism w as du e to a pit uit ar y t u m or th at

ever, w h eth er th is decrease results in any addit ion al ben e ts

cau sed TSH de cien cy.

at su rger y is st ill con t roversial.

TSH or th e hypoth alam u s produces in su releasing h or m on e (TRH; t h is in su

W h en th ere is ch ron ic iodin e de cien cy, m ore iodin e roid-st im ulat ing h orm on e (T4 ) at th e required levels. To do


Answers and Explanations: V-2 Drugs for Thyroid Disorders 307 Learning objective: Identify the drug used for thyroid ablation.

m olecu les are released an d can exer t p h ar m acological ef-

27. B Treat m en t of hyperthyroidism in cludes an t ithyroid drugs,

fect s. In gen eral, th e result ing hypothyroidism is m ild, as in

su rgical t hyroid ectom y, or d est r u ct ion of t h e glan d w it h

th is case, an d it disapp ears in a few days w h en th e drug is

radioact ive iodin e. W h en an t ithyroid drugs are con t rain di-

w ith draw n .

cated , as in t h is case, or w h en t h e d isease is severe, rad io act ive iodin e is cu rren tly th e t reat m en t of ch oice. A Th ioam id e an t it hyroid d r ugs (p ropylt h iou racil an d m et h im azole) can cau se n eu t ropen ia an d agran u locytosis an d are th erefore con t rain dicated in th is p at ien t becau se of

A, C W h en hyp othyroid ism is cau sed by drugs, th e

rst

p rocedu re is to stop th e o en ding agen t . Thyroid h orm on es can be given later if sym ptom s persist . B Potassium iodide can block thyroid h orm on e release. Th erefore, it is con t rain dicated in hyp othyroid ism . D Metform in does n ot a ect thyroid fun ct ion.

p ropylth iou racil-in duced n eu t rop en ia. C−E Th ese drugs can be used to con t rol sym ptom s of hyp erthyroidism but are n ot suit able for th e long-term m an agem en t of th e disease.

Learning objective: Identify the drug used to treat subclinical hypothyroidism. 30. E Th e w om an w as m ost likely a ected by su bclin ical hyp o-

Learning objective: Explain why levothyroxine is used instead of a racemic mixture in thyroid replacement therapy.

thyroidism , w h ich is d e n ed as elevated thyroid-st im u lat ing

28. C Th e u se of th e levo isom er of thyroxin e is an exam p le of

levels. Th e prevalen ce of su bclin ical hyp othyroidism is 4 to

th e stereo select ivit y of d rugs. More th an on e h alf of all u se-

10%bu t can in crease to 26%in th e elderly pop u lat ion , par t ic-

fu l drugs are ch iral m olecu les. Ch iralit y (also called stereo-

u larly w om en . Th e risk of developing overt hypothyroidism

isom erism ) m ean s th at drugs can exist as en an t iom er pairs;

is related to th e level of TSH an d is in creased in p at ien t s w ith

th at is, th ey h ave asym m et ric cen ters. A racem ic m ixt u re is

p osit ive an t ibodies, as in th is case. Treat m en t of subclin ical

a m ixt u re of th ese en an t iom ers. In m ost cases, on e of th ese

hyp othyroidism is con t roversial, bu t thyroid rep lacem en t

en an t iom ers (dext ro or levo) h as greater a

n it y for th e re-

app ears reason able in asym ptom at ic pat ien ts w ith levels

t s bet ter to th e receptor

greater th an 10 m U/L an d in th ose w ith posit ive thyroid

ceptors th an its m irror im age; it

m olecu le. How ever, m ost st u dies of clin ical e

cacy of drugs

h ave been carried out w ith racem ic m ixt u res of th e drug

h orm on e (TSH) in th e presen ce of n orm al thyroid h orm on e

an t ibodies. A−D, F See correct an sw er explan at ion .

rath er th an w ith separate en an t iom ers. Th erefore, on ly a sm all p ercen tage of th e ch iral drugs u sed clin ically are m arketed as th e act ive isom ers. Th e receptor a

DRUGS FOR THYROID DISORDERS Answ er key

n it y of levothy-

roxin e is about 25 t im es h igh er th an th at of dext rothyroxin e, an d th is is th e reason w hy th e levo isom er is used clin ically. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Describe the appropriate therapeutic management of a hypothyroid patient on amiodarone therapy. 29. E Ch ron ic t reat m en t w ith am iodaron e can cau se hyp er- or (m ore often ) hypothyroidism becau se th e drug is rich in iodin e. W h en am iodaron e is m etabolized by th e liver, iodin e

1. 2. 3. 4. 5.

A F D D B

6. 7. 8. 9. 10.

E C A E C

11. 12. 13. 14. 15.

D C C E C

16. 17. 18. 19. 20.

B D D E A

21. 22. 23. 24. 25.

C E C D D

26. 27. 28. 29. 30.

C B C E E

308

Endocrine System

Answers and Explanations: V-3 Corticosteroids and Antagonists Questions 1−5 2. L

Learning objective: Explain why synthetic glucocorticoids are usually preferred over cortisol in the therapy of nonendocrine disorders.

3. E

9. B Syn th et ic glu cocort icoids are u su ally p referred over n at u -

4. A

ral h orm on es for th e t reat m en t of n on en docrin e disorders

5. H

becau se th ey are less p ron e to in du ce salt an d w ater reten -

1. D

t ion w h en given at equ ivalen t an t iin am m ator y doses.

Learning objective: Describe the long-term adverse e ect s of glucocorticoids.

A, C−E All of t h ese e ect s of glu cocor t icoid s are d oserelated an d closely parallel th eir an t iin am m ator y e ect .

6. F Myasth en ia gravis is an autoim m u n e disease th at dest roys apy in cludes ch olin esterase in h ibitors to relieve sym ptom s

Learning objective: Explain the m echanism s of the antiin am m atory action of glucocorticoids.

an d cort icosteroids, im m un osuppressive drugs, an d thym ec-

10. E Acu te bursit is result s from th e in am m at ion of a

acet ylch olin e receptors at th e n eurom uscular jun ct ion . Th er-

uid-

tom y to in terfere w ith autoim m un e path ogen esis. Th e pa-

lled sac, th e bu rsa, w h ich is located bet w een t w o su rfaces

t ien t’s sign s an d sym ptom s in dicate th at h is t reat m en t m ost

th at ru b togeth er w h en m oving. Th e in am m at ion h as a

likely in clu ded a glu cocort icoid, su ch as dexam eth ason e. Glu -

rapid on set an d can be ver y u n com for t able. In t ra-art icular

cocor t icoids can cause h ear tburn (becau se of th e in creased

inject ion s of glu cocor t icoids p rovide rap id relief becau se of

gast ric secret ion an d decreased prost aglan din biosyn th esis),

th eir pow erful an t iin am m ator y act ivit y. Th is e ect is m e-

hyp ocalcem ia (by d ecreasin g in test in al absor pt ion an d in -

d iated by a vast array of act ion s, in clu ding th e in du ct ion of

creasing ren al Ca 2+ excret ion ), an d hyperglycem ia (by st im u -

th e syn th esis of lipocor t in s. Th ese en zym es act as in h ibitors

lat ing glycogen syn th esis an d glu con eogen esis).

of ph osph olipase A2 , th e en zym e th at catalyzes th e release

A, E Flu drocor t ison e an d testosteron e are n ot u sed for t reating m yasth en ia gravis.

of arach idon ic acid from m em bran e ph osph olipids. Because arach idon ic acid is th e p recu rsor of eicosan oids, th e cor t ico-

B−D Edroph on ium , azath ioprin e, an d n eost igm in e are used

steroid -in d u ced in d u ct ion of lip ocor t in s lead s to an in h ibi-

for treating m yasth en ia gravis, but they do not cause the sym p -

t ion of p h osp h olip ase A2 an d , in t u r n , to an in h ibit ion of

tom s repor ted by the pat ien t .

biosyn th esis of all eicosan oids, w h ich are p roin am m ator y com poun ds.

Learning objective: Describe the long-term e ects of glucocorticoids on serum ion values.

(ACTH) release, bu t th is has n oth ing to do w ith th eir an t i-

7. B Glucocorticoids lower Ca 2+ absorption by the gut and increase

in am m ator y act ion .

Ca 2+excret ion by th e kidn ey. Th erefore hypocalcem ia is an exp ected adverse e ect of long-term th erapy w ith th ese drugs. A, C−E Glu cocor t icoids ten d to p rodu ce act ion s op posite to th ose listed .

A Glu cocor t icoid s in h ibit adren ocor t icot rop ic h or m on e

B Glucocort icoids do n ot a ect th e cat abolism of prostaglan din s. C, D Glu cocor t icoids decrease post capillar y perm eabilit y (due to in h ibit ion of h ist am in e release an d kin in act ivit y) an d decrease th e syn th esis of m ost p roin am m ator y in ter-

Learning objective: Describe the e ect s of glucocorticoids on serum glucose levels. 8. D Glu cocor t icoids can lead to hyperglycem ia by cau sing sim -

leu kin s, such as IL-6.

Learning objective: Describe glucocorticoid-induced osteoporosis.

u lat ion of glucon eogen esis, decreased glucose ut ilizat ion by

11. E Th e patient’s sign s and sym ptom s indicate that she w as suf-

cells, and increased glucagon secretion. These e ects are dose-

fering from Cushing syndrom e, m ost likely due to h igh-dose

dep en den t , an d hyp erglycem ia can occu r even w ith a low

glu cocort icoid th erapy. Polym yosit is is a ch ron ic au toim -

dose of daily p redn ison e.

m u n e disease of u n kn ow n cau se ch aracterized by in am m a-

A, B, E Glu cocort icoids ten d to cau se e ect s op posite to th ose listed. C Glu cocort icoids can cause hypokalem ia, but th is is rare w it h syn t h et ic d r ugs t h at h ave ver y low m in eralocor t icoid

tor y an d degen erat ive ch anges in th e m uscles. High -dose glu cocort icoid is u su ally th e t reat m en t of ch oice. Drugs w ith h igh p oten cy an d n egligible salt-retain ing act ivit y, su ch as d exam eth ason e, are com m on ly th e preferred agen t s.

act ivit y, su ch as predn ison e. Moreover, th e pat ien t w as re-

A, B, D Meth ot rexate, azath iop rin e, an d cyclop h osph a-

ceiving captopril, w h ich ten ds to cause hyperkalem ia, th us

m ide are som et im es u sed to t reat polym yosit is, bu t th ey do

balan cing th e possible hyp okalem ic e ect of predn ison e.

n ot cause th e syn drom e sh ow n by th e pat ien t .

Answers and Explanations: V-3 Corticosteroids and Antagonist s 309 C, F Fludrocor t ison e an d m ifepriston e are n ot used to t reat polym yosit is.

glu cose u t ilizat ion , an d in creased glu cagon secret ion ) an d in creased BUN becau se of protein w ast ing. A−D, F Th ese drugs do n ot cause th e syn drom e presen ted

Learning objective: Describe prednisone-precipitated hyperosmolar com a.

by th e pat ien t an d are n ot curren tly used in th e th erapy of polyar terit is n odosa.

12. A Th e n eurologic sign s, togeth er w ith th e h uge glycem ic valu e, th e h igh -serum osm olalit y, an d th e absen ce of u rin ar y

Learning objective: Describe the e ect s of glucocorticoids.

keton es, suggest th e diagn osis of hyp erglycem ic, hyperos-

15. A Th e pat ien t’s sign s an d sym ptom s in dicate th at sh e w as

m olar com a. The syndrom e t ypically occurs in elderly t ype 2

m ost likely su er in g from t h e adverse e ect s of ch ron ic

d iabet ics, bu t occasion ally it m ay be th e in it ial presen t at ion

glu cocort icoid th erapy. Glu cocor t icoids su ch as p redn ison e

of previously laten t diabetes m ellit us. It is frequen tly precip -

are cu rren tly u sed to t reat severe cases of u lcerat ive colit is.

itated by com orbid con dit ion s or by cert ain drugs, in cluding

Th ey can cau se m u scle w eakn ess (becau se of skeletal m u scle

glu cocort icoids, th iazides, an d ph enytoin .

w ast ing, so-called steroid m yopathy) an d ep igast ric dist ress

B Beta-2 st im ulan ts such as albuterol can cause hypergly-

(because of in creased pept ic acid secret ion s an d in h ibit ion

cem ia by st im ulat ing liver glucon eogen esis. Th erefore, th ey

of prost aglan din syn th esis). Osteoporosis is a frequen t seri-

could precipitate diabet ic ketoacidosis if given at h igh doses.

ous com plicat ion of long-term glucocort icoid th erapy an d

How ever, in h aled albu terol rarely cau ses sign i can t hyper-

can exp lain th e du ll, ach ing back p ain of th e pat ien t . Glu co-

glycem ia, an d diabet ic ketoacidosis is un likely, m ain ly be-

cor t icoid s d ecrease t h e n u m ber of lym p h ocytes (d u e to

cau se of th e absen ce of u rin ar y keton es.

in creased e

u x from blood to th e lym p h oid t issu e) an d in -

C See correct an sw er exp lan at ion .

crease t h e n u m ber of n eu t rop h ils (d u e bot h to in creased

D, E The signs and sym ptom s of ventricular tachycardia and

e

cerebral edem a are n ot th e on es exh ibited by th e pat ien t .

u x from bon e m arrow an d to d ecreased m igrat ion from

th e blood vessels). B−F All of th ese d rugs are u sed to t reat u lcerat ive colit is,

Learning objective: Describe glucocorticoid-induced subcapsular cataract.

bu t th ey do n ot cau se th e sign s an d sym ptom s sh ow n by th e pat ien t .

13. B Th e pat ien t’s h istor y an d sym ptom s in dicate th at h e w as m en t . Long-term th erapy w ith a h igh dose of glu cocort icoids

Learning objective: Identify the opportunistic infections that can be triggered by chronic glucocorticoid therapy.

h as been associated w ith th e developm en t of posterior sub -

16. C High -dose glucocort icoid th erapy in creases th e risk of op -

cap su lar cat aract s, w h ich occu r in abou t 20% of p at ien t s

p ort un ist ic in fect ion s because th ey low er th e resistan ce of

t reated for 1 year or m ore.

th e h ost . Th e sign s an d sym ptom s of th e pat ien t in dicate

m ost likely su ering from steroid-in du ced cat aract develop -

A, C Mifep riston e an d u drocor t ison e are n ot u sed to t reat rh eum atoid ar th rit is, n or do th ey cause cat aract s. D−F Meth ot rexate, azath ioprin e, an d cycloph osph am ide are som et im es u sed to t reat rh eu m atoid arth rit is, bu t th ey d o n ot cau se cat aract form at ion .

th at sh e w as m ost likely a ected by pu lm on ar y t u bercu losis, on e of th e m ost com m on diseases th at can be t riggered or react ivated by h igh -dose glu cocort icoid th erapy. A, D Th ese p n eu m on ias can be t riggered by h igh -dose glu cocor t icoid th erapy, bu t o en ding organ ism s are n ot acidfast bacilli.

Learning objective: Describe the long-term e ects of glucocorticoids on glucose and blood urea nitrogen (BUN) levels.

exh ibited by th e pat ien t , but th ey are n ot t riggered by gluco-

14. E Th e pat ien t’s sign s an d sym ptom s in dicate h e w as su er-

cor t icoid th erapy.

B, E, F All of th ese diseases can h ave som e of th e sym ptom s

ing from adverse e ect s of ch ron ic glu cocor t icoid th erapy. kn ow n cau se t h at is u su ally t reated w it h h igh d oses of glu -

Learning objective: Describe the e ects of glucocorticoids on the hematopoietic system.

cocor t icoids. Ch ron ic t reat m en t w ith th ese drugs can cause

17. D Glucocorticoids decrease th e concentration of lym ph ocytes,

ep igast ric dist ress becau se of in creased p ept ic acid secre-

m on ocytes, eosin op h ils, an d basoph ils (du e to in creased ef-

tions and in hibition of prostaglandin synthesis, m uscle weak-

u x from blood to t h e lym p h oid t issu e an d to in creased

n ess becau se of m uscle w ast ing, hyper ten sion (m ech an ism

apoptosis). Th ey also in crease th e con cen t rat ion of n eut ro-

st ill u n cer tain ), an d can didiasis (oral w h ite p laqu es) becau se

p h ils (du e to in creased e

of th e im m un osu ppressive e ect th at in creases th e proba-

creased m igrat ion from blood vessels) an d th e con cen t rat ion

bilit y of op p or t u n ist ic in fect ion s. Th ese drugs can also cau se

of red blood cells an d platelet s.

Polyar ter it is n od osa is a con n ect ive t issu e d isord er of u n -

hyp erglycem ia (du e to in creased glu con eogen esis, decreased

u x from bon e m arrow an d to de-

A−C, E See correct an sw er exp lan at ion .

310

Endocrine System

Learning objective: Explain the m olecular m echanism of action of glucocorticoids.

Learning objective: Identify the risk of osteoporosis in a patient under glucocorticoid therapy.

18. B Glu cocor t icoid s cross th e m em bran e of th e target cell by

21. B Glucocorticoids are rst-line agents to treat relapsing poly-

p assive di u sion . In th e cytop lasm , th e drug bin ds to a glu -

chondritis, an episodic, destructive disorder involving various

cocor t icoid receptor (GR)−h eat sh ock p rotein com p lex in

car t ilages of th e body. Th e disease is fat al after 5 years in

t h e cytop lasm . Th e h eat sh ock p rotein is released, an d th e

abou t 30%of cases. Glu cocor t icoids or im m u n osu p pressan t s

h orm on e receptor com plex is t ran spor ted in to th e n ucleus,

can relieve sym ptom s, bu t t h ey d o n ot a ect m or t alit y. Os-

w h ere it bin ds to speci c n ucleot ide sequen ces along th e

teop orosis is a frequ en t , ser iou s com p licat ion of glu cocor-

DNA, called glucocor t icoid respon se elem en ts (GREs). Bin d-

t icoid t h erapy an d is related to d osage an d d u rat ion of

ing of ligan d-act ivated GRs at GREs regu late (up or dow n )

t reat m en t . Th ese d r ugs d ecrease bon e d en sit y by m u lt ip le

t ran script ion of gen es coding for sp eci c protein s. Ch anges

m echanism s, including inhibition of intestinal absorption and

in th e rate of syn th esis of speci c protein s carr y out m ost

in creased ren al excret ion of Ca 2+ w ith secon dar y in crease of

biologic act ion s of th e h orm on es.

parathyroid h orm on e, th ereby in creasing bon e resorpt ion .

A, C See correct an sw er exp lan at ion .

In addit ion , glu cocor t icoids in h ibit osteoblast act ivit y an d

D−F Glu cocor t icoid s can d ecrease t h e act ivit y of t h ese

lead to u n cou p ling of bon e form at ion an d resorpt ion . Osteo-

en zym es, bu t th is is n ot du e to a blockade of th e en zym es

porosis occu rs in p at ien t s of all ages bu t is m ore frequ en t

follow ing th eir direct bin ding to th e drug-receptor com plex,

w h en addit ion al risk factors (sex an d post m en opausal age)

bu t to an in h ibit ion of th e en zym e syn th esis d u e to su bse-

occur, as in th is case.

qu en t d ow n st ream e ect s of gen e regu lat ion by t h e d r ugreceptor com plex.

A, C−E Th e risk of th ese diseases is n ot in creased by glu cocor t icoid th erapy.

Learning objective: Describe the long-term adverse e ect s of glucocorticoids on the hematopoietic system .

Learning objective: Describe the use of glucocorticoids under stressful conditions in a patient with latent adrenal insu ciency.

19. B Ecchym oses an d easy bru isabilit y are com m on side e ects

22. A W h en glucocort icoids are discon t in u ed in pat ien t s w h o

of prolonged glucocor t icoid use. Th ey occur m ost often in

h ad been t reated w ith h igh doses of th ese drugs for long pe-

th e elderly an d are dose-related . Steroids su ch as p red n ison e

riods, adren al in su

d est roy th e collagen su pp or t of sm all blood vessels, resu lt ing

ch ron ic glu cocort icoid th erapy, a n egat ive feed back m ech a-

in leakage of blood in to surroun ding t issue. Moreover, th eir

n ism in h ibit s cor t icot rop in -releasing h or m on e (CRH) an d

an t iin am m ator y e ect s red u ce t h e n or m al resor pt ion of

ad ren ocor t icot rop ic h or m on e (ACTH) secret ion , resu lt in g

blood leakage, m aking th e bru ise last longer.

in at rop hy of t h e ad ren al cor tex an d d ecreased secret ion of

A, C Warfarin an d h ep arin can cau se bru ises, bu t th ey are n ot u sed to t reat derm atom yosit is. D−F Meth ot rexate, azath ioprin e, an d cyclosporin e are u sed to t reat derm atom yosit is, but th ey do n ot cause bru ises.

cien cy can occu r for som e t im e. Du ring

cor t isol. Th e am ou n t an d t h e d u rat ion of ad ren al in su

-

cien cy depen d on th e dose of glu cocor t icoids an d th e du rat ion of th e steroid t reat m en t . Follow ing long-term th erapy, th is in su

cien cy can last u p to 1 year. W h en th e in su

-

cien cy is n ot p ron ou n ced, th e adren al cor tex can secrete

Learning objective: Outline the use of spironolactone in treating adrenal hyperplasia.

en ough cor t isol u n der n orm al con dit ion s, bu t th is secret ion

20. D Th e p at ien t ’s sym ptom s an d t h e laborator y valu es in d i-

ger y, w h ich m ay require u p to a 10-fold in crease in cor t isol

cate th at h e w as m ost likely su ering from prim ar y hyperal-

secret ion . It is a com m on th erap eu t ic p ract ice to resu m e th e

d osteron ism du e to bilateral adren al hyperplasia. Su rgical

glu cocort icoid t reat m en t in p at ien t s p reviou sly t reated w ith

th erapy of th e disease is n ot recom m en ded becau se m ost

chronic, high-dose glucocorticoids w hen the patient is under

p at ien t s rem ain hyp er ten sive even after bilateral adren al-

st ressfu l con dit ion s (in clu ding su rger y), as in th is case.

ectom y. Hyp erald osteron ism in t h ese p at ien t s can u su ally be con t rolled by sp iron olacton e, a com pet it ive an t agon ist at m in eralocor t icoid receptors. A Abou t on e h alf of pat ien ts w ith prim ar y hyperaldosteron ism n eed addit ion al an t ihyper ten sive t reat m en t , but m in oxidil is an an t ihyper ten sive rarely used today because of its toxicit y. B, C, E, F Th ese drugs are useless, or even dangerou s, in p rim ar y hyperaldosteron ism .

m ay be in su

cien t u n d er st ressfu l con dit ion s, su ch as su r-

B, C Glucocort icoids w ould cause e ects opposite to th ose listed. D Glu cocort icoids can cause gen eral depressive e ect s on in test in al fu n ct ion s (after h igh doses), bu t th is is n ot th e reason for restar t ing p redn ison e t reat m en t in th is pat ien t . E Glucocort icoid t reat m en t can cause a decrease of ACTH release, but th is is n ot th e reason for rest art ing predn ison e t reat m en t in th is p at ien t .

Answers and Explanations: V-3 Corticosteroids and Antagonist s 311 Learning objective: Explain the m echanism s of the im m unosuppressive action of glucocorticoids.

space, th e brain is com p ressed, an d th e con d it ion can be rap -

23. F Polyarterit is n odosa is a system ic vasculit is con sist ing of

preven t ion of cerebral edem a associated w ith cerebral in fec-

segm en tal in am m at ion an d n ecrosis of m ediu m -size vas-

t ion s or n eop lasm s becau se of th eir p ow erfu l an t iin am m a-

cu lar ar teries w ith secon dar y t issu e isch em ia. Th e cau se is

tor y act ion . How ever, th ey are of n o value in case of cerebral

u n kn ow n , but im m un e m ech an ism s appear to be involved.

edem a du e to t rau m a or isch em ic st roke.

idly fat al. Glu cocor t icoids are of valu e for th e redu ct ion or

Un t reated , th e disease is u su ally fatal, often en ding in failu re

A, B, D−F Th ese d r ugs are con t rain d icated in t h is p a-

of t h e h ear t , kid n eys, or ot h er vit al organ s. High -d ose glu -

t ien t becau se th ey cou ld d ecrease th e already low d iastolic

cocort icoids m ay p reven t p rogression an d in du ce p art ial or

p ressure.

n ear-com p lete rem ission in abou t 30% of p at ien t s, likely in cludes th e in h ibit ion of m acroph age-m ediated product ion

Learning objective: Outline the therapeutic uses of glucocorticoids.

of in terleukin s, in cluding t um or n ecrosis factor (TNF).

26. C In th e righ t clin ical set t ing, an in creased n u m ber of eosin -

becau se of th eir p ow erfu l im m u n osu p pressive act ion , w h ich

A Glucocorticoids do not a ect catabolism of leukotrienes.

oph ils in th e bron ch oalveolar lavage is diagn ost ic for acute

B−E Glu cocor t icoids h ave e ects op posite to th ose listed.

eosin oph ilic pn eu m on ia. Th e disord er can be a cau se of acu te resp irator y failu re, as in th is case. Alth ough th e p ath o-

Learning objective: Outline the pharm acotherapy of Addison disease.

gen esis of t h is d isord er is u n kn ow n , a hyp ersen sit ivit y re-

24. E Th e pat ien t’s sign s an d sym ptom s in dicate th at sh e w as

play an etiologic role. Unlike chron ic eosin oph ilic pneum onia,

m ost likely su ering from Addison disease, a progressive hy-

w h ich requires long t reat m en t w ith h igh doses of glucocor-

p ofu n ct ion ing of th e adren al cortex. Min eralocort icoid de -

t icoids, a sh ort cou rse of glu cocort icoids cau ses a com p lete

cien cy resu lt s in in creased excret ion of Na + an d decreased

resolut ion of sym ptom s in m ost cases of acute eosin oph ilic

excretion of K+, w hereas glucocorticoid de cien cy contributes

p n eum on ia.

to post ural hypoten sion an d causes severe in su lin sen sit ivit y. Glucon eogen esis is im p aired, an d hypoglycem ia result s.

act ion to som e u n iden t i ed in h aled an t igen is th ough t to

A, B, D−F Eosin op h ilic p n eu m on ia is n ot an in fect iou s disease, so all th e listed drugs are useless.

Decreased blood cor t isol cau ses in creased p it u it ar y adreblood β-lipot rop in , w h ich h as m elan ocyte-st im u lat ing ac-

Learning objective: Outline the uses of glucocorticoids to treat spinal cord edem a.

t ivit y. Both ACTH an d β-lipot ropin cause hyperpigm en t at ion

27. C Sp in al cord involvem en t w ith can cer m et ast ases occu rs

of th e skin an d m ucous m em bran es ch aracterist ic of Addi-

m ost com m on ly in pat ien ts w ith can cers of th e lu ng, breast ,

son disease. Th e rat ion al p h arm acoth erapy of th e disease

an d p rostate. Cord com pression u su ally resu lts from ver te-

is to provide both m in eralo- an d glucocor t icoid t reat m en t .

bral erosion w ith t u m or exten sion in to th e ep idu ral space.

Flu d rocort ison e is preferred over ald osteron e becau se of its

Glucocor t icoids are adm in istered to all pat ien t s w ith docu-

long d u rat ion of act ion an d it s p ow er fu l salt -ret ain in g ac-

m en ted or su spected cord com p ression to redu ce th e edem a

t ivit y. It is t h e on ly d r ug u sed for m in eralocor t icoid su p -

d ue to com pression an d th e t u m or-in du ced in am m ator y

p lem en t at ion . Cor t isol or a syn t h et ic steroid are u sed for

react ion .

n ocor t icot rop ic h or m on e (ACTH) p rod u ct ion an d in creased

glu cocort icoid su pp lem en t at ion .

A, F Min eralocort icoids su ch as u drocor t ison e an d m in -


eralocor t icoid receptor an t agon ist s su ch as sp iron olacton e are p ract ically devoid of an t iin am m ator y p ropert ies.


as ibu p rofen an d ketorolac can red u ce ed em a d u e to t h e

25. C Cerebral edem a is an excessive accu m u lat ion of w ater in

in am m ator y react ion bu t are m u ch less e ect ive t h an

th e in t ra- or ext racellu lar space of th e brain du e to a breakd ow n of t igh t en doth elial ju n ct ion s th at m ake up th e blood–

B, D Non steroidal an t iin am m ator y drugs (NSAIDs) such

glu cocort icoids. E Diuret ics such as furosem ide can reduce edem a due to

u id to p en et rate in to

con dit ion s th at directly or in directly a ect ren al or circula-

cerebral ext racellu lar sp ace. Th is t yp e of ed em a, called va-

tor y fu n ct ion (i.e., cardiac failure, ren al failure, an d liver dis-

sogen ic, is seen in resp on se to t rau m a, t u m ors, focal in am -

ease) but h ave on ly m argin al e ects in localized edem a due

m at ion , late st ages of cerebral isch em ia, an d hyp er ten sive

to th e in am m ator y react ion .

brain bar r ier. Th is allow s excess

en ceph alopathy. Becau se th e edem a occurs in an en closed

312

Endocrine System

Learning objective: Explain the m olecular m echanism of action of glucocorticoids.

Learning objective: Explain the m olecular m echanism of action of spironolactone.

28. D In m ost adu lt s, im m u n ologic th rom bocytop en ic pu rp u ra

31. D Sp iron olacton e is a com p et it ive an t agon ist of ald oste-

is a ch ron ic d isord er t h at resu lt s from d evelop m en t of an

ron e. By blocking aldosteron e receptors, th e drug in h ibits

an t ibody directed again st a st ru ct u ral p latelet an t igen . Treat-

th e aldosteron e-m ediated produ ct ion of Na +, K+, an d w ater

m en t in th e adu lt u su ally begin s w ith a large dose of an oral

ch an n els in th e collect ing t ubu les. Th e excret ion of Na + an d

glu cocort icoid, su ch as p redn ison e. Th e m ech an ism of ac-

w ater in creases, w h ich explain s th e p at ien t’s n oct u ria. Sp i-

t ion of all steroid drugs involves bin ding to a receptor−h eat

ron olacton e is used as a diuret ic an d som et im es to in hibit

sh ock p rotein com p lex in th e cytop lasm .

h irsut ism in w om en due to its act ion as an an drogen recep -

A, C, E, F Th e m ech an ism of act ion of th ese drugs also in volves bin ding to a receptor−h eat sh ock protein com plex in

tor an tagon ist . A−C, E Spiron olacton e does n ot elicit th ese act ion s.

th e cytop lasm , bu t th ese drugs are n ot u sed in au toim m u n e d iseases. B Azat h iop r in e is an im m u n osu p p ressan t d r ug som et im es u sed in im m u n ologic th rom bocytopen ic p u rp u ra, bu t

Learning objective: Describe the adverse e ect s of m ineralocorticoid excess. 32. B In th e p at ien t being t reated for adren al in su

cien cy, th e

its m ech an ism of act ion is di eren t from th e on e described

h igh blood pressure, th e low K+ levels, an d th e elect rocardio-

above.

gram data suggest th at h is sign s an d sym ptom s are du e to an excessive dose of udrocort ison e, a m in eralocor t icoid cur-


ren tly used as p art of th e th erapy for Addison disease.

29. C Th e p at ien t ’s sign s an d sym ptom s in d icate t h at h e w as

cess w ou ld n ot cause th e pat ient’s sign s an d sym ptom s.

su ering from Cush ing syn drom e due to produ ct ion of cort isol by an adren ocort ical aden om a. Th ese n eop lasm s are

A, D Hyp erglycem ia or m yopathy in du ced by cort isol exC, E Neith er of th ese sit uat ions is con sisten t w ith th e pat ien t’s sign s an d sym ptom s.

t reated by su rgical rem oval, an d p at ien t s m u st receive su p p eriod, as th e adren al cor tex of th e n on t um or glan d is at ro -

Learning objective: Outline the use of glucocorticoids to treat nephrotic syndrom e.

p h ic an d suppressed . Th e suppressed adren al m ay requ ire

33. E Th e p at ien t’s sym ptom s an d th e lab resu lts in dicate th at h e

up to 18 m on th s’ recover y, an d glucocorticoid th erapy sh ould

w as m ost likely su ering from n ep h rot ic syn drom e. In fact ,

be t apered bu t n ot discon t in u ed u n t il th at recover y h as been

th e

d ocum en ted.

u r in e collect ion is d iagn ost ic. Th e syn drom e can be a p r i-

p lem en t ar y cor t isol during surger y an d th e postop erat ive

n ding of m ore th an 3 g u rin ar y p rotein s in a 24-h ou r

A Th e n or m al p ot assiu m levels in d icate t h at t h e aldo-

m ar y glom er u lar d isease (m in im al ch an ge d isease, etc.) or

steron e secret ion is n ot a ected , so t h ere is n o n eed for a

secon dar y to a vast ar ray of disord ers, in clu d ing var iou s

m in eralocor t icoid adm in ist rat ion .

in fect ion s, diabetes, can cer, or im m un ologic disorders. Pro-

B, D−F Th ese dr ugs are useless, or even dangerous, in th is d isease.

tein uria results from dam age of th e kidn ey glom erulus th at causes it to lose its

lt rat ing capacit y. Because th e pat ien t

w as oth er w ise h ealthy, th e syn drom e w as m ost likely du e to

Learning objective: Outline the pharm acotherapy of Cushing syndrome.

m in im al ch ange d isease (also called lipoid n eph rosis). Spon -

30. C In p at ien t s w it h Cu sh in g syn d rom e, t h e m ain goal of

cases, bu t m ost p at ien ts are given glu cocort icoids, su ch as

p h ar m acoth erapy is to block glu cocort icoid secret ion . Ketocon azole is an an t ifungal agen t . In doses h igh er th an th ose em ployed in antifungal therapy, the drug inhibits cytochrom e

t an eou s rem ission of th e disease occu rs in abou t 40% of betam eth ason e. A−D Th ese drugs are n ot used to t reat m in im al ch ange d isease.

P-450 en zym es, th u s blocking several step s of steroidogen eroid biosyn th esis. An oth er drug th at can be used in Cush ing


syn drom e to in h ibit steroid biosyn th esis is am in oglu teth im -

34. B Epin ep h rin e is th e corn erston e of t reat m en t of an aphy-

ide, w h ich in h ibits CYP11A, th e en zym e th at cat alyzes th e

laxis an d sh ou ld be given im m ediately. Glu cocort icoids su ch

conversion of ch olesterol to pregn en olon e, th e rate-lim it ing

as p red n ison e can n ot con t rol t h e im m ed iate sym ptom s

step in steroid biosyn th esis.

(d u e to t h eir slow on set of act ion ) bu t are u su ally given

sis. As a resu lt , th e d rug is th e m ost e ect ive in h ibitor of ste-

A, B, D−F Th ese drugs are u seless, or even dangerou s, in t reat ing Cu sh ing syn drom e.

to alleviate or p reven t later recu r ren ce of bron ch osp asm ,

Answers and Explanations: V-3 Corticosteroids and Antagonist s 313 hyp oten sion , an d u rt icaria becau se of th eir p ow erfu l im m u n osuppressive e ect s. A, C−F Th ese d rugs are u seless, or even con t rain dicated, in an aphylaxis.

E Ben zodiazepin es such as diazepam h ave n o direct an t iem etic e ect. They are som etim es added to the m ain regim en becau se th eir an t ian xiet y e ect cou ld redu ce th e an t icip ator y com pon en t of n ausea an d vom it ing. F Om eprazole is an in h ibitor of gast ric acid secret ion , n ot

Learning objective: Explain the m echanism of the antiin am m atory action of glucocorticoids.

an an t iem et ic dr ug.

u n kn ow n or igin . A con sen su s hyp ot h esis is t h at in gen et i-


cally p redisp osed in d ivid u als, bot h exogen ou s factors an d

38. E Th rom bot ic t h rom bocytop en ic p u r p u ra is an acu te, p o-

35. E Croh n disease is a ch ron ic in am m ator y bow el disease of

en dogen ou s h ost factors in teract to cau se a ch ron ic st ate of

ten t ially fat al disorder ch aracterized by th e pen t ad of

dysregu lated m u cosal im m u n e fu n ct ion . Th e an t iin am m a-

• Severe t h rom bocytop en ia (p latelet s are u t ilized in t h e

tor y e ect of glucocort icoids, w h ich m ay dram at ically re-

for m at ion of di use m icroth rom bi)

d uce fever, diarrh ea, an d abdom in al pain in th e acute stage

• Neu rologic sign s an d sym ptom s

of t h e d isease, h as m u lt ip le com p on en t s, in clu d in g in h ibi-

• Man ifest at ion of isch em ic ch anges in m u lt ip le organ s

t ion of lym p h ocyte-m ed iated p rod u ct ion of in terleu kin -2.

• Fever

Th is cytokin e in du ces p roliferat ion of B an d T cells (in clu d ing

• Microangiop ath ic h em olyt ic an em ia

cytotoxic T cells) an d act ivat ion of n at ural killer cells; th erefore, it plays a cen t ral role in th e im m u n e respon se. A Glu cocor t icoids h ave n o e ect on th e catabolism of p rost aglan din s. B−D Glu cocor t icoids h ave e ects opp osite to th ose listed.

Learning objective: Outline the therapeutic uses of glucocorticoids. 36. D Glucocor t icoids are frequen tly u sed to suppress in am m at ion in th e eye. Th ey are adm in istered top ically in to th e conju n ct ival sp ace w h en t h e in am m at ion occu rs in t h e an terior segm en t of th e eye (e.g., in conju n ct ivit is, kerat it is, ir it is, or ir id ocyclit is), bu t system ic ad m in ist rat ion is requ ired for in am m at ion of th e posterior segm en t of th e eye (e.g., in uveit is an d opt ic n eurit is). A Alth ough in dom eth acin is an an t iin am m ator y drug, it is n ot used topically in th e eye. B, C, E, F Th ese drugs are used to t reat glau com a, n ot in am m ator y diseases of th e eye.

Th e disorder is associated w ith m any con dit ion s, in cluding HIV in fect ion , an d is alm ost alw ays fat al if u n t reated. Th e et iology is un kn ow n . Repeated plasm aph eresis h as dram at ically ch anged th e p rogn osis, an d n ow abou t 85% of p at ien ts recover com p letely. Th e u se of im m u n osu ppressive drugs su ch as rit u xim ab or glu cocor t icoids, in addit ion to p lasm aph eresis, h as fu r th er in creased su r vival an d decreased th e frequ en cy of relapse. A Min eralocor t icoids such as

udrocor t ison e are of n o

valu e in th is disease. B Th rom bolyt ic drugs su ch as alteplase are con t rain dicated in h em orrh agic diseases. C An t ip latelet d r ugs h ave been given to som e p at ien t s w ith ver y qu est ion able ben e t . D Becau se th e an em ia of th rom bot ic th rom bocytopen ic pu rp u ra is n ot du e to iron d e cien cy, iron p reparat ion s are useless. F Th e t h rom bocytop en ia in t h rom bot ic t h rom bocytop en ic pu rpura is n ot due to m yelosuppression ; th us, a m yeloid grow th factor su ch as sargram ost im is n ot u sefu l.

Learning objective: Outline the use of glucocorticoids in treating chemotherapy-induced nausea and vomiting. 37. A Th e best an d m ost com m on regim en to preven t ch em o-


t h erapy-in d u ced n au sea an d vom it in g is a t h ree-d r ug

39. C Glu cocor t icoid s are u sed frequ en tly in th e set t ing of p re-

com bin at ion of a seroton in 5-HT3 receptor an t agon ist , a

m at u re labor to p reven t in fan t respirator y dist ress syn d rom e

glu cocort icoid such as dexam eth ason e, an d aprepit an t . Th is

(RDS). Th e m ain cau se of RDS is pulm on ar y surfact an t de -

com bin at ion preven t s acute em esis in 80 to 90% of pat ien t s

cien cy. With ou t an adequ ate am oun t of su rfactan t , th e su r-

an d delayed em esis in m ore th an 70%of pat ien t s. Th e m ech -

face ten sion w ith in th e alveoli is so great th at th e alveoli

an ism of t h e an t iem et ic act ion of glu cocor t icoid s is st ill

collap se, resu lt in g in p oor gas exch an ge. In t h e fet u s, en -

u n kn ow n , but it is likely m ediated by th eir in h ibit ion of

d ogen ou s cor t isol st im u lates t h e syn t h esis an d secret ion

prost aglan din biosyn th esis in th e cen t ral n er vous system .

of su r fact an t at 30 to 32 w eeks’ gest at ion al age. Matern al

B, C Th ese an t iem et ic drugs are poorly e ect ive in ch em oth erapy-in du ced n au sea an d vom it ing D Loperam ide is an an t idiarrh eal, n ot an an t iem et ic, drug.

adm in ist rat ion of glu cocort icoids can accelerate fet al lu ng m at u rat ion an d decrease th e in ciden ce an d severit y of RDS. A, B, D−F See correct an sw er exp lan at ion .

314

Endocrine System


Learning objective: Identify the drug that can cause gynecom astia in a patient a ected by bilateral adrenal hyperplasia.

40. B Glu cocort icoid th erapy is in dicated in selected p at ien t s

43. D Th e p at ien t’s bilateral adren al hyp erplasia m ost likely

w ith in am m ator y bow el diseases, such as ulcerat ive colit is.

cau sed p rim ar y hyp eraldosteron ism , a disorder th at is u su -

Th e cau se of in am m ator y bow el d iseases is u n clear, bu t

ally con t rolled by sp iron olacton e. Gyn ecom ast ia is a w ell-

one hypothesis includes autoim m unit y. Under norm al condi-

kn ow n adverse e ect of th is drug; th e overall prevalen ce is

t ion s, th e im m u n e system of th e in test in al m u cosa in teract s

abou t 10%. Sp iron olacton e is a com pet it ive ald osteron e re-

w ith lum in al an t igen s an d bacteria to en sure an appropriate

ceptor an tagon ist , but it can bin d to oth er steroid receptors.

im m un e respon se to th ese an t igen s. In in am m ator y bow el

Th e blockade of an drogen receptors is m ost likely th e p ri-

d iseases, t h is im m u n e resp on se is p er p et u ated, an d an au -

m ar y m ech an ism of sp iron olacton e-in du ced gyn ecom ast ia.

toim m u n e cascad e occu rs. Th e ben e cial e ect of glu co -

A−C, E, F All of th ese drugs can cause gyn ecom ast ia, bu t

cor t icoid s m ost likely resu lt s from t h eir p rom in en t an t i-

th ey are n ot u sed to t reat p rim ar y hyp eraldosteron ism .

in am m ator y an d im m un osuppressive propert ies. test in al fun ct ion s w h en given at h igh doses, but th is is n ot

Learning objective: Identify the drug that can cause liver failure in a patient treated for Cushing syndrome

th e p rim ar y reason for th eir u se in u lcerat ive colit is.

44. C Th e pat ien t’s sym ptom s an d laborator y exam s in dicate

A Glucocort icoids h ave gen eral depressive e ect s on in -

C Glu cocort icoids h ave an t iem et ic proper t ies, bu t th is is n ot th e m ain reason for th eir u se in ulcerat ive colit is.

th at h e w as m ost likely su ering from liver failu re. Keto con azole is a drug curren tly used to t reat Cu sh ing syn drom e

D Glucocort icoid act ion s can con t ribute to pain relief, bu t

becau se it in h ibits cytoch rom e P-450 en zym es, th u s block-

th is is n ot th e m ain reason for th eir u se in u lcerat ive colit is.

ing several step s of steroidogen esis. Seriou s h ep atotoxicit y,

E Pat ien ts w ith ulcerat ive colit is h ave an in creased risk of

in clu ding cases w ith a fatal ou tcom e or requiring liver t ran s-

colon can cer, but th e preven t ion of can cer is n ot th e m ain

p lan t at ion , h as occurred w ith th e use of oral ketocon azole.

reason for th e use of glucocor t icoids in ulcerat ive colit is.

Th ese cases occu rred both in pat ien ts receiving h igh d oses for sh or t t reat m en t durat ion s an d in pat ien t s receiving low

Learning objective: Describe the pharm acokinetics of inhaled glucocorticoids

d oses for long du rat ion s.

41. C Th e reason for th e low toxicit y of in h aled glucocor t icoids

liver toxicit y is exceedingly rare.

is related to th eir special ph arm acokin et ics. Approxim ately 80 to 90% of an in h aled dose is dep osited in th e oroph ar yn x,

A Met yrapon e is used to t reat Cush ing syn drom e, but its A, B, D−F Th ese drugs can cau se liver toxicit y bu t are n ot u sed to t reat Cush ing syn drom e.

sw allow ed, an d su bsequ en tly absorbed from th e gast roin test in al t ract . Th is fract ion u n dergoes rst-pass m etabolism CORTICOSTEROIDS AND ANTAGONISTS Answ er key

in th e liver, w h ich is quite h igh (th e oral bioavailabilit y of beclom eth ason e is abou t 10 to 20%).Ten to 20%of an in h aled d ose en ters t h e lu ng. Th is fract ion exer t s th e t h erap eu t ic e ect an d is t h en absorbed in to t h e system ic circu lat ion . Th erefore, w h en given by in h alat ion , th e drug can ach ieve a con cen t rat ion in th e lung th at is adequ ate for th e local th erapeu t ic e ect bu t too sm all for system ic adverse e ect s. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Describe the m ain contraindications of glucocorticoids 42. C Cor t icosteroids are w ell kn ow n to cau se cataracts an d to exacerbate glaucom a during long-term adm in ist rat ion . Th ey are th erefore con t rain dicated, or sh ou ld be u sed ver y cau t iously, in pat ien t s w ith glaucom a. A, B, D, E See correct an sw er exp lan at ion .

1. 2. 3. 4. 5.

D L E A H

6. 7. 8. 9. 10.

F B D B E

11. 12. 13. 14. 15.

E A B E A

16. 17. 18. 19. 20.

C D B B D

21. 22. 23. 24. 25.

B A F E C

26. 27. 28. 29. 30.

C C D C C

31. 32. 33. 34. 35.

D B E B E

36. 37. 38. 39. 40. 41. 42. 43. 44.

D A E C B C C D C

Answers and Explanations: V-4 Drugs for Gonadal Disorders 315

Answers and Explanations: V-4 Drugs for Gonadal Disorders Questions 1−5

A An ast rozole can reduce th e risk of breast can cer but h as

1. A

n o e ect or a n egat ive e ect (due to fur th er decrease in es-

2. K

t rogen levels) on bon e m ass.

3. E

B Alen dron ate can in crease th e bon e m ass in dex m ore

4. G

th an raloxifen e, bu t h as n ot p roven to red u ce breast can cer

5. F

risk. Bisph osp h on ates are u sed to t reat bon e m et ast ases of breast can cer. It h as been suggested th at bisp h osp h on ate

Learning objective: Identify the drug to be used locally in case of vaginal atrophy. 6. A Tot al hysterectom y in cludes rem oval of th e ovaries. Vagin al dr yn ess an d at rop hy du e to est rogen de cien cy is a com m on cau se of dyspareu n ia (pain fu l vagin al in tercou rse) an d can be cu red w ith est rogen adm in ist rat ion . Top ical form s of est rogen s (cream s, vagin al tablet s, etc.) are as e ect ive as or m ore e ect ive th an oral form s for th is in dicat ion an d are u su ally

th erapy m ay decrease th e risk of developing breast can cer, bu t th e e ect iven ess for eith er preven t ion or t reat m en t of breast can cer h as n ot yet been p roven . D, E An drogen s an d progest in s are n ot used to t reat postm en op au sal osteop orosis.

Learning objective: Describe the pharm acological e ect s of drospirenone.

preferred. W hen estrogen cream is used, w om en w ith a uterus

9. B Drosp iren on e is th e on ly p rogest in d r ug w it h d e n ite

are also given a progest in , w h ich is n ot n eeded follow ing hys-

an t ihyper ten sive proper t ies. It is st ru ct u rally related to sp i-

terectom y, as in th is case.

ron olacton e an d act s as an ald osteron e receptor an t agon ist .


Th erefore, it cau ses an in creased ren al sod iu m excret ion , w h ich can accou n t for it s d iu ret ic an d an t ihyp er ten sive

Learning objective: Identify the drug used in a patient with a m et astatic breast cancer resistant to tamoxifen. 7. A Early-st age breast can cer is curable. How ever, if th e pat ien t d evelop s m et ast ases, t h e goal of t reat m en t sh ift s from cu re to palliat ion an d stabilizat ion of disease. An ast rozole is a select ive in h ibitor of arom at ase, th e en zym e th at convert s an drogen s to est rogen s. Th e low levels of est rogen s in post m en opausal w om en are produ ced by arom a-

e ect s. A Pot assium excret ion is decreased, n ot in creased, by aldosteron e an t agon ist s. C−E Th e ren al excret ion of th ese ion s is m in im ally a ected by drospiren on e.

Learning objective: Identify the drug used to induce pubert y in girls with Turner syndrom e.

t izat ion of adren al an d ovarian an d rogen s. Arom at ase in h ibi-

10. F Th e pat ien t’s sign s an d lab exam s in dicate th at th e girl w as

tors cause alm ost a total suppression of est rogen levels. Th ey

a ected by Tu rn er syn drom e, a sex ch rom osom e abn orm al-

are used in post m en opausal w om en w ith a h orm on e recep -

it y in w h ich th ere is a com plete or par t ial absen ce of on e of

tor−posit ive breast can cer w h en t am oxifen is con t rain dicated

th e t w o sex ch rom osom es, p rodu cing a p h en ot ypic fem ale.

or h as proven in e ect ive, as in th is case.

Th e p h en ot ype varies from th at of th e t yp ical Tu rn er syn -


d rom e to n orm al. Failu re to go to p u bert y an d begin m en ses occurs in 90% of a ected person s, as in th is case. Replace-

Learning objective: Identify the drug that can decrease both the risk of breast cancer and the degree of osteoporosis in postm enopausal wom en. 8. C Raloxifen e is a select ive est rogen receptor m odulator. Su ch drugs can h ave est rogen ic e ects in bon e bu t est rogen an t agon ist act ion on breast an d uterin e receptors. Raloxifen e is ap proved both for th e t reat m en t of p ost m en op au sal osteop orosis an d for breast can cer risk reduct ion , an d th erefore can be ap propriate th erapy in a su bset of w om en w ith p ost m en op au sal osteoporosis w h o are at risk of breast can cer, as in th is case.

m en t w ith fem ale h orm on es w ill bring on p u ber t y in m ost cases. A Diethylst ilbest rol is a syn th et ic est rogen but is n ot used in rep lacem en t th erapy becau se of th e risk of aden ocarcin om a in th e o spring. B−E Th ese drugs are of n o valu e in replacem en t th erapy.

316

Endocrine System

Learning objective: Identify the drug used to decrease m enom etrorrhagia due to uterine broid.

Th ese act ion s augm en t th e risk of th rom boem bolic disease

11. E Uterin e

fold com pared to w om en t aking n o h orm on es.

broid, a ben ign uterin e t um or, is th e m ost com -

m on p elvic t u m or, occu rring in abou t 70% of w om en . It frequ en tly cau ses abn orm al vagin al bleeding an d pelvic pain ,

in w om en taking com bin ed oral con t racept ives abou t th reeA−C, E Est rogen s ten d to cause act ion s opposite to th ose listed.

as in th is case. Fibroids ten d to en large du ring reprodu ct ive broids do n ot require

Learning objective: Identify the best horm onal contraceptive for a woman with an abnormal coagulation history.

broid s, m ed ical opt ion s are

14. F Progest in alon e (daily p rogest in t ablet s or im p lan t able

focu sed on su p pression of est rogen st im u lat ion , bu t resu lt s

p reparat ion ) is th e best h orm on al con t racept ive for w om en

are lim ited . Progest in s su ch as m ed roxyp rogesteron e can

w ith an abn orm al coagu lat ion h istor y, as in th is case. In fact ,

p ar t ially suppress est rogen st im ulat ion , w h ich in t u rn can

est rogen s m ust be avoided because th ey in crease blood

d ecrease

coagulabilit y.

years, w h en est rogen produ ct ion is h igh , becau se th ey h ave est rogen receptors. Asym ptom at ic t reat m en t . For sym ptom at ic

broid grow th an d vagin al bleeding. Dan azol, an

an drogen agon ist , can also su p p ress broid grow th bu t h as


a h igh rate of adverse e ect s an d is less frequ en tly u sed.

D Mifepriston e is n ot curren tly available as a regular con -

A Est rogen s such as eth inyl est radiol are con t rain dicated in u ter in e

t racept ive p rep arat ion .

broids becau se t h ey st im u late u ter in e grow t h

B, C Fin asteride inhibits dihydrotestosteron e synthesis, and

Learning objective: Identify the drug that m ost likely caused deep venous throm bosis in a patient taking m ultiple m edications.

ut am ide is an an drogen receptor an tagon ist . By decreasing

15. C Th e est rogen s con tain ed in th e con t racept ive pill can con -

an d rogen act ivit y, t h ese d r ugs can in d irect ly en h an ce es-

t ribu te to th rom boem bolic even ts by several m ech an ism s.

t rogen act ion s an d are th erefore con t rain dicated in u terin e

Th ey in crease plasm a levels of factors II, VII, VIII, IX, X, an d

an d bleeding.

broids. D Mifepriston e is a progest in an t agon ist an d th erefore is con t rain dicated in uterin e broids.

XII, decrease plasm a levels of an t ith rom bin III, an d in crease p latelet p rodu ct ion an d aggregat ion in a m an n er sim ilar to th at seen late in p regn an cy. A Progest in s p lay a m in im al role, if any, in th rom boem bo-

Learning objective: Identify the drug e ective as a contraceptive within 3 days of unprotected intercourse.

lism risk.

12. C Levon orgest rel, a progest in com pou n d, is an e ect ive post-

em bolism .

coit al con t racept ive. Th e e ect iven ess is m ost likely due to a

B, D, E Th ese d r ugs do n ot cau se or favor th rom boF Th is est rogen is n ot used in con t racept ive preparat ion s.

com bin at ion of e ect s of in teract ion w ith progesteron e receptors an d th e t im e of th e cycle. Am ong th e con t racept ive

Learning objective: Explain the mechanism of action of nasteride.

act ion s are in h ibit ion of ovu lat ion , alterat ion s in cer vical

16. C Fin asteride is a com p et it ive in h ibitor of 5α -redu ct ase, th e

m u cu s p rod u ct ion , an d d ecreased fallop ian t u be m ot ilit y,

en zym e th at conver ts testosteron e to dihydrotestosteron e.

all of w h ich can h in d er fer t ilizat ion an d /or d isr u pt d evel-

Dihydrotestosteron e is th e prin cipal an drogen respon sible

op m en t of an en d om et r iu m su it able for im p lan t at ion . Uli-

for st im ulat ion of prostat ic grow th . Th e de n it ive th erapy

p r ist al, a select ive p rogesteron e receptor m od u lator, is also

of ben ign prostat ic hyperplasia is surgical, but drugs can be

e ect ive an d ap pears to be even m ore e ect ive at p reven t ing

u sed w h en su rger y is con t rain dicated, as in th is case.

ovu lat ion .



Learning objective: Explain the m echanism of the throm bo embolic e ect of oral contraceptives. 13. D Est rogen s en h an ce th e coagulabilit y of blood becau se th ey • In crease p lasm a levels of coagu lat ion factors II, VII, VIII, IX, X, an d XII (th e m ain act ion )

Learning objective: Explain the m olecular m echanism of action of combination hormonal contraceptives. 17. E Com bin at ion h orm on al con t racept ives act m ain ly th rough in h ibit ion of ovu lat ion m ost likely d u e to t h e follow in g m ech an ism s: • In th e brain , act ivat ion of est rogen an d p rogest in recep -

• Decrease p lasm a levels of an t ith rom bin III

tors located on arcu ate hypoth alam ic n u clei in h ibits th e

• In crease p latelet p rodu ct ion an d aggregat ion

secret ion of gon ad ot rop in -releasing h or m on e (Gn RH).

Answers and Explanations: V-4 Drugs for Gonadal Disorders 317 In cu r ren t low -d ose p rep arat ion s, t h e p r im ar y hyp ot h a-

sw ings in circu lat ing est rogen levels th at can occu r du ring

lam ic e ect of th e est rogen com p on en t m ay be to in crease

perim en opau se. Horm on al rep lacem en t th erapy is in dicated

expression of progesteron e receptors. Th e progest in com -

for perim enopausal (and som etim es postm enopausal) wom en

pon en t act s to disru pt th e n orm al cyclical p u lsat ilit y of

w h o com plain of over t m en opausal sym ptom s th at disrupt

Gn RH release.

t h eir lives, as in t h is case. Wom en w it h an in t act u ter u s

• Act ivat ion of est rogen receptors in th e an terior p it u itar y

sh ou ld receive est rogen −p rogest in t h erapy to d ecrease t h e

glan d m ain ly in h ibit s follicle-st im u lat ing h orm on e (FSH)

r isk of en d om et r ial an d ovar ian can cers. Th e t h erapy can

secret ion .

often be slow ly w ith draw n on ce th e w om an’s system h as

• Act ivat ion of progest in receptors in th e an terior p it u it ar y gland m ainly inhibits lutein izing horm on e (LH) secretion . W h en com bin at ion h orm on al con t racept ives are given daily, th e m idcycle surge of LH is absen t , an d ovulat ion fails to

progressed to est ablish ed m en op au se. A, B Est rogen s alon e are n ot in dicated becau se of th e in creased risk of en d om et rial an d ovarian can cers. C, D, F Progest in s alon e are n ot e ect ive in redu cing h ot ush es.

occur. A Alth ough com bin ed oral con t racept ives do result in decreased ovarian h orm on e secret ion , th is e ect is n ot p ar t of th e con t racept ive act ion

Learning objective: Describe the adverse e ect s of oral contraceptives.

B, D Act ivat ion of receptors on th ese organ s does n ot de-

21. A Th e pat ien t’s h istor y an d sign s in dicate th at sh e w as af-

crease th e secret ion of a h orm on e involved in th e con t racep -

fected by ch loasm a, an in creased skin pigm en t at ion ch arac-

t ive e ect of est rogen s.

terized by exten sive brow n patch es of irregular sh ape an d

C Act ivat ion of receptors located in th e an terior, n ot posterior, p it u it ar y in h ibits th e secret ion of FSH an d LH.

size. Ch loasm a occu rs in 5%of w om en after 1 year an d in 40% of w om en after 8 years of oral con t racept ive use. It is sim ilar to t h e so-called m ask of p regn an cy t h at som et im es occu rs

Learning objective: Describe the pharm acological actions of progesterone.

in p regn an t w om en . Th e hyp er p igm en t at ion u su ally fad es

18. C Medroxyprogesteron e is a syn th et ic progesteron e deriva-

B−E Th ese drugs do n ot cause skin hyperpigm en tat ion .

slow ly w h en th e h orm on e is w ith draw n .

t ive th at is abou t 15 t im es m ore poten t an d h as th e sam e gesteron e in creases th e sen sit ivit y of th e resp irator y cen ter

Learning objective: Explain the m olecular m echanism of action of anastrozole.

to carbon dioxide, th us leading to an in creased ven t ilator y

22. D An ast rozole an d let rozole are select ive in h ibitors of aro-

resp on se. Th is can exp lain t h e m easu rable redu ct ion of

m atase, th e en zym e resp on sible for th e conversion of an dro-

ar ter ial an d alveolar carbon d ioxid e t h at occu rs d u r ing

gen s to est rogen s, in clu ding th e ext ra-adren al syn th esis of

p regn an cy.

est rogen from an drosten edion e, w h ich takes places in sev-

p h arm acological p ropert ies of th e paren t com poun d. Pro-

A, B, D, E Progesteron e act u ally exh ibits act ion s op posite to th ose listed.

eral t issu es, in clu ding breast . Arom at ase in h ibitors are con sidered secon d-lin e agen t s for h orm on e-dep en den t breast cancers, but they are increasingly used in this disease in post-

Learning objective: Identify the cell site of action of estrogen and progestins.

m en op au sal w om en , in w h om th ey cau se an alm ost tot al

19. A All gon adal steroid h orm on es act prim arily via in t racellu -

A−C, E Arom atase in h ibitors such as an ast rozole are de-

lar receptors to regu late gen e t ran script ion , w h ich occu rs in

su p p ression of est rogen syn th esis. void of th ese act ion s.

th e n u cleu s of target cells, w h ere th e ligan d-act ivated recep tor bin ds to speci c est rogen respon se elem en t s or progest in respon se elem en t s in th e DNA of regulated gen es. B−E See correct an sw er explan at ion .

Learning objective: Describe the contraindications to com bination hormonal contraceptives. 23. B Est rogen s in crease plasm a levels of factors II, VII, VIII, IX, X, an d XII an d are th erefore absolutely con t rain dicated in

Learning objective: Outline the therapeutic uses of com bination hormonal contraceptives. 20. E Alt h ough t h e exact t r igger in g m ech an ism of h ot

u sh es

is u n kn ow n , it h as been sh ow n t h at t h ere is a clear associat ion bet w een th e d evelop m en t of h ot

u sh es an d th e w ide

throm boem bolic diseases. Progestin-only contraceptives m ay be u sed in w om en w ith th rom boem bolic diseases. A, C−E Th ese disord ers do n ot con t rain dicate th e u se of h orm on al con t racept ives.

318

Endocrine System

Learning objective: Identify a drug indicated for m etastatic breast cancer in women resistant to tamoxifen.

(FSH) an d lu tein izing h orm on e (LH) release from th e an te-

24. D Horm on al th erapy in th e m et ast at ic breast can cer set t ing

for m ore th an 25 years to t reat in fer t ilit y w h en oth er cau ses

can p rovide long p rogression -free su r vival in p at ien t s. If th e

h ave been ruled out . How ever, clom iph en e m ay exh ibit n eg-

patient responds to a h orm onal agen t for a long period of

at ive e ect s, in clu ding an in creased in cid en ce of m u lt ip le

t im e, th e likelih ood of respon se to an oth er h orm on al agen t

births, ovarian cysts, and ovarian hyperstim ulation syndrom e.

is h igh . Because th e pat ien t w as w ell con t rolled w ith t am ox-

rior pit u itar y, result ing in ovu lat ion . Th e drug h as been used


ifen for 5 years, an ot h er h or m on al agen t is a reason able n ist , h as been approved for pat ien ts w h o h ave becom e resis-

Learning objective: Identify the m ain reason for the preference of synthetic estrogens and progestins over natural compounds.

t an t to tam oxifen , as in th is case.

27. B Syn t h et ic est rogen s an d p rogest in s are often p refer red

ch oice. Fu lvest ran t , a com pet it ive est rogen receptor an tago-

A An ast rozole is used in m et ast at ic breast can cer but is an arom at ase in h ibitor, n ot an est rogen receptor an t agon ist . B, C, E Th ese drugs are n ot used in th e th erapy of breast carcin om a.

over n at u ral h or m on es m ain ly becau se t h ey h ave greater oral bioavailabilit y due to low er

rst-pass m et abolism . Th e

slow er m et abolism of th ese drugs also accou n ts for th eir longer h alf-life (i.e., est radiol 1 to 2 h ou rs, eth inyl est radiol 8 to 24 h ou rs).

Learning objective: Outline the risk of breast cancer associated with hormone replacement therapy in postmenopausal women.

n at ural h orm on es in th eir h orm on al e

25. B Horm on e replacem en t th erapy is th e m ost e ect ive t reat-

gon adot rop in secret ion , in ciden ce of adverse e ect s, or tera-

m en t opt ion for alleviat ing vasom otor sym ptom s in post-

A, C−E Synthetic com pounds do not di er signi cantly from cacy, in h ibit ion of

togen ic act ivit y.

m en op au sal w om en . Th e risk of m align an t t u m ors in w om en cern for th e use of th ese m edicat ion s in perim en opausal

Learning objective: Describe the pharm acological e ect s of testosterone.

w om en . Alth ough th e issu e is st ill con t roversial, it app ears

28. D Several disorders can cause erectile dysfunction, but w hen

th at th ere is a sm all du rat ion -related in crease in th e risk of

th is is d u e to hyp ogon adism , an drogen rep lacem en t th erapy

breast can cer. Th is prom pted th e U.S. Food an d Drug Adm in -

is in dicated. An drogen s can in crease er yth rop oiet in syn th e-

ist rat ion to m an date th e addit ion of n ew safet y w arn ings to

sis in th e kidn ey, an d th is can explain th e in creased er yth ro-

th e labels of all system ic est rogen s, in clu ding est rogen -on ly

p oiesis th at occu rs w ith th ese h orm on es. Because of th is, in

an d com bin ed est rogen −progest in p rodu ct s. Th e labels cau -

th e past , h igh doses of testosteron e w ere u sed in th e t reat-

t ion t h at t h e u se of est rogen -con t ain in g h or m on e th erapy

m en t of cer tain t yp es of an em ia, bu t today th e direct adm in -

regim en s by p ost m en op au sal w om en m ay be associated

ist rat ion of er yth rop oiet in is largely preferred.

t aking h orm on al con t racept ives is p robably th e m ajor con -

w ith an in creased risk of breast can cer, m yocardial in farct ion , st roke, an d th rom boem bolism .

A−C, E An drogen s ten d to cause e ect s opposite to th ose listed.

A, C−E Th e risk of th ese diseases is act u ally decreased in p ost m en opau sal w om en on h orm on al est rogen plu s progest in th erapy.

Learning objective: Describe the adverse e ect s of anabolic steroids. 29. D Hepatocellular aden om a an d carcinom a, alth ough rare, are

Learning objective: Identify the site of action of clomiphene when given to treat infertilit y.

clearly associated w ith th e use of both oral con t racept ives

26. B Clom ip h en e is an est rogen receptor an t agon ist in m ost

exposed for m ore th an 10 years is 100-fold h igh er th an th at

t arget t issu es. Blockade of est rogen receptors in th e hypo-

of pat ien ts n ot receiving th ese dr ugs. Th e risk m ay be even

th alam u s cou n teract s th e est rogen -in du ced n egat ive feed -

h igh er for at h letes t h an for p at ien t s u sing h or m on es for

back on th e hypoth alam ic-p it u it ar y-ovarian axis. Th is e ect

ot h er p u r p oses, as relat ively ver y h igh d oses are t aken to

often allow s n orm al pulsat ilit y of gon adot ropin -releasing

in crease ath let ic perform an ce.

h orm on e (Gn RH) release from th e hypoth alam us to occur, stim ulating a norm al pat tern of follicle-stim ulating h orm one

an d alkylated an abolic steroid s. Th e relat ive r isk in t h ose

A−C, E, F Th e risk of th ese diseases is n ot in creased by th e u se of an abolic steroids.

Answers and Explanations: V-4 Drugs for Gonadal Disorders 319 Learning objective: Outline the use of horm onal contraceptives to treat polycystic ovary syndrom e.

in crease th e am plit ude of pulsat ile gon adot ropin -releasing

30. F Polycyst ic ovar y syn drom e is th e m ost com m on form of

h orm on e (Gn RH) release.

ch ron ic an ovulat ion associated w ith an drogen excess. It occu rs in 5 to 10%of w om en of rep rodu ct ive age, m aking it th e

D Progest in s d ecrease, n ot in crease, t h e frequ en cy an d

E Progest in s in h ibit , n ot in crease, th e con t ract ilit y of th e m yom et riu m .

leading cause of in fert ilit y an d th e m ost com m on en docrin e to th e disease is un kn ow n , but th ere are at least th ree poten -

Learning objective: Identify the drug class to which tam oxifen belongs.

t ial m ech an ism s th at act syn ergist ically:

32. D Tam oxifen is a com m on h orm on al adju n ct th erapy for

abn orm alit y for th is age grou p . Th e p rim ar y defect leading

• In ap p rop r iate gon ad ot rop in secret ion : t h ere is an in -

breast can cer becau se it h as been sh ow n th at 5-year t reat-

creased frequ en cy of gon ad ot rop in -releasin g h or m on e

m en t red u ces an n u al odds of death by abou t 25% in both

(Gn RH) secret ion leading to an in creased lu tein izing h or-

pre- and postm enopausal wom en regardless of axillary lym ph

m on e (LH) pulse frequen cy an d am plit ude; th us n o dom -

n ode involvem en t . Tam oxifen is classi ed as a select ive es-

in an t follicle d evelop s, an d n o ovu lat ion occu rs.

t rogen receptor m odu lator (SERM). SERMs su ch as tam oxi-

• Excessive an drogen p rodu ct ion in th e th eca cell of th e

di eren t allosteric m odulation e ects than estrogen . The re-

ovar y leads to hyp eran drogen ism . • In su lin resistan ce w ith com p en sator y hyp erin su lin em ia Est rogen −progest in th erapy w ith a com bin at ion h orm on al con t racept ive p rep arat ion is t h e

fen an d raloxifen e bin d to est rogen receptors, but th ey h ave

rst -lin e t reat m en t for

w om en seekin g regu lar m en st r u al cycles an d relief from an drogen ic sym ptom s. Th e h orm on es su p press th e hypoth alam ic-pit uit ar y-ovarian axis, in cluding decreasing LH secret ion , th u s decreasing an drogen p rodu ct ion . Th e pills also provide “replacem en t th erapy,” an d a cycle of 21 days of act ive p ills follow ed by 7 days of in act ive p ills u su ally n orm alizes th e m en st ru al cycle. A−E Mifepriston e an d dan azol are useless in polycyst ic ovar y syn d rom e

su lt is th at th e con form at ion al ch ange follow ing SERM bin d ing allow s th em to be agon ists in th e m odu lat ion of som e gen es in som e target t issu es an d an t agon ist s in th e m odu lat ion of exp ression of oth er gen es. Fu rth erm ore, each SERM h as a di eren t spect rum of act ion s. For exam ple, tam oxifen act s as an est rogen an tagon ist in breast t issu e bu t as an agon ist in bon e an d en dom et rial t issue, w h ereas raloxifen e is an an t agon ist in both breast an d en dom et riu m t issu e bu t an agon ist in bon e. A−C, E, F See correct an sw er explan at ion .

Learning objective: Outline the therapeutic uses of danazol. 33. E Th e sign s an d sym ptom s of th e pat ien t suggest th at h e w as

Learning objective: Identify the m ain m echanism of contraceptive action of daily progestin tablets. 31. C Th e d oses of p rogest in in m in i pills are su

cien t to block

ovu lat ion in on ly 60 to 80% of cycles. Th e e ect iven ess of th ese p rep arat ion s is th ough t to be m ain ly related to a com bin at ion of e ect s, in clu ding: in creased viscosit y of cer vical m u cu s, w h ich d ecreases sp er m p en et rat ion ; a d ecrease in fallop ian t u be m ot ilit y (est rogen s in crease bu t p rogest in s d ecrease t u be m ot ilit y); an d en d om et r ial alterat ion s t h at im pair im plan t at ion . A Th e corpus luteum is form ed from th e rupt ure of ovarian follicle an d produ ces a large am ou n t of p rogesteron e an d est rogen s. Act ivat ion of progesteron e receptors in th e corp us lu teu m h as n oth ing to do w ith th e con t racept ive e ect . B Progest in s do n ot en h an ce follicle-st im ulat ing h orm on e (FSH) release; if th ey did, th is e ect w ould favor, n ot in h ibit , ovu lat ion .

a ected by h eredit ar y angioedem a, a disease cau sed by h eredit ar y im pairm en t of C1 esterase in h ibitor, a p rotein th at regu lates act ivat ion of th e com plem en t , con t act , an d

bri-

n olyt ic system s. C1 in h ibitor is on e of th e m ajor in h ibitors of plasm a kallikrein, th e con t act system protease th at cleaves kininogen and releases bradykinin. Presum ably, uncontrolled act ivat ion of t h e con t act system allow s for t h e release of kin in -like m ediators, resu lt ing in edem a of su bcu t an eou s or su bm u cosal t issu es. Th e d isease is est im ated to occu r in 1 in 50,000 to 150,000 in divid u als, w it h a m or t alit y rate est im ated at 15 to 33%, resu lt in g from lar yn geal ed em a an d asphyxiat ion . Ch ron ic an drogenic t reat m en t of pat ien ts w ith h eredit ar y angioedem a e ectively preven ts the at tacks. An drogen s m ost likely act by st im u lat ing th e h ep at ic syn th esis of C1 esterase in h ibitor. Dan azol is th e drug m ost frequ en tly u sed for th is pu rp ose. A−D, F See correct an sw er explan at ion .

320

Endocrine System

Learning objective: Outline the therapeutic use of leuprolide and utamide.

m ain reason s for discon t in u ing use of com bin ed con t racep -

34. C Th e p at ien t’s sign s an d sym ptom s suggest prost ate can cer,

adverse e ect is m u ch less com m on .

an d th e exam resu lts con rm th e diagn osis of m et ast asized

tives. Today, w ith the use of low -dose contraceptive pills, th is B−E See correct an sw er explan at ion .

p rost at ic carcin om a. Prost ate-speci c an t igen (PSA) is th e spin e m etastases w ith prevalent n ecrotic lesions are the m ost

Learning objective: Describe the adverse e ect s of anabolic steroids.

com m on m et ast ases of prost at ic carcin om a. Th e m ain stay of

37. F High doses of an drogen s or an abolic steroids, used by ath -

t reat m en t for m etastasized prost ate can cer is h orm on al

letes to im prove com pet it ive p erform an ce, can produ ce

th erapy. Because th e can cer is testosteron e-depen d en t , h or-

oligosp erm ia an d redu ct ion in test icu lar size. Th is is th e con -

m on al m an ip u lat ion focu ses on red u cing testosteron e levels.

sequ en ce of n egat ive feedback by an drogen on th e hyp oth al-

Leu p rolide is a syn th et ic gon ad ot rop in -releasing h orm on e

am us th at in h ibits th e secret ion of gon adot ropin -releasing

(Gn RH) an alogu e. W h en adm in istered daily (or as a depot

h orm on e (Gn RH), w h ich in t u rn causes a correspon ding de-

p reparat ion ) to m ain t ain st able blood levels, it in h ibit s th e

crease in both follicle-st im ulating and lutein izing horm ones.

m ost u sed lab test for early detect ion of p rost ate can cer, an d

release of follicle-st im ulat ing h orm on e (FSH) an d lutein izing


h orm on e (LH), likely du e to dow n regulat ion of pit uit ar y receptors. Th is in h ibit ion st rongly reduces test icular an drogen

Learning objective: Outline the therapeutic uses of estrogens.

syn t h esis. Flu t am id e is an an d rogen receptor an t agon ist .

38. B Est rogen replacem en t th erapy is de n itely in dicated to

Com bin ed t reat m en t w it h t h ese d r ugs red u ces sym ptom s

p ost pon e m en opause in you ng w om en w h o u n dergo abla-

in 70 to 80% of pat ien ts, causes an appreciable regression of

t ion of t h e ovar y. Som e r isks associated w it h est rogen re-

est ablish ed m etastases, an d prolongs sur vival. In con t rast ,

p lacem en t th erapy (en dom et rial an d ovarian can cer) can n ot

cytotoxic ch em oth erapy h as failed to prolong sur vival in pa-

occur in th is case because th e organ s are n o longer presen t .

t ien t s w ith advan ced prost ate can cer.

Oth er risks of th is th erapy (breast can cer an d th rom boem -

A Th is is a th erapy for advan ced ovarian can cer.

bolic disorders) are also m in im al in th is case, becau se th e

B Th is is a th erapy for acute lym ph oblast ic leukem ia.

therapy sim ply restores the physiological levels of estrogens.

D Th ese d r ugs are u sed in h or m on e receptor−p osit ive


breast can cer. E Th ese drugs are used in Wilm s t u m or.

Learning objective: Outline the noncontraceptive uses of com bined oral contraceptives.

Learning objective: Identify the m ost com m on adverse e ect of progestin-only horm onal contraceptives.

39. E Th e p at ien t is m ost likely su er in g from en d om et r iosis,

35. D Som e w om en experien ce breakth rough bleeding w h ile

t ion in g en d om et r ial t issu e is p resen t ou t sid e t h e u ter in e

t aking oral con t racept ives, bu t breakth rough bleeding is th e

cavit y. Th e in cid en ce of t h e disord er is h igh , as it is com -

m ost com m on p roblem (in u p to 25% of pat ien ts) in w om en

m on ly fou n d in 10 to 15% of w om en bet w een t h e ages of

u sing th e progest in -on ly pill. It is m ore frequen tly en coun -

25 an d 45 w h o are act ively m en st ru at ing. Medical th erapy

tered in w om en t aking a low dose of progest in s an d often

of en d om et r iosis u su ally involves m ed ical su p p ression of

resolves on its ow n . If it persist s for m ore th an 3 m on th s, th e

ovarian fu n ct ion to arrest th e grow th an d th e act ivit y of en -

best st rategy is to sw itch to a com bin ed oral con t racept ive

d om et rial im plan t s. En dom et riosis is est rogen -depen den t .

w ith a h igh er rat io of est rogen to progest in .

Low -dose oral con t racept ives are ap prop riate in it ial th erapy,

an estrogen-dependent in am m atory disease in w hich func-

A−C, E All of th ese adverse e ect s can occur w ith com bi-

w ith th e goal of su ppressing th e en dogen ous produ ct ion of

n at ion oral con t racept ives but are du e m ain ly to th e est ro-

est rogen . Th e low dose provided by th e pill m ay o er som e

gen com pon en t of th e p reparat ion , an d th e risk is th erefore

protection against bon e loss w ithout signi cantly prom oting

m in im al w ith a progest in -on ly oral con t racept ive.

en dom et rial t issu e form at ion . Dep ot inject ion s of gon ad ot rop in -releasing h orm on e (Gn RH) agon ists are an altern a-

Learning objective: Describe the main adverse e ect of estrogens.

t ive th erapy for en dom et riosis. Dan azol is also ap proved for

36. A Many drugs can cause nausea and vom iting in sensitive pa-

th is u se, bu t th e adverse e ect p ro le is con sidered to be

tients. How ever, the w om an w as m ost likely su ering from

w orse th an th at of low -dose com bin ed oral con t racept ives

n ausea due to th e con t racept ive preparat ion , as sh e h ad

or Gn RH an alogues.

been t aking th e oth er drugs for som e t im e w ith ou t adverse

A Alth ough an ast rozole m ay be useful in t reat ing post-

e ect s. Nau sea from a com bin ed oral con t racept ive can gen -

m en op au sal en dom et riosis by blocking perip h eral conver-

erally be at t ribu ted to th e est rogen com p on en t (eth inyl es-

sion of an drogen s to est rogen s, it is n ot able to fu lly su p p ress

t radiol). It w as a com m on adverse e ect an d w as on e of th e

est rogen produ ct ion in prem en opau sal w om en an d is n ot

Answers and Explanations: V-5 Drugs for Bone Hom eostasis 321

w om en ; it h as been prop osed to u se an ast rozole in com bi-

Learning objective: Describe the interaction bet ween rifam pin and oral contraceptives.

n at ion w ith a Gn RH agon ist , such as leuprolide.

41. E Th e drug cu rren tly u sed to p reven t in fect ion in close con -

e ect ive w h en u sed as m on ot h erapy in p rem en op au sal

B, C, F Th ese d r ugs p rovid e lu tein izin g h or m on e−like

t acts of p at ien t s w ith m en ingococcal m en ingit is is rifam p in .

(h u m an ch or ion ic gon ad ot rop in an d lu t rop in alfa) an d

Historically, several cases of u n exp ected pregn an cies w ere

follicle- st im u lat in g h or m on e (u rofollit rop in ) act ivit y an d

repor ted am ong w om en t aking rifam pin , an d n ow it is w ell

w ou ld n ot be u sefu l in th e t reat m en t of en dom et riosis; fu r-

kn ow n th at th is occurs because rifam pin can st rongly re-

th erm ore, th ey p oten t ially cou ld be cou n terprodu ct ive.

d uce th e plasm a con cen t rat ion of est rogen s an d p rogest in s

D Tam oxifen is a select ive est rogen receptor m od u lator t h at h as est rogen -like act ion s on en d om et r ial t issu es an d w ou ld be con t rain dicated in th is sit u at ion .

by in du cing th eir m et abolism . A, B Ceft riaxon e an d cip ro oxacin are u sed to preven t infect ion in close con t act s of p at ien t s w it h m en in gococcal m en ingit is, bu t th ey are n ot m et abolism in du cers.

Learning objective: Identify the drug that can trigger an acute porphyric at tack in a genetically predisposed patient.

h ibitors, n ot in ducers, an d th ey are n ot u sed for m en ingo-

40. B Th e p at ien t w as m ost likely su er ing from acu te in ter-

coccal prophylaxis.

C, D Er yth rom ycin an d ketocon azole are m etabolism in -

m it ten t p orp hyria th at m an ifest s as in term it ten t at t acks of abdom in al, m en t al, or n eu rologic sym ptom s. Porphyrias reDRUGS FOR GONADAL DISORDERS Answ er key

su lt from gen et ic de cien cies of en zym es in th e h em e bio syn th et ic p ath w ay. A large n um ber of drugs, especially th ose th at can in du ce h ep at ic am in olevu lin ic acid (ALA) syn th ase an d cytoch rom e P-450 en zym es, can precip itate a p orphyric at tack in predisposed pat ien ts. Th ese in clude barbit urates, p h enytoin , valproate, su lfon am ides, rifam p in , progesteron e, an d syn th et ic p rogest in s. Th erefore, it is m ost likely th at th e p rogest in of th e con t racept ive pill (n oreth in dron e) w as th e d rug th at t riggered th e at tack in th is p at ien t .

1. 2. 3. 4. 5.

A K E G F

6. 7. 8. 9. 10.

A A C B F

11. 12. 13. 14. 15.

E C D F C

16. 17. 18. 19. 20.

C E C A E

21. 22. 23. 24. 25.

A D B D B

26. 27. 28. 29. 30.

B B D D F

31. 32. 33. 34. 35.

C D E C D

36. 37. 38. 39. 40. 41.

A F B E B E

A, C−E Th e adm in ist rat ion of th ese d rugs is con sid ered safe in a pat ien t a ected by porp hyrias.

Answers and Explanations: V-5 Drugs for Bone Hom eostasis Questions 1−5

on bon e being dose-depen den t . Th e e ect of excess of PTH is

1. A

a n et in crease in bon e resorpt ion (rem oval of bon e m in eral

2. K

an d m at rix). How ever, in term it ten t low doses of PTH in crease

3. G

bon e form at ion by in creasing osteoblast n u m ber an d act ivit y

4. D

w ith out st im ulat ing bon e resorpt ion . Th is h as led to th e ap -

5. C

proval of terip arat ide for th e t reat m en t of osteop orosis. It is cu rren tly recom m en ded th at teriparat ide be reser ved for

Learning objective: Explain the m echanism of action of teriparatide. 6. A Teriparat ide is a recom bin an t an alogue of parathyroid h orm on e (PTH) w ith physiological act ion s equal to th ose of th e n at ural h orm on e. PTH t argets osteoblasts, w ith th e n et e ect

th ose w h o h ave proven refractor y to oth er th erapies an d/or pat ien ts w ith a h igh risk of fract u res, as in th is case. B, C, E PTH in d uces e ect s op posite to th ose listed. D Collagen syn th esis is n ot involved in bon e t urn over of m at ure bon e.

322

Endocrine System

Learning objective: Describe the pharm acological e ects of vitamin D.

Learning objective: Outline the therapeutic uses of sevelam er. 10. E Th e p at ien t w as m ost likely su ering from en d-stage ren al

7. A Ch olecalciferol (vit am in D3 ), w h ich is a prodrug, is th e m ost

d isease, a con dit ion com m on ly associated w ith hyperph os-

appropriate th erapy for vit am in D de cien cy in anyon e w ith

p h atem ia. Sevelam er is a n on absorbable, calciu m - an d alu -

norm al ren al fun ction . Ch olecalciferol is m etabolized to 25(OH)

m in u m -free, polym eric am in e th at bin ds diet ar y p h osph ate

D by th e liver an d circu lates bou n d to vitam in D−bin ding pro-

w ith in th e gast roin test in al t ract , th ereby preven t ing ph os-

tein , m aking it available for conversion to calcit riol. For th e

p h ate absorpt ion . It h as been approved for th e m an agem en t

regu lat ion of calciu m h om eost asis, th e ren al conversion of

of hyperph osph atem ia in pat ien t s w ith en d-stage ren al

calcit riol plays a m ajor role in st im u lat ing in test in al calciu m

d isease.

absorpt ion , th us adding calcium to th e system . Conversion in oth er t issues con t ributes to non calcem ic e ect s of calcit riol,

A−D Th ese d iseases are n ot associated w it h hyp erp h osph atem ia.

su ch as m u scle st rength an d su pp or t of th e in n ate im m u n e

Learning objective: Identify the drug used to treat rickets.

system . B Adm in ist rat ion of calcit riol as a drug is reser ved for cases

11. A Th e p at ien t’s sign s an d sym ptom s, togeth er w ith th e lab

w h ere th e body is un able to m ake calcit riol, as in ren al failu re,

results, suggest th at h e w as su ering from rickets, a disease

becau se of th e risk of hyp ercalcem ia.

t h at can a ect ch ild ren . Dark-skin n ed are at greater r isk,

C−E None of these drugs would address vitam in D de ciency.

becau se skin p igm en t at ion blocks u lt raviolet ir rad iat ion n eeded for syn th esis of vitam in D. Rickets is due to vit am in

Learning objective: Explain the prim ary m echanism of action of calcitriol.

D de cien cy, w h ich in t u rn causes d e cien t m in eralizat ion

8. D In test in al calciu m absorpt ion is p oten tly augm en ted by cal-

cien cy ten d s to cau se hyp ocalcem ia. W h en th is occu rs, p ara-

cit riol, an d th is is m ost likely th e m ain act ion th at m ediates

thyroid h orm on e (PTH) p rodu ct ion is in creased . Th u s, th e

th e th erapeu t ic e

cacy of calciferols in osteom alacia. Th ere is

seru m level of calciu m is restored to n early n orm al, bu t hy-

lit tle evid en ce th at calcit riol directly p rom otes bon e m in eral-

p oph osph atem ia p ersist s (du e to PTH-m ediated in crease in

izat ion . Rath er, it is th e in creased seru m calciu m level th at

ren al secret ion of ph osph ate), an d m in eralizat ion of bon e is

in directly prom otes bon e m in eralizat ion by decreasing para-

im paired. Th e elevated alkalin e p h osph atase re ect s th e in -

thyroid h orm on e−m ediated bon e resorpt ion .

creased osteoblast act ivit y. Ch olecalciferol (vit am in D3 ) sup -


of epiphyseal car t ilage an d osteoid m at rix. Vitam in D de -

plem en tat ion w ith adequ ate calciu m an d p h osp h ate in t ake is th e st an dard th erapy for ricket s.

Learning objective: Outline the therapeutic uses of alendronate.

C Alth ough calcit riol is th e act ive form of vit am in D3 , it is

9. F Bisph osp h on ates are rst-lin e th erapy for osteoporosis, an d

n ot u sed for rickets, as its act ion is sh or t , an d it can cau se

adding alen dron ate to th e curren t regim en is a rat ion al ch oice,

hyp ercalcem ia in abou t 30% of p at ien t s. W it h ad equ ate

as th e ongoing th erapy failed to preven t th e decrease in bon e

ch olecalciferol, th e body can regulate th e product ion of ap -

m ass.

propriate levels of calcit riol.

A Th is opt ion is ir rat ion al. Hyd roch lorot h iazide is u sefu l

B, D−F See correct an sw er exp lan at ion .

in osteop orosis becau se it d ecreases t h e ren al excret ion of B Selective estrogen receptor m odulators are today preferred

Learning objective: Explain the m echanism of action of cholecalciferol.

over est rogen s for th e th erapy of osteoporosis becau se th ey

12. D Both ch olecalciferol (vitam in D3 ) an d ergocalciferol (vit a-

calciu m .

do n ot in crease th e risk of breast an d en dom et rial can cer. C Calciton in is m u ch less e ect ive th an bisph osph on ates in th e th erapy of osteoporosis.

m in D2 ) are prodrugs an d n eed to be t ran sform ed in th e body in to act ive m et abolites. Th e p rim ar y act ive m et abolite of th ese vitam in s is calcit riol, w h ich bin ds to vitam in D re-

D Th e dose of calcium taken by th e pat ien t is th e st an dard

ceptors w ith in target cells. Th e calcit riol−vit am in D receptor

for calciu m su pplem en t at ion in post m en opausal w om en . It is

com plex bin ds to speci c recogn it ion sites on DNA to m odify

u n likely th at a larger d ose w ould ad d ben e t .

gen e t ran script ion .

E Glucocort icoids are con t rain dicated in osteoporosis becau se th ey cou n teract th e e ects of vitam in D to st im u late in test in al calciu m absorpt ion .


Answers and Explanations: V-5 Drugs for Bone Hom eostasis 323 Learning objective: Describe the reason for the long duration of action of bisphosphonates.

Learning objective: Outline the therapeutic uses of calcitonin. 15. F Th e pat ien t’s sym ptom s, togeth er w ith th e h igh calcium ,

13. B Bisph osph on ates in bon es are often retain ed for m on th s or

low ph osph orus, an d h igh p arathyroid h orm on e (PTH) lev-

years, an d a single inject ion of zoledron ate can be e ect ive

els, are con sisten t w ith th e diagn osis of prim ar y hyp erp ara-

for up to 1 year in th e t reat m en t of osteoporosis. Th e reason

t hyroid ism . In fact , PTH valu es are elevated in m ore t h an

for this exceptionally long duration of action is because these

90% of p arathyroid-related cau ses of hypercalcem ia, u n de-

d rugs are in corporated in to th e hydroxyapat ite cr ystals of

tect able or low in m align an cy-related hyp ercalcem ia, an d

bon e in p lace of pyrop h osph ate, th u s altering th e st ru ct u re

u n detectable or n orm al in h igh bon e t urn over causes of hy-

of th e cr yst al. W h en bisph osph on ates are released from re-

p ercalcem ia. Th e approach to m edical t reat m en t of hyp er-

sorbed bon e m in eral, th ey cau se apoptosis of th e osteoclast s,

calcem ia varies w ith it s severit y. Mild hyp ercalcem ia (< 12

th u s red u cing th e rate of bon e resorpt ion an d decreasing th e

m g/dL) can be m an aged by hyd rat ion . More severe hyp er-

n et bon e loss th at ch aracterizes osteoporosis.

calcem ia (> 13−14 m g/dL) m ust be m an aged aggressively


becau se, above th ose levels, it can be life-th reaten ing. Th erefore, t h e m ore severe t h e hyp ercalcem ia, t h e greater t h e

Learning objective: Outline the therapeutic uses of pam idronate in bone m etastases.

n u m ber of com bin ed t h erap ies t h at sh ou ld be u sed . Th e

14. C Th e p at ien t’s sign s an d sym ptom s, along w ith th e elevated

t ion is to in crease ren al calciu m excret ion w ith in t raven ou s

alkalin e p h osph atase, in dicated th at h e w as m ost likely su f-

salin e an d fu rosem ide, w h ich in h ibits calciu m reabsorpt ion

fering from hypercalcem ia due to m etastat ic prost ate can cer.

in th e th ick ascen ding lim b of Hen le. Bisph osphonates, w hich

In fact , hyperparathyroidism an d can cer, w ith or w ith out

are long-last ing in h ibitors of bon e resorpt ion , h ave becom e

m etastases, are th e t w o m ajor cau ses of hypercalcem ia, ac-

rst-lin e agen ts for th e an t iresorpt ive t reat m en t of hyp er-

coun t ing for over 90% of cases. Th e disorder occu rs in 10 to

calcem ia. How ever, th ey h ave a slow on set of act ion (1 or 2

20% of all adu lt s w ith can cer. Rehydrat ion w ith salin e an d

days). Calciton in h as a rapid , albeit sh ort-lived, blockade of

d iu resis w ith fu rosem ide are th e

rst step in th e t reat m en t

bon e resorpt ion . An e ect on seru m calciu m is obser ved

of severe hypercalcem ia. Bisph osph on ates such as pam idro-

w ith in 4 to 6 h ours an d last s 6 to 10 h ours. Th erefore, an

n ate h ave been approved for th e acu te t reat m en t of hyper-

addit ion of both calciton in an d pam idron ate is th e st an dard

calcem ia of m align an cy. Becau se th ey h ave a slow on set of

t reat m en t .

act ivit y, calciton in is frequen tly given con com itan tly.

m ain st ay of t reat m en t in p at ien t s w ith n orm al ren al fu n c-

A Calcit riol is con t rain dicated in th is case becau se it ten ds

A In t raven ous (IV) sodium ph osph ate is probably th e fast-

to in crease ser u m calciu m level; also, calcit r iol levels m ay

est w ay to low er seru m calcium level, but it is a h azardou s

be elevated in t h is p at ien t secon dar y to t h e hyp er p arat hy-

p rocedu re because of th e risk involved (su dden hyp ocalce-

roid ism .

m ia, ectopic calci cat ion , hyp oten sion , an d acu te ren al failu re). In ligh t of sat isfactor y respon ses to oth er agen ts, IV sodiu m p h osp h ate is u sed on ly after oth er m eth od s of t reatm en t h ave failed to con t rol hyp ercalcem ia. B Hyd roch lorot h iazid e in creases, n ot d ecreases, ser u m

calciu m reabsorpt ion in th e dist al convolute t ubu le. C Fluoride st im ulates bon e form at ion , but th e doses th at cau se hyp ocalcem ia are toxic, an d th e d rug is n ot u sed for th is p u rpose. D Pot assium -sparing diuret ics h ave low e

calciu m level. D Osm ot ic diuret ics su ch as m an n itol are absolutely con t rain dicated in d ehyd rated p at ien t s. E Fludrocor t ison e is used on ly w h en dehydrat ion is caused by adren al in su

B Th iazid es are con t rain d icated becau se t h ey en h an ce

cien cy.

F Cin acalcet decreases parathyroid h orm on e (PTH) secret ion by act ivat ing calciu m -sen sing receptors in th e parathyroid glan d. It can decrease PTH-m ediated hypercalcem ia but n ot can cer-m ediated hypercalcem ia. Th e reason is th at th e m ain h u m oral factor associated w ith can cer-related hyp ercalcem ia is PTH-related p ept ide, w h ose p rod u ct ion is n ot u n der th e con t rol of calcium -sen sing receptors.

cacy an d are

con t rain dicated in th is case, as th ey ten d to en h an ce calcium reabsorpt ion in th e dist al convolute t u bu le. E Teriparat ide is an an alogue of parathyroid h orm on e an d th erefore is con t rain dicated in a p at ien t w ith hyp erp arathyroidism .

324

Endocrine System

Learning objective: Explain the mechanism of action of calcitonin.

an d for p at ien t s w it h hyp ercalcem ia associated w it h p ara-

16. A Calciton in is a h orm on e secreted by th e p arafollicu lar cells

thyroid carcin om a.

of th e thyroid. Th e prin cipal act ion of th e h orm on e is a di-


rect in h ibit ion of osteoclast ic bon e resor pt ion . Th is act ion on osteoclasts, w h ich in t urn causes a profoun d decrease in

Learning objective: Identify the drug used to treat hypocalcem ia in a patient with liver cirrhosis.

th e ru

ed border of th ese cells, th ereby in h ibit ing bon e re-

19. D Th e sym ptom s, th e lab resu lt s, an d th e h istor y of th e pa-

sorption . Calciton in is n ot a rst-line agen t in th e treatm en t of

t ien t in d icate th at h e w as m ost likely su ering from alco-

Paget d isease of bon e, bu t it can be u sed as an alter n at ive

h olic cirrh osis. Th e bon e dem in eralizat ion an d low calciu m

d rug w h en bisp h osph on ates are n ot tolerated, as in th is case.

levels suggest th at liver disease caused an im paired syn th e-

B Alth ough calciton in m ay decrease apoptosis of osteo-

sis of 25(OH)D w it h t h e n al ou tcom e of osteom alacia. Cal-

blast s, Paget disease is m ain ly ch aracterized by u n con t rolled

cit r iol is t h e m ost e ect ive agen t for hyp ocalcem ia in a

osteoclast ic bon e resorpt ion . Th erefore, in h ibit ion of osteo-

p at ien t w ith im p aired liver fu n ct ion becau se it byp asses th e

clast act ivit y, n ot st im u lat ion of osteoblast act ivit y, is th e

im paired syn th esis of th e p recursor essen t ial for p rodu ct ion

m ain act ion th at m ediates th e th erap eu t ic e ect of th e dr ug

of calcit riol. Clin ically, severe calcit riol de cien cy as a con se-

in Paget disease.

qu en ce of liver disease is rare becau se th e degree of h epat ic

is m ediated by th e act ivat ion of calciton in receptors located

C, D Calciton in causes act ion s opposite to th ose listed.

d est r u ct ion n ecessar y to im pair 25-hyd roxylat ion is in com -

E Calciton in does n ot directly a ect in test in al calcium

p at ible w ith long-term su r vival. How ever, it is n ot rare w h en

absorpt ion .

th e p at ien t also h as vitam in D de cien cy, w h ich frequ en tly occurs in h om eless people becau se of a poor diet .

Learning objective: Identify the drug used to treat renal osteo dystrophy.

p roduct ion of parathyroid h orm on e (PTH). Terip arat ide, a

17. C Th e pat ien t’s h igh creat in in e level poin ts out th at h e w as

PTH an alogu e, can add ver y lit tle to th e th erapy.

m ost likely su ering from ch ron ic ren al failu re, presu m ably d ue to diabet ic n eph ropathy (th e m ost com m on cause of ren al failu re in th e Un ited St ates). Ch ron ic ren al failure can cau se ren al osteodyst rophy, a term used to describe collect ively all th e skelet al ch anges in ch ron ic ren al disease. Ren al

A Pat ien ts w ith hypocalcem ia already h ave an in creased

B Vit am in D3 w ou ld be on ly m argin ally e ect ive because of th e im pairm en t of liver 25-hydroxylat ion . C Bisph osph on ates are absolutely con t rain dicated in pat ien t s w ith hypocalcem ia. E Calcipotriene, a vitam in D analogue, is used only locally.

osteodyst rophy is due to several factors, in cluding loss of calcit riol produ ct ion becau se th e dam aged kid n ey n o longer con t ain s su

cien t ren al α 1 hydroxylase to conver t 25(OH)D3

Learning objective: Explain the m echanism of action of alendronate.

in to calcit riol. Th is con t ributes to secon dar y hyp erparathy-

20. D Bisph osp h on ates are drugs of ch oice in osteop orosis. Th ey

roidism due to th e result ing hypocalcem ia (also, calcit riol

are in corp orated in to th e bon e m in eral an d in h ibit th e act iv-

suppresses parathyroid horm one gene expression ). The com -

it y of osteoclast s in a dose-depen d en t m an n er. Th e m ech a-

bin at ion of hyp erp arathyroidism an d calcit riol de cien cy

n ism of th is in h ibit ion is st ill in com pletely un derstood an d

leads to th e developm en t of ren al osteodyst rophy, w h ich h as

likely m u lt ifactorial. Am in o bisp h osp h on ates su ch as alen -

feat ures of both osteom alacia an d osteoporosis. In ch ron ic

dronate in hibit an en zym e, farn esyl pyrophosph ate synthase,

ren al failu re, calcit r iol can h elp alleviate bot h t h e hyp ocal-

in th e m evalon ate p ath w ay th at app ears to be crit ical for os-

cem ia an d th e bon e disease.

teoclast su r vival. Th erefore, prom ot ion of osteoclast apopto-


sis or death seem s an im port an t m ech an ism of th e in h ibit ion of osteoclast act ivit y.

Learning objective: Explain the m olecular m echanism of action of cinacalcet.


th at act ivate th e calciu m -sen sing receptor. Th is receptor is

Learning objective: Explain the m echanism of action of teriparatide.

w idely dist ributed but h as it s greatest con cen t rat ion in th e

21. A Ter ip arat id e is a recom bin an t an alogu e of p arat hyroid

p arathyroid glan d. By act ivat ing th is receptor cin acalcet in -

h or m on e (PTH) w ith physiological act ion s equal to th ose of

h ibit s parathyroid h orm on e (PTH) secret ion . Cin acalcet low -

th e n at u ral h orm on e. PTH exert s both cat abolic an d an abolic

ers ser u m PTH levels in p at ien t s w it h n or m al or red u ced

e ect s on bon e. Cat abolic e ect s p revail w it h ch ron ically

renal fun ction . The drug is approved for the treatm en t of sec-

elevated PTH; th ere is a n et in crease in bon e resorpt ion . An -

on dar y hyperparathyroidism due to ch ron ic kidn ey disease

abolic e ect s p revail w ith in term it ten t low doses of PTH;

18. C Cin acalcet is th e rst represen t at ive of a n ew class of dr ugs

t h ere is a n et in crease in bon e for m at ion (by in creasin g

Answers and Explanations: V-5 Drugs for Bone Hom eostasis 325 osteoblast n um ber an d act ivit y) w ith out st im ulat ing bon e

Learning objective: Outline the therapeutic uses of calcium .

resorption. This h as led to th e approval of teriparatide for the

24. D Th e sym ptom s an d h istor y of th e p at ien t in dicate th at sh e

t reat m en t of osteop orosis. Th e drug is reser ved for advan ced

w as su ering from severe hypocalcem ia secon dar y to hyp o-

osteoporosis w h en bisph osph on ate th erapy h as failed, ex-

p arathyroidism , likely due to acciden t al dam age of p arathy-

t rem e bon e loss h as already occu rred, an d/or fract u re h as

roid glan ds or th eir circulat ion du ring thyroidectom y. Th e

already occu rred, as in th is case. Terip arat ide is th e on ly cu r-

t reat m en t of severe hyp ocalcem ia can be best accom p lish ed

ren tly available th erapy th at results in n et bon e deposit ion .

w ith slow in fusion of calcium glucon ate (th e preferred cal-

B Est rogen s are u sed for p reven t ion , n ot for t reat m en t , of osteop orosis on ly in p ost m en op au sal w om en w h o n eed est rogen t reat m en t for t h e m an agem en t of m en op au sal sym ptom s. C Because alen dron ate w as n ot e ect ive, th e u se of an oth er bisph osph on ate w ould be irrat ion al. Bisph osph on ates

ciu m salt for in t raven ou s th erapy because it is less irritating to th e vein ). A Vit am in D can in crease calciu m levels, but it s on set of act ion is too slow for an em ergen cy th erapy. B, C, E, F All of th ese dr ugs are act u ally con t rain dicated becau se th ey decrease seru m calciu m levels.

are con sid ered an t iresor pt ive agen t s as op p osed to bon e an abolic agen t s. D Calciton in does n ot con sisten tly decrease h ip fract ure risk an d does n ot in crease bon e den sit y. E Paricalcitol is an analogue of calcitriol, used for the treatm ent of secondary hyperparathyroidism in speci c stages of ch ron ic kidn ey disease.

Learning objective: Describe the adverse e ect s of alendronate. 22. F W h en adm in istered orally, bisph osp h on ates (m ain ly alen d ron ate) frequen tly cau se esoph ageal an d gast ric irrit at ion .

Learning objective: Describe the adverse e ects of teriparatide. 25. D Ter ip arat id e is a recom bin an t an alogu e of p arat hyroid h or m on e (PTH) w it h p hysiological act ion s equ al to t h ose of th e n at u ral h orm on e. It is u sed in p at ien t s w ith advan ced osteoporosis an d previous bon e fract ures. Alth ough hypercalcem ia is n ot a com m on adverse e ect , th e h orm on e act s like th e n at u ral PTH; it in creases ren al reabsorpt ion of calciu m an d th e e

u x of calciu m from bon e in to th e seru m .

Several cases of ter ip arat id e-in d u ced hyp ercalcem ia h ave been reported in th e literat u re.

Because of th is, pat ien ts are in st ructed to t ake th e m edica-

B Furosem ide act ually decreases serum calcium levels.

t ion early in th e m orn ing on an em pt y stom ach w ith a large

A, C, E Th ese drugs do n ot a ect seru m calciu m levels.

glass of w ater an d th en to st ay qu iet an d u prigh t for 30 m in u tes to redu ce th e ch an ce of esoph ageal irrit at ion . A Glu cocort icoids can cause gast ric irritat ion , but th ey are con t rain dicated in osteoporosis. B−E Th ese drugs are u sed for osteop orosis, but th eir risk of esoph ageal an d gast ric irrit at ion is ver y low.

Learning objective: Outline the therapeutic uses of calcitonin. 23. A Th e pat ien t’s sign s an d sym ptom s in dicate th at h e w as

Learning objective: Describe the pharm acological e ect s of teriparatide. 26. B Teriparat ide is a recom bin an t an alogu e of parathyroid h orm on e (PTH) w ith p hysiological act ion s equ al to th ose of th e n at ural h orm on e. Th e drug h as been approved for th e t reatm en t of osteoporosis. Th e p rim ar y fu n ct ion of PTH is to m ain t ain a con stan t con cen t rat ion of Ca 2+ an d p h osph ate in th e ext racellu lar

u id. Th e prin cipal processes regulated by

m ost likely a ected by Paget disease of bon e, a ch ron ic dis-

th e h orm on e are ren al Ca 2+ (elevated) an d ph osp h ate (de-

order of the adult skeleton characterized by un cont rolled os-

creased) reabsorpt ion an d m obilizat ion of bon e Ca 2+. Ad m in -

teoclast ic bon e resorpt ion w ith secon dar y in crease in poorly

ist rat ion of terip arat ide w ill t ran sien tly in crease th e ren al

organ ized bon e form at ion . Th e disease is fairly com m on , af-

reabsorpt ion of Ca 2+ after each d ose.

fect ing about 3% of adults over age 40. It is often asym ptom -

A, C Th e drug cau ses act ion s op p osite to th ose listed.

at ic an d u su ally progresses slow ly. Ph arm acological th erapy

D PTH exert s both catabolic an d an abolic e ect s on bon e.

is in dicated (even in th e absen ce of sym ptom s) w h en alka-

Ch ron ically elevated PTH en h an ces bon e resorpt ion by in -

lin e p h osp h atase is m ore th an 2 to 3 t im es th e n orm al levels,

creasing osteoclast activit y, but interm it tent exposure to low

as in th is case. Bisp h osph on ates are rst-lin e agen ts for th is

levels of th e h orm on e (as occu rs w ith daily inject ion of low

disease. Calciton in is an altern at ive to bisph osph on ates w h en

doses of teriparatide) increases bone form ation w ithout caus-

th ese drugs are con t rain dicated, as in th is case (see an sw er

ing n et bon e resorption .

explan at ion B). B Oral bisp h osp h on ates are relat ively con t rain d icated in p at ien t s w it h gast roin test in al re u x d isease, esop h agit is, gast rit is, an d p ept ic u lcer, as th ey can cau se esop h ageal an d gast ric irritat ion . C−F Th ese drugs are useless in Paget disease.

E Th e t ran sien t in crease in ser u m Ca 2+ after each dose w ou ld decrease, n ot in crease, PTH secret ion .

326

Endocrine System

Learning objective: Explain the m echanism of action of denosum ab.

oral calcit riol. It in duces n orm al kerat in ocyte proliferat ion

27. C Den osu m ab is a m on oclon al an t ibody w ith a

n it y for re-

erally n oted follow ing 2 w eeks of th erapy, w ith con t in ued

ceptor act ivator of n u clear factor κ B ligan d (RANKL). In bon e,

im provem en t for u p to 8 w eeks of t reat m en t in u p to 70% of

and di erentiation. Marked im provem ent of psoriasis is gen-

osteoclast form at ion is regu lated by an osteoclast receptor

pat ien ts, alth ough lesion s can recu r w ith in 2 to 3 m on th s

protein called RANK (receptor act ivator of n uclear factor κ B).

follow in g d iscon t in u an ce of t reat m en t . Clin ical t r ials com -

Th e n at u ral ligan d of RANK, called RANKL, is a solu ble p ro-

p ar in g calcip ot r ien e w it h ot h er an t ip sor iat ic agen t s h ave

tein produced by osteoblast s. On bin ding to RANK, RANKL

dem on st rated th at calcip ot rien e is at least as e ect ive as

in d uces osteoclast form at ion .

topical glucocor t icoids. A Glucocor t icoids, n ot m in eralocort icoids, are used for

Den osum ab bin ds an d n eut ralizes RANKL. In th is w ay, osteoclast form at ion an d bon e t urn over are decreased. The

psoriasis. B, D, E, F See correct an sw er explan at ion .

drug is at least as e ect ive as bisp h osph on ates in in h ibit ing bon e resorpt ion . A, B, D, E None of these processes is a ected by denosum ab.

Learning objective: Identify the site of action of cinacalcet. 30. C Th e p at ien t w as d iagn osed w ith severe ren al in su

cien cy.

Learning objective: Outline the therapeutic uses of sevelam er.

Virt u ally all pat ien t s w ith ren al failure h ave secon dar y hy-

28. B Th e laborator y resu lt s sh ow a p ron ou n ced hyp er p h os-

p erp arathyroidism to som e degree. Th ese pat ien ts u su ally

cien cy.

h ave a low -n orm al calcium level an d h igh ph osph ate level,

Sevelam er is a n on absorbable, calciu m - an d alu m in u m -free,

as in th is case. Altern at ively, p h osph ate levels are u su ally

p olym eric am in e. Th e d rug bin ds diet ar y ph osp h ate w ith in

low w h en secon dar y hyperparathyroidism is du e to vit am in

th e gast roin test in al t ract , th ereby p reven t ing p h osp h ate ab -

D de cien cy. Cin acalcet is th e

sorpt ion . It h as been ap p roved for u se as an oral agen t for th e

class of drugs th at act ivate th e calcium -sen sing receptor.

m an agem en t of hyp erp h osp h atem ia in pat ien ts w ith en d -

Th is receptor is w idely dist ribu ted bu t h as it s greatest con -

stage ren al disease, as in th is case.

cen t rat ion in th e p arathyroid glan d an d in th e kidn ey. By

p h atem ia, m ost likely du e to advan ced ren al in su

A, C, D Th ese drugs ten d to redu ce seru m calciu m levels an d are th erefore con t rain dicated in hyp ocalcem ia.

rst represen tat ive of a n ew

act ivat ing th e calciu m -sen sing receptor, cin acalcet in h ibit s parathyroid h orm one secretion. Cinacalcet is approved for th e

E Vit am in D is u seless in t h is case becau se t h e kid n ey

t reat m en t of secon dar y hyp erp arathyroidism du e to ch ron ic

h as lost t h e abilit y to t ran sfor m t h e d r ug in to t h e act ive

kid n ey d isease. Becau se t h e d r ug can rap id ly cau se hyp o -

m et abolite.

calcem ia, it sh ould n ot be used for pat ien t s w ith a serum calciu m level below 8.4 m g/dL. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Identify a drug used to treat plaque psoriasis. 29. C Th e pat ien t’s sign s an d sym ptom s in dicate th at h e w as m ost likely a ected by p laqu e p soriasis, a com m on skin dis-

DRUGS FOR BONE HOMEOSTASIS Answ er key

order th at a ect s 1 to 5% of th e popu lat ion w orldw ide. Th e d isease is diagn osed m ost often by clin ical ap pearan ce an d

1. 2. 3. 4. 5.

A K G D C

6. 7. 8. 9. 10.

A A D F E

11. 12. 13. 14. 15.

A D B C F

16. 17. 18. 19. 20.

A C C D D

21. 22. 23. 24. 25.

A F A D D

26. 27. 28. 29. 30.

B C B C C

d ist r ibu t ion of lesion s. Ar t h r it is d evelop s in u p to 30% of p at ien t s, as in th is case (see th e sw ollen an d ten der join t s). Calcit riol an alogues w ere discovered to be e ect ive in th e t reat m en t of p soriasis. How ever, oral calcit riol h as lim ited u sefuln ess due to hypercalcem ia associated w ith th e large d oses often n eeded for th erapy. Topical calcipot rien e, a calcit riol an alogu e, p rovides a safe an d e ect ive altern at ive to

Answers and Explanations: V-6 Drugs for Diabetes Mellitus Questions 1−7

4. G

1. E

5. M

2. I

6. A

3. N

7. C

Answers and Explanations: V-6 Drugs for Diabetes Mellitus 327 Learning objective: Identify the main risk for a diabetic patient under tight glycemic control.

bon ate level), acidosis is du e to diabetes an d th erefore is

8. D A large, long-term st udy h as sh ow n th at t igh t con t rol of

m etabolic, n ot respirator y. In fact , respirator y frequ en cy is

blood glu cose u sing m u lt ip le in su lin inject ion s or an in su lin

D Even if t h e p at ien t is acid ot ic (see t h e ver y low bicar-

in creased in th is pat ien t .

p u m p is associated w it h a low er in cid en ce of long-ter m com plicat ion s from diabetes. How ever, in ten sively t reated p at ien ts h ad a th reefold greater risk of hyp oglycem ia. A, C Th ese p ath ologic con dit ion s are decreased, n ot in creased, in pat ien ts w ith t igh t con t rol of blood glu cose.

Learning objective: Identify the appropriate drug to treat gestational diabetes. 11. D Gest at ion al diabetes m ellit us is de n ed as any glucose in toleran ce th at develops or is recogn ized du ring p regn an cy,

B Hyperten sion is n ot a ected by t igh t con t rol of blood

regardless of severit y or t im e of on set . Gest at ion al diabetes

glu cose. An ot h er st u dy, h ow ever, h as sh ow n t h at a t igh t

a ects abou t 4% of all p regn an cies in th e Un ited States an d

con t rol of hyp er ten sion h as a ben e cial e ect on diabet ic

is th e m ost com m on m atern al m edical com plicat ion du ring

m icrovascu lar com p licat ion s.

p regn an cy. Becau se gest at ion al diabetes carries several risks

E Tigh tly con t rolled diabet ic pat ien t s h ave an in creased risk of w eigh t gain , n ot w eigh t loss.

for both th e m oth er an d th e o spring, t reat m en t is m an dator y. Most gestat ion al diabet ics can con t rol th eir glu cose

F Allergic react ion s to in sulin are n ot dose-depen den t , so

level w ith d iet an d regu lar exercise; drug th erapy is n eeded

it is u n likely th at th ey are a ected by t igh t con t rol of blood

on ly if th ese procedures are failing, as in th is case. In sulin is

glu cose.

th e hypoglycem ic drug of ch oice d u ring p regn an cy becau se it does n ot cross th e p lacen ta an d h as an establish ed safet y

Learning objective: Describe the m olecular m echanism of action of insulin.

record for both m oth er an d fet us. A−C, E Alth ough recen t eviden ce suggest s th at glyburide

9. B In sulin bin ds to a speci c tran sm em bran e, t yrosine kin ase−

or m etform in can be e ect ive in diabetes during pregn an cy,

lin ked receptor located in th e cell m em bran es of m ost t is-

m ost au th orit ies believe th at oral an t id iabet ic agen t s sh ou ld

su es. Th e receptor con sist s of t w o α su bu n it s lin ked to t w o

be u sed d u ring pregn an cy on ly in th e set t ing of app roved

β su bu n its. In su lin bin ding to th e α su bu n it s cau ses th e act i-

clin ical t rials.

vat ion of th e β-receptor su bun it , w h ich con tain t yrosin e kia cascade of dow n st ream sign aling even ts th at u lt im ately

Learning objective: Describe the pharm acokinetics of di erent insulin preparations.

lead to a hyp oglycem ic e ect .

12. E In sulin glargin e is a long-act ing in su lin an alogue th at w as

n ase. Th e en zym e is ph osph or ylated, w h ich in t urn act ivates

A, C−E All of th ese act ion s w ou ld in crease, n ot decrease, blood glu cose levels.

d esign ed to p rovide a broad plasm a con cen t rat ion plateau . It h as an on set of act ion of 1 to 4 h ours, ach ieves a m axim um e ect after 4 to 6 h ou rs, an d can m ain tain th is e ect for over

Learning objective: Outline the therapy of diabetic ketoacidosis.

24 h ou rs. It is u su ally given on ce daily to p rovide basal levels

10. E Met abolic con dit ion s m ay be th e result of recen t injuries,

of in sulin .

or th ey m ay be th e cause of altered con sciou sn ess leading


to th e t raum at ic even t , as in th is pat ien t . Most likely th e girl acciden t . Th e m arked hyp erglycem ia, glycosu ria, an d ketosis

Learning objective: Identify the drug used in a child with newonset t ype 1 diabetes.

in dicate th at th e pat ien t h as diabet ic ketoacidosis an d th ere-

13. A Th e age, sym ptom s, lab values, an d h istor y of th e pat ien t

h ad un detected diabetes th at led to h er involvem en t in th e

fore m ust receive in t raven ou s (IV) regular in sulin at on ce.

in dicate th at h e w as m ost likely su ering from t yp e 1 diabe-

A Laten t diabetes can lead to hyperosm olar com a, w h ich

tes. An acute viral illn ess can t rigger au toim m un e dest ruc-

sh ou ld be t reated w it h IV regu lar in su lin . How ever, t h e p a-

t ion of th e p an creas in gen et ically su scept ible in dividu als.

t ien t w as n ot u n con sciou s, an d t h e ketot ic bod ies in t h e

Because of the m arkedly dim inished in sulin levels associated

u rin e in dicate th at th e m ost likely diagn osis is diabet ic keto-

w ith t ype 1 diabetes, insulin is crucial to the sur vival of these

acidosis.

p at ien ts.

B Acute ren al failure can resu lt from a m otor acciden t . How ever, the lab results do not indicate kidn ey insu

ciency.

C Acu te liver failure can occu r after t raum a, bu t th e p at ien t h as n o sign s or sym ptom s of acu te liver failu re.

B−F Oral hyp oglycem ic agen t s are n ot u sefu l in t yp e 1 d iabetes.

328

Endocrine System

Learning objective: Describe the m ain daily insulin regim ens for t ype 1 diabetes.

m ech an ism is st im ulat ion of in sulin release, m ost likely due

14. A En docrin ologists h ave developed a variet y of in su lin regi-

dep en d en t K+ ch an n els. Th is cau ses a m em bran e d ep olar-

m en s th at are in ten d ed to m im ic th e release of in su lin from

izat ion , w h ich in t u r n op en s volt age-gated Ca 2+ ch an n els,

th e pan creas. Th e gen eral goal of th ese in su lin regim en s is

allow ing Ca 2+-m ediated exocytosis of in sulin .

to provide a basal level of in sulin over 24 h ours an d to supply addit ion al m ealt im e in su lin coverage. Th is can be don e by

to th e drug-in duced closure of adenosine triph osphate (ATP)−

A−D, F All of th ese act ion s w ou ld d ecrease t h e hyp erglycem ia, bu t th ey are n ot elicited by rep aglin ide.

ad m in ister in g a rap id -act in g in su lin at m eals an d a lon gact ing in su lin at bed t im e to en su re basal coverage for th e follow ing 24 h ours.

Learning objective: Describe the actions of insulin on lipid m et abolism .

B A regular in sulin at breakfast can n ot sup ply a basal level

18. C In sulin in uen ces lipid m etabolism in both th e liver an d

of insulin over 24 hours. Moreover, rapid-acting insulins such

adipose t issu e. In th e liver, in su lin favors esteri cat ion of

as lispro are given to con t rol p ost p ran dial hyp erglycem ia;

fat t y acids w ith glycerol, th us form ing t riglycerides. In adi-

adm in ist rat ion at bedt im e is irrat ion al.

p ose t issu e, in su lin a ect s lipid m et abolism by th e follow ing

C NPH (n eu t ral prot am in e Hagedorn ) in sulin at breakfast an d lu n ch can su p p ly a basal level of in su lin over 24 h ou rs bu t can n ot con t rol p ost p ran dial hyperglycem ia. D Th is regim en can n ot provide a basal level of in su lin over 24 h ou rs. E In sulin glargin e alon e can n ot con t rol post pran dial hyperglycem ia.

act ion s: • It prom otes th e breakdow n of glucose to α -glycerol ph osph ate th at is u sed to syn th esize t riglycerid es. • It in h ibit s th e act ivit y of h orm on e-sen sit ive t riglyceride lip ase, th e en zym e th at m ediates th e conversion of stored t riglycerides to fat t y acids. • It increases the synthesis of lipoprotein lipase, the en zym e th at is t ran sferred to en doth elial cells w h ere it cleaves t ri-

Learning objective: Explain the mechanism of insulin−glucocorticoid interaction.

glycerides in to glycerol an d fat t y acids. A, B, D, E In su lin elicits act ion s opp osite to th ose listed .

15. B In a diabet ic pat ien t on in sulin th erapy, th e daily dose of in su lin is often in creased w h en a n ew th erapy is st arted w ith a drug th at can cause hyperglycem ia, especially if th e n ew drug is given in h igh doses, as in th is case. A See correct an sw er explan at ion . C−E Th ese drugs are approved for t ype 2 diabetes, as th ey can in crease in su lin syn th esis an d release. Th ey are of ver y lit tle value in t ype 1 diabetes, w h ere th e in su lin syn th esis is already severely d ecreased or absen t .

Learning objective: Outline the appropriate therapy for a diabetic patient on insulin treatment, when an acute infection supervenes. 16. A In su lin requ irem en t alw ays in creases in th e p resen ce of st ressfu l sit u at ion s, in clu ding acu te illn esses. Th is is, at least

Learning objective: Explain the mechanism of action of glyburide. 19. C Su lfonylu reas su ch as glybu ride act by bin d ing to a sp eci c receptor th at is closely lin ked to th e aden osin e t riph osph ate (ATP)−sen sit ive K+ ch an n els in p an creat ic β-cell m em bran es. Th is cau ses a blockade of th e e

u x of K+, w h ich in t u rn leads

to m em bran e d ep olar izat ion . Volt age-gated Ca 2 + ch an n els op en in resp on se to d ep olar izat ion , t h u s in creasing in t racellu lar Ca 2+ con cen t rat ion s. Th is in creased con cen t rat ion u lt im ately st im ulates th e release of in su lin by exocytosis. A, D, F Acarbose, m etform in , an d pioglitazon e can be u sed in th e t reat m en t of t ype 2 diabetes, bu t n on e of th em h ave th e described m ech an ism of act ion . B, E In sulin an d exen at ide are n ot orally act ive.

in par t , because of hyperglycem ia brough t abou t by th e h igh p lasm a cor t isol levels associated w ith st ress. B, D Th ese an t ibiot ics are n ot e ect ive again st Mycoplasm a pneum oniae or Chlam ydia pneum oniae, th e m ost frequ en t cau sat ive agen ts of at yp ical pn eu m on ia. C, E Becau se in su lin requ irem en t is in creased , t h e best cou rse of act ion is to in crease t h e daily in su lin d osage, n ot to add an oral an t idiabet ic agen t .

Learning objective: Explain the m echanism of action of repaglinide. 17. E Rep aglin ide is a m eglit in ide derivat ive w ith m ech an ism s of act ion ve r y close to t h ose of su lfonylu reas. Th e m ain

Learning objective: Identify the oral antidiabetic drug that can cause hypoglycemia in a diabetic patient. 20. C Th e low glu cose level in d icates t h at t h e beh avior an d sym ptom s of th e p at ien t are du e to hyp oglycem ia; th at is, th ey are n eu roglycop en ic sym ptom s. Th ese sym ptom s are m ore frequ en t in older p at ien t s u n der an t idiabet ic t reatm en t . In fact , su lfonylu reas accou n t for alm ost all cases of d rug-in duced hypoglycem ia in in dividu als older th an 60. A, B, D Th ese drugs are con sidered euglycem ic, n ot hyp oglycem ic, becau se th ey do n ot cau se hypoglycem ia w h en given alon e.

Answers and Explanations: V-6 Drugs for Diabetes Mellitus 329

ceptor agon ist . It is a pept ide an d th erefore is given by th e

Learning objective: Explain the m olecular m echanism of action of metformin.

paren teral rou te on ly. Moreover, it does n ot cau se hypogly-

24. D Bigu an id es su ch as m et for m in cau se act ivat ion of ad e-

E Exen at ide is a glucagon -like polypept ide 1 (GLP-1) re-

cem ia w h en given alon e.

n osin e m on oph osph ate (AMP)−act ivated protein kin ase, an en zym e th at acts as a sen sor of cellu lar en ergy st at u s in all

Learning objective: Describe hypoglycem ic com a due to excessive alcohol consumption in a diabetic patient.

eu kar yot ic cells. Th e en zym e is act ivated w h en cellu lar en -

21. B Th e pat ien t’s sign s (un con sciou sn ess, sw eat ing, hypoth er-

istered. It s act ivat ion in t u rn cau ses

ergy stores are redu ced or w h en bigu an ide drugs are adm in -

m ia, tachycardia, an d ton ic-clon ic seizu re) an d h is h istor y

• In h ibit ion of glu con eogen esis an d lip ogen esis

(alcoh olic an d in sulin t reat m en t) in dicate th at h e w as suf-

• St im u lat ion of glu cose u pt ake an d u t ilizat ion (glycolysis)

fering from hypoglycem ic com a. Hypoglycem ia often occu rs

• St im u lat ion of fat t y acid oxidat ion

in alcoh olics, likely due to a com bin at ion of st ar vat ion an d

• Red u ct ion of p lasm a glu cagon levels

im paired liver gluconeogenesis. In this case, the insulin treatm en t m ost likely m ade th e pat ien t even m ore sen sit ive to th e hyp oglycem ic e ect s of alcoh ol, th u s precip itat ing th e hyp oglycem ic com a. A, C, D Sign s of hyperglycem ia an d ketoacidosis are di eren t (often opp osite) to th ose sh ow n by th e p at ien t . E Sign s of an an aphylact ic react ion are di eren t from th ose sh ow n by th e p at ien t . F Hyperosm olar com a can follow an excessive dose of alcoh ol. Sign s of th is com a are di eren t from th ose sh ow n by th e p at ien t .

Learning objective: Describe the pharm acological actions of insulin. 22. B In sulin in creases glycolysis an d decreases glycogen olysis an d glu con eogen esis in th e liver. Th e n al e ect is a d ecrease of glucose product ion an d an in crease of glucose ut ilizat ion . A, C−E See correct an sw er explan at ion .

Learning objective: Outline the addition of a second antidiabetic agent in t ype 2 diabetes when a single agent fails to control the disease. 23. A Th e pat ien t’s serum valu es in dicate th at th e con t rol of h is d iabetes w as n o longer adequate. W h en a single oral an t id iabet ic agen t fails to con t rol th e disease, a secon d oral agen t sh ou ld be added to th e th erapy. Many com bin at ion s of an t id iabet ic agen ts can be u sed. Th e key is th at th ey sh ou ld h ave d i eren t m ech an ism s of act ion . Because th e pat ien t w as on m etform in , th e addit ion of a su lfonylu rea is ap p rop riate. B, C Su bst it u t ion of an oral an t id iabet ic agen t w it h an oth er usually does n ot produce any sign i can t ch ange in glycem ic con t rol. D Diabetes is a progressive con dit ion , an d m ost pat ien ts w it h t yp e 2 d iabetes even t u ally requ ire in su lin . How ever, in sulin is usually added to, n ot subst it uted for, oral agen t s w h en diabet ic con t rol is n ot ach ieved. E Because th e pat ien t’s tot al ch olesterol is low, lovast at in is n ot n eeded.

Th e n et result is in creased glycogen storage in skelet al m uscle, decreased glucose product ion by th e liver, an d decreased hyp erglycem ia. A−C, E All of th ese act ion s w ould decrease hyperglycem ia, bu t th ey are n ot elicited by m etform in .

Learning objective: Outline the m ain contraindications to sulfonylureas. 25. A Glyburide is a su lfonylurea-derivat ive an t idiabet ic drug. Su lfonylu reas are su lfa d r ugs (i.e., t h ey h ave a su lfu r grou p in th eir m olecule), an d are th erefore con t rain dicated in pat ien t s w ith a h istor y of p reviou s severe allergic react ion to su lfon am ides, as in th is case. B−E Th ese oral an t idiabet ic agen t s are n ot sulfa drugs.

Learning objective: Describe the adverse e ects of m etform in. 26. B Th e pat ien t’s sym ptom s an d th e lab dat a in dicate th at sh e w as su ering from lact ic acidosis, a seriou s adverse e ect of bigu an ides. Lact ic acidosis is ext rem ely rare, bu t it can resu lt from m etform in overd ose, esp ecially in p at ien t s w ith ren al in su

cien cy (th e drug is all elim in ated by th e kidn ey), as in

th is case. Th e syn drom e is h igh ly leth al (50% m ort alit y) an d seem s to be du e to drug-in du ced in h ibit ion of glu con eogen esis, w h ich in t urn im pairs th e h epat ic upt ake of lact ic acid. A, C−F Overd ose of t h ese d r ugs d oes n ot cau se lact ic acidosis.

Learning objective: Describe the m ain contraindications to the use of metformin. 27. B Bigu an ides can cau se lact ic acidosis an d th erefore are relat ively con t rain dicated in all con dit ion s th at predispose to acidosis. Th is p at ien t is su ering from ch ron ic obst ru ct ive p ulm on ar y disease an d is u n der t reat m en t w ith an angioten sin -convert ing en zym e (ACE) in h ibitor. Th e respirator y d isease p redisp oses to resp irator y acidosis, an d ACE in h ibitors predispose to m et abolic acidosis because th ey low er ald osteron e seru m levels. A, C−E Non e of th ese d rugs are con t rain dicated in th is p at ien t .

330

Endocrine System

Learning objective: Describe the pharm acokinetics of di erent insulin form ulations.

Learning objective: Describe the insulin resistance in a diabetic patient.

28. A In sulin form ulat ion s di er on e from an oth er in th e ab -

31. E Th e sim u lt an eous elevat ion of blood glucose an d in su lin

sorpt ion rate of th e drug from su bcu tan eou s t issu e, w h ich in

levels is st rongly suggest ive of in su lin resist an ce. In su lin

t u rn a ect s th e du rat ion of act ion of th e drug. Th e variat ion

resist an ce can develop especially in diabet ics w h o h ave a

in absorpt ion is accom plish ed in th e follow ing w ays:

clustering of cardiovascular risk factors, in clu ding hyper ten -

• Modi cat ion of th e in su lin m olecu le (by recom bin an t

sion , abd om in al obesit y, an d dyslip id em ia. Th e associat ion

tech n ology)

of in su lin resist an ce w it h t h e above-m en t ion ed clu ster in g

• Conjugat ion of in su lin w ith protam in e in a low solu ble

h as been referred to by a variet y of n am es, in cluding in sulin

com plex. After inject ion , proteolyt ic en zym es degrade

resistance syndrom e, m etabolic syndrom e, and dysm etabolic

prot am in e, allow ing absorpt ion of in su lin .

syn drom e. Th e p revalen ce of th is syn drom e is m ore th an

• Com bin ation of in sulin w ith zin c to form zin c salts. After

30% in th e US p op u lat ion . An est im ated 75% of pat ien ts w ith

inject ion , t h e salt p recip it ates, an d in su lin is slow ly

t ype 2 diabetes h ave m et abolic syn drom e, as in th is case.

released .

Th e syn drom e is st rongly associated w ith an in creased risk

B, C Th ese proper t ies refer to th e elim in at ion of th e drug an d th erefore are n ot a ected by variat ion s in th e rate of absorpt ion . D Th e d ist r ibu t ion of a d r ug is n ot a ected by var iat ion in absorpt ion . E Th e oral bioavailabilit y of all in sulin preparat ion s is zero.

Learning objective: Explain the m olecular m echanism of action of pioglitazone. 29. F Pioglit azon e is a th iazolidin edion e derivat ive. Th iazolidin ediones act by bin ding to a nuclear receptor called peroxisom e proliferator activated receptor gam m a (PPAR-γ), w hich is located m ain ly in adipose t issue, skelet al m uscle, an d liver. Th e receptor regu lates th e t ran script ion of several in su lin resp on sive gen es. Th e overall e ect is an en h an cem en t of t issu e sen sit ivit y to in su lin (i.e., a redu ct ion in in su lin resist an ce). Th erefore, th e n eed for exogen ou s in su lin is redu ced. Because of th is, th ey are called in sulin sen sitizers. A Th is is th e m ech an ism of m iglitol. B Th is is th e m ech an ism of su lfonylureas C Th is is th e m ech an ism of sit aglipt in . D Th is is th e m ech an ism of exen at ide. E Th is is th e m ech an ism of m etform in .

of cardiovascular diseases. A Metform in can cause lact ic acidosis, but sym ptom s of th is d isorder (vom it ing, leth argy, hyper ven t ilat ion , hypoten sion ) are absen t in th is pat ien t . B Because th e pat ien t h as hyperglycem ia an d in sulin resist an ce, a hypoglycem ic react ion is qu ite u n likely. C Th e pat ien t is at in creased risk of un stable angin a, but sym ptom s of u n stable angin a are absen t in th is p at ien t . D Th e sign s an d sym ptom s of ketoacidosis are absen t in th is p at ien t .

Learning objective: Describe the m ain contraindications to the use of metformin. 32. E Th e p at ien t ’s sym ptom s an d ser u m valu es in d icate t h at h e w as m ost likely su ering from kidn ey failure (see h igh creat in in e an d blood u rea n it rogen [BUN] valu es), a frequ en t com plicat ion of long-st an ding diabetes an d hyper ten sion . Metform in is excreted as su ch by th e kid n ey an d is th erefore absolu tely con t rain dicated in a pat ien t w ith ren al failu re. A−D Th ese drugs are n ot con t rain dicated in ren al failure.

Learning objective: Outline the appropriate pharm acotherapy to treat a prediabetic state with high cholesterol and triglycerides. 33. B Th e absen ce of su bject ive sym ptom s an d th e valu es of fast-

Learning objective: Describe the m ain adverse e ect s of thiazolidinediones. 30. D Th e pat ien t’s sign s an d sym ptom s in dicated th at h e w as su ering from edem a, w eigh t gain , an d in it ial h eart failu re. Pioglitazon e is a th iazolid in edion e derivat ive. Most com m on adverse e ect s of th ese dr ugs are edem a (u p to 27%), w eigh t gain (u p to 14%), an d u p p er resp irator y t ract in fect ion s (u p to 15%). In addit ion , th ey can cause h eart failure, m ain ly in at-risk patien ts; these patients should be closely m onitored. A−C, E Th ese drugs do n ot cause all of th e sign s an d sym p tom s repor ted by th e pat ien t .

ing blood glu cose an d glycated h em oglobin (HbA1c; both are in th e p rediabet ic range) in d icate th at th e pat ien t w as m ost likely su ering from prediabetes, a state in w hich som e, bu t n ot all, of th e diagn ost ic criteria for diabetes are m et . Prediabetes is also called im paired glucose toleran ce (IGT) or im paired fast ing glu cose (IFG), dep en ding on th e test u sed to m easu re blood glu cose levels. Having p red iabetes pu ts th e p at ien t at h igh er risk for developing t ype 2 diabetes. People w ith prediabetes are also at in creased risk for developing cardiovascu lar disease. New ly diagn osed p rediabet ic st ates are n orm ally m an aged w ith diet an d physical act ivit y, bu t

Answers and Explanations: V-6 Drugs for Diabetes Mellitus 331 w h en dyslip id em ia is also p resen t , a p h ar m acot h erapy is

Learning objective: Outline the therapeutic uses of glucagon.

u su ally ad m in istered . Met for m in can d ecrease ser u m t r i-

37. C Th e p at ien t’s h istor y an d sym ptom s in dicate th at h e w as

glycer id es by 15 to 20% an d ser u m ch olesterol by 10%. In

su ering from hypoglycem ic com a. Hyp oglycem ia is a seri-

ad d it ion , it can d ecrease body w eigh t an d is t h erefore ap -

ous and often life-threatening com plication of diabetes m an-

p ropriate for obese pat ien ts, as in th is case.

agem en t , especially in ch ildren . Th e m ajor u se of glu cagon


is for em ergency treatm en t of severe hypoglycem ic reactions w h en u n con sciou sn ess precludes oral feeding an d in t rave-

Learning objective: Describe the actions of insulin on glucose metabolism.

n ous glucose is n ot available, as in th is case. Th e drug is u su -

34. B In su lin in u en ces glu cose m et abolism m ain ly in liver, adi-

fam ily m em ber w h o is t rain ed to adm in ister th e drug. Be-

p ose t issu e, an d m uscle. In liver an d m u scle, th e h orm on e

cau se th e act ion of glu cagon is t ran sien t , pat ien ts sh ou ld be

in creases glycogen syn th ase act ivit y, th u s in creasing glyco-

given glu cose as soon th ey regain con sciou sn ess.

gen syn th esis.

ally given in t ram u scu larly, m ost frequen tly by a p at ien t’s

A, B, D–F See correct an sw er exp lan at ion .

A Glucose en ters th e h epatocyte from th e blood th rough glu cose t ran sp or ter 2 (GLUT2), w h ose act ivit y is n ot in u en ced by in su lin . C−E In su lin elicit s act ion s opposite to th ose listed.

Learning objective: Describe the adverse e ects of α-glucosidase inhibitors. 38. C Miglitol is an α -glu cosidase in h ibitor. Th ese drugs are ap p roved for people w ith t yp e 2 diabetes as m on oth erapy an d

Learning objective: Explain the m echanism of action of acarbose.

in com bin at ion w ith oth er oral an t idiabet ic d rugs. Th e pa-

35. B Acarbose an d m iglitol are in h ibitors of α -glu cosidase, an

t ien t’s sym ptom s are classic adverse e ect s of α -glu cosidase

en zym e located on th e bru sh border of in test in al cells th at

in h ibitors, w h ich occu r in m ore th an 50% of su bject s at th e

is involved in th e breakdow n of starch es an d disacch arides

star t of th e th erapy. Th ese drugs decrease th e absorpt ion of

in to sim ple sugars. In h ibit ion of th is en zym e slow s th e ab -

m on osacch arides from th e du oden u m an d u p p er jeju n u m

sorption of carbohydrates from the gastrointestin al tract and

by in h ibit ing th e en zym e th at is involved in th e breakdow n

blu n t s th e rate of rise of post p ran dial glu cose.

of st arch es in to sim p le sugars. Th e adverse e ect s are d u e

A Th is is a liver en zym e th at cat alyzes th e

rst step in

glu con eogen esis. C Th is is a liver en zym e th at ph osph or ylates glu cose to glu cose-6-p h osph ate.

to ferm en tat ion of un absorbed carbohydrates in th e sm all in test in e. A, B, D–F Th ese d rugs d o n ot cau se th e collect ion of sym p tom s repor ted by th e pat ien t .

D, E Th ese are ad ip ocyte en zym es involved in lip id m et abolism .

Learning objective: Outline the therapeutic uses of m etform in. 39. C Th e sym ptom s of th e p at ien t an d th e lab resu lt s in dicate

Learning objective: Explain the m olecular m echanism of action of exenatide.

th at h e h is m ost likely su ering from t yp e 2 diabetes m elli-

36. D Exen at ide is a glucagon -like polypept ide-1 (GLP-1) recep -

resistan ce to in su lin act ion , an d in creased h epat ic glu cose

tor agon ist . GLP-1 is on e of th e so-called in cret in h orm on es,

p roduct ion . Obese in dividu als con st it u te 60 to 90% of th e

a grou p of sm all in test in al p ept id es t h at are released after

t ype 2 diabet ic populat ion . A stepped care approach to t ype

m eals an d st im u late “glu cose-act ivated ” in su lin secret ion .

2 diabetes m ellit u s in d icates lifest yle m odi cat ion s in case

Th is u lt im ately decreases fast ing an d post p ran dial glu cose

of a fast ing plasm a glucose less th an 240 m g/dL an d n o or

excursion s, th us avoiding th e risk of hyper- or hypoglycem ia.

m ild sym ptom s. If th is goal is n ot ach ieved, m on oth erapy

Oth er useful e ect s of th e drug are suppression of glucagon

sh ou ld be in it iated w ith any oral an t idiabet ic drug. Met-

secret ion , slow ing gast ric em pt ying (th u s slow ing th e rate of

form in is th e

glu cose en t r y in to th e circu lat ion ), an d decreased app et ite,

th e seriou s allergic react ion to su lfon am ides con t rain dicates

w h ich in t urn can cau se w eigh t loss. Exen at ide is th erefore

th e u se of su lfonylu reas in th is pat ien t .

especially useful in obese diabet ic pat ien ts, as in th is case. A–C, E, F See correct an sw er explan at ion .

t u s, w h ich is ch aracterized by defect s in in su lin secret ion ,

rst-lin e agen t for t ype 2 diabetes. Moreover,

A To t r y st rict diet ar y con t rol w ould be useless in th is pat ien t becau se of th e h istor y of rep eated p ast failu res. B See correct an sw er explan at ion . D, E In su lin sh ould be used in t ype 2 diabetes on ly w h en con t rol is n ot ach ieved w ith oral an t idiabet ic drugs.

332

Endocrine System

Learning objective: Describe the actions of insulin on lipid m etabolism. 40. A In su lin st im ulates th e syn th esis of protein s an d sim u lt an eously redu ces th e degradat ion of protein s w ith in th e liver. Th e gen eral m ech an ism s of th ese e ect s are st ill n ot w ell d e n ed, bu t th ey are m ost likely m ediated by th e follow ing in su lin act ion s: • In creased am in o acid t ran sp or t in to cells • Ph osp h or ylat ion of several in su lin receptor su bst rate docking protein s (IRSs) in cell cytosol B−E In su lin elicit s act ion s opposite to th ose listed.

ANTIDIABETIC DRUGS Answ er key 1. 2. 3. 4. 5.

E I N G M

6. 7. 8. 9. 10.

A C D B E

11. 12. 13. 14. 15.

D E A A B

16. 17. 18. 19. 20.

A E C C C

21. 22. 23. 24. 25.

B B A D A

26. 27. 28. 29. 30.

B B A F D

31. 32. 33. 34. 35.

E E B B B

36. 37. 38. 39. 40.

D C C C A

VI Respiratory, Gastrointestinal, and Hem atopoietic System s Questions: VI-1 Drugs for Bronchospastic Disorders Directions for questions 1−4

th erapy w as in st it uted, an d later h e w as disch arged from th e

Match each resp irator y drug w ith th e ap prop riate descript ion

h ospital. W h ich of th e follow ing t reat m en t s w ould be m ost


appropriate for h is postdisch arge th erapy?

at all).

A. Oral za rlukast

A. Acet ylcystein e

B. Oral t riam cin olon e

B. Albuterol

C. Paren teral ip rat rop iu m

C. Beclom eth ason e

D. Oral th eophyllin e

D. Codein e

E. Paren teral salm eterol

E. Dext rom eth orph an F.


Dorn ase alfa

G. Iprat ropium

6. A 34-year-old w om an w h o h as been su ering from persisten t

H. Om alizum ab

asth m a for 4 years w as adm it ted to th e em ergen cy depart -

I.

Salm eterol

m ent because of im pending respiratory failure. She w as treated

J.

Th eophyllin e

w ith oxygen , n ebulized albuterol, in t raven ous (IV) th eophyl-

K. Za rlu kast

lin e, an d IV hydrocor t ison e. A h alf h ou r later, a su bstan t ial

L.

clin ical im provem en t w as n oted. Blockade of w h ich of th e fol-

Zileuton

low ing receptors m ost likely con t ribu ted to th e bron ch odilat-


ing e ect of th eophyllin e in th is p at ien t?

1. A long-act ing β 2 adren oceptor agon ist

A. M 3 ch olin ergic B. Aden osin e A1


C. Leukot rien e B4

2. An opioid derivat ive w ith n o addict ion liabilit y, used as an

D. Th rom boxan e A2 E. Beta-2 adren ergic

an t it ussive

F.

Prost aglan din I2

Di cult y level: Easy 3. A bron ch od ilator d r ug th at can block Nn acet ylch olin e re-

Di cult y level: Medium 7. A 34-year-old asth m at ic m an w as brough t to th e em ergen cy

ceptors

dep art m en t w ith a severe asth m a exacerbat ion . Th e p at ien t’s forced expirator y volum e in 1 secon d (FEV1 ) did n ot im prove

Di cult y level: Easy 4. A drug th at blocks h igh -a

n it y im m u n oglobulin E (IgE) re-

ceptors of sen sit ized m ast cells

Di cult y level: Medium 5. A 51-year old m an w as adm it ted to th e h ospit al w ith an asth m at ic at t ack. Th e m an h ad been su er in g from season al asth m a for 1 year. On qu est ion ing, h e repor ted th at h e took t w o asp ir in t ablet s t h e p reviou s even ing for a h eadach e. A d iagn osis of drug hypersen sit ivit y w as m ade, an app rop riate

u pon adm in ist rat ion of in h aled albu terol, an d th e at ten ding p hysician decided to adm in ister paren teral t riam cin olon e. W h ich of th e follow ing w ould be th e m ost likely ben e t provided by paren teral glucocor t icoids in th is set t ing? A. Direct bron ch odilat ion B. Decreased sym path et ic ton e of air w ay sm ooth m uscle C. In creased m ucociliar y clearan ce D. In creased bron ch ial respon siven ess to albuterol E. Im proved diaph ragm at ic perform an ce

333

334

Respiratory, Gastrointestinal, and Hem atopoietic Systems



8. A 51-year-old w om an w ith a long h istor y of ch ron ic ob -

11. A 43-year-old w om an w ith a long histor y of severe persistent

st ru ct ive pu lm on ar y disease w as ad m it ted to th e h osp ital

asth m a w as ad m it ted to th e em ergen cy dep ar t m en t w ith

for an acu te exacerbat ion of h er d isease. Th e p at ien t ’s m ed -

seriou s labored resp irat ion . Physical exam in at ion sh ow ed a

icat ion s on adm ission w ere in h aled ip rat rop iu m an d oral

d ist ressed p at ien t w ith dyspn ea an d severe cyan osis. Vit al

th eophyllin e. W h ich of th e follow ing m olecu lar act ion s on

sign s w ere blood p ressu re 140/90 m m Hg, h ear t rate 130

bron ch ial sm oot h m u scle m ost likely con t r ibu ted to t h e

bp m , resp irat ion s 30/m in . Th e pat ien t’s cyan osis in dicated

bron ch odilat ing e ect of th eophyllin e in th is p at ien t?

a seriou s ven t ilat ion /p erfu sion m ism atch , an d in h aled al-

A. In h ibit ion of ph osph odiesterase 4 (PDE4 )

buterol, given im m ediately, w as able to im prove cyanosis and

B. In h ibit ion of catech olam in e release

to decrease dyspn ea. W h ich of th e follow ing act ion s m ost

C. St im u lat ion of n it ric oxide release

likely m ediated th ese drug e ects in th e p at ien t’s disorder?

D. Act ivat ion of β 2 adren oceptors

A. In creased bron ch ial secret ion s

E. Act ivat ion of aden osin e receptors

B. Decreased pulm on ar y perfusion C. In creased pulm on ar y ven t ilat ion

Di cult y level: Medium 9. A 3-day-old baby girl born after 30 w eeks of pregn an cy h ad

D. Decreased pulm on ar y arter y pressure E. In creased m ucociliar y clearan ce

ve episodes of ap n ea. Th e episodes lasted abou t 30 secon d s an d requ ired oxygen adm in ist rat ion . Bet w een ap n eic sp ells,


the neonate appeared w ell, and physical exam ination and lab

12. A 45-year-old m an h ad been su ering from ch ron ic obst ru c-

test s w ere n orm al for gestat ion al age. An appropriate th er-

t ive p u lm on ar y disease th at w as n ot adequ ately con t rolled

apy w as st arted th at in clu d ed in t raven ou s adm in ist rat ion

by in h aled salm eterol an d iprat ropium . His physician de-

of t h eop hyllin e. W h ich of th e follow ing act ion s m ost likely

cided to add a th ird d rug th at is th ough t to act by m u lt ip le

m ediated th e th erap eu t ic e ect of th e drug in th is p at ien t?

m ech an ism s, in clu ding in h ibit ion of p h osph odiesterase 4 in


in am m ator y cells an d en h an cem en t of h iston e deacet yla-

B. In h ibit ion of m ucociliar y clearan ce

t ion . W h ich of th e follow ing drugs w as m ost likely added to

C. St im u lat ion of th e m ed u llar y respirator y cen ter

th e p at ien t’s th erap eu t ic regim en ?

D. St im u lat ion of diap h ragm con t ract ilit y

A. Iprat ropium

E. In h ibit ion of catech olam in e release

B. Salm eterol C. Zileuton


D. Za rlu kast

10. A 69-year-old m an com plain ed to h is physician of a cough

E. Th eop hyllin e

th at h ad been in creasing over th e p ast few days. Th e m an h ad a 40-pack-year h istor y of cigaret te sm oking an d h ad


been su ering from ch ron ic obst ru ct ive p u lm on ar y d isease

13. A 59-year-old m an w ith a long h istor y of ch ron ic obst ruct ive

for 10 years. He w as curren tly on iprat ropium an d albu terol.

p ulm on ar y disease recen tly h ad th eophyllin e added to h is

Th e p hysician decided to add th eop hyllin e to th e regim en ,

th erap eu t ic regim en . W h ich of th e follow ing act ion s m ost

bu t h e kn ew th at in th is p at ien t th e clearan ce of th eop hyl-

likely occu rred du ring th e rst days of th e n ew th erapy?

lin e w ou ld p robably be in creased . W h ich of t h e follow ing

A. Decreased cardiac con t ract ilit y

factors m ost likely cau sed an in creased th eophyllin e clear-

B. Dilat ion of cerebral blood vessels

an ce in th is p at ien t?

C. Decreased diu resis

A. Ch ron ic lu ng diseases

D. In creased gast ric secret ion

B. Age over 65

E. Depression of th e respirator y cen ter

C. Con com itan t albu terol t reat m en t D. Sm oking


E. Con com itan t ip rat rop iu m t reat m en t

14. A 45-year-old m an w ith a long h istor y of ch ron ic severe asth m a w as ad m it ted to th e em ergen cy dep ar t m en t w ith ext rem e dyspn ea an d w h eezing. His m edical h istor y w as sign i can t for a recen tly diagn osed du oden al u lcer. Cu rren t m ed icat ion s in clu d ed in h aled albu terol, beclom et h ason e, and ipratropium on a chronic basis. Vital signs w ere heart rate

Questions: VI-1 Drugs for Bronchospastic Disorders 335 130 bpm , blood pressure 140/90 m m Hg, respirations 30/m in.

A. Za rlu kast

An elect rocardiogram sh ow ed sin us t achycardia w ith occa-

B. Zileuton

sion al p rem at u re ven t ricu lar con t ract ion s. W h ich of th e fol-

C. Ro u m ilast

low ing t w o even t s m ost likely con t r ibu ted to t h e p at ien t ’s

D. Beclom eth ason e

arrhyth m ia?

E. Om alizum ab

A. Ip rat rop iu m d osage an d t h e hyp er ten sive e ect of beclom eth ason e B. Du oden al ulcer an d th e hyperten sive e ect of beclom eth ason e

Di cult y level: Medium 18. A 30-year-old w om an recen t ly d iagn osed w it h m od erate in term it ten t asth m a st ar ted a t reat m en t w ith in h aled al-

C. Albuterol dosage an d duoden al ulcer

buterol as n eeded. W h ich of th e follow ing e ects on pulm o-

D. Ipratropium dosage and the disease-induced hypoxem ia

n ar y fu n ct ion test ing m ost likely occu r red soon after d r ug

E. Albuterol dosage an d th e disease-in duced hypoxem ia

adm in ist rat ion ? A. In creased tot al lung capacit y


B. Decreased peak expirator y ow

15. A 54-year-old w om an w ith ch ron ic obst ruct ive pulm on ar y

C. Decreased forced vital capacit y

d isease (COPD) w as diagn osed w it h an u p p er resp irator y

D. In creased residual volum e

t ract in fect ion , an d er yth rom ycin w as p rescribed. Her COPD

E. In creased forced expirator y volum e

w as reason ably w ell con t rolled on oral t h eop hyllin e an d in h aled albuterol. W h ich of th e follow ing w ould be an ap -


p ropriate ch ange in th e pat ien t’s th erapeu t ic regim en at th is

19. A 78-year-old fem ale residen t of a reh abilit at ion cen ter ex-

t im e?

h ibited Ch eyn e−Stokes breath ing from t im e to t im e an d suf-

A. Add in h aled dexam eth ason e.

fered from u rge urin ar y in con t in en ce an d spast icit y in h er

B. Add in h aled iprat rop iu m .

left lim b. Th e w om an h ad su ered from an isch em ic st roke

C. In crease th e dose of albu terol.

2 m on t h s earlier. W h ich of th e follow in g d r ugs sh ou ld be

D. Decrease th e dose of th eophyllin e.

in clu ded in th e ph arm acological th erapy of th is pat ien t?

E. Add in h aled salm eterol.

A. Neost igm in e B. Th eop hyllin e


C. Albuterol

16. A 60-year-old m an w as adm it ted to th e em ergen cy depart-

D. Iprat ropium

m en t becau se of n au sea, vom it ing, h eadach e, t rem or, n er-

E. Metoclop ram ide

vousness, tinnitus, and atrial tachycardia for the past 4 hours.

F.

Brom ocript in e

Th e m an , w h o h ad been su ering from ch ron ic obst ru ct ive p u lm on ar y d isease for 3 years, recen t ly h ad a n ew d r ug


ad d ed to h is t h erap eu t ic regim en . W h ich of t h e follow in g

20. A 15-year-old boy w ith a 10-year h istor y of asth m a w as ad-

d rugs m ost likely cau sed th e pat ien t’s adverse e ect s?

m it ted to th e h osp it al for evalu at ion . Th e p at ien t com p lain ed

A. Albuterol

of increasing respirator y di cult y and aw aken ing from sleep

B. Predn ison e

ve to seven tim es per night. Present m edications w ere high-

C. Iprat ropium

dose inh aled uticason e and salm eterol. Pulm onary function

D. Zileuton

test ing in dicated a forced expirator y volum e (FEV1 ) 30% of

E. Th eophyllin e

predicted, an d laborator y exam s sh ow ed total seru m im m un oglobulin E (IgE) level of 615 IU/m L (n orm al > 120 IU/m L).


W h ich of th e follow ing w ould be appropriate to add to th e


pat ien t’s t reat m en t at th is t im e?

creasing dysp n ea an d cough over th e past few days. Th e

A. In h aled albuterol

w om an h ad a 22-pack-year h istor y of cigaret te sm oking an d

B. In h aled beclom eth ason e

h ad been su er in g from ch ron ic obst r u ct ive p u lm on ar y

C. Oral zileu ton

d isease for 5 years. Sh e w as cu rren tly on in h aled iprat ro-

D. Oral za rlukast

p iu m an d albu terol. Her physician decided to add a drug th at

E. Su bcu tan eou s om alizu m ab

act s by select ively in h ibit ing p h osp h odiesterase 4 in bron ch ial m u scle. W h ich of th e follow ing drugs w as m ost likely p rescribed?

336




21. A 46-year-old m an w ith a long h istor y of ch ron ic severe

24. A 52-year-old w om an h ad been on a ven t ilator for 5 days

asth m a w as adm it ted to th e h osp ital w ith ext rem e dysp n ea

becau se of ven t ilator y failu re du e to p olym yosit is w h en th e

an d im p en ding respirator y failu re. Em ergen cy th erapy w as

p hysician n oted in creasing en dot rach eal secret ion s an d de-

star ted w ith in h aled albu terol, glu cocor t icoids, an d oxygen ,

creased oxim et r y. A bron ch oscopy sh ow ed abu n dan t m u cu s

bu t th e pat ien t’s resp on se to th e t reat m en t w as p oor. It w as

p lugs lling th e bron ch ial lum en . Su ct ion ing of th e bron ch ial

d ecided to in it iate in t raven ou s th eophyllin e. Th e goal w as

t ree w as p er for m ed , an d a d r ug w as given to im p rove m u -

to reach an im m ediate th erapeut ic plasm a con cen t rat ion of

cociliar y clearan ce. W h ich of th e follow ing drugs w as m ost

15 m g/L. Kn ow ing th at th e volu m e of dist ribu t ion of th eop h -


yllin e is abou t 0.5 L/kg, w h ich of th e follow ing loading d oses

A. Epin eph rin e

(in m illigram s) w as m ost likely given ?

B. Albuterol

A. 525

C. Iprat ropium

B. 435

D. Zileuton

C. 110

E. Dexam eth ason e

D. 600

F.

Za rlu kast

E. 85

Di cult y level: Easy Di cult y level: Medium

25. A 57-year-old m an com plain ed to h is physician th at h is

22. A 50-year old m an w as adm it ted to th e h ospit al because of

ch ron ic m ucoid cough h ad got ten w orse, an d h e h ad in creas-

severe dysp n ea an d cough ing th at h ad been in creasing over

ing breath ing di cu lt y. Th e m an h ad a long h istor y of sm ok-

the past few days. The m an had been su ering from persisten t

ing an d cu rren tly sm oked on e pack daily. Spirom et r y sh ow ed

severe asth m a for 10 years an d from diabetes for 8 years.

a forced expiratory volum e (FEV1 ) of 50%the predicted value.

Curren t m edicat ion s in cluded in sulin , in h aled beclom eth a-

Th e p hysician decided to st art a th erapy w ith a drug th at can

son e, an d in h aled iprat rop iu m . Sp irom et r y sh ow ed a forced

block acet ylch olin e-m ed iated in crease in Ca 2+ availabilit y in

exp irator y volu m e (FEV1 ) 40% of t h e p red icted valu e. Th e

bron ch ial sm ooth m u scle. W h ich of th e follow ing drugs w as

p at ien t w as in t u bated an d w as given h igh -d ose albu terol

m ost likely adm in istered?

t h erapy by con t in u ou s n ebu lizat ion . W h ich of t h e follow -

A. Beclom eth ason e

ing adverse e ect s w ould m ost likely be associated w ith th is

B. Iprat ropium

t reat m en t?

C. Th eop hyllin e

A. Hyp er ten sion

D. Albuterol

B. Sleepin ess

E. At ropin e

C. Bradycardia D. Hyp oglycem ia


E. Hyp okalem ia

26. A 44-year-old m an presen ted to h is physician com plain ing of in creasing cough produ cing yellow sput um an d m oderate


sh ort n ess of breath on exert ion . Th e m an h ad a long h istor y

23. A 25-year-old w om an w as seen at a clin ic because of epi-

of h eavy cigaret te sm oking an d h ad su ered from an epi-

sodes of sh or t n ess of breath an d cough th at h ad occu rred

sode of sustained ventricular tachycardia 1 year ago. Physical

alm ost ever y day sin ce sh e h ad an u p p er resp irator y in fec-

exam in at ion sh ow ed a pat ien t w ith sh allow breath ing an d a

t ion 2 m on th s earlier. Th e w om an also stated th at several

barrel ch est . Au scu lt at ion dem on st rated w h eezing an d dis-

t im es w eekly sh e aw oke at n igh t w ith th e sam e sym ptom s.

t an t h ear t sou n ds. An in h alat ion th erapy w as p rescribed. A

Spirom etr y show ed a forced expiratory volum e (FEV1 ) 62% of

drug w ith w hich of the follow ing m echanism s of action w ould

th e predicted value. W h ich of th e follow ing drugs w ou ld be


m ost appropriate to be in cluded in th e pat ien t’s t reat m en t at

A. Act ivat ion of aden osin e receptors

th is t im e?

B. In h ibit ion of ph osph olipase A2

A. Th eophyllin e

C. Act ivat ion of β 2 adren oceptors

B. Isoproteren ol

D. Blockade of Nn an d M 3 acet ylch olin e receptors

C. Salm eterol

E. Blockade of leukot rien e receptors

D. Propran olol E. Aspirin

Questions: VI-1 Drugs for Bronchospastic Disorders 337 Di cult y level: Medium

A. Oral t riam cin olon e

27. A 63-year old w om an com plain ed to h er physician of recur-

B. Oral iprat ropium

ren t w h eezing th at caused frequen t n oct urn al aw aken ing.

C. In h aled om alizum ab

Sh e also n oted th at w h eezing occurred w h en sh e w as an x-

D. In h aled th eophyllin e

ious an d ten se. Th e w om an h ad been su ering from allergic

E. Oral zileu ton

rh in it is for 4 years an d from at rial brillat ion for 1 year. A d iagn osis of m ild allergic ast h m a w as m ade. W h ich of t h e


follow in g d r ug t reat m en t s w ou ld be m ost ap p rop r iate for

31. An 11-year-old boy w as recen tly diagn osed w ith m ild sea-

relief of h er bron ch ospasm ?

son al asth m a. Th e boy w as oth er w ise h ealthy an d w as a

A. Oral glu cocor t icoids

m em ber of h is sch ool basketball team . W h ich of th e follow -

B. Oral th eophyllin e

ing drugs w ould be m ost appropriate for th e in itial treatm ent

C. In h aled iprat ropium

of th e pat ien t’s disease?

D. In h aled salm eterol


E. Oral zileuton

B. Oral t riam cin olon e C. In h aled iprat ropium


D. Oral za rlukast

28. A 13-year-old boy recen tly diagn osed w ith asth m a st ar ted

E. In h aled salm eterol

a t h erapy t h at in clu d ed in h aled

u t icason e. W h ich of t h e

follow in g m olecu lar act ion s m ost likely con t r ibu ted to t h e



32. A 45-year-old m an w ith m oderate persisten t asth m a w as in

A. Blockade of M 3 acet ylch olin e receptors

th e ch est clin ic for evalu at ion of h is clin ical st ate. His asth m a

B. Blockade of leukot rien e receptors

w as on ly p ar t ially con t rolled on daily in h aled salm eterol

C. In h ibit ion of phosph olipase A2

an d beclom eth ason e. Recen tly, za rlu kast w as added to th e

D. Act ivat ion of β 1 adren oceptors E. Act ivat ion of α 2 adren oceptors F.

In h ibit ion of lipocor t in biosyn th esis

th erapy w ith sign i can t im p rovem en t of th e d isease, bu t it w as w ith draw n 10 days later becau se of th e ap pearan ce of a severe h eadach e. Physical exam in at ion sh ow ed d i u se exp irator y w h eezes, an d pu lm on ar y fu n ct ion test ing revealed

Di cult y level: Easy 29. A 43-year-old w om an w it h m ild p ersisten t ast h m a st ar ted a daily t reat m en t w it h low -d ose in h aled glu cocor t icoid s.

a p eak exp irator y

ow rate 70% of p redicted. W h ich of th e

follow ing dr ugs w ould be appropriate to add to th e pat ien t’s regim en at th is t im e?

W h ich of th e follow ing adverse e ect s w as m ost likely to



B. Oral zileu ton

A. Hyp okalem ia B. Weigh t gain C. Oral can didiasis D. Restlessn ess E. In creased h ear t rate F.

Osteoporosis

C. In h aled th eophyllin e D. Paren teral om alizu m ab E. Oral m on telu kast

Di cult y level: Easy 33. A 9-year-old girl w ith a long h istor y of cyst ic

brosis pre-

sen ted to th e h osp it al becau se of w orsen ing of resp irator y

Di cult y level: Medium 30. A 21-year-old m an w ith severe persisten t asth m a h ad been on d aily in h aled salm eterol, in h aled beclom et h ason e, an d oral za rlu kast for 2 m on t h s, w it h in h aled albu terol as n eeded. How ever, h is asth m a w as poorly con t rolled, an d h is p hysician decided to add an oth er drug to th e cu rren t t reat-

sym ptom s. An ap p rop r iate t h erapy w as p rescr ibed t h at in clu d ed in h aled d or n ase alfa. W h ich of t h e follow in g best explain s th e m ech an ism of act ion of dorn ase alfa in th e p at ien t’s disease? A. Su p p or t s bacter icidal act ivit y again st Pseudom onas aeruginosa

m en t . W h ich of th e follow ing d rugs w ou ld be m ost app ro-

B. Releases n it ric oxide from air w ay epith eliu m

p riate for th e pat ien t at th is t im e?

C. Depolym erizes th e DNA of purulen t air w ays secret ion s D. St im ulates th e cyst ic brosis t ran sm em bran e regu lator E. In h ibits th e n eut roph il m igrat ion in to lung t issue

338



A. Codein e

34. A 43-year-old m an com plained to his physician that the ther-

B. Th eop hyllin e

apy h e w as t aking im p roved h is breath ing, bu t th at h e st ill

C. Dext rom eth orph an

h ad an an n oying cough from t im e to t im e. He asked th e phy-

D. Iprat ropium

sician for a cough su p p ressan t . Tw o w eeks earlier, th e m an

E. Dorn ase alfa

w as d iagn osed w ith m oderate persisten t asth m a an d star ted

F.

a th erapy w ith in h aled albu terol an d

Fen t anyl

u t icason e. W h ich of

th e follow ing drugs w ou ld be app ropriate to t reat th e p at ien t’s cough ?

Questions: VI-2 Drugs for Gastrointestinal Disorders Directions for questions 1−8 Match each gast roin test in al drug w ith th e ap prop riate descrip t ion (each let tered opt ion can be selected on ce, m ore th an on ce,

Di cult y level: Easy 5. An an t iulcer agen t th at can in h ibit 24-h ou r gast ric acid secret ion u p to 95%

or n ot at all). A. Bisacodyl B. Calcium carbon ate C. Castor oil

Di cult y level: Easy 6. A drug th at can in crease in test in al perist alsis by act ivat ing m ot ilin receptors

D. Docu sate E. Er yth rom ycin F.

Loperam ide

Di cult y level: Easy 7. An opioid dr ug used to t reat diarrh ea

G. Meclizin e H. Mesalam in e I.

Metoclop ram ide

J.

Methylcellu lose

K. Magn esiu m hydroxide L.

Min eral oil

N. Misop rostol O. Om eprazole P.

Aprepitan t

Q. Su cralfate

Di cult y level: Easy 8. A salicylate derivat ive used in in am m ator y bow el diseases

Di cult y level: Easy 9. A 45-year-old w om an h ad been self-m edicat ing for h eartbu r n . Th e p rep arat ion sh e w as u sin g w as a com bin at ion of m agn esiu m hydroxide an d alu m in u m hydroxide. W h ich of th e follow ing reason s best explain s w hy m any an tacid p reparat ion s on th e m arket con tain a com bin at ion of th ese


t w o an t acids in stead of a single produ ct?

1. An an t acid th at also h as laxat ive propert ies

A. To ach ieve a bactericidal e ect on Helicobacter pylori


C. To avoid in teract ion w it h ot h er d r ugs given con -

2. An an t iem et ic drug used prim arily for ch em oth erapy-in duced vom it ing

Di cult y level: Easy 3. A prost aglan din E1 an alogu e th at can h ave a cytoprotect ive e ect on gast ric m ucosa

Di cult y level: Easy 4. An an t iu lcer agen t th at bin ds to n ecrot ic pept ic ulcer t issu e, th us act ing as a barrier to gast ric ju ice

B. To avoid an tacid overd ose toxicit y com it an t ly D. To facilit ate gast ric em pt ying E. To decrease th e occu rren ce of con st ip at ion or d iarrh ea

Di cult y level: Hard 10. A 76-year-old w om an w h o un der w en t su rger y to rem ove a colon polyp com plain ed of epigast ric pain th e day after th e op erat ion . Her gen eral con d it ion rap id ly d eter iorated , an d sh e w as t ran sfer red to th e in ten sive care u n it becau se of sept ic sh ock. W h ich of th e follow ing th erap eu t ic regim en s

Questions: VI-2 Drugs for Gastrointestinal Disorders 339 w ou ld be ap p rop r iate to p reven t st ress-related m u cosal


bleeding in th is p at ien t?

14. A 65-year-old w om an su ering from ch ron ic h eartburn w as

A. Metoclop ram ide by in t raven ou s (IV) in fu sion

rou t in ely t aking a large am ou n t of an an t acid p rep arat ion

B. On dan set ron by IV in fusion

con t ain in g alu m in u m hyd roxid e. Lab exam s of t h is p at ien t

C. Su cralfate by n asogast ric t u be

w ou ld m ost likely sh ow w h ich of th e follow ing resu lt s?

D. Bism uth salicylate by n asogast ric t ube

A. Hyp erglycem ia

E. Misop rostol by n asogast ric t u be

B. Hyp ercalcem ia

F.

C. Hyp ern at rem ia

Fam ot idin e by IV in fusion

D. Hyp okalem ia


E. Hyp op h osp h atem ia

11. A 61-year-old m an w ith n ew ly diagn osed lung can cer w as sch ed uled to receive h is rst course of ch em oth erapy. A pro -


p hylact ic an t iem et ic t reat m en t w as p lan n ed t h at in clu d ed

15. A 45-year-old w om an p resen ted to h er p hysician becau se

on dan set ron . W h ich of th e follow ing brain region s represen t

of a 2-w eek h istor y of p ain less d iarrh ea th at w as u rgen t an d

a site of th e an t iem et ic act ion of th e d rug?

u su ally occu rred during m eals. After physical exam in at ion ,

A. Nucleu s t ract us solitarius

lab tests, an d colon oscopy, a diagn osis of irrit able bow el syn -

B. Pu tam en

d rom e w as m ade, an d th e w om an w as prescribed an ap p ro-

C. Locus ceru leus

p r iate t h erapy t h at in clu d ed lop eram ide. Direct act ivat ion


of w h ich of th e follow ing receptors m ost likely m ediated th e

E. Medial forebrain bu n d le

th erap eu t ic e ect of th e drug in th is p at ien t? A. Beta-2 adren ergic


B. Nn ch olin ergic

12. A 70-year-old w om an com p lain ed to h er p hysician of ob -

C. 5-HT3 seroton ergic

st in ate con st ip at ion . Th e p hysician p rescr ibed a la xat ive

D. Alph a-2 adren ergic

t h at act s in t h e colon by absorbin g w ater in to t h e fecal con -

E. Mu opioid

ten t s, th us prom ot ing perist alsis abou t 1 or 2 days after ad-

F.

M 3 ch olin ergic

m in ist rat ion . W h ich of th e follow ing drugs w as m ost likely p rescribed?


A. Castor oil

16. A 74-year old m an w as adm it ted to th e h ospital because of

B. Docu sate

p ersisten t epigast ric pain an d tarr y stools. Th e p at ien t h ad

C. Sodiu m p h osph ate

been su ering from hyp erten sion for 5 years an d w as being

D. Magn esiu m su lfate

t reated w it h hyd roch lorot h iazid e an d losar t an . Past h is-

E. Methylcellu lose

tor y w as sign i can t for a ser iou s hyp ersen sit ivit y react ion to om ep razole t aken 1 year ago for h ear t bu rn . Per t in en t


laborator y result s on adm ission w ere red blood cell coun t

13. A 58-year-old alcoh olic m an su er ing from h epat ic cirrh o-

3.5 × 10 6 /m m 3 (norm al 4.5−5.5 × 10 6 /m m 3 ), hem oglobin 9 g/dL

sis w as adm it ted to th e h ospital because of drow sin ess an d

(n orm al 14−16 g/dL), creat in in e 4.5 m g/dL (n orm al 0.9−1.3

d isorien tat ion in t im e an d place. Fur th er exam s led to th e

m g/dL). Endoscopy disclosed a large gastric ulcer. Th erapy

d iagn osis of por tal-system ic en ceph alopathy. W h ich of th e

w ith fam ot idin e w as st arted, but th e stan dard dose w as re-

follow ing drugs w ould be appropriate to elim in ate toxic en -

du ced by on e h alf. W h ich of th e follow ing w as th e m ost

teric product s in th is pat ien t?

likely reason for th e use of a redu ced dose of fam ot idin e in

A. Om eprazole

th is p at ien t?

B. Lact u lose

A. Th e p at ien t’s an em ia

C. Loperam ide

B. Th e p at ien t’s hyp er ten sion

D. Su cralfate

C. Th e p at ien t’s age

E. Aprepitan t

D. Th e p at ien t’s ren al in su

F.

E. Th e p at ien t’s hyp ersen sit ivit y to om ep razole

Ran it idin e

cien cy

340



A. Met ron idazole

17. An 18-year-old m an t raveling on vacat ion in Mexico n oted

B. Clarith rom ycin

som e m ild abdom in al cram p s an d th ree or fou r u n form ed

C. Lop eram id e

stools over th e p ast 24 h ou rs. No blood w as seen in th e stool.

D. On dan set ron

W h ich of th e follow ing drugs w ould be appropriate to t reat

E. Predn isolon e

th e p at ien t’s diarrh ea? A. Magn esiu m su lfate B. Bism uth su bsalicylate

Di cult y level: Medium 21. A 50-year-old w om an com plain ed to h er physician of regur-

C. Van com ycin

gitat ion of fou l-t ast ing u id in to h er m ou th an d occasion al

D. Er yth rom ycin

n ausea an d vom it ing. Th e physician prescribed a drug th at

E. Metoclop ram ide

can both p reven t n au sea an d vom it ing an d p rom ote u pp er

F.

gast roin test in al m ot ilit y. Blockade of w h ich of th e follow ing

Su cralfate

receptors m ost likely con t r ibu ted to t h e t h erap eu t ic e ect


of th e d rug in th e pat ien t’s disease?

18. A 45-year-old m an recen tly diagn osed w ith m ild colon ic

A. M 3 ch olin ergic

Croh n disease h ad been receiving sulfasalazin e for 4 w eeks,

B. Nn ch olin ergic

bu t rem ission w as n ot ach ieved. Predn ison e w as added for

C. Beta-2 adren ergic

an oth er 2 w eeks, bu t im provem en t w as n egligible, an d th e

D. H2 h ist am in ergic

gast roen terologist d ecid ed to add a th ird drug to th e th er-

E. D2 dopam in ergic

apy. W h ich of th e follow ing drugs w ould be appropriate for th e p at ien t at th is t im e?


A. Mesalam in e

22. A 61-year-old m an w as seen at a clin ic becau se of h ear t -

B. Daclizu m ab

bu r n an d abd om in al p ain for t h e p ast m on t h . He h ad self-

C. Dexam eth ason e

m ed icated w ith variou s over-th e-cou n ter p rep arat ion s, bu t

D. Am ikacin

h e got on ly tem porar y relief. All rou t in e laborator y test s

E. In ixim ab

w ere w ith in n orm al lim it s except th e seru m gast rin level, w h ich w as 3240 pg/m L (n orm al < 100 pg/m L). Radiograph ic

Di cult y level: Easy 19. A 43-year-old m an su ering from h eartburn h ad been u sing an tacid p rep arat ion s as n eed ed. W h ich of th e follow ing best d escribes th e m ech an ism of act ion of an t acids? A. In h ibit ion of pepsin an d hydroch loric acid secret ion B. St im u lat ion of bicarbon ate secret ion by ep ith elial cells C. React ion w ith hydroch loric acid in th e stom ach lu m en D. Bin ding to n ecrot ic ulcer t issue E. React ion w ith pepsin in th e stom ach lu m en

Di cult y level: Hard 20. A 30-year-old m an w en t to h is physician because of 1 m on th of w orsening interm it tent abdom inal pain, bloating, diarrhea, an d rect al bleeding. Vit al sign s w ere n orm al, an d p hysical exam ination disclosed only di use abdom inal pain. Sigm oidoscopy sh ow ed er yt h em atou s m u cosa in t h e rect u m an d sigm oid an d dist al descen ding colon . Th e m ucosa h ad areas of

n e gran ular appearan ce w ith som e focal h em orrh age

an d en d oscop ic st u dies dem on st rated on e gast ric an d t w o d uoden al ulcers, an d m agn et ic reson an ce im aging sh ow ed a sm all p an creat ic t u m or. A drug w ith w h ich of th e follow ing m ech an ism s of act ion w ou ld be m ost app ropriate for th is p at ien t? A. Blockade of H2 receptors in gast ric pariet al cells B. Act ivat ion EP3 receptors in gast ric ep ith elial cells C. Coat ing th e gast ric u lcer craters D. Neutralization of hydrochloric acid in the stom ach lum en E. In h ibit ion of H+/K+ ATPase in gast ric pariet al cells

Di cult y level: Easy 23. A 61-year-old w om an w ith n ew ly diagn osed ovarian can cer w as sch eduled to receive h er

rst cou rse of ch em oth erapy.

A prophylact ic an t iem et ic m edicat ion w as plan n ed. A drug from w h ich of th e follow ing classes w ou ld be m ost ap p rop riate to in clud e in th e an t iem et ic th erapy of th is p at ien t? A. Seroton ergic an t agon ist s

an d u lcerat ion s. Biop sies dem on st rated abn orm al cr ypt ab -

B. Dopam in ergic agon ist

scesses. A diagn osis w as m ad e, an d a th erapy w as prescribed.

C. Mu scarin ic an t agon ist s


D. Gabaergic agon ists


E. Adren ergic agon ists

Questions: VI-2 Drugs for Gastrointestinal Disorders 341 Di cult y level: Medium

A. Fam ot idin e

24. A 44-year-old m an w h o h as been receiving h is rst course of

B. At ropin e

ch em oth erapy for a n on -Hodgkin lym ph om a st ill com plain s

C. On dan set ron

of recu rren t n ausea an d vom it ing despite an t iem et ic m edi-

D. Dron abin ol

cat ion w it h on dan set ron , d exam et h ason e, an d ap rep it an t .

E. Er yth rom ycin

W h ich of t h e follow ing d r ugs w ou ld be ap p rop r iate to add

F.

Bism uth

to th e pat ien t’s an t iem et ic regim en at th is t im e?


A. Fam ot idin e B. Om eprazole

28. A 60-year-old m an su ering from recurren t h ear tburn rou-

C. Loperam ide

t in ely took large qu an t it ies of di eren t an t acid p rep arat ion s.

D. Dron abin ol

W h ich of th e follow ing an tacids h ad th e h igh est risk of m et -

E. Triam cin olon e

abolic alkalosis in th is p at ien t?

F.

A. NaHCO3

Meclizin e

B. CaCO3


C. Al(OH) 3

25. A 64-year-old w om an su er ing from ep isod ic h ear t bu r n

D. Mg(OH) 2

rout in ely took an over-th e-coun ter m edicat ion as n eeded.

E. Ca(OH) 2

Th e d r ug act s by in h ibit in g t h e act ion of an en d ogen ou s com p ou n d released from en teroch rom a

n -like cells of t h e

stom ach . W h ich of th e follow ing drugs d id th e pat ien t m ost

Di cult y level: Medium 29. A 67-year-old m an com plain ed to h is physician of n er vous-

likely t ake?

n ess, in som n ia, palpit at ion s, an d stom ach ach e. Th e m an

A. On dan set ron

h ad a long h istor y of ch ron ic obst ru ct ive pulm on ar y disease

B. Loperam ide

cu rren tly t reated w ith in h aled iprat rop iu m an d oral th eop h -

C. Metoclop ram ide

yllin e. He told th e p hysician th at h e h ad st arted t aking ci-

D. Fam ot idin e

m et idin e for h ear tbu rn 3 days ago. W h ich of th e follow ing

E. Lorat adin e

best explains the reason for the patient’s current com plaints?

F.

A. Cim et idin e in creased th e clearan ce of th eophyllin e.

Su cralfate

B. Cim et idin e decreased th e clearan ce of th eophyllin e.


C. Cim et idin e in creased th e clearan ce of iprat ropium .

26. A 36-year-old m an com plain ed to h is physician of dizzin ess

D. Th eop hyllin e in creased th e clearan ce of cim et idin e.

an d drow sin ess. Th e m an , recen tly d iagn osed w ith gast ro-

E. Th eop hyllin e decreased th e clearan ce of cim et idin e.

esoph ageal re u x disease, h ad st arted an appropriate t reatm ent 2 w eeks earlier. Laborator y ndings show ed an increase


of th e pat ien t’s prolact in levels. W h ich of th e follow ing drugs

30. A 71-year-old m an w ith term in al m et ast at ic lung can cer h ad

could h ave caused th e sign s an d sym ptom s of th is pat ien t?

been h ospit alized for 3 m on th s. His ren al fu n ct ion h ad dete-

A. Ran it idin e

r iorated , an d laborator y resu lt s sh ow ed ser u m creat in in e

B. Om eprazole

4.5 m g/dL (n orm al 0.9−1.2 m g/dL) an d blood u rea n it rogen

C. Alum in um hydroxide

(BUN) 75 m g/dL (n orm al 6−20 m g/dL). Becau se of poor food

D. Calcium carbon ate

in take, im m obilit y, an d requ irem en t for an op ioid an algesia,

E. Su cralfate

th e p at ien t w as severely con st ip ated an d requ ired daily lax-

F.

at ive th erapy. W h ich of th e follow ing w ould be a su it able

Metoclop ram ide

laxat ive for th is pat ien t?


A. Lact u lose

27. A 51-year-old m an com plain ed to h is physician of in diges-

B. Castor oil

t ion . He described a bu rn ing sen sat ion an d som e belch ing,

C. Magn esiu m hydroxide

often associated w ith foul-t ast ing acid in h is m outh , espe-

D. Sodiu m p h osph ate

cially after large or spicy m eals. If m eals w ere too close to h is

E. Min eral oil

bed t im e, th e bu rn ing kept h im aw ake at n igh t . He w ou ld like to h ave a t reat m en t th at preven ts m eal-related sym ptom s. W h ich of th e follow ing drugs w ould be m ost appropriate for th is p at ien t?

342




31. A 74-year-old pat ien t su ering from ch ron ic con st ipat ion

34. A 34-year-old h ospit alized m ale pat ien t com plain ed of tor t i-

com plain ed of ver y loose stools after a t reat m en t w ith bisac-

collis, grim acing, and spasm of the ocular m uscles 1 day after

odyl, on e t ablet daily for 1 w eek. W h ich of th e follow ing

su rger y. Th e m an h ad received an in t raven ou s d r ug soon

w ou ld be th e best advice to give to th is pat ien t?

after su rger y to t reat n au sea an d vom it in g. W h ich of t h e

A. Th ere is n o cau se for alar m ; t h e sit u at ion is self-

follow ing an t iem et ic drugs m ost likely cau sed th e pat ien t’s sym ptom s?

lim it ing. B. Con t in u e bisacodyl, bu t take th e m edicat ion w ith a sm all sn ack.

B. Scop olam in e

C. Con t in u e bisacodyl, an d add lact u lose. D. Discon t in u e bisacodyl, an d in crease

A. On dan set ron C. Dexam eth ason e

ber an d

u id

in t ake.

D. Metoclop ram ide E. Dron abin ol

E. Discon t in ue bisacodyl, an d sw itch to castor oil.


35. A 59-year-old w om an su ering from ch ron ic con st ipat ion

32. A 43-year-old m an recen tly diagn osed w ith test icular can cer

rou t in ely self-ad m in istered m ilk of m agn esia (m agn esiu m

w as in th e h ospital for h is secon d cycle of ch em oth erapy. A

hydroxide) daily. W h ich of th e follow ing act ion s m ost likely

th ree-d rug com bin at ion w as given to preven t ch em oth era-

m ediated th e laxat ive e ect of th e drug?

py-in du ced n au sea an d vom it ing. Th e com bin at ion in clu ded

A. In h ibit ion of ch olecystokin in release

a d r ug t h at blocks NK1 n eu rokin in receptors in t h e area

B. Reten t ion of w ater in th e vessels by osm osis

p ost rem a. W h ich of th e follow ing drugs h as th is m olecular

C. Lu bricat ion of fecal m aterial

m ech an ism of act ion ?

D. St retch ing of th e in test in al w all

A. On dan set ron

E. Form at ion of a bulky em ollien t gel

B. Dron abin ol C. Aprepitan t


D. Metoclop ram ide


E. Diph en hydram in e

creasing frequ en cy an d u rgen cy of bow el m ovem en ts th at sh e at t ribu ted to in creased st ress at w ork. Th e w om an w as


d iagn osed w ith spast ic colon 4 years ago but w as able to tol-


erate th e sym ptom s u n t il recen tly, w h en sh e n oted th e in -

p ain th at w as st ronger at n igh t an d w as tem porarily relieved

creasing frequ en cy of bow el m ovem en ts. A drug from w h ich

by food. Upper gastrointestinal endoscopy showed t w o sm all

of th e follow ing classes cou ld be appropriate to t reat th e pa-

gast ric u lcers, an d a u rease breath test w as p osit ive for Heli-

t ien t’s disord er?

cobacter pylori in fect ion . Th e physician p rescribed a t rip le

A. Opioid agon ist s

t h erapy w it h om ep razole, clar it h rom ycin , an d m et ron ida-

B. Seroton ergic agon ist s

zole for 14 days, follow ed by om eprazole daily for 6 w eeks.

C. Mu scarin ic agon ist s

W h ich of th e follow ing statem en ts best explain s w hy th is

D. H1 agon ist s

drug regim en is th e rst-line therapy for H. pylori−associated u lcers?

E. Adren ergic an tagon ist s F.

Gabaergic an t agon ist s

A. Om eprazole is rapidly bactericidal again st H. pylori. B. Th e regim en alm ost com pletely elim in ates th e risk of ulcer recu rren ce. C. Clarith rom ycin greatly en h an ces th e bactericidal act ivit y of om ep razole. D. Met ron idazole greatly en h an ces th e bactericidal act ivit y of om eprazole. E. Th e regim en can cure th e ulcer in up to 70% of cases.

Di cult y level: Easy 37. A 46-year-old m an recen tly diagn osed w ith a duoden al ulcer star ted a t reat m en t th at in clu d ed daily su cralfate. W h ich of th e follow ing m ech an ism s m ost likely m ediates th e th erap eut ic e

cacy of th e drug in th e pat ien t’s disease?

Questions: VI-2 Drugs for Gastrointestinal Disorders 343 A. Act ing as a barrier to acid by bin ding to n ecrot ic u lcer t issu e B. React ing w ith gast ric hydroch loric acid to form salt an d w ater

A. Ran it idin e, diazep am , dexam eth ason e B. Scop olam in e, dexam eth ason e, on dan set ron C. On dan set ron , aprepit an t , dexam eth ason e D. Aprepitan t , scopolam in e, loperam ide

C. In h ibit ing hydroch loric acid secret ion

E. Diph en hydram in e, proch lorperazin e, dron abin ol

D. St im u lat ing bicarbon ate secret ion by an t ral pariet al cells

F.

Proch lorperazin e, ran it idin e, loperam ide

E. Exert ing a bactericidal e ect again st Helicobacter pylori


41. A 34-year-old -m an w it h a 2-year h istor y of AIDS w as ad -

38. A 24-year-old w om an in h er secon d t rim ester of pregn an cy

m it ted to t h e h osp it al for evalu at ion . Th e p at ien t ’s on ly

com plain ed of con st ipat ion at a rout in e pren at al visit . Th e

com p lain t w as a poor ap pet ite th at h ad got ten progressively

p hysician in st ructed th e w om an to m ain tain bow el fu n ct ion

w orse over t h e p ast 3 w eeks. He w as cu r ren t ly t akin g a

by drin king plen t y of w ater, in creasing bulk in th e diet w ith

h igh ly act ive an t iret roviral t h erapy (HAART) w it h lam ivu -

veget ables, an d t aking a laxat ive daily. W h ich of th e follow -

d in e, st avu d in e, an d at azan avir. Physical exam in at ion an d

ing laxat ives w ould be m ost appropriate for th is pat ien t?

laborator y exam s sh ow ed t h at t h e p at ien t w as in st able

A. Castor oil

con dit ion except for decreasing body w eigh t . W h ich of th e

B. Bisacodyl

follow ing dr ugs w ould be appropriate to t reat th e pat ien t’s

C. Sen n a

an orexia?

D. Docu sate

A. Metoclop ram ide

E. Magn esiu m hydroxide

B. Om eprazole

F.

C. Fam ot idin e

Sodiu m su lfate

D. Dron abin ol


E. Lop eram id e


F.

Meclizin e

an d su bstern al pain for abou t 3 w eeks. Th e pain u su ally occurred after dinner w h en he w as lying on the couch w atch ing


television an d w as som et im es accom pan ied by regurgitat ion


of foul-t ast ing uid in to h is m outh . Th e m an h ad been suf-

d rug sh e w as t aking did n ot w ork an d th at sh e w as st ill su f-

fering from Parkin son disease for 1 year an d w as cu rren tly

fering from obst in ate con st ipat ion . Th e w om an h ad a long

receiving p ram ip exole an d selegilin e. W h ich of t h e follow -

h istor y of irritable bow el syn drom e an d took several dr ugs

ing drugs w ould be m ost appropriate to t reat th e pat ien t’s

in th e p ast w ith lim ited success. Sh e w as p resen tly t aking

sym ptom s?

lact u lose. Th e physician decided to t r y an oth er drug recen tly

A. At ropin e

app roved for irrit able bow el syn d rom e w ith con st ip at ion in

B. Misop rostol

adu lt w om en . Th e drug is a p rostan oid derivat ive th at act s

C. On dan set ron

by open ing t ype 2 ch loride ch an n els in th e sm all in test in e.

D. Om eprazole

W h ich of th e follow ing drugs w as m ost likely prescribed?

E. Metoclop ram ide

A. On dan set ron

F.

B. Dron abin ol

Cim et id in e

C. Lu biproston e


D. Metoclop ram ide

40. A 63-year-old m an su ering from a sm all cell carcin om a of


th e lu ng w as h ospitalized for h is rst cycle of ch em oth erapy. W h ich of th e follow ing th ree-dr ug regim en s w ould be th e best to p reven t n au sea an d vom it ing in th is p at ien t?

F.

Sorbitol

344


Questions: VI-3 Drugs for Hematopoietic Disorders Directions for questions 1−6

act ion s m ost likely m ed iated t h e t h erap eu t ic e ect of th e

Match each h em atopoiet ic d rug w ith th e app ropriate descript ion

prescribed drug?


A. Act ivat ion of speci c receptors on RBC p rogen itors

at all).

B. Rep lacem en t of a ch em ical w h ose stores are severely d epleted

A. Cyan ocobalam in B. Deferoxam in e

C. In creased life span of RBCs

C. Er yth ropoiet in

D. St im ulat ion of er yth ropoiet in produ ct ion by th e kidn ey

D. Ferrou s su lfate

E. St im ulat ion of t ran sferrin product ion by th e liver

E. Filgrast im F.

Folic acid


G. Iron dext ran

8. A 22-year-old w om an in h er rst w eek of pregn an cy st arted

H. Iron sucrose

on daily folic acid supplem en tat ion . Th e th erapy w as given

I.

Leucovorin

to decrease t h e r isk of w h ich of t h e follow ing congen it al

J.

Oprelvekin

abn orm alit ies?

K. Sargram ost im

A. At rial septal defect B. Sp in a bi da


C. Tet ralogy of Fallot

1. Th is drug is som et im es used to preven t t ran sfusion al iron

D. Esoph ageal at resia

overload.

E. Congen ital cat aract F.

Cr yptorch idism

Di cult y level: Easy 2. An en dogen ous com poun d syn th esized by th e kidn ey in respon se to hypoxia

Di cult y level: Easy 9. A 58-year-old m an recen t ly diagn osed w it h iron d e cien cy an em ia w as fou n d to h ave a severe d ep let ion of tot al body


iron stores. W h ich of th e follow ing com poun ds represen ts

3. Th ere is a lifet im e requirem en t for th is dr ug in pat ien t s w h o

th e m ost im p or tan t store for iron ?

h ave un dergon e gast rectom y.

A. Tran sferrin B. Ferropor t in


C. Ferrit in

4. A recom bin an t form of in terleukin 11

D. Myoglobin E. Hem oglobin

Di cult y level: Easy 5. A m ult ilin eage m yeloid grow th factor

Di cult y level: Medium 10. A 71-year-old m an com plain ed to h is physician of t iredn ess,

Di cult y level: Easy 6. Th is drug is absorbed th rough th e distal ileum by a process of receptor-m ediated en d ocytosis.

Di cult y level: Medium 7. A 62-year-old m an presen ted to h is physician com plain ing of t iredn ess an d abdom in al p ain . Medical h istor y revealed th at th e m an h ad been taking t w o t ablets of n aproxen t w ice daily for arth rit ic pain for th e past 3 m on th s. Per t in en t lab result s on adm ission w ere red blood cell cou n t (RBC) 3.1 × 10 6 /m m 3 (n orm al, m ale 4.3−5.9 × 10 6 /m m 3 ), h em oglobin 8.5 g/dL (n orm al, m ale > 13.5 g/d L), m ean corp u scu lar volu m e 70 fL (n orm al 80−100 fL), ser u m ferrit in 6 ng/m L (n orm al: 30−300). An appropriate th erapy w as prescribed. W h ich of th e follow ing

breat h lessn ess, an d fat igu e. Fou r years earlier, t h e p at ien t h ad u n d ergon e tot al gast rectom y for advan ced Zollinger− Ellison syn d rom e. A blood an alysis sh ow ed m egaloblast ic an em ia. W h ich of th e follow ing statem en t s best explain s w hy folic acid su pplem en t at ion w ould be con t rain dicated in th is p at ien t? A. Th e drug w ou ld m ask h em atologic sign s of vitam in B12 de cien cy. B. Th e drug w ou ld block vit am in B12 act ion s in th e cen t ral n er vous system . C. Th e d rug m ay in crease vit am in B12 m et abolism . D. Older pat ien ts are especially at risk of folic acid toxicit y. E. Gast rectom y com p letely p reven t s folic acid absorpt ion .

Questions: VI-3 Drugs for Hem atopoietic Disorders 345 Di cult y level: Medium


11. A 32-year-old w om an in h er secon d t rim ester of pregn an cy

13. A 22-year-old m an com plain ed to h is physician of in creasing

p resen ted to th e clin ic for a ch eck-up. Th e pat ien t h ad a

fat igue, an orexia, an d irritabilit y over th e past 2 m on th s. Th e

5-year h istor y of excessive alcoh ol in t ake an d h ad been u sing

m an h ad been su ering from glu ten en teropathy sin ce h is

cocain e frequen tly for th e past 3 years. Sh e appeared m al-

in fan cy. Physical exam in at ion revealed p allor, glossit is, p ar-

n ourish ed an d h ad lost 12 poun ds during th e rst t rim ester,

esth esias, an d m uscle w eakn ess. Per t in en t laborator y valu es

secon dar y to an orexia, n au sea, an d vom it ing. Pert in en t lab -

w ere red blood cell count (RBC) 3.4 × 10 6 /m m 3 (norm al, m ale

oratory values were red blood cell count (RBC) 2.7 × 10 6 /m m 3

4.3−5.9 × 10 6 /m m 3 ), m ean corpuscular volum e 116 fL (n or-

(n orm al, fem ale 3.5−5.5 × 10 6 /m m 3 ), m ean corpu scular vol-

m al 80−100 fL), seru m vitam in B12 330 pg/m L (n orm al > 280

um e 112 fL(norm al 80−100 fL), serum vitam in B12 350 pg/m L

pg/m L), ser u m fer r it in 200 n g/m L (n or m al 30−300 n g/m L).

(n orm al > 280 pg/m L), seru m ferrit in 200 ng/m L (n orm al

Blood st ain sh ow ed m acro-ovalocyt ic red blood cells an d

30−300 ng/m L). Blood st ain sh ow ed m acro-ovalocyt ic RBCs

hypersegm en t at ion of n eu t rop h ils. An app ropriate drug w as

an d hypersegm en t at ion of n eut roph ils. W h ich of th e follow -

st ar ted , an d 10 days later, t h e RBC w as n or m al. W h ich of

ing drugs w ou ld be m ost ap prop riate for th is pat ien t?

t h e follow ing act ion s m ost likely m ed iated th e th erapeu t ic

A. Cyan ocobalam in

e ect of th e drug in th e p at ien t’s disease?

B. Folic acid

A. In creased conversion of h om ocystein e to m eth ion in e

C. Ferrou s su lfate

B. In creased syn th esis of tet rahydrofolate

D. Iron dext ran

C. In creased absorpt ion of iron from duoden al m ucosa


D. Decreased er yth rocyte dest ruct ion E. In creased syn th esis of er yth ropoiet in

Di cult y level: Medium 12. A 34-year-old w om an w as seen at a clin ic because of severe


w eakn ess an d d izzin ess for t h e p ast several m on t h s. Th e

14. A 34-year-old w om an recently diagnosed w ith iron de ciency

w om an h ad a lon g h istor y of m en or rh agia an d of ch ron ic

an em ia star ted a t reat m en t w ith ferrou s su lfate. W h ich of

h eadach es for w h ich sh e h ad been using several an algesic

th e follow ing m ech an ism s w as m ost likely involved in th e

m edicat ion s on a daily basis. Physical exam in at ion revealed

d eliver y of iron to th e pat ien t’s er yth roblasts?

a pale, leth argic fem ale ap p earing older th an h er st ated age.

A. Lipid di usion

Notable sign s w ere a sore tongu e, sp oon ing of th e n ails, an d

B. Facilit ated d i u sion

splenom egaly. Pertinent laboratory values w ere red blood cell

C. Aqu eou s di u sion

coun t 2.3 ×

10 6

3

6

3

/m m (n orm al, fem ale 3.5−5.5 × 10 /m m ),

m ean corpu scu lar volu m e 72 fL (n orm al 80−100 fL), h em o-

D. Receptor-m ediated en docytosis E. Bulk ow t ran spor t

globin 5 g/dL (norm al, fem ale > 12 g/dL), serum ferritin 7 ng/m L (n orm al 30−300 ng/m L). W h ich of th e follow ing drugs w ou ld be m ost ap prop riate for th is p at ien t? A. Ferrou s su lfate B. Folic acid C. Er yth ropoiet in D. Iron sucrose E. Vitam in B12 F.

Filgrast im

Di cult y level: Medium 15. A 53-year-old m an recen t ly d iagn osed w it h p er n iciou s an em ia star ted a t reat m en t w ith vit am in B12 . W h ich of th e follow ing m olecular act ion s m ost likely m ediated th e an t ian em ic e ect of th e drug in th is p at ien t? A. Form at ion of su ccinyl−coen zym e A (CoA) B. Hydroxylat ion of folic acid C. Dem ethylat ion of N5 -m ethyltet rahydrofolate D. Hydroxylat ion of d ihydrofolic acid E. Glycin e form at ion from serin e

346





19. A 33-year-old m aln ourish ed w om an in h er eigh th m on th of

of tiredness, breathlessness, and fatigue over the past 3 w eeks.

p regn an cy p resen ted to th e clin ic com p lain ing of ext rem e

Tw o years ago, sh e u n der w en t gast rectom y for severe n on -

leth argy. Th e w om an w as m u lt ip arou s an d living in a p oor

h ealing ulcers. Th e on ly m edicat ion th e pat ien t w as t aking

su bu rban area w ith h er t w o daugh ters. Pert in en t laborator y

w as cyan ocobalam in , in t ram uscu larly, on ce a m on th . Pert i-

valu es on adm ission w ere red blood cell (RBC) cou n t 2.9 ×

n ent laborator y values on adm ission w ere red blood cell count

106/m m 3 (norm al, fem ale 3.5−5.5 × 106/m m 3 ), m ean corpus-

2.8 × 106/m m 3 (n or m al, fem ale 3.5−5.5 × 106/m m 3 ), m ean

cu lar volu m e 90 fL (n orm al 80−100 fL), h em oglobin 7 g/dL

corpuscular volum e 60 fL (n orm al 80−100 fL), h em oglobin

(n orm al, fem ale > 12 g/dL), serum ferrit in 8 µg/dL (n orm al

8.6 g/dL (n orm al, fem ale > 12 g/dL), h em atocrit 32% (n orm al

30−300 µg/d L), seru m vit am in B12 350 pg/m L (n orm al > 280

36−46%). W h ich of th e follow ing d rugs given orally w ou ld

pg/m L), RBC folate 45 ng/m L (n orm al 150−800 ng/m L). Blood

m ost likely im p rove th e pat ien t’s con d it ion ?

stain dem on strated both m icro- and m acrocytic er ythrocytes

A. Vitam in B12

and blood hypochrom ia. W hich of the follow ing pairs of drugs

B. Folic acid

w ould represent an appropriate treatm ent for this pat ien t?

C. Iron dext ran

A. Cyan ocobalam in an d ferrous sulfate

D. Sargram ost im

B. Er yth ropoiet in an d hydroxocobalam in


C. Folic acid an d ferrou s sulfate

F.

D. Iron dext ran an d lgrast im

Ferrou s su lfate

E. Folic acid an d er yth rop oiet in

Di cult y level: Medium 17. A 65-year-old m an w as seen at a clin ic because of m uscle


w eakn ess, em ot ion al in st abilit y, burn ing of th e tongu e, an d

20. A 6-year-old boy recen tly diagn osed w ith th alassem ia m ajor

altern at ing con st ip at ion an d diarrh ea. Physical exam in at ion

w as st arted on w h ole blood t ran sfu sion th erapy. W h ich of

sh ow ed a p ale m an w ith red tongu e, loss of vibrator y sen se

th e follow ing drugs w as m ost likely given du ring th e t ran s-

in th e low er ext rem it ies, an d ataxia. Per t in en t blood values

fu sion to preven t t ran sfu sion al iron overload?

w ere red blood cell cou n t 3.4 × 106/m m 3 (n or m al, m ale

A. Ferrit in

4.3−5.9 × 106/m m 3 ), m ean corpuscular volu m e 110 fL (n or-

B. Folic acid

m al 80−100 fL), vitam in B12 96 pg/m L (n orm al > 280 pg/m L),

C. Filgrast im

seru m ferrit in 250 ng/m L (n orm al 30−300 ng/m L). W h ich

D. Er yth ropoiet in

of th e follow ing drugs w ould be m ost appropriate for th is

E. Sargram ost im

pat ien t?

F.

Deferoxam in e

A. Folic acid B. Ferrou s su lfate


C. Deferoxam in e

21. A 72-year-old m an w as adm it ted to th e h ospit al w ith a

D. Iron dext ran

2-w eek h istor y of w eakn ess, decreased app et ite, an d exer-

E. Cyan ocobalam in

cise in toleran ce. Per t in en t laborator y valu es on ad m ission w ere red blood cell cou n t 3.0 × 10 6 /m m 3 (n or m al, m ale


4.3−5.9 × 10 6 /m m 3 ), m ean corpuscular volum e 96 fL (n orm al

18. A 54-year-old w om an recently diagnosed w ith iron de ciency

80−100 fL), h em oglobin 6 g/d L (n orm al, m ale > 13.5 g/dL),

an em ia st arted a t reat m en t w ith oral ferrou s su lfate. W h ich

seru m iron 45 µg/dL (n orm al 50−150 µg/dL), seru m creat i-

of th e follow ing m ech an ism s w as m ost likely involved in th e

n in e 4.7 m g/dL (n orm al 0.6–1.2 m g/dL). W h ich of th e follow -

p at ien t’s in test in al absorpt ion of th e drug?

ing pairs of drugs w ou ld be m ost appropriate to t reat th e


pat ien t’s disease?

B. Lipid di usion

A. Cyan ocobalam in an d ferrous sulfate


B. Er yth ropoiet in an d ferrous sulfate

D. Act ive t ran sp or t

C. Er yth ropoiet in an d lgrast im

E. Exocytosis

D. Cyan ocobalam in an d iron dext ran E. Folic acid an d oprelvekin F.

Folic acid an d iron dext ran

Questions: VI-3 Drugs for Hem atopoietic Disorders 347 Di cult y level: Easy

m al, m ale 4.3−5.9 × 10 6 /m m 3 ), m ean corpu scular volu m e

22. A 42-year-old m an su er ing from di u se n on -Hodgkin

98 fL (n orm al 80−100 fL), h em oglobin 14 g/dL (n orm al, m ale

lym p h om a w as in t h e h osp it al for au tologou s bon e m ar row

> 13.5 g/dL). Th e pat ien t w as m ost likely at greater risk of

t ran sp lan t at ion . W h ich of t h e follow in g d r ugs sh ou ld be

w h ich of th e follow ing dr ug-related adverse e ects?

ad m in istered after t ran sp lan t at ion to h asten n eu t rop h il

A. Th rom botic com plicat ion s

recover y?

B. Hyp oten sion

A. Leucovorin

C. Angioedem a

B. Filgrast im

D. Hyp okalem ia

C. Oprelvekin

E. Adyn am ic ileu s

D. On dan set ron E. Cyan ocobalam in


F.

26. A 66-year-old w om an com plain ed to h er physician of bleed-

Allopu rin ol

ing gum s. Th e w om an h ad been receiving h er th ird cycle of


ch em oth erapy for m etastat ic ovarian can cer. A blood an aly-

23. A 65-year-old m an su ering from lu ng can cer w as adm it ted

sis sh ow ed th e follow ing resu lts: red blood cell cou n t 3.2 ×

to th e h osp it al for a cycle of ch em oth erapy. After com plet ion

10 6 /m m 3 (n orm al, fem ale 3.5−5.5 × 10 6 /m m 3 ), m ean corpus-

of th e cycle, a t reat m en t w ith oprelvekin w as st ar ted. Th e

cu lar volu m e 96 fL (n orm al 80−100 fL), h em oglobin 9 g/d L

th erap eu t ic e ect of th e drug is m ost likely m ediated by ac-

(n or m al, fem ale > 12 g/d L), n eu t rop h il cou n t 4600/m m 3

t ivat ion of sp eci c receptors located m ain ly on w h ich of th e

(n or m al 3000−7000/m m 3 ), p latelet cou n t 7000/m m 3 (n or-

follow ing cells?

m al 130,000−400,000/m m 3 ). A h em atop oiet ic agen t w as ad m in istered in t raven ou sly. W h ich of t h e follow in g d r ugs

A. Neu t rop h ils B. Lym ph ocytes


C. Macrop h ages

A. Filgrast im

D. Mon ocytes

B. Er yth ropoiet in

E. Megakar yocytes

C. Cyan ocobalam in

F.

D. Leu covorin

Platelet s

E. Folic acid F.

Di cult y level: Easy 24. A 33-year-old w om an recen tly diagn osed w ith severe m icrocyt ic an em ia felt u n easy an d becam e agitated an d u sh ed

Oprelvekin


rst in t raven ou s inject ion of an an t ian em ic


drug. Sh e also com plained of palpitations, coughing, urticaria,

after su ering t w o episod es of brow n ish vom it con t ain ing

an d di cu lt y in breath ing. With in 5 m in u tes, card iovascu lar

p ills, follow ed by a large h em atem esis. Th e m oth er, w h o w as

collapse developed. W h ich of th e follow ing drugs m ost likely

p regn an t , su sp ected h er son h ad ingested several t ablet s

cau sed th e p at ien t’s syn drom e?

of h er m edicat ion . Physical exam in at ion sh ow ed a leth argic

soon after th e

A. Leucovorin B. Ferrou s su lfate C. Iron dext ran D. Cyan ocobalam in E. Filgrast im F.

Sargram ost im

an d cyan ot ic ch ild com p lain ing of abdom in al p ain . Vit al sign s w ere blood pressu re 80/50 m m Hg (n orm al for 2 years 100/65 m m Hg), pulse 130 bpm (norm al for 2 years 115 bpm ) respirat ion s 30/m in (n orm al at 2 years 24/m in ). Laborator y valu es in d icated severe m et abolic acidosis. W h ich of th e follow ing drugs w ou ld be m ost ap prop riate for th is ch ild ? A. Iron dext ran

Di cult y level: Medium 25. A 51-year-old m an u n dergoing am bulator y h em odialysis for end-stage renal disease had been receiving erythropoietin for n orm och rom ic n orm ocyt ic an em ia. A blood an alysis sh ow ed the follow ing results: red blood cell count 4.4 × 10 6 /m m 3 (n or-

B. Deferoxam in e C. Folic acid D. Ferrous su lfate E. Cyan ocobalam in F.

Er yth ropoiet in


348


A. Er yth ropoiet in

28. A 13-year-old boy su ering from acute lym ph oblast ic leuke-

B. Saqu in avir

m ia w as adm it ted to th e h osp it al for th e th ird cycle of an t i-

C. Cyan ocobalam in

can cer t h erapy, w h ich in clu d ed h igh -dose m et h ot rexate.

D. Filgrast im

W h ich of th e follow ing dr ugs sh ould be given to th e pat ien t

E. Ferrous su lfate

to coun teract m eth ot rexate toxicit y? A. Folic acid B. Cyan ocobalam in

Di cult y level: Medium 30. A 15-year-old girl w as seen at a clin ic because of easy fa-

C. Leucovorin

t igu e, ir r it abilit y, an d d ecreased m en t al aler t n ess over t h e

D. Ferrou s su lfate

p ast m on t h . Th e girl w as a st r ict veget ar ian an d rep or ted

E. Oprelvekin

h eavy m en st r u al p er iod s sin ce h er m en arch e. Per t in en t

F.

lab resu lt s on ad m ission w ere red blood cell cou n t 3.1 ×

Filgrast im

10 6 /m m 3 (n orm al, fem ale 3.5−5.5 × 10 6 /m m 3 ), h em oglobin

Di cult y level: Medium 29. A 39-year-old m ale AIDS pat ien t h as h ad recen t episodes of cytom egaloviru s esoph agit is. Th e m an w as being t reated w ith a zidovu din e, lam ivu din e, efaviren z com bin at ion for

9 g/dL (n orm al, fem ale > 12 g/dL), m ean corp uscu lar volu m e 71 fL (n orm al 80−100 fL), seru m ferrit in 5 ng/m L (n orm al 30−300 ng/m L). W h ich of th e follow ing dr ugs w ou ld be m ost app ropriate for th is p at ien t?

AIDS an d w ith gan ciclovir for cytom egaloviru s prophylaxis.

A. Folic acid

His last blood an alysis revealed th e follow ing: red blood cell


coun t 4.1 × 10 6 /m m 3 (n orm al, m ale 4.3−5.9 × 10 6 /m m 3 ),

C. Iron dext ran

w h ite blood cell coun t 1.5 × 10 3 /m m 3 (n orm al 4.5−11.0 ×

D. Sargram ost im

10 6 /m m 3 ), n eut roph il coun t 250/m m 3 (n orm al 3000−7000/

E. Ferrou s sulfate

m m 3 ). W h ich of th e follow ing dr ugs w ould be appropriate to

F.

Iron sucrose

add to th e pat ien t’s th erapeut ic regim en at th is t im e?

Answers and Explanations: VI-1 Drugs for Bronchospastic Disorders Questions 1−4

• Decreased syn th esis of prost aglan din E2 (PGE2 ), w h ich is an

1. I

en dogen ou s bron ch odilator, ver y im p or tan t in m ain t ain ing

2. E

air w ay paten cy for m ost asth m at ics

3. G

Leukot rien e an t agon ist s such as za rlukast an d m on telukast

4. H

are th e drugs m ost frequen tly used for m ain ten an ce th erapy in pat ien t s w ith asp irin -in duced asth m a.

Learning objective: Describe the m ain therapeutic uses of za rlukast.

on ly in case of severe asth m a th at is resistan t to oth er ph ar-

5. A Leu kot rien e in h ibitors an d an tagon ists h ave dem on st rated

m acoth erapies.

th e im port an t role of leu kot rien es in aspirin -in duced asth m a.

B, D System ic glucocort icoids an d th eop hyllin e are u sed

C, E Th ese drugs are used on ly by in h alat ion .

Som e asth m at ic p at ien t s are ver y sen sit ive to asp irin as w ell doses can cau se p rofou n d bron ch ocon st rict ion , u sh ing, an d

Learning objective: Describe the proposed m olecular m echanisms of the bronchodilating action of theophylline.

abdom in al cram ping. Th e syn drom e is n ot allergic in n at u re

6. B Th e m olecu lar basis for th e an t iasth m at ic act ion of m eth -

bu t seem s to be related to th e in h ibit ion of cyclooxygen ase,

ylxan th in es is st ill u n cer tain . Alth ough th e p rim ar y m ech a-

w h ich m ost likely causes

n ism of th e bron ch odilat ing e ect m ost likely involves th e

• A sh ift of arach idon ic acid m etabolism to th e leu kot rien e

inhibition of phosphodiesterase en zym es, an additional m ech-

p ath w ay; leukot rien es are pow erfu l bron ch ocon st rict ing

anism seem s related to the blockade of adenosine A1 receptors.

agen t s.

Aden osin e acts as both an au tacoid an d a t ran sm it ter w ith

as to all n on steroidal an t iin am m ator y drugs, an d even sm all

Answers and Explanations: VI-1 Drugs for Bronchospastic Disorders 349 m yriad biological actions, including bronchoconstriction, m ainly in pat ien t s w ith bron ch ospast ic disease. A, C−F Th eop hyllin e d oes n ot block th ese receptors.

Learning objective: List the m ain condition that can increase the clearance of theophylline. 10. D Th e clearan ce of th eophyllin e can be a ected by m any con dit ion s; som e decrease th e clearan ce, an d som e in crease

Learning objective: Describe the interaction bet ween β 2 adrenoceptor agonists and glucocorticoids in the treatment of asthma.

it . Factors t h at can in crease clearan ce are sm oking, an d

7. D System ic cor t icosteroids are given in cases of severe asth m a

system , su ch as barbit u rates an d r ifam p in . Th eop hyllin e

exacerbat ion for t w o m ain reason s: • Th ey im p rove th e respon siven ess of β 2 receptors. • Th ey in h ibit m any p h ases of th e in am m ator y resp on ses. Th e an t iin am m ator y act ivit y of cort icosteroids is delayed for 4 to 6 h ou rs after adm in ist rat ion . How ever, th e restorat ion of respon siven ess to en dogen ou s catech olam in es, as w ell as to exogen ous β 2 agon ists, occu rs w ith in 1 h ou r of glu cocort icoid

con com it an t t reat m en t w ith drugs th at in du ce th e P-450 clearan ce is also h igh er in ch ildren th an in adu lt s. A, B Th ese factors act u ally can decrease, n ot in crease, th e clearan ce of th eophyllin e. C, E Th ese drugs do n ot a ect th eophyllin e clearan ce.

Learning objective: Describe the mechanism of the improvement of the ventilation/perfusion ratio by albuterol.

adm in ist rat ion in severe ch ron ic asth m at ics. Th is restorat ion

11. C In severe bron ch osp ast ic disorders, th e ven t ilat ion /p erfu -

is th erefore the m ain poten t ial ben e t of in t raven ous adm in-

sion rat io is decreased becau se th e n arrow ing of bron ch ial

ist rat ion of cor t icosteroids to a pat ien t w ith severe asth m a

lum en decreases ven t ilat ion . By dilat ing th e bron ch ial m u s-

exacerbat ion un der t reat m en t w ith β 2 agon ists.

cu lat u re, β 2 agon ist s su ch as albu terol in crease ven t ilat ion ,

A−C, E Cort icosteroids do n ot h ave these e ects.

th us in creasing th e rat io. A h igh rat io in creases th e part ial pressu re of oxygen , w h ich in t u rn decreases cyan osis an d

Learning objective: Describe the proposed molecular mechanisms of the bronchodilating action of theophylline. 8. A Th e m olecular basis for m ethylxan th in e act ion s is st ill u n cer t ain , but th e bron ch odilat ing act ion seem s to be prim arily due to inh ibition of ph osphodiesterase en zym es, m ain ly ph osph odiesterase 4 (PDE4 ). Th e in h ibit ion causes a rise in th e in tracellular cyclic adenosine m onophosphate (cAMP) and cyclic gu an osin e m on oph osph ate (cGMP) con cen t rat ion s, w h ich in t u rn leads to sm ooth m u scle relaxat ion . B Met hylxan t h in es st im u late, n ot in h ibit , catech olam in e release from adren ergic term in als. C, D Methylxan th in es do n ot cause th ese e ect s. E See correct an sw er explan at ion .

dysp n ea. A, E Bet a-2 agon ist s can h ave th ese act ion s, bu t th ey are n ot th e cau se of t h e ben e cial e ect of albu terol in t h is pat ien t . B Becau se act ivat ion of β 2 receptors cau ses vasod ilat ion , albuterol act u ally in creases, n ot decreases, pulm on ar y perfu sion . D Albuterol-in duced vasodilat ion can decrease pulm on ar y arter y pressure, but th is w ou ld decrease, n ot in crease, th e ven t ilat ion /perfusion rat io.

Learning objective: Describe the proposed m echanism s of antiasthmatic action of theophylline. 12. E Th e an t iasth m at ic act ion of th eop hyllin e seem s to resu lt

Learning objective: Describe the m ain action m ediating the therapeutic e ect of theophylline in apnea of preterm infants. 9. C Methylxan th in es, speci cally th eophyllin e an d ca ein e, are w idely accepted as th e in it ial ph arm acological approach for t h e t reat m en t of id iop at h ic ap n ea of p rem at u r it y. Met hylxan t h in es st im u late t h e resp irator y cen ter in t h e m edu lla, in creasing respirator y drive. Th ese cen t ral e ect s m ay be m ediated by aden osin e receptor blockade. Aden osin e is a kn ow n in h ibitor of th e respirator y cen ter, an d m ethylxan th in es are com pet it ive an t agon ist s at aden osin e receptors. A, D Th ese act ion s m ay con t ribu te to th e im p rovem en t of apn eic ep isodes bu t are n ot th e p rim ar y m ech an ism of th e th erap eu t ic e ect of xan th in es in in fan t apn ea. B, E Methylxan th in es cause e ects opposite to th ose listed.

from both bron ch odilat ing an d n on bron ch odilat ing act ion s. The inhibition of phosphodiesterase 4 (PDE4 ) in sm ooth m uscle m ost likely explains the bronchodilating activit y. Proposed n on bron ch odilat ing m ech an ism s involve inh ibit ion of PDE4 in in am m ator y cells, w h ich m ost likely redu ces th e release of in am m ator y cytokin es an d en h an ces h iston e deacet ylat ion (acet ylat ion of h iston e is n eeded for act ivat ion of in am m ator y gen e t ran script ion ). A, B Iprat ropiu m an d salm eterol are bron ch od ilators bu t are devoid of an t iin am m ator y act ion s. C, D Zileuton an d za rlukast h ave an t iin am m ator y act ion s bu t are devoid of bron ch odilat ing act ivit y.

350


Learning objective: Describe the m ain adverse e ect s of theophylline.

Learning objective: Explain the mechanism of action of ro umilast.

13. D Methylxan th in es st im u late gast ric secret ion , w h ich can

bron ch ial sm oot h m u scle t h at h as been ap p roved by t h e

explain the abdom inal discom fort that frequently occurs after

U.S. Food an d Drug Adm in ist rat ion for ch ron ic obst ruct ive

th e adm in ist rat ion of th eop hyllin e. Th e e ect on gast ric se-

p ulm on ar y disease. In h ibit ion of ph osp h odiesterase resu lts

cret ion is m ost likely du e to th eop hyllin e-in du ced in h ibit ion

in h igh er con cen t rat ion s of in t racellu lar cyclic aden osin e

of ph osph odiesterase, w h ich in t urn in creases in t racellular

m on op h osp h ate (cAMP). In com parison to th eop hyllin e, ro-

cyclic aden osin e m on oph osph ate (cAMP), th us cau sing an

um ilast h as low er overdose toxicit y an d less poten t ial for

act ivat ion of H+/K+ ATPase. A−C, E Th eophyllin e causes e ect s opposite to th ose listed.

17. C Ro u m ilast is a select ive p h osp h od iesterase 4 in h ibitor in

d rug−drug in teract ion s. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Explain the likely cause of arrhythm ia in an asthmatic patient under albuterol therapy.

Learning objective: Describe the e ects of albuterol on pulm onary function testing in asthmatics.

14. E Th e pat ien t’s severe asth m a m ost likely caused hypoxem ia,

18. E Albu terol is a β 2 agon ist cu r ren t ly u sed as a bron ch odila-

w h ich by itself can predispose to arrhyth m ias. Moreover, th e

tor in t reat ing asth m a. By dilat ing th e bron ch ial t ree, all

p at ien t w as likely receiving a h igh dose of β agon ist s, as th e

bron ch odilators can in crease th e forced exp irator y volu m e

in creased dyspn ea prom pted h im to in crease th e n um ber of

in 1 secon d (FEV1 ). Th e FEV1 is th e m ost u sefu l param eter in

p u s t aken daily. Tachycardia is a com m on adverse e ect of

diagn osing an d m on itoring p at ien t s w ith obst ru ct ive p u l-

β 2 agon ist s, likely d u e to act ivat ion of β 2 receptors in t h e

m on ar y disease.

h ear t , as w ell as to re ex e ect s th at stem from β 2 receptor− m ediated vasodilat ion . A, B, D Iprat ropiu m an d glu cocor t icoids ver y seldom cau se system ic e ect s w h en t aken by th e in h aled rou te. C Du oden al ulcer is n ot a risk factor for arrhyth m ias.

A Tot al lu ng cap acit y (TLC) is t h e am ou n t of air in t h e lu ngs after m a xim u m in at ion . TLC is n or m al or in creased in obst r uct ive disorders. Bronch odilators do n ot sign i can tly a ect TLC. B Peak expirator y ow (PEF) is th e h igh est forced respirator y ow m easu red by a p eak ow m eter. PEF is d ecreased

Learning objective: Describe the interaction bet ween erythromycin and theophylline.

in obst ruct ive respirator y disorders. All bron ch odilators in -

15. D Er yth rom ycin h as been reported to in h ibit th e cytoch rom e

C Forced vit al capacit y (FVC) is th e m axim um am ou n t of

P-450-m ed iated m etabolism of several drugs, in clu ding th e-

air forcibly expired after m axim um in spirat ion . FVC is n or-

ophyllin e. Because th eophyllin e h as a n arrow th erapeut ic

m al or decreased in obst ruct ive respirator y disorders. All

in dex, it is appropriate to decrease th e dosage of th e drug for

bron ch odilators can in crease, n ot decrease, FVC.

th e du rat ion of th e er yth rom ycin th erapy to avoid overdose

D Residual volum e (RV) can be expressed as

crease, n ot decrease, PEF.

RV = TLC − FVC

toxicit y. A−C, E Becau se th e pat ien t’s asth m a is w ell con t rolled, th ere is n o n eed to ch ange th e th erap eu t ic regim en .

RV is n orm al or in creased in obst ru ct ive resp irator y disorders. All bron ch odilators decrease, n ot in crease, RV.

Learning objective: Describe the m ain adverse e ect s of theophylline.

Learning objective: Describe the m ain therapeutic uses of theophylline.

16. E Th e sign s an d sym ptom s of th e p at ien t suggest th eophyl-

19. B Ch eyn e−Stokes breath ing, w h ich occurs in various disease

lin e overdose toxicit y. Methylxan th in e overdose can cause

states, including follow ing stroke, is a t ype of periodic breath -

n ausea an d vom it ing (likely due to st im ulat ion of th e ch e-

ing in w h ich p er iod s of hyp er p n ea alter n ates w it h p er iod s

m oreceptor t rigger zon e), h eadach e, t rem or, n er vou sn ess,

of apn ea. Methylxan th in es su ch as th eop hyllin e an d ca ein e

t in n it u s (likely du e to st im u lat ion of m any areas of th e cen -

h ave been sh ow n to im prove Ch eyn e−Stokes respirat ion ,

t ral n er vou s system ), an d tachycardia (likely du e to in creased

p robably becau se of th eir st im u lan t e ect on th e resp irator y

cyclic aden osin e m on oph osph ate [cAMP] an d blockade of

cen ter.

aden osin e receptors). A−D Th ese drugs do n ot cause th e e ect s from w h ich th e p at ien t w as su ering.

A Neost igm in e act u ally can w orsen u rge in con t in en ce, becau se it in creases u rin ar y blad der con t ract ilit y. C−F Th ese drugs h ave n o e ect on Ch eyn e−Stokes breath ing, urge urin ar y in con t in en ce, or lim b sp ast icit y.

Answers and Explanations: VI-1 Drugs for Bronchospastic Disorders 351 Learning objective: Explain the therapeutic uses of om alizum ab.

Learning objective: Describe the therapeutic uses of salm eterol.

20. E Om alizum ab is a m on oclon al an t i−im m un oglobu lin E (IgE)

23. C Forced expirator y volu m e (FEV1 ) is on e of th e best in dica-

an t ibody th at bin ds to free IgE in th e seru m , p reven t ing

tors of th e severit y of a bron ch ospast ic disorder. FEV1 be-

bin ding of IgE to h igh -a

n it y receptors on m ast cells, block-

t w een 60 an d 80%of th e predicted valu e in dicates m oderate

ing in it iat ion of th e allergic in am m ator y cascade. Om ali-

disease. Because th e p at ien t’s sym ptom s occu rred daily, h er

zu m ab is e ect ive in redu cing asth m a exacerbat ion s an d th e

asth m a can be classi ed as m oderate p ersisten t . Th e pre-

in h aled an d oral dose requirem en t for glucocor t icoids in pa-

ferred t reat m en t for m oderate persisten t asth m a is a low to

t ien t s w ith severe asth m a. It is ad m in istered su bcu tan eou sly

m ediu m d ose of in h aled cor t icosteroids an d a long-act ing

ever y 2 to 3 w eeks. Poten t ially serious adverse e ects in -

inhaled β 2 agonist such as salm eterol daily, plus a short-acting

clude an aphylaxis, w h ich can occur after any dose, even if

in h aled β 2 agon ist su ch as albu terol, as n eeded .

p reviou s doses h ad been w ell tolerated, an d m ay occur as long as 1 day after adm in ist rat ion . A, B Th e p at ien t is already receiving a β agon ist an d a glu-

A Th eophyllin e is ver y rarely used today for th e th erapy of asth m a. B Th is drug, used in th e past , is n ow obsolete.

cocor t icoid, so th e addit ion of oth er drugs w ith th e sam e

D Bet a-blockers are con t rain dicated in asth m at ics.

m ech an ism of act ion w ou ld be irrat ion al.

E Aspirin is relat ively con t rain dicated in asth m at ics.

C, D, F Th ese drugs are usually m in im ally e ect ive in se-

Learning objective: Describe the m ain therapeutic actions of albuterol in bronchospastic disorders.

vere asth m a.

Learning objective: Calculate the loading dose of theophylline, given su cient data.

24. B A pat ien t w h o is ar t i cially ven t ilated can n ot clear bron -

21. A Th e load ing dose of a dr ug given in t raven ou sly can be cal-

p erform ed . Bet a-2 agon ist drugs im prove m u cociliar y clear-

cu lated as follow s:

ch ial secret ion s, m ain ly because e ect ive cough can n ot be an ce an d are th erefore often given to p at ien t s on ar t i cial

LD = Vd × Cp , w h ere LD = load ing d ose, Vd = volu m e of d ist r ibu t ion , an d Cp = plasm a con cen t rat ion . Because th eophyllin e does n ot dist ribu te in to adip ose t issue, th e id eal body w eigh t (70 kg) can be u sed to calcu late th e LD. Th erefore, LD = 0.5 × 70 × 15 = 525 m g B−E See correct an sw er explan at ion .

ven t ilat ion to decrease air w ay resistan ce an d to rem ove secret ion s from bron ch ial m u cosa. A Ep in ep h r in e, by act ivat ing β 2 receptors, can im p rove m u cociliar y clearan ce bu t w ou ld cau se several adverse effect s in th is pat ien t due to its cardiovascular act ion s. C Iprat ropium h as bron ch odilat ing act ivit y but does n ot im prove m u cociliar y clearan ce, alth ough , un like oth er an t icholinergic drugs, it does not reduce bronchial secretions and th erefore does n ot a ect m u cociliar y clearan ce.

Learning objective: Describe the m ain adverse e ect s of β 2 agonist s.

D−F Cort icosteroids an d leukot rien e path w ay in h ibitors h ave n o e ect on m u cociliar y clearan ce.

22. E Bet a-2 agon ists p rom ote th e u ptake of p ot assiu m in to th e drugs can cau se hypokalem ia, an d th ese drugs are som e-

Learning objective: Explain the m olecular m echanism of action of ipratropium .

t im es u sed in th e th erapy of hyperkalem ic st ates. In th is

25. B Iprat ropium is an an t im uscarin ic drug. By blocking M 3

case, hypokalem ia is even m ore likely becau se of th e earlier

acet ylcholine receptors in the bronchial tree, these drugs pre-

t reat m en t w ith in su lin (in su lin ten ds to cau se hypokalem ia,

ven t th e in creased syn th esis of in ositol t riph osph ate, w h ich

as it prom otes potassium en t r y into cells).

in t urn t riggers th e release of Ca 2+ from storage vesicles.

cells, likely by st im ulat ing Na +/K+ ATPase. High doses of th ese

A Both hyperten sion an d hypoten sion can be adverse effect s of albuterol, but in th is patien t , hypoten sion is m ore likely du e to th e hyp okalem ia. B−D Bet a-2 agon ist s ten d to cause e ects opposite to th ose listed.

A, C, D Th ese drugs do n ot block m u scarin ic receptors. E Like iprat ropium , at ropin e can block M 3 acet ylch olin e receptors in th e bron ch ial t ree, th us coun teract ing th e acet ylch olin e-m ediated in crease in Ca 2+ availabilit y. How ever, an t ich olin ergics (except iprat ropium an d t iot ropiu m ) are usually con t rain dicated in bron ch ospast ic disorders becau se they decrease bronchial secretion and m ucociliar y clearance.


352

Learning objective: Describe the m echanism of action of ipratropium.

ch odilator, bu t it h as th e poten t ial to cause m ore adverse


e ect s, m ay in terfere w ith sleep , an d is less e ect ive th an

m ost likely su er in g from ch ron ic obst r u ct ive p u lm on ar y d isease (COPD). Ip rat rop iu m is a

rst -lin e agen t in COPD

B Oral su stain ed-release th eophyllin e is an e ect ive bron -

iprat rop ium . D See correct an sw er explan at ion .

becau se its act ion in th ese p at ien t s is equ al or su p erior to am m on iu m an t im u scar in ic d r ug. Un like ter t iar y am in es,

Learning objective: Explain the m echanism of the antiasthm atic action of uticasone.

qu atern ar y am m on iu m an t im uscarin ic drugs m ain ly block

28. C Curren t th erapeut ic st rategies available for th e t reat m en t

m uscarin ic receptors but also h ave a sign i can t blocking ac-

of asth m a in clude in h ibit ion of eicosan oid biosyn th esis (glu-

t ivit y on n icot in ic Nn receptors. Th erefore, in h aled ip rat ro-

cocor t icoids), in h ibit ion of leukot rien e biosyn th esis (zileu -

piu m can block both M 3 receptors on bron ch ial sm ooth

ton ), act ivat ion of β 2 receptors (β 2 agon ist s), an d blockad e

m u scle an d Nn receptors located in sm all p arasym p ath et ic

of leu kot rien e receptors (za rlu kast). Th e glu cocor t icoid-

ganglia w ith in th e bron ch ial t ree. Both act ion s can con t rib -

in duced in h ibit ion of eicosan oid biosyn th esis is m ediated by

u te to th e n al bron ch odilat ing e ect of th e dr ug.

th e in h ibit ion of ph osp h olipase A2 , th e en zym e th at releases

t h at ach ieved by β 2 agon ist s. Ip rat rop iu m is a qu ater n ar y

A Th is act ivat ion w ould cause bron ch ocon st rict ion , n ot bron ch odilat ion . B Th is is a m ech an ism of act ion of glucocor t icoids. Th ese

arach idon ic acid from m em bran e-bou n d ph osph olipids. A Th is w ou ld be th e m ech an ism of act ion of iprat ropium . B Th is w ould be th e m ech an ism of act ion of za rlukast .

drugs are n ot bron ch odilators, an d th ey are used on ly in pa-

D, E Th ese receptors are n ot involved in bron ch odilat ion .

t ien t s w ith advan ced COPD an d frequ en t exacerbat ion s.

F Act ivat ion (n ot in h ibit ion ) of lip ocor t in biosyn t h esis

C Th is is th e m ech an ism of act ion of β 2 agon ists. Th ese drugs are con t rain dicated in th is pat ien t because of th e h is-

m ediates th e glu cocor t icoid-in du ced in h ibit ion of p h osp h olip ase A2 .

tor y of ven t ricular tachycardia. Pat ien t s w ho h ave sur vived an ep isode of su stain ed ven t ricu lar tachycardia or ven t ricu lar

brillat ion h ave an ext raord in arily h igh risk of exp eri-

en cing a recu rren t arrhyth m ia. E Leu kot r ien e receptor blockers are n ot bron ch od ilators an d are n ot u sed in COPD.

Learning objective: Describe the m ain adverse e ects of inhaled glucocorticoids. 29. C Local adverse e ect s of in h aled glucocor t icoids in clude cough , dysph on ia, an d oral can didiasis. Candida albicans is a fu ngal organ ism th at is a n orm al con st it u en t of oral ora, bu t it can cau se in fect ion w h en cellu lar im m u n it y is com -

Learning objective: Describe the bronchodilating use of ipratropium when β 2 adrenoceptor agonist s are contraindicated.

p rom ised du e to cor t icosteroids.

27. C Accepted gu id elin es for th e t reat m en t of asth m a in dicate a

glu cocort icoids bu t are ext rem ely rare w ith in h aled glu co-

sh ort-act ing β 2 agon ist as n eeded in all p at ien t s. In th is case,

A, B, D−F All of th ese adverse e ect s can occu r w ith oral cor t icoids.

h ow ever, th e pat ien t’s at rial brillat ion con t rain dicates th e lat ion , on ly 10 to 20% of th e dose can reach th e target site of

Learning objective: Describe the use of oral glucocorticoids in bronchospastic disorders.

act ion (low er air w ays); th e rest is sw allow ed an d can be ab -

30. A Oral steroid s are u su ally ad m in istered to t reat severe

sorbed by th e in test in e, cau sing system ic e ects. Iprat ro-

asth m a th at is n ot con t rolled by oth er an t iasth m at ic dr ugs.

piu m is an e ect ive bron ch odilator agen t , an d th e sw allow ed

Cort icosteroids h ave p oten t an t iin am m ator y act ivit y, an d

dose is n ot absorbed by th e in test in e (th e d rug is a qu ater-

alth ough th ey are n ot direct bron ch od ilators, th ey can re-

n ar y am m on ium com poun d). Moreover, in th is pat ien t

lieve bron ch ial obst ru ct ion by im proving th e resp on siven ess

• Th e bron ch osp asm w as t riggered by em ot ion al u pset , an d

of β 2 receptors to β 2 agon ist s.

use of β 2 agon ists. In gen eral, w h en d rugs are given by in h a-

it h as been sh ow n th at in h aled an t ich olin ergic drugs can

A Iprat ropium is not adm in istered by th e oral route.

block th is resp on se.

C Om alizu m ab is a m on oclon al an t i−im m u n oglobu lin E

• The nocturnal aw akening indicates that the bronchospasm is t riggered by a p revalen ce of th e p arasym path et ic sys-

(IgE) an t ibody approved for th e t reat m en t of allergic asth m a. It is n ot given by in halat ion .

tem (w h ich is predom in an t during th e n igh t), so an an t i-

D Th eophyllin e is n ot given by in h alat ion .

m uscarin ic drug is appropriate.

E Because a leukot rien e an t agon ist (za rlukast) w as n ot

A, E Th ese drugs are n ot bron ch od ilators an d can n ot be used for relief of bron ch osp asm .

e ect ive, it is u n likely th at an in h ibitor of leu kot rien e syn th esis (zileuton ) w ould be e ect ive.

Answers and Explanations: VI-1 Drugs for Bronchospastic Disorders 353 Learning objective: Choose the right drug for the therapy of m ild seasonal asthm a.

Learning objective: Explain the m echanism of action of dornase alfa.

31. A In h aled sh or t-act ing β 2 agon ists are con sidered

rst-lin e

33. C Th e prin cipal sou rce of DNA in th e sput um of cyst ic bro-

d r ugs for t h e t reat m en t of ast h m a. Accord ing to cu r ren t

sis p at ien t s is from th e n u clei of degen erat ing n eu t rop h ils

gu id elin es, a sh or t -act ing β 2 agon ist sh ou ld be given as

th at accu m u late in th e lu ng becau se of ch ron ic bacterial in -

n eeded to all pat ien t s w ith asth m a. Because th e pat ien t’s

fect ion s. DNA is th e prin cipal factor th at in creases th e vis-

asth m a is m ild, in h aled albuterol as n eeded is m ost likely th e

cosit y of th e spu t um in th ese pat ien ts. Dorn ase alfa is a

preferred drug.

recom bin an t h um an deoxyribon uclease th at is adm in istered

B Oral steroids are adm in istered on ly in case of severe asth m a th at is n ot con t rolled by oth er an t iasth m at ic drugs C Ip rat rop iu m alon e is n ot u sed for t h e t reat m en t of asth m a. It can be used w ith albu terol in severely ill pat ien t s

by in h alat ion . It degrades th e DNA, w h ich h as been sh ow n to sign i can tly decrease th e viscosit y of th e sp u t u m , th u s reducing obstruction and the severit y of respiratory infections. A, B, D, E See correct an sw er exp lan at ion .

w h ere it h as been sh ow n to im prove pulm on ar y fun ct ion . D Za rlu kast is an an t iin am m ator y, n ot a bron ch odilating, drug. Th erefore, it is n ever u sed alon e to t reat asth m a.

Learning objective: Identify the appropriate drug to treat cough in an asthmatic patient.

E Salm eterol is a long-acting β 2 agonist. Monotherapy treat-

34. C Op ioids are am ong th e m ost e ect ive drugs available for

m en t of asth m a w ith long-act ing β 2 agon ists is con t rain di-

th e su p p ression of cough . Th eir act ion is prim arily d u e to th e

cated becau se it w as fou n d th at th is th erapy in creases th e

d epression of th e respirator y n eu ron s in th e brain stem , but

risk of asthm a-related events (i.e., asthm a-related hospitali-

th e receptors involved in th e an t it u ssive e ect app ear to dif-

zation, asthm a-related int ubation , an d asth m a-related death).

fer from th ose associated w ith oth er act ion s of opioids. For

A black box w arn ing about m on oth erapy is required by th e

exam ple, dext rom eth orph an , a stereoisom er of a levorph a-

U.S. Food an d Drug Adm in ist rat ion . How ever, com bin at ion

n ol derivat ive, h as lost th e an algesic, sedat ive, an d addict ive

produ cts con t ain ing a long-act ing β 2 agon ist w ith an in h aled

p ropert ies of th e p aren t com pou n d bu t is an e ect ive cough

steroid can ret ain cu r ren t in d icat ion s, in clu d in g ast h m a, as

su p p ressan t w it h p oten cy n early equ al to th at of cod ein e.

an in creased r isk of ast h m a-related com p licat ion s w as n ot

Th e drug can be an ap p rop riate cough su p pressan t in asth -

dem on st rated w ith th is com bin at ion.

m at ic p at ien t s. A Codein e is th e m ost com m on ly used cough suppressan t

Learning objective: Choose the appropriate drug as a substitute for za rlukast when this drug has caused a disturbing adverse e ect.

bu t is n ot in dicated in asth m at ic p at ien t s becau se op ioids

32. B Th e p at ien t im p roved w h en za rlu kast w as added to th e

w ith dext rom eth orph an .

t h erapy, bu t t h e d r ug cau sed a d ist u rbin g adverse e ect . W h en a drug is e ect ive but causes an adverse e ect , a good th erap eu t ic st rategy is to ch ange th e d rug w ith an oth er th at h as a sim ilar e ect bu t di eren t ch em ical st ruct ure. Zileu ton is a lipoxygen ase in h ibitor. Its

n al e ect is sim ilar to th at

can cau se resp irator y depression even w h en given in su b an algesic doses. Th is resp irator y dep ression d oes n ot occu r B, D Th eophyllin e an d iprat ropium are n ot u sed as an t it u ssives. E Dornase alfa is a m ucolytic drug. Mucolytics can help the expectorat ion but can n ot depress th e respirator y n eu ron s. F St rong opioids are n ot used as an t it ussives.

of za rlu kast (i.e., to decrease leukot rien e act ivit y), but it s m ech an ism of act ion is di eren t . Th e clin ical u se of zileu ton DRUGS FOR BRONCHOSPASTIC DISORDERS Answ er key

is lim ited due to th e poten t ial for elevated liver en zym es an d liver inju r y, an d im m ed iate-release t ablet s w ere d iscon t in u ed in t h e Un ited St ates. Exten d ed -release t ablet s are st ill available an d can be u sed in sp eci c cases, as in th is on e. A Th e pat ien t w as already using salm eterol. Th ere is n o n eed to add an in h aled β 2 agon ist . C Th eophyllin e is n ot used by in h alat ion . D Om alizum ab is given on ly in cases of severe refractor y asth m a. E Mon telukast is close ch em ically to za rlu kast an d h as th e sam e m ech an ism of act ion . Th erefore, th e risk of h eadach e w ould be sign i can t in th is pat ien t .

1. 2. 3. 4. 5.

I E G H A

6. 7. 8. 9. 10.

B D A C D

11. 12. 13. 14. 15.

C E D E D

16. 17. 18. 19. 20.

E C E B E

21. 22. 23. 24. 25.

A E C B B

26. 27. 28. 29. 30. 31. 32. 33. 34.

D C C C A A B C C

354


Answers and Explanations: VI-2 Drugs for Gastrointestinal Disorders Questions 1−8 1. K

Learning objective: Identify the site of antiem etic action of ondansetron.

2. P

11. A Seroton ergic an t agon ist s su ch as on dan set ron are cu r-

3. N

ren tly con sidered to be

rst-lin e agen ts for preven t ion of

4. Q

ch em oth erapy-in duced n ausea an d vom it ing. On dan set ron

5. O

an d congen ers block 5-HT3 seroton in receptors located in

6. E

th e n ucleus t ract us solitarius (likely th e m ain site of act ion ),

7. F

ch em oreceptor t r igger zon e, an d visceral a eren t n er ves.

8. H

In t h is w ay, it is t h ough t t h at t h ey can p reven t both periph eral an d cen t ral st im u lat ion of th e vom it ing cen ter.

Learning objective: Explain why m any antacid preparations on the market contain a combination of magnesium hydroxide and aluminum hydroxide.


9. E Because m agn esiu m hydroxide ten ds to cause diarrh ea,

Learning objective: Explain the m echanism of action of m ethylcellulose.

and alum inum hydroxide tends to cause constipation, a com -

12. E Methylcellu lose is an in digest ible hydrop h ilic p olysacch a-

bin at ion of th e t w o can h ave a balan ced e ect on in test in al

ride p olym er th at absorbs w ater, form ing a bu lky gel th at

m ot ilit y w ith ou t any loss of an t acid e ect iven ess.

d isten ds th e in test in e, th u s st im ulat ing peristalt ic act ivit y. It

A An tacid preparat ion s h ave n o bactericidal e ect on Helicobacter pylori. B Overdose toxicit y is ext rem ely rare because in test in al

act s m ain ly in th e colon an d takes 1 or 2 days to w ork. Th e laxat ive e ect is m ild. A−D All of these laxatives act m ainly in the sm all intestine.

absorpt ion of th ese drugs is n egligible. con com itan tly is un com m on an d is m ain ly due to th e in -

Learning objective: Outline the use of lactulose in portal-system ic encephalopathy.

crease of th e p H of in test in al con ten t s, n ot to th e speci c salt

13. B Elim in at ing toxic en teric produ cts (m ain ly fecal am m on ia)

C In teract ion s bet w een an t acids an d oth er drugs given

u sed as an an tacid.

is a t h erap eu t ic goal in p or t al-system ic en cep h alop at hy.

D Because m agn esiu m hydroxide ten ds to in crease gast ric

Pat ien t s w ith severe liver disease h ave an im paired capacit y

em pt ying, an d alu m in u m hydroxide ten d s to do th e opp o-

to detoxify am m on ia com ing from th e colon , w h ere it is pro-

site, th e com bin at ion act u ally h as lit tle e ect on gast ric

d uced by bacterial m et abolism of fecal urea. Am m on ia is an

em pt ying.

im port an t cau se of brain toxicit y. Lact ulose, in h igh doses, can low er colon ic p H, w h ich resu lts in “t rapp ing” of th e am -

Learning objective: Outline the use of H2 antagonists in stressinduced peptic ulcer. 10. F Acute st ress-related m ucosal bleeding is a t ype of erosive

m on ia by it s conversion to p olar am m on iu m ion , w h ich is p oorly absorbed. A, C−F See correct an sw er explan at ion .

gast rit is th at occu rs in crit ically ill p at ien t s w ith severe p syw as in sept ic sh ock, an d h er abdom in al pain suggested th at

Learning objective: Describe the e ects of alum inum hydroxide on serum ions.

st ress-related m u cosal bleeding w as im pen ding. Th erefore,

14. E Alum in u m salt s bin d ph osph ate in th e gut , preven t ing

sh e n eeded aggressive prophylact ic t reat m en t . H2 an t ago-

p h osph ate absorpt ion . Moreover, th ey can in du ce a blood-

n ists are th e m ost w idely used drugs for preven t ion of st ress

to-gu t p h osp h or u s gradien t t h at favors t h e elim in at ion of

u lcer. Th ey m u st be given in t raven ou sly, an d in fu sion is

circu lat in g p h osp h ate. In fact , ch ron ic u se of h igh d oses of

m ore e ect ive th an a single bolus in m ain tain ing the gast ric

alu m in u m salt s is on e of t h e com m on cau ses of hyp op h os-

pH above 4. Alth ough p roton p u m p in h ibitors (n ot listed)

p h atem ia. Th e disorder is u su ally asym ptom at ic, bu t severe

w ou ld app ear to be th e preferred opt ion becau se of th eir

p h osph oru s deplet ion can cause an orexia, m uscle w eakn ess,

greater abilit y to in h ibit gast ric acid secret ion , th ere is ver y

an d osteom alacia.

ch ological st ress (su rger y, t rau m a, sepsis, etc.). Th e p at ien t

lit tle eviden ce to con rm th e clin ical su p eriorit y to H2 an t agon ist s for st ress u lcer p reven t ion . A, B Th ese drugs h ave n o an t iu lcer prop er t ies. C−E Th ese an t iulcer drugs are m uch less e ect ive th an H2 an tagon ist s an d are n ot suited for em ergen cy t reat m en t .

A−D Alu m in um salts usually do n ot cause th is e ect .

Answers and Explanations: VI-2 Drugs for Gastrointestinal Disorders 355 Learning objective: Explain the molecular mechanism of the antidiarrheal action of loperam ide.

n idazole is som et im es used in

15. E Loperam ide is an opioid agon ist th at directly act ivates m u

t ien t s w ith abscesses, bu t am ikacin is n ot e ect ive again st

(µ) receptors in th e en teric n er vous system . Th is act ivat ion

D An t ibiot ics h ave n o role in rem ission in duct ion . Met rost ulizing disease or in pa-

an aerobes, th e prevalen t bacteria in in test in al ora.

of en teric n euron s an d sm ooth m uscle ult im ately causes a d ecrease in con t ract ion of in test in al longit udin al m u scle an d

Learning objective: Explain the m echanism of action of antacids.

a m arked in crease in con t ract ion of circu lar m u scle. Th ere-

19. C An t acids are salts of sodiu m , calciu m , m agn esiu m , an d/or

fore, p rop u lsive p er ist alt ic w aves are d im in ish ed , an d ton e

alu m in u m . Th ey react w it h t h e hyd roch lor ic acid of t h e

is in creased, th us relieving diarrh ea.

stom ach to for m ch lor id es, w ater, an d carbon d ioxid e. In

A−D, F Loperam ide can n ot bin d th ese receptors.

t h is w ay, th ey n eu t ralize gast ric acidit y an d raise th e gast roin test in al pH su

cien tly to relieve th e pain of h ear tbu rn .

Learning objective: Explain why the dose of H2 histamine antagonists must be reduced in patients with renal insu ciency

secret ion of hydroch loric acid an d pep sin is st im u lated, n ot

16. D Th e h igh creat in in e level in dicates th at th e pat ien t w as

in h ibited .

su ering from ch ron ic ren al in su

cien cy. Fam ot idin e is an

H2 h istam in e an t agon ist . All drugs of th is class are cleared

A Becau se an t acids n eu t ralize gast r ic acid , t h e gast r ic

B, D, E An t acids do n ot cause th ese e ects.

m ain ly by th e kidn ey. Alth ough th e overdose toxicit y of H2

Learning objective: Outline the therapy for ulcerative colitis.

an t agon ist s is qu ite low , t h e d osage sh ou ld be red u ced in

20. E Th e pat ien t’s sym ptom s, togeth er w ith m acroscop ic an d

elderly p at ien ts w ith ren al in su

cien cy, as in th is case.


m icroscop ic

n dings, suggest th at h e w as m ost likely af-

fected by ulcerat ive colit is. Th e lim itat ion of th e lesion s to th e su per cial m u cosa an d cr ypt abscesses con rm th e diag-

Learning objective: Outline the therapeutic uses of bism uth subsalicylate.

n osis (Croh n disease involves all layers of th e bow el from

17. B Th e pat ien t is m ost likely a ected by t ravelers’ diarrh ea,

is u su ally accom p lish ed w ith glu cocort icoids. Th eir e ects

w h ich t yp ically begin s w it h in 24 to 48 h ou rs after eat ing

on in am m ator y bow el disease are well docum ented, but the

fecally con t am in ated food. Several en terobacteriaceae can

respon se in in dividual pat ien t s is variable. About 40% of pa-

cau se t ravelers’ d iarrh ea, var ying according to th e area of

t ien t s are resp on sive, 40% h ave on ly p ar t ial respon se, an d

t ravel. Escherichia coli is th e m ost com m on in Cen t ral Am er-

20% are resist an t .

m u cosa to serosa). Rem ission in du ct ion in u lcerat ive colit is

ica. Bism uth subsalicylate is e ect ive in pat ien t s w ith diar-

A, B An t ibiot ics su ch as m et ron idazole an d clar it h rom y-

rhea caused by E. coli, Helicobacter pylori, Cam pylobacter jejuni,

cin are u sed on ly as adju n ct ive t reat m en t along w ith oth er

an d Salm onella species an d also in h ibits en teric secret ion s.

m edicat ion s.

A Magn esium su lfate is an osm ot ic laxat ive an d th erefore is con t rain dicated in th e t reat m en t of diarrh ea.

C, D Th ese d r ugs are n ot e ect ive an d m ay be dan gerou s in in am m ator y bow el disease.

C, D Th ese an t ibiot ics are n ot e ect ive again st en terobacteriaceae. E, F Th ese drugs h ave n o an t idiarrh eal propert ies.

Learning objective: Identify the receptors that can be blocked by metoclopramide. 21. E Metoclopram ide is a dopam in e D2 receptor an t agon ist , a

Learning objective: Outline the therapeutic use of in ixim ab in Crohn disease.

receptor agon ist . In th e en teric n er vou s system , all of th ese

18. E Treat m en t of m ild colon ic Croh n disease can st art w ith su l-

m olecu lar act ion s seem to con t ribu te to th e n al e ect th at

fasalazin e or glucocor t icoids. If rem ission is n ot ach ieved,

is related to an in creased act ivit y of ch olin ergic m otor n eu -

in ixim ab, azath ioprin e, or m eth ot rexate is added. An im -

ron s. In th is w ay, th e drug exert s a prokin et ic e ect; th at is,

p ort an t proin am m ator y cytokin e in Croh n disease is t u m or

it in creases th e low er esop h ageal sph in cter ton e an d en -

n ecrosis factor (TNF). In ixim ab is a m on oclon al an t ibody

h an ces t ran sit in th e upper digest ive t ract . It h as n egligible

th at bin ds to solu ble an d m em bran e-bou n d TNF w ith h igh

e ect s on gast ric secret ion or m ot ilit y of th e large in test in e.

a

In addit ion , th e blockade of D2 receptors an d 5-HT3 receptors

n it y, th us p reven t ing th e bin ding of th e cytokin e to it s

receptors. A, C To add th ese drugs is irrat ion al, as predn ison e an d su lfasalazin e w ere n ot e ect ive. B Daclizum ab is a m on oclon al an t ibody used on ly for t reat m en t of acu te organ reject ion .

serotonin 5-HT3 receptor an tagon ist, an d a seroton in 5-HT4

in t h e ch em oreceptor t r igger zon e can exp lain t h e an t iem et ic act ivit y of th e dr ug. A−D See correct an sw er explan at ion .

356


Learning objective: Outline the therapeutic uses of proton pump inhibitors. 22. E Th e pat ien t is m ost likely su ering from Zollinger−Ellison

Learning objective: Identify the drug that inhibit s the action of a neurotransmit ter released by enterochroma n-like cells of the stom ach.

syn drom e, a rare con dit ion ch aracterized by a t riad of clin i-

25. D Heartburn is caused by gast roesoph ageal re u x disease

cal n dings, in clu ding severe recu rren t p ept ic u lcer disease,

(GERD). Drugs for h ear tbu rn act by decreasing th e secret ion

sign i can t hypersecret ion of gast ric acid, an d a t u m or of th e

of or n eut ralizing hydroch loric acid in th e stom ach . Th ey in -

p an creas (gast r in om a) t h at fu n ct ion s as an ectop ic sou rce

clude an t acids, H2 an t agon ist s, an d proton p u m p in h ibitors.

of gast rin . Th is t u m or is u su ally located in th e p an creas bu t

H2 an t agon ist s su ch as fam ot id in e block H2 receptors, th u s

can be fou n d in oth er region s, p art icu larly th e du oden u m .

in h ibit ing th e act ion of h istam in e th at is released from en -

Cu rren tly, m ost pat ien ts w ith gast rin om as can be e ect ively

teroch rom a

t reated w ith h igh doses of a d rug su ch as om ep razole th at

n -like cells located on th e stom ach w all.


in h ibit s H+/K+ ATPase in gast ric p arietal cells. A−D Th ese are th e m ech an ism s of act ion of H2 -receptor an tagon ist s (A), m isop rostol (B), su cralfate (C), an d an t acid s (D). All of th ese an t iulcer drugs are less e ect ive th an proton pu m p in h ibitors in redu cing gast ric acid secret ion an d th erefore are n ot rst-lin e agen t s in Zollinger−Ellison syndrom e.

Learning objective: Describe the adverse e ect s of m etoclopram ide. 26. F Metoclopram ide is an an tagon ist of D2 an d 5-HT3 recep tors. Blockade of D2 receptors in th e cen t ral n er vous system can cau se d izzin ess an d d row sin ess, an d blockad e of D2 receptors in th e pit uitar y leads to hyperprolactinem ia, a com -

Learning objective: Describe the drug classes used to treat chem otherapy-induced nausea and vomiting.

m on adverse e ect of m etoclopram ide.

23. A Seroton ergic an t agon ist s are cu r ren t ly con sid ered

disease, bu t th ey do n ot cau se hyperp rolact in em ia.

rst -

A−E Th ese drugs can be used for gast roesoph ageal re u x

lin e agen t s to p reven t ch em ot h erapy-in d u ced n au sea an d tors located in t h e n u cleu s of t h e t ract u s solit ar iu s (likely

Learning objective: Outline the therapeutic use of H2 blockers in gastroesophageal re ux disease (GERD).

t h e m ain site of act ion ), ch em o receptor t rigger zon e, an d

27. A Th e pat ien t w as m ost likely su ering from GERD. Because

visceral a eren t n er ves. In th is w ay, it is th ough t that th ey

th e p at ien t requ ested a m edicat ion to speci cally preven t

can p reven t both p erip h eral an d cen t ral st im u lat ion of th e

m eal-related sym ptom s, H2 an tagon ist s su ch as fam ot idin e

vom it in g. On dan set ron an d con gen ers block 5-HT3 recep -

vom it ing cen ter. B, E Th ese drugs can cau se, n ot p reven t , n au sea an d vom it ing. C, D Th ese drugs h ave an t iem et ic proper t ies but are m u ch

are appropriate. Th eir on set of sym ptom relief occu rs w ith in 30 to 45 m in u tes an d persists u p to 10 h ou rs. Th ey also h ave a bene cial e ect of reducing nocturnal acid secretion, w hich is m ainly histam ine-depen dent. Proton pum p in hibitors (not

less e ect ive th an seroton ergic an t agon ist s in ch em oth era-

listed) h ave an e

py-in du ced n au sea an d vom it ing.

w ith regard to sym ptom relief an d du rat ion of suppression ,

cacy h igh er th an th at of H2 an t agon ist s

bu t th eir on set of act ivit y is slow er (2 to 3 h ou rs), an d com -

Learning objective: Describe the antiemetic activit y of dronabinol. 24. D Dron abin ol is a Δ9- tet rahydrocan n abin ol, th e m ost act ive can n abin oid from can n abis. It s m ech an ism of an t iem et ic

plete relief m ay take u p to 4 days of th erapy. B At rop in e is act u ally con t rain d icated , as it m ay favor re u x by relaxing th e low er esoph ageal sp h in cter.

act ion is st ill u n cer tain , bu t th e drug likely act ivates sp eci c

C−E Th ese drug are of n o value in GERD.

can n abin oid receptors in th e vom it ing cen ter. Becau se of th e

F Th is drug w ou ld be in dicated on ly in case of pept ic ulcer,

availabilit y of m ore e ect ive agen ts, dron abin ol is u n com -

w h ich is un likely in th is pat ien t .

m on ly u sed in pat ients receiving can cer ch em oth erapy, bu t can be a u sefu l addit ion w h en oth er an t iem et ic m edicat ion s are n ot e ect ive, as in th is case. A−C Th ese drugs are devoid of an t iem et ic proper t ies. E It w ould be illogical to add a glucocort icoid drug w h en dexam eth ason e w as n ot e ect ive. F Meclizin e is an ant ih ist am in e agen t u seful in preven t ion

Learning objective: Identify the antacid with the greater risk of metabolic alkalosis. 28. A All an t acid s can cau se m et abolic alkalosis, d u e to t h e spared en d ogen ou s bicarbon ate th at is secreted in th e stom ach u n der p rostaglan din E2 con t rol. In add it ion , exogen ou s bicarbon ate is readily an d com pletely absorbed; th erefore,

of m otion sickness−induced vom iting. Antihistam ines are not

th e risk of m etabolic alkalosis is h igh er th an th at of calcium ,

e ect ive in ch em oth erapy-in du ced vom it ing.

m agn esium , an d alum in um salt s th at h ave an oral bioavailabilit y less th an 30%. B−E See correct an sw er explan at ion .

Answers and Explanations: VI-2 Drugs for Gastrointestinal Disorders 357 Learning objective: Describe the e ects of cimetidine−theophylline interaction.

Learning objective: Explain the e cacy of a triple-drug regim en in the therapy of Helicobacter pylori−associated ulcers.

29. B Th e sym ptom s of t h e p at ien t are m ost likely d u e to t h e-

33. B For H. pylori−associated ulcers, th ere are t w o th erapeut ic

op hyllin e overd ose. Cim et id in e (an d , to a lesser exten t ,

goals: eradicate th e H. pylori an d h eal th e ulcer. Th e rst goal

ran it idin e, bu t n ot oth er H2 blockers) st rongly in h ibit s th e

is im p or tan t becau se it h as been sh ow n th at eradicat ion of

cytoch rom e P-450 system , decreasing th e m et abolism of

H. pylori alm ost com p letely elim in ates th e risk of u lcer re-

several dr ugs, in clu ding th eophyllin e. Becau se th eophyllin e

cu rren ce. Th e m ost e ect ive regim en s for H. pylori eradica-

h as a low th erapeut ic in dex, even a sm all in crease in plasm a

t ion are com bin at ion s of t w o an t ibiot ics an d a p roton p u m p

drug concen tration can cause sym ptom s of overdose toxicit y.

in h ibitor. After com plet ion of t rip le-drug th erapy, th e p ro-


ton pum p in h ibitor sh ould be con t in ued for 3 to 6 w eeks to en su re com p lete u lcer h ealing.

Learning objective: Identify the best laxative for a patient with renal insu ciency.

H. pylori. It on ly creates a h ost ile environ m en t for H. pylori

30. A Lact ulose is a n on absorbable sugar th at is hydrolyzed in

by in creasing gast ric pH.

th e colon to organ ic acids. Th ese acids draw w ater in to th e lu m en by osm ot ic forces, st im u lat ing colon ic p rop u lsive

A, C, D Om ep razole h as n o bactericidal act ivit y again st

E Th e t riple-drug regim en can cure th e u lcer in m ore th an 90%, n ot u p to 70%, of cases.

m ot ilit y by st retch ing th e colon ic w all. Th e laxat ive e ect is B Castor oil is too st rong a cath art ic to be used regu larly.

Learning objective: Describe the adverse e ect s of m etoclopram ide.

C, D Magn esium an d ph osph ate preparat ion s are con t ra-

34. D Th e pat ien t’s sym ptom s suggest th at h e is su ering from

m ild.

cien cy because th e sm all am oun t of

acu te dyston ia, an ext rapyram idal syn drom e th at can occu r

absorbed salt can n ot be readily excreted, th u s cau sing sys-

after t reat m en t w ith n eu rolept ics an d oth er drugs th at block

tem ic toxicit y (hyperm agn esem ia or hyperph osph atem ia).

D2 receptors in th e basal ganglia. You ng pat ien t s, especially

in dicated in ren al in su

E Min eral oil h as several adverse e ect s (in terferen ce w ith

m ales w h o receive th ese d rugs in t raven ou sly, are at greater

absorpt ion of fat-solu ble su bst an ces, elicitat ion of foreign -

risk of th is adverse e ect , as in th is case. Metoclopram ide is

body react ion ) th at p reclu de it s regu lar u se.

a drug w ith an t iem et ic prop er t ies, p robably du e to its blocking act ivit y on bot h D2 an d 5-HT3 receptors located in th e

Learning objective: Describe the best treatment in case of laxativeinduced diarrhea.

ch em oreceptor t rigger zon e an d the n u cleu s of th e t ract u s

31. D W h en diarrh ea is experien ced w ith th e use of laxat ives,

vom it ing.

th e laxat ive sh ou ld be discon t in u ed u n t il resolu t ion of th e d iarrh ea. A diet rich in

ber an d abu n dan t

u id in take usu -

solitariu s. It is often u sed to t reat postop erat ive n au sea an d A−C, E Th ese an t iem et ic d r ugs d o n ot cau se acu te dyston ias.

ally h elps to n orm alize th e in test in e. A Th e sit uat ion is n ot self-lim it ing. Toleran ce to bisacodyl is n egligible. B, C Th ese opt ion s w ou ld m ain t ain t h e d r ug-in d u ced d iarrh ea.

Learning objective: Explain the m echanism of action of saline laxatives. 35. D Salin e laxat ives such as m agn esium salts (cit rate an d hyd roxide) an d ph osph ate salt s are poorly absorbed an d h old

E Castor oil is too st rong a cath ar t ic to be used regularly.

w ater in th e in test in e by osm ot ic forces. Th e in creased volu m e of in test in al con ten t st retch es th e in test in al w all, th us

Learning objective: Explain the m olecular m echanism of action of aprepitant.

st im u lat ing perist alsis.

32. C NK1 n eurokin in receptors are located in th e n ucleus of th e

release.

t ract u s solit ar iu s in t h e brain stem . Act ivat ion of t h ese receptors by su bst an ce P an d related su bst an ces cau ses an in crease in

ring to th e vom it ing cen ter. Ap repit an t is an

NK1 -receptor an t agon ist th at is able to cross th e blood−brain bar r ier. It h as an t iem et ic e ect s, esp ecially in cases of d elayed em esis, an d it im p roves t h e e

cacy of st an dard an t i-

em et ic regim en s in p at ien t s receivin g m u lt ip le cycles of ch em oth erapy. A, B, D, E See correct an sw er exp lan at ion .

A Magn esium salts st im ulate, n ot in h ibit , ch olecystokin in B Th e drug causes w ater reten t ion in th e in test in al lu m en , n ot in th e vessels. C Th is is th e m ech an ism of act ion of m in eral oil. E Th is is th e m ech an ism of act ion of diet ar y bers.

358


Learning objective: Describe the therapeutic uses of loperam ide. 36. A Th e pat ien t’s sym ptom s suggest th at sh e w as m ost likely

A At ropin e is con t rain dicated, because it m ay favor re u x by relaxing th e low er esoph ageal sph in cter.

su ering from irritable bow el syn drom e, a con dit ion th at af-

B, C Th ese drugs are n ot e ect ive in t reat ing GERD.

fect s 10 to 15% of th e populat ion in th e Un ited States. Many

E Metoclopram ide is used in th e t reat m en t of GERD be-

p at ien ts w ith th is syn drom e can be m an aged sat isfactorily

cau se it p rom otes gast ric p erist alsis an d also in creases th e

w ith sim ple m edical coun seling an d su ppor t ive m easures,

low er esoph ageal sph in cter rest ing ton e. How ever, it is con -

in cluding diet ar y rest rict ion an d ber supplem en tat ion . Th e

t rain d icated in p at ien t s w it h Parkin son d isease becau se it

p h arm acological t reat m en t of bow el sym ptom s (eith er d iar-

is a D2 an tagon ist .

rh ea or con st ip at ion ) is sym ptom at ic. In th is case, an an t i-

F H2 an t agon ist s are cu rren tly u sed in GERD, bu t cim et i-

d iarrh eal drug is n eeded . Opioid agon ist s such as lop eram ide

din e is n ot ap p rop riate in a p at ien t t aking oth er drugs be-

an d diph en oxylate are com m on ly u sed. Th ey h ave th e ad-

cau se it can in h ibit th e m et abolism of m ost drugs, in clu ding

van tage of n egligible cen t ral n er vou s system (CNS) act ivit y

selegilin e.

becau se p en et rat ion in to th e CNS is p oor. Oth er drugs u sed for th is purpose are m uscarin ic an d 5-HT3 an t agon ists. B−F Drugs from th ese classes w ould in crease, n ot decrease, bow el m ovem en ts.

Learning objective: Identify the best drug regim en to prevent chemotherapy-induced nausea and vomiting. 40. C According to th e guidelin es for th e use of an t iem et ics in on cology from th e Am erican Societ y of Clin ical On cology,

Learning objective: Explain the mechanism of action of sucralfate.

th e best regim en to p reven t n au sea an d vom it ing in p at ien t s

37. A Su cralfate is a m u cosal protect ive agen t . In a st rong acid

u n dergoing ch em oth erapy is a th ree-drug com bin at ion of a

environ m en t (pH < 4), th e n egat ively ch arged su crose su lfate

5-HT3 receptor an t agon ist , a glu cocor t icoid, an d ap repit an t .

u n dergoes exten sive cross-lin king to posit ively ch arged pro-

Th is com bin at ion p reven t s acu te em esis in 80 to 90% of

tein s to p rod u ce a viscou s, st icky p olym er t h at ad h eres to

p at ien t s an d p reven t s d elayed em esis in m ore th an 70% of

ep it h elial cells an d u lcer craters for u p to 6 h ou rs after a

pat ien ts.

single dose.

A Ben zodiazepin es h ave n o direct an t iem et ic e ect . Th ey

B, E Sucralfate does n ot h ave th ese e ects.

are som et im es added to th e m ain regim en becau se th e an t i-

C, D Sucralfate m ay h ave cytoprotect ive e ects, in clu ding

an xiet y e ect cou ld redu ce th e an t icip ator y com p on en t of

st im u lat ion of local produ ct ion of prost aglan din s, w h ich in t u r n can in h ibit acid secret ion an d st im u late bicarbon ate secret ion , but th is is n ot th e m ain m ech an ism of act ion of th e drug.

n ausea an d vom it ing. Ran it idin e h as n o an t iem et ic e ect . B Ant ich olin ergic drugs su ch as scopolam in e are n ot e ect ive in ch em oth erapy-in d u ced n au sea an d vom it ing. D Loperam ide is n ot an an t iem et ic drug. E These drugs are used in ch em oth erapy-in du ced n ausea

Learning objective: Identify the m ost appropriate laxative used during pregnancy 38. D Up to 30%of w om en exp erien ce con st ip at ion du ring pregn an cy. Laxat ives m ust be used caut iously because th ey can in crease m ot ilit y an d blood ow in th e low er abdom en , an d m ild agen ts are preferred. A stool soften er su ch as docu sate or a bu lk-produ cing product su ch as psylliu m is com m on ly u sed.

an d vom it in g on ly w h en ot h er an t iem et ic d r ugs are n ot e ect ive. F See correct an sw er explan at ion .

Learning objective: Describe the use of dronabinol as an appetite stim ulant in treating AIDS. 41. D Appet ite-en h an cing (also called orexigen ic) drugs are a vast array of m ed icat ion s u sed to p reven t u n desired w eigh t

A−C, E, F St im ulan t cath art ics (castor oil, bisacodyl, an d

loss in th e elderly an d in p at ien t s su ering from su ch dis-

sen n a) an d salin e cath art ics (m agn esiu m hydroxide an d so-

eases as AIDS an d can cer, w h ich often result in w ast ing of

d iu m su lfate) are n ot recom m en ded du ring pregn an cy.

the body’s m uscle tissue, as w ell as overall weight loss. Agents w ith orexigenic e ects include 5-HT2C seroton in receptor an -

Learning objective: Identify the drug used to treat gastroesophageal re ux disease (GERD) in a patient with concomitant disorders. 39. D Th e su bstern al p ain an d re u x of gast ric con ten ts in to th e esoph agu s are classic sym ptom s of GERD, a disorder th at affect s 7% of th e populat ion in th e Un ited St ates. Proton pu m p in h ibitors su ch as om eprazole are e ect ive in th e t reat m en t of GERD, an d a on ce-daily dose for 4 w eeks w ill h eal 60 to 80% of p at ien t s w ith severe esoph agit is.

tagon ists (cyproh ept adin e), adren ergic an tagon ists (car vedilol an d m irt azap in e), an abolic steroids (oxandrolone and nandrolone), glucocorticoids (cortisol, predn ison e, an d dexam eth ason e), an t idiabet ic drugs (In sulin an d gliben clam ide), an d can n abin oids. Dron abin ol, th e m ost act ive can n abin oid of can n abis, h as been sh ow n to st im ulate appet ite in pat ien t s w ith AIDS an d is often u sed for th is p u rpose. A−C, E, F Th ese drugs are devoid of orexigen ic propert ies.

Answers and Explanations: VI-3 Drugs for Hem atopoietic Disorders 359 Learning objective: Identify the prokinetic drug that acts by opening t ype 2 chloride channels in the sm all intestine.

im proved, an d long-term dat a suggest a sustain ed respon se

42. C Lubiproston e is a prokin et ic drug th at acts in th e sm all in -

A, B, D−F Th ese drugs d o n ot a ect in test in al t yp e 2 ch lo-

test in e. Several agen ts, com m on ly called laxat ives, can st im -

over a 6- to 12-m on th t reat m en t p eriod. ride ch an n els.

u late in test in al m ot ilit y in n on speci c or in direct w ays, but t h e ter m prok inet ic gen erally is reser ved for agen t s t h at

DRUGS FOR GASTROINTESTINAL DISORDERS Answ er key

en h an ce in test in al t ran sit th rough in teract ion w ith sp eci c receptors. Lubiproston e is a p rostaglan din E1 derivat ive th at app ears to bin d to prost aglan d in E4 receptors lin ked to act ivat ion of adenylyl cyclase. Th is in t urn can open speci c t ype 2 ch loride ch an n els in th e lu m in al cells of th e in test in al epith elium , in creasing ch loride-rich uid secret ion in to th e in test in e. Clin ically, lubiproston e alters stool con sisten cy an d prom otes regu lar bow el m ovem en t s. Sign s an d sym ptom s related to con st ip at ion , in clu d ing abd om in al bloat ing, ab -

1. 2. 3. 4. 5.

K P N Q O

6. 7. 8. 9. 10.

E F H E F

11. 12. 13. 14. 15.

A E B E E

16. 17. 18. 19. 20.

D B E C E

21. 22. 23. 24. 25.

E E A D D

26. 27. 28. 29. 30.

F A A B A

31. 32. 33. 34. 35.

D C B D D

36. 37. 38. 39. 40. 41. 42.

A A D D C D C

dom in al d iscom for t , stool con sisten cy, an d st rain ing, are

Answers and Explanations: VI-3 Drugs for Hem atopoietic Disorders Questions 1−6

Learning objective: Identify the m ost im portant body iron store.

1. B

9. C Iron n ot used for er yth ropoiesis is stored in t w o storage

2. C

p ools. Th e m ost im p or tan t is ferrit in , a h eterogen eou s fam -

3. A

ily of protein s form ed aroun d an iron core. Ferrit in is fou n d

4. J

in h epatocytes, liver, bon e m arrow, m acroph ages, red blood

5. K

cells, an d serum . Th e pool is ver y labile an d readily available

6. A

to m eet any body requirem en t for iron . Th e secon d storage p ool of iron is h em osiderin , w h ich is located prim arily in th e

Learning objective: Explain the purpose of iron adm inistration. 7. B Th e pat ien t’s h istor y an d lab resu lts in dicate th at h e w as

liver an d bon e m arrow. A, B, D, E See correct an sw er exp lan at ion .

m ost likely su ering from iron de ciency anem ia due to blood case, th e loss w as m ost likely cau sed by n aproxen th erapy; th e

Learning objective: Explain why folic acid is contraindicated in megaloblastic anemias due to vitamin B12 de ciency.

prevalen ce of en d oscop ically con rm ed gast roin test in al u l-

10. A Th e pat ien t’s m egaloblast ic an em ia w as m ost likely du e to

cers in n on steroidal an t iin am m ator y drug u sers is 15 to 30%.

vit am in B12 de cien cy resu lt ing from th e p reviou s tot al gas-

Iron is t h e st an dard t h erapy for iron d e cien cy an em ia, an d

t rectom y. Adm in ist rat ion of folic acid can correct th e an em ia

it act s on ly by replacing th e severely depleted stores of th e

cau sed by vit am in B12 de cien cy bu t does n ot preven t th e

m etal.

poten t ially irreversible n eu rologic dam age cau sed by vita-

loss, w h ich is th e m ost com m on cau se of th e d isease. In th is

A Th ere are n o speci c receptors for iron .

m in B12 de cien cy. In th is p at ien t , t reat m en t w ith folic acid

C−E Iron does n ot cau se th ese e ect s.

w ou ld m ask th e h em atologic sign s of an em ia, th u s in creasing th e risk of n eu rologic sym ptom s du e to u n diagn osed vi-

Learning objective: Identify the risk associated with folic acid de ciency during pregnancy.

t am in B12 de cien cy. B−E See correct an sw er explan at ion .

8. B It h as been sh ow n th at n eural t u be defects are associated w ith folic acid de cien cy du ring pregn an cy. Folate sup ple-

Learning objective: Outline the therapeutic uses of folic acid.

m en tat ion during early pregn an cy m ay substan t ially reduce

11. B Th e p at ien t’s lab valu es in dicate th at sh e w as su ering

t h e r isk of n eu ral t u be d efect s, su ch as sp in a bi da an d

from m egaloblast ic an em ia. Becau se th e seru m vit am in B12

en ceph alocele.

is n orm al, th e an em ia is m ost likely du e to folic acid de -

A, C−F Th e risk of th ese congen it al abn orm alit ies is n ot related to folic acid de cien cy.

cien cy. Th e disorder is n ot rare in a pregn an t w om an w ith m aln u t rit ion an d excessive alcoh ol in t ake, as in th is case. A, C−E See correct an sw er explan at ion .

360


Learning objective: Outline the use of parenteral iron preparation in case of severe iron de ciency anem ia.

p roliferat ing er yth roid cells. Th e com plex is th en in tern al-

12. D Th e pat ien t’s sign s an d sym ptom s, togeth er w ith lab val-

ferrin an d th e receptors are recycled.

u es, in dicate th at sh e w as su ering from severe iron de -

ized by en docytosis, releasing iron w ith in th e cell, an d t ran sA−C, E See correct an sw er explan at ion .

cien cy an em ia, p robably related to ch ron ic blood loss du e to d rugs. Because th e h em oglobin an d ferrit in levels are ver y

Learning objective: Explain the m echanism of antianem ic action of vitam in B12 .

low , p aren teral iron t h erapy is m an dator y. Iron su crose is

15. C Megaloblast ic an em ias (both folate an d vit am in B12 de -

a p rep arat ion given by t h e p aren teral rou te. It ap p ears to

cien cy an em ias) are du e to a decreased availabilit y of tet ra-

be less likely t h an iron d ext ran to cau se hyp ersen sit ivit y

hyd rofolate (THF). Vit am in B1 2 t ran sfers a m et hyl grou p

react ion s.

from N5 -m ethyltet rahydrofolate to h om ocystein e, form ing

m en orrh agia an d overu se of n on steroidal an t iin am m ator y


m eth ion in e an d THF. In vit am in B12 de cien cy, N5 -m ethyltet rahydrofolate accum ulates w ith associated deplet ion of

Learning objective: Explain the m echanism of action of folic acid.

THF (m ethylfolate t rap p ing). Th e adm in ist rat ion of vit am in

13. B Th e pat ien t’s sym ptom s an d lab exam s in dicate th at h e

B12 restores th e dem ethylation of N5 -m ethyltetrahydrofolate,

w as m ost likely su ering from m egaloblast ic an em ia. Th e n orm al serum vit am in B12 levels suggest th at th e an em ia is

th us correct ing th e m egaloblast ic anem ia. A Th is form at ion is an oth er ch em ical react ion cat alyzed

du e to folic acid de cien cy, w h ich can occur in p eople su f-

by vit am in B12 , bu t th e react ion is n ot n eeded for th e syn th e-

fering from m alabsorpt ion syn drom es, as in th is case (see

sis of THF.

glu ten en terop athy). Adm in ist rat ion of folic acid can cu re

B, D, E Th ese react ion s are n ot cat alyzed by vitam in B12 .

th e an em ia becau se folic acid is n eeded for th e syn th esis of be t ran sform ed in to several THF cofactors th at par t icipate

Learning objective: Describe the therapeutic uses of ferrous sulfate.

in m any on e-carbon un it t ran sfer react ion s. Th e react ion

16. F Th e p at ien t’s sym ptom s an d lab resu lts in d icate th at sh e

n eeded for purin e an d DNA syn th esis t ran sfers on e carbon

w as su ering from m icrocyt ic an em ia, m ost likely secon d-

u n it of N5 -N10 -m ethylen etet rahydrofolate to deoxyuridin e

ar y to iron de cien cy du e to total gast rectom y. Rem oval of

m on op h osp h ate to form thym idin e 5′-m on oph osph ate. In

t h e stom ach lead s to m arked d ecrease in t h e p rod u ct ion

rapidly proliferat ing t issu es, con siderable am oun t s of THF

of gast ric acid, w h ich is n ecessar y to conver t dietar y iron to

are con su m ed in th e react ion , an d con t in u ed DNA syn th esis

a form th at is readily absorbed by th e d u oden u m . Iron de -

requ ires con t inued regen erat ion of THF. Th erefore, in folate

cien cy an em ia does n ot occu r for a few years after gast rec-

de cien cy, thym idin e 5′-m on oph osph ate form at ion is de-

tom y because iron is stored in m oderately large am oun t s in

creased, w h ich in t u rn decreases th e syn th esis of DNA. RNA

bon e m arrow. W h en an em ia is cau sed by iron de cien cy,

syn th esis con t in u es, resu lt ing in in creased cytop lasm ic m ass

oral iron supplem en tat ion is appropriate.

an d m at u rat ion . Th erefore, cytop lasm ic m at u rit y is greater


tet rahydrofolate acid (THF). Th is m olecu le can subsequen tly

th an n uclear m at u rit y, an d m egaloblast s are produ ced in th e bon e m arrow. A Th is is an act ion of vitam in B12 in th e t reat m en t of vit am in B12 de cien cy, w h ich w as n ot th e case in th is pat ien t . C This is an action of ferrous sulfate in the treatm ent of iron de ciency an em ia, w h ich w as n ot th e case in th is p at ien t .

Learning objective: Outline the therapeutic uses of vitam in B12 . 17. E Th e p at ien t’s sign s an d sym ptom s are classic for p ern iciou s an em ia. Th e disease occu rs equ ally in both gen ders, w ith an average on set of age 60. Th e an em ia is cau sed by vit am in B12 m alabsorpt ion d u e to severe at rophy of th e gast ric glan ds

D Th e pat ien t’s an em ia w as n ot caused by h em olysis.

w it h loss of p ar iet al cells an d in abilit y to secrete in t r in sic

E Th e pat ien t’s an em ia w as n ot cau sed by er yth ropoiet in

factor. Th e cau se of t h e d isease is u n kn ow n , bu t several

de ciency

n d ings p oin t to an im m u n ologic or in h erited basis of th e disease. Approxim ately 90% of pat ien ts h ave an t ibodies to

Learning objective: Describe the transport of iron to m aturing erythroid cells.

pariet al cells, an d 2 to 10% of relat ives of th ese pat ien t s ex-

14. D Iron is t ran sp or ted in p lasm a bou n d to t ran sferrin , a β

be given daily to replenish tissue stores, and a m onthly m ain-

globulin th at speci cally binds ferric iron. The com plex bin ds to a sp eci c receptor located on er yt h roblast s an d ot h er

h ibit sim ilar an t ibodies. Paren teral cyan ocobalam in sh ould ten an ce dose sh ould be given for life. A−D See correct an sw er explan at ion .

Answers and Explanations: VI-3 Drugs for Hem atopoietic Disorders 361 Learning objective: Describe the intestinal absorption of iron. cells by t w o m ech an ism s: act ive t ran sp or t of fer rou s iron

Learning objective: Identify the myeloid growth factor that can stim ulate proliferation and di erentiation of neutrophil progenitor cells only.

by a carrier n am ed divalen t m et al t ran spor ter 1 (DMT1) an d

22. B Bon e m arrow t ran splan t at ion is associated w ith profoun d

18. D Iron crosses th e lu m in al m em bran e of duoden al m ucosal

absorpt ion of iron com p lexed w ith h em e. Becau se th e pat ien t received ferrous sulfate, th e drug w as act ively t ran sported by DMT1. A−C, E See correct an sw er explan at ion .

gran ulocytopen ia due to th e m yeloablat ive preparat ive regim en . Filgrast im is a h u m an gran u locyte colony-st im u lat ing factor th at st im u lates th e product ion of gran ulocyte progen itor cells. Th erefore, once engraftm en t occurs, h em atopoietic recover y can be accelerated.

Learning objective: Outline the appropriate therapeutic treatment in case of m ixed anem ia.


m ost likely su ering from a m ixed an em ia, du e to both iron

Learning objective: Identify the m ain location of oprelvekin receptors.

an d folate de cien cy. Th e com bin at ion of both m acro- an d

23. E Op relvekin is th e recom bin an t form of in terleu kin -11. Th e

m icrocyt ic red blood cells o set each ot h er to p rod u ce a

d r ug act ivates sp eci c receptors located on m egakar yo -

n or m al m ean corpu scu lar volum e. Th ere are m any exam ples

cytes an d m egakar yocyte progen itors, th us st im u lat ing th e

of sit uat ion s in w h ich m ixed an em ia occurs, in cluding preg-

p roduct ion of p latelet s. It is u sed clin ically to p reven t severe

n an cy, as both iron an d folate requirem en ts in crease du ring

chem otherapy-induced throm bocytopenia and to reduce the

gestat ion . W h en an em ia is both m icrocyt ic an d m egaloblas-

n eed for platelet t ran sfusion s follow ing ch em oth erapy for

t ic, t reat m en t w ith iron an d folic acid is in dicated.

n on m yeloid m align an cies.

19. C Th e pat ien t’s blood values in dicate th at th e w om an w as

A, B Vit am in B12 precursors are n ot n eeded because blood


con cen t rat ion of vitam in B12 is n orm al D, E See correct an sw er explan at ion .

Learning objective: Describe the anaphylactoid reaction to iron dextran.

Learning objective: Outline the therapeutic uses of deferoxamine.

24. C Th e sign s an d sym ptom s of th e pat ien t in dicate th at sh e

20. F In th alassem ic ch ildren w ith severe an em ia, blood t ran sfu -

w as m ost likely su er in g from an an ap hylactoid react ion ,

sion s are n ecessar y to m ain tain life an d n orm al act ivit y. To

w h ich is a rare bu t p oten t ially fat al adverse e ect of iron

p reven t iron overloading as a resu lt of repeated blood t ran s-

d ext ran t h erapy. Ot h er p aren teral p rep arat ion s, su ch as so -

fu sion s, deferoxam in e is often given du ring th e t ran sfu sion .

d iu m fer r ic glu con ate an d iron su crose, ap p ear to cau se

Th e drug can rem ove iron from h em osiderin , ferrit in , an d

few er hypersen sit ivit y react ion s th an iron dext ran an d are

t ran sferrin , bu t n ot iron from h em oglobin an d cytoch rom es.

n ow p referred for paren teral iron th erapy.

Th erefore, th e drug can elim in ate iron excess w ith ou t a ecting h em oglobin form at ion . A−E See correct an sw er explan at ion .

A, D Leu covorin an d cyan ocobalam in do n ot cau se an ap hylactoid react ion s an d are n ot u sed to t reat m icrocyt ic an em ia. B Ferrou s sulfate is given on ly by th e oral route.

Learning objective: Outline the therapeutic treatm ent for hypoproliferative anem ia due to renal insu ciency

E, F Filgrast im an d sargram ost im can cause an aphylactoid react ion s, but th ey are n ot used to t reat m icrocyt ic an em ia.

21. B Th e p at ien t’s lab resu lt s in dicate th at h e w as m ost likely su ering from a hyp op roliferat ive an em ia du e to ren al in su f-

Learning objective: Describe the adverse e ects of erythropoietin.

cien cy. An em ia u su ally occurs w h en creat in in e clearan ce is

25. A Th e m ost com m on adverse e ect s of er yth rop oiet in are

less th an 45 m L/m in (w h ich corresp on ds rough ly to serum

hypertension and throm botic com plications. The m echanism

creat in in e > 3 m g/dL in a n orm al m an over age 70). W h en

of th e th rom bot ic e ect is st ill un cer tain but is likely related

an em ia is d u e to ren al d isease, er yt h rop oiet in is t h e t reat -

to an excessive in crease of h em oglobin levels. Recen tly, th e

m en t of ch oice. Iron su p p lem en t s m u st also be given to

U.S. Food an d Dr ug Ad m in ist rat ion issu ed a w ar n ing t h at

ach ieve an adequ ate er yth ropoiet in respon se.

patients w ith renal failure or can cer w hose hem oglobin rises


to m ore th an 12 g/dL are at greater risk of th rom bot ic even ts, as in th is case. B−E See correct an sw er explan at ion .

362


Learning objective: Outline the therapeutic uses of oprelvekin

step in tetrahydrofolate syn th esis, th us rescuing norm al cells

26. F Th e patien t’s lab results indicate severe th rom bocytopenia,

w h ile can cer cells are less a ected.

likely du e to cytotoxic an t ican cer ch em oth erapy. Oprelvekin ,

A Folic acid is u seless in t h is sit u at ion becau se it can n ot

th e recom bin an t form of in terleu kin -11, h as been app roved

be t ran sfor m ed to THF d u e to t h e d ihyd rofolate red u ct ase

for t reat m en t of severe th rom bocytopen ia due to ch em o-

in h ibit ion . B, D−F See correct an sw er explan at ion .

th erapy for n on m yeloid m align an cies. A Filgrast im is h u m an gran u locyte colony-st im ulat ing factor th at st im ulates th e product ion of gran ulocyte progen itor

Learning objective: Outline the therapeutic uses of lgrastim .

cells. Th e n orm al n eu t roph il coun t in dicates th at th ere is n o

29. D Th e p at ien t’s lab resu lt s in dicate a p rofou n d n eu t ropen ia,

gran ulocytopen ia.

w h ich can occur in AIDS pat ien t s t aking zidovudin e. Filgras-

B Er yth rop oiet in is given w h en th e an em ia is hypoprolif-

t im is recom bin an t h u m an gran u locyte colony-st im u lat ing

erat ive (i.e., du e to a de cien t respon se to cytokin e h u m oral

factor t h at st im u lates p roliferat ion an d d i eren t iat ion of

st im u li). Th ere is n o eviden ce th at th e pat ien t’s an em ia is

p rogen itors already com m it ted to n eu t roph il lin eage. It h as

hyp op roliferat ive.

been sh ow n th at zidovu din e-in du ced n eu t ropen ia can be

C−E Th ese d rugs are used for m egaloblast ic an em ias. Th e n orm al m ean corpuscular volum e indicates that the patient’s

p ar t ially or com pletely reversed by lgrast im t reat m en t . A−C, E See correct an sw er explan at ion .

an em ia is n ot m egaloblast ic.

Learning objective: Describe the therapeutic uses of ferrous sulfate. Learning objective: Identify the drug used to treat iron poisoning.

30. E Th e p at ien t’s lab resu lts in dicate th at sh e w as su ering

27. B Th e large h em atem esis an d th e pregn an cy of th e m oth er

from m icrocyt ic an em ia, m ost likely du e to iron de cien cy

suggest th e p ossible ingest ion of iron t ablet s. Th e sign s an d

(see th e vegetarian diet an d h eavy m en st rual periods). Oral

sym ptom s of th e p at ien t are in d icat ive of

rst-st age acu te

iron sh ould correct th e an em ia rapidly an d com pletely an d

iron poison ing. As few as 10 to 12 pren at al m ult ivit am in

th erefore is th e preferred star t ing th erapy. Paren teral iron

w ith iron tablet s can cause serious illn ess in a young ch ild.

adm in ist rat ion (iron dext ran or iron su crose) w ou ld m ost

Deferoxam in e is an iron -ch elat ing com pou n d th at can bin d

likely also be e ect ive, bu t sh ould be u sed on ly w h en clearly

iron th at h as already been absorbed. Th e iron −deferoxam in e

in dicated, th at is, w h en th e an em ia is ver y severe, or w h en

com plex is n ot toxic an d is excreted by th e kidn ey.

oral th erapy fails.

Deferoxam in e th erapy sh ould be prom ptly in it iated w h en


severe sym ptom s of iron toxicit y are p rom in en t , as in th is case. DRUGS FOR HEMATOPOIETIC DISORDERS Answ er key


Learning objective: Outline the therapeutic uses of leucovorin. 28. C Meth ot rexate in h ibits dihydrofolate redu ct ase, preven t ing th e form at ion of tet rahydrofolate (THF), an essen t ial factor for DNA syn th esis. Th e blockade of th is syn th esis in can cer cells m ediates th e th erapeut ic act ion of th e dr ug, but th e blockade of th e syn th esis in n orm al cells cau ses m eth ot rexate toxicit y. Leucovorin bypasses th e dihydrofolate reductase

1. 2. 3. 4. 5.

B C A J K

6. 7. 8. 9. 10.

A B B C A

11. 12. 13. 14. 15.

B D B D C

16. 17. 18. 19. 20.

F E D C F

21. 22. 23. 24. 25.

B B E C A

26. 27. 28. 29. 30.

F B C D E

VII Inf am m ation and Im m unom odulation Questions: VII-1 Histam ine and Serotonin: Agonists and Antagonists Directions for questions 1−3


Match each h ist am in e an d seroton in receptor agon ist an d an t ag-

5. A 46-year-old w om an recently diagnosed w ith classic m igraine

on ist w ith th e appropriate descript ion (each let tered opt ion can

h ad a h eadach e at t ack at least on ce a w eek. Ergotam in e w as

be selected on ce, m ore th an on ce, or n ot at all).

prescribed to p reven t th e im pen ding at t acks. W h ich of th e

A. Cyproh ept adin e

follow ing act ion s m ost likely con t ributed to th e th erapeut ic

B. Ergon ovin e

e ect of th e drug in th e p at ien t’s disorder?

C. Lorat adin e

A. Con st rict ion of cerebral vessels

D. On dan set ron

B. Ext ravasat ion of plasm a in to perivascular space

E. Prom eth azin e

C. Prost aglan din release from vascular en doth eliu m

F.

D. Platelet aggregat ion in th e cerebral vascu lar bed

Su m at ript an

E. In creased ring of t rigem in al n euron s

Di cult y level: Easy 1. An an t ih istam in e drug w ith pron oun ced sedat ive propert ies

Di cult y level: Easy 6. A 30-year-old m an presen ted to th e clin ic w ith a 2-m on th


h istor y of righ t-side h ead pain recurring on a w eekly basis.

2. A h istam in e an d seroton in receptor an t agon ist som et im es

His h eadach es w ere u su ally preceded by u n form ed ash es of

u sed for t reat m en t of in test in al hyperm obilit y of carcin oid

ligh t , bilaterally, an d w ere associated w ith n ausea, vom it ing, an d ph otoph obia. Th e h eadach es w ere n ot relieved by aspirin

Di cult y level: Easy 3. This drug can act as an agonist at serotonergic and α -adrenergic receptors.

Di cult y level: Medium 4. A 64-year-old m an su ering from ben ign prost at ic hyperplasia p resen ted to h is p hysician com p lain ing of gen eralized itch ing. Th e p roblem began 1 w eek earlier, after an aftern oon of prolonged su n exposure. Th e pat ien t reported th at th e itch ing w as dist ressing, esp ecially du ring th e n igh t . Physical exam in at ion sh ow ed an en larged prost ate an d n o oth er eviden ce of ongoing disease. W h ich of th e follow ing drugs w ould be appropriate for th is pat ien t? A. Cyproh ept adin e B. Diph en hydram in e C. Fam ot idin e D. Lorat adin e E. Acetam in op h en F.

Ibuprofen

or ibuprofen an d usually lasted all day un less h e w as able to sleep . A d r ug act ing on w h ich of t h e follow ing receptors w ou ld be m ost ap prop riate to stop th e m igrain e at t ack in th is pat ien t? A. Beta-2 adren ergic B. GABAergic C. M 1 ch olin ergic D. 5-HT1B/1D seroton ergic E. Alph a-2 adren ergic F.

D1 dopam in ergic

Di cult y level: Easy 7. A 34-year-old w om an u n der w en t m agn et ic reson an ce im aging (MRI) to invest igate an acou st ic n eurin om a. Becau se th e w om an h ad h ad a m ild allergic react ion to con t rast m ed ia in th e past , sh e w as given a prescript ion for drugs to be t aken before th e MRI. W h ich of th e follow ing d rugs sh ou ld be in cluded in th at prescript ion ? A. Fludrocort ison e B. Fam ot idin e C. Za rlu kast D. Diph en hydram in e E. On dan set ron F.

Brom ocript in e

363

364

In am m ation and Imm unomodulation

Di cult y level: Easy 8. A 30-year-old prim ipara w om an h ad visible vagin al bleed-

su bcu t an eou s adm in ist rat ion of a d rug to block an im pen d ing acu te at t ack. W h ich of th e follow ing drugs m ost likely

ing w ith in a few h ours after delivering her baby. Uterin e m as-


sage an d in fu sion of oxytocin did n ot con t rol th e bleeding.

A. Ibuprofen

Up on exam in at ion , it w as felt th at th e h em orrh age w as du e

B. Propran olol

to uterin e atony. An in t ram uscu lar inject ion of ergon ovin e

C. Su m at ript an

w as given . W h ich of th e follow ing act ion s m ost likely m edi-

D. Valproic acid

ated th e th erap eut ic e ect of th e drug in th is pat ien t?


A. Select ive con st rict ion of u terin e ar teries

F.

Aspirin

B. En doth elin release in th e uterin e vascular bed C. Platelet aggregat ion in th e u terin e vascu lar bed


D. Act ivat ion of coagu lat ion cascad e in u terin e cap illaries

12. A 25-year-old m an su er in g from h ay fever st ar ted t reat -

E. In du ct ion of pow erfu l uterin e con t ract ure

m en t w it h an over-t h e-cou n ter an t ih ist am in e p rep arat ion . W h ich of th e follow ing st atem en ts best explain s th e m olec-

Di cult y level: Easy 9. A 24-year-old w om an experien ced severe m ot ion sickn ess

u lar m ech an ism of act ion of th e prescribed dr ug to t reat th is p at ien t’s h ay fever?

w h en ever sh e t raveled by air or sea. Diph en hydram in e taken

A. Reversible bin ding to H3 receptors

before a t rip w as e ect ive in m in im izing h er sym ptom s. Th e

B. Irreversible bin ding to H3 receptors

th erap eu t ic e ect of th e drug w as m ost likely du e to block-

C. Reversible bin ding to H2 receptors

ade of w h ich of th e follow ing p airs of cen t ral receptors?

D. Irreversible bin ding to H2 receptors

A. Dopam in ergic an d β-adren ergic

E. Reversible bin ding to H1 receptors

B. GABAergic an d seroton ergic

F.

Irreversible bin ding to H1 receptors

C. Alph a-adren ergic an d m uscarin ic D. Histam in ergic an d m u scarin ic


E. Seroton ergic an d p ept idergic

13. A 34-year-old m an presen ted to h is physician com plain ing of dr y m outh , con st ipat ion , an d di cult y in urin at ion . He


also n ot iced an in crease in ap p et ite. Th e m an h ad st ar ted a

10. A 33-year-old w om an w as h ospit alized after 1 w eek of in -

th erapy w ith cyp roh ept adin e 2 w eeks earlier to t reat cold-

creasing p ain , ten dern ess, an d cyan osis in h er legs. Sh e ad -

induced urticaria. Drug-induced blockade of w hich of the fol-

m it ted to t aking several m edicat ion s to relieve a m igrain e

low ing p airs of receptors m ost likely m ed iated th e pat ien t’s

h eadache. Physical exam ination revealed that no pulses could

sym ptom s?

be p alpated below th e fem oral vessels, an d an aortogram

A. Dopam in ergic an d α 1 -adren ergic

sh ow ed a pron oun ced con st rict ion of th e vessels distal to th e

B. H2 -h ist am in ergic an d m uscarin ic

iliac ar teries. Th e vasocon st rict ion disappeared after 3 h ours

C. H2 -h ist am in ergic an d α 1 -adren ergic

of n it roprusside in t raven ous in fusion . W h ich of th e follow -

D. Seroton ergic an d GABAergic

ing drugs m ost likely caused th e vessel con st rict ion ?

E. Mu scarin ic an d seroton ergic

A. Aspirin

F.

Dopam in ergic an d GABAergic

B. Propran olol C. Ergotam in e

Di cult y level: Medium.


14. A 43-year-old m an w ith a long h istor y of exer t ion al angin a

E. Naproxen

w as recen t ly d iagn osed w it h m igrain e. W h ich of t h e fol-

F.

low ing an t im igrain e drugs w ould be con t rain dicated in th is

Diclofen ac

p at ien t?


A. Aspirin

11. A 33-year-old m an com plain ed to h is physician th at th e dr ug


h e w as t aking m ade h im feel t igh t n ess in h is ch est an d th roat

C. Su m at ript an

soon after th e inject ion . Th e m an , recen tly diagn osed w ith

D. Ibuprofen

classic m igrain e, h ad st ar ted a t reat m en t th at in cluded th e

E. Propran olol

Questions: VII-1 Histam ine and Serotonin: Agonists and Antagonists 365 Di cult y level: Easy

A. Ibuprofen

15. A 40-year-old w om an su ering from chronic classic m igraine

B. Valproic acid

h eadach es took th ree sublingual t ablets of ergotam in e to

C. Ergotam in e

abor t an im p en ding m igrain e at tack. W h ich of th e follow ing

D. Propran olol

adverse e ects w ere m ost likely to occu r in th is pat ien t?

E. Acetam in op h en

A. Visual h allucin at ion s B. Post ural hypoten sion C. Facial u sh ing D. Adyn am ic ileu s E. Nausea an d vom it ing

F.

Aspirin

Di cult y level: Easy 19. A 59-year-old m an w ith a body m ass in dex of 42 an d a long h istor y of poorly con t rolled hyperten sion w as recen tly diagn osed w ith m igraine headaches. W hich of the follow ing anti-


m igrain e drugs w ou ld be con t rain dicated in th is p at ien t?

16. A 48-year-old w om an su ering from allergic urt icaria started

A. Aspirin

a t reat m en t w ith lorat adin e. Th e decreased syn th esis of


w h ich of th e follow ing substan ces m ost likely m ediated th e

C. Ergotam in e


D. Ibuprofen

A. Cyclic aden osin e m on oph osph ate (cAMP) B. Cyclic guan osin e m on oph osph ate (cGMP) C. In ositol t riph osph ate D. Cyclooxygen ase-1 E. Cyclooxygen ase-2

E. Propran olol F.

Verapam il

Di cult y level: Medium 20. A 29-year-old w om an su ering from allergic rh in it is st arted t reat m en t w ith lorat adin e. Th e dr ug can com p letely cou n ter-

Di cult y level: Easy 17. A 10-year-old boy developed prurit u s an d skin w h eals after

act th e h istam in e-in du ced release of w h ich of th e follow ing en dogen ou s com p ou n ds?

eat ing fried eggs. He w as diagn osed w ith food allergy, an d

A. Pepsin

lorat adin e w as p rescribed. W h ich of th e follow ing st ate-

B. Gast ric acid

m en ts best exp lain s w hy lorat adin e is u sed in several aller-

C. Cyclic aden osin e m on oph osph ate (cAMP)

gic disorders?

D. Nit ric oxide

A. It blocks th e an t igen -in duced release of h ist am in e from m ast cells. B. It preven ts th e an t igen −an t ibody react ion on th e surface of m ast cells. C. It elicit s e ect s t h at are op p osite to t h ose elicited by h istam in e. D. It blocks m uscarin ic an d adren ergic receptors in sm ooth m uscle. E. It preven t s m any h ist am in e-in duced e ects in periph eral t issu es.

E. Bradykin in

Di cult y level: Hard 21. A 47-year-old m an presen ted to th e clin ic com plain ing of a recen t on set of repeat ing episodes of ver t igo associated w ith n ausea and vom iting. The pat ient w as other w ise h ealthy an d d en ied u se of alcoh ol or illicit drugs. Physical exam in at ion w as u n rem arkable, bu t a p rovocat ive test elicited severe ver t igo. A d iagn osis w as m ade, an d a ph arm acoth erapy w as p rescribed. W h ich of th e follow ing d rugs w ould be app rop riate for th is p at ien t?


A. Diph en hydram in e

18. A 33-year-old w om an com plained to her physician of num b-

B. On dan set ron

n ess and tingling in h er ngers and toes. The w om an had been

C. Dron abin ol

taking a drug for 1 m on th to abort h eadach e. W h ich of th e

D. Ergotam in e

follow ing drugs m ost likely caused the patient’s sym ptom s?

E. Lorat adin e F.

Propran olol

366




22. A 43-year-old w om an com plain ed to h er physician of an n oy-


ing dayt im e sleepin ess. Th e w om an , w h o w as t reated in th e

p ar t m en t becau se of fever (103.1°F, 39.5°C), ush ing, sw eat-

p ast w ith several drugs for gen eralized an xiet y, h ad been

ing, t rem ors, an d altered con sciou sn ess. Medical h istor y

receiving diazepam for th e past m on th . On e w eek ago, sh e

in dicated th at sh e h ad been su ering from dep ression for 8

star ted taking an over-th e-cou n ter p rep arat ion for season al

years, cu rren tly t reated w ith paroxet in e, an d for in som n ia,

allergic rh in it is. W h ich of th e follow ing d r ugs m ost likely

cu rren tly t reated w ith zolpidem . Th e p at ien t also reported

p recipitated th e pat ien t’s dayt im e sleepin ess?

th at 24 h ou rs earlier, sh e h ad self-adm in istered th ree t ablets

A. Lorat adin e

of a drug given to h er by a frien d to t reat a severe h eadach e.

B. Predn ison e

Fu r th er exam s con rm ed th e p relim in ar y diagn osis, an d an

C. Diph en hydram in e

app ropriate t reat m en t w as st ar ted. W h ich of th e follow ing

D. Zolpidem

d rugs m ost likely t riggered th e pat ien t’s disorder?

E. Trazodon e


F.

B. Su m at ript an

Mir tazapin e

C. Ibuprofen


D. Zolp idem

23. A 53-year-old m an presen ted to th e clin ic com plain ing of

E. Cyproh ept adin e

itch ing, ush ing, ar th ralgia, h eartburn , an d diarrh ea. Fur th er

F.

Diclofen ac

exam s led to th e diagn osis of system ic m astocytosis. W h ich of th e follow ing pairs of drugs sh ou ld be in cluded in th e


th erap eu t ic t reat m en t of th is pat ien t?

27. A 48-year-old m an h ad a long h istor y of classic m igrain e th at

A. Aspirin an d ergotam in e

w as recen t ly w ell con t rolled by su m at r ipt an . W h ich of t h e

B. Misop rostol an d ergot am in e

follow in g p ar t s of t h e cen t ral n er vou s system w as m ost

C. Lorat adin e an d fam ot idin e

likely a prim ar y site of th erap eu t ic act ion of th e drug in th e

D. Lorat adin e an d diph en hydram in e


E. Aspirin an d fam ot idin e

A. Nucleu s accum ben s B. Trigem in al n er ve


C. Vest ibular n uclei

24. A 28-year-old w om an w h o w as 26 w eeks’ pregnant h ad been

D. Ch em oreceptor t rigger zon e

recen tly diagn osed w ith classic m igrain e. W h ich of th e fol-

E. Olfactor y n er ve

low ing drugs w ou ld be appropriate to reduce th e frequ en cy

F.

Nucleu s caudalis

an d severit y of h er m igrain e at t acks? A. Ergon ovin e


B. Propran olol


C. Ergotam in e

w ith h igh body tem perat u re (104 °F, 40°C), u sh ed an d dr y

D. Valproic acid

skin , an d w idely dilated p u pils u n resp on sive to ligh t . He w as

E. Su m at ript an

agit ated an d un der w en t a brief ton ic-clon ic convu lsion . His m ot h er st ated t h at t h e boy ap p aren t ly sw allow ed several

Di cult y level: Medium 25. A 66-year-old m an su ering from benign prostatic hyperpla-

t ablet s of h er allergy m ed icat ion . W h ich of t h e follow in g drugs m ost likely cau sed th e pat ien t’s p oison ing?

sia w as adm it ted to the hospital because of severe suprapubic

A. Ibuprofen

p ain an d an in abilit y to pass urin e for th e past 24 h ou rs. On

B. Diph en hydram in e

qu est ion ing, h e said h e h ad been t aking diph en hydram in e

C. Ph enyleph rin e

for a few days to relieve itch ing. W h ich of th e follow ing ac-

D. Celecoxib

t ion s m ost likely m ediated th e adverse e ect of th e drug in

E. Lorat adin e

th is p at ien t?

F.

A. Relaxat ion of th e det ru sor m u scle B. Con st rict ion of th e bladder extern al sp h in cter C. Con st rict ion of th e p rost ate capsu le

At ropin e

Di cult y level: Medium 29. A 54-year-old m an at a sch eduled oph th alm ic ch eck-up w as

D. Relaxat ion of th e blad der in tern al sph in cter

fou n d to h ave in creased in t raocular pressure. Th e m an h ad

E. In creased diu resis

been su ering from open -angle glau com a for 2 years, bu t u p

Questions: VII-2 Eicosanoids: Agonists, Antagonist s, and Inhibitors 367 u n t il t h e cu r ren t visit , t h e d isease w as fou n d to be w ell

A. Negligible e ect s on p u pil size an d accom m odat ion

con t rolled by local t reat m en t w it h t im olol an d lat an op rost .

B. Negligible pen et rat ion in to th e cen t ral n er vou s system

Drugs taken recently by the patient included over-the-counter

C. High er dilat ing act ivit y on conju n ct ival vessels

preparation s for episodic h eadache, heartburn, and in som n ia.

D. High er an t ibacter ial act ivit y again st conju n ct ival in -

W h ich of th e follow ing drugs could h ave caused th e pat ien t’s in creased in t raocular p ressure?

fect ion s E. High er blocking act ivit y on lacrim al glan d secret ion

A. Acetam in op h en B. Om eprazole


C. Ibuprofen

31. An 8-year-old girl w as d iagn osed w it h season al allergic

D. Diph en hydram in e

conju n ct ivit is t riggered by exp osu re to airborn e p ollen . Sh e

E. Fam ot idin e

star ted a top ical th erapy w ith crom olyn sodiu m . W h ich of th e follow ing act ion s m ost likely m ed iated th e th erapeu t ic


e ect iven ess of crom olyn in th is p at ien t?

30. A 21-year-old w om an su ering from season al allergic con -

A. Blockade of H1 receptors

jun ct ivit is st arted a t reat m en t w ith eye drops of azelast in e,

B. Blockade of m ediator release from m ast cells

a secon d-gen erat ion h istam in e H 1 an t agon ist . Secon d-gen -

C. In h ibit ion of prostaglan din biosyn th esis

erat ion H1 an t agon ist s are used locally in th e conju n ct iva

D. Blockade of leukot rien e receptors

in stead of rst-gen erat ion H1 an t agon ists to p rovide w h ich

E. Con st rict ion of conju n ct ival vessels

of th e follow ing th erapeut ic advan t ages?

Questions: VII-2 Eicosanoids: Agonists, Antagonists, and Inhibitors Directions for questions 1−5


Match each drug act ing on th e eicosan oid p ath w ay w ith th e ap -

6. A 48-year-old m an w ith open -angle glaucom a st ill h ad ele-

propriate d escript ion (each let tered opt ion can be selected on ce,

vated in t raocular pressu re despite 1 m on th of t reat m en t w ith

m ore th an on ce, or n ot at all).

tim olol an d dorzolam ide. Th e oph th alm ologist decided to add

A. Alprost adil

lat an op rost to th e th erapeu t ic regim en . W h ich of th e follow -

B. Din oproston e

ing e ect s on aqu eou s h u m or m ost likely m ediated th e th era-

C. Latan oprost

peu t ic e ect of th e drug in th e p at ien t’s disease?

D. Misop rostol

A. In creased out ow th rough Sch lem m can al

E. Epoprosten ol

B. Decreased product ion by ciliar y epith elium

F.

C. In creased out ow th rough uveoscleral route

Predn ison e

D. Decreased product ion by eye vessel con st rict ion


E. In creased out ow th rough t rabecu lar m esh w ork

1. Th is drug can in h ibit th e biosyn th esis of all eicosan oids.


7. A 47-year-old m an com plain ed to h is physician of an in abilit y

2. Th is drug is a syn th et ic prostaglan din I2 .

to m ain t ain an erect ion . After a com plete m edical w orku p, h e


be u sed before in tercou rse. W h ich of th e follow ing m olecu lar

3. Th is drug is a prost aglan din E1 an alogu e.

Di cult y level: Easy 4. Th is drug is a prost aglan din F2α an alogue.

w as prescribed in t rau reth ral adm in ist rat ion of alp rost adil to m ech an ism of act ion m ost likely m ediated th e e

cacy of th e

drug in th e pat ien t’s erect ion disorder? A. Act ivat ion of prost aglan din E1 receptors B. Blockade of α 1 adren oceptors C. Act ivat ion of m u scarin ic M 3 acet ylch olin e receptors


D. Blockade of th rom boxan e A2 receptors

5. Th is drug is a syn th et ic prostaglan din E2 .

F.

E. Act ivat ion of β 2 adren oceptors Release of n it ric oxide

368


Di cult y level: Easy 8. A 22-year-old p r im ip ara w om an w as ad m it ted to t h e ob -

A. Qu in idin e B. Ergon ovin e

stet rical u n it for labor in du ct ion becau se of a postdated

C. Norgest rel

p regn an cy. Her obstet rical exam in at ion w as n orm al, but h er

D. Clom iph en e

cer vix w as u n favorable for in duct ion of labor w ith oxytocin .

E. Misop rostol

W h ich of th e follow ing drugs given in t ravagin ally w ould be app ropriately adm in istered at th is t im e?


A. Th rom boxan e A2

12. A 2-day-old prem at u re m ale baby, born by n orm al vagin al

B. Din oproston e

d eliver y, p resen ted w it h severe cyan osis. Ch est x-rays an d

C. Ergon ovin e

ech ocard iograp hy con r m ed t h e d iagn osis of con gen it al

D. Diclofen ac

t ran sposit ion of th e great arteries, an d th e baby w as sch ed-

E. Albuterol

u led for su rger y. W h ich of t h e follow in g d r ugs w as m ost

F.

likely adm in istered by in t raven ou s in fusion to th e baby u n t il

Ibuprofen

su rger y?

Di cult y level: Easy 9. A 35-year-old w om an at 24 w eeks gest at ion w as adm it ted to

A. In dom eth acin B. Alprost adil

the obstetrical unit because of signs of severe fetal distress.

C. Din oproston e

Fetal death w as diagn osed on adm ission , an d in du ct ion of

D. Latan oprost

labor w as plan n ed . An oxytocin drip w as in it iated, an d a vag-

E. Misop rostol

in al suppositor y w as in ser ted. W h ich of th e follow ing drugs w as m ost likely given in t ravagin ally?


A. Metop rolol

13. A 35-year-old w om an w as seen at th e clin ic because of pro-

B. Albuterol

gressive exer t ion al dyspn ea an d ar th ralgias. Fur th er exam s

C. Beth an ech ol

led to the diagn osis of prim ary pulm on ary hypertension , and

D. Ergon ovin e

an in t raven ou s in fu sion of ep op rosten ol w as st arted. W h ich

E. Din oproston e

of th e follow ing m olecular act ion s m ost likely m ediated th e th erap eu t ic e

cacy of th e drug in th e p at ien t’s disease?


A. Blockade of Ca 2+ ch an n els

10. A 22-year-old w om an recen t ly d iagn osed w it h m ild p er-

B. Act ivat ion of β 2 adren oceptors

sisten t ast h m a st ar ted t reat m en t w it h albu terol as n eed ed

C. Open ing of K+ ch an n els

an d oral zileu ton daily. W h ich of t h e follow in g m olecu lar

D. Blockade of α 1 adren oceptors

m ech an ism s of act ion m ost likely m ediated th e th erap eu t ic

E. Act ivat ion of prost aglan din I2 receptors

e ect of zileu ton in th e p at ien t’s d isease? A. Act ivat ion of β 2 receptors B. In h ibit ion of 5-lipoxygen ase

Di cult y level: Easy 14. A 26-year-old m an w as brough t to th e em ergen cy depar t-

C. Com p et it ive blockade of leu kot rien e receptors

m en t becau se of a gu n sh ot w ou n d in h is r igh t leg. Physical

D. In h ibit ion of cyclooxygen ase-2

exam in at ion sh ow ed a d ist ressed p at ien t w it h abu n dan t

E. Com p et it ive blockade of m u scarin ic M 3 receptors

h em or rh age from t h e w ou n d . Th e syn t h esis an d release of w h ich of t h e follow ing en d ogen ou s com p ou n d s w as m ost


likely in creased in th is p at ien t?


A. Prost acyclin

ing of recen t on set of n ausea an d vom it ing in th e m orn ings.

B. Prost aglan din E2

A pregn an cy test con rm ed sh e w as pregn an t . Past m edical

C. Bradykin in

h istor y w as sign i can t for ch ron ic h ear t failure, n ecessitat-

D. Histam in e

ing a m edical abort ion . A drug t reat m en t for abor t ion in duc-

E. Aden osin e

t ion w as prescribed. W h ich of th e follow ing drugs w as m ost

F.

likely in clu ded in th at t reat m en t?

Th rom boxan e A2

Questions: VII-2 Eicosanoids: Agonists, Antagonist s, and Inhibitors 369 Di cult y level: Medium


15. A 64-year-old m an recen t ly diagn osed w it h op en -angle

18. A 64-year-old w om an recen tly diagn osed w ith osteoarth ri-

glau com a st ar ted a t reat m en t w it h lat an op rost . W h ich of

t is star ted t reat m en t w ith ibu p rofen an d m isop rostol. W h ich

t h e follow ing set s of ocu lar e ects (from A to E) m ost likely

of th e follow ing adverse e ect s is m ost likely expected from

occurred after th e adm in ist rat ion of th e drug?

m isop rostol t reat m en t?

Drug

Pupillary Diameter

Lens Curvature

Ocular Pressure

A

+

−

+

B

−

+

−

C

+

0

0

D

0

0

−

E

+

0

−

Note: +, increased; −, decreased; 0, negligible e ect.

Di cult y level: Easy 16. A 42-year-old m an w as seen in th e clin ic w ith gen eral m alaise, fever (102.5°F, 39.2°C), cough , an d dysp n ea. Fu r t h er exam s led to th e diagn osis of acute bron ch it is. W h ich of th e follow ing en zym es w as prim arily involved in th e pat ien t’s

A. Pept ic u lcer B. Drow sin ess C. Hyp er ten sion D. Diarrh ea E. In creased in t raocular pressure

Di cult y level: Easy 19. A 54-year-old m an com p lain ed to h is p hysician t h at t h e alprost adil h e w as u sing before in tercou rse w as able to im prove h is erect ile dysfu n ct ion bu t cau sed p en ile p ain . W h ich of th e follow ing act ion s m ost likely m ediated th e adverse e ect of th e drug? A. Sen sit izat ion of su bst an t ia gelat in osa in th e sp in al cord B. Decreased ring of cort icospin al project ion to th e dorsal h orn

in am m ator y disease?

C. In creased sen sit ivit y of th e brain periaqueductal area

A. Creat in in e kin ase

D. Low ering th resh old of n ocicept ive a eren t n eu ron s

B. Cyclooxygen ase-2

E. In creased sen sit ivit y of th e fron tal cor tex

C. 5-lipoxygen ase D. Lact ic dehydrogen ase


E. 12-lip oxygen ase

20. A 59-year-old w om an com plain ed to h er physician of per-

F.

Cyclooxygen ase-1


sisten t h eartbu rn . Sh e h ad been taking ibu profen for osteoarth rit is of th e righ t h ip for th e p ast 2 m on th s. Sh e refu sed to stop th e m edicat ion , w h ich sh e said w as ver y good for h er

17. A 13-year-old girl com plain ed to h er physician of pain ful

p ain . Th e p hysician p rescr ibed an ot h er d r ug, to be t aken

m en st ru at ion accom p an ied by h eadach e an d n au sea. Sh e

togeth er w ith ibu profen , to preven t pept ic ulcer form at ion .

u n der w en t m en arch e 6 m on th s earlier, an d dysm en orrh ea

W h ich of th e follow ing act ion s m ost likely con t ributed to

h ad occurred sin ce th en . Th e physician prescribed ibuprofen

th e p reven t ive e ect of th e prescribed drug?

to be st arted on th e day prior to th e expected st ar t of m en -

A. Bin ding to n ecrot ic ulcer t issue, act ing as a barrier for

st ru at ion . In h ibit ion of syn th esis of w h ich of th e follow ing en dogen ou s com p ou n ds m ost likely m ediated th e th erap eu t ic e ect of ibu p rofen in th e pat ien t’s disorder?

acid an d p ep sin B. Blockade of m uscarin ic M 3 receptors on gast ric p ariet al cells

A. Magn esiu m

C. Blockade of gast rin receptors on gast ric parietal cells

B. Nit ric oxide

D. St im u lat ion of bicarbon ate an d m u cu s secret ion by su -

C. Prost aglan din E2 D. Epin eph rin e E. Prost aglan din I2

per cial ep ith elial cells E. Bactericidal e ect again st Helicobacter pylori

370


Questions: VII-3 Nonsteroidal Antiin am m atory Drugs Directions for questions 1−7

A. Blockade of prostaglandin receptors in the hypothalam us


B. In h ibit ion of ph osph olipase A2 in th e hypoth alam u s


C. Decreased interleukin concentration in the hypothalam us

A. Acetam in op h en B. Aspirin C. Celecoxib D. Diclofen ac E. In dom eth acin F.

Ketorolac

G. Mesalam in e

D. Decreased con cen t rat ion of prostaglan din s in th e hypoth alam u s E. In h ibit ion of cyclooxygen ase in periph eral t issues F.

Blockade of oxidative ph osphorylation in skeletal m uscle

Di cult y level: Medium 9. A 66-year-old m an com plain ed to h is physician th at h e h ad

H. Naproxen

u r in ated ver y lit t le over t h e p ast 24 h ou rs. Th e m an w as

I.

Piroxicam

bein g t reated w it h d igoxin , fu rosem id e, an d captop r il for

J.

Salicylic acid

con gest ive h ear t failu re, an d t h e t h erapy h ad im p roved h is card iac con d it ion s. Tw o d ays ago, t h e p at ien t h ad p ain on

Di cult y level: Easy 1. An irreversible in h ibitor of cyclooxygen ase

Di cult y level: Easy 2. A salicylate derivative m ain ly used in in am m atory bow el disease

Di cult y level: Easy 3. A select ive in h ibitor of cyclooxygen ase-2


m ovem en t of h is left leg th at got bet ter w ith t w o ibu p rofen t ablet s. Th e p hysician fou n d n o clin ical sign s of in t ravascu lar volum e deplet ion an d in creased th e dose of furosem ide, but 6 h ou rs later, u rin at ion w as n ot im proved . W h ich of th e follow ing act ion s m ost likely m ediated th e pat ien t’s oligu ria? A. Ibuprofen-m ediated decrease of the glom erular ltrat ion rate B. Worsen ing of cardiac failu re d esp ite th e th erapy C. Fu rosem id e-m ediated decrease of ren in secret ion D. Digoxin -m ediated decrease of th e glom erular

lt rat ion

rate E. Fu rosem id e-in du ced hyp okalem ia

4. Th is d r ug follow s zero -ord er kin et ics w h en given at in term ediate to h igh doses.

Di cult y level: Easy 5. Th is d r ug can in h ibit bot h cyclooxygen ase an d p h osp h olip ase A2 .

Di cult y level: Medium 10. A 45-year-old alcoh olic w om an , brough t to th e em ergen cy depart m en t by h er h usban d, w as disorien ted, com bative, an d com plain ed of h eadach e, vert igo, an d “ringing in m y ears.” Th e h u sban d rep or ted th at sh e recen tly said sh e w an ted to com m it suicide. Vital sign s w ere tem perat ure 103.8°F, p u lse


108 bpm , resp irat ion s 6/m in , blood pressu re 85/60. Per t i-

6. Th e an algesic e ect of th is drug is prim arily m ediated by cen -

n en t lab dat a on adm ission w ere ar terial blood pH 7.25, cre-

t ral im p airm en t of p ain t ran sm ission .

at in in e 2.2 m g/dL (n orm al 0.9−1.2 m g/dL), bicarbon ate 18 m Eq/L (n orm al 22−26 m Eq/L), glu cose 170 m g/dL (n orm al


70−110 m g/dL). Ar terial blood gases w ere Pa CO2 48 m m Hg

7. Th e long h alf-life of th is drug (m ore th an 50 h ours) perm its

(n orm al 35−45 Pa CO2 ), Pa O2 75 m m Hg (n orm al > 80 Pa O2 ).

on ce-daily dosing.

Di cult y level: Easy 8. Th e m oth er of a 17-m on th -old girl took th e baby to th e pediat rician becau se sh e fou n d th at h er daugh ter’s rect al tem perat ure w as 103.1°F (39.5°C). After physical exam ination , the pediat rician said th e fever w as m ost likely d u e to a viral in fect ion an d p rescribed ibu profen . W h ich of th e follow ing m olecu lar act ion s m ost likely m ediated th e an t ipyret ic e ect of th e drug in th is p at ien t?

W h ich of th e follow ing drugs m ost likely caused th e pat ien t’s p oison ing? A. Eth an ol B. Celecoxib C. Ibuprofen D. Propran olol E. Aspirin F.

Diph en hydram in e

Questions: VII-3 Nonsteroidal Antiin am m atory Drugs 371 Di cult y level: Medium




p ar t m en t because of serious breath ing di cu lt y. Tw o h ou rs

w it h n au sea, h eadach e, d izzin ess, t in n it u s, d i cu lt y in

earlier, sh e h ad t aken a drug for a h eadach e. Th e pat ien t h ad

h ear ing, an d sw eat ing. His body tem perat ure w as 103.1°F

been su ering from sin u sit is an d n asal polyp s for 6 m on th s.

(39.5°C). Th e pat ien t w as su ering from osteoar th rit is an d

Physical exam in at ion sh ow ed severe bron ch ospasm . W h ich

h ad been overt reat ing h im self w ith aspirin for 4 days in an

of th e follow ing drugs m ost likely caused th e pat ien t’s sign s

at tem pt to relieve severe pain in h is righ t h ip . W h ich of th e

an d sym ptom s?

follow in g act ion s m ost likely m ed iated t h e d r ug-in d u ced

A. Ergotam in e

hyp erth erm ia in th is p at ien t?


A. Reset t ing th e hypoth alam ic th erm ost at

C. Acet ylsalicylic acid

B. In am m ator y react ion in th e join t s

D. Su m at ript an

C. In creased release of in terleukin -10

E. Cyp roh ept adin e

D. Uncoupling oxidative ph osphorylation in skeletal m uscle E. Met abolic alkalosis

Di cult y level: Easy 12. A 32-year-old m an su ering from h em oph ilia h ad been re-


cen tly diagn osed w ith ten sion h eadach e. Th e h eadach es oc-

15. A 42-year-old w om an h ad been recovering from breast can -

curred t w o to four t im es w eekly, usu ally tow ard th e en d of

cer surger y. Becau se h er postop erat ive p ain w as severe, sh e

h is w orkday. Th e p ain w as con st an t , d u ll in ch aracter, an d

received an in t raven ous inject ion of ketorolac th at w as able

u su ally lasted t h e rest of t h e day w it h var iable in ten sit y.

to redu ce th e pain . W h ich of th e follow ing m olecular act ion s

W h ich of th e follow ing an algesic drugs w ould be appropri-

m ost likely m ediated th e an algesic e ect of th e drug?


A. Drug bin ding to prost aglan din receptors in th e surgical

A. In dom eth acin B. Acetam in op h en C. Aspirin

area B. Decreased con cen t rat ion of prostaglan din s in th e surgical area

D. Ketorolac

C. Decreased oxygen radical production in the surgical area

E. Piroxicam

D. In h ibit ion of prost aglan din biosyn th esis in th e cen t ral

F.

Naproxen

n er vou s system E. Low ering of an xiet y, fear, an d su ering evoked by p ain

Di cult y level: Medium 13. A 20-year-old m an , d iagn osed w it h acu te rh eu m at ic fever,


st ar ted h igh -d ose salicylate t reat m en t . A few d ays later,

16. A 60-year-old m an recen tly diagn osed w ith osteoar th rit is

laborator y values in dicated in creased blood pH, decreased

asked h is p hysician for an an algesic drug becau se of in ter-

Pa CO2 , an d decreased plasm a bicarbon ate con ten t . W h ich of

m it ten t p ain in bot h h ip s. Past h istor y of t h e p at ien t w as

th e follow ing acid−base dist urban ces w as m ost likely caused

sign i can t for m yocard ial in farct ion 2 years ago an d for

by salicylate t reat m en t?

p ron oun ced asp irin hypersen sit ivit y. W h ich of th e follow ing

A. Resp irator y acidosis

w ou ld be th e best advice to give to th is pat ien t at th is t im e?

B. Resp irator y alkalosis

A. To u se a prop ion ic acid derivat ive like n aproxen

C. Met abolic acidosis

B. To t ake on ly ver y low doses of asp irin

D. Met abolic alkalosis

C. To t ake asp irin w ith m isop rostol

E. Mixed acidosis

D. To u se in dom eth acin E. To avoid all n on steroidal an t iin am m ator y d rugs

372





20. A 59-year-old obese w om an presen ted to th e em ergen cy de-

m en t becau se of p ersisten t n au sea an d vom it ing, gen eral

p ar t m en t because of severe colicky p ain in th e righ t lu m bar

m alaise, an d diap h oresis for th e p ast 6 h ou rs. Th e m an h ad

region . Th e pat ien t h ad a long h istor y of osteoarth rit is an d

been overt reat ing h im self for 4 days w ith an an algesic m ed -

experien ced frequen t episodes of st rong ar th rit ic pain for

icat ion to relieve severe pain from a n eck inju r y. Tw o days

w h ich sh e h ad been t aking several di eren t pain killers daily

earlier, h e h ad got ten dr un k at a par t y. Physical exam sh ow ed

for th e past year. Curren t m edicat ion s in cluded ator vast at in

a sligh tly con fu sed an d dehydrated p at ien t w ith icteru s an d

and ezetim ibe for hyperlipidem ia and hydrochlorothiazide for

a

app ing t rem or. Per t in en t lab resu lt s on ad m ission w ere

m ild hyp er ten sion . A ren al biop sy con rm ed th e diagn osis

alan in e am in ot ran sferase 300 U/L (n orm al 8−20 U/L), asp ar-

of papillar y n ecrosis an d t u buloin terst it ial in am m at ion of

t ate am in ot ran sferase 480 U/L (n orm al 8−20 U/L). Th e p a-

th e kidn ey. W h ich of th e follow ing drugs m ost likely cau sed

t ien t h ad m ost likely t aken an excessive dose of w h ich of th e


follow ing drugs?

A. Codein e

A. Aspirin

B. Tram adol

B. In dom eth acin

C. Diclofen ac

C. Acetam in op h en

D. Hydroch lorot iazide

D. Ibuprofen

E. Ator vast at in

E. Ketorolac

F.

Ezet im ibe



18. A 65-year-old m an h ad been recen tly diagn osed w ith osteo-

21. A 32-year-old w om an h ad been su ering severe pain during

arth rit is. Six m on th s ago, th e p at ien t su ered from p ept ic

m en ses. Th e on ly relevan t h istor y w as th at sh e h ad u n der-

ulcer disease that h ealed after triple an tiulcer th erapy. W hich

gon e con izat ion 6 m on th s earlier for a broid of th e cer vix.

of th e follow ing n on steroidal an t iin am m ator y drugs w ould

Ibuprofen as n eeded w as able to relieve th e m en st rual pain .



A. Ibuprofen

ated th e analgesic e ect of the drug in th e patient’s disorder?

B. Piroxicam

A. Bin ding of th e drug to prostaglan din receptors in th e m yom et riu m

C. In dom eth acin D. Ketorolac

B. Decreased p rod u ct ion of p rost aglan d in s by t h e en d o m et r iu m

E. Celecoxib F.

Aspirin

C. In h ibit ion of prost aglan din biosyn th esis in th e spin al cord


D. An t iin am m ator y act ion of th e drug in th e pelvic area

19. A 32-year-old m an called h is p hysician becau se of fever

E. Decreased p rod u ct ion of leu kot r ien es by t h e en d o m et r iu m

(102.2°F, 39.0°C) for t h e p ast 4 h ou rs. Past m ed ical h istor y of th e p at ien t w as sign i can t for a seriou s allergic react ion to sulfon am ides. A diagn osis of u w as m ade. W h ich of th e


follow ing an t ipyret ic drugs w ould be con t rain dicated in th is

22. A 6-year-old boy su ering from in uen za received an an t i-

p at ien t?

pyretic drug for 4 days. On the fth day, he lapsed into a com a

A. Aspirin

an d died . Th e au top sy disclosed di u se m icrovescicu lar

B. Celecoxib

fat t y in lt rat ion of th e liver, h ear t , an d kidn eys, as w ell as

C. Naproxen

cerebral edem a. W h ich of th e follow ing an t ipyret ics m ost


likely cau sed th e p at ien t’s death ?

E. Ibuprofen

A. Acetam in op h en B. Piroxicam C. Ibuprofen D. In dom eth acin E. Ketorolac F.

Aspirin

Questions: VII-3 Nonsteroidal Antiin am m atory Drugs 373 Di cult y level: Easy

er yth em a m u lt iform e, app aren tly d u e to an allergic react ion

23. A 58-year-old m an com plain ed to h is physician of m orn ing

to n aproxen . W h ich of th e follow ing w ould be an appropri-

st i n ess in th e h ip an d kn ee an d som e join t st i n ess after

ate an algesic drug for th is p at ien t?

in act ivit y. Past m edical h istor y of th e pat ien t w as sign i can t

A. Aspirin

for a m yocardial in farct ion 6 m on th s earlier. Fur th er exam s


led to th e diagn osis of osteoarth rit is, an d an an algesic ph ar-

C. Piroxicam

m acoth erapy w as p rescribed . W h ich of th e follow ing an al-

D. Ibuprofen

gesic drugs w ou ld be con t rain dicated for th is pat ien t?


A. Ibuprofen B. Piroxicam


C. Celecoxib

27. An 850-g (1.87-lb) baby boy, prem at u rely born at 27 w eeks’


gestat ion al age, w as in t u bated im m ediately an d p laced on

E. Diclofen ac

p osit ive pressure assisted ven t ilat ion . On th e th ird day of life, h is n urse n ot iced th at h e h ad tachycardia an d a w iden ed


p ulse pressu re. Color Dop pler ech ocardiograp hy sh ow ed re-

24. A 14-year-old girl w as seen in th e clin ic because of severe

verse pulm on ar y arter y

ow in diastole. A t reat m en t w ith

abdom in al pain secon dar y to h er m en st ru al p eriods. Th e

in t raven ou s in dom eth acin w as st ar ted. W h ich of th e follow -

p ain began w ith th e on set of h er m en st rual

ing best explain s th e reason for th at th erapy?

ow an d h ad

occurred m on th ly sin ce h er rst m en st rual period at age 13.

A. To sp eed u p th e m at u rat ion of th e lu ngs

Her physical exam in at ion w as u n rem arkable. A diagn osis of

B. To in crease lu ng su rfact an t form at ion

p r im ar y dysm en or rh ea w as m ad e. W h ich of t h e follow ing

C. To decrease at rial con t ract ilit y

d rugs w ou ld be m ost appropriate for th is pat ien t?

D. To p reven t th rom bi on cardiac valves


E. To close th e p aten t du ct u s ar teriosu s

B. Albuterol C. Din oproston e


D. Ibuprofen

28. A 51-year-old w om an com plain ed to h er physician of fat igue

E. Misop rostol

an d sh ort n ess of breath . Th e w om an , w h o w as vegetarian ,

F.

realized sh e h ad recen tly developed an u n explain ed desire

Ergon ovin e

to eat ice an d also n oted th at h er stools h ad becom e dark.


Sh e h ad been receiving piroxicam for 6 m on th s to t reat h er

25. A 10-year-old boy w as brough t to t h e clin ic w it h fever

rh eu m atoid arth rit is. Physical exam in at ion w as u n rem ark-

(102.2°F, 39.0°C), gen eral m alaise, an d t h e ch aracter ist ic

able. W h ich of th e follow ing disorders m ost likely cau sed th e

rash of a m easles in fect ion . Past m edical h istor y w as sign i -


can t for an ep isode of h em olyt ic an em ia, m ost p robably re-

A. Iron de cien cy an em ia

lated to his congen ital de ciency of red blood cell glutathione

B. Resp irator y alkalosis

syn th ase. W h ich of th e follow ing drugs w ou ld be a su it able

C. Reye syn drom e

an t ipyret ic for th is boy?

D. An algesic n eph ropathy

A. Aspirin

E. Aspirin hypersen sit ivit y

B. In dom eth acin C. Acetam in op h en


D. Ibuprofen

29. A 63-year-old w om an recently diagnosed w ith osteoarthritis

E. Predn ison e

star ted t reat m en t w ith ibu p rofen . Th e biosyn th esis of w h ich

F.

of th e follow ing pairs of en dogen ous com poun ds w as m ost

Su l npyrazon e

likely in h ibited by th e d rug?


A. Th rom boxan es an d leu kot rien es

26. A 58-year-old m an com plain ed to h is physician of du ll, con -

B. Prost aglan din s an d leukot rien es

t in u ou s bon e p ain th at h ad been in creasing over th e p ast few

C. Prost acyclin an d th rom boxan es

days. Th e p at ien t h ad been su ering from prost at ic carci-

D. Prost aglan din s an d bradykin in

n om a for 2 years. Past h istor y w as sign i can t for an episode

E. Th rom boxan es an d bradykin in

of h em olyt ic an em ia, ascribed to h is congen ital glucose-

F.

6 - p h osp h at e d ehyd roge n ase (G6 PD) d e cie n cy, an d for

Prost acyclin an d leukot rien es

374



A. Gast rin


B. Hydroch loric acid

pain . Th e m an h ad been taking several ibuprofen tablets each

B. Bicarbon ate secret ion

day for th e p ast 2 w eeks becau se of ar th rit ic p ain . En doscopy

D. Gast ric m u cu s

d isclosed t w o su p er cial u lcers n ear th e stom ach an t r u m .

E. Ch olecystokin in

In creased gast ric secret ion of w h ich of th e follow ing com p ou n ds m ost likely con t ribu ted to th e pat ien t’s disorder?

Questions: VII-4 Im m unom odulating Drugs Directions for questions 1−4

A. Predn ison e

Match each im m u n om odu lat ing d rug w ith th e app ropriate de-

B. Azath iop rin e


C. Tacrolim u s


D. Mu rom on ab - CD3

A. Aldesleukin B. Azath iop rin e C. Basilixim ab

E. Cycloph osph am ide


D. Cyclosporin e

6. A 27-year-old w om an w as adm it ted to th e h ospit al w ith

E. Le un om ide

fever, m alar but ter y er yth em a, ar th ralgia, in term it ten t pleu-

F.

r it ic p ain , an d oral u lcers. Her lab test s revealed t h e follow -

Mycoph en olate m ofet il

G. Mu rom on ab - CD3

ing: serum creat in in e 3.2 m g/dL, blood urea n it rogen (BUN)

H. Sirolim u s

35 m g/dL, an d a h igh seru m level of an t in u clear an t ibodies. A

I.

Tacrolim u s

diagn osis w as m ade, an d an ap prop riate th erapy w as st arted.

J.

Ustekin um ab

W h ich of th e follow ing drugs m ost likely sh ould be in cluded in th e th erapeu t ic m an agem en t of th is pat ien t?


A. Ustekin um ab

1. A recom bin an t form of a n at ural cytokin e

B. Predn ison e C. BCG (bacilli Calm et te- Gu érin ) vaccin e

Di cult y level: Easy 2. Th is drug bin ds to th e CD25 α ch ain of th e in terleukin -2 receptor on act ivated T lym ph ocytes.

Di cult y level: Easy 3. A speci c inhibitor of inosine m on ophosphate dehydrogenase

Di cult y level: Easy 4. A prodrug th at is conver ted in to m ercaptopurin e in th e body


D. In terferon bet a-1b E. Aldesleukin

Di cult y level: Medium 7. A 39-year-old w om an w h o h as been su ering from m yasth en ia gravis for 4 years developed progressive dyspn ea several days after an u p p er resp irator y t ract in fect ion . Physical exam ination disclosed bilateral ptosis, bilateral facial weakness, an d dim in ish ed u pp er an d low er m otor st rength . An in t raven ou s edroph on iu m inject ion im p roved m u scle st rength . A seru m assay for an t iacet ylch olin e receptor an t ibody w as 4.8 (n orm al < 0.5). A p rom ptly in st it u ted t reat m en t in clu ded a p aren teral

5. A 56-year-old m an w ith en d-st age ren al disease un der w en t a

inject ion of p red n ison e. W h ich of th e follow ing st atem en ts

kidn ey t ran splan t . He received im m un osuppressive th erapy

best explain s th e m ost likely m ech an ism of act ion of th e drug

th at in clu d ed a d r ug th at su p p resses cellu lar im m u n it y, in -

in th is case?

h ibit s both prost aglan din an d leu kot rien e syn th esis, an d in -

A. In h ibit ion of plasm a ch olin esterase

creases th e cat abolism of im m u n oglobu lin G (IgG) an t ibod ies. W h ich of th e follow ing drugs h as all of th ese act ion s?

B. Act ivat ion of ch olin ergic Nm receptors C. St im u lat ion of syn th esis of in terleu kin -2 D. In h ibit ion of T-cell act ivat ion an d proliferat ion E. St im u lat ion of syn th esis of in terleu kin -1

Questions: VII-4 Im m unomodulating Drugs 375 Di cult y level: Easy 8. A 53-year-old m an w ith a h eart t ran splan t un der w en t im -

A. Jan us-kin ase lin ked B. Met abot rop ic

m u n osu pp ressive t reat m en t th at in clu ded oral cyclosp orin e.

C. Ion ot ropic

W h ich of th e follow ing cells represen t th e m ain site of act ion

D. In t racellular

of th is drug?

E. Tyrosin e-kin ase lin ked

A. Macrop h ages B. Den drit ic cells C. T-h elp er cells

Di cult y level: Easy 12. A 44-year-old w om an w as in th e coron ar y un it after a h ear t

D. Plasm a cells

t ran sp lan t p er for m ed 2 w eeks earlier. Per t in en t blood test

E. Nat u ral killer cells

resu lt s w ere w h ite blood cell cou n t 1.2 × 10 3 /m m 3 (n orm al 4.5−11.0 × 10 3 /m m 3 ), platelet s 40,000/m m 3. (n orm al

Di cult y level: Medium 9. A 54-year-old w om an w h o u n der w en t a kidn ey t ran splan t

150,000−400,000/m m 3 ). W h ich of th e follow ing drugs m ost likely cau sed th ese n dings?

d eveloped n au sea, vom it ing, an d diarrh ea a few days after

A. Cyclosporin e

th e surger y. Th e p at ien t h ad received post t ran splan t th erapy

B. Dobutam in e

w ith cyclosporin e an d predn ison e. A decision w as m ade to

C. Dopam in e

su bst it u te sirolim u s for th e cyclosporin e. W h ich of th e fol-

D. Azath iop rin e

low ing actions m ost likely m ediated the im m unosuppressive

E. Flu orou racil

e ect of sirolim u s? A. St im u lat ion of th e syn th esis of t u m or n ecrosis factor B. St im u lat ion of B-cell p roliferat ion

Di cult y level: Medium 13. A 41-year-old m an cam e to th e clin ic com plain ing of an ex-

C. In h ibit ion of h ist am in e release

ten sive rash , w h ite plaquelike lesion s in h is m outh , dr y eyes,

D. In h ibit ion of T-cell proliferat ion

hyp erpigm en tat ion of th e t issu es su rrou n ding th e eyes, an d

E. In h ibit ion of calcin eurin

d iarrh ea. Th ree m on th s earlier, th e m an , w h o w as su ering from ch ron ic m yelogen ou s leu kem ia, u n d er w en t an alloge-

Di cult y level: Medium 10. A 57-year-old m an com plain ed of a t ingling sen sat ion in h is h an ds an d periph eral edem a. Th e m an , w h o h ad received a h ear t t ran splan t 1 m on th earlier, w as in th e h ospit al an d sch ed uled for en dom yocardial biopsy. Sign i can t blood test results w ere pot assium 6.1 m Eq/L (n orm al 3.5−5.0 m Eq/L),

n eic bon e m ar row t ran sp lan t from h is sister. He w as su ccessfully t reated for h is acute graft-versus-h ost disease an d h ad n o m ajor h ealt h p roblem s after t h at d isease. W h ich of t h e follow in g t w o -d r ug com bin at ion s w ou ld rep resen t an app ropriate im m u n osu p pressive p h arm acoth erapy for th e p at ien t at th is t im e?

creat in in e 3.8 m g/d L (n orm al 0.6−1.2 m g/d L), blood u rea n i-

A. Predn ison e an d cyclosporin e

t rogen (BUN) 42 m g/dL (n orm al 7−18 m g/dL). Cu rren t m ed -

B. Cyclosporin e an d er yth rom ycin

icat ion s w ere cyclosporin e, predn ison e, an d azath ioprin e to

C. Cycloph osph am ide an d doxorubicin

p reven t reject ion , om ep razole for h ear tbu rn , an d dilt iazem

D. Vin blast in e an d predn ison e

for arrhyth m ia. Biopsy resu lt s in dicated n o acu te reject ion .

E. Doxor ubicin an d vin blast in e

If th e laborator y results w ere drug-related, w h ich of th e follow ing w as th e m ost likely causat ive agen t?


A. Predn ison e

14. A 43-year-old m an w h o un der w en t a kidn ey t ran splan t h ad

B. Cyclosporin e

been receivin g an im m u n osu p p ressive t reat m en t t h at in -

C. Azath iop rin e

cluded a m acrolide antibiotic. The drug binds to a FK-binding

D. Om eprazole

p rotein s located in T cells, th u s blocking gen e exp ression for

E. Dilt iazem

production of several cytokin es. W hich of the follow ing drugs m ost likely w orks w ith th is m ech an ism of act ion ?


A. Azith rom ycin

11. A 66-year-old w om an su ering from m et ast at ic ren al can cer

B. Azath iop rin e

started a ph arm acotherapy that included aldesleukin. W h ich

C. Tacrolim u s

of the follow ing classes of receptors m ost likely m ediated the

D. Cyclosporin e


E. Tobram ycin

376



A. Blockade of t um or n ecrosis factor-α (TNF-α ) receptors

15. A 42-year-old w om an w ho underw ent a liver transplant com -

B. In h ibit ion of clon al expan sion of T an d B lym ph ocytes

p lain ed of n au sea an d vom it ing, severe abdom in al pain , an d

C. In h ibit ion of an t igen presen t at ion by den drit ic cells

d iarrh ea 1 w eek after th e surger y. Th e pat ien t h ad been re-

D. St im ulat ion of gen et ic exp ression of in terleu kin -2

ceiving a m u lt idrug im m u n osuppressive th erapy. If th e pa-

E. St im ulat ion of m acrop h age p h agocyt ic act ivit y

t ien t’s sym ptom s w ere drug-related, w h ich of th e follow ing d rugs m ost likely cau sed th e repor ted adverse e ect s?


A. Et an ercept

19. A 42-year-old w om an un dergoing h ear t t ran splan t received

B. Mycoph en olate m ofet il

m ycop h en olate m ofet il, cyclosp orin e, an d predn ison e before

C. Doxor ubicin

surgery. W hich of the follow ing statem ents best explains w hy

D. Le un om ide

m ycop h en olate m ofet il is cu rren tly u sed in stead of azath io-

E. Paclitaxel

p rin e to p reven t reject ion in solid organ t ran splan t at ion ?

F.

A. It s im m un osu ppressive act ivit y is de n itely superior to

Fluorou racil

th at of azath ioprin e.

Di cult y level: Easy 16. A 35-year-old w om an w h o received a cadaveric liver t ran sp lan t w as t reated w ith in t raven ous in fu sion of basilixim ab im m ediately postoperat ively. A few m in utes later, sh e began to sh ow w h eezing, cyan osis, diaph oresis, prurit us, an d a diffuse skin rash . Vital signs w ere pulse 128 bpm , blood pressure 98/50 m m Hg, resp irat ion s 22/m in . W h ich of th e follow ing p ath ologic even ts m ost likely caused th e pat ien t’s sign s an d

B. It h as sign i can t ly few er adverse e ect s t h an azat h io p r in e. C. It h as drast ically reduced th e risk of graft-versus-h ost d isease. D. It select ively in h ibit s m acroph age-m ediated product ion of several in terleukin s. E. It select ively in h ibit s an t igen recogn it ion by an t igen p resen t ing cells.

sym ptom s? A. Met abolic acidosis B. Acu te cardiac failu re

Di cult y level: Medium 20. A 30-year-old m an recen tly diagn osed w ith Croh n disease

C. Acu te ren al failu re

experienced substantial im provem ent after 1 m onth of pred-

D. Acu te en cep h alop athy

n ison e th erapy. W h ich of th e follow ing drugs w ould be ap -

E. An aphylactoid react ion

propriate to m aintain rem ission of sym ptom s in this patient? A. Sirolim u s


B. Flu orou racil

17. A 35-year-old m an w h o un der w en t ren al t ran splan t sh ow ed

C. Tacrolim u s

sign s of acu te allograft reject ion th at w as resist an t to cor t i-

D. Th alidom id e

costeroid t reat m en t . He w as t reated w ith m urom on ab - CD3

E. Azath iop rin e

th at w as able to reverse th e reject ion . W h ich of th e follow ing act ion s m ost likely m ediated th e th erap eu t ic e ect of th e


d rug in th e pat ien t’s disease?

21. A 42-year-old w om an w h o h ad been un dergoing h em odial-

A. In h ibit ion of an t ibody form at ion by plasm a cells

ysis for 3 years w as adm it ted to th e h osp ital for a kid n ey

B. In h ibit ion of several en zym es involved in p u r in e m e-

t ran splan t . Before an d after su rger y, sh e received cyclospo-

t abolism

rin e, azath ioprin e, an d pred n ison e. Fou r days after su rger y,

C. In h ibit ion of calcin eurin en zym e in T-cell cytoplasm

sh e d evelop ed acu te allograft reject ion . High -d ose p red n i-

D. St im u lat ion of in terleu kin -1 syn th esis in T cells

son e failed to resolve t h e reject ion . W h ich of t h e follow ing

E. Neu t ralizat ion of a su rface protein receptor com plex in

d r ugs cou ld be u sed to t reat t h is case of steroid -resist an t

T cells

reject ion ? A. Dexam eth ason e


B. Mu rom on ab - CD3

18. A 42-year-old m an w ith en d-st age ren al disease u n der w en t

C. Aldesleukin

a kidn ey t ran splan t . Th erap eu t ic m an agem en t of th e p at ien t

D. Meth ot rexate

in cluded an in t raven ous inject ion of azath ioprin e just before

E. Cycloph osph am ide

surgery. W hich of th e follow ing m olecular actions m ost likely m ediated th e im m u n osu p pressive e ect of th e drug in th is p at ien t?

Questions: VII-4 Im m unomodulating Drugs 377 Di cult y level: Easy

A. Et an ercept

22. A 37-year-old m an w h o w as sch eduled for a h ear t t ran splan t

B. Cyclosporin e

received a t r ip le im m u n osu p p ressive t h erapy ju st before

C. Tacrolim u s

su rger y th at in clu ded azath iop rin e an d predn ison e. W h ich

D. Sirolim u s

of th e follow ing drugs w as m ost likely th e th ird agen t of th at

E. Azath iop rin e

com bin at ion drug regim en ?

F.

A. Aldesleukin B. Cyclosporin e C. Triam cin olon e

In ixim ab

Di cult y level: Easy 26. A 45-year-old w om an w h o u n d er w en t a liver t ran sp lan t

D. In ixim ab

star ted an im m u n osu p pressive th erapy th at in clu ded t acro-

E. Et an ercept

lim us. Th e risk of w h ich of th e follow ing drug-related disorders w as m ost likely in creased in th is pat ien t?


A. Hyp oten sion

23. A 48-year-old w om an w h o un der w en t a liver t ran splan t h ad

B. Hyp okalem ia

been receiving im m u n osu p pression t reat m en t w ith p redn i-

C. Hyp oglycem ia

son e an d cyclosporin e. Despite th e th erapy, a liver biopsy

D. Hem olyt ic an em ia

st ill sh ow ed reject ion 12 days after surger y, an d th e th era-

E. Neu rotoxicit y

p eu t ic team decided to su bst it ute tacrolim us for cyclosp orin e. W h ich of th e follow ing cells represen t th e m ain site of


act ion of tacrolim u s?

27. A 51-year-old m an presen ted to th e clin ic w ith com plain ts

A. Macrop h ages

of an en larged, pain ful lym ph n ode in h is groin . On e year

B. Den drit ic cells

earlier, h e h ad un dergon e su rgical resect ion of st age 2 m alig-

C. T-h elp er cells

n an t m elan om a. A lym ph n ode biopsy con rm ed th e recur-

D. Plasm a cells

ren ce of m align an t m elan om a. Th e pat ien t st arted a course

E. Nat u ral killer cells

of ch em oth erapy th at in clu ded th e in t raven ous adm in ist ration of aldesleukin . W h ich of the follow ing m olecular actions

Di cult y level: Easy 24. A 53-year-old m an w h o u n d er w en t liver t ran sp lan t at ion

m ost likely m ediated th e th erap eu t ic e ect of th e d rug in th e p at ien t’s disorder?

for advan ced biliar y cirrh osis h ad been receiving im m u n o-

A. Proliferat ion an d di eren t iat ion of B an d T lym ph ocytes

su p p ression t reat m en t w ith predn ison e an d cyclosp orin e.

B. In h ibit ion of m acroph age ph agocyt ic act ivit y

Despite th e th erapy, a liver biopsy st ill sh ow ed reject ion 14

C. In h ibit ion of an t igen presen t at ion by den drit ic cells

days after surgery. W hich of the follow ing drugs could be sub-

D. Decreased syn th esis of calcin eu rin

st it u ted for cyclosp orin e to t reat th is case of cyclosp orin e-

E. In h ibit ion of act ivit y of n at ural killer cells

resistan t reject ion ? A. Aldesleukin


B. Vin blast in e

28. A 48-year-old w om an p resen ted to h er op h t h alm ologist

C. Tacrolim u s

becau se of loss of cen t ral vision an d p ain on m ovem en t of

D. Fluorou racil

h er left eye. Sh e repor ted th at in th e past sh e h ad h ad recur-

E. Paclitaxel

ren t ep isod es of w eakn ess an d abn or m al sen sat ion s in h er ar m s an d legs. Th e p at ien t w as refer red to t h e n eu rologic

Di cult y level: Easy 25. A 65-year-old w om an recen t ly d iagn osed w it h p olym yosit is h ad n ot im p roved after 2 w eeks of t reat m en t w it h p red n ison e. A d ecision w as m ad e to rep lace p red n ison e w it h an im m u n osu p p ressive d r ug t h at act s by in h ibit ing en zym es essen t ial for p u r in e biosyn t h esis. W h ich of t h e follow in g d rugs w as m ost likely prescribed?

clin ic, w h ere laborator y exam s an d brain m agn et ic reso n an ce im aging con rm ed th e diagn osis of m ult iple sclerosis. Th e p at ien t w as prescribed a su pp or t ive th erapy th at in cluded a recom bin an t cytokin e en dow ed w ith im m un ost im u lan t proper t ies. W h ich of th e follow ing dr ugs w as m ost likely adm in istered? A. Trast u zu m ab B. In ixim ab C. In terferon bet a-1b D. Predn ison e E. Tacrolim u s

378


Di cult y: Medium


29. A 27-year-old p r im ip ara w om an d elivered a baby boy at

30. A 45-year-old w om an received a d eceased -d on or kid n ey

ter m . Th e w om an w as Rh o(D) n egat ive, an d h er h u sban d

t ran sp lan t . W it h in 12 h ou rs of t h e t ran sp lan t at ion , sh e

w as Rh o(D) posit ive. Th e w om an received an in t raven ou s

star ted im m u n osu p pressive ph arm acoth erapy th at in clu ded

inject ion of Rh o(D) im m un e globulin just after th e deliver y.

cyclosp or in e. W h ich of t h e follow in g act ion s m ost likely

Th e reason for th is t reat m en t w as m ost likely to preven t

m ediated th e th erapeu t ic e ect of th e drug in th e p at ien t’s

w h ich of th e follow ing even ts?

d isease?

A. Placen t al crossing of fet al er yth rocytes in su bsequ en t

A. St im ulat ion of syn th esis of t u m or n ecrosis factor

pregn an cies

B. St im ulat ion of B-cell di eren t iat ion in to m em or y B cells

B. Product ion of an t ibodies again st fetal Rh o(D)-posit ive

C. In h ibit ion of th e apoptosis path w ay in target cells

er yth rocytes

D. St im ulat ion of gen e expression for in terleukin -2 prod uct ion

C. Th e m ot h er’s h em olyt ic d isease in su bsequ en t p regn an cies

E. In h ibit ion of calcin eurin en zym e

D. Product ion of fetal Rh o(D)-posit ive er yth rocytes in su b sequ en t p regn an cies E. Placen t al crossing of fetal Rh o(D) an t ibodies in su bsequ en t pregn an cies

Questions: VII-5 Drugs for Arthritis and Gout Directions for questions 1−4

drugs (NSAIDs), bu t 2 m on th s later, th e physician d ecid ed to


ad d a d isease-m od ifyin g an t irh eu m at ic d r ug (DMARD) to


th e th erapeut ic regim en . W h ich of th e follow ing is m ost likely

A. Allopu rin ol B. Azath iop rin e

th e m ain advan t age of DMARDs over NSAIDs in th e t reat m en t of rh eum atoid arth rit is?

C. Colch icin e

A. To cau se few er adverse e ect s

D. Cyclosporin e

B. To slow d ow n t h e p rogression of bon e an d car t ilage dest r u ct ion

E. Et an ercept F.

In ixim ab

G. Hydroxych loroqu in e

C. To im p rove sym ptom s after on e w eek of th erapy D. To com pletely cu re th e disease, after 2 to 4 m on th s of th erapy

H. Le un om ide I.

Meth ot rexate

J.

Rit u xim ab

E. To com pletely abolish acu te join t pain

Di cult y level: Easy Di cult y level: Easy 1. An an t im alarial drug used in rh eum atoid arth rit is

6. A 33-year-old m an com plain ed to h is physician of low back p ain an d st i n ess t h at w ere greatest on aw aken ing in t h e m or n in g an d grad u ally im p roved t h rough ou t t h e day. Th e

Di cult y level: Easy 2. A m on oclon al an t ibody th at bin ds to CD20 B lym ph ocytes

Di cult y level: Easy 3. A m on oclon al an t ibody th at bin ds to t um or n ecrosis factor-α

Di cult y level: Easy 4. Th is drug can in h ibit th e syn th esis of in osin ic acid.

Di cult y level: Easy 5. A 52-year-old wom an recently diagnosed w ith m ild rheum atoid arthritis started a therapy w ith nonsteroidal antiin am m ator y

in term it ten t use of ibuprofen h ad been able to im prove th e sym ptom s in th e p ast , bu t recen tly h e h ad n o relief. Magn et ic reson an ce im aging con rm ed th e diagn osis of an kylosing spon dylit is. W h ich of th e follow ing drugs w ou ld be ap prop riate for th e p at ien t at th is t im e? A. Hydroxych loroqu in e B. Trast u zu m ab C. Et an ercept D. Naproxen E. Colch icin e F.

Aldesleukin

Questions: VII-5 Drugs for Arthritis and Gout 379 Di cult y level: Easy

A. Cyclooxygen ase-1

7. A 50-year-old w om an w ith rheum atoid arthritis w as recently

B. Typ e II top oisom erase

d iagn osed w ith refractor y disease, an d in ixim ab w as ad ded

C. Dihydrofolate reduct ase

to h er ongoing t reat m en t . W h ich of th e follow ing en doge-

D. Dihydroorot ate dehydrogen ase

n ous com poun ds w as m ost likely th e m olecular t arget of th e

E. Reverse t ran scriptase

d rug?

F.

A. In terleukin -1 B. Vascular en doth elial grow th factor

Pept idyl t ran sferase

Di cult y level: Easy 11. A 55-year-old m an com plain ed to h is physician th at a rash

C. In terleukin -10 D. Epiderm al grow th factor

h ad appeared th e previous day on h is th orax an d legs. Th e

E. Tum or n ecrosis factor-α

p at ien t w as recen tly diagn osed w ith hyp eru ricem ia an d h ad been receiving allopu rin ol for 2 w eeks. Th e p hysician su spected the rash w as due to the ongoing pharm acotherapy an d

Di cult y level: Medium 8. A 48-year-old m an w as adm it ted to th e em ergen cy depar tm en t w ith th e ch ief com p lain t of an excru ciat ing p ain in h is left an kle. Th e pain h ad st ar ted th e previous n igh t an d in -

decided to discon t in u e allop u rin ol an d to st art a t reat m en t w ith probenecid. The physician should advise the patient not to con curren tly use w h ich of th e follow ing drugs?

creased over several h ou rs. Th e p at ien t rep or ted th at h e


sprain ed h is an kle 1 w eek ago. On p hysical exam in at ion , th e

B. Ibuprofen

an kle ap peared w arm an d ten der, an d th e en t ire area w as

C. Ph enyleph rin e

red an d sw ollen . A syn ovial

D. Aspirin

uid an alysis sh ow ed cr ystals

engu lfed by ph agocytes. A diagn osis w as m ad e, an d a ph ar-

E. Lorat adin e

m acoth erapy w as p rescribed. W h ich of th e follow ing drugs

F.

Diph en hydram in e

w ou ld be m ost app ropriate to t reat th e p at ien t’s pain ? A. Codein e


B. In dom eth acin

12. A 53-year-old w om an recen tly diagn osed w ith gou t y ar th ri-

C. Meth ot rexate

t is st arted a t reat m en t w ith a drug th at in h ibit s leu kocyte

D. Aspirin

m igrat ion an d p h agocytosis secon dar y to in h ibit ion of t u -

E. Et an ercept

bu lin polym erizat ion . W h ich of th e follow ing drugs did th e

F.

p at ien t m ost likely t ake?

Allopu rin ol

A. In dom eth acin

Di cult y level: Easy 9. A 57-year-old m an recen tly diagn osed w ith m ild rh eu m a-

B. Predn ison e C. Colch icin e

toid arth rit is com plain ed to h is physician of join t pain de-

D. Allopu rin ol

spite ongoing th erapy w ith ibu p rofen . Th e m an w as a h eavy

E. Proben ecid

sm oker and had a history of chronic bronch itis w ith frequent

F.

Piroxicam

acu te exacerbat ion s u su ally t reated w it h an t ibiot ics. Th e p hysician decided to add a disease-m odifying an t irh eum at ic


drug (DMARD) to the treatm ent. W h ich of the follow ing drugs

13. A 54-year-old Black w om an w as ad m it ted to t h e h osp it al

w ou ld be m ost app ropriate for th e p at ien t at th is t im e?

becau se of join t p ain an d a rash are of er yth em atou s m ac-

A. Le un om ide

u lopapular lesion s on h er n eck, upper ch est , an d elbow s. Th e

B. Hydroxych loroqu in e

p at ien t w as diagn osed w ith system ic lu pu s er yth em atosu s

C. Rit u xim ab

5 m onths earlier and had been receiving piroxicam since then.

D. Et an ercept

After furth er exam s, an oth er dr ug w as added to h er curren t

E. Azath iop rin e

p h arm acoth erapy. W h ich of th e follow ing drugs w ou ld be app ropriate to ad m in ister at th is t im e?


A. Aspirin

10. A 44-year-old w om an su ering from rh eum atoid ar th rit is

B. In dom eth acin

recen tly h ad le un om ide added to h er m eth ot rexate th er-

C. Am picillin

apy. Inhibition of w hich of the follow ing enzym es m ost likely

D. Hydroxych loroqu in e


E. Clarith rom ycin

d isease?

F.

Cipro oxacin

380



A. In dom eth acin

14. A 39-year-old w om an com plain ed to h er physician of join t

B. Et an ercept

p ain th at h ad w orsen ed over th e past m on th . Th e pain w as

C. Meth ot rexate

w orst in th e m orn ing an d p reven ted h er from p erform ing

D. Predn ison e

h er h ouseh old t asks for at least an h our after w aking. Sh e

E. Colch icin e

t ried ibu p rofen th ree t im es daily for 2 w eeks, bu t relief w as p oor, an d sh e stopp ed th e m edicat ion because of epigast ric


p ain . Th e w om an w as also su er ing from ch ron ic act ive

17. A 55-year-old m an recen tly diagn osed w ith hyperuricem ia

h epat it is B, cu rren tly t reated w ith lam ivudin e. On physical

star ted a t reat m en t w ith allopu rin ol. Plasm a levels of w h ich

exam in at ion , th e pat ien t appeared un com fort able w ith any

of th e follow ing pairs of en dogen ous com poun ds m ost likely

m ovem ent. Her w rists, m etacarpophalangeal joints, and knees

in creased after a few days of th erapy?

sh ow ed bilaterally sym m et r ical sw elling, ten d er n ess, an d

A. Guan in e an d xan th in e

w arm th. Further exam s con rm ed the diagnosis, and a phar-

B. Xan th in e an d hypoxan th in e

m acoth erapy w as p rescribed. W h ich of th e follow ing drugs

C. In osin e an d guan in e


D. Aden in e an d in osin e

A. Meth ot rexate

E. Aden in e an d hyp oxan th in e

B. Aspirin C. Et an ercept


D. Piperacillin

18. A 44-year-old w om an at a rout in e ch eck-up w as foun d to

E. Cipro oxacin

h ave a seru m urate level of 18 m g/dL an d a urin e urate level

F.

of 800 m g/24 h . Sh e st arted an appropriate t reat m en t , an d

Er yth rom ycin

3 w eeks later h er seru m u rate level w as 7.2 m g/dL an d u ri-


n ar y urate level w as 530 m g/24 h . W h ich of th e follow ing

15. A 32-year-old m an diagn osed w ith rh eum atoid arth rit is h ad

drugs did th e pat ien t m ost likely t ake?

been t akin g m et h ot rexate for 4 m on t h s. Th e d isease w as

A. Proben ecid

con t rolled in it ially, bu t t h e p ain ret u r n ed , an d h is rh eu m a-

B. Aspirin

tologist decided to add a drug to th e t reat m en t regim en . Th e

C. Fu rosem id e

secon d drug is a recom bin an t fu sion protein con sist ing of

D. Allopu rin ol

th e ext racellu lar port ion of t w o t u m or n ecrosis factor (TNF)

E. In dom eth acin

receptor m oiet ies. W h ich of th e follow ing drugs w as m ost

F.

Naproxen

likely prescribed ? A. In ixim ab


B. Et an ercept

19. A 43-year-old m an su er ing from rh eu m atoid ar th rit is

C. Le un om ide

com plain ed to h is physician th at h is join t pain h ad in creased

D. Triam cin olon e

recen tly despite curren t n aproxen an d hydroxych loroquin e

E. Cyclosporin e

t h erapy. Th e p at ien t w as ot h er w ise h ealthy, an d h is p ast

F.

m ed ical h istor y w as u n rem arkable. W h ich of th e follow in g

Piroxicam

d rugs w ou ld be ap prop riate to add to th e pat ien t’s th erapy


at th is t im e?

16. A 15-year-old girl w as adm it ted to th e em ergen cy depar t-

A. Diclofen ac

m en t becau se of a su dden at tack of severe abdom in al pain


accom p an ied by fever (103.5°F, 39.7°C). Th e p at ien t h ad

C. Meth ot rexate

h ad t w o sim ilar at t acks 3 an d 2 w eeks ago th at subsided

D. Fen t anyl

spon tan eou sly over th e cou rse of 48 h ou rs. Mu lt iple oth er


fam ily m em bers h ad sim ilar com plain t s. Physical exam in a-

F.

Carbam azepin e

t ion sh ow ed a p at ien t in m od erate dist ress w ith eviden ce of p leu ral e u sion in th e righ t lung. Gen et ic test ing sh ow ed a m u t at ion in a gen e of ch rom osom e 16. W h ich of th e follow ing drugs w ould m ost likely preven t th e recurren ce of th e at tacks in th is pat ien t?

Di cult y level: Medium 20. A 55-year-old m an com plain ed to h is physician of blu rred vision , n igh t blin dn ess, ligh t

ash es, an d ph otoph obia. Th e

m an w as diagnosed w ith m ild rheum atoid arthritis 6 m onths

Answers and Explanations: VII-1 Histam ine and Serotonin: Agonists and Antagonist s 381 ago an d w as t aking a com bin at ion th erapy th at in clu ded a

A. Hydroxych loroqu in e

disease-m odifying an t irh eu m at ic drug (DMARD). Oph th al-

B. Et an ercept

m oscopy disclosed a m acular area of hyperpigm entation sur-

C. Meth ot rexate

roun ded by a zon e of hypopigm en t at ion on th e left ret in a.

D. In ixim ab

W h ich of the follow ing drugs m ost likely caused the patien t’s

E. Ibuprofen


F.

Celecoxib

Answers and Explanations: VII-1 Histamine and Serotonin: Agonists and Antagonists Questions 1−3

ergot alkaloids in th e acu te t reat m en t of m igrain e at t ack.

1. E

Th ere are t w o m ajor proposed m ech an ism s for e ect iven ess

2. A

of t ript an s in acute m igrain e h eadach e:

3. B

• Vasocon st rict ion of cerebral vessels via th e act ivat ion of vascular 5-HT1B receptors

Learning objective: Outline the use of antihistam ines to treat systemic itching. 4. D Itch ing is som et im es caused by exposure to sun ligh t , espe-

• In h ib it ion of release of n e u rop e p t id es w it h in am m ator y p rop e r t ies via t h e act ivat ion of p resyn ap t ic 5 -HT1 D receptors

cially in th e elderly. Because h ist am in e is m ost often involved

Tr ipt an s are n ot in ten d ed for u se in t h e p rop hyla xis of

in itching, h istam ine H1 antagonists are e ective antipruritics.

m igrain e.

In th is case, a secon d-gen erat ion an t ih istam in e is th e appro-

A Bet a-blockers are e ect ive for th e prophylaxis of m i-

priate ch oice, as th e patien t h as p rost at ic hyper t rop hy, w h ich

grain e in som e pat ien t s, bu t th ey are of n o value in th e t reat -

con t rain dicates

m en t of an ongoing m igrain e at t ack.

rst -gen erat ion an t ih ist am in es becau se of

th eir an t im uscarin ic propert ies. A, B See correct an sw er explan at ion .

B, C, E, F Dr ugs act ing on t h ese receptors can n ot cu re a m igrain e at t ack.

C, E, F Th ese drugs lack an t iprurit ic proper t ies.

Learning objective: Outline the clinical uses of antihistam ines. Learning objective: Explain the m echanism of antim igraine action of ergot alkaloids.

7. D Drugs u su ally given to preven t an acute allergic react ion in

5. A Th e e ect iven ess of ergot alkaloids in m igrain e seem s to

n ists. First-gen erat ion H1 an t agon ists are gen erally preferred

be p rim arily related to th eir cerebral vasocon st rict ing e ect s,

w h en drug-in duced sedation m ay be useful to redu ce fear re-

w h ich are apparen tly du e to act ivat ion of both α adren ocep -

lated to th e p rocedu re, as in th is case.

tors an d seroton in (5-HT) receptors. Th e path ophysiology of

pat ien ts at risk are glu cocor t icoids an d h ist am in e H1 an t ago-

A−C, E, F Th ese drugs are devoid of an t iallergic propert ies.

m igrain e seem s to in clude a vasom otor com pon en t , because am plitude of tem poral artery pulsat ions; ergotam ine can di-

Learning objective: Explain the reason for ergonovine use in postpartum bleeding.

m in ish these pulsations. Other m echan ism s are probably also

8. E Uterin e atony (absen ce of u terin e con t ract u re follow ing th e

operat ive. For exam ple, ergotam in e blocks in am m at ion of

deliver y of th e p lacen ta) is th e m ost com m on cau se of p ost-

t h e t r igem in al n eu rovascu lar system . Th is act ion , p ossibly

par t u m h em orrh age. W h en th e h em orrh age d oes n ot resp on d

m ediated by act ivat ion of 5-HT receptors, m ay be respon sible

to oxytocin adm in ist rat ion , ergot alkaloids m ay be u sed to

for both th e pain -relieving an d th e vasocon st rict ing e ects of

decrease bleeding. Th e u teru s at term is ext rem ely sen sit ive

ergot alkaloid s.

to th e st im u lan t act ion of ergot alkaloids, an d even an in ter-

th e on set of h eadach e is som et im es associated w ith increased

B−E Ergotam in e does n ot cause th ese e ect s. Moreover,

m ediate dose produces a prolonged an d pow erful spasm of

th ese e ect s w ould in crease, n ot decrease, th e risk of a m i-

th e m u scle th at squ eezes th e uterin e vessels, th us con t rolling

grain e at t ack.

bleeding. A Ergot am in e can con st rict u terin e ar teries, but th is is n ot

Learning objective: Explain the m echanism of the antim igraine action of 5-HT1B/1D serotonin agonists. 6. D Tript an s (e.g., sum at ript an an d zolm it ript an ) are speci c 5-HT1B/1D agon ist s th at are equ ally as or m ore e ect ive th an

the m ain reason w hy the drug can stop postpartum bleeding. B−D Ergot am in e does n ot h ave th ese e ect s.

382


Learning objective: Explain the m echanism of action of histam ine H1 -receptor antagonists. 9. D Dip h en hyd ram in e is a

rst -gen erat ion h ist am in e H 1 -

5-HT2 receptors in th e hyp oth alam u s. In fact , cyp roh ept adin e h as been u sed to t reat an orexia, w ith m ixed resu lts. A−D, F See correct an sw er explan at ion .

receptor an t agon ist . Most drugs of th is class can also block m uscarin ic receptors. Th e dr ug easily crosses th e blood−

Learning objective: Describe the contraindications of triptans.

brain bar r ier an d can block H1 receptors an d m u scar in ic

14. C Tript an s are con t rain dicated in pat ien ts w ith kn ow n or

receptors located in vest ibular nuclei an d in th e n ucleu s of

su spected coron ar y arter y d isease, becau se rare bu t seriou s

th e t ract u s solitariu s, th u s decreasing th e

adverse card iac e ects, in clu ding h ear t at tacks, life-th reat-

ring from th ese

n u clei to th e vom it ing cen ter. A−C, E All of t h ese opt ion s h ave at least on e receptor t h at is n ot involved in th e m ech an ism of n ausea an d vom it ing.

en ing dist u rban ces of cardiac rhyth m , an d death , h ave been repor ted w ith in a few h ours of receiving on e of th ese drugs. Th e m ech an ism of th is adverse e ect is likely related to th e vasocon st rict ing act ion s of th ese drugs.

Learning objective: Describe the adverse e ects of ergot alkaloids. 10. C Ergot alkaloids con st rict m ost h u m an blood vessels an d

A, B, D, E All of th ese drugs are u sed in th e acu te th erapy an d/or in preven t ion of m igrain e h eadach e.

can cau se p rolonged vasosp asm w h en h igh d oses are given . result in gangren e. Th e vasospasm is refractor y to m ost va-

Learning objective: Describe the m ost com m on adverse e ect s of ergotamine.

sodilators, bu t n it rop ru sside or n it roglycerin in fu sion m ay

15. E Ergot alkaloid s cau se n au sea an d vom it ing in abou t 10%

Th e vasospasm m ain ly a ect s th e arm s an d legs an d m ay

be su ccessfu l, as in th is case. A, B, D−F All of th ese drugs can be u sed to relieve h eadach e, bu t th ey do n ot cau se p erip h eral vasospasm .

of p at ien t s. Th e e ect is m ost likely d u e to act ivat ion of d op am in e D2 an d seroton in 5-HT3 receptors in t h e ch em o receptor t rigger zon e. A Hallucin at ion s occu r on ly after adm in ist rat ion of toxic

Learning objective: Describe the adverse e ect s of sum atriptan. 11. C Sym ptom s of ch est p ressu re or t igh t n ess h ave been rep orted in u p to 40% of pat ien t s t reated w ith subcu tan eou s su m at riptan . Th ese sym ptom s, m ost likely du e to th e seroton in 5-HT1B-m ediated vasocon st rict ing act ion of th e drug,

doses of ergot alkaloids. B, C Ergot am in e h as pow erfu l vasocon st rict ing act ion s. Th erefore, th ese e ects are u n likely. D Adyn am ic ileu s is un likely because ergot am in e h as st im u lan t e ect s on sm ooth m u scle.

are rarely serious, but in som e cases th e drug can cause corA, B, D, F Th ese drugs are u sed for th e t reat m en t or p ro-

Learning objective: Describe the postreceptor m echanism of histamine H1 -receptor antagonists.

phylaxis of m igrain e, bu t th ey do n ot cau se th e sym ptom s

16. C Lorat ad in e is a h ist am in e H 1 -receptor an t agon ist . Act i-

on ar y vasospasm an d m yocardial in farct ion .

repor ted by th e pat ien t . E Antihistam ines are not used for m igraine prophylaxis, and they do not cause the sym ptom s reported by the patient.

vat ion of H1 receptors in creases t h e syn t h esis of in ositolt r ip h osp h ate an d diacylglycerol, w h ich in t u rn in creases th e cytoplasm ic Ca 2+ con cen t rat ion in target cells. Most h ist am ine e ects due to activation of H1 receptors are m ediated by

Learning objective: Describe the m echanism of action of antihistamines.

th is in creased availabilit y of cytoplasm ic Ca 2+. By blocking

12. E Drugs e ective against hay fever are histam ine H1 -receptor

t riph osp h ate an d diacylglycerol, th u s an t agon izing all h ista-

com pet it ive an tagon ists. Com pet it ive m ean s th at th e bin ding to th e receptor is reversible; th at is, th e an t agon ism is

H1 receptors, loratadin e decreases th e syn th esis of in ositolm in e e ects m ed iated by act ivat ion of H1 receptors. A, B, D, E See correct an sw er exp lan at ion .

ph arm acological an d surm ou n table. A−D, F H1 an t agon ists h ave n egligible blocking act ivit y again st H2 an d H3 receptors.

Learning objective: Explain the m echanism of action of cyproheptadine.

Learning objective: Explain the mechanism of action of loratadine. 17. E Hist am in e H1 an tagon ist s such as lorat adin e are used in allergic d isorders becau se th ey block H1 receptors in m ost periph eral organ s an d t issu es. In th is w ay, th ey p reven t m ost h istam in e-in du ced e ects.

rst-gen erat ion H1 an tagon ist . Like

A Alth ough som e secon d-gen erat ion an t ih ist am in es can

oth er dr ugs of th is class, it can also block m uscarin ic an d

block h istam in e release, th is is n ot th e m ain m ech an ism of

seroton ergic receptors (m ain ly 5-HT2 ). Th e blockade of M 3

th e an t iallergic act ion of th ese drugs.

13. E Cyproh eptadin e is a

receptors explain s th e dr y m outh , con st ipat ion , an d dysuria, w h ile th e in crease in appet ite w as likely due to blockade of

B−D Loratadin e does n ot cause th ese e ect s.

Answers and Explanations: VII-1 Histam ine and Serotonin: Agonists and Antagonist s 383 Learning objective: Describe the adverse e ects of ergot alkaloids.

B, C On dan set ron an d dron abin ol are an t iem et ic d rugs,

18. C Ergot alkaloids can cau se periph eral vasospasm th at can

bu t th ey are n ot e ect ive w h en n au sea an d vom it ing are du e

lead to pain , n u m bn ess, an d t ingling of th e ngers an d toes. The vasospasm , likely due to activation of α adrenoceptors and seroton in receptors, is often refractor y to m ost vasodilators. A, B, D, E Th ese drugs do n ot cau se p erip h eral vasospasm .

to vest ibular dist urban ces. D, F Ergot am in e an d propran olol h ave n o e ect on vest ib ular dist u rban ces. E Lorat ad in e is a secon d -gen erat ion H 1 receptor an t ago n ist t h at d oes n ot cross t h e blood −brain bar r ier e ect ively

Learning objective: Describe the m ain contraindications of ergot alkaloids. 19. C Ergot alkaloid s such as ergotam in e are con t rain dicated in p at ien ts w ith coron ar y arter y d isease an d periph eral vascu-

an d so can n ot reach th e n u cleu s of th e t ract u s solitariu s.

Learning objective: Describe the adverse e ect s of diphenhydramine.

lar d isease becau se of th e vasocon st rict ing p rop er t ies of

22. C First-gen erat ion h ist am in e H1 an tagon ists su ch as diph en -

t h ese d r ugs. It is even recom m en d ed t h at ergot am in e n ot

hyd ram in e can cau se p ron ou n ced sedat ion becau se t h ey

be given to p at ien t s in w h om u n recogn ized coron ar y ar ter y

are able to cross th e blood−brain barrier. Th is e ect is m ore

d isease can be p red icted by t h e p resen ce of r isk factors (hy-

likely if th e p at ien t is already receiving an oth er sedat ive

p erten sion , hyperch olesterolem ia, sm oking, obesit y, etc.), as

drug, as in th is case.

in th is case. A, B, D−F Th ese drugs are u sed for th e t reat m en t of m igrain e, an d th ey are n ot con t rain dicated in th is pat ien t .

A Secon d-gen erat ion H1 an tagon ists are devoid of cen t ral dep ressive e ects. B Glu cocort icoid-in duced cen t ral depressan t e ect s are ver y rare.

Learning objective: Identify the endogenous compound that has its histamine-induced release blocked by H1 -receptor antagonists. 20. D Loratadin e is a h ist am in e H1 -receptor an t agon ist . Act ivat ion of H1 receptors on vascular en doth elium causes th e release of n itric oxide, w h ich is involved in th e vasodilat ion ,

D−F All of th ese drugs can cause sedat ion , bu t th ey are n ot used to t reat allergic disorders.

Learning objective: Outline the pharm acotherapy of system ic mastocytosis.

vascu lar p erm eabilit y, an d ed em a associated w it h acu te

23. C System ic m astocytosis is a disease of un kn ow n origin

in am m at ion . By blocking H1 receptors, lorat adin e in h ibit s

ch aracterized by an excessive accum ulat ion of m ast cells in

n it ric oxide release, th u s exer ting a u seful an t iin am m ator y

variou s body t issu es. Most sym ptom s of th e d isease are du e

resp on se.

to th e ext rem ely h igh plasm a levels of h istam in e. Treat m en t

A–C Hist am in e can in duce th e release of th ese en dogen ous com poun ds, but th is release is m ediated by th e act ivat ion of H2 receptors an d th erefore can n ot be an t agon ized by H1 -receptor an t agon ist s. E Hist am in e does n ot cause th e release of bradykin in .

w ith H1 an d H2 an t agon ist s rep resen t s a rat ion al th erapy. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Identify the drug used for m igraine prophylaxis in a pregnant wom an. 24. B Prop ran olol is th e drug of ch oice for m igrain e h eadach e

Learning objective: Outline the use of antihistam ines in benign positional vertigo.

p rop hyla xis becau se of it s e

21. A Th e sym ptom s of th e pat ien t an d th e provocat ive test in di-

an d Drug Adm in ist rat ion for preven t ion of m igrain e h ead -

cate th at h e w as m ost likely a ected by ben ign posit ion al

ach e, bu t th eir m ech an ism of act ion in th is disease rem ain s

vert igo, a violen t vert igo last ing less th an 30 secon ds an d

u n cert ain .

cacy an d favorable adverse

e ect p ro le. Beta-blockers are app roved by th e U.S. Food

induced by certain head positions. The disorder is m ost likely

A, C Ergot alkaloids are absolu tely con t rain dicated in preg-

d ue to form at ion of gran u lar m asses in th e cupu la of th e

n an t w om en becau se th ey could cause abor t ion due to th e

sem icircu lar can als. First-gen erat ion an t ih istam in es su ch as

in duct ion of p ow erfu l u terin e con t ract u re.

d iph en hydram in e are often used to t reat vest ibu lar dist u r-

D Valproic acid is an an t iepilept ic drug approved for pre-

ban ces su ch as p osit ion al vert igo an d Men iere syn drom e.

ven t ion of m igrain e h eadach e. How ever, it is con t rain dicated

Th e ben e cial e ect is m ost likely du e to blockad e of h ist a-

in p regn an t w om en becau se of it s su bst an t ial teratogen ic

m in e H1 receptors in th e n u cleus of th e t ract us solitarius

risk.

(vest ibu lar path w ays in clude h istam in ergic a eren ts to th e n ucleus of th e t ract u s solitarius an d to vest ibu lar n uclei).

E Tript an s are used to t reat an im pen ding m igrain e at t ack, n ot for ch ron ic prophylaxis.

384


Learning objective: Describe the pharm acological e ects of histamine H1 -receptor antagonists.

Learning objective: Identify the drug that likely caused anticholinergic symptoms of drug overdose poisoning.

25. A First-gen erat ion h ist am in e H1 an tagon ists su ch as dip h en -

28. B Th e p at ien t’s syn drom e in dicated th at h e w as p oison ed by

hydram in e h ave sign i can t blocking act ivit y on m u scarin ic

an anticholinergic drug. First-generation antihistam ines such

receptors. Th is act ion relaxes the bladder det ru sor, an e ect

as diph en hydram in e h ave sign i can t an t im u scarin ic e ects,

th at is w ith out clin ical con sequen ces in n orm ally h ealthy

an d acu te poison ing by th ese drugs is rem arkably sim ilar to

peop le, bu t th at can fu r th er im pair th e voiding of th e blad -

th at of at ropin e p oison ing.

der in m en w ith prostat ic hypert rophy, as in th is case.

A, C, D Th ese drugs do n ot h ave an t im u scarin ic e ect s.

B Th e bladder extern al sph in cter in cludes st riated m u scle

E Th is d r ug is a secon d -gen erat ion an t ih ist am in e. Un -

an d is n ot u n d er t h e con t rol of t h e au ton om ic n er vou s

like rst-gen erat ion , secon d -gen erat ion drugs are devoid of

system .

blocking act ivit y on m u scarin ic receptors.

C The prostate capsule is con stricted via α 1 receptors. Most an t ih ist am in es h ave n egligible e ect s on th ese receptors. D Th e bladder in tern al sph in cter h as m ainly α 1 receptors.

F As st ated above, th e pat ien t w as p oison ed by an an t im u scarin ic d r ug. How ever, at rop in e is u n likely, as th e d r ug is n ot used to t reat allergic sym ptom s.

Most an t ih ist am in es h ave n egligible e ect s on t h ese receptors. E An t ih istam in es h ave n egligible e ects on diuresis.

Learning objective: Identify a drug that can aggravate open-angle glaucoma. 29. D Diph en hydram in e is a

rst-gen erat ion h istam in e H1 an -

Learning objective: Describe the adverse e ect s due to selective serotonin reuptake inhibitor−triptan interaction.

t agon ist w it h p ron ou n ced sedat ive p rop er t ies. Becau se of

26. B Th e pat ien t’s h istor y an d sym ptom s in dicate th e sh e w as

t ion s for in som n ia. First -gen erat ion H1 an t agon ist s h ave

m ost likely su ering from seroton in syn drom e, a rare bu t

prom in en t an t im uscarin ic act ion s. By blocking M 3 receptors

p oten t ially fat al disorder th at is related to an in ap propriate

in th e ciliar y m u scle, th ese drugs can n arrow th e sp aces of

in crease of seroton ergic t ran sm ission in th e cen t ral n er vou s

th e t rabecu lar m esh w ork an d th e lu m en of Sch lem m can al,

system (CNS). Th e syn d rom e can be cau sed by several d rugs

th u s h in d ering th e ou t ow of th e aqu eou s h u m or.

eith er alon e or in com bin at ion , especially w h en given in

t h is, t h e d r ug is a com p on en t of over-t h e-cou n ter p rep ara-


h igh doses. Th e com bin at ion of t w o dr ugs th at en h an ce seroton in t ran sm ission can be par t icularly dangerous. In th is case, th e pat ien t w as t aking paroxet in e, a select ive seroton in reupt ake in h ibitor (SSRI). Th e addit ion of sum at ript an , a seroton in agon ist , m ost likely t riggered th e syn drom e. Th e U.S. Food an d Drug Adm in ist rat ion h as issued a w arn ing again st th e con com it an t u se of SSRIs an d t ript an s.

Learning objective: Explain why second-generation histam ine H1 antagonists are preferred over rst-generation for the local treatm ent of allergic conjunctivitis. 30. A Un like rst-gen erat ion H1 an tagon ist s, secon d-gen erat ion H1 an tagon ists are devoid of blocking act ivit y on m u scarin ic receptors. Th erefore, th ey do n ot h ave e ects on p u p il size

A, C−F Non e of t h ese d r ugs cau se an in crease in seroto n ergic t ran sm ission in th e CNS.

an d accom m odat ion w h en applied in to th e conjun ct ival sac. This explains w hy only second-generation H1 antagonists are u sed locally in allergic conju n ct ivit is.

Learning objective: Identify the central site of action of sumatriptan.

B Secon d -gen erat ion H1 an t agon ist s d o n ot ap p reciably

rst -lin e

cross t h e blood −brain bar r ier an d are t h erefore free of cen -

agen t s for th e abort ive th erapy of acu te, severe m igrain e at-

t ral n er vou s system p rop er t ies. How ever, at m ost , t h is is a

t acks. Th e path ophysiology of m igrain e rem ain s u n kn ow n ,

m in or advan t age w h en t h ey are u sed locally in t h e eye be-

bu t th e cu rren t view is th at a com plex series of n eu ral an d

cau se t h e system ic absor pt ion of t h ese d r ugs from t h e eye

vascu lar even t s in it iates m igrain e (th e so-called n eu rovas-

is n egligible.

27. B Su m at r ipt an an d it s con gen ers are cu r ren t ly

cu lar th eor y). Th e th eor y states th at act ivat ion of th e n u -

C By blocking H1 receptors, bot h rst - an d secon d -gen er-

cleu s cau dalis of th e t rigem in al n er ve leads to th e release

at ion H 1 an t agon ist s an t agon ize h ist am in e-in d u ced vaso-

of several poten t vasodilat ing n europept ides, w h ich in t urn

dilat ion .

cau ses dilat ion of cerebral blood vessels. Th is vasodilat ion

D An t ih istam in es are devoid of an t ibacterial act ivit y.

seem s to be a m ajor cau se of th e th robbing h eadach e of th e

E Un like

rst-gen erat ion , secon d-gen erat ion H1 an t ago-

m igrain e at t ack. By act ivat ing p resyn apt ic seroton in 5-HT1D

n ist s do n ot a ect secret ion of lacrim al glan ds becau se th ey

receptors on t rigem in al n er ve en dings, t riptan s can p reven t

are devoid of m uscarin ic M 3 - -receptor blocking act ivit y.

th e release of vasodilat ing n eu rop ept ides. A, C−F See correct an sw er exp lan at ion .

Answers and Explanations: VII-2 Eicosanoids: Agonists, Antagonists, and Inhibitors 385 Learning objective: Explain the m echanism of action of crom olyn sodium . 31. B Th e available t h erap eu t ic opt ion s for m an agem en t of allergic conju n ct ivit is in clu d e ocu lar adm in ist rat ion of an t ih istam in es, decongestan t s, n on steroidal an t iin am m ator y drugs (NSAIDs), an d m ast cell stabilizers. Ch rom on e derivat ives su ch as crom olyn sodiu m are drugs th at can stabilize m ast cells (but n ot basoph ils), th u s in h ibit ing th e release of ch em ical m ediators from th ese cells. A Th is is th e m ech an ism of act ion of an t ih ist am in es.

HISTAMINE AND SEROTONIN: AGONISTS AND ANTAGONISTS Answ er key 1. 2. 3. 4. 5.

E A B D A

6. 7. 8. 9. 10.

D D E D C

11. 12. 13. 14. 15.

C E E C E

16. 17. 18. 19. 20.

C E C C D

21. 22. 23. 24. 25.

A C C B A

26. 27. 28. 29. 30. 31.

B B B D A B

C Th is is th e m ech an ism of act ion of NSAIDs. D Th is is th e m ech an ism of act ion of za rlukast . E Th is is th e m ech an ism of act ion of decongestan ts.

Answers and Explanations: VII-2 Eicosanoids: Agonists, Antagonists, and Inhibitors Directions: questions 1−6

Learning objective: Outline the therapeutic uses of dinoprostone.

1. F

8. B Prostaglan din s E an d F are able to term in ate p regn an cy at

2. E

any stage by prom ot ing uterin e con t ract ion s. Th ey are also

3. D

able to ripen th e cer vix (i.e., to m ake it softer) by in creasing

4. C

proteoglycan con ten t an d ch anging th e biop hysical p rop er-

5. B

t ies of collagen . Din oproston e, a syn th et ic prost aglan din E2 , is adm in istered

Learning objective: Explain the m echanism of the antiglaucom a action of latanoprost.

in t ravagin ally for rip en ing of th e cer vix in pregn an t w om en at

6. C Latan oprost is a prost aglan din F2α an alogu e th at low ers th e

in du ct ion of labor.

or n ear term w h ose cer vix is n ot yet soft en ough for oxytocin

in t raocu lar p ressure by in creasing th e ou t ow of aqu eous

A Th rom boxan es are n ot used as drugs.

h u m or th rough th e uveoscleral route. Th e e ect iven ess of th e

C Ergon ovin e can cau se u ter in e con t ract ion s bu t h as n o

d rug is sim ilar to th at of t im olol. Moreover, latan op rost h as addit ive e ects w h en adm in istered w ith β-blockers or α 2 adren ergic agon ist s. A, E Th ese are m ech an ism s of act ion of ch olin ergic drugs. B Th is is t h e m ech an ism of act ion of β-blockers or α 2 agon ists. D Th is is t h e m ech an ism of act ion of α agon ist s su ch as ep in ep h rin e an d p h enylep h rin e.

cer vical ripen ing proper t ies. D−F Beta-2 agon ists an d n on steroidal ant iin am m ator y drugs h ave u terin e relaxan t p ropert ies, an d th ey are devoid of cer vical ripen ing proper t ies.

Learning objective: Outline the therapeutic uses of dinoprostone. 9. E In case of in t rau terin e fet al death , p rostaglan din s alon e or w ith oxytocin can cause d eliver y e ect ively. Din op roston e (p rostaglan din E2 ) is th e prostaglan din curren tly used for th is

Learning objective: Explain the m olecular m echanism of action of alprostadil in erection disorders. 7. A Alp rost ad il is syn t h et ic p rost aglan din E1 . W h en given by

pu rp ose. A−C Th ese drugs do n ot h ave oxytocic propert ies. D Ergot alkaloids such as ergon ovin e can evoke rhyth m ic

in t raureth ral adm in ist rat ion , alprost adil acts by act ivat ing

con t ract ion an d relaxat ion of th e uteru s w h en given in ver y

prostaglandin E1 G protein−coupled receptors in penile vessels.

sm all doses. At h igh er con cen t rat ion s, h ow ever, th ese drugs

Th is act ivat ion st im u lates adenylyl cyclase, th u s in creasing

elicit p oten t ially dangerou s pow erfu l an d p rolonged con t rac-

th e produ ct ion of cyclic aden osin e m on op h osp h ate (cAMP).

t u re an d th erefore are n ot u sed to cau se deliver y.

An in creased cAMP level in creases Ca 2+ e

u x an d decreases

ph osp h or ylat ion of m yosin ligh t ch ain both in vascu lar an d n onvascu lar sm oot h m u scle, t h u s leading to m u scle rela xat ion . Th is rela xat ion allow s in creased in ow of blood in to corpora cavern osa, th us causing pen ile erect ion . B−F See correct an sw er explan at ion .

386


Learning objective: Explain the m olecular m echanism of action of zileuton.

Learning objective: Explain the m olecular m echanism of action of epoprostenol.

10. B Zileuton is an in h ibitor of 5-lipoxygen ase, preven t ing leu -

13. E Epoprosten ol is a syn th et ic prost acyclin (prost aglan din I2 )

kot rien e syn th esis. It im proves asth m a con t rol an d redu ces

th at h as pow erful vasodilat ing act ivit y. Th e dr ug h as been

t h e frequ en cy of ast h m a exacerbat ion , alt h ough it s e ect s

approved for th e t reat m en t of prim ar y pulm on ar y hyper-

are less m arked t h an t h ose of in h aled glu cocor t icoid s. Th e

ten sion , a disease of un kn ow n cause involving obliterat ion

m ain advan tage of th e d rug is th at it can be t aken orally.

of m edium an d sm all pulm on ar y ar teries an d resu lt ing in


righ t ven t ricu lar failu re or fat al syn cop e 2 to 5 years after detect ion . Ep op rosten ol act ivates sp eci c p rost aglan d in I2

Learning objective: Identify the drug used to induce m edical abortion.

receptors, cau sing rela xat ion of p u lm on ar y ar ter ies. Long-

11. E The prescribed treatm ent m ost likely included m ifepriston e

e ect ive in im proving sym ptom s an d p rolonging su r vival.

an d m isop rostol, th e m ost com m on

rst-t rim ester m ed ical

ter m t h erapy w it h t h is d r ug h as been fou n d to be h igh ly A−D See correct an sw er explan at ion .

abor t ion regim en . In th e p resen ce of p rogesteron e, m ifep risin h ibit ion of progesteron e act ion s on th e uterus in th e early

Learning objective: Identify the eicosanoid that is increased during bleeding episodes.

stage of p regn an cy cau ses decidu al breakd ow n , w h ich leads

14. F Activation of the th rom boxan e pathw ay is on e of th e body’s

to d et ach m en t of t h e blastocyst . Misop rostol, t aken 24 to

d efen ses again st bleed ing. W h en bleed ing occu rs, th rom -

48 h ou rs later cau ses u terin e con t ract ion s th at exp el th e

boxan es (m ain ly A2 ) are syn th esized an d released from cells

u terin e con ten t s. Th is m edical abor t ion regim en term in ates

in th e bleeding area. Th rom boxan es are p ow erfu l vasocon -

p regn an cy in over 95% of w om en t reated du ring th e

st rict ing agen ts th at p rom ote p latelet aggregat ion an d am -

ton e act s as an an t agon ist at progesteron e receptors. Th e

rst 7

w eeks after con cept ion . A, B Large d oses of th ese drugs can cau se abort ion an d w ere u sed in th e p ast to in du ce st reet abort ion s, bu t th ey are n ot u sed for m edically in du ced abor t ion . C, D Th ese drugs do n ot cause abort ion .

plify the e ect of other platelet-aggregating substances, such as th rom bin . Both vasocon st rict ion an d platelet aggregat ion h elp to block bleeding. A−E All of th ese en dogen ou s substan ces are vasodilators, so th eir release follow ing bleed ing is un likely.

Learning objective: Outline the therapeutic uses of alprostadil.

Learning objective: Describe the ocular e ects of latanoprost.

12. B W h en a baby is born w ith a congen ital h eart disease

15. D Lat an oprost is a syn th et ic p rostaglan din F2α th at low ers

(t ran sposit ion of th e great arteries, pulm on ar y arter y sten o-

th e in t raocular pressure w ith ou t a ect ing th e len s cur va-

sis, etc.), it is im p or t an t to m ain t ain th e p aten cy of th e du c-

t u re or pu p illar y diam eter. Th is is becau se it in creases th e

t u s ar teriosus before correct ive surger y. Paten cy of th e fetal

out ow of the aqueous hum or through the uveoscleral route,

d u ct u s ar ter iosu s d ep en ds p r im ar ily on p rost aglan d in E2

w h ich is di eren t from th e Sch lem m can al route. Drugs th at

an d to a lesser exten t on prost aglan din E1 . At bir th , p rost a-

in crease ou t ow of th e aqueous h u m or th rough th e Sch lem m

glan din E1 an d E2 levels are redu ced becau se th e in creased

can al cau se in creased len s cu r vat u re an d m iosis.

blood oxygen speeds u p prost aglan din m et abolism , so th e


du ct u s ar teriosu s closes in 1 or 2 days. Alp rost adil is a syn du ct u s ar teriosu s w h en given after bir th . Becau se it is m e-

Learning objective: Identify the enzym e that catalyzes prostaglandin biosynthesis during in ammation.

tabolized qu ickly (th e h alf-life is abou t 10 m in u tes), it m u st

16. B Cyclooxygen ases are th e en zym es th at catalyze prost a-

th et ic prostaglan din E1 th at can m ain tain th e paten cy of th e

be given by con t in u ou s in fu sion .

glan din an d th rom boxan e biosyn th esis. Tw o di eren t iso-

A Cyclooxygen ase in hibitors su ch as in dom eth acin in h ibit

form s of cyclooxygen ase h ave been foun d: cyclooxygen ase-1

th e syn th esis of prost aglan din E2 an d th erefore are u sed to

(COX-1) an d cyclooxygen ase-2 (COX-2). W h ereas COX-1 is

speed u p th e closu re of th e du ct us arteriosu s in case of de-

expressed in m ost t issues of th e body an d ten ds to be h o-

layed closu re, w h ich is com m on in p rem at u re in fan t s.

m eost at ic in fu n ct ion , in am m ator y m ed iators su ch as cy-

C, E Din oproston e, a syn th et ic prostaglan din E2 , an d m iso-

tokin es upregulate COX-2 expression , leading to h igh levels

p rostol, a p rost aglan d in E1 an alogu e, h ave act ivit y on t h e

of COX-2 in in am ed t issues. COX-2, in t urn , catalyzes th e

d u ct u s ar ter iosu s, bu t t h ey are n ot available for p aren teral

syn th esis of prost aglan din E2 an d prost aglan din I2 , th e p re-

u se. D Latanoprost is devoid of actions on the ductus arteriosus.

dom inant prostaglan din s associated w ith in am m ation . Both m arkedly en h an ce edem a form at ion an d leukocyte in lt rat ion in th e in am ed area.

Answers and Explanations: VII-3 Nonsteroidal Antiin am m atory Drugs 387

D Th is en zym e is involved in liver disease.

Learning objective: Describe the action that m ediates the therapeutic use of m isoprostol.

C, E, F See correct an sw er explan at ion .

20. D Th e pat ien t’s h istor y an d sym ptom s suggest th at sh e w as

A Th is en zym e is involved in t issue n ecrosis.

at risk of n on steroidal an t iin am m ator y drug (NSAID)−in -

Learning objective: Describe the adverse e ect s of prostaglandin E2 .

d uced u lcer. Th e p revalen ce of en doscop ically con rm ed

17. C Dysm en orrh ea is a com m on disorder th at u su ally star t s

W h en pept ic ulcers develop in pat ien t s taking NSAIDs, th e

d uring adolescen ce an d ten d s to decrease w ith age an d after

p referred app roach is to stop th e NSAID an d to give an an t i-

p regn an cy. Prost aglan d in E2 , p rod u ced by t h e secretor y en -

u lcer drug, usually a proton pum p in h ibitor or a h ist am in e

dom et r iu m , h as a p ow er fu l con t ract in g e ect on u ter in e

H2 an t agon ist . Prophylact ic th erapy sh ould be con sidered for

sm oot h m u scle an d is m ost likely t h e p r im ar y factor re-

patien ts w h o are un able to discon t in ue NSAID th erapy, as in

sp on sible for dysm en or rh ea. Ibu p rofen is a n on steroidal

th is case. Misoprostol, a syn th et ic an alogu e of prostaglan din

an t iin am m ator y d r ug from t h e p rop ion ic acid class. By

E1 , is th e drug m ost often p rescribed, as it is able to preven t

blocking p rost aglan d in biosyn th esis, th ese drugs can relieve

(but n ot to t reat) NSAID-in duced u lcers. Th is preven t ive ef-

dysm en orrh ea.

fect is m ost likely due to th e follow ing m ech an ism s:

p ept ic u lcer in NSAID u sers is 15 to 30% in th e Un ited States.

A, B, D, E All of th ese com p ou n d s are u terin e relaxan t s, n ot

• At low doses, m isop rostol act ivates p rost aglan d in re-

st im u lators of con t ract ion .

ceptors on su p er cial ep it h elial cells of t h e stom ach , in creasing bicarbon ate an d m u cu s secret ion (th e so-called

Learning objective: Describe the adverse e ect s of m isoprostol.

cytoprotect ive e ect). • At h igh er d oses, it act ivates p rost aglan d in receptors on

18. D Misoprostol is a prost aglan din E1 an alogue approved for preven t ion of n on steroidal an t iin am m ator y drug-in d u ced

pariet al cells of th e stom ach , decreasing gast ric acid se-

pept ic u lcers. Diarrh ea is th e m ost com m on adverse e ect of

cret ion (m ost likely th e m ain m ech an ism ).

th e drug (up to 30%of pat ien t s) an d is th e m ain reason for its

A Th ese are th e m ech an ism s of act ion of su cralfate or of

in frequ en t clin ical u se.

bism u t h com p ou n d s. Th ese d r ugs are m u ch less e ect ive


t h an m isop rostol w h en t h e u lcer is secon d ar y to ch ron ic ingest ion of NSAIDs.

Learning objective: Explain the algesic e ect of prostaglandins.

B Th is is th e m ech an ism of act ion of an t im u scarin ic drugs. These drugs are n o longer u sed as an t iulcer agen ts.

19. D W h en alp rostad il, a syn th et ic p rostaglan din E1 , is u sed in t rau reth rally to im p rove erect ile dysfu n ct ion , p en ile pain is

C Gast rin receptor blockers are n ot yet available.

th e m ost frequen t adverse e ect . Th e m ech an ism of th is ef-

E An t ibiot ic drugs are n ot used in NSAID-in duced pept ic

fect is m ost likely related to th e algesic act ion of prostaglan -

ulcer unless there is evidence of Helicobacter pylori infection .

din s. Th ese agen ts can low er th e th resh old of n ocicept ive a eren t n euron s, facilit at ing pain t ran sm ission to th e spin al

EICOSANOIDS: AGONISTS, ANTAGOINISTS, AND INHIBITORS Answ er key

cord. A−C, E All of th ese are act ion s in th e cen t ral n er vous sys-

1. 2. 3. 4. 5.

tem (CNS). Prost aglan din s h ave ver y sh or t h alf-lives an d do n ot reach th e CNS w h en adm in istered periph erally.

F E D C B

6. 7. 8. 9. 10.

C A B E B

11. 12. 13. 14. 15.

Answers and Explanations: VII-3 Nonsteroidal Antiin amm atory Drugs Questions 1−7

4. J

1. B

5. E

2. G

6. A

3. C

7. I

E B E F D

16. 17. 18. 19. 20.

B C D D D

388


Learning objective: Explain the m echanism of antipyretic action of nonsteroidal antiin ammatory drugs (NSAIDs).

Learning objective: Describe the poisoning due to salicylate overdose.

8. D Ibuprofen is an NSAID of th e propion ic acid derivat ive class

10. E Th e pat ien t’s sym ptom s, th e m arked hyper th erm ia, an d

th at is approved for ch ildren younger th an 2 years. All NSAIDs

th e resp irator y dep ression suggest severe p oison ing by salic-

in h ibit p rostaglan din biosyn th esis by blocking cyclooxygen -

ylates. Th is is su p ported by th e lab resu lts in dicat ing m ixed

ase both in th e periph eral t issues an d in th e cen t ral n er vous

respirator y an d m et abolic acidosis (low pH, in creased Pa CO2 ,

system . Th e release of prost aglan din s (PGE1 , PGE2 ) in th e hy-

an d decreased plasm a bicarbon ate con ten t). Th is acid−base

p oth alam us seem s to be th e u lt im ate factor th at adjust s th e

dist u rban ce is t ypical of a h igh salicylate con ten t in blood . In

hypothalam ic therm oregulatory m echanism to m aintain body

salicylate poison ing, th e in it ial even t (w h en salicylate con -

tem perat ure at a h igh er th an n orm al level. By in h ibit ing pros-

cen t rat ion in blood is n ot yet h igh ) is respirator y alkalosis

t aglan din syn th esis, NSAIDs p rom ote th e ret u rn of th e hyp o-

cau sed by salicylate-in du ced st im u lat ion of th e respirator y

th alam ic th erm ostat to th e n orm al set p oin t . On ce th e n orm al

cen ter. Par t ial com p en sat ion is ach ieved , as u su al, by in -

set p oin t is restored , th e tem p erat u re-regu lat ing m ech an ism s

creased ren al excret ion of bicarbon ate. Th erefore, th e in it ial

operate (by dilation of super cial blood vessels, sw eating, etc.)

p h ase of p oison ing (or w h en t h e p oison ing is m ild) is ch ar-

to reduce tem perat ure.

acterized by respirator y alkalosis (h igh pH, decreased levels

A−C All of t h ese act ion s can lead to an an t ipyret ic e ect , bu t NSAIDs do n ot h ave th ese act ion s.

of Pa CO2 an d bicarbon ate). In a later ph ase, w h en salicylate blood levels becom e qu ite h igh , th e respirator y cen ter be-

E Th e in h ibit ion of cyclooxygen ase in p er ip h eral t issu es

com es depressed, an d respirator y acidosis super ven es. Th is

can lead to an an t iin am m ator y e ect th at can redu ce fever.

acidosis is un com pen sated becau se a sign i can t am oun t of

How ever, th e m ain m ech an ism of th e an t ipyret ic e ect of

bicarbon ate h as already been elim in ated . Moreover, salicy-

NSAIDs is cen t ral rath er th an p eriph eral.

lates cau se u n cou p ling of m itoch on d r ial oxidat ive p h os-

F Blockade of oxidat ive ph osph or ylat ion in skeletal m uscle leads to hyp er th erm ia, n ot to an an t ipyret ic e ect .

ph or ylation (w h ich lead s to hyperth erm ia) an d in h ibits th e en zym es of th e Krebs cycle, resu lt ing in in creased pyruvic and lactic acids. Lipolysis, gluconeogenesis, and glycolysis are

Learning objective: Identify the cause of ibuprofen-induced oliguria.

also st im ulated, leading to hyperglycem ia an d product ion of

9. A Norm al glom erular

an d m et abolic acidosis, as in th is case.

lt rat ion rate (GFR) is m ain tain ed by

keto acids. Th erefore, th e

n al p ict u re is m ixed respirator y

n e balan ce bet w een prost aglan din -m ediated dilat ion of

A Acute alcoh ol poison ing can cause com bat ive beh avior,

a eren t arterioles an d angioten sin II−m ediated vasocon st ric-

bu t hyp ot h er m ia an d hyp oglycem ia are t yp ical sign s of al-

tion of e erent arterioles. Drugs that interrupt this hom eo-

coh ol p oison ing, an d t in n it u s is u su ally absen t .

a

st at ic m ech an ism can cau se ren al failu re. Becau se of t h e

B, C Poison ing by n on steroidal an t iin am m ator y drugs

th erapy w ith captopril, th e angioten sin II−m ediated vasocon -

oth er th an salicylates does n ot usually cau se profoun d im -

st rict ion of th e e eren t arterioles w as already lost . W h en a

pairm en t of th e acid−base balan ce.

n on steroidal an t iin am m ator y drug (NSAID) w as added to th e pat ien t’s regim en , h is kidn eys n o longer h ad con t rol of th e

D, F Poison ing by th ese drugs does n ot cause th e set of sym ptom s sh ow ed by th e p at ien t .

a eren t or e eren t ar teriolar ton e, an d ren al failure en su ed. d iu ret ic e ect of m ost diuret ic agen t s, w h ich can explain w hy

Learning objective: Identify the drug that can cause nonsteroidal antiin ammatory drug (NSAID) hypersensitivit y.

in th is pat ien t even an in crease in fu rosem id e dosage h ad n o

11. C Th e pat ien t’s h istor y an d sym ptom s suggest th at th e cul-

In ad d it ion , it h as been sh ow n t h at NSAIDs can in h ibit t h e

e ect .

p rit drug w as aspirin an d th at sh e w as a ected by asp irin

B Worsen ing of cardiac failure m ay be associated w ith oli-

hyp ersen sit ivit y, a syn drom e th at can occu r in 20 to 25% of

gu ria, bu t th is is u n likely in th is case becau se th e p at ien t did

m iddle-aged patients w ith asthm a, chronic urticaria, or nasal

sh ow im provem en t w ith th erapy.

p olyp s, as in th is case. Th e react ion does n ot ap pear to be

C Furosem ide can in crease, n ot decrease, ren in secret ion

im m u n ologic in n at ure, bu t in stead seem s to be a pseudoal-

secon dar y to in h ibit ion of Na + an d Cl− t ran sp or t in to th e m ac-

lergic react ion . Th e m ech an ism is n ot kn ow n , bu t it is likely

u la den sa.

related to t h e for m at ion of in creased am ou n t s of leu kot -

D In pat ien t s w ith cardiac failu re, digoxin usually in creases,

rien es an d oth er p rodu ct s of th e lip oxygen ase p ath w ay du e

n ot decreases, GFR secondar y to the increased cardiac output.

to in h ibit ion of th e cyclooxygen ase p ath w ay. Pat ien ts w ith

E Severe hypokalem ia im pairs th e con cen t rat ing abilit y of

th is syn d rom e exp erien ce a h igh d egree of cross-sen sit ivit y

the kidney and therefore tends to cause polyuria, not oliguria.

to oth er NSAIDs, w h ich su ppor ts th e con clusion th at th is react ion rep resen t s an abn orm al respon se to a com m on ph arm acological act ion .

Answers and Explanations: VII-3 Nonsteroidal Antiin am m atory Drugs 389 A, D Bron ch osp asm in du ced by th ese dr ugs is exceedingly rare.

D In h ibit ion of prost aglan din biosyn th esis in th e cen t ral n er vou s system can occu r an d could con t ribute to th e an al-

B, E Th ese drugs do n o n ot cau se bron ch osp asm .

gesic e ect , bu t th e e ect is m ain ly a p eriph eral on e.

Learning objective: Outline the therapeutic use of acetam inophen in a patient with hem ophilia.

Learning objective: Describe the m ain contraindications of nonsteroidal antiin am m atory drugs (NSAIDs).

12. B Because th e pat ien t is su ering from h em oph ilia, all n on -

16. E Th e h istor y of th e pat ien t in dicated aspirin hypersen sit iv-

steroidal an t iin am m ator y drugs (NSAIDs) are con t rain d i-

it y. Th is syn drom e occu rs in 0.3%of pat ien ts, bu t it can occu r

cated because they can decrease platelet aggregation and can

in 20 to 25%of m iddle-aged p at ien t s w ith asth m a, n asal p ol-

p rovoke gast roin test in al bleed ing. Acet am in op h en is free

yps, or ch ron ic ur t icaria. Th e syn drom e is n ot dose-related

from t h e above-m en t ion ed e ect s an d can be u sed as an

(it can occu r w ith sm all am ou n ts of asp irin ) an d does n ot

an algesic in th is p at ien t .

app ear to be im m u n ologic in n at u re. Becau se th ere is a h igh


degree of cross-sen sitivit y bet w een aspirin and other NSAIDs, severe asp irin hyp ersen sit ivit y is a con t rain dicat ion to th e

Learning objective: Describe disturbances of acid−base m etabolism caused by high therapeutic doses of salicylates.

u se of any NSAIDs. A−D See correct an sw er explan at ion .

13. B Th e lab valu es in d icate th at th e acid−base dist u rban ce w as d oses of salicylates. Th ese drugs st im ulate respirat ion both

Learning objective: Identify the antipyretic drug causing poisoning associated with extrem ely high transam inase levels.

d irectly (by a direct e ect on th e respirator y cen ter in th e

17. C Th e pat ien t’s h istor y an d sym ptom s suggest th at h e w as

m edu lla) an d in directly (by in creased produ ct ion of carbon

m ost likely su ering from acet am in oph en p oison ing. Th is

d ioxide du e to in creased oxygen con su m pt ion ). Com p en sa-

p oison ing is d u e to toxic m et abolites (m ain ly N-acet yl-p-

t ion is ach ieved by in creased ren al excret ion of bicarbon -

ben zoqu in on e) t h at accu m u late w h en glu t at h ion e is n ot

ate. Un less toxic doses are given , th is stage seldom proceeds

available for conjugat ion . Usu ally t h ese m et abolites are

fu r th er.

rap idly conjugated w ith glut ath ion e, but in th e absen ce of

respirator y alkalosis, w h ich is an e ect of h igh th erapeut ic


glu tath ion e, th ey react w ith cellu lar protein s, resu lt ing in h epatotoxicit y. Th is occurs after th e ingest ion of toxic d oses

Learning objective: Explain the reason for hypertherm ia due to salicylate overdose.

or w h en alcoh ol is t aken togeth er w ith acetam in oph en , as

14. D Th e pat ien t’s sign s an d sym ptom s in dicate h e w as su er-

gen erated. Th e alcoh ol−acet am in op h en syn drom e occu rs in

ing from salicylate overd ose toxicit y. Alt h ough salicylates

a clin ical set t ing in w h ich acu te, som et im es fu lm in an t , h e-

h ave an an t ipyret ic act ion , t h ey can cau se hyp er th er m ia

p at ic n ecrosis develops after large doses of acetam in op h en

w h en given in too-h igh doses. Th is seem s to be prim arily

are taken during an alcoholic binge or a period of chronic, ex-

d ue to th e un cou pling of oxidat ive p h osph or ylat ion in skele-

cessive alcohol intake. Peculiar to the alcohol−acetam inophen

t al m u scle; t h at is, oxidat ion p roceed s w it h ou t p h osp h or y-

syndrom e are th e extrem ely high serum transam in ase levels,

lat ion , t h u s p rodu cing h eat . Th is act ion is sim ilar to t h at

as in th is case. Early t reat m en t con sist s of th e adm in ist rat ion

p rodu ced by din it roph en ol.

of N-acet ylcystein e, alth ough at 48 h ou rs or m ore after th e


in both cases glut ath ion e is depleted faster th an it can be

ingest ion , it s u se rem ain s con t roversial. A, B, D, E Overdose of all of th e oth er listed drugs does n ot

Learning objective: Explain the m echanism of analgesic action of nonsteroidal antiin ammatory drugs (NSAIDs) in surgical pain. 15. B Prost aglan din s are en d ogen ou s com p ou n ds th at are released from dam aged t issu es an d can sen sit ize n ociceptors,

cau se a sign i can t in crease in seru m t ran sam in ase levels.

Learning objective: Outline the therapeutic uses of celecoxib in a patient with a relevant past m edical history.

cau sing p ain . By in h ibit ing prost aglan din biosyn th esis in th e

18. E Celecoxib is a select ive in h ibitor of cyclooxygen ase-2.

dam aged area, NSAIDs cau se an an algesic e ect . Ketorolac is

Drugs of th is class (som et im es called coxibs) h ave an algesic,

an e ect ive an algesic bu t on ly a m oderately e ect ive an t i-

an t ipyret ic, an d an t iin am m ator y act ion s. How ever, th ey

in am m ator y dr ug. It s an algesic e

lack act ion on platelet aggregat ion an d h ave low er adverse

cacy seem s greater th an

th at of m ost oth er NSAIDs.

e ects on the gastric m ucosa than nonselective inhibitors

A NSAIDs do n ot act on prost aglan din receptors.

of cyclooxygen ases. Th ese drugs are th erefore preferred in

C, E NSAIDs do n ot cau se th ese e ect s.

p at ien ts at risk of pept ic ulcer disease, as in th is case. A−D, F See correct an sw er explan at ion .

390


Learning objective: Describe the contraindications to the use of celecoxib.

presen t on ly du ring m en ses, so it is u n likely th at it is du e to

19. B Celecoxib is a select ive cyclooxygen ase-2 (COX-2) in h ibitor

E Leukot rien es can in crease n ocicept ive n er ve en ding sen -

w ith antipyretic, analgesic, and antiin am m ator y e ects sim -

pelvic in am m ator y disease. sit ivit y, but NSAIDs do n ot a ect leu kot rien e syn th esis.

ilar to th ose of oth er n on steroidal an t iin am m ator y drugs (NSAIDs). It is a sulfa derivat ive an d th erefore is relat ively

Learning objective: Describe salicylate-induced Reye syndrom e.

con t rain dicated in th is pat ien t because of h is previous seri-

22. F Th e result s of th e autopsy an d th e h istor y of th e pat ien t

ous allergic react ion to sulfon am ides, even th ough th e risk of

suggest th at th e cau se of death w as Reye syn drom e. Th e syn -

an allergic react ion after ad m in ist rat ion of a su lfa derivat ive

d rom e con sists of acute en cep h alop athy w ith fat t y degen er-

in a pat ien t w ith sulfon am ide hypersen sit ivit y appears to be

at ion of th e viscera. It is exceedingly rare an d occu rs alm ost

ver y low.

exclu sively in ch ild ren you n ger t h an 18 years. Let h alit y is


est im ated to be abou t 20%. Th e cau se of t h e syn d rom e is u n kn ow n , but risk factors involve use of salicylates in viral

Learning objective: Describe the nephropathy due to long-term use of nonsteroidal antiin ammatory drugs (NSAIDs).

in fect ion s, as in th is case. A−E Th ese dr ugs do n ot cause Reye syn drom e.

20. C Th e cu lprit drug w as m ost likely an NSAID su ch as dian algesics can cau se a n ep h ropathy th at is ch aracterized by

Learning objective: Describe the contraindications to the use of celecoxib.

ren al papillar y n ecrosis (th e prim ar y lesion ) an d ch ron ic in -

23. C Pain from osteoarth rit is is usually t reated in it ially w ith

terst it ial n eph rit is. Th e cause of th e disease is st ill un cert ain ,

n on steroidal an t iin am m ator y drugs. How ever, clin ical data

bu t it seem s to be related , at least in p ar t , to t h e ch ron ic

suggest th at cyclooxygen ase-2 (COX-2) in h ibitors su ch as ce-

in h ibit ion of p rost aglan d in biosyn t h esis, as p rost aglan d in s

lecoxib are m ore likely to cause ar terial th rom bot ic even ts,

p lay im port an t roles in regulat ing ren al fun ct ion . Th e risk

p robably becau se th ey do n ot in h ibit platelet aggregat ion

in creases w ith th e use of an algesic com bin at ion s, as in th is

th at is m ediated by th rom boxan e p rodu ced by th e COX-1 en -

case.

zym e. Th erefore, COX-2-select ive an algesics are con t rain di-

clofen ac. Ch ron ic use (6 to 8 m on th s or m ore) of an t ipyret ic

A, B Th e r isk of n ep h rop at hy w it h ch ron ic u se of t h ese an algesics is n egligible. D−F See correct an sw er explan at ion .

cated in p at ien t s w ith a h istor y of p reviou s th rom boem bolic d isease, as in th is case. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Explain the use of nonsteroidal antiin ammatory drugs (NSAIDs) in dysmenorrhea.

Learning objective: Outline the uses of nonsteroidal antiin am matory drugs (NSAIDs) in dysmenorrhea.

21. B Th e p ain occu r r in g d u r ing m en ses (dysm en or rh ea) is

24. D Pr im ar y dysm en or rh ea is cyclic p ain associated w it h

th ough t to resu lt from u terin e con t ract ion s an d isch em ia,

m en ses d u ring ovu lator y cycles bu t w ith ou t dem on st rable

likely m ediated by prost aglan din s produced by th e secretor y

lesion s a ect ing th e reproduct ive cycle. Th e p ain is th ough t

endom etrium . Contributing factors m ay include an extrem ely

to result from uterin e con t ract ion an d isch em ia, m ost likely

t igh t cer vical os becau se of th erm ocau ter y or con izat ion , as

m ediated by th e act ion s of p rostaglan din s p rodu ced by th e

in th is case. Pain occurs w h en th e uter us at tem pt s to expel

secretor y en dom et riu m . NSAIDs t aken 2 days before m en ses

t issu e t h rough t h e os. Th e an algesic e ect s of NSAIDs su ch

an d con t in u ed for 2 or 3 days or as n eed ed rep resen t s th e

as ibu p rofen in th e t reat m en t of dysm en orrh ea are m ain ly

rst -lin e p h ar m acot h erapy. Prop ion ic acid d er ivat ives are

d ue to th e in h ibit ion of prost aglan din biosyn th esis in th e

ver y e ect ive in dysm en orrh ea for m any p at ien t s; in a vari-

en dom et riu m .

et y of clin ical t rials, good to com plete pain relief w as re-

A NSAIDs do n ot act on prost aglan din receptors.

p orted for 40 to 100% of w om en u sing ibu p rofen .

C Even if a cen t ral act ion (in h ibit ion of prost aglan din bio-

A Alth ough acetam in oph en is adver t ised as an an algesic

syn th esis in th e cen t ral n er vou s system [CNS]) m ay con t rib -

for dysm en orrh ea, it is m uch less e ect ive th an NSAIDs be-

u te to t h e an algesic e ect of NSAIDs, t h e e ect is m ain ly

cau se it is a ver y poor in h ibitor of cyclooxygen ase in p erip h -

p erip h eral. Acet am in op h en is th e on ly an algesic-an t ipyret ic

eral t issu es.

d rug w h ose an algesic e ect is th ough t to be prim arily m ediated by th e in h ibit ion of p ain t ran sm ission in th e CNS. D Pelvic in am m ator y d isease m ay cau se d i u se, con t in u ous, low abdom in al pain . In th is case, h ow ever, th e pain is

B Beta-2 agon ist s can relax th e uterus, but th eir act ion is m u ch less e ect ive th an th at of NSAIDs in dysm en orrh ea, w h ere prost aglan din s play th e m ain role. C, E, F Th ese drugs w ould in crease, n ot decrease, uterin e con t ract ion s.

Answers and Explanations: VII-3 Nonsteroidal Antiin am m atory Drugs 391 Learning objective: Outline the use of ibuprofen in a patient with a relevant past medical history.

D All propion ic acid derivat ives are con t rain dicated becau se of th e seriou s allergic react ion to n ap roxen .

25. D Ibu p rofen h as been ap proved for u se as an an t ipyret ic in

E Tricyclic antidepressants such as am itript yline are som e-

ch ildren an d is curren tly available over th e coun ter. Because

tim es useful analgesics in neoplastic disorders w hen the pain

m ost n on steroidal an t iin am m ator y drugs h ave an t ipyret ic

is n eu rop at h ic (i.e., d u e to t h e dam age of n eu ron al st r u c-

act ivit y, th e in it ial ch oice is often based on speci c pat ien t-

t u res) bu t n ot w h en th e p ain is n ocicept ive (i.e., p ain t ran s-

related con t rain dicat ion s.

m it ted over in t act n eural path w ays), as in th is case.

In th is pat ien t: syn drom e. Th is seriou s disorder m ain ly a ects ch ildren or

Learning objective: Describe the use of indom ethacin in a newborn baby with patent ductus arteriosus.

you ng ad u lts, an d p redisp osing factors in clu de viral in fec-

27. E Th e pat ien t’s sym ptom s an d th e ech ocardiography results

A Aspirin is con t rain dicated because of th e risk of Reye

t ion an d salicylate th erapy. B In d om et h acin is n ot in d icated for gen eral u se as an an algesic or an t ipyret ic because of it s toxicit y.

suggest h e h ad a p aten t du ct u s ar teriosu s, w h ich can occu r in u p to 80% of prem at u re in fan ts w ith a birth w eigh t less th an 1200 g (2.65 lb). Paten cy of th e du ct u s ar teriosu s is

C Acet am in op h en is con t rain d icated in t h is p at ien t be-

m ain t ain ed in u tero by th e low p ar t ial p ressu re of oxygen

cau se of h is congen it al d e cien cy of red blood cell glu t a-

an d h igh con cen t rat ion of p rostaglan din s, m ain ly PGE1 an d

t h ion e syn th ase. Acet am in op h en is p art ially m etabolized to

PGE2 , w h ich h ave vasodilator y act ion s. Becau se of th is, n on -

N-acet yl-p-ben zoqu in on eim in e, w h ich is rapidly conjugated

steroidal an t iin am m ator y drugs h ave been fou n d to speed

w it h glu t at h ion e. If glu t at h ion e stores are d e cien t , t h e

up the closu re of th e du ct us arteriosu s in n ew born babies.

m et abolite react s w ith h ep atocyte m acrom olecu les, resu lt-

Indom ethacin given intravenously is the treatm ent of choice

ing in h ep atotoxicit y. Pat ien t s w ith congen ital de cien cy of

an d can ach ieve closure in m ore th an 70% of n eon ates.

glu tath ion e syn th ase are th erefore at in creased risk of acet-


am in oph en toxicit y. E, F Th ese drugs are n ot used as an t ipyret ics.

Learning objective: Describe nonsteroidal antiin am m atory drug (NSAID)−induced iron de ciency anem ia.

Learning objective: Outline the analgesic uses of piroxicam in a patient with a relevant past m edical history.

28. A Th e p at ien t’s h istor y an d sym ptom s suggest th at sh e w as

26. C Th e sym ptom s an d th e h istor y of th e pat ien t suggest th e

t ric bleeding) an d pica (craving to eat n on edible su bstan ces)

p ain w as cau sed by bon e m etastases, w h ich are th e m ost

are sym ptom s of iron de cien cy an em ia. Ch ron ic occu lt

frequ en t m et ast ases in p rostat ic carcin om a. Osseou s m et as-

bleeding is th e m ost com m on cau se of iron de cien cy an e-

t ases in du ce an in am m ator y react ion w ith th e produ ct ion

m ias in adu lt s. It is p resen t in u p to 30% of p at ien t s ch ron -

of p rost aglan d in s t h at m ay cau se osteolysis an d sen sit ize

ically treated w ith NSAIDs. Iron de ciency from an inadequate

free n er ve en d in gs, augm en t in g p ain p ercept ion . Non ste-

d iet can also con t r ibu te to t h e an em ia, as m ay be relevan t

roidal an t iin am m ator y drugs (NSAIDs) e ect ively decrease

in th is case (see th e veget arian h abit of th e pat ien t).

p rost aglan din an d en doperoxide produ ct ion an d th erefore

a ected by iron de cien cy an em ia. Dark stools (du e to gas-


can be u sefu l for an in it ial t reat m en t of m et ast at ic bon e in h ibitor of cyclooxygen ase t h at also in h ibit s p olym or p h o-

Learning objective: Describe the m echanism of action of nonsteroidal antiin am m atory drugs (NSAIDs).

n u clear cell m igrat ion an d d ecreases oxygen radical p ro-

29. C Ibuprofen is an NSAID of th e propion ic acid derivat ive

d u ct ion . All NSAIDs could be useful as an algesics, an d th e

class. By in h ibit ing cyclooxygen ases, th ese drugs im pair th e

su p eriorit y of any par t icu lar d rug for a p ar t icu lar p at ien t

biosyn t h esis of bot h p rost acyclin (p rost aglan d in I2 ) an d

p ain . Piroxicam is a long-act ing, n on select ive, com p et it ive

can n ot be p redicted. Th erefore, th e in it ial ch oice is often based on sp eci c pat ien t-related con t rain dicat ion s. In th is pat ien t: A Asp ir in is con t rain dicated becau se of h is congen it al glu cose-6-ph osph ate dehydrogen ase (G6PD) de cien cy (salicylates can cau se h em olyt ic an em ia in pat ien t s w ith th is d e cien cy). B Acet am in oph en is a ver y w eak in h ibitor of cyclooxygen ase in th e p resen ce of h igh con cen t rat ion s of p eroxide th at are fou n d in in am m ator y lesion s.

th rom boxan es. A, B, D−F All of these options have at least one endogenous com poun d w h ose biosyn th esis is n ot in h ibited by NSAIDs.

392


Learning objective: Explain the mechanism of peptic ulcer form ation by nonsteroidal antiin ammatory drugs (NSAIDs).

m em bran e by lip id d i u sion . In th e n eu t ral environ m en t of

30. B Erosive gast rit is, bleeding, an d p ept ic u lcer are w ell recog-

are t rap p ed in side th e cell, cau sing cell dam age.

n ized adverse e ect s of NSAIDs. Th e e ects are th e con sequ en ce of both system ic an d local act ion s. System ic act ion s are related to in h ibit ion of prostaglan din

th e cytoplasm , th ey becom e ion ized (i.e., w ater solu ble) an d A, E Gast rin an d ch olecystokin in secret ion s are n ot affected by NSAIDs. C, D See correct an sw er explan at ion .

biosyn th esis, w h ich in t u rn leads to • In creased gast ric acid secret ion (p rost aglan din s decrease

NONSTEROIDAL ANTIINFLAMMATORY DRUGS Answ er key

th is secret ion by in h ibit ing cyclic aden osin e m on oph osph ate (cAMP)−m ediated act ivat ion of th e proton p u m p ) • Decreased bicarbon ate an d m u cu s secret ion by gast ric m ucosa (w h ich is in creased by prost aglan din s) Local act ion s occur via an ion -t rapping m ech an ism . Most NSAIDs are w eak acid s w ith an acid dissociat ion con stan t (pKa ) less th an 5. Th erefore, th ey are m ain ly n on ion ized (i.e., lip id soluble) in th e stom ach lu m en an d can cross th e cell

1. 2. 3. 4. 5.

B G C J E

6. 7. 8. 9. 10.

A I D A E

11. 12. 13. 14. 15.

C B B D B

16. 17. 18. 19. 20.

E C E B C

21. 22. 23. 24. 25.

B F C D D

26. 27. 28. 29. 30.

C E A C B

Answers and Explanations: VII-4 Im m unom odulating Drugs Questions 1−4

oral ulcers, ren al disorder, an d n uclear an t ibodies). According

1. A

to th e Am erican College of Rh eu m atology, th e diagn osis of

2. C

lu pu s er yth em atosu s is m ade w h en th e pat ien t h as 4 or m ore

3. F

of th ese 11 sign s an d sym ptom s. Th e cause of lupus er yth e-

4. B

m atosus is un kn ow n but is th ough t to involve autoim m un e m ech an ism s. Th e th erapy alm ost alw ays in cludes cor t icoste-

Learning objective: Identify the immunosuppressive mechanisms of prednisone. 5. A An im m u n osu p p ressive drug th erapy m u st be given to all pat ien ts u n d ergoing organ t ran splan t . No con sen su s exist s on th e best in duct ion an d m ain ten an ce im m un osuppressive regim en , bu t m ost regim en s rely on th ree or fou r agen ts, an d on e of th ese is alm ost alw ays a glucocort icoid, su ch as predn ison e. Glucocorticoids suppress prim arily cellular im m unit y because of th eir abilit y to m odify cellular fun ct ion . In addit ion , th ey can in h ibit ph osp h olip ase A2 , blocking both p rost aglan d in an d leukot rien e syn th esis, and th ey in crease th e fract ion al catabolic rate of im m u n oglobulin G ( IgG), th e m ajor class of an t ibody im m un oglobulin s, thus low ering th e con cen t rat ion of speci c an t ibodies.

roids, w h ich are especially valu able for th e m ore severe an d life-t h reaten ing m an ifest at ion s of t h e d isease. Becau se in th is case th ere are sign s of ren al in su

cien cy (see creat in in e

an d blood urea n it rogen [BUN] values), steroid th erapy is clearly in dicated. A Ustekin um ab is approved for th e t reat m en t of plaque psoriasis on ly. C−E Th ese are im m u n ost im u lan t drugs an d th erefore are con t rain dicated in autoim m u n e disease.

Learning objective: Describe the m echanism of glucocorticoids in autoimmune diseases. 7. D Myast h en ia gravis is an acqu ired au toim m u n e d isease ch aracterized by exercise-induced m uscle fat igue that resolves

B−E All of th ese im m u n osuppressive drugs can sup p ress

after rest . Th e path ogen esis is due to an t ibody-m ediated de-

cellu lar im m un it y, but th ey do n ot a ect eicosan oid syn th esis

st ru ct ion of ch olin ergic Nm receptor sites. Th e in it iat ing even t

or th e catabolism of IgG an t ibodies.

leading to an t ibody p rod u ct ion is u n kn ow n . Th is p at ien t m ost likely d evelop ed a m yasth en ic crisis (edroph on iu m im p roved

Learning objective: Identify the drug used for the therapy of lupus erythematosus. 6. B Th e sign s an d sym ptom s of th e patien t in dicate th at sh e w as m ost likely a ected by lupus er ythem atosus. In fact , the patien t sh ow ed 5 of th e 11 sign s an d sym ptom s m ost often associated w ith this disease: m alar (but ter y) er ythem a, arth rit is,

m uscle st rength ), w h ich m ay be precipitated by in fect ion but also can occur w ith out apparen t cause. Myasth en ic crisis requ ires in ten sive m an agem en t th at in cludes selected an t ich olin esterase drugs su ch as n eost igm in e an d im m u n osu pp ressive t reat m en t w ith glu cocort icoids an d cyclosporin e. Th e im m u nosuppressive e ect of glucocorticoids is likely due to m ultiple

Answers and Explanations: VII-4 Imm unomodulating Drugs 393 m ech an ism s of act ion . Esp ecially im port an t in th is regard is

Learning objective: Describe the adverse e ects of azathioprine.

th e in h ibit ion of T-cell act ivat ion (d u e to in h ibit ion of syn -

12. D Th e profoun d leukopen ia an d th rom bocytopen ia exh ib -

th esis of in terleu kin -1) an d T-cell p roliferat ion (du e to in h i-

ited by th e p at ien t suggest bon e m arrow su pp ression . Tran s-

bit ion of syn th esis of in terleu kin -2).

p lan t p at ien t s alw ays receive im m u n osup p ressive th erapy

A, B Glu cocor t icoid s h ave n o e ect on plasm a ch olin esterase or n icot in ic receptors. C, E Glucocor t icoids act u ally decrease th e syn th esis of th ese in terleu kin s (see correct an sw er exp lan at ion ).

to preven t organ allograft reject ion . Cyclosporin e, azath iop rin e, an d a glucocor t icoid are th e drugs m ost frequ en tly u sed for th is purpose. Azath ioprin e is a prodrug th at is con verted in th e body to m ercaptopurin e, an an t im et abolite an t ican cer dr ug. It is th erefore a cytotoxic agen t th at can cau se

Learning objective: Identify the cell t ype representing the site of action of cyclosporine. 8. C Cyclosp orin e is a select ive in h ibitor of T-h elp er cells, su p p ressing th e early cellu lar respon se to an t igen ic st im u li. It s site of act ion is w ith in th e cytop lasm of T-h elp er cells, w h ere it bin ds to an im m un oph ilin called cycloph ilin . A, B, D, E These cells are not direct targets for cyclosporine.

sign i can t m yelosu p p ression . A Cyclosporin e is th e drug m ost frequ en tly given for im m u n osu p p ression in t ran sp lan t p at ien t s, bu t it d oes n ot cau se m yelosu p pression . B, C Dobut am in e an d dopam in e are often given to h ear t tran splant patients to in crease cardiac output an d renal blood ow, but th ey do n ot cause m yelosuppression . E Fluorouracil is an an t ican cer drug th at is n ot used for

Learning objective: Explain the m echanism of action of sirolim us.

im m u n osup pression .

9. D Sirolim us (form erly called rapam ycin ) resem bles tacroliHow ever, w h ereas tacrolim u s an d cyclosp orin e block gen e

Learning objective: Describe the immunosuppressive therapy used to treat chronic graft-versus-host disease (GVHD).

t ran script ion , sirolim u s act s later to block in terleu kin -2-

13. A Th e p at ien t m ost likely su ered from ch ron ic GVHD,

d epen den t lym p h ocyte proliferat ion . Th is blockade is likely

w h ich occu rs in up to 70% of allogen eic bon e m arrow t ran s-

d u e to t h e in h ibit ion of m am m alian kin ase (called m am -

p lan t pat ien ts. Th e m ost im por tan t risk factor for developing

m alian t arget of rap am ycin ), an en zym e th at is essen t ial for

ch ron ic GVHD is a prior diagn osis of acute GVHD. Th e m ain -

cell-cycle progression . Th erefore, th e drug substan t ially in -

stay of th erapy of GVHD is long-term im m u n osu p pressive

h ibit s T- an d B-cell proliferat ion .

th erapy. Predn ison e an d cyclosp orin e are am ong th e m ost

m u s an d bin ds to th e sam e in t racellu lar FK-bin ding p rotein s.


com m on ly used agen t s for th is purpose. Th e com bin at ion of cyclosporin e an d predn ison e h as resulted in h igh er su r vival

Learning objective: Describe the adverse e ect s of cyclosporine. 10. B Th e lab tests suggest th at th e p at ien t is su ering from ren al in su

cien cy. Nep h rotoxicit y is th e m ost com m on ad-

w h en com pared w ith predn ison e or cyclosporin e alon e. B−E Er yth rom ycin , doxorubicin , an d vin blast in e are n ot im m u n osup pressive drugs.

verse e ect of cyclosporin e, occurring in up to 80%of t reated p at ien ts. Th e path ophysiology of th is adverse e ect is st ill u n cer t ain . A, C−E These drugs have a negligible risk of nephrotoxicit y.

Learning objective: Explain the m olecular m echanism of action of tacrolimus. 14. C An t ibiot ics en dow ed w ith im m u n osu p pressan t p ropert ies in clu de cyclosp orin e, tacrolim us, an d sirolim us. Th ey in ter-

Learning objective: Identify the receptor class activated by cytokines.

fere w ith T-cell fun ct ion by bin ding to im m un oph ilin s, sm all

11. A Aldesleu kin is a cytokin e (recom bin an t in terleu kin -2).

to cytokin es. Cyclosporin e bin ds to cycloph ilin ; t acrolim us

Most cytokin es act ivate receptors th at belong to th e Jan u s-

an d sirolim u s bin d to FK-bin ding p rotein s. Th e tacrolim u s−

kin ase fam ily. Th ese receptors are polyp ept ides con sist ing of

p rotein com p lex bin ds to calcin eu r in , a cytop lasm ic p h os-

an ext racellu lar cytokin e-bin d ing dom ain an d a cytop lasm ic

p h at ase, t h u s in h ibit ing calcin eu r in -m ediated exp ression

en zym e dom ain . W h en a cytokin e bin ds to th e ext racellu lar

for p rodu ct ion of several cytokin es.

d om ain , th e in t racellular dom ain bin ds to an d ph osp h or ylates a separate in t racellular t yrosin e kin ase term ed Jan u s

in t racellular protein s th at p lay a key role in T-cell respon se

A Azith rom ycin is a m acrolide an t ibiot ic w ith an t ibacterial act ivit y. It is devoid of im m u n osup pressive prop er t ies.

kin ase. Th is t yrosin e kin ase in t urn ph osph or ylates oth er

B Azath ioprin e is a cytotoxic drug w ith im m un osuppres-

p rotein s called STAT (sign al t ran sduct ion an d act ivat ion of

sive properties, but it does not bin d to an FK-bin ding protein .

t ran script ion ) th at t ran slocate to th e n u cleu s an d regu late

D Cyclosporin e also in h ibit s calcin eu rin act ion s, but it

t ran script ion of sp eci c gen es. B−E See correct an sw er explan at ion .

bin ds to cyclop h ilin , n ot to an FK-bin ding p rotein . E Tobram ycin is an am in oglycosid e an t ibiot ic d evoid of im m u n osup pressive prop er t ies.

394


Learning objective: Identify the im m unosuppressant drug used to prevent allograft rejection that frequently causes gastrointestinal adverse e ects.

Becau se azath iop rin e in h ibit s th e early st ages of cell di er-

15. B Mycoph en olate m ofet il is cu rren tly u sed w ith p redn ison e

A Azath ioprin e h as n o blocking act ivit y on receptors of

an d cyclosp or in e to p reven t reject ion in t ran sp lan ted p a-

en t iat ion an d p roliferat ion , th e d rug is u sefu l for preven t ing rejection but is ine ective for the treatm ent of acute rejection. t u m or n ecrosis factor-α (TNF-α ).

t ien ts. Gastroin testin al e ects are th e m ost com m on adverse

C An t igen presen tat ion by di eren t an t igen -p resen t ing

react ion s associated w ith th is drug an d in clude severe ab -

cells is an early step in th e adapt ive im m un e respon se. Th is

d om in al pain (up to 60%) n au sea an d vom it ing (u p to 30%),

step is n ot in h ibited by azath ioprin e. D, E Th ese t w o act ion s w ould act ually in crease, n ot de-

d iarrh ea (u p to 50%), an d con st ipat ion (u p to 40%). A, C−F Th ese d r ugs are n ot u sed to p reven t allograft

crease, th e im m un ologic respon se of th e body.

reject ion .

Learning objective: Explain the anaphylactoid reaction to m onoclonal antibodies.

Learning objective: Explain why mycophenolate m ofetil currently replaces azathioprine to prevent rejection in a solid organ transplant.

16. E Th e p at ien t w as m ost likely exp er ien cin g an in fu sion -

19. B Mycoph en olate m ofet il is a prodrug th at is biot ran sform ed

related react ion , w h ich is a m ajor adverse e ect of m ost

in to m ycoph en olic acid. Th is act ive m etabolite in h ibit s in o-

m on oclon al an t ibodies. Th is react ion can be du e to a cyto-

sin e m on op h osp h ate d ehyd rogen ase, an en zym e involved

kin e release syn drom e or an an aphylactoid react ion . Th e

in th e de n ovo path w ay of purin e biosyn th esis. How ever, u n -

sym ptom s an d sign s of th is p at ien t s p oin t ou t th at th e syn -

like azat h iop r in e, it d oes n ot in h ibit en zym es involved in

d rom e w as m ost likely an an aphylactoid react ion .

t h e salvage p ath w ay of pu rin e or pyrim idin e biosyn th esis.

A−D Th ese are n ot adverse e ect s of basilixim ab.

Th u s, it select ively in h ibit s th e proliferat ion of lym p h ocytes (in clu ding B an d T lym p h ocytes), as th ese cells lack th e en -

Learning objective: Explain the m olecular m echanism of action of muromonab-CD3. 17. E Murom on ab - CD3 is a m on oclon al an t ibody again st CD3 m olecu les p resen t on th e su rface of h u m an thym ocytes an d m at u re T cells. CD3 m olecu les are n ecessar y for a sign al to be t ran sd u ced to th e cytop lasm after th e T-cell receptor bin ds to th e an t igen . Th e drug bin ds an d n eut ralizes th e CD3 protein receptor com plex, cau sing th e death of T cells. A Murom on ab -CD3 h as n egligible e ect s on B cells. B Th is is th e m ech an ism of act ion of azath ioprin e. C Th is is th e m ech an ism of act ion of cyclosporin e an d t acrolim u s. D Stim ulation of the synthesis of interleukin-1 w ould cause an im m u n ost im u lan t , n ot an im m u n osu pp ressive, e ect .

Learning objective: Explain the m echanism of the im m unosuppressive action of azathioprine. 18. B Azathioprine is an im m unosuppressive agent used in organ t ran splan t at ion to p reven t reject ion . It is a p rodr ug th at is conver ted in th e body to m ercaptopurin e, an an t im et abolite an t ican cer drug th at blocks p u rin e biosyn th esis. Th is leads to cytotoxicit y m ain ly tow ard cells w ith a h igh t urn over rate, w h ich in clu d es T an d B lym p h ocytes. Becau se t h e p roliferat ion of th ese lym ph ocytes is in h ibited, both cell- an d an t ibody-m ediated im m u n e resp on ses are in h ibited. Th is also explain s w hy m ost an t im et abolite an t ican cer drugs h ave im m unosuppressive actions. Azathioprine, however, appears to be a m ore e ect ive im m u n osu p p ressive t h an m ercap top u r in e it self. Th e basis for t h is su p er ior it y is u n kn ow n .

zym es of t h e alter n at ive salvage p at h w ay. Becau se of t h is, m ycop h en olate m ofet il is cytotoxic on ly for lym p h ocytes, w h ereas azat h iop r in e is cytotoxic for all rap id ly grow ing cells. Th is explain s w hy m ycoph en olate m ofet il h as sign i can tly few er adverse e ect s th an azath iop rin e. A Th e im m u n osuppressive act ivit y of m ycoph en olate an d azathioprine is roughly the sam e because both drugs are able to kill B an d T lym ph ocytes. C Graft-versus-h ost disease occurs after stem cell t ran sp lan t at ion , n ot after solid organ t ran splan t at ion . D Mycoph en olate m ofet il h as n egligible e ect s on m acrop h ages becau se th ese cells can u t ilize th e salvage path w ay for purin e biosyn th esis. E Mycophenolate m ofetil has no e ect on antigen-presenting cells.

Learning objective: Identify the drug used to m aintain rem ission in Crohn disease. 20. E Several st u dies h ave sh ow n th at glu cocor t icoid s are in effect ive in m ain tain ing rem ission in Croh n disease, alth ough a su bset of p at ien t s requ ire ch ron ic ad m in ist rat ion of glu cocor t icoid s to p reven t recu r ren ce of sym ptom s (ter m ed steroid- depen den t Croh n disease). Given th e poor long-term e

cacy of glu cocor t icoid s, m any exp ert s at tem pt t reat m en t

w ith oth er im m un osu ppressive drugs. Azath ioprin e, m eth otrexate, an d in ixim ab are e ective in m ain tain ing rem ission an d are also u sed as a steroid-sp aring st rategy in p at ien t s w ith steroid-depen den t Croh n disease. A−D See correct an sw er explan at ion .

Answers and Explanations: VII-4 Imm unomodulating Drugs 395 Learning objective: Describe the use of m urom onab-CD3 to treat steroid-resistant organ allograft rejection.

act ion ver y close to th at of cyclosp orin e. Never th eless, p a-

21. B A h igh -dose glucocor t icoid (usu ally in t raven ous m ethyl-

t ran sp lan t pat ien ts w h o w ere conver ted from cyclosporin e

tient sur vival rates exceeding 80%have been reported in liver

prednisolon e) is considered rst-line th erapy for acute rejec-

to t acrolim u s because of failu re of cyclosporin e th erapy.

tion becau se it w orks ver y qu ickly in decreasing lym ph ocyte

A, B, D, E Th ese drugs are n ot im m u n osu pp ressan t s.

responsiveness an d can reverse at least 75%of acute rejection episodes. Murom onab-CD3 is usually reser ved for steroidresistan t reject ion . A Because predn ison e failed to resolve th e reject ion , adm in ist rat ion of an oth er steroid w ou ld be irrat ion al. C Aldesleukin is an im m un ost im ulan t , n ot an im m u n osu p p ressive drug.

Learning objective: Identify the im m unosuppressive drug that can inhibit enzym es of de novo purine nucleotide biosynthesis. 25. E Azath ioprin e It is a p rodrug th at is biot ran sform ed in to m ercaptopu rin e an d th en in to th e corresp on ding false n u cleot ide. Th e false n ucleot ide in h ibit s en zym es crit ical for th e syn th esis of p h osp h oribosylam in e, w h ich is an essen t ial

D, E Becau se a cytotoxic drug (azath ioprin e) failed to pre-

step in p u rin e biosyn th esis, as w ell as in th e salvage p ath w ay

ven t reject ion , th e ch oice of oth er cytotoxic drugs is n ot

for purin e con ser vat ion . Th e false n ucleot ide also cau ses

app ropriate.

DNA dam age upon in tercalat ion . A−D, F Th ese im m u n osu p p ressive d r ugs d o n ot a ect

Learning objective: Identify the im m unosuppressive drug therapy given prior to heart transplant. 22. B Im m un osuppressive th erapy is given aggressively du ring

p u rin e biosyn th esis.

Learning objective: Describe the adverse e ects of tacrolim us.

th e early t ran sp lan t period becau se th e risk of organ rejec-

26. E Neu rotoxicit y an d n eph rotoxicit y are th e t w o m ajor ad -

t ion is greater at th is t im e. Azath iop rin e w ith predn ison e

verse e ect s of t acrolim u s, occu r r in g in m ore t h an 50% of

w as associated w ith a 50% organ su r vival rate. W h en cyclo-

p at ien t s receivin g t h is d r ug. Neu rotoxicit y in clu d es h ead -

sporin e w as added, m ore th an an 80% rate of organ su r vival

ach e, in som n ia, t rem or, p aresth esias, an d seizu res.

w as obt ain ed . A Ald esleu kin is an im m u n ost im u lan t d r ug, so it s u se w ou ld be irrat ion al in th is set t ing. C Triam cin olon e is a syn th et ic glucocort icoid. Th e com -

A−C Tacrolim us act ually can cau se hyper ten sion , hyperkalem ia, an d hyperglycem ia. D Hem olyt ic an em ia h as been repor ted ver y rarely during t acrolim u s t reat m en t .

bin ed u se of p redn ison e an d t riam cin olon e (t w o di eren t D, E In ixim ab an d etan ercept are im m un osu ppressive

Learning objective: Explain the m olecular m echanism of action of aldesleukin.

d rugs th at n eu t ralize t um or n ecrosis factor-α (TNF-α ). Th ey

27. A Ald esleu kin is recom bin an t in terleu kin -2 (IL-2) w it h a

are used only in Crohn disease and rheum atoid arthritis, both

m ech an ism of act ion essen t ially id en t ical to th at of IL-2.

au toim m u n e diseases.

Aldesleu kin act ivates IL-2 receptors expressed on T-h elper

glu cocort icoids w ith equ ivalen t e ect s) is su p er u ou s.

cells an d st im ulates a cytokin e cascade involving various in -

Learning objective: Identify the cell t ype representing the site of action of tacrolimus.

terferon s, in terleukin s, an d t um or n ecrosis factors. In th is

23. C Tacrolim u s is n ot ch em ically related to cyclosp orin e bu t

toxic T cells) an d act ivat ion of n at ural killer cells an d lym -

h as a sim ilar site an d m ech an ism of act ion . Both drugs bin d

p h okin e-act ivated killer cells. Th e dr ug is ap p roved for th e

to im m un oph ilin s located in th e cytoplasm of T-h elper cells,

adju n ct ive t reat m en t of ren al cell carcin om a an d m align an t

su p p ressing th e early cellu lar resp on se to an t igen ic st im u li.

m elan om a. Th e m ech an ism of an t it u m or act ivit y is u n -

A, B, D, E Th ese cells are n ot direct target s for t acrolim u s.

kn ow n bu t is probably related to th e act ivat ion of cytotoxic

w ay, it in du ces proliferat ion of B an d T cells (in clu ding cyto-

T cells. Aldesleukin is associated w ith serious cardiovascular,

Learning objective: Describe the therapeutic uses of tacrolim us.

ren al, an d cen t ral n er vou s system toxicit y, so exten sive

24. C Pat ien t s w h o receive an in it ial im m u n osu pp ressan t th er-

m on itoring is requ ired during th erapy.

apy w ith cyclosp orin e are som et im es converted to t acrolim u s, eith er becau se of p ersisten t drug react ion s or of a poor resp on se, as in t h is case. Tacrolim u s h as a m ech an ism of

B−E All of th ese act ion s w ould lead to im m un osuppressive, n ot im m u n ost im u lan t , e ect s.

396


Learning objective: Identify the im m unostim ulant cytokine used in the therapy of m ultiple sclerosis.

subsequent pregn ancies is n ot preven ted, so the m other m ust

28. C In terferon beta-1b is a cytokin e produced by various cells,

receive th e Rh o(D) im m un e globu lin after each deliver y to

A Placen tal crossing of Rh o(D)-posit ive er yth rocytes in

broblast s an d m acroph ages. Like oth er in terfer-

preven t sen sit izat ion . It sh ou ld be rem em bered th at p assive

on s, it h as an t iviral, im m un om odulat ing, an d an t iprolifera-

im m u n izat ion last s for th e lifet im e of th e adm in istered an t i-

t ive act ivit ies. In terferon bet a-1b w as th e

bod ies. Th e h alf-life of Rh o(D) im m u n e globu lin is 20 to

in cluding

rst agen t sh ow n

to h ave an e ect on th e course of m ult iple sclerosis (MS). Th e exact m ech an ism of its act ion is st ill u n kn ow n , bu t it is likely related to it s im m un om odu lat ing propert ies, in clu d ing th e d ow n regu lat ion of th e exp ression of class II m ajor h istocom pat ibilit y com plex an d of in terferon -γ (gam m a). It is th ough t th at in terferon -γ is a m ajor factor respon sible for t riggering th e au toim m u n e react ion leading to MS. It st im u -

25 days. C Th e drug act ually preven ts th e h em olyt ic disease of th e n ew born , n ot of th e m oth er. D Th e product ion of Rh o(D)-posit ive fet al er yth rocytes is gen et ically determ in ed. E Rh o(D) an t ibodies are produced by th e m oth er, n ot by th e fet u s.

lates cytotoxic T cells an d in duces m acroph ages to produce p rotein ases th at degrade th e m yelin sh eath arou n d th e spin al cord. A, B, D, E Th ese drugs are n ot recom bin an t cytokin es.

Learning objective: Explain the m olecular m echanism of action of cyclosporine. 30. E Th e act ivit y of cyclosporin e is m ediated th rough reversible in h ibit ion of T-cell fu n ct ion , par t icu larly T-h elper cells. Th e

Learning objective: Explain the m echanism of action of Rho(D) im m une globulin.

d rug bin ds to a T-h elper cell cytop lasm ic cyclop h ilin , th en

29. B Becau se t h e w om an w as Rh o(D) n egat ive, an d h er h u s-

it s it s act ion . Th is in h ibit ion is th ough t to p reven t act ivat ion

ban d w as Rh o(D) p osit ive, t h e baby h ad a 100% ch an ce (if

of n u clear factors involved in t h e gen e t ran scr ipt ion of in -

t h e fath er w as h om ozygou s) or a 50% ch an ce (if th e fath er

terleu kin -2 an d ot h er cytokin es. Becau se in terleu kin -2 is

w as h eterozygou s) of being Rh o(D) p osit ive. W h en a Rh o(D)-

n eeded for T-cell act ivat ion an d proliferat ion , th ese T-cell

n egat ive m ot h er car r ies a Rh o(D)-p osit ive fet u s, sh e w ill

fu n ct ion s are su p pressed.

p rodu ce an t ibodies again st Rh o(D)-posit ive er yth rocytes if th ese er yth rocytes leak in to th e m atern al circu lat ion . Th is

th e com p lex bin ds to calcin eu rin (a ph osp h at ase) an d in h ib -

A−D All of t h ese act ion s w ou ld act ivate, n ot in h ibit , im m u n it y processes.

can occur during pregn an cy, an d th e risk of th is fetom atern al t ran sfer in creases as th e pregn an cy progresses. Th e risk

IMMUNOMODULATING DRUGS Answ er key

is th e h igh est during deliver y. In su bsequen t pregn an cies, th ese m atern al an t ibodies are t ran sferred to th e fet u s, leading to th e developm en t of h em olyt ic disease in th e n ew born (called er yth roblastosis fet alis). If Rh o(D) im m un e globulin is adm in istered just after deliver y, it d est roys th e Rh o(D)-p osit ive fetal cells in th e m atern al bloodst ream before sh e h as an opport un it y to m ake h er ow n an t ibodies, th u s preven t ing er yth roblastosis fetalis in subsequen t pregn an cies. Th is is an exam ple of passive

1. 2. 3. 4. 5.

A C F B A

6. 7. 8. 9. 10.

B D C D B

11. 12. 13. 14. 15.

A D A C B

16. 17. 18. 19. 20.

E E B B E

21. 22. 23. 24. 25.

B B C C E

26. 27. 28. 29. 30.

E A C B E

im m un izat ion .

Answers and Explanations: VII-5 Drugs for Arthritis and Gout Questions 1−4 2. J

Learning objective: Identify the advantage of disease-m odifying antirheumatic drugs (DMARDs) over nonsteroidal antiin ammatory drugs (NSAIDs) in the treatm ent of rheum atoid arthritis.

3. F

5. B NSAIDs w ere on ce con sidered th e

1. G

4. B

rst-lin e t reat m en t of

rh eu m atoid ar th rit is, bu t today th ey are u sed on ly as n eeded to con t rol pain because it h as been sh ow n th at th ey h ave lit tle e ect on bon e an d car t ilage d est r u ct ion . On t h e con t rar y,

Answers and Explanations: VII-5 Drugs for Arthritis and Gout 397 DMARDs can arrest , or at least slow dow n , th e progression of

by gout at tack, oth er join t s can be involved. Th e gout at t ack

th e disease. Th ey are slow -act ing drugs, an d th eir e ect m ay

can be precip itated by overin du lgen ce in p u rin e-rich foods,

t ake 6 w eeks to 6 m on t h s to becom e evid en t . Th erefore,

alcoh ol, in fect ion , or m in or t rau m a, as in th is case. System ic

DMARD t reat m en t sh ou ld n ot be d elayed beyon d 3 m on t h s

t reat m en t of acu te gou t at t acks in clu d es oral n on steroidal

of ar th rit is diagn osis for th e m ajorit y of pat ien ts.

an t iin am m ator y d rugs (NSAIDs) or colch icin e. NSAIDs su ch

A Most DMARDs can h ave frequen t , an d som et im es ver y seriou s, adverse e ect s.

as in dom eth acin are often p referred becau se of th e frequ en t an d som et im es seriou s adverse e ect s of colch icin e. Glu co-

C See correct an sw er explan at ion .

cor t icoids adm in istered in t ra-art icularly after join t aspira-

D Th ere is n o com plete cure for rh eum atoid ar th rit is. Th e

t ion can be an e ect ive an d safe t reat m en t for a gou t at t ack.

p rogression of th e d isease can be arrested, but th erapy m u st

A Codein e is a w eak opioid an algesic devoid of an t iin am -

be con t in ued in de n itely.

m ator y prop er t ies an d is of n o valu e in gou t at tack.

E Acute join t pain is n ot quickly abolish ed by DMARDs. NSAIDs rem ain an e ect ive t reat m en t for acu te p ain .

C, E Meth ot rexate an d et an ercept are e ect ive in rh eu m atoid ar th rit is but are of n o value in gout y ar th rit is. D NSAIDs oth er th an in dom eth acin h ave been proved ef-

Learning objective: Outline the pharm acotherapy of ankylosing spondylitis.

fect ive in th e t reat m en t of acute gout y arth rit is. W h en given

6. C An kylosing spon dylit is is a system ic rh eum at ic disorder of

by th e kidn ey, so it sh ould n ot be u sed for an algesia in pa-

u n kn ow n cau se ch aracterized by in am m at ion w h ere liga-

in sm all doses, asp irin can in h ibit th e excret ion of u ric acid t ien t s w ith gou t .

m en ts at t ach to bon e, m ain ly in th e axial spin e. Th e disorder

F Allopurin ol can decrease seru m u ric acid levels in pa-

is m ore frequ en t in m en an d u su ally begin s bet w een t h e

tients w ith gout but cannot relieve th e pain of a gout y attack.

ages of 20 an d 40. In th e past , th e m ain st ay ph arm acoth erapy

t u m or n ecrosis factor agen t s su ch as et an ercept are able to

Learning objective: Identify the appropriate disease-m odifying antirheum atic drug (DMARD) in a patient with concom itant disease.

cau se a rapid an d su st ain ed redu ct ion in all clin ical an d labo-

9. B Th e th erapy of m ild rh eu m atoid arth rit is u su ally in clu des

rator y m easures of disease act ivit y. NSAIDs an d cyclooxygen -

n on steroidal an t iin am m ator y d r ugs (NSAIDs) t h at can

ase-2 select ive in h ibitors are st ill used in m ild cases.

con t rol sym ptom s of pain an d sw elling, bu t DMARD t reat-

of an kylosing spon dylit is w as n on steroidal an t iin am m ator y drugs (NSAIDs). More recen tly, it h as been sh ow n th at an t i−

D Because ibuprofen w as n ot e ect ive, th e e

cacy of an -

oth er propion ic acid derivat ive w ould be un likely. A, B, E, F Th ese d r ugs are of n o valu e in an kylosin g spon dylit is.

m en t is alm ost alw ays ad d ed w it h in 3 m on t h s of t h e ar t h r it is d iagn osis. Hyd roxych loroqu in e seem s to be t h e least toxic am ong DMARDs an d is usually th e in it ial ch oice. Moreover, in th is p at ien t , im m u n osu pp ressan t d rugs are relat ively con t rain dicated because of h is frequen t respirator y t ract

Learning objective: Identify the m olecular site of action of iniximab.

in fect ion s. A, C−E See correct an sw er explan at ion .

7. E In ixim ab is a m on oclon al an t ibody th at bin ds w ith h igh n it y to soluble an d possibly m em bran e-boun d t um or n e-

Learning objective: Explain the mechanism of action of le unomide.

crosis factor-α (TNF-α ). TNF-α is a proin am m ator y cytokin e

10. D Le u n om ide is a disease-m odifying an t irh eum at ic drug

th at appears to be especially im por tan t in th e in am m ator y

(DMARD) im m un osuppressan t approved for th e t reat m en t

p rocesses associated w it h au toim m u n e d isord ers, su ch as

of rh eu m atoid an d psoriat ic ar th rit is. Its m ech an ism of ac-

rh eu m atoid ar t h r it is, an kylosing sp on dylit is, Croh n d isease,

tion involves the in hibition of dihydroorotate dehydrogen ase,

an d psoriasis. TNF-α -blocking agen ts such as in ixim ab are

an en zym e involved in pyrim idin e syn th esis. As a con se-

u sed in rh eu m atoid ar th rit is, especially w h en refractor y dis-

qu en ce, t h ere is a red u ct ion in u r id in e t r ip h osp h ate levels

ease is diagn osed, as in th is case.

an d pyr im id in e syn t h esis in leu cocytes an d ot h er rap id ly

a

A−D In ixim ab does n ot bin d to th ese m olecu les.

d ividing cells. Le un om ide is abou t as e ect ive as m eth ot rexate in rh eu m atoid arth rit is an d en h an ces m eth ot rexate

Learning objective: Identify the appropriate drug to treat an attack of gout. 8. B Th e pat ien t’s sign s an d sym ptom s suggest th at h e is su ering from an acu te gou t at tack. Alth ough th e m et at arsop h alan geal join t of th e great toe is th e m ost com m on join t a ected

act ivit y w h en given con com it an t ly. Th erefore, it is often added to m eth ot rexate th erapy, as in th is case. A−C, E, F See correct an sw er explan at ion .

398


Learning objective: Identify the drug that is contraindicated in patients taking probenecid.

case. Th is drug h as been sh ow n to p reven t relap ses an d to

11. D In h um an s, uric acid elim in at ion is h an dled by th e kidn ey

of hydroxych loroqu in e is st ill u n clear bu t is likely related to

th rough th e follow ing fou r act ive t ran sp or t m ech an ism s lo-

its an t iin am m ator y p roper t ies. A com bin at ion of an an t i-

cated in su bsequ en t segm en t s of th e p roxim al t u bu le:

m alar ial an d an NSAID is som et im es u sed in m ild cases. How ever, a com bin at ion of glu cocort icoids an d im m u n osu p -

• Glom eru lar lt rat ion : all u ric acid is freely ltered.

pressive d rugs is a rst-lin e ph arm acoth erapy for t reat m en t

• Tu bu lar reabsorpt ion : 98% is reabsorbed.

of severe SLE.

• Tu bu lar secret ion : 50% is secreted. • Post secretor y t u bu lar reabsorpt ion : 40% is reabsorbed. Th erefore, about 10% of th e

ltered uric acid load is

red u ce m orbid it y an d m or t alit y. Th e m ech an ism of act ion

n ally

elim in ated by th e kidn ey. Uricosu ric drugs su ch as salicylates an d p roben ecid com pete w ith u ric acid for th ese t ran sport m ech an ism s. Th ey h ave a paradoxical e ect because, depen ding on dosage, th ey m ay eith er decrease or in crease th e elim in at ion of uric acid. It seem s th at th e secretor y m ech an ism is m ore sen sit ive to th e blocking act ion of u ricosu ric drugs, so low doses block u ric acid secret ion on ly. High er doses are able to block both m ech an ism s; th erefore, as m ost u ric acid is reabsorbed, t h e n et resu lt is in creased elim in at ion . Salicylates su ch as asp irin can com pletely an t agon ize th e u ricosu ric act ion of probenecid. Th is interaction probably involves several m ech an ism s, in clu ding com pet it ion for ren al t ubular t ran sport . A−C, E, F Th ese drugs are n ot con t rain dicated in a pat ien t receiving p roben ecid.

Learning objective: Explain the mechanism of action of colchicine.

A, B Becau se th e p at ien t w as already receiving an NSAID, adding an oth er drug of th e sam e class w ould be irrat ion al. C, E, F An t ibiot ics are of n o valu e, u n less an in fect ion su per ven es.

Learning objective: Outline the use of etanercept in rheum atoid arthritis. 14. C Th e p at ien t ’s sign s an d sym ptom s in d icate t h at sh e w as m ost likely su er in g from rh eu m atoid ar t h r it is. W h en n on steroidal an t iin am m ator y d r ugs (NSAIDs) are p oorly e ect ive an d /or p oorly tolerated , p h ar m acot h erapy w it h d isease-m odifying an t irh eu m at ic drugs (DMARDs) is in dicated. Meth ot rexate is th e in it ial DMARD of ch oice for m ost p at ien ts becau se of its e

act ion . How ever, it can h ave dose-related h ep atotoxicit y an d th erefore is relat ively con t rain dicated in th is p at ien t becau se of th e presen ce of act ive h epat it is. Et an ercept , a t um or n ecrosis factor-α an t agon ist ap p roved for t h e t reat m en t of rh eu m atoid ar th rit is, w ou ld be app ropriate in th is case. A See correct an sw er explan at ion .

12. C Colch icin e can be u sed to stop an acu te gou t at t ack or, m ost often , for t h e p reven t ion of fu r t h er at t acks, as in t h is case. Th e d r ug bin d s to t h e in t racellu lar p rotein , t u bu lin , thereby preventing its polym erization into m icrotubules and th u s blocking m itosis in m et aph ase. Cells w ith th e h igh est rate of division are a ected early. Granulocyte m igration into t h e in am ed area an d p h agocytosis of u rate cr yst als by m acrop h ages are in h ibited, th u s relieving th e pain an d in am m at ion of gou t y arth rit is. Th ese act ion s are speci c, an d th e d rug is devoid of gen eral an algesic or an t iin am m ator y e ect s. A, B, F Th ese drugs are e ect ive in gou t y ar th rit is bu t h ave d i eren t m ech an ism s of act ion s. D, E Th ese drugs can decrease th e risk of gout at tacks by d ecreasing t h e u rate p ool, n ot by in h ibit in g t u bu lin p olym erizat ion .

Learning objective: Outline the use of hydroxychloroquine in the treatment of systemic lupus erythematosus (SLE). 13. D Th e ph arm acoth erapy of SLE in cludes n on steroidal an t iin am m ator y dr ugs (NSAIDs), an t im alar ials, im m u n osu p p ressan t s, an d glu cocor t icoid s. An t im alar ials su ch as hyd roxych loroquin e are especially e ect ive w h en th e disease is m ild an d skin m an ifestat ion s are prom in en t , as in th is

cacy an d relat ively rapid on set of

B Asp ir in is associated w it h a h igh er in cid en ce of gast roin test in al bleed ing th an ot h er NSAIDs an d is n o longer com m on ly u sed for th e t reat m en t of rh eu m atoid arth rit is. Moreover, in th is pat ien t , ibu p rofen w as n ot e ect ive an d p oorly tolerated. D−F An t ibiot ics are n ot cu rren tly u sed in th e t reat m en t of rh eu m atoid arth rit is, bu t m in ocyclin e seem s to be a u seful adju n ct ive agen t in som e cases. Th e su ccessfu l u se of th is d rug su pport s th e specu lat ion th at rh eu m atoid ar th rit is m ay h ave an in fect ious com pon en t .

Learning objective: Identify the drug that consist s of the extracellular portion of t wo tum or necrosis factor (TNF) receptor moieties. 15. B Com bin at ion th erapy w ith disease-m odifying an t irh eum atic drugs (DMARDs) is currently a w ell-accepted approach becau se it h as been sh ow n th at m any DMARDS, w h en added to m eth ot rexate, sh ow im proved e

cacy. Et an ercept is a re-

com bin an t fusion protein con sist ing of t w o por t ion s of th e ext racellular dom ain of th e TNF-α receptor lin ked to a port ion of h u m an im m u n oglobu lin G1 . Th e drug bin ds w ith h igh a

n it y to TNF-α m olecules. A, C−E All of th ese d rugs can be e ect ive in rh eu m atoid

arth rit is, bu t th ey h ave di eren t chem ical st ruct ures.

Answers and Explanations: VII-5 Drugs for Arthritis and Gout 399 Learning objective: Identify the drug used in the therapy of fam ilial Mediterranean fever.

Learning objective: Outline the use of m ethotrexate in rheum atoid arthritis.

16. E Th e p at ien t’s h istor y, sym ptom s, an d lab test s suggest sh e

19. C Meth ot rexate is curren tly a

rst-lin e t reat m en t for m ost

w as m ost likely su ering from fam ilial Mediterran ean fever,

p at ien ts w ith rh eu m atoid ar th rit is becau se of it s h igh rate of

an in h erited au tosom al recessive disorder ch aracterized by

response, relatively rapid on set of action (1 to 2 m on ths), an d

recurren t fever an d serosit is (m ain ly periton it is but also

long su st ain ed e

p leu rit is, arth rit is, an d pericardit is). Because of th e ch ron ic

drug can enhance the action of som e other disease-m odifying

in am m ator y process, th ese pat ien ts h ave a h igh in ciden ce

an t irh eu m at ic dr ugs (DMARDs), in clu ding hydroxych loro-

of am yloidosis an d ren al failu re due to perivascular deposi-

qu in e, so it w ould be an appropriate drug to add to th e ongo-

t ion of seru m am yloid A protein . Th e u se of colch icin e h as

ing th erapy in th is case.

cacy. Moreover, it h as been sh ow n th at th e

been associated w ith a d ram at ic redu ct ion in th e in cid en ce

A, B Th e p at ien t w as already receiving a n on steroidal an t i-

of th ese com plicat ion s. In fact , prophylact ic colch icin e pro-

in am m ator y drug, so th e addit ion of an oth er drug of th e

vides com plete rem ission or dist in ct im provem en t in abou t

sam e class w ou ld be of lit tle valu e.

85% of p at ien t s. Th e m ech an ism of th is e ect is st ill u n cer-

D Fen t anyl is a p ow er fu l op ioid d r ug. Op ioid an algesics

t ain bu t is likely related to th e an t iin am m ator y p ropert ies

are used in rh eum atoid ar th rit is on ly except ion ally, on an

of th e drug.

as-n eeded basis, w h en th e p ain is excru ciat ing.

A−D Th ese drugs are n ot e ect ive in fam ilial Mediterran ean fever.

E, F Som e antidepressants, such as am itript yline, and som e an t iconvu lsan t s, su ch as carbam azep in e, are often e ect ive in cases of n eu rop ath ic pain , bu t n ot for t reat m en t of n oci-

Learning objective: Identify the t wo endogenous compounds that are increased after a few days of therapy with allopurinol.

cept ive pain such as occurs in rh eum atoid ar th rit is.

h ibit s th e t ran sform at ion of hypoxan th in e in to xan th in e an d

Learning objective: Describe the adverse e ect s of hydroxychloroquine.

of xan th in e in to uric acid. Th erefore, th e plasm a level of uric

20. A Th e p at ien t’s sign s an d sym ptom s suggest h e w as m ost

acid w ill decrease w ith a sm all, con com itan t rise of hyp ox-

likely su er in g from ret in op at hy, a rare adverse e ect of

an th in e an d xan th in e.

hyd roxych loroqu in e after long-term t reat m en t . Th e drug

17. B By in h ibit ing th e en zym e xan th in e oxidase, allop u rin ol in -


is a disease-m odifying an t irh eum at ic dr ug (DMARD) u sed in rh eu m atoid ar th rit is, often in com bin at ion w ith oth er

Learning objective: Identify the drug able to decrease uric acid in both serum and urine.

DMARD d r ugs. Th e d r ug h as h igh a

18. D Becau se th e p at ien t’s u rate levels are decreased after th er-

ret in a after long-term t reat m en t .

apy bot h in ser u m an d in u r in e, t h e d r ug m u st h ave d ecreased th e form at ion of u ric acid. Allop u rin ol in h ibit s th e

n it y for p igm en ted

(m elan in -con t ain in g) st r u ct u res an d accu m u lates in t h e B−F All of th ese drugs can be used in rh eu m atoid ar th rit is, bu t th ey d o n ot cau se ret in al dam age.

conversion of hypoxan th in e to xan th in e an d xan th in e to uric acid, th u s decreasing u ric acid form at ion .

DRUGS FOR ARTHRITIS AND GOUT (Answ er key)

A Proben ecid in creases th e ren al excret ion of uric acid an d w ou ld h ave decreased u ric acid in p lasm a bu t w ou ld h ave in creased uric acid in th e urin e. B Aspirin w ould h ave decreased uric acid secret ion at low / in term ediate doses (causing hyperuricem ia) an d w ould h ave in creased secret ion at h igh doses (causing uricosuria). C Fu rosem ide can cause hyperuricem ia. E, F Th ese d r ugs h ave n egligible e ect s on u r ic acid secret ion .

1. 2. 3. 4. 5.

G J F B B

6. 7. 8. 9. 10.

C E B B D

11. 12. 13. 14. 15.

D C D C B

16. 17. 18. 19. 20.

E B D C A

VIII Chem otherapeutic Drugs Questions: VIII-1 Bacterial Cell Wall Synthesis Inhibitors Directions for questions 1−4


Match each an t ibiot ic d r ug w it h t h e ap p rop r iate d escr ipt ion

6. A 51-year-old w om an recen tly diagn osed w ith acu te bacterial


cyst it is star ted an ap p ropriate an t ibiot ic t reat m en t . Th e ad-

at all).

m in istered drug ach ieves th erapeu t ic con cen t rat ion in th e

A. Am picillin

u rin e becau se it is prim arily elim in ated by th e kidn ey th rough

B. Azt reon am

act ive secret ion in th e proxim al t ubu le. W h ich of th e follow -

C. Cefep im e

ing drugs did th e pat ien t m ost likely t ake?

D. Cefotaxim e

A. Cep h alexin

E. Cefotetan

B. Azith rom ycin

F.

C. Met ron idazole

Ceftazidim e

G. Ceft riaxon e

D. Tobram ycin

H. Cloxacillin

E. Tet racyclin e

I.

Ticarcillin

J.

Piperacillin

K. Van com ycin

Di cult y level: Easy 7. A 23-year-old w om an com plain ed to h er physician of urin ar y frequ en cy, p ain u p on urin at ion , an d a m u copu ru len t vagin al


d isch arge. On e year earlier, t h e p at ien t h ad u n dergon e an

1. A pen icillin ase-resistan t pen icillin

an ap hylact ic react ion to p en icillin . A Gram st ain of th e exu date revealed gram -n egat ive cocci. W h ich of t h e follow ing


drugs w ou ld be con t rain dicated for th is p at ien t?

2. A pen icillin act ive again st Klebsiella species

A. Doxycyclin e B. Cipro oxacin


C. Ceft riaxon e

3. A th ird-gen erat ion ceph alosporin act ive again st Pseudom onas

D. Er yth rom ycin

aeruginosa

E. Trim eth op rim -su lfam etoxazole



4. Th is drug sh ow s n o cross-allergen icit y w ith oth er β-lact am

8. A 32-year-old w om an w as seen at a clin ic becau se of 2 days

an t ibiot ics.

of h eadach e w ith join t an d m uscle pain . Physical exam in at ion revealed n uch al rigid it y an d a petech ial rash on th e low er ex-

Di cult y level: Easy 5. A 68-year-old m an diagn osed w ith st reptococcal pn eum on ia star ted t reat m en t w ith a th ird-gen erat ion cep h alosp orin . W h ich of th e follow ing steps in th e t urn over of bacterial cell w alls is speci cally in h ibited by th is an t ibiot ic? A. Au tolysin -m ed iated breaking of pept idoglycan ch ain s B. Elongat ion of lin ear am in o sugar ch ain s C. Con n ect ion of t w o am in o sugar ch ain s by p ept ide bridges D. Syn th esis of N-acet ylm uram ic acid E. Lin king of t w o am in o sugars by a glycosidic bon d

400

t rem it ies. A Gram st ain of h er sp in al u id sh ow ed m any n eu t rop h ils an d m any gram -n egat ive, bean -sh ap ed d ip lococci. W h ich of th e follow ing drugs w ou ld be m ost appropriate for th e th erapy of th is pat ien t? A. Tet racyclin e B. Pen icillin G C. Er yth rom ycin D. Azt reon am E. Tobram ycin F.

Met ron idazole

Questions: VIII-1 Bacterial Cell Wall Synthesis Inhibitors 401 Di cult y level: Medium 9. A 30-year-old w om an w as in labor w ith h er secon d ch ild.

vom it ing, an d diarrh ea. Vital sign s on adm ission w ere tem perature 103°F (39.4°C), pulse 134 bpm , blood pressure 85/52

rst baby h ad con t racted n eon at al m en in git is d u e to

m m Hg, respirat ion s 28/m in . Physical exam in at ion sh ow ed a

con t am in at ion w ith St reptococcus agalact iae du ring deliv-

crit ically ill pat ien t w ith an abdom in al er yth em atou s in d u -

er y. To preven t recurren ce of th is in fect ion in th e secon d

rated area below th e u m bilicu s an d an 8-m m (0.31-in ch )

ch ild, w h ich of th e follow ing drugs w ould be m ost appropri-

cen t ral ulcer. A uorescen t an t ibody test of a specim en from

ate for t reat m en t of both th e m oth er an d th e baby?

th e ulcer iden t i ed group A st reptococci. W h ich of th e fol-

Her

A. Levo oxacin B. Trim eth op rim -su lfam eth oxazole

low ing p airs of d r ugs w ou ld be m ost ap p rop r iate for th e em ergen cy t reat m en t of th is p at ien t?

C. Tet racyclin e

A. Pen icillin G an d clin dam ycin

D. Gen t am icin

B. Tobram ycin an d m et ron idazole

E. Am picillin

C. Ch loram ph en icol an d tet racyclin e D. Er yth rom ycin an d am ikacin

Di cult y level: Medium 10. A 24-year-old w om an cam e to th e clin ic w ith a sore th roat an d low -grade fever. Physical exam in at ion sh ow ed ton sil ex-

E. Pip eracillin an d azt reon am


u dates an d ten der cer vical aden opathy. A Gram st ain of th e

13. A 54-year-old m an w as adm it ted to th e h ospit al w ith fever

ton sil exudate dem on st rated th e presen ce of a h igh n um ber

(100.6°F, 38.1°C), n igh t sw eats, arth ralgias, an d 15 lb (6.8 kg)

of bacteria. A diagn osis w as m ade, an d pen icillin G w as pre-

of u n in ten t ion al w eigh t loss. Past h istor y w as sign i can t

scribed, as th e p hysician kn ew th at th e m ost likely o en ding

for rh eu m at ic fever at th e age of 9 an d for d en t al su rger y

p ath ogen w as sen sit ive to th e an t ibiot ic. W h ich of th e fol-

1 m on th ago. Th e sym ptom s st ar ted abou t 2 w eeks after th e

low ing bacteria did th e physician m ost likely believe caused

d en t al p roced u re. Physical exam in at ion w as sign i can t for

th e p at ien t’s in fect ion ?

m it ral regu rgit at ion , su bu n gu al sp lin ter h em or rh ages, an d

A. Pseudom onas aeruginosa B. Staphylococcus aureus C. Clost ridium di cile D. St reptococcus pyogenes

h em orrh agic plaqu es on th e soles of both feet . Th ree blood cu lt u res w ere ordered, an d an em p iric th erapy w as star ted . W h ich of th e follow ing sh ou ld be an appropriate t reat m en t for th e pat ien t at th is t im e?

E. Enterococcus faecalis

A. Am picillin an d er yth rom ycin

F.

B. Pip eracillin an d ch loram p h en icol

Haem ophilus in uenzae

G. Klebsiella pneum oniae

C. Azt reon am an d am ikacin D. Pen icillin G an d gen tam icin

Di cult y level: Medium 11. A 34-year-old m an presen ted to th e clin ic w ith a pain ful u lcer on h is pen is. Region al lym ph n odes w ere en larged an d

E. Dicloxacillin an d cipro oxacin


p ain ful. Th e m an adm it ted to unprotected in tercou rse w ith

14. A previously h ealthy 3-year-old ch ild w as adm it ted to th e

a n ew p ar t n er w h ile on a recen t vacat ion . Dark eld m icros-

h ospital w ith sore th roat , fever, ch ills, pain ful sw allow ing,

copy an d an FTA-ABS ( uorescen t t repon em al an t ibody ab -

an d dysp n ea for th e p ast 10 h ou rs. Physical exam in at ion re-

sorpt ion ) test for syp h ilis w ere n egat ive. A Gram st ain of pu s

vealed a seriously ill pat ien t w ith edem atous er yth em a over

revealed sh ort gram -negative bacilli in parallel chain s. W hich

th e an terior n eck, cer vical lym p h n ode en largem en t , crack-

of th e follow ing w ould be th e m ost appropriate ph arm aco-

les in th e left lung base, an d di use w h eezing best h eard as

th erapy for th is p at ien t?

st rid or over th e n eck. Sp u t u m Gram stain sh ow ed n u m erou s

A. Van com ycin B. Nafcillin C. Pen icillin G D. Ceft riaxon e E. Met ron idazole

gram -n egat ive coccobacilli. A diagn osis of acute supraglot t it is w as m ade, an d an em ergen cy th erapy w as st ar ted. W h ich of t h e follow in g d r ugs w ou ld be m ost ap p rop r iate for t h e p at ien t’s disease? A. Dicloxacillin B. Pen icillin G

Di cult y level: Hard 12. A 41-year-old w om an collapsed at h om e an d w as brough t to th e em ergen cy depar t m en t . Her h usban d st ated sh e h ad com plain ed recen tly of severe abdom in al cram ping, n ausea,

C. Ceft riaxon e D. Van com ycin E. Cefazolin

Chemotherapeutic Drugs

402



15. A 63-year-old h om eless m an w as adm it ted to th e h ospital

18. An 8-year-old girl w as brough t to th e clin ic because of fever

w ith fever, gen eral m alaise, an d a sw ollen , pain ful leg. Phys-

(101.5°F, 38.6°C) an d exten sive skin abrasion s on th e righ t

ical exam in at ion sh ow ed a m an in obvious dist ress w ith th e

leg. Her m oth er explain ed th at th e girl h ad fallen o h er bi-

follow ing vital signs: blood pressure 88/50 m m Hg, heart rate

cycle a few days earlier an d su ered several abrasion s. Phys-

115 bp m , resp irat ion s 22/m in , tem p erat u re 103.1°F (39.5°C).

ical exam in at ion sh ow ed th e skin of th e righ t leg w as h ot ,

His righ t leg h ad a large w ou n d an d ap peared sw ollen w ith

red, an d edem atous w ith a surface “peau d’orange” appear-

a “bron ze” d iscolorat ion an d crep it at ion of t h e t issu e. A

an ce. Region al lym ph ad en op athy w as also p resen t . A Gram

p resum pt ive diagn osis w as m ade. An em piric th erapy w as

stain from scrap ings of th e lesion s sh ow ed th e p resen ce of

star ted th at in clu ded exten sive debridem en t of th e w ou n d

a large n u m ber of gram -p osit ive cocci. W h ich of th e follow -

an d adm in ist rat ion of a dr ug th at w as able to cu re th e in fec-

ing drugs w ou ld be ap p rop riate for th e t reat m en t of th is

t ion . Th e m ech an ism of act ion of th e given drug m ost likely

pat ien t?

involved th e in h ibit ion of w h ich of th e follow ing bacterial

A. Pip eracillin

en zym es?

B. Azt reon am

A. Acet yl t ran sferase

C. Dicloxacillin

B. Beta-lact am ase

D. Tet racyclin e

C. Tran sp ept idase

E. Am ikacin

D. Au tolyt ic en zym es


E. Tran sglycosylase

19. A 55-year-old w om an recen tly diagn osed w ith bacterial py-


elon eph rit is st ar ted a t reat m en t w ith a β-lactam an t ibiot ic

16. A 56-year-old farm er presen ted to th e clin ic w ith a sm all,

th at is resist an t to m ost β-lact am ases. W h ich of th e follow -

at , h ard sw elling un der th e oral m ucosa th at form ed a

s-

ing drugs w as m ost likely adm in istered?

t u la disch arging yellow gran u les. On e m on th earlier, h e h ad

A. Cep h alexin

several teeth ext racted becau se of p araden t al abscesses. An -

B. Am picillin

aerobic cu lt u res of t h e biop sy m ater ial sh ow ed sm all, sp i-

C. Pip eracillin

d er y colon ies con tain ing gram -posit ive, n on -acid-fast rods

D. Ticarcillin

an d bran ch ing lam en ts. A diagn osis w as m ade, an d an an t i-

E. Cefepim e

biot ic th erapy w as prescribed. W h ich of th e follow ing d rugs

F.

Cefazolin

w ou ld be m ost app ropriate for th is pat ien t? A. Pen icillin G


B. Azt reon am

20. A 52-year-old m an presen ted to h is physician w ith an exten -

C. Met ron idazole

sive skin rash on h is t ru n k an d lim bs. Th e m an h ad been su f-

D. Gen t am icin

fering from n on -Hodgkin lym ph om a for 2 years. A few days

E. Cipro oxacin

earlier, h e w as diagn osed w ith acute bacterial ph ar yngit is an d star ted on an an t ibiot ic. Th e physician said th e rash w as


m ost likely an allergic react ion to th e an t ibiot ic. W h ich of

17. A 75-year-old m an w as adm it ted to th e h ospit al for h ip re-

th e follow ing drugs m ost likely cau sed th is react ion ?

p lacem en t . W h ich of th e follow ing an t ibiot ics w ou ld be an

A. Am ikacin

app ropriate prop hylact ic agen t to be given before su rger y?

B. Am oxicillin

A. Met ron idazole

C. Doxycyclin e

B. Tet racyclin e

D. Van com ycin

C. Su lfam eth oxazole

E. Su lfam eth oxazole

D. Azt reon am E. Cefazolin


F.


Er yth rom ycin

w ith sudden on set of fever (101.1°F, 38.5°C), oliguria, an d a skin rash . Th e m an h ad been receiving system ic p h arm acot h erapy for p r im ar y syp h ilis. Laborator y

n d in gs sh ow ed

eosin op h ilu r ia an d p rotein u r ia. Fu r t h er exam s led to t h e

Questions: VIII-1 Bacterial Cell Wall Synthesis Inhibitors 403 diagnosis of drug-induced t ubuloin terstitial n eph ritis. W hich

th e follow ing drugs w ould be appropriate for th e pat ien t’s

of th e follow ing an t ibiot ics m ost likely caused th e pat ien t’s

disease?

disease?

A. Er yth rom ycin

A. Pen icillin G

B. Clin dam ycin

B. Cefep im e

C. Van com ycin

C. Rifam pin

D. Cep h alexin

D. Nafcillin

E. Pen icillin G


Di cult y level: Hard Di cult y level: Medium

25. A 32-year-old m ale h eroin add ict w as ad m it ted to t h e h os-

22. A 73-year-old m an diagn osed w ith pn eum on ia due to Pseu-

p ital w ith a 2-day h istor y of fever, sh aking ch ills, rigors, an d

dom onas aeruginosa w as st arted on piperacillin , but 2 days

n igh t sw eats. His vit al sign s w ere blood pressu re 100/60 m m

later, th e disease w as n ot im proved, an d th e physician su s-

Hg, pulse 120 bpm , respirations 24/m in, tem perat ure 102.2°F

p ected th at th e in fect ive organ ism w as resist an t to th e drug.

(39°C). Tw o-dim en sion al ech ocardiography revealed th ree

W h ich of th e follow ing w as m ost likely th e m ech an ism of

sm all vegetation s on the tricuspid valve. Th ree blood cultures

bacterial resistan ce to th is an t ibiot ic?

w ere draw n , an d em piric th erapy w as in it iated. Th e cu lt u res

A. In creased a

t u rn ed ou t to be posit ive for Pseudom onas aeruginosa, w ith

n it y of p en icillin -bin d ing p rotein to t h e

th e follow ing an t ibiot ic su scept ibilit ies:

dr ug B. In h ibit ion of drug bin ding to th e 50S subun it

Drug

C. Decreased perm eabilit y of th e bacterial cell m em bran e to th e dr ug D. In h ibit ion of t h e e

u x p u m p of t h e bacter ia cell

m em bran e E. In creased product ion of autolyt ic en zym es


Minimum Inhibitory Concentration

Gent am icin

16 µg/m L

Tobram ycin

2 µg/m L

Piperacillin

64 µg/m L

Ceft azidim e

4 µg/m L

Im ipenem

2 µg/m L

23. A 70-year-old fem ale residen t in a n ursing facilit y w as ad-

Su rgical excision of t h e in fected valve an d a 6-w eek p ost -

m it ted to t h e h osp it al becau se of fever (101.4°F 38.6°C),

operat ive t reat m en t w ere plan n ed. W h ich of th e follow ing

d iarrh ea, an d severe abdom in al pain . Four days earlier, th e

d rug com bin at ion s w ou ld be m ost ap propriate for th e pa-

p at ien t h ad st ar ted an t ibiot ic t reat m en t because of acute

t ien t at th is t im e?

ton sillit is due to β-h em olyt ic st reptococci. Physical exam in at ion sh ow ed a crit ically ill pat ien t w ith abdom in al disten t ion an d absen t bow el sou n ds. Colon oscopy revealed di u se u lcerat ion s an d exudat ive plaques lin ing th e colon ic m ucosa. W h ich of t h e follow in g an t ibiot ics m ost likely cau sed t h e p at ien t’s disease? A. Gen t am icin B. Van com ycin C. Rifam pin D. Azt reon am E. Am picillin

Di cult y level: Easy 24. A 34-year-old w om an w ith n o previou s h istor y of disease com plained to her physician of burning on urination, bladder p ain , an d frequ en t urin at ion of a sm all volu m e. A m icroorgan ism isolated from h er u rin e grew on EMB (eosin m ethylen e blue) agar, p roduced green colon ies, w as m ot ile, an d w as u rease-n egat ive. A d iagn osis of u rin ar y t ract in fect ion w as m ade, an d an t ibiot ic th erapy w as prescribed. W h ich of

A. Tobram ycin an d gen t am icin B. Ceftazidim e an d tobram ycin C. Im ipen em an d gen t am icin D. Ceftazidim e an d im ip en em E. Pip eracillin an d tobram ycin

Di cult y level: Medium 26. A 22-year-old w om an con su lted h er physician because of a post p ar t u m breast in fect ion . A Gram st ain of th e p u s revealed gram -positive bacteria, and a susceptibilit y test showed resistan ce to all β-lactam an t ibiot ics. W h ich of th e follow ing bacteria w as m ost likely th e o en d ing path ogen ? A. Listeria m onocytogenes B. Meth icillin -resist an t Staphylococcus aureus C. Escherichia coli D. St reptococcus pyogenes E. Enterococcus faecalis F.

Clost ridium tetani

G. Serrat ia m arcescens

404



sign . Pu p ils w ere equ al, p oorly react ive to ligh t , an d pap ill-

27. A 4-year-old boy w as brough t to t h e p ed iat r ician by h is

edem a w as presen t . An em p irical in t raven ou s th erapy w as

m oth er becau se of respirator y di cu lt ies. Medical h istor y of

started w ith am p icillin , ceft riaxon e, an d van com ycin . W h ich

th e boy w as sign i can t for recu rren t p u lm on ar y in fect ion s.

of th e follow ing best explain s th e m ech an ism of act ion com -

A Gram st ain of th e spu t um revealed gram -posit ive cocci in

m on to all of th e given drugs?

grap elike clu sters. W h ich of t h e follow ing d r ugs w ou ld be

A. Misreading of m essenger RNA tem p late code

an ap p rop riate em p iric t reat m en t at th is early st age?

B. In h ibit ion of tet rahydrofolate syn th esis

A. Pen icillin G

C. In h ibit ion of RNA polym erizat ion

B. Am picillin

D. Blockade of pept idyl-t ran sfer RNA t ran slocat ion

C. Piperacillin

E. In h ibit ion of pept idoglycan syn th esis

D. Dicloxacillin


E. Am oxicillin

31. A 61-year-old w om an w it h p oor d en t it ion w as sch ed u led


to h ave all of h er rem ain ing teeth ext racted for subsequen t

28. A 79-year-old fem ale resident of a nursing facilit y com plained

t t ing of den t u res. Past m edical h istor y w as sign i can t for

of burn ing on urin at ion an d bladder pain . Microscopic ex-

n um erous in fect ion s of th e oral cavit y. Th e w om an h ad been

am in at ion of u rin e sedim en t revealed m any gram -p osit ive

su ering from m itral sten osis w ith m ild cardiac insu

bacteria, an d a u rin e cu lt u re in dicated Enterococcus faecalis

for 5 years. W h ich of th e follow ing drugs w ould be th e m ost

as th e sole cau sat ive agen t . W h ich of th e follow ing p airs of

appropriate agent to prescribe to this w om an before and after

d rugs w ou ld be m ost appropriate for th e t reat m en t of th is

th e ext ract ion ?

p at ien t?

A. Am oxicillin

A. Cefotetan an d n et ilm icin

B. Gen t am icin

B. Cefep im e an d am ikacin

C. Azt reon am

C. Pen icillin G an d er yth rom ycin

D. Pip eracillin

D. Am picillin an d tobram ycin

E. Met ron idazole

ciency

E. Azt reon am an d gen t am icin


32. A 5-year-old boy w as brough t to th e clin ic by h is m oth er be-


cau se of a localized, cru sted lesion on h is left leg. Th e m oth er

ing of vaginal itching and a thick, w hite vaginal discharge. One

repor ted th at 3 days earlier, th e boy h ad been bit ten by h is

w eek earlier, th e w om an h ad st arted t reat m en t w ith am oxi-

p et dog. A pu ru len t disch arge from th e lesion w as fou n d to

cillin becau se of a skin in fect ion . Su bsequ en t exam s led to

contain m any sm all gram -negative coccobacilli. W hich of the

th e diagn osis of can dida vagin it is th at th e p hysician th ough t

follow ing correctly pairs th e m ost likely o en ding path ogen

w as a su p er in fect ion related to t h e am oxicillin t reat m en t .

w ith th e appropriate t reat m en t?

W h ich of th e follow ing best explain s w hy broad-spect rum

A. Staphylococcus epiderm idis: oxacillin

p en icillin s can cau se superin fect ion s?

B. Clost ridium di cile: m et ron idazole

A. Im pairm en t of h ost im m u n ologic defen se

C. Klebsiella pneum oniae: van com ycin

B. Select ion of viral-resist an t m u tan t s

D. Serrat ia m arcescens: er yth rom ycin

C. Masking disease sym ptom s

E. Pasteurella m ultocida: pen icillin G

D. Im pairm en t of n orm al m icro ora of th e h ost E. Im pairm en t of n orm al in am m ator y react ion

Di cult y level: Easy 33. A 6-year-old boy presen ted to h is pediat rician w ith fever


(101.3°F, 38.5°C) an d sh arp pain in h is left ear. On physical


exam in at ion , th e left t ym pan ic m em bran e w as red, opaque,

partm ent w ith altered consciousness, fever, nausea, and vom -

an d bu lgin g. Am oxicillin w as p rescr ibed , bu t 3 days later,

it ing. Vit al sign s on adm ission w ere blood pressure 90/50

t h e sym ptom s w ere n ot redu ced. Th e pediat rician decided to

m m Hg, pu lse 115 bp m , resp irat ion s 20/m in , tem p erat u re

m od ify th e th erapy an d p rescribed am oxicillin /p otassiu m

103.6°F (39.8°C). Physical exam in at ion sh ow ed a pat ien t in

clavulan ate. W h ich of th e follow ing best explain s th e advan -

obviou s d ist ress w it h a st i

t age of adding p ot assiu m clavu lan ate to am oxicillin ?

n eck an d p osit ive Br u d zin ski

Questions: VIII-1 Bacterial Cell Wall Synthesis Inhibitors 405 A. In h ibit ion of bacterial in act ivat ion of am oxicillin

A. Van com ycin

B. Exten ded an t ibacterial spect rum again st Pseudom onas

B. Cipro oxacin

aeruginosa

C. Pen icillin G

C. In h ibit ion of ren al secret ion of am oxicillin

D. Tobram ycin

D. In creased am oxicillin en t r y in to bacteria

E. Met ron idazole

E. Decreased am oxicillin allergen icit y

F.

Azt reon am




37. A 71-year-old diabet ic m an w as adm it ted to th e h ospit al

m en t becau se of u sh ing, itch ing, n au sea, sn eezing, an d ab -

w ith fever (101.2°F, 38.4°C) an d a th robbing foot pain for th e

d om in al cram p s. Five days earlier, th e pat ien t w as diagn osed

p ast 10 h ou rs. Physical exam in at ion revealed a p u t rid sm ell-

w ith syph ilis an d st ar ted on an t ibiot ic t reat m en t . Vit al sign s

ing, pu s- lled u lcer on th e righ t foot . A m et al p robe in ser ted

on adm ission w ere blood pressu re 98/56 m m Hg, pu lse 125

in to th e w ou n d detected bon e an d a deep cavit y. A Gram

bp m , respirat ion s 22/m in . Physical exam in at ion sh ow ed a

stain of th e p u s sh ow ed gram -posit ive cocci in ch ain s, gram -

cyan ot ic p at ien t w ith ur t icaria, angioedem a, an d w h eezing.

n egat ive diplococci, an d gram -posit ive an d -n egat ive rods.

W h ich of t h e follow in g an t ibiot ics m ost likely cau sed t h e

W hich of the follow ing antibiotics w ould be m ost appropriate


to give w h ile blood an d drain age cult ures w ere processed?

A. Azith rom ycin

A. Am oxicillin /clavulan ate

B. Doxycyclin e

B. Clin dam ycin

C. Met ron idazole

C. Lin ezolid

D. Pen icillin G

D. Met ron idazole

E. Am ikacin

E. Van com ycin

F.

Clin dam ycin


38. A 53-year-old w om an presen ted to th e clin ic com plain ing of

35. A 57-year-old w om an con su lted h er p hysician becau se of

3 w eeks of n igh t sw eats, cough produ ct ive of fou l-sm elling

fever (101°F, 38.3°C), ch ills, n au sea an d vom it ing, an d p ain

spu t u m , an d abou t 10 lb (4.5 kg) of w eigh t loss. Physical ex-

in th e upper righ t quadran t . Subsequen t exam s led to th e

am in at ion sh ow ed fever (101.3°F, 38.5°C), clear lung

d iagn osis of acu te ch olecyst it is. An app ropriate th erapy w as

an d m ild clu bbing. Ch est rad iography sh ow ed a th ick-w alled

star ted, in clu ding a cep h alosp orin th at is p rim arily elim i-

abscess in th e left lobe. Gram st ain of th e sp u t u m revealed

n ated in th e bile. W h ich of th e follow ing drugs w as m ost

gram -n egat ive rod s, an d aerobic cu lt u res w ere n egat ive.


W h ich of th e follow ing correctly pairs th e m ost likely cau s-

A. Ceftazidim e

at ive path ogen w ith th e appropriate t reat m en t?

B. Cefop erazon e

A. Legionella pneum ophila: am picillin

C. Cefotetan

B. Act inom yces israelii: gen tam icin

D. Cefep im e

C. Bacteroides fragilis: im ipen em

E. Cep h aloth in

D. St reptococcus pneum oniae: azt reon am

elds,

E. Listeria m onocytogenes: ceftazidim e

Di cult y level: Easy 36. A 33-year-old m an presen ted to th e clin ic because h e h ad


n ot iced a red , p ain less n od u le on t h e glan s of h is p en is 1

39. A 31-year-old w om an recen t ly d iagn osed w it h acu te ton -

w eek earlier. Th ree days after it ap p eared , t h e n od u le be-

sillit is st ar ted a t reat m en t w ith am oxicillin . W h ich of th e

cam e u lcerated, bu t on ly m in im ally p ain fu l. Physical exam -

follow ing m olecular act ion s m ost likely con t ributed to th e

in at ion sh ow ed an ulcer w ith an in durated base th at exuded


clear serum . Dark eld m icroscopy from th e exudate sh ow ed

A. Act ivat ion of au tolyt ic en zym es in th e bacterial cell w all

n um erous slen der spiral m icroorgan ism s th at w ere act ively

B. Bin ding to th e 30S bacterial ribosom al subu n it

m ot ile. A d iagn osis w as m ad e, an d a su it able t h erapy w as

C. Activation of the e u x pum p in bacterial cell m em branes

p rescr ibed . W h ich of t h e follow ing d r ugs w ou ld be m ost

D. In h ibit ion of t ran sglycosylase in th e bacterial cell w all

ap propriate for th is pat ien t?

E. In h ibit ion of DNA-depen den t RNA polym erase

406




40. A 76-year-old m an com plain ed to h is physician of a foul-

43. A 7-year-old boy w as adm it ted to th e h ospit al w ith fever

sm elling secret ion from h is left ear for th e p ast 2 w eeks. Fu r-

(102°F, 38.8°C) an d join t pain in h is kn ees an d w rist s. He h ad

th er exam s led to th e diagn osis of ch ron ic ot it is m edia, an d

a h istor y of a severe sore th roat for 3 w eeks. Vit al sign s on

cu lt u res from

u id secret ion s in dicated Bacteroides fragilis

adm ission w ere blood p ressu re 122/80 m m Hg, h ear t rate

as th e m ain cau sat ive agen t . An ap prop riate an t ibiot ic t reat-

110 bp m , resp irat ion s 24/m in . Physical exam in at ion sh ow ed

m en t w as st arted. Fou r days later, blood resu lt s in dicated

red, h ot , an d pain ful kn ees an d a n onpr urit ic rash w ith dis-

a p roth rom bin t im e of 25 secon d s (n orm al 10−14 secon ds).

t in ct d isklike bord ers on h is th igh s an d stom ach . Su bcu t an e-

W h ich of t h e follow ing d r ugs m ost likely cau sed t h is lab

ous, pain less n odules w ere presen t over th e bon e surface of

result?

h is elbow s an d kn ees. Hear t auscult at ion revealed a m it ral

A. Clin dam ycin

valve regu rgit at ion m u r m u r. Per t in en t lab resu lt s on ad -

B. Ch loram p h en icol

m ission w ere er yth rocyte sedim en tat ion rate 80/h (n orm al

C. Im ipen em

< 10/h for ch ildren ), an t ist reptolysin - O t iter 410 IU (n orm al

D. Met ron idazole

< 200 IU). A diagn osis w as m ade, an d a suitable th erapy w as

E. Cipro oxacin

p rescribed. W h ich of th e follow ing p airs of drugs w ould be

F.

m ost app ropriate for th e in it ial t reat m en t of th is p at ien t?

Cefotetan

A. Pen icillin G an d n aproxen


B. Am oxicillin an d er yth rom ycin

41. A 74-year-old m an w as recen tly diagn osed w ith pn eum on ia

C. Ceft riaxon e an d acetam in op h en

d u e to Pseudom onas aeruginosa. Past h istor y of t h e p at ien t

D. Tobram ycin an d asp irin

w as sign i can t for a severe allergic react ion to am p icillin .

E. Pen icillin G an d acet am in oph en

A t reat m en t w as star ted w ith a β-lactam an t ibiot ic th at is

F.

Am oxicillin an d ceft riaxon e

h igh ly resist an t to β-lactam ases an d is act ive on ly again st m ost gram -n egat ive aerobic bacteria. W h ich of th e follow -


ing drugs w as m ost likely given ?

44. A 7-year-old girl w as adm it ted to th e em ergen cy depart-

A. Im ipen em

m en t w ith fever (101.8°F, 38.8°C) an d a p rodu ct ive cough of

B. Ceftazidim e

th ick, green ish sp u t u m . Her m edical h istor y w as sign i can t

C. Am oxicillin

for cyst ic

D. Azt reon am

th e past 3 years. Gram stain of th e spu t u m revealed gram -

E. Cefep im e

n egat ive rods. Grow th of bacteria on agar cult ure exh ibited a

brosis an d several episodes of pn eum on ia over

blu e-green p igm en t . W h ich of th e follow ing β-lactam dr ugs

Di cult y level: Easy 42. An 11-year-old girl w as t aken to th e clin ic because of fever

w ou ld be app ropriate to in clu d e in th e th erapeu t ic regim en of th is pat ien t?

(102°F, 38.8°C), sh or t n ess of breath , an d cough product ive of

A. Pip eracillin

p uru len t sp ut um . A ch est radiograph sh ow ed several areas

B. Cep h aloth in

of in lt rat ion w ith possible abscess form at ion . Coagu lase-

C. Am oxicillin

p osit ive bacteria w ere cult ured from th e blood, an d a su s-

D. Clavulan ic acid

cept ibilit y test sh ow ed th at th ey w ere m eth icillin -resist an t .

E. Oxacillin

Treat m en t w ith van com ycin w as st ar ted . In h ibit ion of w h ich

F.

Pen icillin G

of th e follow ing m olecular act ion s m ost likely m ediated th e th erap eu t ic e ect of th e drug in th e p at ien t’s disease?


A. Elongat ion of pept idoglycan

45. A 32-year-old m an recen tly diagn osed w ith cellu lit is caused

B. Relaxat ion of su p ercoiled DNA

by St reptococcus pyogenes st ar ted a t reat m en t w ith am picil-

C. Bin ding to ribosom al RNA

lin . Th e drug act s by bin ding to pen icillin -bin ding p rotein s.

D. Tran slocat ion of p ept idyl t ran sfer RNA (tRNA)

W h ich of t h e follow ing m olecu lar act ion s is cat alyzed by

E. Act ivat ion of au tolyt ic en zym es

p en icillin -bin d ing protein s? A. Tran spor t of p en icillin s th rough porin ch an n els B. Tran spept idat ion react ion C. Breakdow n of th e β-lact am ring D. In h ibit ion of m urein hydrolases E. Bin ding of pen icillin s to th e pept idoglycan layer

Questions: VIII-1 Bacterial Cell Wall Synthesis Inhibitors 407 Di cult y level: Medium

A. Im ipen em

46. A 64-year-old h om eless m an w as taken to th e em ergen cy

B. Van com ycin

d ep ar t m en t becau se of ch ills, fever, n au sea an d vom it ing,

C. Cefazolin

an d a lacerat ion in h is left h arm . Vit al sign s on adm ission

D. Oxacillin

w ere blood pressu re 100/52 m m Hg, pu lse 124 bp m , respira-

E. Am picillin

tions 32/m in , tem perature (102.2°F, 39°C). Physical exam ina-

F.

Cefepim e

t ion sh ow ed a crit ically ill p at ien t w ith an in fected w ou n d , an d m icrobiological test s from a w ou n d specim en sh ow ed


vancomycin-resistant Staphylococcus aureus. Em ergency ther-

49. A 49-year-old w om an recen t ly d iagn osed w ith an u n com -

apy w as st ar ted. W h ich of th e follow ing drugs w ou ld be ap -

p licated u r in ar y t ract in fect ion st ar ted a t reat m en t w it h


an an t ibiot ic t h at im p airs cell w all syn t h esis by in h ibit in g

A. Cep h alexin

en olpyruvate t ran sferase. W h ich of th e follow ing drugs h as

B. Tobram ycin

th is m ech an ism of act ion ?

C. Azt reon am

A. Cep h aloth in

D. Daptom ycin

B. Van com ycin

E. Im ipen em

C. Azt reon am

F.

D. Fosfom ycin

Gen t am icin

E. Im ipen em

Di cult y level: Medium 47. A 49-year-old m an hospitalized for bacterial endocarditis had


been receiving a t reat m en t w ith t w o drugs given in t rave-

50. A 53-year-old w om an h osp it alized for resect ion of breast

n ou sly. On e w eek in to th erapy, a rout in e urin alysis sh ow ed

carcin om a p resen ted w it h fever (103.8°F, 39.4°C), cough ,

album inuria, m icroscopic hem aturia, and hyaline casts. Which

dysp n ea, an d viscid , cu r ran t jelly−like sp u t u m 3 days after

of t h e follow in g p airs of d r ugs m ost likely cau sed t h ese

su rger y. A Gram st ain sh ow ed n u m erou s gram -n egat ive

n dings?

bacilli w ith large cap su les. A ch est radiograp h sh ow ed d en se

A. Am picillin an d ceph alexin

righ t u pp er eld in lt rates. A diagn osis of n osocom ial p n eu-

B. Am ikacin an d tobram ycin

m on ia w as m ad e. W h ich of th e follow ing pairs of an t ibiot ics

C. Er yth rom ycin an d tobram ycin

w ou ld be m ost app rop riate for th e em ergen cy th erapy of

D. Van com ycin an d gen t am icin

th is p at ien t?

E. Azt reon am an d er yth rom ycin

A. Van com ycin an d oxacillin B. Er yth rom ycin an d n afcillin


C. Cefoxit in an d tobram ycin

48. A 42-year-old m an h osp it alized for st ap hylococcal en -

D. Pen icillin G an d gen t am icin

d ocard it is d evelop ed hyp oten sion , t achycard ia, gen eralized p r u r it us, an d facial

u sh ing 15 m in utes after receiving an

in t raven ous inject ion of an an t ibiot ic. W h ich of th e follow ing drugs m ost likely caused th e pat ien t’s syn drom e?

E. Tet racyclin e an d su lfam etoxazole

408


Questions: VIII-2 Bacterial Protein Synthesis Inhibitors Directions for questions 1−5

A. Pip eracillin


B. Ceftazidim e

(each let tered opt ion can be selected on ce, m ore t h an on ce, or

C. Im ipen em

n ot at all).

D. Azt reon am

A. Am ikacin B. Azith rom ycin C. Ch loram p h en icol D. Clin dam ycin

E. Gen t am icin

Di cult y level: Easy 7. A 69-year-old m an recen tly diagn osed w ith a Proteus m ira-

E. Dem eclocyclin e

bilis in fect ion st ar ted t reat m en t w ith a daily in t ram uscu lar

F.

inject ion of gen t am icin . W h ich of t h e follow ing p airs of

Doxycyclin e

G. Er yth rom ycin

p rop er t ies best exp lain s w hy t h e d r ug is u su ally ad m in is-

H. Gen t am icin

tered on ce daily d esp ite t h e sh or t h alf-life of gen t am icin

I.

Lin ezolid

(about 2 h ours)?

J.

Neom ycin

A. Tim e-depen den t killing an d bactericidal e ect

K. Sp ect in om ycin

B. Extensive plasm a protein binding and bactericidal e ect

L.

St reptom ycin

C. Concentration-dependent killing and bacteriostatic e ect

M. Parom om ycin

D. Con cen tration-depen dent killing an d long postantibiotic

N. Tet racyclin e O. Tigecyclin e

Di cult y level: Easy 1. A glycylcyclin e an t ibiot ic act ive again st van com ycin -resist an t stap hylococci

e ect E. Tim e-depen den t killing an d long post an t ibiot ic e ect

Di cult y level: Easy 8. A 3-year-old girl developed w h ooping cough . Paren t s an d oth er close con tact s of th e pat ien t sh ould receive a 10-day course of w h ich of th e follow ing drugs?


A. Tet racyclin e

2. An am in oglycoside an t ibiot ic act ive again st am ebiasis an d

B. Ch loram ph en icol

giardiasis

C. Er yth rom ycin D. Cipro oxacin


E. Ceft riaxon e

3. A m acrolide an t ibiot ic w ith a ver y long h alf-life (about 40

F.

Am picillin

h ours)

Di cult y level: Easy Di cult y level: Easy 4. A tet racyclin e an t ibiot ic som et im es used in syn drom e of in appropriate an t idiuret ic h orm on e secret ion (SIADH)

9. A 60-year-old m an recen tly diagn osed w ith carcin om a of th e colon w as adm it ted to th e h ospital for colectom y. W h ich of th e follow ing drugs w ould be appropriate to be in clu ded in th e oral p rop hylact ic t reat m en t of th is p at ien t to p reven t


su rgical in fect ion ?

5. An am in oglycoside an t ibiot ic som et im es u sed in h ep at ic en -

A. St reptom ycin

cep h alop athy

B. Pen icillin G C. Trim eth op rim

Di cult y level: Easy 6. A 45-year-old diabet ic w om an com plain ed to h er physician of pain in h er righ t ear for th e p ast 5 h ou rs. Fu rth er exam s led to th e diagn osis of extern al ot it is, an d later th e cult ure of ear exudate sh ow ed Pseudom onas aeruginosa as th e m ain o en d -

D. Neom ycin E. Cep h aloth in F.

Van com ycin


ing p ath ogen . Th e p at ien t w as given an an t ibiot ic th at cau ses

10. A 45-year-old far m er p resen ted to t h e clin ic w it h fever

m isreading of th e bacterial m essenger RNA tem plate leading

(103.2°F, 39.5°C), ch ills, h eadach e, an d a d r y cough . Ch est

to the production of aberrant bacterial proteins. W hich of th e

x-ray sh ow ed exten sive n odular in lt rates radiat ing from

follow ing drugs w as m ost likely adm in istered?

th e h ilu m . Histor y revealed th at th e m an raised ch icken s an d

Questions: VIII-2 Bacterial Protein Synthesis Inhibitors 409 th at approxim ately 2 w eeks ago h e h ad lost a large n um ber

A. Plasm id-m ediated product ion of bacterial t ran sferases

of t h em to an u n d iagn osed d isease. Th e p resu m pt ive d iag-

B. Decreased a

n osis of pn eum on ia w as m ade, an d an appropriate drug w as

su bu n it

n it y of t h e d r ug for t h e 50S r ibosom al

prescribed. W h ich of th e follow ing correctly p airs th e m ost

C. Developm en t of an act ive e

likely o en ding p ath ogen w ith th e app ropriate t reat m en t?

D. Mu t at ion -in du ced ch ange of bacterial p eroxidase

A. Mycobacterium t uberculosis: ceftazidim e

E. Mu t at ion -in du ced ch ange of bacterial top oisom erases

u x pu m p

B. Chlam ydia pneum oniae: m et ron idazole C. Mycoplasm a pneum oniae: piperacillin


D. Chlam ydia t rachom at is: gen tam icin

14. A 60-year-old m an presented w ith fever (102°F, 38.9°C), gen eral m alaise, an d t achyp n ea. Th e m an h ad been h osp italized

E. Chlam ydia psit taci: doxycyclin e

for th e past 4 days for evalu at ion of st age C cardiac failure.


Medical th erapy on adm ission in clu ded fu rosem ide, losarcien cy

t an , asp irin , an d aten olol. Fu r th er test s led to th e diagn osis

w as abou t to receive gen t am icin an d pip eracillin for sep sis,

of n osocom ial pn eum on ia due to Pseudom onas aeruginosa,

ap p aren t ly d u e to gram -n egat ive bacter ia. Th e p at ien t ’s

an d a t h erapy w it h ceft azid im e an d am ikacin w as st ar ted .

creat in in e clearan ce w as abou t on e h alf th e n orm al valu e.

Becau se of h is cu r ren t cardiac t h erapy, t h e p at ien t w as at

Th e physician ch ose to ch ange th e dosage of gen tam icin an d

in creased r isk of w h ich of t h e follow ing adverse e ect s of

m aintain the norm al dosing inter val. Assum ing that the usual

am ikacin ?

gen tam icin dose for sep sis is 100 m g ever y 8 h ou rs, w h ich of

A. Su p erin fect ion s

th e follow ing (in m illigram s) w ou ld be an app ropriate in it ial

B. Nep h rotoxicit y

d ose of gen t am icin for th is pat ien t?

C. Neu rom u scu lar blockade

A. 110

D. Ototoxicit y

B. 75

E. Periph eral n eurit is

C. 200

F.

11. A 54-year-old m an su ering from ch ron ic ren al in su

Opt ic n er ve dysfun ct ion

D. 50 E. 150


F.


33

on urin at ion an d bladder pain . Th e m an w as w earing a per-


m an en t u rin ar y cath eter becau se of in operable p rostate hy-

12. A 51-year-old w om an w as adm it ted to the hospital w ith fever

p erp lasia. A u rin e cu lt u re w as ordered, an d a su scept ibilit y

(102.7°F, 39.3°C), sh aking ch ills, n au sea an d vom it ing, an k p ain , an d h em at uria. Sh e h ad been su ering from ch ron ic u rin ar y t ract in fect ion s for 1 year an d from t ype II diabetes for 10 years. Fu rth er test s led to th e diagn osis of acute pyelon eph rit is due to Pseudom onas aeruginosa. W h ich of th e follow ing pairs of drugs w ou ld be ap propriate for th is p at ien t? A. Piperacillin an d tobram ycin B. Am picillin an d gen tam icin C. Im ipen em an d er yth rom ycin D. Cep h aloth in an d am ikacin E. Am picillin an d doxycyclin e

test gave th e follow ing results: Organism

Ticarcillin

Amikacin

Ceftazidime

Ciprof oxacin

TMPSMX

Escherichia coli

S

S

I

S

S

Klebsiella pneumoniae

R

S

S

I

S

Pseudomonas aeruginosa

S

S

S

S

R

Proteus vulgaris

S

I

I

I

R

Abbreviations: I, interm ediate; R, resistant; S, susceptible; TMP-SMX, trim ethoprim -sulfam etoxazole.



13. A 66-year-old w om an com p lain ed to h er p hysician of u r i-

th is pat ien t?

n ar y u rgen cy an d bu r n ing p ain d u r ing u r in at ion . A u r in e

A. Ticarcillin

cu lt u re revealed t h at Escherichia coli w as t h e o en d in g or-

B. Am ikacin

gan ism , an d a su scept ibilit y test sh ow ed th at th e bacteriu m

C. Ceftazidim e

w as resist an t to am in oglycosid e an t ibiot ics. W h ich of t h e

D. Cip ro oxacin

follow in g m ech an ism s can accou n t for t h e bacter ial resis-


t an ce to am in oglycosides?

410




16. A 72-year-old fem ale residen t of a n ursing facilit y w as ad-

19. A 15-year-old girl w as adm it ted to th e h ospit al because of

m it ted to th e h ospit al becau se of steadily d eclin ing u rin e

fever (103.2°F, 39.5°C) an d severe pain in h er left leg. A bon e

ou t p u t over t h e p ast 3 days. Th e w om an h ad been receiv-

scan sh ow ed in am m at ion in h er left d ist al fem u r. Tw o

ing an an t ibiot ic for 2 w eeks to t reat a urin ar y t ract in fec-

blood cu lt u res w ere posit ive for Staphylococcus aureus, an d

t ion ap p aren tly du e to Pseudom onas aeruginosa. A u rin alysis

su scept ibilit y test ing sh ow ed th at th e bacteriu m w as m eth -

sh ow ed albu m in u r ia, h em at u r ia, an d hyalin e cast s. W h ich

icillin - an d van com ycin -resist an t . Th erapy w as st arted w ith

of t h e follow in g d r ugs m ost likely cau sed t h e p at ien t ’s

an an t ibiot ic th at bin ds to th e 23S port ion of th e 50S ribo-

disorder?

som al su bu n it an d in h ibit s t h e for m at ion of t h e in it iat ion

A. Piperacillin

com plex. W hich of the follow ing drugs w as m ost likely given?

B. Tobram ycin

A. Tet racyclin e

C. Azt reon am

B. Er yth rom ycin

D. Van com ycin

C. Im ipen em

E. Rifam pin

D. Gen t am icin E. Lin ezolid


F.

Tigecyclin e

17. A 35-year-old m an presen ted w ith fever (101°F, 38.3°C), cough , an d dyspn ea. Th e m an w as h ospitalized 1 w eek ago


becau se h e w as fou n d to be HIV posit ive, bu t n o an t iviral

20. A 70-year-old w om an com plain ed to h er physician of h ead-

th erapy h ad been in it iated yet . Fu rth er exam s led to th e d i-

ach e, n au sea an d vom it ing, ver t igo, t in n it u s, an d p rogressive

agn osis of pn eum on ia, an d 10 days of gen t am icin th erapy

loss of h earing. Th e w om an h ad been receiving an an t ibiot ic

w as able to cu re th e d isease. W h ich of th e follow ing m icro-

for 2 w eeks to t reat a urin ar y t ract in fect ion apparen tly due

organ ism s w as m ost likely th e cause of th e pat ien t’s acute

to Serrat ia m arcescens. Th e d r ug u sed w as m ost likely a

illn ess?

m em ber of w h ich of th e follow ing an t ibiot ic classes?

A. Clost ridium di cile

A. Macrolides

B. Mycoplasm a pneum oniae

B. Tet racyclin es

C. Bacteroides fragilis

C. Cep h alosporin s

D. Borrelia recurrent is

D. Su lfon am ides

E. Enterobacter aerogenes

E. Am in oglycosides

F.

Legionella pneum ophila


21. A 14-year-old girl diagn osed w it h a resp irator y t ract in fec-

18. A 45-year-old w om an w as diagn osed w ith a urin ar y t ract

t ion st ar ted t reat m en t w ith er yt h rom ycin . W h ich of t h e

in fect ion due to gram -n egat ive rods. Th e w om an h ad been

follow ing m olecu lar act ion s on bacterial cells m ost likely

su ering from m yasth en ia gravis for 5 years. W h ich of th e


follow ing an t ibiot ics w ou ld be relat ively con t rain dicated in

d isease?

th is p at ien t?

A. In h ibit ion of DNA-depen den t RNA polym erase

A. Ceft riaxon e

B. In h ibit ion of DNA gyrase

B. Azt reon am

C. Product ion of aberran t bacterial protein s

C. Er yth rom ycin

D. Blockade of t ran slocat ion react ion

D. Cipro oxacin

E. Blockade of transfer RNA (tRNA) binding to th e ribosom e

E. Tobram ycin F.

Cefep im e

Di cult y level: Easy 22. A 48-year-old-w om an com plain ed to h er physician of fever (103.5°F, 39.7°C), n ausea, vom it ing, an d bloody d iarrh ea for th e past 3 days. Fu r th er exam s id en t i ed th e m ost likely offen ding path ogen , an d a th erapy w ith azith rom ycin w as able to elim in ate t h e d iar rh ea. W h ich of t h e follow ing bacter ia m ost likely cau sed th e p at ien t’s disease?

Questions: VIII-2 Bacterial Protein Synthesis Inhibitors 411 A. Escherichia coli


B. Cam pylobacter jejuni

26. A 15-day-old baby boy w as adm it ted to th e pediat ric w ard

C. Shigella dysenteriae

w ith m ucopurulen t ocular disch arge, edem a of th e eyelids,

D. Salm onella enterit idis

an d peu dom em bran e form at ion . A Gram st ain of th e exu -

E. Clost ridium di cile

date revealed n o m icroorgan ism s, bu t a Giem sa st ain sh ow ed

F.

cells w ith cytoplasm ic in clusion s. Both topical an d system ic

Entam oeba histolyt ica

t reat m en t s w ere p rescribed . W h ich of th e follow ing drugs


w as m ost likely adm in istered?

23. A 17-year-old girl com p lain ed to h er p hysician of w ater y

A. Tet racyclin e

d iarrh ea. Th ree days ago, sh e w as diagn osed w ith st repto-

B. Am picillin

coccal ph ar yngit is, an d t reat m en t w ith er yth rom ycin w as

C. Cipro oxacin

star ted. W h ich of th e follow ing best exp lain s th e m ost likely

D. Trim eth op rim -su lfam eth oxazole

reason for th is adverse e ect of er yth rom ycin ?

E. Er yth rom ycin

A. Killing m ost bacteria of in test in al ora

F.

Tobram ycin

B. Act ivat ion of m ot ilin receptors in th e gu t C. In h ibit ion of w ater reabsorpt ion by colon ic m ucosa


D. An t ibiot ic-in duced acute ch olest at ic h epat it is

27. A 65-year-old m an com plain ed to h is physician of n er vous-

E. Allergic react ion to er yth rom ycin

n ess, in som n ia, an d palpitat ion s. Th e m an h ad been su ering from ch ron ic obst ruct ive p ulm on ar y disease for several


years an d h ad been receiving th erapy th at in clu ded th eop h -

24. A 23-year-old w om an com plain ed to h er physician of pain

yllin e. A few days earlier, h e h ad been diagn osed w ith st rep -

d uring u rin at ion an d a m u coid-like vagin al disch arge th at

tococcal ph ar yngit is an d star ted an appropriate t reat m en t .

star ted abou t 14 days after h er last in tercou rse. A Gram st ain

Th e p hysician t h ough t t h at t h e p at ien t ’s sym ptom s w ere

of th e exudate revealed gram -n egat ive cocci. Treat m en t w ith

m ost likely d u e to an an t ibiot ic−t h eop hyllin e in teract ion .

ceft riaxon e w as prescribed. W h ich of th e follow ing drugs

W h ich of t h e follow ing an t ibiot ics w as m ost likely resp on -

w ou ld be app ropriate to ad d to th e p at ien t’s regim en ?

sible for th is in teract ion ?

A. Ceft riaxon e

A. Pen icillin G

B. Im ipen em

B. St reptom ycin

C. Azith rom ycin

C. Doxycyclin e

D. Azt reon am

D. Ceft riaxon e

E. Am ikacin

E. Er yth rom ycin

F.

F.

Van com ycin

Rifam pin



25. A 68-year-old m an h ospitalized because of advan ced ren al

28. A 63-year-old alcoh olic m an presen ted to th e em ergen cy de-

in su

cien cy w as foun d to h ave pn eum on ia du e to Pseudo-

p ar t m en t w ith fever (102.2°F, 39°C), ch est p ain , an d a cough

m onas aeruginosa. An ap p rop riate an t ibiot ic t reat m en t w as

p roducing m u coid sp u t u m . Physical exam in at ion revealed a

p lan n ed, but th e dose of th e drug w as reduced becau se its

m an in obviou s d ist ress w ith th e follow ing vit al sign s: blood

h alf-life can be 20 to 40 t im es longer in p at ien t s w it h kid -

p ressure 140/85 m m Hg, p u lse 55 bpm , respirat ion s 22/m in .

n ey failu re. W h ich of th e follow ing dr ugs w as m ost likely

Sp u t u m cu lt u re sh ow ed gram -n egat ive rods able to grow

p rescribed?

on ly on ch arcoal yeast ext ract agar. W h ich of th e follow ing

A. Cefop erazon e

an t ibiot ics w ou ld be m ost app ropriate for th is pat ien t?

B. Am ikacin

A. St reptom ycin

C. Er yth rom ycin

B. Pen icillin G

D. Clin dam ycin

C. Azith rom ycin

E. Met ron idazole

D. Van com ycin

F.

E. Gen t am icin

Van com ycin

F.

Met ron idazole

412




29. A 53-year-old m an w as adm it ted to th e h ospital w ith th e

32. A 73-year-old m an presen ted w ith fever (101.9°F, 38.8°C)

adm it t ing diagn osis of p n eu m on ia. Fu r th er exam s in dicated

an d p ain in th e p erin eu m an d left bu t tock. Fou r days earlier,

th at th e pn eu m on ia w as d u e to Mycoplasm a pneum onia, an d

th e m an h ad u n dergon e bow el su rger y for colon can cer,

t reat m en t w ith an app ropriate bacteriostat ic an t ibiot ic w as

w h ich w as com plicated by escape of bow el con ten ts in to th e

star ted. Th e given drug m ost likely belonged to w h ich of th e

p er iton eal cavit y. Med ical h istor y of t h e p at ien t w as sign if-

follow ing classes?

ican t for allergic react ion s to several an t ibiot ics, in clu d ing

A. Cep h alosp orin s

p en icillin s an d m et ron idazole. Fu r th er exam s led to th e di-

B. Am in oglycosides

agn osis of acute periton it is. Th e pat ien t’s illn ess respon ded

C. Macrolides

to an em piric em ergen cy t reat m en t th at in cluded paren teral

D. Carbapen em s

adm inistration of clindam ycin. W hich of the follow ing m icro-

E. Pen icillin s

organ ism s w as m ost likely th e m ain cause of th e pat ien t’s

F.

in fect ion ?

Fluoroquin olon es

A. Legionella pneum ophila


B. Klebsiella pneum oniae

30. A 48-year-old w om an w as h ospitalized w ith th e adm it t ing

C. Bacteroides fragilis

diagnosis of polym orphic ventricular tachycardia. Th e w om an

D. Enterobacter aerogenes

h ad been su ering from depression an d h ad been on am i-

E. Proteus m irabilis

t ript ylin e for 3 m on th s. Th ree days earlier, sh e com p lain ed

F.

Enterococcus faecalis

of fever an d sore t h roat an d w as st ar ted on an t ibiot ics. W h ich of th e follow ing an t ibiot ics m ost likely t riggered th e


p at ien t’s tachycardia?

33. A 34-year-old pregn an t w om an developed severe ph ar yngi-

A. Van com ycin

t is th at t u rn ed ou t to be du e to St reptococcus pyogenes. Past

B. Er yth rom ycin

h istor y of t h e p at ien t w as sign i can t for an an ap hylact ic

C. Gen t am icin

react ion to am p icillin . W h ich of t h e follow ing an t ibiot ics

D. Ceft riaxon e

w ou ld be m ost app ropriate for th is p at ien t?

E. Am picillin

A. Ceft riaxon e

F.

B. Ceftazidim e

Su lfam etoxazole

C. Im ipen em

Di cult y level: Medium 31. A 3-year-old boy w as brough t to th e pediat rician’s o

D. Er yth rom ycin ce by

h is m oth er because of a low -grade fever an d a pain ful, en -

E. Doxycyclin e F.

Azt reon am

larged ingu in al lym p h n ode. On qu est ion ing, th e m oth er stated th at th e boy w as scratch ed on h is righ t leg by h is pet


cat 1 w eek earlier. A Gram st ain of p u s aspirated from th e

34. A 58-year-old w om an com plain ed to h er physician of bruis-

lym ph node revealed m any sm all, gram -negative rods. W hich

ing and nose bleeds. Th e w om an, diagnosed w ith atrial bril-

of th e follow ing correctly pairs th e m ost likely o en ding

lat ion , h ad been taking w arfarin for 1 year. On e w eek earlier,

p ath ogen w ith th e appropriate t reat m en t?

sh e w as diagn osed w ith m ycoplasm al p n eu m on ia an d w as

A. Enterococcus faecalis: van com ycin

star ted on an t ibiot ic th erapy. W h ich of th e follow ing drugs

B. Clost ridium di cile: m et ron idazole

m ost likely m ediated th e pat ien t’s bleeding?

C. Bartonella enselae: er yth rom ycin

A. Am oxicillin

D. Bacteroides fragilis: tobram ycin

B. Er yth rom ycin

E. Act inom yces israelii: pen icillin G

C. Am ikacin D. Van com ycin E. Pip eracillin F.

Ceft riaxon e

Questions: VIII-2 Bacterial Protein Synthesis Inhibitors 413 Di cult y level: Easy


35. A 23-year-old m an com plain ed to h is physician of a severe

38. A 30-year-old m an w as adm it ted to th e h ospital w ith fever

sore th roat an d fever. Becau se th e m an w as allergic to pen i-

(103°F, 39.4°C), ch ills, t achycard ia, vom it ing, an d m u scle

cillin , er yt h rom ycin w as p rescr ibed , bu t 3 days later, t h e

p ain . He h ad t h e sam e sym ptom s 10 days earlier, ju st after

clin ical p ict u re w as n ot im p roved . Th e p hysician ch an ged

a cam p ing t rip n ear th e Un ited States−Mexico border. Th e

th e an t ibiot ic becau se h e su spected bacterial resistan ce to

fever rem ain ed h igh for 3 days, th en cleared abru ptly. A th ick

er yth rom ycin . W h ich of th e follow ing m ech an ism s can ac-

blood sm ear w ith Giem sa stain revealed m any th read like

coun t for resist an ce to m acrolides?

bacteria w ith large, irregu lar coils. W h ich of th e follow ing

A. In h ibit ion of th e m ult idrug e

u x pum p

correctly pairs th e m ost likely disease w ith th e appropriate

B. Product ion of drug-in act ivat ing RNA polym erases

t reat m en t?

C. Alterat ion of th e ribosom al bin ding site th at preven t s

A. Syp h ilis: st reptom ycin

drug bin d ing

B. Brucellosis: st reptom ycin

D. Production of drug-inactivating glucuronosyl transferases

C. Rocky Mou n t ain spot ted fever: doxycyclin e

E. In h ibit ion of m ethylase en zym es th at act ivate th e drug

D. Relapsing fever: doxycyclin e E. Psit tacosis: piperacillin


F.

Histoplasm osis: am picillin

36. A 49-year-old w om an on vacat ion in th e south of It aly presen ted w it h fever, h eadach e, an d a sm all, bu t ton like skin


u lcer, 5 m m (about 0.2 in ch ) in diam eter, w ith a black cen ter.

39. A 32-year-old w om an on a vacat ion t rip in East Asia w as di-

Th e d iagn osis of Mediterran ean spot ted fever w as m ade, an d

agn osed w ith acu te conjun ct ivit is. A top ical t reat m en t w ith

th e w om an w as p rescribed d oxycyclin e. W h ich of th e fol-

ch loram ph en icol w as able to com pletely h eal th e disease.

low ing m olecu lar act ion s m ost likely m ediated th e th era-

W h ich of t h e follow ing m olecu lar act ion s m ost likely m e-

p eu t ic e ect of th e drug in th e p at ien t‘s disease?

d iated t h e t h erap eu t ic e

A. In h ibit ion of DNA-depen den t RNA polym erase

d isease?

B. Blockade of the form ation of ribosom al initiation com plex

A. In h ibit ion of cross-lin king of lin ear pept idoglycan ch ain s

C. Blockade of t ran spept idat ion react ion

B. Blockad e of t h e t ran sp ept idat ion react ion of p rotein syn th esis

D. Blockade of bin ding of am in oacyl-t ran sfer RNA (tRNA) to bacterial ribosom es E. In h ibit ion of t ran spept idase en zym es

cacy of t h e d r ug in t h e p at ien t ’s

C. In h ibit ion of relaxat ion of supercoiled bacterial DNA D. In h ibit ion of ergosterol syn t h esis in t h e bacter ial cell m em bran e


E. Misreading of th e m essenger RNA (m RNA) tem p late in th e ribosom al su bu n it

37. A 34-year-old w om an presen ted to th e clin ic w ith m ild fever (99.5°F, 37.5°C), fat igue, m u scle an d join t pain , an d m u lt iple red rash es w it h a clear cen ter. Sh e rep or ted t h at 10 days


ago sh e w as bit ten on th e arm by a t iny t ick. A circular skin

40. An 1168-g (2.57-lb) preterm m ale born to a febrile m oth er

lesion star ted at th e bite site, exp an ded to 15 cm (about 6

p resen ted w it h resp irator y d ist ress a few h ou rs after t h e

in ch es) or so, an d w as follow ed by m ult iple, pain less rash es.

d eliver y. Physical exam in at ion an d lab resu lt s suggested

Physical exam in at ion con rm ed th e diagn osis of er yth em a

n eon at al sepsis, an d an em pirical an t ibiot ic th erapy w as in -

m igran s. W h ich of th e follow ing drugs w ou ld be app ropriate

st it u ted . Later, blood cu lt u res in d icated Listeria m onocyto-

for th e pat ien t at th is st age?

genes as t h e o en d in g organ ism . W h ich of t h e follow in g

A. Gen t am icin

drugs w ou ld be m ost app rop riate to adm in ister in com bin a-

B. Met ron idazole

t ion w ith am p icillin for th e t reat m en t of h is in fect ion ?

C. Lin ezolid

A. Doxycyclin e

D. Doxycyclin e

B. Gen t am icin

E. Van com ycin

C. Ceft riaxon e D. Er yth rom ycin E. Azt reon am F.

Met ron idazole

414




41. A 31-year-old p regn an t w om an w h o recen t ly ar r ived from

44. A 33-year-old w om an w as h ospit alized w ith fever (103.5°F,

Ugan da w as d iagn osed w it h lym p h ogran u lom a ven ereu m .

39.7°C), chills, m ental confusion, vom iting, and diarrhea. On e

Th e p hysician p rescr ibed a t reat m en t w it h er yt h rom ycin ,

w eek earlier, t h e w om an h ad ret u r n ed from a vacat ion in

as tetracyclines are contraindicated during pregnancy. W hich

cen t ral Afr ica. A Giem sa st ain con r m ed t h e d iagn osis of

of th e follow ing drug-in duced adverse e ect s best describes

Plasm odium falciparum m alar ia. Becau se t h e p at ien t cam e

th e reason for th is con t rain dicat ion ?

from a region w ith m u lt idrug-resistan t st rain s of P. falci-

A. Im pairm en t of fetal grow th

parum , p aren teral qu in idin e th erapy w as st arted. W h ich of

B. Su p erin fect ion s in th e n ew born

th e follow ing w ould be a u seful agen t to add to h er th era-

C. Severe m yelosu p pression in th e n ew born

peu t ic regim en ?

D. Mu lt iple fet al m alform at ion s

A. Im ipen em

E. Kern icterus in th e n ew born

B. Azith rom ycin

F.

C. Doxycyclin e

Early fet al death

D. Gen t am icin


E. Pip eracillin

42. A 31-year-old m an w as h ospit alized because of severe w a-

F.

Cefepim e

ter y diarrh ea, vom it ing, an d altered m en tal st at us. Th e m an ret urn ed 1 day earlier from Lat in Am erica, w h ere h e visited


w ith relat ives, several of w h om w ere recovering from an in -


test in al in fect ion . Physical exam in at ion sh ow ed a crit ically

of fever (102.6°F, 39.2°C), sh ortness of breath, and cough pro-

ill pat ien t w ith m arked loss of t issue t urgor, sun ken eyes,

ductive of purulent sputum . X-ray of the ch est sh ow ed several

an d w rin kled skin . Lab test s on adm ission revealed h em o-

areas of in lt rat ion w ith possible abscess form at ion . A blood

concentration and severe m etabolic acidosis. A diagnosis w as

cu lt u re in d icated t h e in fect ion w as d u e to st ap hylococci,

m ade, an d an em ergen cy t reat m en t w as in it iated th at in -

an d a su scept ibilit y test sh ow ed t h at t h ey w ere resist an t

cluded th e paren teral adm in ist rat ion of doxycyclin e. W h ich

to m eth icillin an d van com ycin . W h ich of th e follow ing an t i-

of t h e follow in g bacter ia m ost likely cau sed t h e p at ien t ’s

biot ic th erapies w ou ld be m ost ap prop riate for th is p at ien t?

d isease?

A. Nafcillin

A. Vibrio cholerae

B. Tet racyclin e

B. Bacteroides fragilis

C. Am ikacin

C. Enterobacter aerogenes

D. Cefop erazon e

D. Pseudom onas aeruginosa

E. Er yth rom ycin

E. Clost ridium di cile

F.

Qu in uprist in /dalfoprist in




46. A 42-year-old farm er presen ted to h is physician because h e

severe er yth em a th at occu rred a few m in u tes after exp osu re

h ad fever th at usually rose in th e aftern oon , su bsided du ring

to sun ligh t . He repor ted th at past an d m ore prolonged expo-

th e n igh t , an d w as follow ed by dren ch ing sw eat s. Fu r th er

su res to su n h ad cau sed on ly a m ild er yth em a. A few days

exam s led to the diagnosis of brucellosis, and a suitable phar-

earlier, th e m an h ad st ar ted on an t ibiot ic t reat m en t for n on -

m acoth erapy w as prescribed. W h ich of th e follow ing p airs

gon ococcal urethritis. W hich of the follow ing an tibiotics m ost

of drugs w ould be appropriate for th e pat ien t at th is t im e?

likely caused th e p at ien t’s er yth em a?

A. Rifam pin an d m et ron idazole

A. Cefotetan

B. St reptom ycin an d doxycyclin e

B. Gen t am icin

C. Van com ycin an d am picillin

C. Met ron idazole

D. Er yth rom ycin an d ceph aloth in

D. Doxycyclin e

E. Pen icillin G an d tobram ycin

E. Am oxicillin F.

Lin ezolid

Di cult y level: Easy 47. A 38-year-old m an p resen ted to t h e h osp it al w it h fever (1 02 .7°F, 39.2 °C), seve re ret rob u lb ar h ead ach e, ch ills,

Questions: VIII-3 Inhibitors of Bacterial Nucleic Acid Synthesis or Function 415 p h ot oph obia, m uscular pain s, an d prost rat ion . He repor ted


h e foun d a t ick at tach ed to h is scalp 7 days earlier w h ile

49. A 25-year-old w om an presen ted to th e clin ic because of vul-

cam p ing in th e m ou n tain s of Colorado. Physical exam in at ion

var itch ing an d bu rn ing an d a th ick, ch eesy vagin al disch arge

revealed a rash of p in k m acu les 2 to 5 m m (0.08−0.2 in ch )

for th e past 5 days. Th e w om an h ad been t aking an oral an t i-

spread all over h is body. A presum pt ive diagn osis w as m ade,

biot ic for 2 m on th s to t reat m oderate acn e. Gram st ain of a

an d an em piric th erapy w as st arted. W h ich of th e follow ing

vagin al sm ear in dicated Candida albicans as th e o en ding

an t ibiot ics w ould be appropriate for th is pat ien t?

p ath ogen . W h ich of th e follow ing drugs m ost likely con t rib -

A. Im ipen em

u ted to th e appearan ce of th e pat ien t’s in fect ion ?

B. Doxycyclin e

A. Cefazolin

C. Piperacillin

B. Am ikacin

D. Gen t am icin

C. Azt reon am

E. Ceftazidim e

D. Flu con azole

F.

E. Tet racyclin e

Trim eth op rim -su lfam eth oxazole

F.

Met ron idazole

Di cult y level: Easy 48. A 50-year-old w om an recen tly diagn osed w ith gast ric ulcer


star ted a t riple t reat m en t for Helicobacter pylori in fect ion

50. A 25-year-old m an recen tly diagn osed w ith severe acn e in -

th at in clu ded tet racyclin e. Tw o w eeks later, th e H. pylori test

volvin g t h e face, back, an d ch est st ar ted a t reat m en t t h at

w as st ill posit ive, an d th e p hysician su spected th e develop -

in clu ded tet racyclin e. Th e physician in st ructed th e pat ien t

m en t of resist an ce to tet racyclin e. W h ich of th e follow ing

to avoid m ilk or dair y produ ct s w ith in 2 h ours of t aking th e

m ech an ism s cou ld accou n t for th e bacterial resist an ce to

m edicat ion , becau se dair y p rodu ct s can in teract w ith tet ra-

tet racyclin es?

cyclin e. W h ich of th e follow ing best explain s th e ou tcom e of

A. In creased access to th e ribosom al bin ding site

th e in teract ion bet w een tet racyclin e an d dair y p rod u ct s?

B. Product ion of acet ylt ran sferase en zym es

A. Decreased drug bin ding to bacterial ribosom e

C. Increased perm eabilit y of the outer bacterial m em brane

B. In creased dr ug toxicit y

D. Product ion of RNA polym erase en zym es

C. In creased dr ug elim in at ion

E. In creased act ivit y of th e m ult idrug e

D. Decreased bacterial perm eabilit y to th e drug

u x pum p

E. Decreased drug oral bioavailabilit y

Questions: VIII-3 Inhibitors of Bacterial Nucleic Acid Synthesis or Function Directions for questions 1−3



3. Resist an ce to th is drug m ay be du e to a ch ange in DNA


gyrase

at all). A. Cipro oxacin


B. Met ron idazole

4. An 83-year-old fem ale residen t in a n ursing facilit y presen ted

C. Su lfadiazin e

w ith fever (100.5°F, 38°C), dr y cough , an d gen eral m alaise.

D. Su lfam eth oxazole

Fu r th er exam s led to th e diagn osis of h osp ital-acqu ired pn eu -

E. Trim eth op rim

m on ia du e to Pseudom onas aeruginosa. Treat m en t w as st ar ted w ith a drug th at is e ect ive again st m ost gram -n egat ive bac-


ter ia, as w ell as again st som e m ycobacter ia, m ycop lasm as,

1. A prodrug th at requ ires bacterial act ivat ion

ch lam yd iae, an d r icket t siae. W h ich of t h e follow ing d r ugs w as m ost likely given ?


A. Piperacillin

2. Th is drug blocks th e last t w o steps in bacterial tet rahydro-

B. Ceftazidim e

folate biosyn th esis

C. Cipro oxacin D. Er yth rom ycin E. Van com ycin

416



A. Th ey d ecrease quin olon e oral bioavailabilit y.

5. A 53-year-old w om an su ering from a u rin ar y t ract in fect ion

B. Th ey in crease t h e r isk of qu in olon e-in d u ced car t ilage erosion .

star ted a t reat m en t w ith t rim eth op rim -su lfam eth oxazole. On e w eek later, burn ing upon urin at ion w as st ill pron oun ced,

C. Th ey d ecrease qu in olon e u rin ar y excret ion .

an d th e physician suspected th at resist an ce to su lfam eth ox-

D. Th ey n ar row t h e an t ibacter ial act ivit y sp ect r u m of qu in olon es.

azole h ad occurred. Th is resist an ce w as m ost likely due to

E. Th ey in crease th e risk of qu in olon e-in du ced torsades de

w h ich of th e follow ing m ech an ism s?

p oin tes.

A. In creased perm eabilit y of bacterial cell m em bran e B. Decreased sulfon am ide bin ding to bacterial ribosom es C. In creased product ion of para-am in oben zoic acid D. Decreased sulfonam ides binding to dihydrofolate reductase E. Decreased act ivit y of th e m ult idrug e

u x pum p

Di cult y level: Easy 9. A 22-year-old m an w h o w as on vacat ion in Mexico w as seen at a local clin ic becau se of m alaise, fever (103.2°F, 39.5°C), t achycard ia, n au sea an d vom it ing, abdom in al cram p s an d

Di cult y level: Medium 6. A 59-year-old m an com plain ed to h is physician th at h is skin itch ed all over h is body. Tw o w eeks earlier, h e h ad begu n oral an t ibiot ic th erapy for acute ph ar yngit is. Physical exam in at ion sh ow ed a di u se m acu lopap u lar rash . W h ich of th e follow ing drugs m ost likely cau sed th e p at ien t’s derm at it is? A. Azt reon am B. Piperacillin C. Trim eth op rim -su lfam eth oxazole D. Van com ycin E. Gen t am icin

Di cult y level: Easy 7. A 50-year-old obese m an com plained to his physician of a sharp pain in h is left calf. Med ical h istor y in dicated th at 1 w eek ago h e h ad st arted an an t ibiot ic t reat m en t for acu te prost at it is. Fu r th er exam s led to th e diagn osis of Ach illes ten don ru pt u re.

six loose, unform ed, an d bloody stools. The sym ptom s started 24 h ou rs after a din n er at a local rest au ran t . A p resu m pt ive d iagn osis w as m ade, an d ph arm acoth erapy w as st arted. W h ich of th e follow ing drugs w ould be appropriate for th is p at ien t? A. Flucon azole B. Cip ro oxacin C. Cep h alexin D. Van com ycin E. Dicloxacillin F.

Lin ezolid

Di cult y level: Easy 10. A 49-year-old w om an recen tly diagn osed w ith urin ar y t ract in fect ion st arted t reat m en t w ith com bin ed t rim eth oprim su lfam eth oxazole. W h ich of th e follow ing best exp lain s th e m ain reason for com bin ing th ese t w o drugs?

W h ich of th e follow ing drugs m ost likely led to th e pat ien t’s

A. To retard th e biot ran sform at ion of both drugs

leg p ain ?

B. To decrease th e risk of allergic react ion s

A. Am picillin B. Doxycyclin e C. Ceft riaxon e D. Er yth rom ycin E. Cipro oxacin

Di cult y level: Easy 8. A 46-year-old w om an w ith a long h istor y of recurren t urin ar y t ract in fect ion com plain ed to h er p hysician of bu rn ing on u rin at ion an d bladder pain . Th e w om an used an tacids from t im e to t im e to t reat an n oying h ear tburn . Th e physician prescribed cip ro oxacin for 1 w eek an d in st ru cted th e pat ien t to avoid th e u se of an t acids du ring th e th erapy. W h ich of th e follow ing statem en ts best exp lain s w hy an t acids are con t rain dicated in pat ien ts t aking u oroqu in olon es?

C. To in crease p at ien t com p lian ce by adm in istering a single preparat ion D. To obt ain a bactericidal e ect th at is u n likely w ith eith er drug given alon e E. To

ach ieve

lon ger

d u rat ion

of act ion

of su lfa-

m eth oxazole

Di cult y level: Medium 11. A 64-year-old m an w as adm it ted to th e h ospital because of a 3-day h istor y of fever, ch est pain , cough , n ausea, vom it ing, an d diarrh ea. His past m edical h istor y w as relevan t for h eavy cigaret te sm okin g, su rger y for p rost at ic hyp er p lasia, an d in toleran ce to m acrolide an t ibiot ics. Vital sign s w ere blood pressu re 135/80 m m Hg, p u lse 50 bp m , respirat ion s 16/m in , body tem perat u re 102°F (38.8°C). A ch est x-ray revealed a patchy in lt rate in th e low er left lobe, an d u rin alysis sh ow ed m icroh em at u r ia. W h ich of t h e follow in g d r ugs w ou ld be ap prop riate for th e th erapy of th e pat ien t’s disease?

Questions: VIII-3 Inhibitors of Bacterial Nucleic Acid Synthesis or Function 417 A. Van com ycin


B. Gen t am icin

15. A 50-year-old w om an recently diagnosed w ith a urinar y tract

C. Piperacillin

in fect ion st ar ted t reat m en t w it h t r im et h op r im -su lfam e-

D. Cipro oxacin

t h oxazole. All sym ptom s d isap p eared after 1 w eek. W h ich

E. Er yth rom ycin

of th e follow ing bacteria w as m ost likely th e cau se of th e

F.

p at ien t’s in fect ion ?

Ceft riaxon e

Di cult y level: Medium 12. A 30-year-old m an recen tly diagn osed w ith ot it is m edia

A. Pseudom onas aeruginosa B. Enterococcus fecium C. Chlam ydia t rachom at is

started treatm ent w ith cipro oxacin. A 7-day course w as able

D. Bacteroides fragilis

to com pletely h eal th e disease. W h ich of th e follow ing bacte-

E. Escherichia coli

ria m ost likely cau sed th e pat ien t’s in fect ion ? A. Leptospira interrogans


B. Clost ridium di cile

16. A 46-year-old w om an com plain ed of bu rn ing on urin at ion

C. Nocardia asteroides

an d bladder p ain . Her m edical h istor y w as sign i can t for re-

D. Borrelia burgdorferi

cu rren t u rin ar y t ract in fect ion s an d for a congen it al long QT

E. Haem ophilus in uenzae

syn drom e d etected du ring a rou t in e visit 1 year ago. A clean catch m idst ream u rin e sam p le sh ow ed m any gram -n egat ive


rod s. W h ich of t h e follow ing an t ibiot ics w ou ld be con t ra-


in dicated for th is pat ien t?

fever (103.1°F, 39.5°C), severe headache, weakness in his right

A. Ceftazidim e

arm an d leg, an d in creasing drow sin ess. Th e pat ien t h ad a

B. Azt reon am

h istor y of ch ron ic sin usit is t reated w ith a variet y of oral an -

C. Im ipen em

t ibiot ics. His last ep isode of sin u sit is occu rred 1 m on th ago

D. Am oxicillin -clavulan ate

an d ap paren tly resolved w ith clin dam ycin th erapy. A com -

E. Pip eracillin

pu ted tom ography scan revealed a left fron t al lesion w ith a

F.

Cipro oxacin

sm all am ou n t of su rrou n ding cerebral edem a. A diagn osis of brain abscess w as m ade, an d th e p at ien t u n der w en t stereotact ic asp irat ion of th e abscess u n der local an esth esia. W h ich of t h e follow in g an t ibiot ics w ou ld h ave been m ost ap p rop r iately in clu d ed in t h e in it ial p ost su rgical t h erapy of t h is pat ien t?

Di cult y level: Medium 17. A 37-year-old w om an w ith AIDS w as adm it ted to th e h ospit al becau se of fever (100.4°F, 38°C), dren ch ing n igh t sw eat s, p oor appet ite, an d an 18-lb (about 8-kg) w eigh t loss over th e p ast 3 m on th s. Sh e h ad a p ast m ed ical h istor y of in test in al

A. Am ikacin

can didiasis an d cr yptococcal m en ingit is. Physical exam in a-

B. Met ron idazole

t ion revealed a cach ect ic w om an w ith h epatosp en om egaly.

C. Er yth rom ycin

Chest radiography w as unrem arkable, an d lab results sh ow ed

D. Azt reon am

a CD4+ lym p h ocyte cou n t of 50 cells/m m 3 . A p resu m pt ive

E. Van com ycin

diagn osis of Mycobacterium avium com p lex in fect ion w as m ade an d later con rm ed by a DNA probe test . W h ich of th e


follow ing drugs sh ould be in clu ded in th e init ial th erapy of

14. A 42-year-old m an recen t ly d iagn osed w it h m ycop lasm a

th is pat ien t?

p n eu m on ia st ar ted a t reat m en t w it h cip ro oxacin . W h ich

A. Pip eracillin

of th e follow ing m olecu lar act ion s m ost likely m ediated th e

B. Acyclovir


C. Cipro oxacin

A. In h ibit ion of bacterial cell w all syn th esis

D. Ceftazidim e

B. In h ibit ion of relaxat ion of supercoiled bacterial DNA

E. Trim eth op rim -sulfam eth oxazole

C. St im u lat ion of syn th esis of abn orm al bacterial p rotein s

F.

D. In h ibit ion of ergosterol syn t h esis in bacter ial cell m em bran e E. St im u lat ion of bacterial DNA h elicase F.

Stim ulation of bacterial DNA−dependent RNA polym erase

Met ron idazole

418




18. A 44-year-old w om an p resen ted to t h e clin ic w it h fever

21. A 52-year-old w om an com p lain ed to h er p hysician of re-

(101°F, 38.3°C) an d cough produ ct ive of a sm all am oun t of

cu r ren t epigast ric pain . En d oscopy revealed a gast ric u lcer,

green ish , th ick sput um . Th e w om an , su ering from pem ph i-

an d biop sy resu lt s w ere p osit ive for Helicobacter pylori. To

gu s, h ad been receiving h igh -dose predn ison e for 6 m on th s.

eradicate H. pylori, th e physician prescribed a th erapy th at

Physical exam in at ion revealed coarse breath soun ds in th e

in clu ded om ep razole an d t w o an t ibiot ics. W h ich of th e fol-

righ t low er lu ng, an d a ch est x-ray sh ow ed a 4-cm (1.6-in ch )

low in g p airs of an t ibiot ics w ou ld be ap p rop r iate for t h is

n odule w ith cen t ral cavit at ion . Exam in at ion of th e spu t um

p at ien t?

sh ow ed long bran ch ing lam en t s of gram -posit ive, acid-fast

A. Am oxicillin an d gen t am icin

rods. W h ich of th e follow ing drugs w ould be appropriate to

B. Met ron idazole an d tet racyclin e

t reat th e p at ien t’s in fect ion ?

C. Er yth rom ycin an d van com ycin

A. Ketocon azole

D. Am oxicillin an d rifam pin

B. Rifam pin

E. Met ron idazole an d van com ycin

C. Er yth rom ycin D. Su lfadiazin e


E. Am ph otericin B

22. A 44-year-old m an recen t ly diagn osed w it h n ocard iosis st ar ted a t reat m en t w ith a h igh d ose of su lfadiazin e. In h ibi-


t ion of w h ich of th e follow ing bacterial en zym es m ost likely

19. A 47-year-old w om an su ering from ulcerat ive colit is w as


ad m it ted to t h e h osp it al w it h fever (103.5°F, 39.7°C) an d

d isease?

severe abdom in al pain . Physical exam in at ion sh ow ed an ex-

A. Pu rin e ph osph oribosyl t ran sferase

t rem ely ill p at ien t w ith di u se abdom in al ten dern ess, p ro-

B. Tran spept idase

fou n d dehydrat ion , an d bloody diarrh ea. Fu rth er exam s led

C. Topoisom erase II

to th e diagn osis of fulm in an t colit is, an d an em ergen cy th er-

D. Dihydropteroate syn th et ase

apy w as star ted . W h ich of th e follow ing an t ibiot ics sh ou ld

E. Dihydrofolate reduct ase

be in clu ded in th e t reat m en t of th is p at ien t?

F.

RNA polym erase

A. Met ron idazole B. Van com ycin


C. Am picillin


D. Am ikacin

(101.7°F, 38.7°C), severe abdom in al p ain , an d loose, bloody

E. Er yth rom ycin

stools. Fu r th er exam s led to th e diagn osis of Clost ridium dif-

F.

Trim eth orp im -su lfam eth oxazole

cile−associated colit is. Th erapy w ith oral van com ycin w as st ar ted , bu t 2 d ays later, t h e d iar rh ea w as n ot im p roved .


W h ich of t h e follow ing ch anges in t h e t h erapy w ou ld be

20. A 36-year-old m an presented to the clinic w ith fever (100.4°F,

ap prop riate at th is t im e?

38.6°C), n onp rodu ct ive cough , m ild dysp n ea, an d facial

A. St art on oral m et ron idazole.

seborrh eic derm at it is. Th e m an w as HIV seroposit ive, an d

B. In crease th e dose of van com ycin .

h is CD4 lym ph ocyte coun t w as

100/m m 3

. A silver-st ain ed

C. St art on in t raven ou s (IV) van com ycin .

preparat ion from bron ch ial lavage revealed a large n u m ber

D. St art on oral ceft azidim e.

of cysts containing sporozoites. A diagnosis of pneum onia w as

E. St art on IV am ikacin .

m ade, and a treatm ent w ith trim ethoprim -sulfam ethoxazole for 14 days w as able to cure th e in fect ion . W h ich of th e follow ing bacteria w as m ost likely th e cau se of th e p at ien t’s in fect ion ?

Di cult y level: Medium 24. A 54-year-old alcoh olic w om an com plain ed to h er physician of w eakn ess, drow sin ess, an d dyspn ea on exer t ion . Medical

A. Pseudom onas aeruginosa

h istor y in dicated sh e w as diagn osed w ith acute cyst it is 10

B. Clost ridium di cile

days earlier an d st arted an an t ibacterial th erapy. Pert in en t

C. Mycoplasm a pneum oniae

results of blood test s w ere red blood cell cou n t 3.2 × 10 6 /

D. Ricket tsia rickettsii

m m 3 (norm al, fem ale 3.5−5.5 × 10 6 /m m 3 ), m ean corpuscular

E. Treponem a pallidum

volum e 115 fL (n orm al 80−100 fL). W h ich of th e follow ing

F.

drugs m ost likely cau sed th ese lab results?

Pneum ocyst is jiroveci

G. Enterococcus faecalis

Questions: VIII-3 Inhibitors of Bacterial Nucleic Acid Synthesis or Function 419 A. Cipro oxacin

A. Pip eracillin

B. Van com ycin

B. Gen t am icin

C. Met ron idazole

C. Trim eth op rim

D. Trim eth op rim

D. Ceft riaxon e

E. Doxycyclin e

E. Cipro oxacin

F.

F.

Ceftazidim e

Su lfam eth oxazole

G. Piperacillin


28. A 55-year-old w om an com plain ed to h er physician of bu rn -

25. A 75-year-old w om an w as adm it ted to the hospital w ith fever

ing on u rin at ion , frequ en t u rin at ion , an d blad der p ain . A

(102.6°F, 39.2°C), abdom in al cram ping, an d fou l-sm elling,

u rin e cult ure an d suscept ibilit y test sh ow ed th at Escherichia

w ater y stools. A colon oscopy revealed exu dat ive p laqu es

coli w as th e m ain in fect ing organ ism an d th at it w as resis-

at t ach ed to th e su rface of th e in am ed colon ic m ucosa. Th e

tan t to am p icillin , cefot axim e, cip ro oxacin , an d am ikacin .

w om an h ad been receivin g h igh d oses of am p icillin for 2

W h ich of th e follow ing an t ibiot ics w ould be m ost appropri-

w eeks to t reat a u r in ar y t ract in fect ion . W h ich of t h e fol-

ate to t reat th e pat ien t’s in fect ion ?

low ing drugs w ould be m ost appropriate for th is pat ien t?

A. Am oxicillin

A. Piperacillin

B. Moxi oxacin

B. Gen t am icin

C. Van com ycin

C. Doxycyclin e

D. Lin ezolid

D. Er yth rom ycin

E. Trim eth op rim -su lfam eth oxazole

E. Met ron idazole

F.

F.

Clin dam ycin

Cipro oxacin


29. A 34-year-old w om an recen t ly d iagn osed w it h salp ingit is

26. A 36-year-old w om an com plain ed to h er physician th at sh e

d u e to Bacteroides fragilis st ar ted a t reat m en t w it h a d r ug

becam e dizzy and su ered ushing and vom iting after drink-

th at is redu ced by an aerobes to a h igh ly react ive n it ro radical

ing a double scotch . Th e w om an , recen tly diagn osed w ith

an ion able to dam age bacterial DNA. W h ich of th e follow ing

bacterial vagin osis, star ted an oral an t ibiot ic th erapy 1 w eek

d rugs did th e pat ien t m ost likely t ake?

ago. W h ich of t h e follow in g d r ugs m ost likely cau sed t h is

A. Cefoxit in

in teract ion w ith alcoh ol?

B. Clin dam ycin

A. Im ipen em

C. Im ipen em

B. Levo oxacin

D. Met ron idazole

C. Clin dam ycin

E. Cefotetan

D. Piperacillin E. Ceft riaxon e


F.

30. A 28-year-old w om an late in h er th ird t rim ester of preg-

Met ron idazole

n an cy com plain ed to h er physician of persisten t burn ing


upon urination. The patient’s m edical history w as sign i can t

27. A 56-year-old Black w om an com plain ed to h er physician of

for recu rren t urin ar y t ract in fect ion s. An an t ibiot ic t reat-

t iredn ess an d fat igu e. Sh e also n ot iced th at h er u rin e h ad be-

m en t w as prescribed. W h ich of th e follow ing dr ugs w ou ld

com e dark. Medical h istor y w as sign i can t for glucose-6-

be con t rain d icated in t h is p at ien t becau se of a r isk of ker-

p h osph ate dehydrogen ase de cien cy an d recurren t u rin ar y

n icterus in th e n ew born ?

t ract in fect ion . Five days earlier, th e pat ien t com p lain ed of

A. Pip eracillin

bu rn ing sen sat ion u pon u rin at ion an d star ted th e prescribed

B. Su lfam eth oxazole

an t ibiot ic t h erapy. Ur in alysis revealed bilir u bin an d u ro -

C. Ceft riaxon e

bilin ogen . W h ich of th e follow ing dr ugs cou ld h ave cau sed

D. Im ipen em

th e p at ien t’s sign s an d sym ptom s?

E. Gen t am icin F.

Cipro oxacin

420


Questions: VIII-4 Antimycobacterial Drugs Directions for questions 1 and 2


Match each an t im ycobacterial drug w ith th e ap p ropriate descrip -

5. A 49-year-old Asian w om an recen tly diagn osed w ith t ubercu -

t ion (each let tered opt ion can be selected on ce, m ore th an on ce,

losis star ted an ap propriate m ult idrug th erapy. W h ich of th e

or n ot at all).

drugs sh e w as t aking is in act ivated by h ep at ic acet ylat ion , th e

A. Am ikacin

rate of w h ich dep en ds on gen et ic backgrou n d?

B. Cipro oxacin

A. St reptom ycin

C. Clarith rom ycin

B. Eth am bu tol

D. Eth am bu tol

C. Rifam pin

E. Eth ion am ide

D. Ison iazid

F.

E. Pyrazin am id e

Ison iazid

G. Pyrazin am ide H. Rifam pin


I.

6. A 36-year-old Black m an recen tly diagn osed w ith pulm on ar y

St reptom ycin

t u bercu losis star ted a drug t reat m en t th at in clu ded rifam p in .


In h ibit ion of w h ich of th e follow ing en zym es m ost likely m e-

1. Th is drug im part s a h arm less orange color to urin e, sw eat ,

d iated t h e t h erap eu t ic e

an d tears.

cacy of r ifam p in in t h e p at ien t ’s

disease? A. DNA-depen den t RNA polym erase


B. Arabin osyl t ran sferase

2. Th is drug is e ect ive again st som e at ypical m ycobacteria but

C. Tran sp ept idase

n ot again st Mycobacterium t uberculosis.

D. Topoisom erase II E. RNA-d ep en den t DNA polym erase

Di cult y level: Easy 3. A 31-year-old h om osexu al m an w as foun d to be HIV posit ive.


Curren tly, h e did n ot h ave sym ptom s of t uberculosis, but h is

7. A 63-year-old m an recen tly diagn osed w ith pu lm on ar y t u -

t u bercu lin skin test w as posit ive. A t reat m en t w ith ison iazid

bercu losis star ted a m u lt idr ug t reat m en t th at in clu ded eth -

w as prescribed. Th e in h ibit ion of syn th esis of w h ich of th e

am butol. In h ibit ion of w h ich of th e follow ing en zym es m ost

follow ing en dogen ou s com poun ds m ost likely m ediated th e

likely m ed iated t h e t h erap eu t ic e

th erapeut ic e ect of th e drug in th is pat ien t?


A. Mycolic acids

A. Dihydrofolate reduct ase

B. Pept idoglycan

B. Pept idyl t ran sferase

C. Arabin osyl t ran sferase

C. Arabin osyl t ran sferase

D. Topoisom erase II

D. En olpyruvate t ran sph erase

E. DNA-depen den t RNA polym erase

E. Dihydropteroate syn th et ase F.

cacy of t h e d r ug in t h e

Tran sglycosylase

Di cult y level: Medium 4. A 56-year-old Hisp an ic m an d iagn osed w it h bon e t u bercu lo-


sis st ar ted a m u lt id r ug t reat m en t , bu t 4 m on t h s later, t h e

8. A 34-year-old w om an w h o w as HIV posit ive presen ted w ith

d isease w as m in im ally im proved, an d suscept ibilit y test ing

fever (100.8°F, 38.2°C), p rofu se n igh t sw eat s, p oor app et ite,

sh ow ed a com p lete resistan ce to ison iazid. A h igh level of re-

an d a 20-lb (4.5-kg) w eigh t loss over th e past 5 m on th s. Phys-

sistan ce of t u bercle bacilli to ison iazid involves a d ecrease in

ical exam in at ion revealed a cach ect ic fem ale w ith prom in en t

th e act ivit y of w h ich of th e follow ing en zym es?

oral th r u sh an d m ild sp len om egaly. Her CD4+ lym p h ocyte

A. Cat alase-peroxidase

coun t w as 45 cells/m m 3 (n orm al > 500 cells/m m 3 ), an d a DNA

B. DNA-depen den t RNA polym erase

probe test con rm ed th e diagn osis of Mycobacterium avium

C. Topoisom erase II

com p lex in fect ion . An ap p rop r iate m u lt idr ug regim en w as

D. Acet ylt ran sferase

started. W hich of the follow ing drugs w as m ost likely included

E. Tran sp ept idase

in th e pat ien t’s ph arm acoth erapy?

Questions: VIII-4 Antimycobacterial Drugs 421 A. Ceft riaxon e

A. Pip eracillin an d tobram ycin

B. Lin ezolid

B. Trim eth op rim -su lfam eth oxazole

C. Met ron idazole

C. Cipro oxacin an d azith rom ycin

D. Clarith rom ycin

D. Ison iazid an d rifam pin

E. Van com ycin

E. St reptom ycin an d er yth rom ycin



9. A 28-year-old m an un der w en t a t uberculin skin test (Man -

12. A 10-year-old girl w as brought to the em ergency departm ent

tou x m ethod) th at turn ed out to be positive. The m an w as th e

by h er m oth er, w h o said th at h er daugh ter h ad h igh fever

h u sban d of a w om an w h o h ad u n com p licated p u lm on ar y

(103.3°F, 39.6°C) an d w as irritable an d leth argic. Physical ex-

t u bercu losis t reated at h om e w it h a m u lt ip le-d r ug regi-

am in at ion sh ow ed n u ch al rigidit y an d a p osit ive Bru dzin ski

m en . Th e m an w as p rescribed a drug to be t aken daily for 6

sign . Su bsequ en t exam s led to t h e d iagn osis of m en ingo-

m on th s. W h ich of th e follow ing drugs w as m ost likely given ?

coccal m en ingit is. W h ich of th e follow ing dr ugs w ou ld h ave

A. Am ikacin

been ap prop riate prop hylaxis for th e h ealth person n el as-

B. Eth am bu tol

sist ing th is girl?

C. Ison iazid

A. Am ikacin

D. Cipro oxacin

B. Pip eracillin

E. Pyrazin am ide

C. Ison iazid D. Doxycyclin e


E. Rifam pin

10. A 44-year-old w om an com p lain ed of blu r red vision an d in abilit y to d ist inguish green objects from red objects. Th e


w om an , recen tly diagn osed w ith cavit ar y p u lm on ar y t u ber-

13. A 47-year-old Hispan ic m an recen tly diagn osed w ith pulm o-

cu losis, h ad been receiving a th ree-drug com bin at ion regi-

n ar y t uberculosis st ar ted a m ult idrug t reat m en t . On e of th e

m en for 2 m on th s. An eye exam in at ion in d icated a n arrow ing

drugs he w as given is active against m ost m ycobacteria, m any

of h er visual eld. W h ich of th e follow ing drugs m ost likely

gram -posit ive an d -n egat ive bacteria, ch lam ydiae, ricket t-

cau sed th ese adverse e ects?

siae, an d poxviru ses. W h ich of th e follow ing dr ugs h as su ch

A. Ison iazid

a broad an t ibacterial sp ect ru m ?

B. Pyrazin am ide

A. Ison iazid

C. St reptom ycin

B. Rifam pin

D. Eth am bu tol

C. St reptom ycin

E. Cipro oxacin

D. Eth am bu tol E. Pyrazin am id e

Di cult y level: Hard 11. A 34-year-old HIV-p osit ive w om an w as ad m it ted to t h e


h ospit al because of a 4-w eek h istor y of fat igue, in creasing

14. A 66-year-old m an recen t ly d iagn osed w it h p u lm on ar y

abdom inal girth, exertional dyspnea, nocturnal dyspnea, and

t u berculosis st arted a th ree-drug t reat m en t w ith ison iazid,

p erip h eral edem a. Vit al sign s w ere pulse 80, blood pressure

rifam p in , an d eth am bu tol. Th e m an , w h o h ad been su ering

90/70 m m Hg. Physical exam in at ion revealed prom in en t ex-

from atrial brillation for 4 years, w as currently being treated

tern al jugular vein s th at becam e m ore disten ded during in -

w ith propran olol an d w arfarin . At th is poin t , w h ich of th e

spirat ion . Th e h eart w as sligh tly en larged, an d a th ird sou n d

follow ing changes in the patient’s therapeutic regim en w ould

w as n oted in early diastole. A com pu ted tom ograp hy scan

be ap prop riate?

sh ow ed a large p ericardial e u sion , an d p ericardiocen tesis

A. In crease th e dose of w arfarin .

rem oved 500 m L of bloody uid w ith a h igh protein con ten t .

B. Decrease th e dose of propran olol.

A diagn osis of h em orrh agic pericardit is w as m ade, an d an

C. Add pyrazin am ide to th e curren t th erapy.

app ropriate th erapy w as p rescribed. W h ich of th e follow ing

D. Su bst it u te ison iazid w ith st reptom ycin .

p airs of drugs w ould be m ost ap propriately in clu ded in th e

E. Su bst it u te p rop ran olol w ith digoxin .

p at ien t’s regim en ?

422



pairs of drugs w ou ld be m ost ap prop riate for th e p at ien t at

15. A 64-year-old alcoh olic w om an su ering from pulm on ar y

th is t im e?

t u bercu losis com p lain ed of an orexia, n au sea, an d abdom in al

A. Am ikacin an d van com ycin

d iscom for t . Sh e h ad been receiving ison iazid, eth am butol,

B. Eth ion am ide an d azith rom ycin

an d rifam p in for 2 m on th s. Lab resu lts revealed an aspar tate

C. Im ipem en an d doxycyclin e

am in ot ran sferase level of 330 U/L (n orm al 8−20 U/L). W h ich

D. Ceft riaxon e an d lin ezolid

of t h e follow in g best exp lain s t h e reason for t h e p at ien t ’s

E. St reptom ycin an d m oxi oxacin

sign s an d sym ptom s? A. Rifam pin -in duced h em olyt ic an em ia


B. Rifam pin -in duced in duct ion of th e P-450 system

19. A 57-year-old m an com plain ed of a t ingling sen sat ion in h is

C. Ison iazid-in duced n europathy

lim bs an d th at h is arm s som et im es felt h eavy. Th e m an , w h o

D. Ison iazid-in duced h epat it is

h ad been su ering from t ype II diabetes for 10 years, h ad

E. Eth am bu tol-in du ced p erip h eral n eu rit is

been recen tly diagn osed w ith pu lm on ar y t u bercu losis an d

F.

h ad been receiving ison iazid an d rifam pin for 1 m on th . Th e

Eth am bu tol-in du ced h ep at it is

concom itant use of w hich of the follow ing drugs w ould have


m ost likely p reven ted th e pat ien t’s n eu rologic sym ptom s?

16. A 30-year-old m an w ith AIDS w as recen tly diagn osed w ith

A. Folic acid

p ulm on ar y t uberculosis an d st arted a m ult idrug t reat m en t

B. Pyridoxin e

w it h ison iazid , r ifam p in , pyrazin am id e, an d et h am bu tol.

C. Cyan ocobalam in

W h ich of th e follow ing best explain s w hy eth am butol w as

D. Vitam in B2

added to th e th erap eu t ic regim en ?

E. Folin ic acid

A. To en h an ce th e an t ibacterial act ivit y of pyrazin am ide B. To p rovide an t ibacterial act ivit y again st at yp ical m ycobacteria

Di cult y level: Easy 20. A 13-year-old boy h ad been receiving a m ult idr ug t reat m en t

C. To p reven t th e n eu rotoxic e ect s of ison iazid

for bon e t u berculosis. After 4 m on th s of th erapy, su scept i-

D. To p reven t Pneum ocyst is jiroveci pn eu m on ia

bilit y test ing sh ow ed th at th e m ycobacteriu m w as resistan t

E. To delay th e em ergen ce of d rug resist an ce

to ison iazid an d rifam pin . W h ich of th e follow ing w as m ost likely th e m ech an ism of m ycobacterial resistan ce to rifam -


p in in th is pat ien t?

17. A 62-year-old m an presen ted to th e h ospital com plain ing of

A. Blockade of m ycolic acid syn th esis

an orexia, n au sea an d vom it ing, an d abd om in al discom for t .

B. Gen e-in duced ch anges in bacterial topoisom erase II

He also h ad p ain on m ot ion an d st i n ess in several join t s.

C. Gen e-in duced ch anges in bacterial RNA polym erase

Th e m an , recen tly diagn osed w ith ren al t u bercu losis, started

D. Gen e-in duced ch anges in bacterial pept idyl t ran sferase

a fou r-drug com bin at ion regim en 1 m on th ago. Lab resu lt s

E. In creased bacterial acet ylat ion of th e drug

sh ow ed seru m asp ar tate am in ot ran sferase of 280 U/L (n orm al 8−20 U/L) an d ser u m u r ic acid of 25 m g /d L (n or m al 3.0−8.2 m g/d L). W h ich of t h e follow in g d r ugs m ost likely


cau sed th e p at ien t sym ptom s an d sign s?

21. A 44-year-old m an w h o recen t ly m oved from Mexico to

A. Rifam pin

Los Angeles presen ted to th e h ospit al becau se of a di u se

B. Pyrazin am ide

skin disease. Skin exam ination showed m acules, nodules, and

C. Ison iazid

p laques over h is face an d th orax. Fu r th er exam s led to th e

D. St reptom ycin

d iagn osis of leprom atou s leprosy, an d an app rop riate th er-

E. Azith rom ycin

apy w as st ar ted . W h ich of t h e follow in g d r ugs sh ou ld be in clu ded in th e th erapeut ic regim en of th is pat ien t?


A. Am picillin

18. A 35-year-old m an recen tly diagn osed w ith pulm on ar y t u-

B. Ceft riaxon e

bercu losis star ted a t reat m en t w ith ison iazid, rifam p in , pyr-

C. Met ron idazole

azin am ide, an d eth am bu tol, bu t 2 m on th s later, su scept ibilit y

D. Dap son e

test ing revealed a Mycobacterium t uberculosis resistan t to

E. Flu con azole

ison iazid an d pyrazin am ide. Th ese drugs w ere discon t in ued,

F.

and t w o other drugs w ere prescribed. W hich of the follow ing

Iverm ect in

Questions: VIII-5 Antifungal Drugs 423 Di cult y level: Easy

A. Gen e-in duced ch anges in bacterial topoisom erase II

22. A 33-year-old m an h ad been receiving a m u lt idrug t reat-

B. In creased bacterial m et abolism of th e dr ug

m en t for pulm on ar y t uberculosis. After 3 m on th s of th erapy,

C. Gene-in duced changes in bacterial arabinosyl tran sferase

su scept ibilit y test ing sh ow ed th at th e m ycobacteriu m w as

D. Decrease act ivit y of th e bacterial m u lt ie

resistan t to ison iazid an d eth am butol. W h ich of th e follow -

E. Gen e-in duced ch anges in bacterial RNA polym erase

ing w as m ost likely th e m ech an ism of m ycobacterial resis-

F.

u x pum p

Decreased bacterial perm eabilit y to th e drug

t an ce to eth am bu tol in th is p at ien t?

Questions: VIII-5 Antifungal Drugs Directions for questions 1−3

A. Act ivat ion of fu ngal cytoch rom e P-450 en zym es

Match each an t ifu n gal d r ug w it h t h e ap p rop r iate d escr ipt ion

B. Pore form at ion in fungal cell m em bran e


C. In h ibit ion of fungal cytoch rom e P-450 en zym es

at all).

D. In h ibit ion of fungal m itosis

A. Am ph otericin B B. Caspofungin C. Flucon azole D. Flucytosin e

E. Pore form at ion in th e fungal cell w all

Di cult y level: Easy 5. A 39-year-old m an living in New Mexico w as recen t ly d i-

E. Griseofulvin

agn osed w it h p u lm on ar y coccid ioid om ycosis. A t reat m en t

F.

w as st ar ted w it h a d r ug t h at act s by in h ibit in g t h e fu n gal

It racon azole

G. Nyst at in

P-450 system . W h ich of t h e follow in g d r ugs w as m ost likely

H. Terbin a n e

ad m in istered ? A. Am ph otericin B


B. Nyst at in

1. Th e an t ifu n gal sp ect r u m of t h is d r ug is lim ited to Candida

C. Flucon azole

an d Aspergillus sp ecies.

D. Flucytosin e E. Griseofu lvin

Di cult y level: Easy 2. Th is drug h as th e broadest an t ifungal spect ru m but is used on ly in case of severe m ycoses because of it s toxicit y.

F.

Terbin a n e

Di cult y level: Easy 6. A 42-year-old m an w ith AIDS w as adm it ted to th e h ospit al

Di cult y level: Easy 3. Th e m ech an ism of act ion of th is drug involves th e in h ibit ion of th e syn th esis of β-glu can , an essen t ial con st it uen t of a fun gal cell w all.

Di cult y level: Easy 4. A 42-year-old HIV-posit ive w om an w as recen tly diagn osed w ith invasive h istoplasm osis an d st arted a th erapy w ith am ph otericin B. W h ich of th e follow ing m olecu lar act ion s m ost likely m ediated th e th erap eu t ic e ect of th e d rug in th e p at ien t’s d isease?

becau se of a recen t on set of ton ic-clon ic seizu res. Physical exam in at ion suggested acute m en ingit is, an d lab test s in dicated cr yptococcal in fect ion . A t reat m en t w ith am p h otericin B an d ucytosin e w as in it iated but h ad to be suspen ded due to th e appearance of severe adverse e ects. An alternative treatm ent w as in it iated. W h ich of th e follow ing dr ugs w ou ld be m ost appropriate for th e pat ien t at th is t im e? A. Terbin a n e B. Griseofu lvin C. Nyst at in D. Caspofungin E. Flucon azole

424


Di cult y level: Hard 7. A 53-year-old m an presen ted to th e clin ic because of pain -

exam ination show ed sti neck and Kerning sign. Microscopic an alysis of t h e sp in al

u id revealed sp h er u les

lled w it h

fu l, erosive, m arkedly pru rit ic lesion s on th e glan s p en is,

en d osp ores. W h ich of th e follow ing drugs w as m ost likely

scrot u m , an d ingu in al region for th e p ast w eek. Th e m an h ad

adm in istered to th is pat ien t for an appropriate th erapy?

a 10-year history of poorly controlled diabetes m ellitus. Phys-

A. It racon azole

ical exam in at ion sh ow ed ir regu lar, sh allow , er yt h em atou s

B. Nyst at in

u lcerat ion s. A w et p rep arat ion of u lcer secret ion s sh ow ed

C. Terbin a n e

bu dding cells w ith p seu d ohyph ae. A diagn osis w as m ade,

D. Flu con azole

an d an oral th erapy w as prescribed. W h ich of th e follow ing

E. Flu cytosin e


F.

Zidovudin e

A. Nyst at in B. Met ron idazole


C. Flucon azole

11. A 31-year-old m an w ith AIDS w as adm it ted to th e em er-

D. Acyclovir

gen cy depar t m en t w ith fever (102.4°F, 39.1°C), h eadach e,

E. Meben dazole

con fusion , m uddled th in king, an d vom it ing. Physical exam -

F.

in at ion revealed n uch al rigidit y, diplop ia, an d loss of vision .

Griseofu lvin

An agglu t in at ion test of t h e sp in al u id for cap su lar p oly-

Di cult y level: Easy 8. A 40-year-old w om an w ith AIDS w as adm it ted to th e h ospi-

sacch ar id e an t igen t u r n ed ou t to be p osit ive. W h ich of t h e follow ing t reat m en t s w ou ld be m ost app ropriate for th is

t al becau se of fever (103.2°F, 39.5°C), cough , an d ch est pain

p at ien t?

over th e past 12 h ou rs. Physical exam in at ion revealed verru -

A. Am picillin an d er yth rom ycin

cose an d vesicular skin lesion s on h er arm s an d face, an d a

B. Saqu in avir an d foscarn et

ch est x-ray sh ow ed scat tered pulm on ar y lesion s com pat ible

C. Pyrim eth am in e an d su lfad iazin e

w ith a gran ulom atous process. A blood cult ure displayed

D. Am ph otericin B an d u cytosin e

t ypical yeast s w ith ch lam ydospores. W h ich of th e follow ing

E. Toln aftate an d nyst at in

correctly pairs th e m ost likely o en ding path ogen w ith th e

F.

Terbin a n e an d griseofu lvin

app ropriate t reat m en t? A. Cryptococcus neoform ans: am ph otericin B


B. Trichophyton tonsurans: griseofu lvin

12. A 68-year-old m an h ospitalized becau se of prostate can cer

C. Histoplasm a capsulat um : u con azole

d eveloped fever (103.8°F, 39.9°C) 4 days after prost atectom y

D. Aspergillus fum igat us: ucon azole

despite em pirical antibacterial therapy. He had a urinary cath-

E. Candida albicans: am ph otericin B

eter an d w as t reated w ith a com bin at ion of broad-spect rum antibiotics. The patient had been su ering from chronic renal


in su

cien cy for th e p ast year. Urin alysis sh ow ed m any bu d-

9. A 43-year-old w om an recen tly diagn osed w ith ch rom oblas-

d ing yeast s an d cu lt u res th at w ere posit ive for Candida albi-

tom ycosis star ted a t reat m en t th at in clu ded a drug th at act s

cans. W h ich of th e follow ing drugs w ou ld be ap p rop riate for

by in h ibit ing fungal DNA syn th esis. W h ich of th e follow ing

system ic an t ifu ngal t reat m en t of th is p at ien t?

d rugs w as m ost likely given ?

A. Am ph otericin B

A. Fluorou racil

B. Caspofungin

B. Cyt arabin e

C. Pip eracillin

C. Flucytosin e

D. Met ron idazole

D. Griseofu lvin

E. Griseofulvin

E. Flucon azole

F.

F.

Nyst at in

Terbin a n e


13. A 37-year-old w om an su er ing from AIDS w as recen t ly

10. A 30-year-old Mexican m an w h o w as a lifelong residen t of

d iagn osed w it h system ic can d id iasis, an d an in t raven ou s

t h e San Joaqu in Valley, Califor n ia, w as ad m it ted to t h e h os-

an t ifu ngal t reat m en t w as p rescribed. On e w eek later, th e

p ital because of a 4-day h istor y of low -grade fever (99.9°F,

follow ing lab result s w ere obtain ed: serum creat in in e 5.9

37.7°C), severe h eadach e, irrit abilit y, an d fat igue. Physical

m g/dL (n orm al: 0.6−1.2 m g/dL), blood u rea n it rogen (BUN)

Questions: VIII-5 Antifungal Drugs 425 53 m g/dL (norm al 7−18 m g/dL), plasm a potassium 2.3 m m ol/L

A. Red m an syn drom e

(n orm al 3.5−5.0 m m ol/L). W h ich of th e follow ing drugs m ost

B. Nep h rotoxicit y

likely cau sed th ese abn orm al lab resu lt s?

C. Hepatotoxicit y

A. Am ph otericin B

D. In fusion react ion

B. Flucon azole

E. Hem olyt ic an em ia

C. Griseofulvin

F.

Exfoliat ive derm at it is

D. Flucytosin e E. Cyclosporin e


F.

17. A 33-year-old w om an presen ted to h er gyn ecologist w ith

Tobram ycin

a 4-day h istor y of p erin eal p ru rit u s an d a n on m alodorou s,


t h ick, ch eesy vagin al d isch arge. Th e on ly m ed icat ion t h e

14. A 29-year-old m an presen ted to h is physician w ith an an n u -

w om an w as t aking w as an oral con t racept ive. A w et prepa-

lar lesion w ith raised borders on h is left h an d. Microscop ic

rat ion of vagin al secret ion sh ow ed budding yeast cells an d

exam in at ion of skin scrapings revealed bran ch ing hyph ae.

pseudohyphae. A diagnosis was m ade, and a local therapy was

Th e d iagn osis of t in ea m an u s w as m ad e, an d t h e p at ien t

p rescribed. W h ich of th e follow ing correctly p airs th e m ost

w as prescribed terbina ne. W hich of the follow ing skin struc-

likely o en ding p ath ogen w ith th e appropriate t reat m en t?

t ures w as m ost likely the site of action of the prescribed drug?

A. Candida albicans: griseofu lvin

A. St rat u m basale

B. C. albicans: terbin a n e

B. St rat u m sp in osu m

C. C. albicans: nyst at in

C. St rat u m corn eu m

D. Blastom yces derm at it idis: caspofu ngin

D. Pigm en t layer

E. B. derm at it idis: terbin a n e

E. Hair follicle

F.

F.

B. derm at it idis: nyst at in

Hair sh aft


18. A 34-year-old m an presen ted w ith fever (103.5°F, 39.6°C),

15. A 9-year-old girl w as brough t to th e pediat rician by h er

cough , in creasin g dysp n ea, an d bloody sp u t u m . Th e m an ,

m oth er becau se th e girl h ad several sm all h airless p atch es

su er ing from a n on -Hodgkin lym p h om a, w as in th e h os-

on h er scalp. Upon close physical exam in at ion , patch es look-

p it al for t h e secon d cycle of ch em ot h erapy. A ch est x-ray

ing like black dot s w ere seen on th e skin surface. Microscopic

disclosed d i u se alveolar in lt rates on t h e r igh t lobe an d

exam in at ion revealed a den se sh eath of spores aroun d th e

m ult iple sm all cavitar y lesion s on th e left lobe. Bron ch oalve-

h air. W h ich of th e follow ing drugs given orally w ould be ap -

olar lavage revealed fungal form s t ypical of th e Aspergillus


gen u s. W h ich of th e follow ing dr ugs w ou ld be ap prop riate

A. Acyclovir


B. Met ron idazole

A. Flucytosin e

C. Terbin a n e

B. Terbin a n e

D. Van com ycin

C. Griseofu lvin

E. Am ph otericin B

D. Voricon azole

F.

E. Nyst at in

Flucytosin e



16. A 34-year-old m an w ith AIDS w as adm it ted to th e h ospital

19. A 63-year-old w om an recen t ly diagn osed w it h onych om y-

because of fever (103.7°F, 39.8°C), severe headach e, an d m en -

cosis started a treatm ent w ith terbina ne. Inhibition of w hich

tal con fusion . Furth er exam s led to th e diagn osis of cr ypto-

of th e follow ing en zym es m ost likely m ediated th e th era-

coccal m en ingit is. An in t raven ous (IV) dose of hydrocor t ison e

peu t ic e ect of th e drug in th e p at ien t’s disease?

w as adm in istered, th en an an t ibiot ic th erapy w as star ted

A. Thym idylate syn th ase

th at in clu ded an IV in fu sion of am ph otericin B. Hydrocor t i-

B. Lan osterol syn th et ase

son e w as m ost likely given to decrease w h ich of th e follow -

C. Squ alen e ep oxidase

ing drug-related adverse e ect s?

D. Tran sp ept idase E. 7α -hydroxylase

426




20. A 36-year-old HIV-posit ive m an living n ear th e Mississippi

22. A 42-year-old HIV-p osit ive w om an w as ad m it ted to t h e

River w as ad m it ted to th e h ospit al w ith a 3-w eek h istor y of

em ergen cy d ep ar t m en t w it h t h e ad m it t in g d iagn osis of

cough , product ive yellow sput um , an d progressive dyspn ea

p n eum on ia. Fu rth er exam s led to th e diagn osis of cr yptococ-

of exer t ion , as w ell as a 14-lb (6.4-kg) w eigh t loss. Physical

cal p n eu m on ia, an d a t reat m en t w ith liposom al am p h oteri-

exam in at ion disclosed prom in en t h epatospen om egaly an d

cin B w as st arted. W h ich of th e follow ing best exp lain s th e

d i u se lym ph aden op athy. Pert in en t lab results on adm is-

p rim ar y advan t age of liposom al p rep arat ion s over th e regu -

sion w ere CD4+ lym ph ocyte cou n t 320 cells/m m 3 (n orm al

lar colloidal suspen sion of am p h otericin B?

> 500 cells/m m 3 ), lactate dehydrogen ase 5000 IU/L (n orm al

A. Decreased in teract ion s w ith oth er drugs

< 600 IU/L). A blood st ain sh ow ed n eut roph ils con t ain ing

B. In creased an t ifu ngal act ivit y spect rum

sm all u n in u cleated, en cap su lated m icroorgan ism s. A diag-

C. Decreased system ic toxicit y

n osis w as m ade, an d an appropriate ph arm acoth erapy w as

D. Decreased drug clearan ce

star ted . W h ich of th e follow ing drugs w ou ld be m ost ap pro-

E. In creased oral bioavailabilit y

priate for th is p at ien t? A. Am ph otericin B


B. Ison iazid

23. A 34-year-old m an w ith AIDS w as adm it ted to th e em er-

C. Terbin a n e

gen cy dep ar t m en t an d diagn osed w ith severe invasive can -

D. St reptom ycin

d idiasis. He w as in it ially t reated w ith an an t ifu ngal drug

E. Nyst at in

to rapidly redu ce fungal burden , an d th e drug w as th en replaced w ith an oth er agen t for ch ron ic th erapy. W h ich of th e


follow ing pairs of drugs w ere m ost likely given ?

21. A 45-year-old farm er com plain ed to h is physician of a red

A. Am ph otericin B an d terbin a n e

itchy rash over h is th orax an d arm s. On e w eek earlier, th e

B. Caspofungin an d griseofulvin

m an h ad been diagn osed w ith a fu ngal in fect ion on h is face

C. Caspofungin an d m et ron idazole

an d st ar ted an ap prop riate drug t reat m en t . After p hysical

D. Am ph otericin B an d u con azole

exam in at ion , th e physician told th e pat ien t th at th e rash w as

E. Am ph otericin B an d m eben dazole

m ost likely a p h otosen sit ivit y react ion to t h e d r ug. W h ich

F.

Caspofungin an d terbin a n e

of th e follow ing drugs m ost likely cau sed th e adverse e ect in th is pat ien t?


A. Flucytosin e

24. A 45-year-old w om an w ith AIDS h ad been receiving

u co-

B. Am ph otericin B

n azole for an esoph ageal Candida in fect ion . Th e th erapy w as

C. Caspofungin

in it ially e ect ive, bu t over t im e it s e

D. Griseofu lvin

th e p hysician th ough t th at develop m en t of resist an ce h ad

E. Doxycyclin e

occurred. W h ich of th e follow ing w as m ost likely th e m ech -

F.

an ism of fu ngal resist an ce to u con azole in th is p at ien t?

Cipro oxacin

cacy decreased, an d

A. Gen e-in duced ch anges in fungal topoisom erase II B. In creased fungal m etabolism of th e drug C. Gen e-in d u ced ch an ges in fu n gal cytoch rom e P-450 en zym es D. Decreased act ivit y of fungal m ult ie

u x pum p

E. Gen e-in duced ch anges in fungal RNA polym erase F.

Decreased fungal perm eabilit y to th e drug

Questions: VIII-6 Antiviral Drugs 427

Questions: VIII-6 Antiviral Drugs Directions for questions 1−3


Match each an t iviral drug w ith th e ap prop riate descript ion (each

5. A 35-year-old m an w ith AIDS st ar ted a th erapy th at in clu ded

let tered opt ion can be selected on ce, m ore th an on ce, or n ot at

a com bin at ion of lopin avir−riton avir. W h ich of th e follow ing

all).

statem en ts best explain s th e m ain reason for th is com bin a-

A. Abacavir

t ion regim en ?

B. Didan osin e

A. Lopin avir preven t s riton avir resist an ce.

C. Efaviren z

B. Lopin avir in h ibit s riton avir m etabolism .

D. En fuvirt ide

C. Lopin avir en h an ces riton avir in test in al absorpt ion .

E. Fom ivirsen

D. Riton avir preven t s lopin avir resistan ce.

F.

E. Riton avir in h ibits lopin avir m et abolism .

Lam ivu din e

G. Maraviroc

F.

Riton avir en h an ces lopin avir in test in al absorpt ion .

H. Oselt am ivir I.

Raltegravir


J.

Riton avir

6. A 30-year-old m an w it h AIDS p resen ted to t h e clin ic com -

K. St avu din e

p lain ing of recen t w eigh t gain . Th e m an h ad been u sing a

L.

Tri u ridin e

h igh ly act ive an t iret roviral t h erapy for 6 m on t h s. Physical

M. Zalcit abin e

exam in at ion sh ow ed a p at ien t w ith t ru n cal obesit y an d cu sh ingoid app earan ce. Lab tests revealed hyperglycem ia an d hy-


perlip idem ia. A d rug from w h ich of th e follow ing an t iret roviral

1. A n u cleosid e reverse t ran scr ipt ase in h ibitor u sed to t reat

drug classes m ost likely cau sed th ese adverse e ect s?

bot h HIV an d h epat it is B viral in fect ion s

A. En t r y in h ibitors B. Nucleoside reverse t ran script ase in h ibitors


C. Non n u cleosid e reverse t ran script ase in h ibitors

2. Th is drug is act ive again st HIV-1 bu t n ot again st HIV-2 or

D. In tegrase in h ibitors

oth er ret roviru ses.

E. Protease in h ibitors



3. Th is d r ug is ad m in istered by in t ravit real inject ion to t reat

7. A 34-year-old w om an repor ted to h er physician th at sh e h ad

cytom egaloviru s ret in it is.

experien ced gen ital bu rn ing pain for th e past 2 days. Th e pain an d bu rn ing w ere w orse during urin at ion an d accom pan ied


by fever an d m alaise. Physical exam in at ion revealed m ult iple

4. At a rou t in e clin ic visit , a 40-year-old m an w it h a long h is-

blisters an d u lcerat ive lesion s in th e vagin al area. A p resu m p -

tor y of AIDS w as foun d to h ave a CD4+ lym ph ocyte coun t of

t ive diagn osis of h erp es gen it alis w as m ad e, an d an oral drug

122 cells/m m 3 (n orm al > 500 cells/m m 3 ) despite h is curren t

w as p rescr ibed . W h ich of t h e follow in g step s of t h e viral

h igh ly act ive an t iret roviral th erapy. Th e physician d ecided to

grow th cycle w as m ost likely p rim arily in h ibited by th e p re-

ch an ge t h e t h erapy an d to in clu d e a d r ug t h at blocks th e in -

scribed drug?

tegrat ion of reverse-t ran scribed HIV DNA in to th e ch rom o-

A. En t r y

som es of h ost cells. W h ich of th e follow ing d rugs w as m ost

B. Un coat ing

likely given ?

C. Tran script ion

A. Zidovudin e

D. Tran slat ion

B. Atazan avir

E. Proteolyt ic cleavage

C. Lop in avir

F.

D. Riton avir E. Raltegravir

Assem bly

428




8. A 33-year-old wom an w ith AIDS w as recently diagnosed w ith

11. A 74-year-old diabet ic w om an w as brough t to th e em er-

cytom egalovirus ret in it is. Th e oph th alm ologist prescribed

gen cy departm en t w ith fever (102.7°F, 39.3°C), shaking chills,

a drug th at m u st be ph osp h or ylated

rst by viru s-speci c

cough , h eadach e, an d m alaise. Physical exam in at ion sh ow ed

en zym es, th en by h ost cell en zym es to becom e act ive. W h ich

profou n d dyspn ea, an d rales w ere au dible on au scu lt at ion

of th e follow ing drugs w as m ost likely given ?

of both lungs. Ch est x-ray sh ow ed bilateral in lt rates, an d

A. Foscarn et

blood gas an alysis revealed sign i can t hypoxia. A Gram st ain

B. Ribavirin

of th e spu t um sh ow ed n o bacteria. Fluorescen t an t ibodies

C. Gan ciclovir

id en t i ed in u en za A vir u s on cells of n asal asp irates. An

D. Acyclovir

ap prop riate th erapy w as star ted th at in clu ded a drug th at

E. Vidarabin e

act s by in h ibit ing viral u n coat ing. W h ich of th e follow ing

F.

d rugs w as m ost likely given ?

Zidovudin e

A. Foscarn et

Di cult y level: Easy 9. An 80-year-old m an w as brough t from a n ursing h om e to

B. Gan ciclovir C. Zidovudin e

t h e em ergen cy d ep ar t m en t w it h ch ief com p lain t s of fever

D. Am an t adin e

(102.8°F, 39.3°C), cough , h eadach e, m alaise, an orexia, an d

E. Cidofovir

p h otoph obia. Conven t ion al an t ibiot ic th erapy w as in e ec-

F.

In din avir

t ive, an d 3 days later, in u en za viru s w as detected from sp u t u m . Over th e n ext w eek, th ree oth er n u rsing h om e p at ien t s


d evelop ed sim ilar sym ptom s. Vaccin at ion an d ch em op ro-

12. A 34-year-old m an presen ted to th e clin ic w ith jaun dice an d

p hylaxis w ere plan n ed for all n ursing h om e residen t s an d

com plain ts of in capacitat ing fat igue an d vagu e in term it ten t

sta . W h ich of th e follow ing drugs w ou ld be app ropriate to

abdom in al p ain for th e p ast m on th . Th e p at ien t h ad a h is-

adm in ister as a prophylact ic m easure?

tor y of in t raven ous drug abuse an d alcoh ol abuse. Hepat it is

A. Acyclovir

serologic test s w ere posit ive for h ep at it is B su rface an t igen .

B. Foscarn et


C. Ribavirin

p at ien t?

D. Gan ciclovir

A. En fuvirt ide

E. Oselt am ivir

B. Atazan avir

F.

C. Am an t adin e

Zidovudin e

D. In terferon alfa-2a


E. Gan ciclovir

10. A 72-year-old m an w as ad m it ted to t h e h osp it al w it h a

F.

Foscarn et

1-week histor y of m alaise, night sw eats, and increasing shortn ess of breath . Blood tests on adm ission w ere n otable for


h em oglobin 10 m g/dL (n orm al > 13.5 m g/dL) an d creat in in e


3.2 m g/dL (n orm al 0.6−1.2 m g/dL). On adm ission , p hysical

cytom egalovir u s ret in it is, an d a t h erapy w it h gan ciclovir

exam in at ion sh ow ed a cyan ot ic an d dyspn eic pat ien t in ob -

w as st arted. Tw o w eeks later, th e disease w as n ot m u ch im -

vious dist ress. Au scultat ion revealed decreased lung soun ds

p roved , an d th e oph th alm ologist decided to add a drug th at ,

bilaterally. A viral cult ure from bron ch oalveolar lavage w as

unlike ganciclovir, can directly inhibit DNA polym erase w ith -

p osit ive for h er p es sim p lex vir u s. Paren teral t h erapy w it h

out requiring act ivat ion by ph osph or ylat ion . W h ich of th e

acyclovir w as st ar ted . Th e p at ien t w as at in creased r isk of


d eveloping w h ich of th e follow ing adverse e ect s as a resu lt of th is th erapy?

A. Acyclovir B. Lop in avir

A. Hepat ic cirrh osis

C. Ribavirin

B. Ren al failu re

D. Foscarn et

C. Hem olyt ic an em ia

E. Tri u ridin e

D. Neu t rop en ia

F.

E. Agran u locytosis F.

Pan creat it is

Nevirapin e

Questions: VIII-6 Antiviral Drugs 429 Di cult y: Easy


14. A 23-year-old m an h ad recurren t gen it al h erpes th at w as ef-

17. A 35-year-old m an w ith AIDS w as foun d to h ave a CD4+ lym -

fect ively t reated each t im e by acyclovir. Th e pat ien t asked

p h ocyte coun t of 190 cells/m m 3 (n orm al > 500 cells/m m 3 ) at

h is physician w hy th e t reat m en t w as n ot able to preven t re-

h is last follow -up visit . Th e pat ien t h ad an exten sive h istor y

cu rren ce. W h ich of th e follow ing w ou ld be th e m ost ap pro-

of t reat m en t w ith a variet y of drug regim en s. He w as cur-

p riate an sw er for th e physician to give?

rently taking, lopinavir, ritonavir, lam ivudine, m araviroc, and

A. Acyclovir h as a ver y sh or t du rat ion of act ion .

raltegravir. W h ich of th ese drugs acts by in h ibit ing th e viral

B. Recu r ren ce is d u e to a n ew con t act w it h in fected

en zym e th at u ses viral RNA to m ake a com p lem en tar y DNA

par t n ers. C. An t iviral drugs h ave n o e ect on th e laten t st ate of viral disease. D. Recu rren ce is d u e to a hyp ersen sit ivit y react ion to viral protein s. E. Resist an ce to acyclovir is t h e r u le after on e cycle of

copy? A. Lop in avir B. Riton avir C. Maraviroc D. Raltegravir E. Lam ivu din e

th erapy.


18. A 43-year-old m an w ith AIDS com plain ed to h is physician of

15. A 56-year-old m an su ering from viral hepatitis B had started

m u lt ip le pain fu l u lcers on h is tongu e an d p alate. Exfoliat ive

a t reat m en t w ith in terferon alfa-2a, bu t 9 m on th s later, h e

cytology led to t h e d iagn osis of h er p es sim p lex in fect ion ,

w as st ill p osit ive for h ep at it is B early an t igen . Th e gast ro -

an d t h erapy w it h oral acyclovir w as in it iated . Tw o w eeks

en terologist d ecid ed to stop in ter feron an d st ar t an ot h er

later, n o im p rovem en t w as seen , an d t h e dose of t h e d r ug

d rug. W h ich of th e follow ing drugs w ou ld be appropriate for

w as in creased, bu t w ith ou t su ccess. W h ich of th e follow ing


w as m ost likely th e cau se of failu re of acyclovir th erapy?

A. Gan ciclovir

A. Mu t at ion of aspar tate p rotease

B. Lopin avir

B. Viral t ran spept idase de cien cy

C. Raltegravir

C. Viral thym idin e kin ase de cien cy

D. Nevirapin e

D. Viral n eu ram in idase de cien cy

E. Didan osin e

E. Mu t at ion of reverse t ran script ase

F.

Lam ivu din e


19. A 5-m on th -old baby girl born prem at urely at 31 w eeks’ ges-

16. A 34-year-old w om an w ith AIDS w as fou n d to h ave a CD4+

t at ion w as fou n d to h ave bron ch opu lm on ar y dysp lasia an d

lym p h ocyte cou n t of 45 cells/m m 3 (n orm al > 500 cells/m m 3 )

required oxygen adm inistration . A respirator y syncytial virus

at h er last clin ic visit . Th e pat ien t h ad an exten sive h istor y

(RSV) ou t break w as on goin g in th e com m u n it y, an d t h e

of t reat m en t w ith a variet y of an t iret roviral drugs an d h ad

p ediat rician decid ed to prescribe a drug to preven t RSV in -

been t akin g zid ovu d in e, lam ivu d in e, an d r iton avir. A t ro -

fect ion . W h ich of th e follow ing drugs w ould be appropriate

p ism test sh ow ed t h at h er HIV u sed t h e CCR5 receptor to

for th is baby?

en ter th e h ost cells. Th erapy w as st ar ted w ith a drug th at

A. Raltegravir

preven ts en t r y. W h ich of th e follow ing drugs w as m ost likely

B. Lop in avir

given ?

C. Am an t adin e

A. Ribavirin

D. Lam ivu din e

B. En fuvirt ide

E. Palivizum ab

C. Didan osin e

F.

D. Maraviroc E. In din avir F.

Atazan avir

Trast u zu m ab

430



A. Tran spept idase

20. A 61-year-old w om an su er ing from t h e h ep at it is B vir u s

B. DNA polym erase

(HBV) u n d er w en t a follow -u p exam in at ion . Sh e w as fou n d

C. Aspar t ate p rotease

to h ave m ore t h an 10 5 HBV DNA cop ies/m L an d alan in e

D. Reverse t ran scriptase

t ran sam in ase of 210 U/L (n orm al 8−20 U/L). Th erapy w ith

E. Neu ram in idase

en tecavir w as st arted. In h ibit ion of w h ich of th e follow ing

F.

In tegrase

viral en zym es m ost likely m ediated th e th erap eu t ic e ect of th e drug in th e pat ien t’s disease?


A. DNA polym erase


B. Ph osp h ot ran sferase

m en t becau se of fever (103.2°F, 39.6°C), ch ills, dyspn ea, an d

C. RNA polym erase

gen eralized ach es in h is back an d legs. Social h istor y of th e

D. HIV protease

p at ien t w as sign i can t for an outbreak of u in th e com m u-

E. Thym idin e kin ase

n it y. A clin ical diagn osis of in u en za w as m ade, an d t reat-

F.

m en t w ith a n eu ram in idase in h ibitor w as st arted. W h ich of

Neu ram in idase

th e follow ing act ion s m ost likely m ed iated th e th erapeu t ic


e ect of th e drug in th e p at ien t’s disease?

21. A 47-year-old m an w ith AIDS w as foun d to h ave a CD4+ lym -

A. Preven t ion of virus release from in fected cells

p h ocyte cou n t of 170 cells/m m 3 (n or m al > 500 cells/m m 3 )

B. Blockade of fu sion of th e virus w ith th e h ost cell

at h is last clin ic visit . Th e pat ien t h ad an exten sive h istor y

C. In h ibit ion of viral t ran script ion

of t reat m en t w ith a variet y of an t iret roviral drugs an d h ad

D. In h ibit ion of viral proteolyt ic cleavage

been cu rren tly taking abacavir, lam ivu din e, an d atazan avir.

E. In h ibit ion of viral protein syn th esis

The physician decided to add enfuvirtide to the current therapy. W h ich of th e follow ing steps of th e viral grow th cycle


w as m ost likely in h ibited by th e prescribed d rug?


A. En t r y

cytom egalovirus pn eu m on ia. Th e p at ien t’s cu rren t m edica-

B. Un coat ing

t ion s in clu d ed zid ovu d in e, d idan osin e, an d at azan avir. In -

C. Tran script ion

t raven ou s th erapy w ith gan ciclovir w as st ar ted. W h ich of

D. Tran slat ion

th e follow ing adverse e ects w ou ld be p redicted to be m ost

E. Proteolyt ic cleavage

likely to occu r du e to th e con cu rren t adm in ist rat ion of gan -

F.

ciclovir an d th e an t iret roviral drugs?

Assem bly

A. An em ia an d n eut ropen ia


B. Ret in al det ach m en t

22. A 40-year-old m an w as recen tly fou n d to be HIV posit ive,

C. Cat aract

an d h e st arted a h igh ly act ive an t iret roviral th erapy (HAART)

D. Sexu al dysfu n ct ion

w ith lam ivudin e, stavudin e, an d atazan avir. W h ich of th e

E. Hyp erglycem ia

follow in g t w o step s in t h e HIV grow t h cycle w ere sp eci -

F.

Lact ic acid osis

cally a ected by th is drug regim en ? A. En t r y an d proteolyt ic cleavage B. En t r y an d un coat ing

Di cult y level: Medium 26. A 34-year-old w om an w ith AIDS h ad been t aking an an t i-

C. Tran script ion an d at tach m en t

ret roviral th erapy th at in cluded zalcit abin e an d stavudin e.

D. At t ach m en t an d u n coat ing

W h ich of th e follow ing adverse e ects w ould be predicted

E. Tran script ion an d proteolyt ic cleavage

to be m ost likely, as it is sh ared by both drugs? A. Nep h rolith iasis


B. Myelosu p pression

23. A 32-year-old w om an visited h er physician com plain ing of

C. Hallu cin at ion s

ver y pain fu l blisters on h er abdom en . Physical exam in at ion

D. Periph eral n europathy

show ed localized blisters on her left abdom en consisten t w ith

E. Altered body fat dist ribut ion

a cu t an eou s zoster in fect ion . Th erapy w it h acyclovir w as st ar ted . W h ich of t h e follow in g en zym es w as m ost likely in h ibited by th e adm in istered drug?

Questions: VIII-6 Antiviral Drugs 431 Di cult y level: Easy


27. A 35-year-old m an recen tly diagn osed w ith h erpes sim plex

31. A 34-year-old m an w ith AIDS presen ted to th e clin ic becau se

kerat it is started a top ical th erapy w ith eye drops. W h ich of

of fever (103.4°F, 39.7°C), m alaise, m yalgias, n ausea, an d di-


arrh ea. Th ree w eeks earlier, th e pat ien t h ad star ted a h igh ly

A. Adefovir

act ive an t iret roviral th erapy. He st ated th at th e sym ptom s

B. Lopin avir

w ere m ost p rom in en t several h ou rs after each dose an d th at

C. Nevirapin e

t h ey seem ed to be get t in g p rogressively w orse w it h each

D. Zidovudin e

d ose. Physical exam in at ion disclosed a

E. Tri u ridin e

rash over h is face, t ru n k, an d arm s. W h ich of th e follow ing

F.

d rugs m ost likely cau sed th e p at ien t’s syn drom e?

Zan am ivir

n e m acu lop ap u lar

A. Zidovudin e


B. Ribavirin

28. A 35-year-old HIV-posit ive m an presen ted for a follow -u p

C. Foscarn et

visit . His CD4+ lym ph ocyte cou n t w as 350 cells/m m 3 (n or-

D. Abacavir

m al > 500 cells/m m 3 ). A h igh ly act ive an t iret roviral th erapy

E. Lam ivu din e

(HAART) w as in it iated. W h ich of th e follow ing t riple-drug

F.

Zan am ivir

regim en s w as m ost likely u sed? A. Flucytosin e + acyclovir + atazan avir B. Didan osin e + ganciclovir + zidovudin e

Di cult y level: Medium 32. A 12-day-old prem at ure baby boy developed a poor feeding

C. Vidarabin e + foscarn et + didan osin e

p at ter n , ir r it abilit y, an d resp irator y d ist ress. His m ot h er,

D. Ribavirin + atazanavir + zidovudin e

w h o h ad su ered several ep isod es of gen it al h er p es, h ad

E. Zidovudin e + didan osin e + at azan avir

p resen ted to th e h ospital in labor w ith prem at u re ru pt u re of th e m em bran es. Physical exam in at ion of th e baby revealed

Di cult y level: Easy 29. A 34-year-old pregn an t w om an w as adm it ted to th e h ospital at term for deliver y. Tw o w eeks earlier, th e w om an w as d iagn osed w ith asym ptom at ic HIV. An oral dose of n evirapin e

several sm all vesicu lar skin lesion s located on th e scalp , an d d en drit ic kerat it is w as presen t in both eyes. W h ich of th e follow ing drugs w ould be appropriate to in clude in th e th erapeu t ic t reat m en t of th is baby?

w as given to th e w om an at th e on set of labor. W h ich of th e

A. Atazan avir

follow ing best explain s th e reason for th is adm in ist rat ion ?

B. Acyclovir

A. To st ar t a h igh ly e ect ive an t iret roviral th erapy B. To redu ce AIDS sym ptom s in th e n ear fu t u re C. To p reven t bleed ing after deliver y D. To p reven t HIV t ran sm ission in th e n ew born E. To prevent respiratory distress syndrom e in the new born

Di cult y level: Medium 30. A 31-year-old HIV-posit ive m an at a rou t in e clin ic visit w as fou n d to h ave a CD4+ lym ph ocyte cou n t of 122 cells/m m 3 (norm al > 500 cells/m m 3 ). A highly active antiretroviral th er-

C. Zidovudin e D. Pen t am idin e E. Flu con azole F.

Met ron idazole

Di cult y level: Easy 33. A 25-year-old m an recen tly diagn osed w ith AIDS star ted an an t iret roviral th erapy th at in clu ded atazan avir. W h ich of th e follow ing steps of th e viral grow th cycle w as prim arily in h ibited by th is drug?

apy w as st ar ted th at in clu ded a drug th at does n ot require

A. En t r y

p h osp h or ylat ion to becom e act ive. W h ich of t h e follow ing

B. Un coat ing

is an an t iret roviral drug w ith th is proper t y?

C. Tran script ion

A. Efaviren z B. Foscarn et C. St avu din e D. Lam ivu din e E. Abacavir F.

Didan osin e

D. Tran slat ion E. Proteolyt ic cleavage F.

Assem bly

432



sign s on ad m ission w ere: blood p ressu re 100/50 m m Hg,

34. A 39-year-old m an w ith AIDS w as t aking an an t iret roviral

h ear t rate 130 bpm , respirat ion s 32/m in an d sh allow. Physi-

th erapy th at in clu ded a drug w ith a p ron ou n ced in h ibitor y

cal exam in at ion sh ow ed an acu tely ill an d sw eat y p at ien t

e ect on CYP3A4. W h ich of th e follow ing drugs m ost likely

w ith abdom inal distention, tenderness in the epigastric area,

h as th is in h ibitor y act ion ?

an d absen t bow el soun ds. Lab result s on adm ission revealed seru m am ylase of 520 IU/L (n orm al < 115 IU/L). A p relim i-

A. Atazan avir

n ar y diagn osis w as m ade. W h ich of th e follow ing an t iviral

B. Zidovudin e

drugs m ost likely cau sed th e p at ien t’s disorder?

C. Lam ivu din e D. Riton avir

A. Zidovudin e

E. En fuvirt ide

B. Lam ivu din e C. Didan osin e D. Abacavir

Di cult y level: Hard 35. A 71-year-old w om an w as adm it ted to th e h ospit al w ith a 2-day h istor y of progressive dysp n ea, fever, cough , an d w h eezing. A ch est radiograph w as n orm al, but a bron ch oscopy sh ow ed m arked er yth em a of th e t rach ea an d bron ch i,

E. Ribavirin F.

Acyclovir


w ith m ult iple ulcerat ion s. A bron ch ial biopsy con rm ed th e

38. A 5-year-old girl w as adm it ted to th e em ergen cy depart-

d iagn osis of h erpet ic t rach eobron ch it is. Th e p at ien t received

m en t becau se of fever (102°F, 38.8°C) an d disorien tat ion in

in t raven ous acyclovir for 3 days, but n o im provem en t w as

t im e an d sp ace. Soon after ad m ission , t h e p at ien t h ad a

seen . Resist an ce to acyclovir w as su sp ected, an d an altern a-

seizu re. Ceft riaxon e an d d exam eth ason e w ere in it iated, bu t

t ive d r ug w as given in t raven ou sly. W h ich of th e follow in g

th e n ext day, th e pat ien t becam e leth argic an d lapsed in to

drugs w ou ld be m ost appropriate for th e patien t at th is tim e?

a com a. Exam in at ion of th e cerebrosp in al u id revealed n o bacteria. A com p u ted tom ography scan of th e h ead sh ow ed

A. Foscarn et

d ecreased den sit y in a sm all area of th e righ t parietal lobe of

B. Atazan avir

th e brain . In t raven ou s acyclovir w as star ted, an d 5 days later,

C. Am an t adin e

th e ch ild w as alert , respon sive, an d act ively m oving. W h ich

D. Zidovudin e

of t h e follow in g d iseases m ost likely cau sed t h e p at ien t ’s

E. Tri u ridin e

sign s an d sym ptom s? A. Neisseria m en ingit is

Di cult y level: Easy 36. A 43-year-old w om an w ith AIDS st arted a h igh ly act ive an t iret roviral t h erapy w it h zid ovu d in e, lam ivu d in e, an d at azan avir. W h ich of t h e follow ing reason s best exp lain s an im port an t rat ion ale for t riple th erapy in AIDS pat ien ts? A. To dest roy both th e rep licat ing an d n on rep licat ing viral gen om e B. To in crease th e h alf-life of any on e of th e agen t s C. To delay th e app earan ce of dr ug resist an ce D. To in h ibit each oth er’s dr ug m et abolism E. To exp an d th e an t im icrobial e

cacy to op p or t u n ist ic

in fect ion s

B. Toxop lasm ic en ceph alit is C. Cr yptococcal m en ingit is D. Cytom egalovirus en ceph alit is E. Herp es en ceph alit is

Di cult y level: Medium 39. A 41-year-old w om an w it h AIDS st ar ted a h igh ly act ive an t iret roviral th erapy th at in cluded abacavir an d efaviren z. W h ich of th e follow ing adverse e ects w ould m ost likely be p redicted because it w as sh ared by both drugs? A. Er yth em atous skin rash B. Hallu cin at ion s

Di cult y level: Hard 37. A 43-year-old HIV-p osit ive w om an w as ad m it ted to t h e h ospit al w ith a 2-day h istor y of n ausea, vom it ing, an d severe ep igast ric p ain radiat ing th rough to th e back. Th e w om an h ad been t aking an an t iret roviral th erapy for 3 m on th s. Vital

C. Liver cirrh osis D. Pan creat it is E. Macrocyt ic an em ia F.

Lact ic acid osis

Questions: VIII-7 Antiprotozoal Drugs 433 Di cult y level: Medium

A. Am an t adin e

40. A 23-year-old w om an w ith AIDS cam e to the clinic com plain-

B. Ribavirin

ing of oat ing spot s in h er vision an d di cult y in reading.

C. Gan ciclovir

Fu n du scopic exam in at ion revealed th e presen ce of altern at-

D. Lop in avir

ing areas of h em orrh agic t issue an d

E. Gen t am icin

u y w h ite patch es in

th e proxim it y of th e ret in as of both eyes, con sisten t w ith

F.

Doxycyclin e

h em orrh agic ret in it is. W h ich of th e follow ing dr ugs w ould be ap prop riate for th e t reat m en t of th e p at ien t’s ocu lar d isorder?

Questions: VIII-7 Antiprotozoal Drugs Directions for questions 1−5


Match each an t iprotozoal dr ug w ith th e app ropriate d escript ion

6. A 45-year-old m ale reporter w h o w as about to leave for Hon -


duras started a prophylactic antim alarial treatm en t w ith chlo-

at all).

roqu in e. W h ich of th e follow ing m olecu lar act ion s m ost likely

A. Ch loroquin e

m ediated th e prophylact ic e ect of th e dr ug in th is m an ?

B. Clin dam ycin

A. In h ibit ion of dihydropteroate syn th ase

C. Doxycyclin e

B. Blockade of t ran slocat ion of pept idyl t ran sfer RNA (tRNA)

D. Iodoquin ol

C. In correct am in o acid in corporat ion in to th e polypept ide ch ain

E. Me oqu in e F.

Met ron idazole

G. Parom om ycin

D. In h ibit ion of DNA-depen den t RNA polym erase E. Prevention of polym erization of free hem e into hem ozoin

H. Prim aquin e I.

Pyrim eth am in e


J.

Qu in in e

7. A 55-year-old m an w h o w as about to leave for a vacat ion t rip

K. Sodiu m st iboglu con ate

to Cen t ral Africa star ted a prophylact ic t reat m en t w ith m e o-

L.

qu in e. W h ich of th e follow ing plasm odia can be e ect ively

Su lfadoxin e

M. Nifu rt im ox

Di cult y level: Easy 1. An e ect ive blood sch izon t icid e also u sed in t h e t reat m en t of rh eu m atoid arth rit is

killed by th e drug? A. Plasm odium vivax hyp n ozoites B. P. falciparum gam etocytes C. P. vivax t issu e sch izon ts D. P. falciparum t issu e sch izon t s E. P. m alariae blood sch izon ts


F.

P. m alariae t issu e sch izon ts

2. Th is d r ug can kill m ost an aerobic bacter ia an d an aerobic protozoa.

Di cult y level: Easy 8. A 43-year-old m an w h o w as about to leave for a vacat ion in


th e Am azon basin w as advised by h is physician to take m alar-

3. An antim alarial drug w ith a very long half-life (about 20 days)

on e (atovaqu on e an d p rogu an il) as a p rop hylact ic m easu re, as ch loroqu in e resist an ce w as w id esp read in t h ose region s.


W h ich of th e follow ing reason s best explain s th e likely m ech -

4. Th is an t im alarial drug can kill th e late t issue sch izon t s of

an ism of plasm odial resist an ce to ch loroqu in e?

Plasm odium vivax an d Plasm odium ovale.

A. In creased in act ivat ion of th e drug B. In creased act ivit y of th e DNA repair m ech an ism


C. In creased dr ug t ran spor t out of plasm odia cells

5. Th e

D. Decreased ch loroquin e-bin ding sites on plasm odia cells

rst-lin e agen t to t reat acute Am erican t r ypan osom iasis

(Ch agas disease)

E. Decreased conversion of free h em e in to h em ozoin

434


Di cult y level: Easy 9. A 45-year-old Black m an rep or ted to h is p hysician t h at a

A. Prim aquin e−quin in e B. Me oqu in e−m et ron idazole

few days earlier h e h ad n ot iced a p ersisten t yellow color in

C. Atovaqu on e−progu an il

h is eyes. On e w eek ago, com ing back from a t rip to Cen t ral

D. Doxycyclin e−iodoquin ol

Am er ica, t h e m an h ad st ar ted a t reat m en t t h at in clu d ed

E. Ch loroquin e−parom om ycin

p r im aquin e. Blood tests disclosed th e follow ing: • Red blood cell cou n t: 3.8 × 10 6 /m m 3 (n orm al, m ale 4.3−5.9 × 10 6 /m m 3 )

Di cult y level: Medium 12. A 30-year-old epilept ic w om an presen ted to th e clin ic w ith

• Hem oglobin : 9 g/dL (n orm al, m ale 13.5−17.5 g/dL)

a 5-day h istor y of loose stools con tain ing bloody m u cu s.

• Ret icu locytes: 3.7% of red cells (n orm al 0.5−1.5%)

Up on p hysical exam in at ion , h er abd om en w as soft bu t n on -

• W h ite blood cell cou n t: 15,000/m m 3 (n or m al 4500−

ten der. Laborator y exam in at ion of fresh stool sh ow ed En-

11,000/ m m 3 ) Th e physician told th e pat ien t th at h e probably h ad a gen etically in du ced en zym e defect th at cou ld explain h is blood

tam oeba histolyt ica t roph ozoites. A com p uted tom ography scan w as n egat ive for gu t w all or liver am ebiasis. W h ich of th e follow ing drugs w ou ld be ap prop riate for th is pat ien t?

test result s. W h ich of th e follow ing en zym es w as m ost likely

A. Met ron idazole

abn orm al in th is pat ien t?

B. Ch loroquin e

A. Thym idylate syn th ase B. Urop orphyrin ogen decarboxylase C. Pyruvate kin ase D. Dihydrofolate reduct ase E. Glu cose-6-ph osph ate-dehydrogen ase

Di cult y level: Medium 10. A 41-year-old w om an w h o h ad recen tly ret u rn ed from a t rip to Kenya w as adm it ted to th e h ospital because of m alaise, m yalgia, abd om in al p ain , an d fever (104°F, 40°C). Recen t h istor y w as sign i can t for t w o paroxysm al at t acks of ch ills, fever, an d vom it ing. Th e rst at tack lasted a day an d w as fol-

C. Clin dam ycin D. Parom om ycin E. Pyrim eth am in e F.

Su lfadoxin e

Di cult y level: Medium 13. A 30-year-old m an w ith AIDS w as adm it ted to th e h ospital w ith th e prelim in ar y diagn osis of pn eum on ia. Fur th er test s led to th e d iagn osis of toxop lasm osis, an d an app ropriate com bin at ion th erapy w as st ar ted. In h ibit ion of w h ich of th e follow ing protozoal enzym es m ost likely m ediated the therap eut ic e ect of th e th erapy in th is p at ien t?

low ed by a secon d, 36 h ours later. Physical exam in at ion re-

A. Pu rin e ph osph oribosyl t ran sferase

vealed an acutely ill pat ien t com plain ing of severe abdom in al

B. Orn ith in e decarboxylase

p ain . Palpat ion sh ow ed a ten der, soft , an d en larged sp leen .

C. Ferredoxin oxidoreduct ase

Exam in at ion of a stain ed blood specim en revealed ringlike

D. Glucose-6-ph osph ate dehydrogen ase

an d crescen tlike form s w ith in th e red blood cells. W h ich of

E. Dihydrofolate reduct ase

th e follow ing pairs of drugs w ou ld be app ropriate for th is p at ien t?


A. Artesu n ate an d doxycyclin e

14. A 31-year-old m an ret u r n in g from a t r ip to Malaysia w as

B. Prim aquin e an d clin dam ycin

ad m it ted to th e h osp it al w ith a 2-day h istor y of fever, ch ills,

C. Pyrim eth am in e an d m et ron idazole

an d bou ts of diarrh ea. A Giem sa blood sm ear dem on st rated

D. Ch loroquin e an d parom om ycin

Plasm odium vivax t rop h ozoites. Th e p at ien t w as placed on

E. Me oqu in e an d cip ro oxacin

ch loroquin e for 5 days an d w as th en in st ructed to take an oth er drug for 14 days. W h ich of th e follow ing drugs w ou ld


be ap prop riate for th e 14 days of th erapy?

11. A 38-year-old m an w as plan n ing a vacat ion to sub-Sah aran

A. Prim aquin e

Africa, w h ere ch loroquin e-resistan t st rain s of Plasm odium

B. Me oqu in e

falciparum are presen t . W h ich of th e follow ing drug com bi-

C. Qu in idin e

n at ion s w ould be appropriate to preven t m alaria in fect ion in

D. Pyrim eth am in e

th is m an ?

E. Doxycyclin e F.

Su lfadoxin e

Questions: VIII-7 Antiprotozoal Drugs 435 Di cult y level: Medium


15. A 29-year-old m arried w om an com plain ed to h er physician

18. A 1700-g (3.8-lb) preterm fem ale n ew born presen ted w ith

of soren ess of h er vulva an d pain during in tercourse. Fur th er

hydroceph alu s an d seizu res. Fu rth er test s led to th e diagn o-

test s led to a de n it ive diagn osis, an d an appropriate th er-

sis of congen it al toxop lasm osis, an d an ap p rop riate th erapy

apy w as star ted . Th e p rescribed an t ibiot ic act s by dam aging

w as started. W hich of the follow ing drug com binations w ould

m icrobial DNA th rough a h igh ly react ive n it ro radical an ion .

be m ost ap prop riate for th is baby?

W h ich of th e follow ing drugs w as m ost likely adm in istered

A. Gen t am icin an d piperacillin

to th e pat ien t an d to h er h usban d?

B. Su lfadiazin e an d pyrim eth am in e

A. Am picillin

C. Van com ycin an d ceft azidim e

B. Gen t am icin

D. Ison iazid an d rifam pin

C. Er yth rom ycin

E. St reptom ycin an d tet racyclin e

D. Met ron idazole E. Cefop erazon e

Di cult y level: Medium 19. A 51-year-old alcoh olic w om an com plain ed to h er physician


of abdom in al discom fort an d occasion al foul-sm elling diar-

16. A 38-year-old w om an w h o h ad recen t ly ret u r n ed from a

rh ea altern at ing w ith con st ipat ion for th e p ast 3 w eeks. Th e

vacat ion in Greece developed a red p ap u le on h er righ t arm

sym ptom s star ted after h er ret u rn from a vacat ion t rip to

t h at en larged slow ly an d began to u lcerate bu t cau sed n o

Guatem ala. Heart-sh aped t roph ozoites w ith four pairs of a-

p ain . A few days later, m u lt ip le skin lesion s d evelop ed . A

gella an d rou n d cyst s w ere obser ved in h er stool sp ecim en .

sm ear t aken from th e skin lesion s dem on st rated th e p res-

W h ich of th e follow ing drugs w ould be m ost appropriate to

en ce of am ast igotes. W h ich of th e follow ing drugs w ou ld be

p rescribe to th is pat ien t?

m ost app ropriate for th is pat ien t?

A. Parom om ycin

A. Met ron idazole

B. Met ron idazole

B. Sodiu m st iboglu con ate

C. Prim aquin e

C. Doxycyclin e

D. Cipro oxacin

D. Ceft riaxon e

E. Pyrim eth am in e

E. Ch loroquin e

F.

F.

Flu con azole

Clin dam ycin


20. A 34-year-old black m an living in th e Un ited St ates w as

17. A 31-year-old h om osexual m an presen ted to th e clin ic w ith

p lan n ing to visit h is seriou sly ill fath er w h o lives in Ugan da.

a 10-day h istor y of abdom in al p ain an d m u lt ip le brow n , w a-

He w as going to be accom pan ied by h is w ife an d son . Kn ow -

ter y stools. Physical exam in at ion revealed a t all m an w ith

ing th at ch loroquin e-resist an t st rain s of m alaria are presen t

abdom in al dist ress. Vit al sign s w ere blood p ressu re 125/75

in Ugan da, w h ich of th e follow ing drugs u sed alon e w ou ld

m m Hg, pu lse 78 bp m , tem p erat u re 103.5°F (39.7°C). His ab -

be th e m ost ap p rop riate prop hylaxis for th e m an , h is w ife,

d om en w as sligh tly disten ded w ith a ten der m ass p alpable

an d th eir son before en tering Ugan da?

in th e low er righ t qu adran t , w h ich an ult rasoun d exam in a-

A. Prim aquin e

t ion revealed to be an abdom in al abscess. A serologic test

B. Met ron idazole

w as posit ive for Entam oeba histolyt ica. W h ich of th e follow -

C. Pyrim eth am in e

ing pairs of drugs w ould be appropriate for th is pat ien t?

D. Me oqu in e

A. Met ron idazole an d iodoqu in ol

E. Ch loroquin e

B. Ch loroquin e an d clin dam ycin

F.

C. Met ron idazole an d pyrim eth am in e D. Doxycyclin e an d iodoquin ol E. Ch loroquin e an d cipro oxacin F.

Pyrim eth am in e an d cip ro oxacin

Qu in in e

436




21. A 32-year-old w om an com plain ed to th e n urse of a sudden


in crease in h er h eart rate. Four days earlier, th e w om an , w h o

d rug sh e w as t aking cau sed an oral th ru sh . On e w eek earlier,

h ad recen t ly ret u r n ed from a t r ip to Ugan da, w as h osp it al-

th e w om an w as diagn osed w ith am ebiasis an d st arted an

ized w it h t h e p resu m pt ive diagn osis of m alar ia. Th e w om an

appropriate treatm ent. Exam ination of the oral cavit y show ed

h ad been su er ing from an orexia n er vosa for 1 year. Th e

w h ite patch es of a ch eesy substan ce on a friable oral m ucosa.

Plasm odium vivax in fect ion w as con rm ed, an d th e pat ien t

W h ich of th e follow ing dr ugs m ost likely cau sed th e adverse

started an appropriate th erapy. An electrocardiogram led to

e ect in th is p at ien t?

th e d iagn osis of torsades de p oin tes. W h ich of th e follow ing

A. Parom om ycin

d rugs m ost likely cau sed th e pat ien t’s arrhyth m ia?

B. Iodoquin ol

A. Qu in in e

C. Tobram ycin

B. Ch loroquin e

D. Met ron idazole

C. Met ron idazole

E. Meben dazole

D. Iodoquin ol

F.

Flu con azole

E. Artesu n ate F.

Pyrim eth am in e

Questions: VIII-8 Anthelm intic Drugs Directions for questions 1−5


Match each an th elm in t ic drug w ith th e ap prop riate descript ion

6. A 14-year-old boy living in a rural area of th e south ern Un ited


St ates w as diagn osed w ith st rongyloidiasis. Treat m en t w ith

at all).

iverm ect in w as st ar ted. W h ich of th e follow ing m olecu lar ac-

A. Alben dazole

t ion s on th e w orm cells m ost likely m ediated th e th erap eu t ic

B. Diethylcarbam azin e

e ect of th e drug in th is p at ien t?

C. Iverm ect in

A. In h ibit ion of DNA polym erase

D. Meben dazole

B. Blockade of n icot in ic receptors

E. Praziquan tel

C. In h ibit ion of protein syn th esis

F.

D. Act ivat ion Cl− ch an n els

Pyran tel pam oate

E. In creased m em bran e Ca 2+ p erm eabilit y

Di cult y level: Easy 1. Th e agen t of ch oice for ech in ococcosis

Di cult y level: Easy 7. A 56-year-old h om eless m an living in a poor area of south ern


California w as seen at a local clinic because of abdom inal pain ,

2. A drug act ive again st m ost t rem atodes an d cestodes

n ausea, an d vom it ing over th e past 12 h ours. Physical exam in at ion revealed a m aln ourish ed m an w ith di u se abdom in al

Di cult y level: Easy 3. A ben zim idazole d er ivat ive w it h less t h an 10% oral bioavailabilit y

lum bricoides an d Trichuris t richiura, as w ell as rh abdit iform lar vae of St rongyloides stercoralis. An appropriate t reat m en t w as ord ered . W h ich of t h e follow in g d r ugs w ou ld be m ost

Di cult y level: Easy 4. Th e agen t of ch oice for on ch ocerciasis

Di cult y level: Easy 5. Th is d r ug m ost likely act s by in creasin g w or m cell p er m eabilit y to

ten d er n ess. Stool exam sh ow ed n u m erou s eggs of Ascaris

Ca 2+

.

ap prop riate to t reat th e p at ien t’s m ixed w orm in fect ion ? A. Met ron idazole B. Diethylcarbam azin e C. Iverm ect in D. Praziquan tel E. Meben dazole

Questions: VIII-8 Anthelm intic Drugs 437 Di cult y level: Medium


8. A 10-year-old boy w h o recen tly m oved from In dia to th e

11. A 24-year-old m an living in th e US Great Lakes region w as

Un ited St ates w as ad m it ted to t h e h osp it al w it h fever

recen t ly d iagn osed w it h dip hyllobot h r iasis. Th e p hysician

(103.4°F, 39.6°C) an d acu te lym p h ed em a of t h e scrot u m .

p rescribed a single tablet of p raziqu an tel. W h ich of th e fol-

Fu r th er exam s led to th e diagn osis of ban croft ian

low in g m olecu lar act ion s on t h e w or m cells m ost likely

lariasis,

an d ph arm acoth erapy w as p rescribed. W h ich of th e follow -

m ediated th e th erap eu t ic e ect of th e drug in th is p at ien t?

ing drugs w ould be m ost appropriate for th is boy?

A. Act ivat ion of topoisom erase II

A. Meben dazole

B. Blockade of m u scarin ic receptors

B. Praziquan tel

C. Inhibition of gam m a-am inobut yric acid (GABA)−m ediated n eurot ran sm ission

C. Met ron idazole D. Ch loroquin e

D. In creased m em bran e perm eabilit y to calcium

E. Diethylcarbam azin e

E. Act ivat ion of GABA-m ed iated n eu rot ran sm ission

Di cult y level: Medium 9. A 5-year-old boy w as seen in h is pediat rician’s o

Di cult y level: Easy ce. His

12. A 6-year-old girl w h o w as living in a ru ral area of Texas w as

m oth er said th e boy h ad been ver y irritable an d com p lain ed

recen tly diagn osed w ith t rich uriasis. Tablets of m eben dazole

of abdom in al discom for t an d perian al prurit us on t w o occa-

w ere p rescribed for 3 days. W h ich of th e follow ing m olecu -

sion s th e p reviou s w eek. Th e m oth er also n ot iced som e ver y

lar act ion s on th e w orm cells m ost likely m ediated th e th er-

sm all m ot ile w orm s in th e boy’s stools. Exam of a cellop h an e

apeu t ic e ect of th e dr ug in th is p at ien t?

t ap e sw ab p laced over th e perian al skin dem on st rated t ran s-

A. St im ulat ion of n icot in ic receptors at th e n eu rom u scu lar

lu cen t eggs. W h ich of th e follow ing drugs w ould be appro-

jun ct ion

p riate for th is ch ild?

B. In h ibit ion of dihydrofolate reduct ase

A. Iverm ect in

C. En h an cem en t of gam m a-am in obu t yr ic acid (GABA)− m ediated n eu rot ran sm ission

B. Praziquan tel C. Pyrim eth am in e

D. In h ibit ion of h em e polym erase

D. Met ron idazole

E. In creased m em bran e perm eabilit y to calcium

E. Meben dazole

F.

F.

In h ibit ion of m icrot ubule polym erizat ion an d assem bly

Diethylcarbam azin e


13. A 53-year-old w om an w h o h ad spen t m ost of h er adult life

10. A 31-year-old m an w as seen at a clin ic w ith fever (103.2°F,

as a m ission ar y in Sen egal w as referred to an op h th alm olo-

39.5°C), chills, nausea, abdom in al pain, m yalgia, an d urticaria

gist for evalu at ion of dim in ish ed visual acu it y. An eye exam

rash es. Th e m an h ad t aken a vacat ion t rip to th e Am azon

sh ow ed sclerosing kerat it is an d ch or ioret in al lesion s. Phys-

River 4 w eeks earlier. Stool exam s u p on ad m ission disclosed

ical exam in at ion d isclosed

eggs w it h a lateral sp in e an d m iracid iu m lar vae in sid e. A

n odules on h er elbow s, iliac bon es, an d kn ees. A skin biopsy

d iagn osis w as m ade, an d a p h ar m acot h erapy w as st ar ted .

sh ow ed m icro lariae. W h ich of th e follow ing drugs w ou ld

W h ich of t h e follow ing p airs cor rect ly m atch es t h e m ost

be ap prop riate for th is pat ien t?

likely o en ding path ogen w ith th e app ropriate t reat m en t?

A. Diethylcarbam azin e

A. Schistosom a m ansoni: p raziqu an tel

B. Praziquan tel

B. Taenia solium : m et ron idazole

C. Iverm ect in

C. Echinococcus granulosus: iverm ect in

D. Flu con azole

D. Enterobius verm icularis: praziquan tel

E. Met ron idazole

E. Necator am ericanus: m et ron idazole F.

Diphyllobothrium lat um : iverm ect in

r m , n on ten d er su bcu t an eou s

438



cyst . Aspirat ion of th e cyst revealed hydat id san d. Ph arm a-

14. A 32-year-old w om an w h o recen tly m oved to th e Un ited

cot h erapy w as st ar ted, an d t h e p at ien t w as sch ed u led for

St ates from Japan w as seen at th e clin ic because of dyspn ea,

su rgical rem oval of t h e cyst . W h ich of t h e follow ing d r ugs

ch est pain , an d blood in h er spu t um . Ch est x-rays sh ow ed a


d i u se in lt rate w ith pleu ral e usion . Lab exam of spu t u m

A. Met ron idazole

w as n egat ive for p ath ogen bacteria bu t disclosed n u m erou s

B. Ch loroquin e

large operculated eggs. A presu m pt ive diagn osis w as m ade,

C. Iverm ect in

an d ph arm acoth erapy w as st ar ted . W h ich of th e follow ing

D. Diethylcarbam azin e


E. Alben dazole

A. Met ron idazole

F.

Ketocon azole

B. Meben dazole C. Diethylcarbam azin e


D. Iverm ect in

18. A 13-year-old boy w h o h ad recen tly m oved from Costa Rica

E. Praziquan tel

to Los Angeles com plain ed to th e sch ool n u rse of vagu e ab d om in al pain an d th at h e kept seeing “w h ite n oodle-like”


object s in h is stools. Exam in at ion of a celloph an e t ape sw ab

15. A 7-year-old girl w h o w as living in a poor san itat ion area of

p laced over t h e p er ian al area an d stool sam p les d em on -

Mexico w as brough t by h er m oth er to th e fam ily p hysician’s

st rated p roglot t id s an d n u m erou s free eggs. W h ich of t h e

o

follow ing drugs w ould be appropriate for th is boy?

ce. Th e m oth er reported th at th e p revious day, th e girl

h ad com p lain ed of abd om in al cram p s an d w as fr igh ten ed

A. Iverm ect in

by seeing som e large, m ot ile w orm s in h er stools. W h ich of

B. Artem isin

th e follow ing drugs w ou ld be app ropriate for th is girl?

C. Praziquan tel

A. Prim aquin e

D. Met ron idazole

B. Meben dazole

E. Am ph otericin B

C. Flucon azole

F.

Flu con azole

D. Met ron idazole E. Praziquan tel


F.

19. A 10-year-old boy w h o w as livin g in a p oor r u ral area of

Me oqu in e

t h e sou th eastern Un ited St ates w as seen at a clin ic becau se


of w eakn ess, t achycardia, abdom in al cram ps, an d diarrh ea


over th e p ast 2 days. Physical exam in at ion disclosed a pale

(103.5°F, 39.7°C), dizzin ess, prost rat ion , skin rash es, tachy-

boy w it h evid en t sign s of grow th ret ardat ion . Blood test s

cardia, hyp oten sion , an d pain in th e m u scles, join t s, an d

revealed hypoch rom ic-m icrocyt ic an em ia, eosin oph ilia, an d

lym p h glan ds. Th e m an , w h o h ad lived in Gu atem ala for sev-

th rom bocytop en ia. A stool an alysis sh ow ed occu lt blood an d

eral years, w as recen tly diagn osed w ith on ch ocerciasis an d

n um erous th in -sh elled oval eggs in th e four-cell stage of seg-

h ad star ted an appropriate m edical th erapy th e day before.

m entation. A diagnosis w as m ade, and a m edical therapy w as


p rescribed. W h ich of th e follow ing pairs correctly m atch es

syn drom e?

t h e m ost likely o en d in g p at h ogen w it h t h e ap p rop r iate

A. Iverm ect in

t reat m en t?

B. Praziquan tel

A. Schistosom a m ansoni: iverm ect in

C. Meben dazole

B. Onchocerca volvulus: m et ron idazole

D. Ketocon azole

C. Ascaris lum bricoides: m et ron idazole

E. Am ph otericin B

D. Enterobius verm icularis: iverm ect in

F.

E. Necator am ericanus: m eben dazole

Me oqu in e

F.

Diphyllobothrium lat um : m eben dazole

Di cult y level: Medium 17. A 45-year-old m an w ho raised sheep in California com plained


to h is p hysician of abd om in al p ain over t h e p ast 3 days.

20. A 6-year-old girl recently diagnosed w ith enterobiasis started

Physical exam in at ion d isclosed an abd om in al m ass, an d a

a t reat m en t w ith m eben dazole, bu t after t w o cycles of th er-

su bsequ en t com p u ted tom ograp hy scan sh ow ed a large liver

apy, m any worm s w ere still found in her stools. The physician

Questions: VIII-9 Antineoplastic Drugs 439 decided to p rescribe an altern at ive t reat m en t . W h ich of th e

cells an d act ive in am m at ion . W h ich of th e follow ing drugs


m ost likely caused th e pat ien t’s syn drom e?

t im e?

A. Meben dazole

A. Pyran tel pam oate

B. Praziquan tel

B. Praziquan tel

C. Diethylcarbam azin e

C. Diethylcarbam azin e

D. Met ron idazole

D. Met ron idazole

E. Flu con azole

E. Flucon azole


22. A 34-year-old m an com plain ed to h is physician th at th e drug


h e w as taking caused n ausea, abdom in al pain , loose stools,

p ar t m en t w ith fever (102.2°F, 39°C), diarrh ea, p oor app et ite,

an d itch ing. Th ree days earlier, th e m an h ad been diagn osed

an d fat igu e over th e p ast 48 h ou rs. Histor y revealed th at

w ith Taenia solium in fect ion an d h ad st arted an app ropriate

2 w eeks earlier, th e w om an h ad been diagn osed w ith ascari-

th erapy. Th e p hysician told th e pat ien t th at h is sym ptom s

asis an d st ar ted an appropriate t reat m en t for 3 days. Th e

w ere com m on adverse e ect s of th e drug an d sh ou ld su b -

t reat m en t w as rep eated 4 days before adm ission . Physical

side in 1 or 2 days. W h ich of th e follow ing drugs m ost likely

exam in at ion sh ow ed a febrile pat ien t w ith an er yth em atous


rash over th e ch est an d t run k. Per t in en t blood exam resu lts

A. Diethylcarbam azin e

on adm ission w ere alan in e am in ot ran sferase 350 U/L (n or-

B. Iverm ect in

m al > 40 U/L), eosin oph ils 18%(n orm al > 3%). Tests for h epa-

C. Pyran tel pam oate

t it is A, B, an d C w ere n egat ive. Ult rasou n d of th e abdom en

D. Praziquan tel

w as n egat ive. Stools w ere n egat ive for ova an d p arasites. A

E. Met ron idazole

liver biopsy showed m ultiple gran ulom as w ith m ultinucleate

F.

Micon azole

Questions: VIII-9 Antineoplastic Drugs Directions for questions 1−4


Match each an t ican cer d r ug w it h t h e ap p rop r iate m olecu lar

4. In h ibit ion of a m ut ated t yrosin e kin ase presen t in cer tain

m ech an ism of act ion (each let tered opt ion can be selected on ce,

can cer cells

m ore th an on ce, or n ot at all). A. Asparagin ase


B. Carm ust in e

5. A 63-year-old w om an com plain ed to h er physician of in ter-

C. Etoposid e

m it ten t back pain th at w as w orse at n igh t . Histor y revealed

D. Fluorou racil

th at th e w om an h ad un dergon e a m odi ed radical m astec-

E. Hydroxyu rea

tom y 2 years earlier for in lt rat ing ductal carcin om a of th e

F.

Im at in ib

breast th at t u rn ed ou t to be HER-2 (h u m an epiderm al grow th

G. Meth ot rexate

factor receptor 2) posit ive. A com puted tom ography scan re-

H. Paclitaxel

vealed bon e m et ast ases, an d sh e w as sch eduled for h igh -dose

I.

Trast u zu m ab

com bination chem otherapy. W hich of the follow ing drugs w as

J.

Vin crist in e

m ost likely in cluded in h er t reat m en t regim en ? A. Clom iph en e


B. Leuprolide

1. Covalen t bin ding w ith n u cleop h ilic grou p s on DNA bases

C. Trast u zu m ab D. Flut am ide


E. Asparagin ase

2. In h ibit ion of ribon ucleot ide reduct ase

F.

Di cult y level: Easy 3. In h ibit ion of thym idylate syn th etase

Fin asteride

440



A. Cycloph osph am ide

6. A 15-year-old boy su ering from acu te lym ph oblast ic leuke-

B. Doxor ubicin

m ia received a con solidat ion an t ican cer th erapy th at in cluded

C. Predn ison e

h igh -d ose m et h ot rexate. Leu covor in w as also given after

D. Vin crist in e

m et h ot rexate. W h ich of th e follow in g con cept s sp eci cally

E. Rit u xim ab

u n derlies th is th erapeut ic st rategy? A. log kill B. Recru it m en t

Di cult y level: Medium 10. A 13-year-old boy w as adm it ted to th e h ospit al w ith a 10-

C. Pu lsing

day h istor y of fever, gen eral m alaise, dizzin ess, an d n ose-

D. Com bin ed m odalit y st rategy

bleed. He h ad a 1-w eek h istor y of an u pp er resp irator y t ract

E. Rescu e th erapy

in fect ion . A blood test revealed n orm och rom ic, n orm ocyt ic an em ia, an d a d i eren t ial w h ite blood cell cou n t sh ow ed

Di cult y level: Easy 7. A 52-year-old w om an recen t ly d iagn osed w it h m align an t glioblastom a received rad iat ion t h erapy follow ed by a cycle

11% lym p h oblasts. A bon e m arrow biop sy sh ow ed 95% lym p h oblast s. W h ich of th e follow ing p airs of d rugs w ould be m ost app ropriate for th e p at ien t at th is t im e?

of com bin at ion th erapy th at in clu ded carm u st in e. W h ich of

A. Cisplat in an d etoposide

the follow ing statem ents best explains w hy carm ustine is m ost

B. Flu t am ide an d goserelin

often used to t reat cen t ral n er vous system n eoplasm s?

C. Vin crist in e an d predn ison e

A. It in h ibits on ly n eu ron al t u m or cells. B. It can easily en ter th e brain . C. It h as n egligible n eurologic adverse e ect s. D. It is t aken u p in to n euron s by th e am in e pum p. E. It h as a ver y long h alf-life (10 days).

D. Tam oxifen an d an ast rozole E. Flu orou racil an d cisp lat in

Di cult y level: Easy 11. A 61-year-old m an w as foun d to h ave recurren t colon can cer. Th e p rim ar y t u m or w as rem oved 8 m on th s p reviou sly,

Di cult y level: Easy 8.

A 61-year-old w om an w ith advan ced Hodgkin lym ph om a began ch em ot h erapy w it h t h e ABVD (d oxor u bicin , bleo m ycin , vin blast in e, an d dacarbazin e) regim en . W h ich of th e follow ing m olecular act ion s m ost likely m ediated th e th erap eu t ic e ect of doxorubicin in th e pat ien t’s disease? A. It in tercalates bet w een DNA st ran ds an d in h ibits topoisom erase II. B. It p reve n t s m icrot u b u le d isasse m b ly in to t u b u lin m on om ers. C. It p reven t s assem bly of t u bu lin d im ers in to m icrot u bu les. D. It alkylates n ucleoph ilic grou ps on DNA bases. E. It blocks th e syn t h esis of bot h r ibon u cleot ides an d deoxyn u cleot ides.

at w h ich t im e adjuvan t ch em oth erapy w ith u orouracil an d carbop lat in w as begu n . Th e on cologist su sp ected th at th e can cer recu rren ce w as related to resistan ce to

u orou racil.

W h ich of th e follow ing m ech an ism s best explain s th e resist an ce to th is drug? A. Decreased abilit y to ph osph or ylate pyrim idin es B. Decreased act ivit y of th e cell e

u x pum p

C. In creased in t racellular con cen t rat ion of a reduced folate D. Decreased act ivit y of topoisom erase E. Decreased act ivit y of thym idylate syn th ase

Di cult y level: Easy 12. A 24-year-old m an w as adm it ted to th e h ospital because of abd om in al d iscom for t an d sh or t n ess of breat h . Th e m an w as d iagn osed w it h test icu lar can cer 16 m on t h earlier, for w h ich h e un der w en t a radical inguin al orch iectom y. An ab -

Di cult y level: Easy 9. A 47-year-old m an w it h n on -Hodgkin lym p h om a w as ad m it ted to t h e h osp it al to receive h is fou r t h cycle of CHOP (cyclophospham ide, doxorubicin, vincristin e, and prednison e) regim en plu s rit u xim ab. Physical exam in at ion revealed t achycard ia, sh or t n ess of breat h t h at w orsen ed soon after lyin g at , n eck vein disten t ion , pulm on ar y rales, an d an kle edem a.

d om in al com pu ted tom ography revealed a 10-cm m ass, an d a ch est rad iograph sh ow ed m u lt ip le n odu les in th e lu ng. Th e rst cou rse of a th ree-drug com bin at ion ch em oth erapy w as st ar ted . W h ich of th e follow in g d r ugs w as m ost likely in cluded in th e pat ien t’s com bin at ion ch em oth erapy? A. Carm ust in e B. Meth ot rexate


C. Cyt arabin e

verse e ects?

D. Cisplat in E. Mercaptop u rin e F.

Asparagin ase

Questions: VIII-9 Antineoplastic Drugs 441 Di cult y level: Easy


13. A 26-year-old m an com p lain ed of n u m bn ess in h is

ngers

17. A 55-year-old m an presen ted to h is physician w ith com -

an d t h e soles of h is feet . Th ree w eeks p reviou sly, h e h ad

p lain t s of sw ollen lym p h n od es, occasion al fevers, an d n igh t

st ar ted ch em ot h erapy for acu te lym p h oblast ic leu kem ia.

sw eat s. Th e biop sy of a su praclavicu lar lym p h n ode led to

Physical exam in at ion sh ow ed loss of an kle jerk an d depres-

th e diagn osis of d i u se B-cell lym p h om a. A st an dard th era-

sion of deep ten don re exes. W h ich of th e follow ing drugs

p eut ic regim en w as im plem en ted w ith cyclop h osph am ide,


d oxoru bicin , vin crist in e, an d predn ison e. W h ich of th e fol-

A. Vin crist in e

low ing m olecu lar act ion s m ost likely m ediated th e th era-

B. Predn ison e

p eut ic e ect of cyclop h osph am ide in th e pat ien t’s d isease?

C. Meth ot rexate

A. Form at ion of covalen t bon ds w ith DNA bases

D. Mercaptop u rin e

B. Preven t ion of DNA ch ain elongat ion

E. Doxor ubicin

C. In h ibit ion of thym idylate syn th ase D. Preven t ion of DNA resealing


E. In h ibit ion of m icrot ubule assem bly

14. A 44-year-old m an recen t ly d iagn osed w it h Hodgkin lym p h om a w as abou t to receive h is

rst MOPP (m ech loret h -


am in e, vin cr ist in e, p rocarbazin e an d p red n ison e) regim en .

18. A 59-year-old w om an recen tly diagn osed w ith stage IV ade-

W h ich of th e follow ing com pon en t s of th is regim en is given

n ocarcin om a of th e lung started th e rst cycle of an t ican cer

in t raven ously an d h as vesican t act ivit y th at m ay cau se t is-

ch em ot h erapy. Th e regim en in clu d ed a d r ug t h at bin d s to

su e n ecrosis an d slough ing in case of ext ravasat ion ?

t ubulin an d prevents m icrot ubule disassem bly. W hich of the

A. Predn ison e

follow ing drugs h as th is m ech an ism of act ion ?

B. Vin crist in e

A. Asparagin ase

C. Procarbazin e

B. Trast u zu m ab

D. Mech loreth am in e

C. Paclitaxel D. Meth ot rexate


E. Cyt arabin e

15. A 47-year-old w om an recen t ly d iagn osed w it h acu te m y-

F.

Hydroxyu rea

elogen ous leu kem ia st ar ted rem ission ch em oth erapy w ith dau n oru bicin an d cyt arabin e. W h ich of th e follow ing m olec-


u lar act ion s m ost likely m ediated th e th erapeut ic e ect of

19. A 53-year-old m an recen tly diagn osed w ith sm all cell lung

cyt arabin e in th e pat ien t’s disease?

can cer st arted ch em oth erapy w ith cisplat in an d etoposid e.

A. In h ibit ion of topoisom erase II

W h ich of t h e follow ing m olecu lar act ion s m ost likely m e-

B. In h ibit ion of DNA ch ain elongat ion

d iated t h e t h erap eu t ic e ect of etop osid e in t h e p at ien t ’s

C. In h ibit ion of aden osin e deam in ase

d isease?

D. In h ibit ion of m icrot ubule assem bly

A. In h ibit ion of dihydrofolate reduct ase

E. In h ibit ion of m icrot ubule disassem bly

B. In h ibit ion of thym idylate syn th ase C. Preven t ion of resealing of n icked st ran ds of DNA


D. Alkylat ion of n ucleoph ilic groups on RNA bases

16. A 4-year-old boy diagn osed w ith Wilm s t um or un der w en t

E. In h ibit ion of m icrot ubule disassem bly

su rger y, follow ed by 18 w eeks of vin crist in e an d dact in om ycin th erapy. W h ich of th e follow ing m olecular act ion s m ost likely m ediated th e th erap eu t ic e ect of dact in om ycin in th e p at ien t’s disease? A. Alkylat ion of n ucleoph ilic groups on RNA bases B. In h ibit ion of dihydrofolate reduct ase C. In h ibit ion of pyrim idin e biosyn th esis D. Bin ding to dou ble-st ran ded DNA E. In h ibit ion of free radical form at ion F.

In h ibit ion of t yrosin e kin ases

442



showed evidence of tum or involvem ent, adjuvant therapy was

20. A 60-year-old m an w as adm it ted to th e h ospital w ith fever

in it iated after su rger y. W h ich of th e follow ing dr ugs w ou ld

(100.1°F, 38.4°C), dyspn ea, an d n onproduct ive cough . Tw o

be m ost app ropriately in clu ded in th e th erap eu t ic regim en

w eeks earlier, th e pat ien t h ad com pleted ve cou rses of ch e-

of th is pat ien t?

m otherapy w ith cyclophospham ide, doxorubicin, vincristine,

A. Cyt arabin e

p redn ison e, an d bleom ycin for large-cell lym ph om a. Ch est

B. Flu darabin e

x-ray sh ow ed di u se bilateral in lt rates, an d a lung biopsy

C. Asparagin ase

revealed in am m at ion an d brosis w ith n o eviden ce of lym -

D. Hydroxyu rea

p h om a. Bacterial, fungal, an d viral cult ures w ere n egat ive.

E. Flu orou racil

W h ich of th e drugs adm in istered to th e pat ien t m ost likely cau sed h is p u lm on ar y disorder?



24. A 45-year-old m an recen tly diagn osed w ith sm all cell lung

B. Doxor ubicin

can cer st ar ted h is rst cou rse of com bin at ion ch em oth erapy

C. Vin crist in e

w ith cisplat in , topotecan , an d etoposide. W h ich of th e fol-

D. Predn ison e

low ing p erip h eral blood cells m ost likely decreased

E. Bleom ycin

th is p at ien t?

rst in

A. Lym ph ocytes


B. Platelet s

21. A 59-year-old w om an w ith in operable lung can cer h ad been

C. Mon ocytes

receiving com bin at ion ch em ot h erapy. Lab test s revealed

D. Gran ulocytes

t h e follow ing p lasm a levels: creat in in e 5.5 m g/d L (n orm al

E. Er yth rocytes

0.6−1.2 m g/d L), blood u rea n it rogen (BUN) 45 m g/d L (n orm al 7−18 m g/dL), Mg 2+ 0.2 m m ol/L (n orm al 1.5−2.0 m m ol/L).


W h ich of th e follow ing drugs m ost likely caused th ese lab

25. A 50-year-old w om an u n der w en t su rger y to rem ove an

resu lts?

ovarian carcin om a. Follow ing surger y, sh e st ar ted h er

A. Fluorou racil

course of com bin at ion ch em oth erapy in order to eradicate

B. Doxor ubicin

th e rem ain ing t u m or cells. W h ich of th e follow ing pairs of

C. Vin crist in e

drugs were m ost likely included in her com bination regim en?

D. Cisplat in

A. Mercaptop u rin e an d asp aragin ase

E. Paclitaxel

B. Meth ot rexate an d hydroxyu rea

rst

C. Cyt arabin e an d predn ison e


D. Meth ot rexate an d t am oxifen

22. A 6-year-old boy su ering from acu te lym ph oblast ic leu ke-

E. Cisplat in an d paclitaxel

m ia star ted com bin at ion m ain ten an ce th erapy. On e of th e adm in istered drugs is in act ive in it s paren t form an d m u st


be m et abolized by th e en zym e hypoxan th in e-gu an in e ph os-

26. A 10-year-old boy su er ing from acu te lym p h oblast ic leu -

p h or ibosyl t ran sferase in to a m on op h osp h ate n u cleot ide.

kem ia st ar ted m ain ten an ce th erapy th at in clu d ed h igh d ose

W h ich of th e follow ing drugs un dergoes th is act ivat ion ?

m et h ot rexate. Tw o w eeks later, a blood test w it h d i eren -

A. Meth ot rexate

t ial sh ow ed a w h ite blood cell cou n t of 1800/m m 3 (n orm al

B. Fluorou racil

4500−11,000/m m 3 ). Th e on cologist believed th e result w as

C. Cyt arabin e

related to an excessive d ose of m et h ot rexate an d ord ered

D. Asparagin ase

an an t idote agen t . W h ich of th e follow ing drugs w ou ld be

E. Doxor ubicin

appropriate for th e pat ien t at th is t im e?

F.

A. Vitam in B12

Mercaptop u rin e

B. Pyridoxin e


C. Folic acid

23. A 60-year-old m an un der w en t surger y to rem ove an aden o-

D. Vitam in B3

carcin om a of th e colon . Becau se th e region al lym p h n odes

E. Leu covorin

Questions: VIII-9 Antineoplastic Drugs 443 Di cult y level: Medium


27. A 49-year-old m an presen ted to th e clin ic w ith in creasing

31. A 6-year-old h ospit alized ch ild com plain ed of pain w h en

fat igue, an orexia, w eigh t loss an d w idespread ecchym oses. A

u rin at ing. A urin e sam ple w as clou dy an d red. Th e ch ild, di-

blood test revealed a w h ite blood cell cou n t of 70,000/m m 3

agn osed w ith n eu roblastom a, h ad begu n a ch em oth erapy

w ith 90% m yeloblasts, an d a bon e m arrow biopsy sh ow ed

p rogram 5 days earlier. W h ich of th e follow ing drugs m ost

blast cells th at m ad e u p abou t 40% of t h e n u cleated cells

likely cau sed th e p at ien t’s sym ptom s?

in t h e m ar row (n or m al < 5%). A d iagn osis w as m ade an d a

A. Paclitaxel

ph arm acoth erapy w as prescribed. W h ich of th e follow ing

B. Vin crist in e

d r ugs sh ou ld be in clu d ed in t h e in it ial t reat m en t of t h is

C. Topotecan

pat ien t?

D. Cisplat in

A. Cisplat in

E. Doxor ubicin

B. Paclitaxel

F.

Cycloph osph am ide

C. Bleom ycin D. Cyt arabin e


E. Fluorou racil

32. A 7-year-old girl w as seen by h er pediat rician because of a 1-w eek h istor y of u pp er resp irator y t ract in fect ion , in creas-


ing w eakn ess, an d bleed ing gu m s. Physical exam in at ion

28. A 32-year-old m an recen tly diagn osed w ith acute m yeloge-

revealed h ep atosplen om egaly. A blood test w ith di eren t ial

n ous leukem ia received st an dard rem ission ch em oth erapy

sh ow ed a w h ite blood cell cou n t of 65,000/m m 3 (n orm al

w ith dau n orubicin an d cyt arabin e. Drug dosage w as m axi-

4500−11,000/m m 3 ) w ith 43% lym ph oblast s. A bon e m arrow

m ized to a toxicit y lim it of a 2-log decrease in blood p late-

biop sy revealed 92% lym p h oblasts. A diagn osis w as m ade,

let s. W h ich of th e follow ing represen ts th e p ercen tage of

an d th e girl received a th erapy th at in cluded th e in t rath ecal

p latelets killed by th e drug regim en ?

adm in ist rat ion of a drug. W h ich of th e follow ing drugs w as

A. 99.9%

m ost likely injected in t rath ecally?

B. 99%

A. Meth ot rexate

C. 90%

B. Paclitaxel

D. 80%

C. Etoposid e

E. 70%

D. Bleom ycin E. Cisplat in


F.

Ch loram bucil

29. A 10-year-old h ospitalized boy com plain ed of t in n it us an d h earing loss. Th e boy h ad been diagn osed w ith n eu roblas-


tom a an d w as receiving h is rst cou rse of com bin at ion ch e-

33. A 36-year-old w om an recen t ly d iagn osed w it h Hodgkin

m oth erapy. W h ich of th e follow ing drugs m ost likely cau sed

lym phom a started her rst cycle of ABVD (doxorubicin , bleo-

th e p at ien t’s sym ptom s?

m ycin , vin blast in e, an d dacarbazin e) ch em oth erapy. W h ich


of th e follow ing m olecular act ion s m ost likely m ediated th e

B. Vin crist in e

th erap eu t ic e ect of bleom ycin in th e pat ien t’s disease?

C. Doxor ubicin

A. Form ation of free radicals that cause DNA fragm en tation

D. Dact in om ycin

B. In h ibit ion of t ubulin polym erizat ion

E. Cisplat in

C. In h ibit ion of thym idylate biosyn th esis D. DNA alkylat ion th at blocks DNA st ran d scission

Di cult y level: Medium 30. A 42-year-old m an w ith st age III Hodgkin lym ph om a received six courses of ch em oth erapy w ith th e ABVD (doxoru bicin , bleom ycin , vin blast in e, an d dacarbazin e) regim en . W h ich of th e drugs in th is regim en act s m ain ly in th e G2 ph ase of th e t u m or cell cycle? A. Doxor ubicin B. Bleom ycin C. Vin blast in e D. Dacarbazin e

E. In h ibit ion of tet rahydrofolate biosyn th esis

444



A. Vin crist in e

34. A 40-year-old w om an recen t ly d iagn osed w it h lym p h o-

B. Asparagin ase

blast ic T-cell lym p h om a received h er rst com bin at ion ch e-

C. Dau n oru bicin

m ot h erap eu t ic regim en t h at in clu d ed cyclop h osp h am id e,

D. Predn ison e

vin crist in e, doxoru bicin , an d predn ison e. From w h ich of th e

E. Meth ot rexate

follow ing adverse e ect s w as th e pat ien t m ost likely to suf-

F.

Cyt arabin e

fer during th e rst day of t reat m en t? A. Neu ropathy B. Hem orrh agic cyst it is

Di cult y level: Medium 38. A 69-year-old w om an d iagn osed w it h colon can cer st ar ted

C. Pu lm on ar y brosis

adju van t ch em ot h erapy w it h in t raven ou s

u orou racil fol-

D. Congest ive h eart failu re

low ing surger y to rem ove th e p rim ar y t um or. W h ich of th e

E. Nausea an d vom it ing

follow ing drugs w as m ost likely given con com itan tly w ith th e u orou racil to in crease it s cytotoxic act ivit y?


A. Folic acid

35. A 46-year-old w om an w h o h ad u n dergon e a rad ical m as-

B. Asparagin ase

tectom y for in lt rat ing duct al carcin om a star ted adjuvan t

C. Leu covorin

com bination therapy w ith the CMF (cyclophospham ide, m eth-

D. Trast u zu m ab

ot rexate, an d

E. Sargram ost im

u orouracil) regim en . W h ich of th e follow ing

w as the initial m olecular action that m ost likely m ediated the

F.

Tam oxifen

th erap eu t ic e ect of m eth ot rexate in th e pat ien t’s disease? A. In h ibit ion of purin e biosyn th esis B. In h ibit ion of DNA ch ain elongat ion

Di cult y level: Easy 39. A 62-year-old m an w ith test icu lar can cer w as un dergoing

C. In h ibit ion of single-st ran ded DNA resealing

h is rst cycle of com bin at ion ch em oth erapy (cisplat in , vin -

D. DNA fragm en tat ion th rough free radical form at ion

blast in e, an d n eom ycin ). Tw o years earlier, th e pat ien t h ad

E. In h ibit ion of m icrot ubule assem bly

su ered from m yocardial in farct ion . W h ich of th e follow ing p rocedu res sh ould be im p lem en ted to cou n teract th e m ost


com m on organ toxicit y of cisplat in ?

36. A 47-year-old m an presen ted to th e clin ic because of a

A. Adm in ist rat ion of leu covorin

1-week history of low -grade fever, anorexia, increasing w eak-

B. Vigorous hydrat ion an d furosem ide

n ess, an d w eigh t loss. A blood test sh ow ed a w h ite blood cell

C. Adm in ist rat ion of sargram ost im

cou n t of 90,000/m m 3 (n or m al 4500−11,000/m m 3 ) w it h

D. Sh ort th erapy cycles

90% n eu t rop h ils an d a p latelet cou n t of 500,000/m m 3 (n or-

E. Adm in ist rat ion of p redn ison e

m al 150,000−400,000/m m 3 ). Chrom osom al studies on a bone m arrow aspirate found the presence of the Philadelphia chro-


m osom e. A diagn osis w as m ade, an d a th erapy w as st arted.

40. A 5 year-old girl w as fou n d to h ave a lung n odu le during a

W h ich of th e follow ing drugs w ould be m ost appropriate to

sch ed u led follow -u p visit . Th e girl h ad u n dergon e su rger y

in clude in th e p at ien t’s th erapeu t ic regim en ?

for stage III Wilm s t u m or an d th en h ad been receiving a t ri-

A. Hydroxyu rea

p le th erapy w ith vin crist in e, doxoru bicin , an d dact in om ycin


for 10 w eeks. Th e on cologist con cluded th at th e t um or h ad

C. Oprelvekin

becom e m u lt idrug resistan t . W h ich of th e follow ing m ech a-

D. Etoposid e

n ism s m ost likely m ediated th e sim ultan eous resistan ce to

E. Asparagin ase

d oxoru bicin , vin crist in e, an d dact in om ycin in th is pat ien t?

F.

A. Decreased act ivit y of DNA repairing path w ays

Fluorou racil

B. Decreased sen sit ivit y of a target en zym e


C. Decreased cellular upt ake of th e drug

37. An 8-year-old girl recen tly diagn osed w ith acute lym ph o-

D. Loss of en zym es n eeded for drug act ivat ion

blast ic leu kem ia st ar ted h er rst cycle of rem ission ch em o-

E. En h an ced act ivit y of an out w ard t ran spor t system

therapy. The antineoplastic regim en included a drug that acts by deplet ing th e body of an am in o acid th at can be syn th e-


sized by n or m al cells bu t n ot by n eop last ic cells. W h ich of

41. A 53-year-old w om an recen tly diagn osed w ith ovarian can -

th e follow ing drugs h as th is m ech an ism of act ion ?

cer st ar ted h er rst cycle of com bin at ion ch em oth erapy w ith

Questions: VIII-9 Antineoplastic Drugs 445 paclitaxel, cisp lat in , an d cycloph osp h am ide. W h ich of th e


follow ing drugs sh ould also be adm in istered to coun teract a

45. An 8-year-old girl su er ing from acu te lym p h oblast ic leu -

speci c adverse e ect of cycloph osp h am ide?

kem ia com pleted h er rem ission ch em oth erapy w ith a m u lt i-

A. Er yth ropoiet in

d r ug regim en an d st ar ted m ain ten an ce t h erapy w it h a

B. Leucovorin

regim en th at in cluded a cell cycle−speci c an t ican cer drug

C. Mercaptoeth an e su lfon ate

adm in istered daily, for 7 days ever y 4 w eeks. W h ich of th e

D. Acet ylcystein e

follow ing drugs did th e pat ien t m ost likely take for m ain te-

E. Vitam in K

n an ce th erapy? A. Dau n oru bicin


B. Doxor ubicin

42. A 65-year-old m an presen ted to h is fam ily physician w ith

C. Mercaptop u rin e

a p ersisten t cough . A rou t in e com plete blood cou n t sh ow ed

D. Cisplat in

th e follow ing: h em oglobin 9 g/dL (n orm al, m ale 13.5−17.5

E. Carm ust in e

g/d L), w h ite blood cell cou n t 40,000/m m 3 (n or m al 4500− 10,500/m m 3 ) w it h 85% lym p h ocytes (n or m al 25−33%),


platelet count 90,000/m m 3 (n orm al 150,000−400,000/m m 3 ).

46. A 7-year-old boy recen t ly d iagn osed w it h W ilm s t u m or

Bon e m arrow exam in at ion revealed n orm al cellu larit y w ith

star ted a com bin at ion an t ican cer th erapy th at in clu ded vin -

45% of n u cleated cells lym ph ocytes. A diagn osis of leu kem ia

crist in e. In h ibit ion of w h ich of th e follow ing fu n ct ion s in

w as con rm ed . W h ich of th e follow ing an t ican cer drug reg-

can cer cells m ost likely m ediated th e th erap eu t ic e ect of

im en s w ou ld be m ost ap prop riate for th is pat ien t?

th e drug in th e p at ien t’s disease?

A. Etoposid e an d asparagin ase

A. Tu bu lin p olym erizat ion

B. Vin crist in e an d cisplat in

B. Resealing of single-st ran ded DNA

C. Hydroxyu rea an d top otecan

C. Resealing of double-st ran ded DNA

D. Meth ot rexate an d p aclitaxel

D. Pu rin e biosyn th esis

E. Ch loram bucil an d predn ison e

E. RNA biosyn th esis



43. A 54-year-old m an recen tly diagn osed w ith in operable lung

47. A 53-year-old w om an recen tly diagn osed w ith ovarian can -

can cer st ar ted in du ct ion ch em oth erapy th at in clu d ed a d rug

cer st arted a t reat m en t th at in cluded paclitaxel. Th e pat ien t

th at act s by form ing both in ter- an d in t rast ran d cross-lin ks

w as m ost likely at in creased risk of w h ich of th e follow ing

in th e DNA m olecule. W h ich of th e follow ing drugs w as m ost

adverse e ects as a resu lt of h er th erapy?

likely given ?

A. Kidn ey failure

A. Paclitaxel

B. Liver failure

B. Etoposid e

C. Periph eral n europathy

C. Vin crist in e

D. Urin ar y t ract in fect ion

D. Cisplat in

E. Tu bercu losis

E. Fluorou racil


48. A 56-year-old w om an w ith a long h istor y of h eavy sm oking

44. A 35-year-old m an diagn osed w ith m align an t test icular ter-

p resen ted w ith cough , fever, ch est pain , an d bloody sp u t u m .

atom a w as h ospitalized to receive h is fou rth cycle of th e BEP

A ch est x-ray revealed a 3.5-cm (1.4-in .) h ilar m ass, an d a

(bleom ycin , etoposide, an d cisplat in ) regim en . Th e pat ien t

t ran sbron ch ial biopsy sh ow ed in lt rat ing grou ps of an ap las-

w as m ost likely at in creased risk of w h ich of th e follow ing

t ic sm all cells w ith hyperch rom at ic n u clei an d n o n u cleoli.

adverse e ects as a resu lt of h is th erapy?

W h ich of th e follow ing drugs w as m ost likely appropriately

A. Ch ron ic m yelogen ous leukem ia

in clu ded in th e th erapeut ic regim en of th is pat ien t?

B. Syndrom e of inappropriate antidiuretic horm one (SIADH)

A. Ison iazid

secret ion

B. Ceftazidim e

C. Polym orph ic ven t ricular tachycardia

C. St reptom ycin

D. Pu lm on ar y em bolism

D. Asparagin ase

E. Pn eum on it is leading to lung brosis

E. Cyt arabin e F.

Etoposid e


446



49. A 56-year-old m an recen tly h ad a rout in e blood test during

50. A 10-year-old girl recen t ly d iagn osed w it h acu te lym p h o -

h is an n ual ch eckup. Th e test sh ow ed a w h ite blood cell coun t

blast ic leu kem ia received h er rst cycle of in du ct ion ch em o-

of 42,000/m m 3 (n orm al 4500−11,000/m m 3 ). Th e on ly per t i-

th erapy, w h ich in clu ded asparagin ase. Risk of w h ich of th e

n en t physical n ding w as splen om egaly. A bon e m arrow as-

follow ing adverse e ect s w as m ost likely in creased because

pirate revealed hypercellu lar m arrow w ith 15% blast s, an d

of th e adm in ist rat ion of th is drug?

cytogen et ic an alysis fou n d th e presen ce of th e Ph iladelp h ia

A. Myelosu p pression

ch rom osom e. A d iagn osis w as m ad e, an d a t h erapy w as

B. Ren al failu re

star ted. W h ich of th e follow ing drugs w ou ld be m ost ap pro-

C. Hyp oglycem ia

priate to in clu de in th e pat ien t’s th erap eu t ic regim en ?

D. Hear t failu re

A. Meth ot rexate

E. Hyp ersen sit ivit y react ion s

B. Trast u zu m ab C. Bleom ycin D. Etoposid e E. Asparagin ase F.

Im at in ib

Answers and Explanations: VIII-1 Bacterial Cell Wall Synthesis Inhibitors Questions 1−4

D Am in oglycosides are excreted alm ost en t irely by glom eru lar lt rat ion on ly.

1. H

E Ren al excret ion of tet racyclin es occurs by glom erular l-

2. J

t rat ion an d t u bu lar reabsorpt ion .

3. F 4. B

Learning objective: Explain the m echanism of action of β-lactam antibiotics. 5. C Cep h alosp orin s are β-lact am an t ibiot ics. Th e m ech an ism

Learning objective: Identify the drug contraindicated in a patient with previous allergic reaction to β-lactam drugs. 7. C Th e sign s of th e pat ien t an d th e lab result s st rongly suggest th e diagn osis of gon orrh ea. Ceft riaxon e w ould be th e

rst-

of act ion of all β-lact am an t ibiot ics involves th e in h ibit ion of

lin e agen t for gon orrh ea, bu t a p reviou s an aphylact ic react ion

t ran spept idase, th e en zym e th at cat alyzes th e

to pen icillin con t rain dicates th e use of m ost β-lact am drugs.

n al con n ec-

t ion (cross-lin k) of t w o am in o sugar ch ain s by pept id e bridges. In th is w ay, th e syn th esis of p ept idoglycan s is in h ibited. A, B, D, E See correct an sw er exp lan at ion .

A, B, D, E All of t h ese an t ibiot ics are e ect ive again st Neisseria gonorrhoeae; th ey are n ot

rst-lin e agen ts, but n on e of

th em are con t rain dicated in th is case.

Learning objective: Describe the renal elim ination of cephalosporins.

Learning objective: Identify the drug used to treat Neisseria meningitidis.

6. A Most com m u n it y-acqu ired u rin ar y t ract in fect ion s are du e

8. B Th e pat ien t’s sym ptom s an d lab resu lt s in dicate th at sh e

to Escherichia coli. First-, second-, and third-generation cephalo-

w as m ost likely su ering from m en ingit is d u e to N. m eningit-

sporin , u oroqu in olon es, an d t rim eth oprim -su lfam etoxazole

idis. In th is disease, th e p referred t reat m en t s are p en icillin G

are rst-lin e agen ts for th ese in fect ion s. Most ceph alosporin s

(4 m illion u n it s in t raven ou sly ever y 4 h ou rs) an d a t h ird -

are elim in ated by th e kidn ey, m ain ly by act ive secret ion in th e

gen erat ion cep h alosp orin (m ain ly ceft riaxon e).

proxim al t u bu le (t w o n ot able except ion s are ceft riaxon e an d

A, C Alt h ough N. m eningit idis is sen sit ive to t h ese an t ibi-

cefoperazon e, w h ich are excreted m ain ly th rough th e biliar y

ot ics, a bactericidal drug m u st be given in serious in fect ious

t ract). In m ost cases, con cen t rat ion s in u rin e are h igh er th an

diseases.

th ose in plasm a. B Macrolides are m ain ly elim in ated by biliar y excret ion . C Met ron idazole is m ain ly elim in ated by liver m et abolism .

D, E Th ese an t ibiot ics are m ain ly act ive again st gram n egat ive bacilli. F N. m eningit idis is n ot sen sit ive to m et ron idazole.

Answers and Explanations: VIII-1 Bacterial Cell Wall Synthesis Inhibitors 447 Learning objective: Identify the antibiotic given to prevent infections due to Streptococcus agalactiae.

long m in im u m bactericidal con cen t rat ion (m ost β-lact am

9. E Beta-lactam an t ibiot ics are drugs of ch oice for st reptococ-

A−C Th ese an t ibiot ics are n ot e ect ive again st gram -

cal in fect ion s. S. agalact iae is a grou p B st reptococcu s sen sit ive to pen icillin s. Pen icillin G or am picillin is used w ith

an t ibiot ics exh ibit t im e-depen den t killing). n egat ive bacteria. E Met ron idazole is n ot e ect ive again st H. ducreyi.

excellen t results for an t im icrobial prophylaxis again st group A−C St reptococci m ay be sen sit ive to quin olon es, sulfon -

Learning objective: Identify the t wo antibiotics used to treat streptococcal septic shock syndrom e.

am ides, an d tet racyclin es, but th ese an t ibiot ics are n ot rec-

12. A In addit ion to being am ong th e m ost com m on of all h u m an

om m en d ed in ch ild ren an d n ew bor n s becau se of several

p ath ogen s, group A st reptococci h ave em erged in recen t

poten t ial adverse e ect s.

years as im p or tan t cau ses of life-th reaten ing invasive an d

B st reptococci.

D W h en given alon e, am in oglycoside an t ibiot ics are n ot e ect ive again st st reptococci.

su p p u rat ive in fect ion s. Th is pat ien t likely h ad st reptococcal sept ic sh ock syn d rom e, w h ich is an esp ecially let h al st rep tococcal disease. In 60% of pat ien t s w ith th is syn drom e, th e

Learning objective: Identify the bacterium still sensitive to penicillin G.

organ ism is con t racted t h rough t h e skin or t h e gen it al m u -

10. D Th e pat ien t w as m ost likely su ering from st reptococcal

adu lts. Pyrogen ic exotoxin s are th ough t to play a cr u cial role

p h ar yngit is, th e m ost com m on disease cau sed by St reptococ-

in th e path ogen esis. St reptococcal sept ic sh ock syn drom e

cus pyogenes, a grou p A β-h em olyt ic st reptococcu s. Grou p A

follow s a fulm in an t clin ical course w ith a m or talit y rate of

st reptococci are st ill exqu isitely sen sit ive to p en icillin G.

50%. Th e p rin cip les of m an agem en t in clu de aggressive re-

Pen icillin th erapy of st reptococcal ph ar yngit is reduces th e

su scit at ion , p rom pt su rgical exp lorat ion an d d ébr id em en t

risk of su bsequ en t acu te rh eu m at ic fever. How ever, cu rren t

of soft t issu e in fect ion s, an d an t ibiot ic th erapy. Pen icillin -

eviden ce suggest s th at th e in ciden ce of glom erulon eph rit is

resistan t isolates h ave yet to be obser ved for group A st rep -

th at follow s st reptococcal in fect ion s is n ot redu ced to a sig-

tococci, so pen icillin G rem ain s an agen t of ch oice. Pat ien ts

n i can t degree by t reat m en t w ith pen icillin .

m ay fail to ach ieve opt im al resp on se to p en icillin G becau se

A−C, E−G All of th ese bacteria are n ow resistan t to pen icillin G.

cosa. Pat ien t s are u su ally ot h er w ise h ealt hy ch ild ren or

large con cen t rat ion s of bacteria in th e lesion reach a st at ion ar y grow th p h ase (in th e absen ce of cell division , p en icillin can n ot h ave a bactericidal e ect). Clin dam ycin h as m u lt ip le

Learning objective: Identify the drug used to treat chancroid. 11. D Th e h istor y of th e pat ien t an d th e site of th e u lcer suggest a sexu ally t ran sm it ted disease. Am ong th ese diseases, th ose characterized by ulcer on the penis include chancroid (caused by Haem ophilus ducreyi), lym phogranulom a venereum (caused by Chlam ydia t rachom at is), gran ulom a inguin ale (caused by Donovania granulom at is), syp h ilis (cau sed by Treponem a pallidum ), an d gen it al h er p es (cau sed by h er p es sim p lex viru s). Th e p resen ce of gram -n egat ive bacilli exclu d es viral in fect ion s su ch as gen it al h erpes, as w ell as ch lam ydia an d don ovan ia in fect ion s (ch lam ydia an d don ovan ia are in t racellu lar bacteria). Syp h ilis is u n likely becau se of th e n egat ive dark eld m icroscopy an d FTA-ABS ( u orescen t t rep on em al an t ibody absor pt ion ) test . Th erefore, t h e p at ien t ’s d isease is m ost likely cau sed by H. ducreyi, a gram -n egat ive bacter iu m th at is sen sit ive to secon d- an d th ird-gen erat ion ceph alosporin s, t rim eth oprim -sulfam etoxazole, quin olon es, an d tet racyclin es. Ceft riaxon e is m ost often used because it h as a long h alf-life (abou t 7 h ou rs) an d th erefore can p rovide a

e ect s again st grou p A st reptococcal in fect ion s. It s e

cacy

is not a ected by in oculum size or grow th stage; it is a potent su p p ressor of bacterial toxin syn th esis, facilitates p h agocytosis of St reptococcus pyogenes by in h ibit ing protein syn th esis, and suppresses the synthesis of penicillin-binding proteins, w h ich are en zym es involved in cell w all syn th esis. Th erefore, m ost clin ician s recom m en d com bin ed th erapy w ith p en icillin an d clin dam ycin . B Tobram ycin an d m et ron idazole are n ot e ect ive again st gram -posit ive bacteria. C Ch loram p h en icol an d tet racyclin e are bacter iost at ic agen t s, an d m ost st rain s of st reptococci are n ow resist an t to th ese drugs. D Er yt h rom ycin is e ect ive again st st reptococci bu t is a bacteriost at ic dr ug, an d am ikacin is e ect ive m ain ly again st gram -n egat ive bacteria. E Pip eracillin an d azt reon am are β-lact am an t ibiot ics m ain ly e ect ive again st gram -n egat ive bacteria.

448


Learning objective: Outline the therapy for infective endocarditis most likely due to viridans streptococci.

Learning objective: Explain the m echanism of action of β-lactam antibiotics.

13. D Th e p at ien t ’s h istor y an d clin ical p resen t at ion suggest

15. C Th e ap p earan ce of th e lesion (crep it at ion , bron ze discolor-

t h at th e m an is su ering from in fect ive en docardit is. He ap -

at ion ) in dicates th at th e p at ien t w as m ost likely su ering

p ears ch ron ically ill an d rep resen t s th e t ypical p at ien t w ith

from gas gangren e (m yon ecrosis). Th e disease can be cau sed

su bacu te disease. He h as m it ral valve p rolap se, w h ich is th e

by m any bacteria, in cluding bacteroides, en terobacteriaceae,

p red om in an t d efect in in fect ive en d ocard it is, an d h e also

streptococci, and staphylococci, but the m ost frequen t patho-

exh ibit s several perip h eral m an ifest at ion of in fect ive en do-

gen is Clost ridium perfrigens. Pen icillin G, in h igh doses, is

cardit is, in clu ding h em orrh ages in th e h an d s an d feet . Th e

st ill th e drug of ch oice for C. perfrigens in fect ion . Th e m ech -

gram -posit ive bacteria m ost com m on ly involved in in fect ive

an ism of act ion of β-lactam an t ibiot ics involves th e in h ibi-

endocarditis are streptococci and staphylococci. Streptococci

t ion of t ran spept idase, th e en zym e th at catalyzes th e

of th e viridan s group are th e prin cipal cau se of en docardit is

cross-lin k step in th e syn th esis of p ept idoglycan .

in an abn orm al h ear t valve (w h ich is presen t in th is case),

n al

A, B, D, E Th ese en zym es are n ot in h ibited by pen icillin s.

and they reach the bloodstream t ypically after dental traum a. Th e tem p oral relat ion sh ip bet w een th e den t al p rocedu re

Learning objective: Identify the drug used to treat actinomycosis.

an d th e on set of sym ptom s m akes it th e m ost obviou s cau se

16. A Th e pat ien t’s h istor y (a lesion after a local t raum a), th e site

of th e disease. Most viridan s st reptococci are sen sit ive to

an d t yp e of lesion , an d th e ap pearan ce of th e biop sy m aterial

penicillin s an d ceph alosporins. Single-drug regim ens include

suggest t h at t h e p at ien t w as su er ing from act in om ycosis.

h igh -dose pen icillin G or ceft riaxon e for 2 to 4 w eeks. W h en

Th e d isease is a ch ron ic, su p p u rat ive, an d gran u lom atou s

em p irical th erapy is n eeded, th e gu idelin es suggest h igh -

in fect ion caused m ost often by Act inom yces israelii. Th e bac-

d ose pen icillin G plus an am in oglycoside, as in th is case. Th is

terium is sensitive to penicillins, cephalosporins, m acrolides,

is a syn ergist ic com bin at ion t h at can ach ieve bacter icidal

tet racyclin es, an d sulfon am ide-t rim eth oprim . Pen icillin G

act ivit y again st resist an t st reptococcal sp ecies.

rem ain s th e t reat m en t of ch oice.

A, B Th ese are com bin at ion s of a bacter icidal p lu s a bacteriost at ic an t ibiot ic. In gen eral, th ese com bin at ion s sh ou ld

B−E Non e of t h e ot h er listed d r ugs are e ect ive in act in om ycosis.

be avoided (w ith few except ion s), as an an t agon ist ic in teract ion can occu r in m any cases. C Th ese an t ibiot ics are m ain ly e ect ive again st gram n egat ive bacteria. E Dicloxacillin is e ect ive again st m ut an t st reptococci, but m any st rain s of st reptococci are n ow resist an t to

u oro -

qu in olon es, an d th ere is n o syn ergism bet w een pen icillin s an d u oroqu in olon es.

Learning objective: Identify the antibiotic used to treat acute supraglot titis. 14. C Acute su p raglot t it is can occu r at any t im e in life, bu t it s

Learning objective: Identify the antibiotic used for surgical prophylaxis in high-risk patients. 17. E Becau se su rgical w ou n d in fect ion s are m ajor n osocom ial in fect ion s, an t im icrobial p rop hyla xis is advisable in op en h ear t su rger y, su rger y for p lacem en t of prosth et ic m aterials, any su rgeries perform ed on an im m u n ocom p rom ised h ost , h igh -risk patients in preparation for con tam inated and clean con t am in ated su rgical p rocedu res, an d orth op edic su rger y, as in th is case. Th e goal of an t im icrobial p rop hylaxis is to d ecrease bacterial coun ts below th e crit ical level n ecessar y to cau se in fect ion . Cefazolin is t h e d r ug m ost frequ en t ly

in ciden ce is h igh est in ch ildren ages 2 to 5 years. Most p a-

u sed for su rgical p rop hyla xis w h en skin

t ien t s are febrile, m any h ave cer vical lym p h n od e en large-

of con t am in at ion becau se of it s excellen t act ivit y again st

m en t , an d occasion ally cellu lit is ap p ears over th e an terior

stap hylococci.

n eck. Acute supraglot t it is can be fulm in an t in on set an d, if su spected clin ically, m u st alw ays be con sidered an em er-

ora is t h e sou rce

A Met ron idazole is n ot u sed for surgical prophylaxis, as it is act ive on ly again st an aerobic m icroorgan ism s.

gen cy, as sudden, com plete airw ay obstruction is im pending.

B, C, F Bacteriost at ic agen t s are n ot used for m icrobial pro-

Th e d isease is alm ost alw ays du e to Haem ophilus in uenzae

p hylaxis becau se bacterem ia can reoccu r w h en th e drug is

t ype b. A th ird-gen erat ion ceph alosporin (ceft riaxon e) an d

n o longer presen t .

am picillin -su lbact am are th e an t ibiot ics of ch oice. A, B, D, E H. in uenzae is n ot sen sit ive to any of th e oth er listed an t ibiot ics.

D Azt reon am is act ive on ly again st gram -n egat ive bacteria an d t h erefore is n ot su it able to p reven t in fect ion d u e to stap hylococci.

Answers and Explanations: VIII-1 Bacterial Cell Wall Synthesis Inhibitors 449 Learning objective: Identify the drug used to treat cellulitis. 18. C Th e p at ien t w as m ost likely su ering from cellu lit is. Acu te

Learning objective: Identify the antibiotic m ost likely responsible for tubulointerstitial nephritis in a patient treated for syphilis.

bacterial infection of the skin and subcutaneous tissue is m ost

21. A Th e sign s an d sym ptom s of th e p at ien t (th e skin rash an d

often caused by st reptococci or staphylococci. For m ost pa-

eosin oph ilu ria) suggest th at th e t u bu loin terst it ial n eph rit is

t ien t s, em p iric t reat m en t e ect ive again st both bacteria is

is du e to d rug allergy. Pen icillin is th e drug of ch oice for p ri-

adequate. Because m ost staphylococcal isolates produce pen-

m ar y syp h ilis, so it is th e m ost likely o en ding dr ug.

icillin ase, the best initial treatm ent is a β-lactam ase-resistant

B−E Allergic t ubuloin terst it ial n eph rit is can occur w ith all

p en icillin , such as dicloxacillin , or a th ird-gen erat ion ceph a-

of th e dr ugs listed, but th ese drugs are n ot cu rren tly used to

losporin , or a carbap en em .

t reat p rim ar y syph ilis.

A, B, E Th ese d r ugs are m ain ly e ect ive again st gram n egat ive bacteria. D Most gram -p osit ive cocci are n ow resist an t to tet racyclin es.

Learning objective: Describe the m echanism s of bacterial resistance to β-lactam drugs. 22. C Resist an ce to β-lact am an t ibiot ics is du e to fou r m ain m ech an ism s:

Learning objective: identify the β-lactam antibiotic that is resistant to most β-lactamases.

• Prod u ct ion of β-lact am ase en zym es (by far t h e m ost

19. E Cefepim e is a fourth -generation ceph alosporin. The drugs of

β-lact am ring, th u s produ cing p en icilloic acids th at are

this class are resistant to m ost plasm id- and chrom osom ally m ediated β-lactam ases. In general, resistance to β-lactam ases in creases from

rst- to fourth -gen erat ion ceph alosporin s.

A, F Th ese drugs are rst-gen erat ion cep h alosp orin s w ith a lim ited resist an ce to β-lact am ases. B−D Th ese pen icillin s are β-lactam ase sen sit ive.

im p or t an t m ech an ism ). Bet a-lact am ases hyd rolyze t h e devoid of an t ibacterial act ivit y. • Develop m en t of p en icillin -bin d ing p rotein s t h at h ave d ecreased a

n it y for th e an t ibiot ic (th e m ech an ism for

pen icillin resist an ce in p n eu m ococci) • Decreased perm eabilit y of th e cell m em bran e to th e drug (t h e m ech an ism for resist an ce in m any gram -n egat ive bacteria)

Learning objective: Describe the adverse e ects to β-lactam drugs. 20. B Acute ph ar yngit is is predom in an tly a viral in fect ion but is also often cau sed by grou p A β-h em olyt ic st reptococci. Becau se th e p at ien t w as diagn osed w ith bacterial p h ar yngit is, h e w as m ost likely t reated w it h a p en icillin . Allergic react ion s are t h e m ost frequ en t adverse e ect s of p en icillin s.

• Developm en t of an act ive e

u x pu m p (th e m ech an ism

for resist an ce in som e gram -n egat ive bacteria) A, D, E Th ese m ech an ism s w ou ld in crease, n ot decrease, th e sen sit ivit y of bacteria to β-lact am an t ibiot ics. B Th is is a m ech an ism of resist an ce to an t ibiot ics th at in h ibit p rotein syn th esis.

Th ey occu r in u p to 10% of p at ien t s p reviou sly exp osed to th e drug. Pat ien ts su ering from in fect iou s m on on u cleosis, fu ngu s in fect ion , leu kem ia, an d lym p h om a are esp ecially at risk, as in th is case. Alth ough allergic react ion s can be cau sed by t h e in t act d r ug m olecu le, m ost an t igen ic d eter m in an t s of p en icillin hyp ersen sit ivit y are breakd ow n p rodu ct s. Both th e in t act m olecu le an d th e breakdow n p rodu cts act as h ap ten s after th eir covalen t react ion w ith protein s. Th e m ajor an t igen ic determ in an t is th e pen icilloyl m oiet y, w h ich is form ed w h en th e β-lactam ring is open ed. W h en an allergic react ion occurs during th e cou rse of th e th erapy, th e dr ug sh ou ld be d iscon t in u ed (if a valid altern at ive drug is available), becau se th ere is a ch an ce, alth ough sm all, th at th e react ion cou ld w orsen . A, C−E All of th ese an t ibiot ics can cau se allergic react ion s, bu t th ey are n ot cu rren tly u sed to t reat acu te p h ar yngit is.

Learning objective: Identify the drug that poses the highest risk of antibiotic-associated colitis. 23. E Th e pat ien t m ost likely developed an t ibiot ic-associated p seu dom em bran ou s colit is (AAPC) du e to Clost ridium di cile. Th e disease h as em erged as a m ajor th reat to eld erly pat ien ts. Am picillin , clin dam ycin , cep h alosp orin s, an d

u o-

roqu in olon es are t h e m ost com m on an t ibiot ics associated w it h t h e con dit ion . Ot h er cau sat ive agen t s are p en icillin s, er yt h rom ycin , t r im et h op r im -su lfam et h oxazole, an d tet racyclin es. Am p icillin w as m ost likely given to t h e p at ien t to cu re ton sillit is an d th erefore w as th e m ost p lau sible o en ding agen t . A−D All of th ese an t ibiot ics ver y rarely cause AAPC, an d th ey are n ot used to t reat st reptococcal ton sillit is.

450


Learning objective: Identify the antibiotic used to treat urinary tract infection due to Escherichia coli.

E Th e ver y h igh MIC of piperacillin in dicates th at th e Pseudom onas st rain of th is p at ien t is resistan t to th e drug.

24. D Th e lab test s suggest t h at t h e p at ien t ’s u r in ar y t ract in th at accou n t s for abou t 80%of u rin ar y t ract in fect ion s. E. coli

Learning objective: Describe the st aphylococcal resistance to β-lactam antibiotics.

is sen sit ive to ceph alosporin s, broad-spect rum pen icillin s,

26. B Staphylococcus aureus is th e m ost com m on causative patho-

am in oglycosid es, t r im et h op r im -su lfam etoxazole, tet racy-

gen of m astitis. Methicillin-resistant staphylococci are resis-

clin es, an d

tan t th rough acqu isit ion (via t ran sp oson ) of pen icillin -bin d ing

fect ion w as m ost likely d u e to E. coli, a gram -n egat ive rod

u oroqu in olon es. How ever, several st rain s are

n ow resist an t to broad -sp ect r u m p en icillin s, tet racyclin es, an d t r im et h op r im -su lfam etoxazole. Cep h alosp or in s an d u oroqu in olon es rem ain rst-lin e agen ts. A−C, E All of t h ese d r ugs are e ect ive m ain ly again st gram -posit ive bacteria.

protein s w ith a ver y low a

n it y for all β-lactam an t ibiot ics.

A, D, F Th ese bacteria are sen sit ive to m ost p en icillin s. C, E, G These bacteria are sensitive to broad-spectrum pen icillins, im ipenem , and aztreon am , as well as to som e th irdan d four th -gen erat ion ceph alosporin s.

Learning objective: Identify the t wo antibiotics used to treat valve endocarditis after susceptibilit y testing.

Learning objective: Identify the antibiotic used to treat staphylococcal infections.

25. B Th e clin ical pict u re suggests th at th e p at ien t h ad a valve

27. D The appearance of gram -positive cocci arranged in clusters

en docardit is. En docardit is occu rring in inject ion drug u sers,

suggest s th at th e cau sat ive agen t is st ap hylococcal. Staphylo-

especially w h en in fect ion involves th e t ricuspid valve, is

coccus aureus is th e m ost com m on p ath ogen of st aphylococ-

com m on ly cau sed by Staphylococcus aureus st rain s, m any

cal resp irator y t ract disease. Becau se abou t 90% of S. aureus

of w h ich are m eth icillin -resist an t , bu t th e resu lts of su scep -

isolates produce p en icillin ase, th e best in it ial t reat m en t is a

t ibilit y test ing in dicated th at Pseudom onas aeruginosa w as

β-lact am ase-resistan t p en icillin .

th e cau se of valve en docardit is in th is p at ien t . Th ere is su b -

A−C, E All of th ese pen icillin s are β-lact am ase-sen sit ive.

stan t ial evid en ce th at a β-lact am an d an am in oglycosid e an by a n um ber of bacteria, in cluding P. aeruginosa. It app ears

Learning objective: Outline the therapeutic uses of ampicillin plus tobramycin in urinary tract infection due to Enterococcus faecalis.

t h at β-lact am d r ugs t h at are cell w all act ive in crease t h e

28. D Th e w om an m ost likely h ad a u rin ar y t ract in fect ion . Esch-

act ive t ran sp or t of am in oglycosid es in to m any bacter ia, in -

erichia coli is st ill th e predom in an t p ath ogen in n osocom ial

clu d in g st ap hylococci, en terococci, an d P. aeruginosa. In

acquired urin ar y t ract in fect ion s, but oth er path ogen s are

ch oosing th e righ t an t ibiot ic com bin at ion , th e results of sus-

in creasingly involved, in clu ding Enterococcus faecalis. Broad-

cept ibilit y test ing m ust be t aken in to accou n t . Th eoret ically,

spect ru m pen icillin s, as w ell as van com ycin an d teicop lan in ,

all of th e tested drugs can be e ect ive again st P. aeruginosa.

are act ive again st th is bacteriu m . How ever, m on oth erapy

Never th eless, th e com bin at ion of ceft azidim e an d tobram y-

in h ibit s bu t does n ot kill th e en terococci. Th erefore, an am i-

cin or im ip en em an d tobram ycin (n ot listed) ap p ears to be

n oglycoside is alw ays given togeth er w ith th e rst drug.

t ibiot ic exert a syn ergist ic e ect in seriou s in fect ion s cau sed

th e best in th is case (see below ). A Alt h ough both tobram ycin an d gen t am icin are act ive again st P. aeruginosa, a β-lact am p lu s an am in oglycosid e m u st be given to p rovide in vivo syn ergy an d p reven t resis-

A, B No ceph alosp orin s are act ive again st en terococci. C Most en terococcal st rain s are n ow resistan t to pen icillin . Macrolides are n ot act ive again st en terococci. E Aztreonam is active only against gram -negative bacteria.

t an t subpopulat ion s from em erging du ring th erapy. C Because both im ipen em an d gen t am icin are e ect ive again st P. aeruginosa, th e com bin at ion cou ld seem ap p rop riate. Alth ough th e sen sit ivit y of gen t am icin is less th an th at of tobram ycin , th is could be overcom e by in creasing th e gen tam icin dose. How ever, am in oglycoside an t ibiot ics h ave sign i can t dose-dep en den t toxicit y, an d a m in im um in h ibitor y con cen t rat ion (MIC) h igh er t h an 3 to 4 µg/m L is p red ict ive of toxicit y. D P. aeruginosa is ver y sen sit ive to bot h im ip en em an d ceft azidim e. How ever, th e com bin at ion of th ese t w o drugs w ou ld be add it ive, n ot syn ergist ic, as both sh are th e sam e m ech an ism of act ion .

Learning objective: Explain the m ain reason for antibiotic-induced superinfections. 29. D Su p erin fect ion s are n ew in fect ion s th at occu r du ring an t ibacterial th erapy of a prim ar y in fect ion . Su p erin fect ion is d ue to rem oval of th e in h ibitor y in u en ce of th e m icro ora that norm ally inhabits certain parts of the body (oropharynx, in test in e, vagin a, etc.). In fact , m any m em bers of th e n orm al m icro ora app ear to p rodu ce an t ibacterial su bstan ces, an d th ey also presu m ably com p ete for essen t ial n u t rien ts. Th e broader th e sp ect ru m of an an t ibiot ic, th e greater th e alterat ion of th e n orm al m icro ora. W h en th e n orm al m icro ora

Answers and Explanations: VIII-1 Bacterial Cell Wall Synthesis Inhibitors 451 is altered, a single m icroorgan ism can becom e predom in an t , invade th e h ost , an d cause in fect ion . A−C, E An t ibiot ics do n ot cause th ese act ion s.

Learning objective: Identify the antibiotic used to treat Pasteurella multocida infection. 32. E P. m ultocida is p ar t of t h e n or m al oral

ora of d ogs an d

cat s an d th erefore is th e m ost com m on m icroorgan ism in

Learning objective: Explain the m echanism of action com m on to ampicillin, ceftriaxone, and vancomycin.

h um an w oun ds in icted by bites from th ese an im als. It is

30. E Th e sign s an d sym ptom s of th e p at ien t st rongly suggest a

A, B Staphylococcus epiderm idis an d Clost ridium di cile

d iagn osis of m en ingit is. W h en th e pat ien t is ver y ill an d th e

sen sit ive to pen icillin G, w h ich is st ill th e drug of rst ch oice. are gram -posit ive bacteria.

o en ding organ ism is un kn ow n , an em piric t riple an t ibiot ic

C, D Klebsiella pneum oniae an d Serrat ia m arcescens are

th erapy is u su ally given pen ding cerebrospin al u id test re-

en terobacteriaceae th at on ly except ion ally in fect super cial

su lt s. Th ird -gen erat ion cep h alosp orin s su ch as ceft riaxon e

w ou n ds. Moreover, th ey are n ot sen sit ive to er yth rom ycin

are active against m ost gram -positive and -negative bacteria.

an d van com ycin .

Because m any m ethicillin -resistant cocci are in creasingly to cover Listeria species. All of th ese an t ibiot ics act by in h ib -

Learning objective: Explain the mechanism of action of potassium clavulanate.

iting th e synthesis of peptidoglycan. Am picillin and ceftriax-

33. A Th e pat ien t’s sym ptom s an d p hysical exam in at ion suggest

on e in h ibit th e t ran spept idat ion react ion , blocking cross-lin k

th e diagn osis of acu te ot it is m edia, on e of th e m ost com m on

form at ion . Van com ycin in h ibit s t ran sglycosylase, blocking

in fect iou s diseases a

fu r th er elongat ion of pept idoglycan ch ain s.

bacteria cau sing ot it is m edia in ch ildren are St reptococcus

p revalen t , van com ycin is usually added. Am picillin is added

ict ing in fan ts an d ch ild ren . Th e m ain

A Th is is th e m ech an ism of act ion of am in oglycosides.

pneum oniae, Haem ophilus in uen zae, an d Moraxella ca-

B Th is is t h e m ech an ism of act ion of t r im et h op r im -

tarrhalis. Most clin ician s advocate a step p ed app roach to th e

su lfam etoxazole.

an t im icrobial th erapy, w h ich involves in it ial t reat m en t w ith

C Th is is th e m ech an ism of act ion of rifam pin .

am oxicillin or t rim eth oprim -sulfam eth oxazole. If th is regi-

D Th is is th e m ech an ism of act ion of m acrolides.

m en does n ot redu ce sym ptom s w ith in 3 days, am oxicillin /

Non e of th e above-m en t ion ed drugs are u sed alon e to

clavulan ate or cefuroxim e or ceft riaxon e sh ould be subst i-

t reat gram -negative bacillary m eningitis, eith er because th ey

t u ted for th e in it ial th erapy, as w as d on e in th is case. Pot as-

d o n ot cross th e blood−brain barrier (am in oglycosides) or

sium clavulanate is a β-lactam ase inh ibitor that blocks m any,

becau se th ey are n ot e ect ive again st som e gram -n egat ive

but not all, β-lactam ase enzym es, protecting am oxicillin from

bacteria (i.e., Pseudom onas aeruginosa).

in act ivat ion by β-lact am ase-p rodu cing bacteria. B Bet a-lact am ase in h ibitors exten d th e an t ibacterial sp ec-

Learning objective: Identify the antibiotic used prophylactically in at-risk patients undergoing dental surgery.

t r u m of am oxicillin , bu t Pseudom onas aeruginosa rem ain s

31. A An t ibiot ic p rophylaxis is gen erally recom m en ded for pa-

C, D Beta-lactam ase in h ibitors do n ot sign i can tly a ect

tients at risk w h o are undergoing procedures associated w ith sign i can t bacterem ia. Th ese in clu de any den t al procedu re th at is likely to cau se bacterem ia secon dar y to bleeding from

resistan t . th e kin et ics of pen icillin s. E Bet a-lactam ase in h ibitors do n ot a ect th e allergen icit y of β-lactam an t ibiot ics.

t issu es. Becau se t h is p at ien t is at r isk of in fect ive en d ocarp rop hyla xis is advisable. An t im icrobial p rop hyla xis sh ou ld

Learning objective: Describe the acute anaphylactic reaction to penicillin G.

be ad d ressed to vir idan s st reptococci, as t h ey are t h e m ost

34. D Th e signs and sym ptom s of the patient indicate that h e w as

com m on cause of en docardit is follow ing den t al procedures.

m ost likely su ering from an acu te an ap hylact ic react ion to

Am oxicillin is curren tly recom m en ded for prophylaxis in

p en icillin G, w h ich is th e t reat m en t of ch oice in all st ages of

su scept ible in dividu als u n dergoing u p per resp irator y t ract

syp h ilis.

d it is as a resu lt of t h e ongoin g h ear t d isease, an t ibiot ic

or den tal su rger y, as in th is case. B−D All of t h ese an t ibiot ics are m ain ly act ive again st gram -n egat ive bacteria an d th erefore n ot su itable to preven t st reptococcal in fect ion s. E Met ron idazole is n ot act ive again st st reptococci.

A, B Th ese drugs are som et im es u sed in th e t reat m en t of syp h ilis for pen icillin -allergic pat ien ts, bu t th ey h ave a m u ch low er risk of allergic react ion s. C, E, F Th ese drugs are n ot used in th e t reat m en t of syph ilis because Treponem a pallidum is intrinsically resistant to th ese an t ibiot ics.

452


Learning objective: Identify the cephalosporin that is m ainly elim inated with the bile. 35. B Th e an t ibiot ic t h erapy for acu te ch olecyst it is is u su ally in it iated to t reat p ossible in fect ion , bu t eviden ce of ben e t is st ill m odest . Em piric th erapy is directed again st gram n egative enteric organism s such as Escherichia coli, Klebsiella, an d Enterobacter species. Cefoperazon e an d ceft riaxon e are th e t w o cep h alosp orin s prim arily elim in ated w ith th e bile.

A Legionella pneum ophila is an aerobic, gram -n egat ive rod an d is n ot sen sit ive to am picillin . B Actinom yces israelii is an anaerobic rod, but it is gram p osit ive an d n ot sen sit ive to gen tam icin . D St reptococcus pneum oniae is an aerobic, gram -p osit ive coccus an d is n ot sen sit ive to azt reon am . E Listeria m onocytogenes is an aerobic, gram -p osit ive rod an d is n ot sen sit ive to cep h alosp orin s.

Both are act ive again st th e above-m en t ion ed bacteria; th erefore, cefoperazon e can be appropriate for th e em piric t reatm en t of acu te ch olecyst it is, as in th is case. A, C−E Th ese d r ugs are m ain ly elim in ated by t u bu lar secret ion .

Learning objective: Explain the m echanism of action of β-lactam antibiotics. 39. A Th e m ech an ism of act ion of β-lactam an t ibiot ics in clu des th e follow ing t w o act ion s: • Th ey bin d to speci c β-lact am receptors called pen icillin -

Learning objective: Describe the appropriate antim icrobial therapy for primary syphilis.

bin ding protein s located on th e cytoplasm ic m em bran e.

36. C Th e sign s an d sym ptom s of th e pat ien t , as w ell as th e dark-

lyt ic fu n ct ion s t h at are in h ibited by bin d in g to t h e an t i-

eld exam , suggest th at h e is su ering from prim ar y syp h i-

biot ic. Th e m ost im p or t an t en zym es in h ibited are t ran s-

lis. Pen icillin G is th e drug of ch oice for th e t reat m en t of all

p ept idases, w h ich cat alyze t h e n al cross-lin k step in th e

stages of syp h ilis. A single in t ram u scu lar inject ion of ben za-

syn th esis of m u rein (also called pept idoglycan ). Becau se

th in e p en icillin G is ap prop riate for th e early st age, as in th is

peptidoglycan layers are constit uents of bacterial cell w alls,

p at ien t . If pen icillin G is con t rain dicated, doxycyclin e or cef-

th e syn th esis of th e cell w all is blocked.

t riaxon e can be u sed . A, B, D−F Th ese d rugs are n ot e ect ive again st Treponem a pallidum .

Th ese p rotein s are en zym es en d ow ed w it h var iou s cat a-

• Autolytic en zym es (called autolysins or m urein hydrolases) are presen t in th e cell w all an d degrade th e pept idoglycan . Beta-lact am an t ibiot ics can act ivate th ese au tolysin s (apparen tly by blocking an autolysin in h ibitor), th us pro-

Learning objective: Identify the drug given to treat acute osteomyelitis.

B Th is is th e m ech an ism of act ion of tet racyclin es.

37. A Th e sign s an d sym ptom s of th e pat ien t suggest th at h e w as

C Th is is a m ech an ism of resist an ce to an t ibiot ics.

m ost likely su ering from acu te osteom yelit is follow ing a

D Th is is th e m ech an ism of act ion of van com ycin .

d iabet ic foot u lcer. Th e Gram st ain w as polym icrobial, an d

E Th is is th e m ech an ism of act ion of rifam pin .

m ot ing th e lysis of bacteria.

th e pu t rid sm ell w as speci c for an aerobic m icroorgan ism s. t ive again st gram -p osit ive cocci, gram -n egat ive rod s, an d

Learning objective: Identify the antibiotic that can cause hypoprothrom binem ia.

an aerobic bacteria. If th e p at ien t h ad a h istor y of m eth icil-

40. F Bacteroides fragilis h as been isolated from up to 28% of pa-

lin -resistan t st aphylococci, th e addit ion of van com ycin or

t ien t s w ith ch ron ic ot it is m ed ia. An t ibiot ics e ect ive again st

lin ezolid w ou ld be ap prop riate.

bacteroides are m et ron idazole, clin dam ycin , an d β-lactam

Am oxicillin /clavu lan ate is a broad-sp ect r u m an t ibiot ic ac-

B Clin dam ycin is act ive again st gram -posit ive cocci an d an aerobes bu t n ot again st gram -n egat ive rods. C, E Lin ezolid an d van com ycin are act ive on ly again st gram -posit ive cocci. D Met ron idazole is act ive on ly again st an aerobes.

d rugs, in clud ing im ip en em , broad-spect rum pen icillin s plu s β-lact am ase in h ibitors, cefoxit in , an d cefotet an . Hyp op rot h rom bin em ia h as been associated w it h t h e u se of cer t ain ceph alosporin s, in cluding cefoperazon e, cefotetan , an d cefam an dole. Th e m ech an ism of hyp op roth rom bin em ia is st ill u n cert ain but seem s to be related to th e m ethylth iotet razole

Learning objective: Identify the antibiotic used to treat bacteroides abscess.

side ch ain of th ese cep h alosporin s, as th is grou p can in h ibit

38. C Th e p u t rid spu t u m an d th e n egat ive aerobic cu lt u re poin t

step in th e syn th esis of clot t ing factors. Becau se of th is, th e

out that the o ending pathogen w as m ost likely an anaerobic

hyp op roth rom bin em ia can be rap idly reversed by th e ad-

bacteriu m . Bacteroides fragilis is th e m ost com m on path ogen

m in ist rat ion of vit am in K.

associated w ith an aerobic in fect ion s. It is ver y sen sit ive to im ipenem , clin dam ycin, and broad-spectrum penicillins plus β-lact am ase in h ibitors. Oth er e ect ive an t ibiot ics are m et ron idazole an d som e ceph alosporin s.

the carboxylation of glutam ic acid, the vitam in K−dependent

A−D Th ese drugs are act ive again st bacteroides, but hypop roth rom bin em ia is exceedingly rare. E Most qu in olon es h ave n egligible act ivit y again st bacteroid es.

Answers and Explanations: VIII-1 Bacterial Cell Wall Synthesis Inhibitors 453 Learning objective: Identify the antibiotic to be used in a patient allergic to β-lactam drugs.

D Am in oglycoside an t ibiot ics are poorly e ect ive again st st reptococci.

41. D Azt reon am is a β-lactam an t ibiot ic w ith excellen t act ivit y

E Acet am in oph en is an an t ipyret ic but n ot an an t iin am -

again st on ly m ost gram -n egat ive, aerobic bacter ia, in clu d -

m ator y drug. Th erefore, it is n ot useful in acu te rh eum at ic

ing Pseudom onas aeruginosa. It h as n egligible allergic cross-

fever, for w h ich NSAIDs are given m ain ly to cou n teract th e

react ivit y w ith oth er β-lact am an t ibiot ics an d is th erefore

acute in am m ator y react ion .

u seful for t reat ing gram -n egat ive in fect ion s in pat ien ts w ith a h istor y of prior allergic react ion to β-lactam drugs, as in th is case. A−C, E All of th ese an t ibiot ics are con t rain dicated in th is p at ien t because of h is hypersen sit ivit y to β-lact am drugs.

Learning objective: Identify the antibiotic used to treat Pseudomonas aeruginosa infections. 44. A Th e p at ien t’s h istor y an d th e lab resu lt s suggest th at sh e is su ering from a pu lm on ar y in fect ion due to Pseudom onas aeruginosa. All p at ien t s w ith cyst ic

brosis even t u ally de-

Learning objective: Explain the m echanism of the antim icrobial action of vancomycin.

velop en dobron ch ial colon izat ion an d in fect ion . Com m on ly

42. A Th e pat ien t’s sign s, sym ptom s, an d lab tests in dicate th at

Haem ophilus in uenzae, an d P. aeruginosa. Of th ese, P. aeru-

sh e w as m ost likely su ering from p n eu m on ia du e to m eth -

ginosa h as becom e th e m ost com m on path ogen isolated in

icillin -resist an t (MR) Staphylococcus aureus. Th e p at ien t re-

ch ron ically colon ized pat ien ts. For in fect ion s due to P. aeru-

ceived van com ycin , a drug of ch oice for MR staphylococcal

ginosa, a com bin at ion of t w o bactericidal an t ibiot ics is th e

in fect ion s. Van com ycin bin ds to th e term in us of n ascen t

r u le, an d an an t ip seu d om on al pen icillin , su ch as pip eracillin

p ept idoglycan p en t apept ides. Th e bin ding in h ibits t ran sgly-

(or an an t ipseudom on al ceph alosporin ), plus an am in ogly-

cosylase, th e en zym e th at cat alyzes th e elongat ion of pept i-

coside is th e m ost com m on ly used t reat m en t .

doglycan chains, preventing form ation of linear peptidoglycan ch ain s. Th e bin ding also in h ibits t ran spept idase, but because

o en ding respirator y path ogen s are Staphylococcus aureus,

B−F Non e of t h ese an t ibiot ics are act ive again st P. aeruginosa.

t ran sglycosylat ion p recedes t ran sp ept idat ion , in h ibit ion of t ran sglycosylase is th e p rim ar y m ech an ism of act ion of th e

Learning objective: Explain the action of penicillin-binding proteins.

d rug.

45. B Penicillin-binding proteins are speci c targets for β-lactam

B−E Th ese act ion s are n ot in h ibited by van com ycin .

an t ibiot ics. Th ey are located in th e bacterial cytoplasm ic m em bran e, an d som e of th em are t ran spept idases th at cata-

Learning objective: Identify the t wo drugs used for the initial treatment of acute rheumatic fever.

lyze the cross-linking of the peptidoglycan am ino sugar chain

43. A Th e pat ien t’s clin ical p ict u re suggests th at h e w as a ected

gidit y. By binding to these tran speptidase en zym es, β-lactam

by acute rh eum at ic fever. Th e disease is a n on suppurat ive

an t ibiot ics block th e t ran spept idat ion react ion an d th erefore

com plicat ion of an in fect ion w ith group A st reptococci. Th e

th e syn th esis of pept idoglycan .

by pept ide bridges. Th is gives th e cell w all it s st ruct ural ri-

diagnosis of acute rh eum atic fever requires t w o of th e follow -

A Por in ch an n els are aqu eou s ch an n els p resen t on t h e

ing m ajor m an ifest at ion s of th e illn ess: cardit is, m igrator y

ou ter m em bran e of gram -n egat ive bacter ia. Bet a-lact am

p olyar th rit is, ch orea, er yth em a m argin at um , an d subcuta-

an t ibiot ics en ter th e cell th rough th ese ch an n els. Pen icillin -

n eou s n odules. Th e pat ien t h as four such feat ures. In acute

bin ding p rotein s do n ot a ect th is process.

rh eum at ic fever, it is appropriate to adm in ister a th erapeu t ic course (at least 10 days) of paren teral pen icillin . In severe

C Th e breakd ow n of t h e β-lact am r in g is cat alyzed by β-lact am ases, n ot by t ran sp ept idases.

cases, aggressive u se of an t iin am m ator y drugs is requ ired.

D Beta-lact am an t ibiot ics can act ivate, n ot in h ibit , m urein

Salicylates rem ain th e drugs of ch oice, bu t oth er n on steroi-

hydrolases, w h ich are en zym es able to dest roy th e cell w all.

dal an t iin am m ator y drugs (NSAIDs, e.g., n aproxen ) can also

E Bet a-lact am an t ibiot ics bin d to pen icillin -bin ding pro-

be u sed in ch ild ren . If a t h erap eu t ic e ect h as n ot been ach ieved after th e four th day, NSAIDs sh ou ld be aban don ed in favor of a glucocor t icoid. B, C, F Am oxicillin an d ceft riaxon e are less e ect ive again st st reptococci th an p en icillin G. Moreover an an t iin am m ator y drug m u st be given in acute rh eum at ic fever.

tein s, n ot to th e pept idoglycan layer.

454


Learning objective: Outline the therapeutic uses of daptomycin.

an d in clu des hypoten sion , tachycardia, gen eralized prurit us,

46. D Th e pat ien t’s sign s, sym ptom s, an d lab tests in dicate th at

an d facial

h e w as m ost likely su ering from sepsis due to van com ycin -

likely cau sed by h istam in e release. A, C−F Alth ough all of th ese an t ibiot ics are e ect ive again st

resistan t Staphylococcus aureus. Cu rren tly available an t ibiotics for van com ycin -resistan t staphylococci are daptom ycin ,

u sh in g, as in t h is case. Th e syn d rom e is m ost

staphylococci, th ey do n ot cau se h ist am in e release.

qu in uprist in /dalfoprist in , lin ezolid, an d t igecyclin e. Daptom ycin is a bactericidal antibiotic active again st gram -positive

Learning objective: Explain the mechanism of action of fosfomycin.

bacteria, in clu ding van com ycin -resistan t st aphylococci an d

49. D Fosfom ycin is an an t ibiot ic m ain ly act ive again st en tero -

en terococci. It s m ech an ism of act ion is n ot fu lly u n derstood,

bacter iaceae, in clu d ing Escherichia coli, en terococci, an d

bu t it is kn ow n th at th e drug bin ds to bacterial cell m em -

Klebsiella, Enterobacter, Proteus, an d Serrat ia sp ecies. Th e

bran es via calciu m -dep en den t in ser t ion of it s lip id t ail. Th is

d r ug is ap p roved for u r in ar y t ract in fect ion d u e to su scep -

likely result s in form at ion of a p ore, causing a loss of cellular

t ible bacteria becau se it is elim in ated m ain ly by th e kidn ey

p ot assiu m an d result ing in rapid cell death . Becau se of th is

an d at t ain s h igh con cen t rat ion in th e u rin e. Fosfom ycin act s

u n ique m ech an ism of act ion , th ere is n o cross-resist an ce

by in h ibit ing en olpyruvate t ran sferase, th e en zym e th at cat-

w ith oth er an t ibiot ics, an d resist an ce m ech an ism s are n ot

alyzes th e syn th esis of N-acet ylm uram ic acid, an essen t ial

kn ow n . A rare but serious adverse e ect of th e drug is m yop -

p recu rsor for pept idoglycan syn th esis. In th is w ay, bacterial

athy, and creatine phosphokinase levels should be m onitored.

cell w all syn th esis is in h ibited.

A, C, E Van com ycin -resist an t st ap hylococci are resist an t to all β-lact am drugs.

A−C, E All of th ese drugs can block bacterial cell w all syn th esis, bu t th ey act w ith d i eren t m ech an ism s of act ion .

B, F Am in oglycoside an t ibiot ics are n ot e ect ive again st

Learning objective: Identify the t wo antibiotics used to treat Klebsiella pneumonia.

m ost gram -p osit ive bacteria.

Learning objective: Describe the nephrotoxicit y due to concom itant treatment with vancomycin and gentamicin.

50. C Nearly 1% of h ospit alized pat ien ts develop pn eum on ia,

47. D Treat m en t of bacterial en docardit is requires th e u se of on e

gan ism s cau sing n osocom ial pn eu m on ia are aerobic gram -

or m ost often t w o bactericidal an t ibiot ics. A cell w all syn -

n egat ive bacilli, in cluding Klebsiella pneum oniae, Escherichia

th esis in h ibitor p lu s an am in oglycoside is th e rst-lin e t reat -

coli, Proteus m irabilis, and Pseudom onas aeruginosa. Less com -

m en t , as a syn ergist ic e ect can be obt ain ed (th e cell w all

m on causes are Staphylococcus aureus, Streptococcus pneum o-

syn th esis in h ibitor en h an ces th e bacterial u pt ake of th e am i-

niae, and anaerobes. The m ost frequent and best characterized

n oglycoside). In th is case, van com ycin plus gen t am icin w as

p ath ogen is Klebsiella pneum oniae, w h ich causes Friedlan der

th e m ost likely t reat m en t becau se th e pat ien t sh ow ed sign s

p n eu m on ia, a disease th at can h ave a fulm in an t course an d a

of nephrotoxicit y. The incidence of nephrotoxicit y associated

m or talit y rate of abou t 50%, desp ite th e availabilit y of e ec-

w ith van com ycin alon e is ver y low, but it in creases subst an -

t ive an t ibiot ics. In th is case, th e t ypical ap pearan ce of th e

t ially (u p to 20%) in p at ien t s receiving van com ycin p lu s an

sp u t u m (a h om ogen eou s m ixt u re of blood an d m u cu s re-

am in oglycoside, as in th is case.

sem bling cu rran t jelly) an d th e resu lt s of lab test s an d x-ray

A, E Th ese com bin at ion s are n ot u sed for bacterial en docardit is an d are n ot n eph rotoxic.

w h ich h as a 20 to 50% m or talit y rate. Th e predom in an t or-

suggest Friedlan der p n eu m on ia. Cep h alosp orin s are drugs of rst ch oice again st Klebsiellae. How ever, du e to th e seriou s-

B Th is com bin at ion can cause n eph rotoxicit y, bu t it is irrat ion al to u se togeth er t w o an t ibiot ics w ith th e sam e m ech a-

n ess of th e disease, m ost auth orit ies suggest th e use of an am in oglycoside togeth er w ith a ceph alosporin .

n ism of act ion .

A, B, D, E All of th e oth er listed opt ion s h ave at least on e

C Th is com bin at ion can cause n eph rotoxicit y (d ue to th e

an t ibiot ic th at is n ot e ect ive again st Klebsiellae.

am in oglycoside), bu t it is n ot u sed for bacterial en docardit is. In gen eral, a com bin at ion of a bactericidal plu s a bacterioBACTERIAL CELL WALL SYNTHESIS INHIBITORS Answ er key

stat ic an t ibiot ic sh ou ld be avoided, as an an tagon ist ic in teract ion w ou ld occu r in m any cases.

Learning objective: Describe the infusion reaction associated with vancomycin. 48. B Th e pat ien t m ost likely received van com ycin , a

rst-lin e

agen t for m et h icillin -resist an t st ap hylococci. A com m on react ion to van com ycin is th e so-called red m an syn drom e, w h ich can occur after in t raven ous in fusion of th e an t ibiot ic

1. 2. 3. 4. 5.

H J F B C

6. 7. 8. 9. 10.

A C B E D

11. 12. 13. 14. 15.

D A D C C

16. 17. 18. 19. 20.

A E C E B

21. 22. 23. 24. 25.

A C E D B

26. 27. 28. 29. 30.

B D D D E

31. 32. 33. 34. 35.

A E A D B

36. 37. 38. 39. 40.

C A C A F

41. 42. 43. 44. 45.

D A A A B

46. 47. 48. 49. 50.

D D B D C

Answers and Explanations: VIII-2 Bacterial Protein Synthesis Inhibitors 455

Answers and Explanations: VIII-2 Bacterial Protein Synthesis Inhibitors Questions 1−5

B Protein bin ding is tot ally u n related to th e durat ion of th e an t ibiot ic e ect .

1. O

C Am in oglycosides are bactericidal, n ot bacteriostat ic.

2. L 3. B

Learning objective: Identify the drug used for prophylaxis of whooping cough.

4. E 5. J

8. C Er yth rom ycin an d azith rom ycin are agen ts of ch oice for

Learning objective: Explain the mechanism of action of gentamicin.

w h ooping cough . If th ey are given during th e catarrh al stage,

6. E Gen t am icin is an am in oglycoside an t ibiot ic. Th ese drugs

th ey can am eliorate th e disease. After paroxysm s are estab -

bin d irreversibly to speci c 30S ribosom al su bu n its an d in -

lish ed, th ese drugs h ave n o clin ical e ect , bu t th ey decrease

h ibit bacterial protein syn th esis in at least th ree w ays:

th e du rat ion of in fect iou sn ess, th u s preven t ing sp read. Con -

• Blockade of th e “in it iat ion com p lex,” th e com plex form ed for in it iat ion of t ran slat ion t h at con sist s of t h e 30S m icrosom al su bu n it , m essenger RNA (m RNA), t ran sfer RNA (tRNA), an d som e in it iat ion factors. Th is blockade leads to an m RNA ch ain w ith on ly a single ribosom e on it , th e socalled m on osom e. • Misreading of m RNA tem plates, w h ich leads to th e p rod u ct ion of aberran t protein s. Th ese p rotein s m ay be in ser ted

t acts of all ages, w h eth er vaccin ated or n ot , sh ou ld receive a 10-day cou rse of er yth rom ycin . A, B, D Th ese d rug are act ive again st Bordetella pert ussis bu t are con t rain dicated in ch ildren . E, F Th ese drugs are n ot act ive again st B. pert ussis.

Learning objective: Identify the antibiotic used for antim icrobial prophylaxis in colorectal surgery.

in to cell m em bran es, altering p erm eabilit y an d fu rth er

9. D An t ibiot ic prophylaxis is w idely u sed for surgical proce-

st im u lat ing am in oglycoside t ran sp or t (en ergy-dep en den t

d ures to decrease th e degree of bacterial con t am in at ion

p h ase II t ran sp or t).

d uring su rger y. Prop hylaxis is esp ecially advisable for col-

• Blockade of t ran slocat ion (i.e., th e ribosom e advan cem en t

p rising th e in test in al

of th ree n ucleot ides is blocked) For exter n al ot it is, t h e d r ug w ou ld be given top ically as ear d rop s. Gen t am icin can be ototoxic, esp ecially if given system ically. A−D All of th ese an t ibiot ics are act ive again st Pseudom onas aeruginosa, bu t th ey do n ot cau se m isread ing of th e bacterial m RNA tem plate.

7. D Th e am in oglycoside bactericidal e ect is con cen t rat ion dep en den t; th at is, in creasing con cen t rat ion s kill an in creasing p roport ion of bacteria an d at a m ore rap id rate. Th ey also h ave a long postan t ibiot ic e ect , th at is, persisten t suppression of bacterial grow th for several h ou rs beyon d th e t im e th at m easurable drug is presen t . Most an t ibiot ics exh ibit th is e ect again st gram -p osit ive cocci. An t ibiot ics th at p ossess th is e ect again st gram -n egat ive bacilli are am in oglycosides, uoroquin olon es, an d tet racyclin es. Because of th ese t w o propert ies, a given tot al am ou n t of cacy an d low er toxicit y

w h en adm in istered as a h igh er single daily dose th an w h en given as a low er dose t w o or th ree t im es daily. A, E The bactericidal e ect of am inoglycosides is not tim edep en den t .

ora. Oral n on adsorbable an t ibiot ics

fu n ct ion e ect ively as in test in al decon tam in an t s becau se h igh intralum in al drug concentrations can be easily achieved. An oral an t im icrobial regim en used for colorectal surgical prophylaxis is neom ycin (for aerobic enterobacteriaceae) plus er yth rom ycin (for an aerobes). Neom ycin is preferred over oth er am in oglycosides because of its w ider spect rum of an t ibacterial act ivit y.

Learning objective: Explain concentration-dependent killing and the postantibiotic e ect.

am in oglycoside m ay h ave bet ter e

orect al su rger y, ow ing to th e large n um ber of bacteria com -

A See correct an sw er explan at ion . B Pen icillin G given orally is rapidly dest royed by gast ric juices. C, E, F Th ese an t ibiot ics are n ot act ive again st en terobacteriaceae or an aerobes.

Learning objective: Identify the antibiotic used to treat psit tacosis. 10. E Th e p at ien t ’s h istor y suggest s t h at h e w as a ected by p sit t acosis, a pn eu m on ia caused by Chlam ydia psittaci. Th e organ ism is foun d m ain ly in psit tacin e birds, bu t oth er birds can also be a ected . Hu m an in fect ion u su ally occu rs by in h alat ion of dust from feath ers of in fected birds. Ch lam ydiae are sen sit ive to tet racyclin es, m acrolid es, an d qu in olon es. Doxycyclin e is often th e preferred drug. A−D All of th e listed bacteria can cause pn eum on ia, but n on e of th em are sen sit ive to th e paired drug.

456


Learning objective: Calculate the dose of gentam icin to be given to a patient with renal insu ciency, given su cient data.

Learning objective: Identify the risk of drug reaction with an aminoglycoside in a patient taking furosemide.

11. D Am in oglycosides are excreted alm ost en t irely by th e kid-

14. D Am in oglycosid es can cau se ototoxicit y, w h ich is m ore

n ey, an d t h eir clearan ce is essen t ially equ al to th e glom er-

likely in p at ien t s receiving ot h er ototoxic d r ugs, in clu d in g

u lar

loop diu ret ics su ch as fu rosem ide.

lt rat ion rate. Becau se t h ese d r ugs h ave a n ar row

th erap eu t ic in dex, dosing m u st be redu ced in p at ien t s w ith im paired ren al fun ct ion .

A, C−F All of th ese are poten t ial adverse e ects of am in oglycosides, bu t th eir risk is n ot in creased by th e con com it an t

In gen eral, th e dose in a pat ien t w ith ren al im pairm en t

adm in ist rat ion of th e drugs u sed by th e pat ien t .

m ay be corrected by m u lt ip lying th e average dose for a n or-

w ords, th e dose m u st be redu ced p roport ion ally to th e re-

Learning objective: Identify the antibiotic m ost appropriate for a patient with urinary tract infection based on result s of a susceptibilit y test.

d uct ion of creat in in e clearan ce. In th is case, as th e pat ien t’s

15. B Approxim ately 20% of cath eterized pat ien t s develop uri-

creat in in e clearan ce is abou t on e h alf th e n orm al valu e, th e

n ar y t ract in fect ion s. In th is disease, th e ch oice of th e m ost

d ose sh ould be on e h alf th e n orm al dose.

su it able an t ibiot ic is often dictated by an t im icrobial su scep -

m ally h ealthy person by th e rat io of th e pat ien t’s altered to n orm al creat in in e clearan ce (about 100 m L/m in ). In oth er


t ibilit y test s, as th e disease does n ot requ ire im m ediate em p iric an t im icrobial th erapy. Th e resu lt s of su scept ibilit y test s

Learning objective: Identify the pair of drugs used to treat acute pyelonephritis due to Pseudomonas aeruginosa.

are rep or ted qu alitat ively by in dicat ing for each m icroorgan -

12. A Acu te pyelon ep h r it is is a w ell-kn ow n com p licat ion of

an t ibiot ics. In th is case, am ikacin w as th e dr ug collect ively

ch ron ic low er urin ar y t ract in fect ion s. Am ong pat ien ts ages

ism if it is suscept ible, in term ediate, or resist an t to a given m ost act ive again st th e tested bacteria.

20 to 50 years, u rin ar y t ract in fect ion is abou t 50-fold greater

A, C−E On th e w h ole, th ese drugs are less e ect ive th an

in w om en , an d pyelon eph rit is occu rs by th e ascen ding route

am ikacin again st t h e bacter ia isolated from t h e p at ien t ’s

d espite th e dyn am ics of u rin e ow. In th is pat ien t , diabetes

u rin e.

cou ld p red isp ose to ren al in fect ion s, p ossibly becau se d iacau se t h e p at ien t is acu tely ill, an d P. aeruginosa is t h e

Learning objective: Identify the antibiotic that caused nephrotoxicit y in a patient su ering from infection.

cau sat ive agen t of h er disease, sh e sh ou ld be t reated w ith an

16. B Th e p at ien t’s u rin alysis in dicates n ep h rotoxicit y. Am in o-

an t i-Pseudom onas p en icillin (or ceph alosporin ) plu s an am i-

glycoside an t ibiot ics are act ive again st Pseudom onas aerugi-

n oglycoside. Both drugs are bactericidal again st P. aerugi-

nosa and can cau se n ep h rotoxicit y in 8 to 26% of pat ien ts

nosa, and penicillins are synergistic w ith am inoglycosides by

receiving t h ese d r ugs for m ore t h an 1 w eek. Risk factors

in creasing th e u pt ake of th ese drugs by m any gram -posit ive

in clu de old age, as in th is case.

bet ics h ave altered an t ibacter ial d efen se m ech an ism s. Be-

an d -n egat ive bacteria.

A, C Piperacillin an d azt reon am are act ive again st P. aeru-

B−D On ly on e of t h e t w o listed an t ibiot ics is e ect ive again st P. aeruginosa.

ginosa, bu t th ey d o n ot cause n ep h rotoxicit y. D, E Van com ycin an d rifam pin can cause n eph rotoxicit y,

E Am p icillin an d tet racyclin es are n ot e ect ive again st

bu t th ey are n ot act ive again st P. aeruginosa.

P. aeruginosa.

Learning objective: Describe the bacterial resistance to am inoglycosides.

Learning objective: Identify the bacterium sensitive to am inoglycosides. 17. E Th e e

cacy of gen t am icin th erapy in d icated t h at an aer-

13. A Resist an ce to am in oglycosides is prim arily due to p lasm id-

obic gram -n egat ive rod w as t h e m ost likely o en d in g or-

m ed iated p rod u ct ion of bacter ial t ran sferases t h at p h os-

gan ism . Am in oglycosides are m ain ly act ive again st aerobic

p h or ylate, acet ylate, an d adenylate th e drug. Less com m on

gram -n egat ive rods, in clu ding Klebsiella pneum oniae, Pseu-

m ech an ism s of resist an ce are d ecreased perm eabilit y of th e

dom onas aeruginosa, Haem ophilus in uenzae, Escherichia coli,

bacteriu m to th e drug an d d ecreased a

n it y of th e drug for

Proteus m irabilis, Proteus vulgaris, Enterobacter aerogenes, and

th e 30S ribosom al su bu n it . Resistan ce ap pears m ost fre-

Serrat ia m arcescens, as w ell as again st som e m ycobacteria

qu en tly to gen t am icin an d least frequen tly to am ikacin .

(Mycobacterium t uberculosis and Mycobacterium avium -

B Resistan ce can be due to decrease in th e a

n it y of th e

d rug for th e 30S (n ot for th e 50S) ribosom al subun it . C Th is is a m ech an ism of resistan ce to pen icillin s. D Th is is th e m ech an ism of resist an ce to ison iazid. E Th is is th e m ech an ism of resist an ce to qu in olon es.

int racellulare). Enterobacter p n eu m on ia is u su ally h osp italacquired and occurs m ainly in im m unocom prom ised patients, as in th is case. A−D, F Am in oglycosides are n ot act ive again st Clost ridia, m ycop lasm a, bacteroides, Borrelia, an d Legionella sp ecies.

Answers and Explanations: VIII-2 Bacterial Protein Synthesis Inhibitors 457 Learning objective: Identify the antibiotic that is contraindicated in a patient su ering from myasthenia gravis.

pept idyl-t ran sfer RNA (tRNA) from th e acceptor site to th e

18. E Tobram ycin is an am in oglycoside an t ibiot ic. Th ese drugs

bu t th ey m ay be bactericidal at h igh er d oses.

don or site of th e ribosom e. Th ey are m ain ly bacteriost at ic,

are associated w ith n eu rom u scu lar blockad e an d m ay cau se

A Th is is th e m ech an ism of act ion of rifam pin .

n eurom uscular w eakn ess last ing h ours to days. Th erefore,

B Th is is th e m ech an ism of act ion of qu in olon es.

th ey are relat ively con t rain dicated in pat ien ts receiving an -

C Th is is th e m ech an ism of act ion of am in oglycosides.

esth et ics or n eurom uscular-blocking agen ts an d in pat ien t s

E Th is is th e m ech an ism of act ion of tet racyclin es.

w ith n eu rom uscular diseases such as m yasth en ia gravis an d p arkin son ism . Th e U.S. Food an d Drug Adm in ist rat ion h as

Learning objective: Identify the bacterium sensitive to macrolides.

a black box w arn ing for u se of tobram ycin in p at ien t s w ith

22. B Cam pylobacter jejuni accou n ts for m ost cases of diarrh ea in

th ese diseases. A−D Th ese drugs are e ect ive in urin ar y t ract in fect ion s an d do n ot en h an ce th e n eu rom u scu lar blockade cau sed by d iseases or drugs.

th e Un ited States. Th e diarrh ea is u sually bloody, especially w h en fever is presen t , as in th is case. Macrolides such as azith rom ycin are e ect ive again st Cam pylobacter species. A, C, D, F Th ese bacteria can cau se diarrh ea, bu t th ey are resistan t to m acrolides.

Learning objective: Explain the m echanism of action of linezolid. 19. E Th e pat ien t’s sign s an d sym ptom s in dicate th at sh e w as

E Som e Clost ridia species are sen sit ive to m acrolides, but Clost ridium di cile is n ot .

m ost likely su ering from acu te h em atogen ou s osteom yeliis a relat ively n ew an t ibiot ic th at in h ibits protein syn th esis

Learning objective: Describe the m echanism of erythromycininduced diarrhea.

by bin ding to th e 23S por t ion of th e 50S ribosom al subun it

23. B Nau sea, vom it in g, d iar rh ea, an d abd om in al p ain m ay

an d p reven t in g for m at ion of t h e in it iat ion com p lex. Th e

accom pany th e adm in ist rat ion of m acrolides. Th ese e ects

u lt im ate e ect is m ain ly bacter iost at ic. Th e d r ug is act ive

are dose-related an d occur m ore com m on ly in ch ildren an d

again st m eth icillin -resistan t (MR) an d van com ycin -resist an t

young adu lt s. Th e m ech an ism th at un derlies th ese adverse

(VR) staphylococci.

react ion s is st ill un cer tain bu t is m ost likely related to m ac-

t is, w h ich classically h as been a disease of ch ildren . Lin ezolid

A−D All of t h ese an t ibiot ics h ave a di eren t m ech an ism of act ion , an d t h ey are n ot act ive again st MR an d VR stap hylococci F Tigecyclin e is act ive again st MR an d VR staphylococci bu t h as a di eren t m ech an ism of act ion ; it bin ds in stead to th e 30S ribosom al su bu n it an d preven t s bin ding of th e am in oacyl-t ran sfer RNA (tRNA) to th e acceptor site.

rolide-m ediated act ivat ion of m ot ilin receptors in th e gu t . A Er yt h rom ycin is n ot act ive again st m ost en terobacter iaceae. In fact , su perin fect ion s are exceedingly rare. C Er yt h rom ycin d oes n ot a ect w ater reabsor pt ion by colon ic m u cosa. D Macrolides (m ain ly er yth rom ycin estolate) can rarely cau se ch olest at ic h ep at it is, bu t diarrh ea is n ot a sym ptom of th at disease.

Learning objective: Identify the class of antibiotics that can cause dose-dependent ototoxicit y.

E Allergic react ion s to m acrolide an t ibiot ics are ver y rare an d in clude m ain ly fever an d skin erupt ion s.

20. E Am in oglycosides cau se dose-dep en den t ototoxicit y th at it ing, an d vert igo in dicate im pairm en t of vest ibu lar fu n c-

Learning objective: Describe the use of m acrolides in gonococcal urethritis.

t ion , an d t in n it u s an d decreased h earing capacit y poin t ou t

24. C Th e pat ien t’s sym ptom s an d lab resu lt s suggest th e diag-

involves both cochlear and vestibular fun ction. Nausea, vom -

th at coch lear fu n ct ion is a ected. A Macrolides can rarely cau se ototoxicit y, bu t th ey are n ot act ive again st Serrat ia m arcescens. B Som e tet racyclin es (m in ocyclin e) can cau se vest ibu lar d ist u rban ces, but th ey are n ot act ive again st S. m arcescens. C, D Cep h alosp or in s an d su lfon am ides d o n ot cau se ototoxicit y.

n osis of gon ococcal ureth rit is. Because up to 50% of w om en w ith gon orrh ea h ave coin fect ion w ith Chlam ydia t rachom at is, azith rom ycin is u su ally add ed to ceft riaxon e t reat m en t. Ot h er o en d in g p at h ogen s som et im es resp on sible for coin fect ion are Ureaplasm a urealyt icum and Mycoplasm a genitalium ; bot h are also sen sit ive to m acrolid es. Azit h rom ycin is often p referred becau se a single dose is u sually e ect ive. A, B, D−F Non e of th ese an t ibiot ics are e ect ive again st

Learning objective: Explain the mechanism of action of macrolides. 21. D Macrolide an t ibiot ics in h ibit bacterial protein syn th esis m ain ly by blocking t ran slocat ion of th e n ew ly syn th esized

ch lam ydiae, m ycoplasm as, or ureaplasm as.

458


Learning objective: Identify the antibiotic that should be used in a patient with renal insu ciency and an infection due to Pseudomonas aeruginosa.

tetracyclines, trim ethoprim -sulfam ethoxazole, and rifam pin .

25. B Am ikacin is an am in oglycoside an t ibiot ic. Becau se am in o-

L. pneum ophila.

Azith rom ycin , alon e or w ith rifam p in , is a rst-lin e agen t . A, B, D−F Non e of th ese an t ibiot ics are e ect ive again st

glycosid es are ver y p olar d r ugs, t h ey are w ater solu ble, u n lt rat ion . As a resu lt , th eir h alf-lives

Learning objective: Identify a class of antibiotics that exhibit s mainly bacteriostatic activit y.

can in crease en orm ou sly in pat ien ts w ith kidn ey failu re.

29. C Macrolid es are m ain ly bacteriost at ic an t ibiot ics w ith ex-

d ergo lit t le h ep at ic m et abolism , an d are excreted alm ost en t irely by glom eru lar

Am in oglycosides h ave a n arrow th erapeut ic w in dow, so t w o d osing sch edu les are cu rren tly used to avoid toxicit y: redu ct ion of th e dose or exten sion of d osing in ter vals. Both m eth ods h ave advan tages an d disadvan tages. A Cefoperazon e is an an t i-Pseudom onas ceph alosporin but

cellen t act ivit y again st m ycoplasm as. A, B, D, E All of th ese an t ibiot ics h ave bactericidal act ivit y. Moreover, th ey are n ot act ive again st m ycoplasm as. F Flu oroqu in olon es are act ive again st m ycoplasm as, bu t th ey are bactericidal, n ot bacteriost at ic.

is excreted m ain ly in th e bile, so its dosage does n ot n eed to be ch anged in th e presen ce of kidn ey failu re. C−F These antibiotics are not e ective against P. aeruginosa.

Learning objective: Identify the antibiotic that can trigger polymorphic ventricular tachycardia in patients at risk. 30. B Macrolide an t ibiot ics can cau se p rolongat ion of th e elec-

Learning objective: Identify the drug used to treat inclusion conjunctivitis.

t rocardiogram QT in ter val, a con dit ion th at in creases th e

26. E Th e pat ien t’s sym ptom s an d th e lab resu lt s in dicate th at

occurs w h en m acrolides are given in h igh doses or are given

th e baby m ost likely h as inclusion conjunctivitis, an infection

togeth er w ith oth er drugs th at can prolong th e QT in ter val.

due to Chlam ydia t rachom at is th at th e n ew born acqu ired

Th ese in clu de several an t iarrhyth m ic dr ugs, H1 an tagon ists,

d uring passage th rough an in fected bir th can al. Macrolides,

n eu rolept ics, t r icyclic an t id ep ressan t s, an t im alar ials, an d

tet racyclin es, quin olon es, an d t rim eth oprim -sulfam eth ox-

qu in olon es. In th is case, th e pat ien t w as t aking am it ript y-

azole are e ect ive again st ch lam ydiae, bu t tet racyclin es,

lin e, a t ricyclic an t idep ressan t , so sh e w as at in creased risk

qu in olon es, an d sulfon am ides are relat ively con t rain dicated

of developing ven t ricular tachycardia w h en er yth rom ycin

in ch ildren . Er yth rom ycin rem ain s th e rst-lin e agen t for in -

w as t aken .

clusion conjun ct ivit is in th e n ew born . A, C, D See correct an sw er exp lan at ion .

risk of p olym orph ic ven t ricu lar t achycardia. Th is p rim arily

A, C−F Th ese d r ugs d o n ot ap p ear to p rolon g t h e QT in ter val.

B, F Bet a-lactam an t ibiot ics an d am in oglycosid es are n ot e ect ive again st ch lam ydiae.

Learning objective: Identify the antibiotic used to treat cat scratch disease.

Learning objective: Describe the m ain drug interactions involving macrolides.

31. C Th e boy m ost likely su ered from cat scratch disease, a be-

27. E Th e pat ien t’s sym ptom s w ere m ost likely du e to an in -

rod th at in fects at least 30%of dom est ic cat s. Cat scratch dis-

creased plasm a con cen t rat ion of th eophyllin e. Er yth rom ycin

ease is u su ally self-lim ited an d d oes n ot requ ire t reat m en t

m etabolites in h ibit th e P-450 system , th u s in creasing p lasm a

in n orm al adults. In ver y young ch ildren or in im m un ocom -

con cen t rat ion of several drugs given con com itan tly, in clud-

p rom ised p at ien t s, a m acrolide is th e drug of ch oice.

ing th eophyllin e, carbam azep in e, valproic acid, cort icosteroids, digoxin , an d w arfarin . A−D, F Th ese drugs do n ot in teract w ith th eophyllin e.

n ign illn ess caused by Bartonella enselae, a gram -n egat ive

A, B, E Enterococcus faecalis, Clost ridium di cile, an d Act inom yces israelii are gram -posit ive bacteria. D Bacteroides fragilis is an an aerobic gram -n egat ive rod t h at cau ses m ain ly in t ra-abd om in al in fect ion s an d is n ot

Learning objective: Identify the drug used to treat Legionnaires’ disease.

sen sit ive to am in oglycosides.

lab resu lt s in d icate th at h e w as m ost likely su ering from

Learning objective: Identify the m icroorganism sensitive to clindamycin.

Legion n aires’ d isease, a p n eu m on ia cau sed by Legionella

32. C Th e fact th at th e p at ien t’s in fect ion star ted after su rger y

sp ecies (m ain ly Legionella pneum ophila). More t h an 60% of

w ith con tam in at ion of th e periton eu m an d th at clin dam ycin

p at ien t s w ith Legion n aires’ disease exh ibit bradycardia, an d

w as ch osen for th erapy p oin t s ou t th at th e m ain o en d ing

positive cultures in charcoal yeast extract agar are diagnostic.

p at h ogen w as m ost likely Bacteroides fragilis. Clin dam ycin

L. pneum ophila is sen sit ive to m acrolides, u oroqu in olon es,

is a lin cosam ide an t ibiot ic w ith ver y good act ivit y again st

28. C Th e pat ien t’s sym ptom s (h igh fever w ith bradycardia) an d

Answers and Explanations: VIII-2 Bacterial Protein Synthesis Inhibitors 459 Bacteroides (in cluding B. fragilis). Th e drug is n ot rst ch oice

su bu n it an d block t h e access of am in oacyl-t ran sfer RNA

in bacteroides in fect ion s becau se β-lactam an t ibiot ics an d

(t RNA) to t h e acceptor sid e of t h e m essen ger RNA (m RNA)

m et ron idazole are usually preferred, but th e pat ien t w as al-

r ibosom e com p lex. Th is p reven t s t h e ad d it ion of am in o

lergic to both .

acid s to t h e grow in g p ept id e ch ain an d t h erefore in h ibit s

A, B, D, E All of th ese m icroorgan ism s are resistan t to clin dam ycin .

bacterial protein syn th esis. A Th is is th e m ech an ism of act ion of rifam pin . B Th is is on e of th e m ech an ism s of act ion of am in o-

Learning objective: Identify the antibiotic used for streptococcal pharyngitis in a person allergic to penicillins. 33. D Er yth rom ycin is th e drug of ch oice for st reptococcal in fec-

glycosid es. C Th is is th e m ech an ism of act ion of ch loram ph en icol. E Th is is th e m ech an ism of act ion of β-lact am an t ibiot ics.

t ion s in a pat ien t allergic to pen icillin s. A−C A seriou s allergic react ion to pen icillin s con t rain dicates th e u se of all β-lact am an t ibiot ics except azt reon am . E Many st reptococcal st rain s are n ow resist an t to tet racy-

Learning objective: Identify the drug used to treat Lym e disease. 37. D Th e h istor y an d th e sym ptom s of th e pat ien t in dicate th at sh e w as m ost likely su er ing from Lym e d isease, a t ick-

clin es, an d th ese an t ibiot ics are con t rain dicated in pregn an t

bor n e bor reliosis cau sed by Borrelia burgdorferi. Th e

w om en .

st age of t h e d isease begin s as a red m acu le t h at exp an d s

F Aztreonam is active only against gram -negative bacteria.

rst

(h en ce th e n am e er yth em a m igran s), often w ith a cen t ral clearing, to a diam eter as large as 50 cm (about 20 in ch es).

Learning objective: Describe the m ain erythromycin drug interactions.

Th e secon d st age occu rs w ith in w eeks to m on th s of th e

34. B Macrolides are rst-lin e agen t s for in fect ion d u e to Myco-

50% of p at ien t s) an d/or n eu rologic an d cardiac abn orm ali-

on set of er yth em a an d is ch aracterized by ar th rit is (about t ies (less th an 20% of p at ien t s). B. burgdorferi is suscept ible

plasm a pneum oniae. Er yth rom ycin m etabolites in h ibit th e P-450 system , so

to th e act ion of tet racyclin es, m acrolides, pen icillin s, an d

th ey can in crease th e plasm a con cen t rat ion of several drugs

som e secon d- an d th ird-gen erat ion ceph alosporin s. Tet racy-

given con com itan tly, in cluding w arfarin . Th erefore, th e pa-

clin es are st ill th e drug of ch oice for th e er yth em a m igran s,

t ien t’s bleeding w as m ost likely du e to an in creased p lasm a

w h ereas ceft riaxon e is th e preferred dr ug for th e secon d

con cen t rat ion of w arfarin .

stage of th e d isease.

A, C−F Th ese drugs do n ot a ect p lasm a con cen t rat ion of

A−C, E Th ese an t ibiot ics are n ot e ect ive again st Borrelia.

w arfarin an d are n ot act ive again st m ycoplasm a sp ecies.

Learning objective: Identify the drug used to treat relapsing fever. Learning objective: Describe the m echanism s of bacterial resistance to macrolides.

38. D Th e lab resu lt s in dicate th at spiroch etes are th e o en ding

35. C Resistan ce to m acrolides is m ain ly plasm id-m ediated. Th e

t h e d iagn osis of relap sin g fever. Th e d isease is cau sed by

t w o m ain m ech an ism s of th is resistan ce are • Mod i cat ion of t h e bin d in g site on t h e 50S r ibosom al su bun it . Th is m odi cat ion is due to th e product ion of a m ethylase en zym e th at adds a m ethyl group to th e ribosom al bin ding site, “p rotect ing” th e site from bin ding by m acrolides. • In creased act ivit y of th e m ult idrug e

u x pum p

A, E See correct an sw er exp lan at ion . B, D RNA polym erases an d glucu ron osyl t ran sferases are n ot drug-in act ivat ing en zym es.

Learning objective: Explain the m echanism of action of tetracyclines. 36. D Med iterran ean spot ted fever is a disease cau sed by Rickettsia conorii. Doxycyclin e is a tet racyclin e an t ibiot ic th at h as becom e th e drug of ch oice for m ost ricket t sial diseases because of its e

cacy, long h alf-life, an d ver y good oral bio-

availabilit y. Tetracyclines bind reversibly to the 30S ribosom al

p ath ogen s, an d th e pat ien t’s sym ptom s are con sisten t w ith several Borrelia species an d t ran sm it ted by lice or t icks. In th e Un ited States, th e d isease is en dem ic in areas w h ere th ere are t icks th at h arbor Borrelia (u su ally rem ote set t ings in th e w estern m ou n tain s an d sem iarid p lain s). Th e d isease is ch aracterized by recurren t febrile paroxysm s last ing 3 to 5 days an d sep arated by in ter vals of app aren t recover y, as in th is case. Borrelia species are sen sit ive to tet racyclin es, m acrolides, pen icillin s, an d som e secon d- an d th ird-gen erat ion ceph alosporin s. Doxycyclin e is often th e preferred drug. A Syp h ilis is cau sed by a sp iroch ete, bu t t h e sym ptom s are qu ite d i eren t , an d th e d isease can n ot be cu red by st reptom ycin . B Brucellosis can be cured by st reptom ycin but is n ot cau sed by a spiroch ete. C Rocky Moun t ain spot ted fever can be cured by tet racyclin es but is n ot cau sed by a spiroch ete. E, F Th ese diseases are n ot caused by spiroch etes an d can n ot be cured by β-lactam an t ibiot ics.

460


Learning objective: Explain the m echanism of action of chloram phenicol.

Learning objective: Identify bacterium sensitive to tetracyclines. 42. A Th e p at ien t’s sign s an d sym ptom s an d th e fact th at doxy-

39. B Ch loram ph en icol en ters th e cell by facilitated di u sion

cyclin e w as ch osen for th erapy in dicate th at th e o en ding

an d bin ds reversibly w ith th e 50S ribosom al su bu n it . At th is

p ath ogen w as m ost likely Vibrio cholerae. Ch olera is en dem ic

site, it p reven t s bin d ing of t h e am in o acid −con t ain ing en d

in p ort ion s of Asia, Africa, an d Sou th an d Cen t ral Am erica.

of th e am in oacyl t ran sfer RNA (tRNA) to th e acceptor site of

Th e d isease can be su bclin ical, m ild , or fu lm in an t an d p o-

th e 50S ribosom al su bu n it . Th u s, th e pept ide at th e don or

ten t ially leth al. Early t reat m en t w ith an e ect ive an t ibiot ic

site can n ot be t ran sferred to it s am in o acid acceptor, an d th e

can stop diarrh ea in 48 h ou rs (th u s decreasing u id loss) an d

t ran sp ept id at ion react ion can n ot occu r. Th e d r ug is u sed

sh orten th e du rat ion of th e carrier state. V. cholerae is sen si-

ver y rarely for system ic t reat m en t because of it s toxicit y bu t

t ive to m acrolides, tet racyclin es, an d u oroqu in olon es. Dox-

is frequen tly used top ically, as in th is case, as it h as a ver y

ycyclin e is often th e preferred agen t .

broad act ivit y spect ru m .

B−E All of th ese bacteria are resist an t to tet racyclin es.

A Th is is th e m ech an ism of act ion of β-lact am drugs. C Th is is th e m ech an ism of act ion of u oroquin olon es.

Learning objective: Describe the adverse e ects of doxycycline.

D Th is is th e m ech an ism of act ion of an t ifungal azoles.


E Th is is th e m ech an ism of act ion of am in oglycosides.

m ost likely su ering from a p h ototoxic react ion du e to doxycyclin e. Tet racyclin es can cau se ph ototoxicit y th at u su ally

Learning objective: Outline the therapy for neonatal listeriosis.

h as th e clin ical appearan ce of an exaggerated su n burn reac-

40. B Neon at al sep sis occu rs in abou t 1 in 1000 live bir t h s.

t ion . Oth er an t ibiot ics th at can cau se p h ototoxicit y are u o-

Preter m n ew bor n s are esp ecially at r isk. Mor t alit y ran ges

roquin olon es an d sulfon am ides.

from 10 to 50% an d is h igh er in th ose w ith early-on set dis-

A−C, E, F Th e r isk of a p h ototoxic react ion w it h t h ese

ease. Th e m ost com m on path ogen s foun d in n eon at al sepsis

d r ugs is n egligible. Moreover, th ese an t ibiot ics are n ot act ive

are st reptococci an d st aphylococci, bu t an oth er im port an t

again st n ongon ococcal ureth rit is, w h ich is u sually cau sed by

an d often overlooked path ogen is Listeria m onocytogenes. A

Chlam ydia t rachom at is or Ureaplasm a urealyt icum .

p en icillin (am p icillin or p en icillin G) w it h an am in oglycon eon at al listeriosis. Am picillin is ver y e ect ive again st Liste-

Learning objective: Identify the drug used together with quinidine to treat Plasmodium falciparum malaria.

ria, an d th e am in oglycoside m ay provide syn ergy.

44. C Tet racyclin es are e ect ive again st som e p rotozoa, in clu d-

sid e (m ain ly gen t am icin ) is t h e st an dard t h erapy again st

A, D Tet racyclin es an d m acrolides are both act ive again st

ing P. falciparum . Th ey are m ain ly u sed, togeth er w ith qu i-

Listeria, bu t bacteriostat ic an t ibiot ics are rarely rst-ch oice

n in e or quin idin e, in cases of severe m alarial at tack, as in th is

agen ts in case of severe, life-th reaten ing in fect ion s.

case. Doxycyclin e is th e p referred drug an d sh ou ld overlap

C, E, F Cephalosporins, aztreonam , and m etronidazole are n ot act ive again st Listeria.

qu in idin e for 2 or 3 days before th e lat ter is discon t in u ed. A, B, D−F Th ese drugs are n ot e ect ive again st Plasm odia.

Learning objective: Explain the reason for contraindication of tetracyclines during pregnancy.

Learning objective: Identify the antibiotic used to treat infection due to vancomycin-resistant Staphylococcus aureus.

41. A Lym ph ogran u lom a ven ereu m is a ch lam ydial disease en -

45. F In recen t years, m eth icillin -resist an t (MR) st ap hylococci

d em ic in part s of Africa, ch aracterized by a t ran sitor y pri-

h ave been associated w ith th e em ergen ce of resist an ce to

m ar y skin lesion follow ed by su pp u rat ive lym ph aden it is an d

van com ycin , too. Becau se van com ycin w as con sid ered t h e

lym p h angit is. Doxycyclin e an d er yt h rom ycin rap id ly h eal

last -lin e t h erapy for MR st ap hylococci, t h ese

th e disease. Tet racyclin es are bou n d to calciu m dep osited in

w or r isom e. Th e com bin at ion of qu in u p r ist in p lu s d alfo -

n ew ly form ed bon e an d teeth of young ch ildren an d in fetal

p r ist in , t w o an t ibiot ics of th e st reptogram in fam ily, h as been

bon es. Th erefore, t h ey m ay cau se in h ibit ion of fet al grow t h

sh ow n to be e ect ive again st van com ycin -resistan t (VR)

if given during pregn an cy.

stap hylococci, as w ell as VR Enterococcus faecium , an d cu r-

B−E Tet racyclin es h ave a n egligible risk of th ese adverse e ect s.

n d ings are

rently represents a rst-line treatm ent against these bacteria. A−E VR staphylococci are usually resist an t to all th e listed an t ibiot ics.

Answers and Explanations: VIII-2 Bacterial Protein Synthesis Inhibitors 461 Learning objective: Identify the pair of drugs used to treat brucellosis.

Learning objective: Identify the antibiotic causing candidiasis in a patient with acne.

46. B Brucellosis is a zoon ot ic in fect ious disease ch aracterized

49. E Th e pat ien t’s gen ital can didiasis w as m ost likely a su per-

by an acu te febr ile st age an d a ch ron ic st age w it h relap ses

in fect ion cau sed by an t ibiot ic-m ed iated alterat ion of t h e

of fever, sw eat s, an d vagu e p ain s. Brucellae are sen sit ive to

n or m al gen it al m icro ora. Becau se t h e w om an h ad acn e,

several an t ibacter ial d r ugs, in clu d ing am in oglycosid es, tet -

sh e m ost likely received tet racyclin e, t h e m ost com m on

racyclin es, ch loram p h en icol, im ip en em , r ifam p in ,

u oro -

an t ibiot ic u sed in m oderate to severe acn e. Propionibacte-

qu in olon es, an d t r im et h op r im -su lfam et h oxazole. Becau se

rium acnes is an an aerobic cor yn ebacteriu m th at resides in

t reat m en t w it h a sin gle agen t h as been associated w it h a

norm al skin and participates in the pathogenesis of acne. The

h igh incidence of relapse, com bination therapy is used w hen -

bacteriu m is ver y sen sit ive to tet racyclin es an d m acrolides.

ever possible. Th e com bination of doxycycline and an am ino-

Th e risk of superin fect ion is h igh er w ith broad-spect rum

glycoside (streptom ycin , gen tam icin, or am ikacin ) for 4 w eeks

an t ibiot ics such as tet racyclin es. Long-term t reat m en t w ith

follow ed by th e com bin at ion of doxycyclin e an d rifam pin for

th ese drugs, as in th is case, furth er in creases th e risk.

4 to 8 w eeks seem s to be th e m ost e ect ive regim en . A Rifam pin is e ect ive again st br ucellae, but m et ron ida-

A−D, F Non e of th ese dr ugs are used to t reat acn e, an d th ey rarely cau se su perin fect ion s.

zole is n ot . C−E Brucellae are n ot sen sit ive to van com ycin , m acrolides, p en icillin s, an d cep h alosporin s.

Learning objective: Describe the outcom e of interaction bet ween tetracyclines and dairy products. 50. E Tet racyclin e absorpt ion (except th at of d oxycyclin e an d

Learning objective: Identify the drug used to treat Rocky Mountain spot ted fever.

m in ocyclin e) is im p aired by som e cat ion s (Ca 2+, Mg 2+, Fe 2+,

47. B Th e classic t riad of fever, rash , an d h istor y of t ick exp osu re

a com plex th at can n ot perm eate th e in test in al w all. Th ere-

st rongly suggest s th e diagn osis of Rocky Mou n t ain sp ot ted

fore, product s th at con tain a large am oun t of th ese cat ion s

fever. Th e d isease is cau sed by Rick et t sia rick et t sii an d can

(e.g., m ilk an d dair y produ ct s, an tacids, an d iron an d zin c

be seriou s, w ith a m or talit y rate of abou t 5%, largely du e to

su pplem en t s) m u st n ot be ad m in istered w ith tet racyclin es.

d elay in in it iat ing speci c t reat m en t . Ricket t siae are sen si-

Th e d ecrease in d r ug oral bioavailabilit y is p ron ou n ced

t ive to tet racyclin es, ch loram p h en icol, m acrolides, an d u o-

(50−90 %).

Al3+) because tetracyclines can chelate these cations, form ing

roquin olon es, but tet racyclin es such as doxycyclin e rem ain


th e drugs of ch oice. A, C−F Th ese dr ugs are n ot e ect ive again st ricket t siae.

Learning objective: Describe the m echanism s of bacterial resistance to tetracyclines. 48. E Resistan ce to tet racyclin es is m ain ly p lasm id m ediated. Th e m ajor m ech an ism s are • In creased act ivit y of th e m ult idrug e

u x pum p

• Decreased u ptake of th e d rug • Produ ct ion of ribosom e p rotect ion protein s th at preven t th e access of tet racyclin es to th e ribosom e Plasm ids th at in clu d e gen es involved in th e p rodu ct ion of th e tet racyclin e e

u x pu m p com m on ly in clude resistan ce

gen es for several an t ibiot ics. A−D See correct an sw er explan at ion .

BACTERIAL PROTEIN SYNTHESIS INHIBITORS Answ er key 1. 2. 3. 4. 5.

O L B E J

6. 7. 8. 9. 10.

E D C D E

11. 12. 13. 14. 15.

D A A D B

16. 17. 18. 19. 20.

B E E E E

21. 22. 23. 24. 25.

D B B C B

26. 27. 28. 29. 30.

E E C C B

31. 32. 33. 34. 35.

C C D B C

36. 37. 38. 39. 40.

D D D B B

41. 42. 43. 44. 45.

A A D C F

46. 47. 48. 49. 50.

B B E E E

462


Answers and Explanations: VIII-3 Inhibitors of Bacterial Nucleic Acid Synthesis or Function Questions 1−3

t r im eth op rim -su lfam eth oxazole h as been reported to cau se

1. B

u p to th ree t im es as m any derm atologic react ion s as do su l-

2. E

fon am ides alon e. A, B, D, E Th ese drugs are n ot cu rren tly u sed to t reat acu te

3. A

ph ar yngit is, an d th ey are n ot given orally.

Learning objective: Describe the antibacterial spectrum of uoroquinolones. 4. C Cipro oxacin is a

u oroqu in olon e an t ibiot ic. Th ese drugs

Learning objective: Describe the adverse e ect s of quinolones.

uoro-

h ave a broad an t ibacterial spect rum th at in cludes som e gram -

7. E Fluoroquin olon es h ave been associated w ith an in creased

p osit ive bacter ia, m ost gram -n egat ive bacter ia, an d som e

risk of ten d on ru pt u re th at can occu r even after sh ort-term

m ycobacteria, m ycoplasm as, ch lam ydiae, an d ricket t siae.

u se of th ese drugs. Th is adverse e ect h as been o

cially re-

A, B Pip eracillin an d ceftazidim e are e ect ive again st Pseu-

ported in literally h u n dreds of p at ien t s. Th e m ech an ism of

dom onas aeruginosa bu t n ot again st m ycobacter ia, m yco -

th is act ion seem s related to a direct cytotoxic e ect of th e

p lasm as, ch lam ydiae, an d ricket tsiae.

drug on th e ligam en t t issu e. In fact , in vit ro exp osu re of ten -

D Er yth rom ycin is e ect ive again st m ycobacteria, m yco-

don t issu e to cipro oxacin resulted in a decrease in broblast

plasm as, ch lam ydiae, an d ricket t siae bu t n ot again st P. aerugi-

proliferat ion , a decrease in collagen syn th esis, an d a sign i -

nosa an d m ycobacteria.

can t in crease in m at rix-d egrad ing proteolyt ic act ivit y.

E Van com ycin is e ect ive on ly again st gram -p osit ive

A−D Th ese drugs do n ot cause ten don rupt ure.

bacter ia.

Learning objective: Explain the m echanism of resistance to sulfonam ides.

Learning objective: Describe the m ain drug interactions with uoroquinolones. 8. A Products con t ain ing divalen t an d t rivalen t cat ion s (Mg 2+,

5. C Many bacteria origin ally sen sit ive to su lfon am ides are n ow

Ca 2+, Zn 2+, Al3+, Fe 2+), such as an tacids, m ilk product s, an d

resistant. Resistance to trim ethoprim -sulfam eth oxazole is less

Fe 2+-con t ain ing m edicat ion s, invariably cause a sign i can t

frequ en t th an resistan ce to eith er of th e agen t s alon e, bu t it

d ecrease in in test in al absorpt ion of u oroquin olon es (u p to

st ill occu rs in several cases. W h en resist an ce develops, it is

70%) becau se u oroqu in olon es can ch elate th e cat ion s, form -

u su ally persisten t an d irreversible. Mech an ism s of resist an ce

ing in solu ble com pou n ds. Th is m ay resu lt in th erap eu t ic fail-

to sulfon am ides are

u res. It is th erefore im perat ive th at clin ician s quest ion pat ien ts

• Decreased a

n it y for sulfon am ides by dihydropteroate

syn th et ase • Decreased bacterial p erm eabilit y to th e d rug • In creased p rodu ct ion of p ara-am in oben zoic acid (PABA). For exam p le, som e resistan t st aphylococci m ay syn th esize 70 t im es as m u ch PABA as d o t h e su scept ible p aren t al st rain s. A, E Th ese m ech an ism s w ou ld in crease, n ot decrease, th e bacterial sen sit ivit y to su lfon am ides. B Sulfonam ides do not act by binding to bacterial ribosom es. D Su lfon am ides do n ot act by bin ding to dihydrofolate reduct ase.

Learning objective: Identify the drug that can cause derm atitis in a previously sensitized person. 6. C Th e p at ien t ’s h istor y an d sym ptom s suggest t h at h e h ad an allergic react ion to t rim eth op rim -su lfam etoxazole. Rash is a com m on adverse e ect associated w ith su lfon am ide u se an d is m ost frequ en t ly d u e to hyp ersen sit ivit y. Moreover,

regarding oth er m edicat ion s, both p rescript ion an d n onp rescript ion , th at th ey m ay be t aking an d in st ru ct th em to avoid cer tain produ ct s, as in th is case. B−E See correct an sw er explan at ion .

Learning objective: Outline the therapeutic uses of cipro oxacin. 9. B Th e pat ien t’s h istor y an d sym ptom s in dicate th at h e w as m ost likely su ering from t raveler’s diarrh ea, a disease den ed as th ree or m ore loose stools per day plus at least on e en teric sym ptom . Th e disease is du e to en terobacteriaceae, w ith Escherichia coli being th e cau sat ive agen t in m ore th an 50% of cases. Many an t im icrobial agen t s h ave been sh ow n to sh or ten t h e d u rat ion an d sever it y of diar rh ea, bu t becau se of th e in creasing resist an ce of en terobacteriaceae, cu rren tly uoroquin olon es, an d to a lesser exten t t rim eth oprim -sulfam eth oxazole, are recom m en ded for th e em piric t reat m en t of t raveler’s d iarrh ea. A, C−F Th ese d r ugs are n ot act ive again st m ost en tero bacteriaceae.

Answers and Explanations: VIII-3 Inhibitors of Bacterial Nucleic Acid Synthesis or Function 463 Learning objective: Explain the rationale of the trim ethoprim sulfam ethoxazole com bination.

com bin at ion of pen icillin G an d m et ron idazole is used in

10. D The trim eth oprim -sulfam ethoxazole com bination kills sen -

t rat ion equ al to or in excess of ser u m levels an d is bacter i-

sit ive bacteria, w h ereas su lfon am ides an d t rim eth op rim are

cid al again st an aerobes. Moreover, in th is case, th e ap p aren t

both bacteriostat ic drugs. Th e syn ergist ic e ect of th e com -

good act ivit y of clin dam ycin in th e p reviou s sin u sit is p oin t s

bin at ion is m ost likely du e to th e in h ibit ion of t w o con secu -

out th at an aerobes are m ost likely th e m ain bacteria of th e

t ive step s in th e syn th esis of tet rahydrofolic acid, w h ich is

pat ien t’s abscess.

essen t ial for th e syn th esis of purin es an d th en for th e syn -

m ost cases. Met ron idazole ach ieves abscess

u id con cen -

A, C−E Th ese an t ibiot ics are n ot act ive again st an aerobes.

th esis of DNA. A, E Th e com bin at ion d oes n ot a ect t h e p h ar m acokin et ics of eith er drug.

Learning objective: Explain the m echanism of action of uoro quinolones.

B Because both dr ugs can cause allergic react ion s, th e risk

14. B Cip ro oxacin is a u oroqu in olon e an t ibiot ic. Flu oroqu in o-

of th ose react ion s, if anyth ing, sh ould be in creased, n ot

lon es in h ibit bacterial DNA syn th esis by blocking th e follow -

d ecreased.

ing en zym es:

C It is w ell kn ow n th at pat ien t com plian ce is in creased

• Topoisom erase II (also called DNA gyrase). Th e blockade

w h en few er pills m ust be taken , but th is is n ot th e reason for

preven ts th e relaxat ion of su p ercoiled DNA, w h ich is re-

th e drug com bin at ion .

qu ired for n orm al t ran script ion (prevalen t m ech an ism in gram -n egat ive bacteria).

Learning objective: Outline the therapeutic uses of cipro oxacin.

• Topoisom erase IV. Th e blockade in terferes w ith separa-

11. D Th e pat ien t’s sign s an d sym ptom s in dicate th at h e w as

t ion of replicated ch rom osom al DNA d u ring cell division

su ering from pn eu m on ia. Th e associated relat ive bradycar-

(p revalen t m ech an ism in gram -p osit ive bacteria).

d ia, gast roin test in al sym ptom s, an d m icroh em at u r ia sug-

A Th is is th e m ech an ism of act ion of β-lact am an t ibiot ics.

gest Legion n aires’ disease, a pn eu m on ia cau sed by Legionella

C Th is is th e m ech an ism of act ion of am in oglycosides.

sp ecies (m ain ly Legionella pneum ophila), w h ich accou n t s

D Th is is th e m ech an ism of act ion of an t ifungal azoles.

for 1 to 3% of all p n eu m on ias. L. pneum ophila is sen sit ive to

E Helicases are en zym es involved in DNA st ran d separa-

m acrolides,

u oroqu in olon es, tet racyclin es, t rim eth op rim -

sulfam eth oxazole, an d rifam pin. Eryth rom ycin, alone or w ith rifam p in , is th e t reat m en t of ch oice. Flu oroqu in olon es su ch

t ion du ring rep licat ion . Flu oroqu in olon es h ave n o act ivit y on th ese en zym es. F Th is is th e m ech an ism of act ion of rifam pin .

as cip ro oxacin m ay be u sefu l in case of in toleran ce to m acrolides, as in th is case. A, B, C, F L. Pneum ophila is n ot sen sit ive to th ese an t ibiot ics. E See correct an sw er explan at ion .

Learning objective: Describe the antibacterial spectrum of uoroquinolones. 12. E Haem ophilus in uen zae can cau se ot it is m ed ia in ad u lt s, alt h ough St reptococcus pneu m oniae an d Staphylococcus aureus are m ore com m on . H. in uenzae is ver y sen sit ive to

Learning objective: Identify the bacterium that is sensitive to trimethoprim -sulfamethoxazole. 15. E Th e su ccessfu l t reat m en t in d icates t h at t h e o en d in g p ath ogen w as sen sit ive to t rim eth oprim -sulfam eth oxazole. Escherichia coli is t h e m ost com m on cau sat ive agen t of u r in ar y t ract in fect ion an d is sen sit ive to t r im et h op r im su lfam eth oxazole, even th ough resist an ce h as sign i can tly in creased in recen t years. A−D All of th ese bacteria are resistan t to t rim eth oprim su lfam eth oxazole.

uoroquin olon es, such as cipro oxacin . A−D Th ese bacteria do n ot cause ot it is m edia an d are resistan t to u oroqu in olon es.

Learning objective: Outline the therapeutic uses of metronidazole.

Learning objective: Describe the m ain contraindications of uoroquinolones. 16. F Flu oroqu in olon es are largely u sed for u rin ar y t ract in fect ion s becau se of th eir excellen t act ivit y again st m ost gram -

13. B Brain abscesses m ost com m on ly arise from a con t iguous,

n egat ive bacteria, bu t th ey are con t rain dicated in people

su p p u rat ive sou rce of in fect ion (sin u sit is, m astoidit is, an d

w ith long QT in ter val of any cause, as th ey can in crease QT

d en t al in fect ion ), as in th is case. St reptococci are im plicated

interval, predisposing to polym orphic ventricular tachycardia.

in about 60% of cases an d in clude both an aerobic an d m i-

A−E All of th ese an t ibiot ics are act ive again st gram -n ega-

croaeroph ilic st reptococci. Bacteroides are fou n d in abou t

t ive rods an d are n ot con t rain dicated in p erson s w ith long

40% of cases. An t ibiot ic t h erapy for brain abscess n eed s to

QT in ter vals.

be su

cien tly broad to cover th e m ost likely p ath ogen s. A

464


Learning objective: Outline the therapeutic uses of cipro oxacin.


17. C Dissem in ated Mycobacterium av ium com p lex (MAC) in -

21. B A variet y of regim en s h ave been u sed to eradicate Helico-

fect ion is com m on in en d-st age AIDS p at ien t s. Th e risk of

bacter pylori, each w ith di eren t dosing sch edu les, adverse

d eveloping th e in fect ion is st rongly associated w ith a CD4+

e ect s, an d cost . Com bin at ion t h erapy w it h t w o or t h ree

lym p h ocyte cou n t of less th an 100 cells/m m 3 . Tran sien t bac-

an t ibiot ics plu s an H2 an t agon ist or a p roton pu m p in h ibitor

terem ia is follow ed by invasion of t issues result ing in organ

is associated w ith th e h igh est rate of eradicat ion . An t ibiot ics

dysfu n ct ion . Any organ can be involved, an d p at ien t s often

e ect ive again st H. pylori are am oxicillin , clarith rom ycin ,

presen t w ith n on sp eci c sym ptom s, as in th is case.

m et ron idazole, an d tet racyclin e.

Th e curren t recom m en ded regim en for MAC in fect ion in cludes th ree drugs. Clarith rom ycin plus eth am butol are th e

A, C−E Non e of th ese p airs in clu de t w o an t ibiot ics e ect ive again st H. pylori.

preferred t w o, an d th e th ird agen t m ay be cip ro oxacin , rifam bu t in , or im ipen em . A, B, D−F Non e of th ese drugs are e ect ive again st MAC.

Learning objective: Explain the m echanism of action of sulfonam ides. 22. D Su lfon am ides are com p et it ive in h ibitors of th e bacterial

Learning objective: Outline the therapeutic uses of sulfonam ides.

en zym e dihydropteroate syn th et ase, w h ich is resp on sible

18. D Th e pat ien t’s sign s (a cavitar y lesion seen on a ch est x-ray)

for th e in corporat ion of para-am in oben zoic acid (PABA) in to

an d lab resu lt s suggest th e diagn osis of n ocardiosis. Nocar-

d ihydropteroic acid, th e im m ediate p recu rsor of folic acid.

dia asteroides is th e m ost com m on path ogen in n ocardiosis,

Because bacterial cells use PABA to syn th esize folic acid, th e

an opp ort u n ist ic in fect ion associated w ith several risk fac-

syn th esis of folic acid is in h ibited. Th is in t u rn in h ibit s th e

tors, in clu ding im m u n osuppression , as in th is case (see th e

syn th esis of bacterial p u rin es th at are n eeded for th e syn -

p rolonged cort icosteroid t reat m en t). In n ocardiosis, su lfon -

th esis of n u cleic acids. In con t rast , m am m alian cells u se pre-

am ides are rst-lin e agen ts. Altern at ive drugs in clu de p en i-

form ed folic acid th at is presen t in th e diet an d th erefore are

cillin s, am in oglycosides, an d tet racyclin es (doxycyclin e an d

n ot sen sit ive to th e act ion of sulfon am ides.

m in ocyclin e).

A−C, E Th ese en zym es are n ot in h ibited by sulfon am ides.

A−C, E Th ese antibiotics are not e ective against Nocardia.


Learning objective: Describe the use of m etronidazole in Clostridium dif cile−associated colitis.

19. A Fu lm in an t colit is is a rare bu t severe for m of p an colit is,

23. A Th e oral agen t s m ost com m on ly u sed to t reat p seu do-

an in am m at ion a ect ing th e en t ire colon . Pat ien t s w ith

m em bran ou s colit is du e to C. di cile are van com ycin an d

p an colit is are at risk of developing toxic m egacolon , an d an

m et ron idazole. Th e t w o drugs h ave com p arable e

em ergen cy t reat m en t m u st in clu de in t raven ou s

w h en van com ycin fails, a t reat m en t w ith m et ron idazole is

u id an d

elect rolyte th erapy, h igh -dose cort icosteroids, an d an t ibiot-

cacy, but

th e m ost appropriate course of act ion .

ics. Because Bacteroides fragilis is th e m ost abun dan t bacte-

B, C Oral van com ycin p roduces fecal con cen t rat ion s th at

riu m in th e h u m an colon , m et ron idazole rem ain s a rst-lin e

are 100 t im es th e con cen t rat ion n eeded to in h ibit C. di cile,

agen t. Fluoroquinolon es, clindam ycin, cefoxitin, an d cefotetan

so in creasing th e dose or u sing in t raven ou s van com ycin are

m ay be altern at ives.

n ot u seful opt ion s.

B−F Th ese an t ibiot ics are n ot e ect ive again st B. fragilis.

D, E Th ese an t ibiot ics are n ot e ect ive again st C. di cile in fect ion s.

Learning objective: Identify the bacterium that is sensitive to trimethoprim -sulfamethoxazole. 20. F Th e pat ien t’s h istor y, th e lab resu lts, an d th e prescribed

Learning objective: Identify the antibiotic that can cause m egaloblastic anem ia.

th erapy suggest th at th e pn eu m on ia w as du e to Pneum ocys-

24. D Th e pat ien t w as m ost likely t reated w ith t rim eth oprim -

t is jiroveci, a w ell-recogn ized op p or t u n ist ic in fect ion in AIDS

su lfam eth oxazole, a

pat ien ts. Th e p ath ogen grow s ext racellu larly in th e su rfac-

t ract in fect ion . Th e p at ien t’s sym ptom s an d th e lab resu lts

tan t layer of th e lu ng. Th e blockad e of th e oxygen exch ange

in dicate th at sh e w as m ost likely su ering from m egaloblas-

in terface resu lt s in hypoxem ia an d cyan osis. Th e m edicat ion

t ic an em ia. Trim eth op rim m ay cau se th e p redict able adverse

of ch oice for p n eu m ocyst is p n eu m on ia is t r im et h op r im -

e ect s of an an t ifolate drug, in clu ding m egaloblast ic an e-

su lfam et h oxazole; p en t am id in e is also e ect ive an d m ay

m ia. Th e an em ia is rare in h ealthy in dividu als bu t can occu r

be given as an altern ate drug.

in p at ien ts w h o are already folate-de cien t from di eren t

A−E, G Pseudom onas aeruginosa, Clost ridium di cile, m ycoplasm as, ricket tsiae, spiroch etes, an d en terococci are resistan t to t rim eth oprim -su lfam eth oxazole.

rst-lin e drug com bin at ion for u rin ar y

cau ses, su ch as poor diet , m alabsorpt ion syn drom es, m align an cy, or alcoh olism , as in th is case. A−C, E−G Th ese drugs do n ot a ect folate m et abolism .

Answers and Explanations: VIII-3 Inhibitors of Bacterial Nucleic Acid Synthesis or Function 465 Learning objective: Outline the therapeutic uses of metronidazole.

th e drug is e ect ive again st several en terobacteriaceae (w ith

25. E Th e p at ien t’s h istor y an d sym ptom s in dicate th at sh e w as

th e except ion of P aeruginosa an d an aerobes) th at are usu -

m ost likely a ected by Clost ridium di cile−associated p seu-

ally presen t in urin ar y t ract in fect ion s.

dom em bran ou s colit is. Th e disease h as em erged as a m ajor

A, B Becau se t h e bacter iu m w as resist an t to am p icillin

t h reat to eld erly p at ien t s receivin g cer t ain an t ibiot ics. Am -

an d cip ro oxacin , it w ou ld be illogical to u se am oxicillin or

p icillin , clin dam ycin , an d ceph alosporin s are th e an t ibiot ics

m oxi oxacin becau se cross-resistan ce w ould be likely.

m ost com m only associated w ith the condition. Other drugs are

C, D, F Th ese an t ibiot ics are n ot e ect ive again st E. coli.

pen icillin s, er yth rom ycin , t rim eth oprim -su lfam eth oxazole, likely t h e cau sat ive an t ibiot ic in t h is case. Met ron idazole

Learning objective: Explain the m echanism of action of m etronidazole.

an d van com ycin are th e t w o rst-lin e agen ts for C. di cile−

29. D Met ron idazole is an an t ibiot ic act ive again st m ost m icro-

u oroqu in olon es, an d tet racyclin es. Am p icillin w as m ost

associated colit is.

aerop h ile an d an aerobic bacter ia an d an aerobic p rotozoa.

A−D, F Non e of t h ese an t ibiot ics are e ect ive again st

Th ese m icroorgan ism s, u n like t h eir aerobic cou n ter p ar t s, con t ain elect ron t ran sp or t com p on en t s called fer red oxin s

C. di cile.

th at can d on ate elect ron s to m et ron idazole. Th is don at ion

Learning objective: Describe the m ain drug interactions with metronidazole.

form s a h igh ly react ive n it ro radical an ion th at dam ages bac-

26. F Bacterial vagin osis is due to a com plex alterat ion of vagin al

A−C, E All of th ese an t ibiot ics are act ive again st Bacteroi-

ora in w h ich lactobacilli decrease an d an aerobic path ogen s

des fragilis, bu t th ey h ave m ech an ism s of act ion di eren t

overgrow. Topical or oral m etronidazole is the agent of choice.

terial DNA. Th e ult im ate e ect is bactericidal.

from th at of m et ron idazole.

Th e drug can in h ibit aldehyde dehydrogen ase an d th erefore acet aldehyde in people drin king alcoh ol con com itan tly. Th e

Learning objective: Explain the adverse fetal e ect s of trim ethoprim -sulfam ethoxazole in pregnant wom en.

reaction m ay cause ushing, throbbing h eadache, nausea and

30. B Trim eth oprim -sulfam eth oxazole com bin at ion is curren tly

can cau se a d isu l ram -like e ect d u e to accu m u lat ion of

vom it ing, hypoten sion , an d m en tal con fusion .

u sed for u r in ar y t ract in fect ion , bu t su lfon am id es h ave a

A−E Non e of th ese an t ibiot ics in teract w ith alcoh ol.

d e n ite r isk of cau sing ker n icter u s in n eon ates if given to m others during the third trim ester of pregnancy. These drugs

Learning objective: Identify the antibiotic that can cause acute hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase de ciency.

displace unconjugated bilirubin from plasm a album in, thereby

27. F Th e p at ien t m ost likely received t r im et h op r im -su lfam e-

d ue to th e low levels of glu curon osyl t ran sferase.

t h oxazole, a d r ug com bin at ion frequ en t ly u sed to t reat u r in ar y t ract in fect ion . Th e p at ien t ’s sign s an d sym ptom s (t iredn ess, dark urin e) suggest th at sh e w as su ering from

allow ing free biliru bin to en ter th e brain . Th e risk is h igh in n eon ates because bilirubin conjugat ion is already defect ive A, C, D Th ese drugs are u sed in u rin ar y t ract in fect ion s an d are n ot con t rain dicated in pregn an cy. E, F Am in oglycosides an d

uoroquin olon es are relat ively

acu te h em olyt ic an em ia, a d isease t h at can d evelop in p er-

contraindicated in pregnancy, but not because they can cause

son s w it h congen it al de cien cy of glu cose-6-p h osp h ate

kern icteru s. Am in oglycosides can in du ce fetal ototoxicit y,

d ehydrogen ase w h en given oxidan t ch em icals. Glu cose-6-

an d u oroqu in olon es can cau se ar t icu lar car t ilage erosion .

p h osp h ate d ehydrogen ase is a key en zym e in red u ct ion react ion s, an d t h ese react ion s ap p ear to be essen t ial for m ain ten an ce of cellu lar in tegr it y. A d e cien cy of t h is en zym e results in an exaggerated sen sit ivit y to th e h em olyt ic e ect of cert ain oxidan t dr ugs su ch as su lfon am ides, an t im alarials, an d cer tain n on steroidal an t iin am m ator y drugs. A−E These drugs do not have signi cant oxidant properties.

Learning objective: Outline the therapeutic use of trimethoprim sulfam ethoxazole. 28. E Trim eth op rim -su lfam eth oxazole is st ill a

rst-lin e agen t

again st u rin ar y t ract in fect ion du e to E. coli, even th ough resistan ce h as in creased over th e past several years. Moreover,

INHIBITORS OF BACTERIAL NUCLEIC ACID SYNTHESIS OR FUNCTION Answ er key 1. 2. 3. 4. 5.

B E A C C

6. 7. 8. 9. 10.

C E A B D

11. 12. 13. 14. 15.

D E B B E

16. 17. 18. 19. 20.

F C D A F

21. 22. 23. 24. 25.

B D A D E

26. 27. 28. 29. 30.

F F E D B

466


Answers and Explanations: VIII-4 Antimycobacterial Drugs Questions 1 and 2

Learning objective: Explain the mechanism of action of ethambutol.

1. H

7. C Eth am butol in h ibit s arabin osyl t ran sferase, disrupt ing th e

2. C

syn th esis of arabin ogalact an , an essen t ial com p on en t of th e m ycobacterial cell w all. Th e ult im ate e ect is bacteriost at ic.

Learning objective: Explain the m echanism of action of isoniazid.

A Th is en zym e is in h ibited by t rim eth oprim .

3. A Ison iazid is u sed alon e for th e prophylaxis of t u bercu losis

B Th is en zym e is in h ibited by ch loram ph en icol.

in at-risk p at ien t s, in clu ding th ose w h o are HIV p osit ive, as in

D Th is en zym e is in h ibited by fosfom ycin .

th is case. Th e dr ug in h ibits th e syn th esis of m ycolic acids,

E Th is en zym e is in h ibited by sulfon am ides.

w h ich are speci c con st it u en t s of th e m ycobacterial cell w all.

F Th is en zym e is in h ibited by van com ycin .

Th is can explain , at least in part , w hy ison iazid is e ect ive on ly again st m ycobacteria. B Th e syn th esis of pept idoglycan is in h ibited by β-lact am an t ibiot ics.

Learning objective: Identify the antibiotic that is m ost likely included in the pharmacotherapy of Mycobacterium avium complex (MAC) infection.

C Arabin osyl t ran sferase is in h ibited by eth am bu tol.

8. D MAC in fect ion is com m on in en d -st age AIDS p at ien t s,

D Topoisom erase II is in h ibited by uoroquin olon es.

an d th e risk of develop ing th e in fect ion is th e h igh est w h en

E DNA-d ep en d en t RNA p olym erase is in h ibited by

th e CD4+ lym p h ocyte cou n t is less th an 50 cells/m m 3 , as in

rifam ycin s.

th is case. MAC is m u ch less suscept ible th an Mycobacterium t uberculosis to m ost an t im ycobacterial drugs, an d in m ost

Learning objective: Identify the enzym e involved in mycobacterial resistance to isoniazid.

cases d issem in ated MAC is in cu rable an d th erapy is lifelong.

4. A Ison iazid is a prodrug th at m ust be conver ted in to th e act ive

an d on e of th ese m u st be a m acrolide, such as clarith rom ycin

com pound by a m ycobacterial catalase-peroxidase. Resistance

or azith rom ycin , as th ese are th e on ly an t ibiot ics for w hich a

is often associated w it h t h e delet ion of t h e k atG gen e t h at

correlat ion bet w een in vit ro suscept ibilit y tests for MAC an d

cod es for t h e syn t h esis of cat alase p eroxidase. In t h is w ay,

clin ical respon se h as been dem on st rated. Oth er dr ugs act ive

act ivat ion of th e p rodr ug can n ot occu r.

again st MAC are rifam p in , eth am bu tol, eth ion am ide, im ip e-

B−E Th ese en zym es are n ot involved in th e m ech an ism of resistan ce of m ycobacteria to ison iazid.

Learning objective: Describe the m etabolism of isoniazid. 5. D Ison iazid is m etabolized by h epat ic acet ylat ion , w h ich is

Drug regim en s for MAC sh ould in clude at least th ree drugs,

n em , an d uoroquin olon es. A−C, E Th ese drugs are n ot act ive again st MAC.

Learning objective: Describe the prophylactic use of isoniazid in close contacts of people with active tuberculosis.

u n der gen et ic con t rol. Pat ien ts m ay be fast acet ylators (m ain ly

9. C Ison iazid is th e d r ug of ch oice to p reven t t u bercu losis in

am ong people of Asian origin ) or slow acet ylators (m ain ly

skin test conver ters an d in close con t act s of p at ien t s w ith

am ong people of European an d African origin ). Fast acet yla-

act ive d isease, as in th is case. Th e d r ug is given as th e sole

tors require h igh er dosage th an slow acet ylators to obt ain

agen t for at least 6 an d u p to 12 m on th s. In people at h igh

equ ivalen t th erap eu t ic e ect s.

risk of in fect ion w ith m u lt idrug-resistan t st rain s (i.e., HIV-

A−C, E Th ese drugs are n ot m et abolized by acet ylat ion .

p osit ive p at ien t s), p reven t ive th erapy is usually perform ed w ith m ore th an on e drug.

Learning objective: Explain the m echanism of action of rifampin. 6. A Rifam pin in h ibits DNA-d ep en den t RNA polym erase in m ycobacteria an d oth er sen sit ive m icroorgan ism s by bin ding to th e β subun it of th e en zym e to form a st able drug−en zym e com plex. Th is leads to suppression of in it iat ion of ch ain form at ion in RNA syn th esis. Th e ult im ate e ect is bactericidal.

A, B, D, E Th ese drugs are n ot u sed for p rophylaxis of t u bercu losis u n less th e pat ien t is at h igh risk of in fect ion .

Learning objective: Describe the adverse e ects of etham butol. 10. D Th e sign s an d sym ptom s of th e pat ien t are m ost likely du e to eth am butol-in duced opt ic n eurit is, a serious adverse ef-

B Th is en zym e is in h ibited by eth am butol.

fect of th e dr ug th at is dose- an d du rat ion -related. Because

C Th is en zym e is in h ibited by β-lact am an t ibiot ics.

of th is, periodic visual acuit y test ing is desirable during eth -

D Th is en zym e is in h ibited by uoroquin olon es.

am bu tol th erapy. Recover y is u sually, bu t n ot alw ays, com -

E Th is en zym e is in h ibited by reverse t ran scr ipt ase

p lete w h en th e drug is discon t in u ed.

in h ibitors.

A−C, E Th ese drugs do n ot cause opt ic n eurit is.

Answers and Explanations: VIII-4 Antimycobacterial Drugs 467 Learning objective: Outline the pharmacotherapy for hemorrhagic mycobacterial pericarditis.

glu cocort icoids, oral con t racept ives, m eth adon e, β-blockers,

11. D Th is pat ien t dem on st rates m any of th e clin ical feat ures

creased to m ain tain an app rop riate an t icoagu lan t e ect .

of con st rict ive pericardit is, in cluding an in spirator y in crease of system ic ven ous pressure (Ku ssm aul sign ), th ird h ear t sou n d, an d n arrow pu lse p ressu re. Th e slow develop m en t

an d w arfarin . Th erefore, th e dose of w arfarin sh ould be in B Th e dose of propran olol sh ould be raised, n ot reduced, becau se th e m et abolism of th e drug is in creased . C−E All of th ese opt ion s are irrat ion al.

of sym ptom s an d th e large am oun t of bloody uid rem oved by pericardiocen tesis in dicate su bacute e u sive-con st rict ive

Learning objective: Describe the hepatotoxicit y of isoniazid.

p ericardit is. Th e t w o m ost com m on cau ses for h em orrh agic

15. D Th e sym ptom s of th e pat ien t an d th e lab results in dicate

p ericardit is are t u berculosis (TB) an d m et ast at ic carcin om a.

th at sh e w as m ost likely su ering from ison iazid-in du ced

Because th e p at ien t is HIV posit ive, TB is m uch m ore likely.

h epat it is, w h ich is th e m ost frequen t m ajor toxic e ect of

In fact , TB is th e leading cau se of death in HIV-in fected peo-

ison iazid. It occu rs in about 1% of p at ien t s an d can lead to

p le w orldw ide. An t im ycobacterial th erapy sh ould be carried

potentially fatal m ultilobular necrosis. The risk increases w ith

out if a TB origin can be diagn osed, is suspected, or can n ot be

age an d in alcoh olics, as in th is case.

excluded in a pat ien t w ith ch ron ic con st rict ive pericardit is.

A−C, E Th ese disorders cause n eith er th e sym ptom s re-

Ison iazid an d rifam pin are th e leading drugs for TB even if, as

ported by th e pat ien t n or an in crease in am in ot ran sferase

in th is case, a four-drug regim en in cluding pyrazin am ide

level.

an d eth am bu tol sh ou ld be adm in istered becau se TB pericar-

F Eth am butol-in duced h epat it is is a ver y rare disorder.

d it is is a ser iou s in fect ion , an d HIV p at ien t s are also at r isk of develop ing TB m en ingit is. A−C, E Th ese com bin at ion s con t ain at least on e drug n ot act ive again st Mycobacterium t uberculosis.

Learning objective: Describe the m ain reason for the use of ethambutol in the pharmacotherapy of tuberculosis (TB). 16. E Th e m ain reason for t h e u se of any d r ug com bin at ion in t h e t h erapy of TB is to d elay t h e em ergen ce of resist an ce.

Learning objective: Identify the drug to be used prophylactically in close contact s of patients with m eningococcal m eningitis.

In th e case of eth am bu tol, th is is by far th e p rim ar y reason ,

12. E Rifam pin is th e drug of rst ch oice for ch em oprophylaxis

Mycobacterium t uberculosis an d can n ot add sign i can t an t i-

of close con tact s of pat ien t s w ith m en ingococcal m en ingit is. Th e p oten t ial for a close con tact to becom e in fected w ith

as t h e d r ug h as on ly w eak bacter iost at ic act ivit y again st bacterial e ect to a given th erap eu t ic regim en . A−D All of th ese opt ion s are irrat ion al.

Neisseria m eningit idis is 500 to 800 t im es greater th an for th e tot al p op u lat ion . Th e drug sh ou ld be adm in istered as

Learning objective: Describe the adverse e ects of pyrazinam ide.

soon as p ossible becau se th e risk of secon dar y disease is

17. B Th e gast roin test in al sym ptom s an d th e h igh am in ot ran s-

greatest w ith in 2 to 5 days after exposu re to th e in dex case.

ferase levels (w h ich suggest som e liver dysfunction), together

Oth er drugs used for ch em oprophylaxis in clude ceft riaxon e

w ith th e join t pain an d hyperuricem ia, st rongly in dicate th at

an d cipro oxacin .

pyrazin am id e is th e d rug th at cau sed th ese adverse e ect s.

A−D These antibiotics are not active against N. m eningitidis.

Hepatotoxicit y is th e m ajor lim it ing adverse e ect of pyrazin am ide, is dose-related, an d is far less com m on today w ith

Learning objective: Describe the antibacterial spectrum of rifampin.

cu r ren t d osin g regim en s. Ar t h ralgia is also com m on an d

13. B Th e an t im icrobial sp ect ru m of rifam p in is broad . Th e drug

d ose-related. Hyperu ricem ia is seen in m ore th an 50%of pa-

is active again st m ost m ycobacteria; m ost gram -positive bac-

t ien t s t aking th e drug an d is likely d u e to in h ibit ion of u ric

teria, including m ethicillin-resistant staphylococci; and m any

acid secret ion .

gram -n egat ive bacteria, in clu ding Escherichia coli, Proteus,

A Rifam p in ver y rarely cau ses h ep at it is bu t can su bst an -

Klebsiella, Legionella, Brucella, Haem ophilus, Chlam ydia, an d

t ially in crease t h e r isk of h ep atotoxicit y w h en given to -

Ricket tsia sp ecies an d p oxviru ses.

get h er w it h pyrazin am id e. How ever, it d oes n ot cau se

A, D, E Th ese drugs are act ive on ly again st m ycobacteria. C Am in oglycosid e an t ibiot ics are act ive m ain ly again st gram -n egat ive aerobic bacteria.

hyp er u r icem ia. C Ison iazid can cau se h ep atotoxicit y, bu t hyp eru ricem ia is ver y rarely repor ted. D, E Th ese drugs do n ot cause h epatotoxicit y or hyper-

Learning objective: Describe the appropriate therapy for a patient treated with rifampin when another drug is given concomitantly. 14. A Rifam pin is a st rong in du cer of th e h epat ic P-450 system an d can in crease th e m etabolism of m any drugs, in clu ding

u ricem ia.

468


Learning objective: Describe the therapeutic strategy for m ultidrug-resistant tuberculosis (TB).

Learning objective: Identify the rst-line agent to treat leprosy. 21. D Leprosy is an exceedingly rare disease in th e develop ed

18. E Th e st ar t in g t reat m en t of th is p at ien t is st an dard for ac-

w orld, bu t abou t 5000 cases are reported each year in th e

t ive TB, bu t w h en resist an ce occu rs, t h e t reat m en t m u st

Un ited St ates, m ain ly in im m igran t s from Mexico an d Cen -

be ch anged. Th ere is n o stan dard regim en for m u lt idrug-

tral Am erica, as in th is case. Leprom atous leprosy is the m ost

resistan t TB, but it is crit ical to avoid adding or subst it ut ing

severe form of the disease because life-th reatening com plica-

a single drug to a failing regim en . Adding on e drug at a t im e

t ion s (er yth em a n odosu m lep rosu m an d n ecrot izing skin

leads to th e sequ en t ial select ion of drug resistan ce. Th ere-

react ion ) can develop. Dapson e, a su lfon e derivat ive, is th e

fore, t w o or m ore previously un used drugs, ch osen am ong

m ain st ay of th erapy. Th e drug con cen t rates in th e in fected

th e secon d-lin e agen t s, sh ou ld be su bst it u ted . Secon d-lin e

skin , w h ich explain s, at least in part , it s u n d ispu ted e

agen t s in clude som e am in oglycoside an t ibiot ics (m ain ly

Other drugs active against Mycobacterium leprae are rifam pin,

streptom ycin; am ikacin is also active), ethion am ide, cycloser-

clofazim ine, m acrolides, tetracyclines, and uoroquinolones.

in e, p-am in osalicylic acid, an d

uoroquin olon es. Most

uo-

roquin olon es h ave excellen t an t im ycobacterial act ivit y in

cacy.

A−C, E, F Th ese an t ibiot ics are n ot e ect ive again st M. leprae.

vit ro; m oxi oxacin seem s th e m ost act ive clin ically. A−D All of th ese com bin at ion s con t ain at least on e drug th at is n ot act ive again st Mycobacterium t uberculosis.

Learning objective: Explain the m echanism of bacterial resistance to ethambutol. 22. C A gen eral m ech an ism of resist an ce to an t im ycobacterial

Learning objective: Describe the use of pyridoxine to prevent isoniazid-induced neurotoxicit y.

d rugs is related to m u t at ion of gen es th at en code for th e syn -

19. B Th e pat ien t is m ost likely su ering from ison iazid-in du ced

t ion in h ibits bin ding of th e drug to th e en zym e, p reven t ing

peripheral neuropathy. Neurotoxicit y is the m ost com m on ad-

an t ibacterial act ivit y. Eth am butol resist an ce is th ough t to

verse e ect of isoniazid w hen the daily dose exceeds 6 m g/kg

result prim arily from m utat ion in th e gen e th at en codes for

(u n less pyridoxin e is given con curren tly), likely because th e

m ycobacterial arabin osyl transferase, th e en zym e speci cally

d rug prom otes th e excret ion of pyridoxin e, a vit am in in -

in h ibited by th e drug.

volved in several m etabolic t ran sform at ion s, in clu ding th e syn th esis of som e n eu rot ran sm it ters (gam m a-am in obu t yric

th esis of en zym es th at are in h ibited by th e drug. Th is m u ta-

A, B, D−F Th ese act ion s are n ot involved in t h e m ycobacterial resist an ce to eth am butol.

acid, n orepin eph rin e, an d seroton in ). Th e risk of n eu rotoxicit y is in creased in slow acet ylators, alcoh olics, an d diabet ics, ANTIMYCOBACTERIAL DRUGS Answ er key

as in th is case. Perip h eral n eu ropathy is th e m ain sign of ison iazid n eurotoxicit y (it can a ect as m any as 20% of pat ien t s at risk), bu t h igh doses can also provoke m em or y loss, con fu sion, hallucination s, and seizures. Most n eurotoxic e ects can be preven ted or corrected by pyridoxin e su p p lem en tat ion w ith out losing th e an t ibacterial e ect , A, C−E Th ese drug are u seless in ison iazid-in du ced n eu rotoxicit y.

Learning objective: Explain the m ost com m on m echanism of bacterial resistance to rifampin. 20. C Resist an ce to rifam p in resu lts p rim arily from m u t at ion in th e gen e th at codes for th e β su bu n it of RNA p olym erase. Th is m u tat ion preven t s bin d ing of rifam pin to th e en zym e. A, B, D, E Th ese en zym es are n ot involved in th e bacterial resistan ce to rifam pin .

1. 2. 3. 4. 5.

H C A A D

6. 7. 8. 9. 10.

A C D C D

11. 12. 13. 14. 15.

D E B A D

16. 17. 18. 19. 20. 21. 22.

E B E B C D C

Answers and Explanations: VIII-5 Antifungal Drugs 469

Answers and Explanations: VIII-5 Antifungal Drugs Questions 1−3

becau se it easily crosses t h e blood −brain bar r ier. AIDS p a-

1. B

t ien t s w ith cr yptococcal m en ingit is frequ en tly are t reated in -

2. A

de n itely w ith

3. B

disease.

u con azole to p reven t recu rren ce of clin ical

A, B Terbin a n e an d griseofu lvin are e ect ive on ly again st

Learning objective: Explain the m echanism of action of amphotericin B. 4. B Am ph otericin B bin ds to fungal cell m em bran es an d causes th e form at ion of ar t i cial pores th rough w h ich ion s an d sm all m olecules are lost . Th is causes th e death of th e fungal cell. A, C−E See correct an sw er explan at ion .

Learning objective: Identify the antifungal drug that acts by inhibiting the fungal P-450 system . 5. C Coccidioides im m it is is sen sit ive to am ph otericin B an d an t ifu ngal azoles. Azole an t ifu ngals, prim arily

u con azole an d

it racon azole, h ave replaced am ph otericin B as in it ial th erapy for m ost ch ron ic p u lm on ar y an d d issem in ated in fect ion s. Am ph otericin B is n ow usually reser ved for pat ien ts w ith rap id ly progressive coccidioidal in fect ion s. Azoles act by in h ibiting th e cytoch rom e P-450 system in fu ngal cells. Th e in h ibit ion blocks t h e syn t h esis of ergosterol in t h e fu n gal cell m em bran e, lead in g to an an t ifu n gal e ect . Relat ive select ivit y occurs becau se th e a

n it y for m am m alian P-450 isozym es

is less th an th at for th e fu ngal isozym es. How ever, azoles can also block m am m alian P-450 isozym es in th e liver, w h ich can explain th e in creased plasm a con cen t rat ion of m any oth er drugs w h en coadm in istered w ith azoles. A, B, D−F Th ese d rugs do n ot block th e fu ngal syn th esis of ergosterol.

Learning objective: Identify the alternative drug to be used to treat cryptococcal meningitis when amphotericin B is not tolerated. 6. E Cr yptococcal m en ingit is is com m on in p at ien t s w ith AIDS an d is alw ays fat al if un t reated. Am ph otericin B an d

ucyto-

sin e represen t s th e stan dard th erapy bu t is associated w ith frequ en t adverse react ion s, in clu ding ren al in su

cien cy an d

bon e m arrow su p p ression . Flu con azole is a u sefu l altern at ive in pat ien ts w h o exp erien ce severe adverse e ects. Th e an t ifu ngal sp ect ru m of azoles in clu d es Cryptococcus neoform ans, bu t

u con azole is t h e p refer red azole in case of m en in git is

su per cial m ycoses du e to derm atop hytes. C Nystat in is st ru ct u rally sim ilar to am p h otericin B an d h as th e sam e m ech an ism of act ion an d th e sam e an t ifungal spect rum in vit ro, bu t it is too toxic to be u sed system ically. D Caspofungin is e ect ive on ly again st Candida an d Aspergillus species.

Learning objective: Identify the drug used to treat genital candidiasis. 7. C Th e p at ien t ’s sym ptom s an d lab resu lt s suggest h e w as su ering from gen ital can didiasis, w h ich can occur in p eople w ith out u n derlying illn esses but is m ore com m on in th ose w ith diabetes m ellit u s or w ith th e use of cer tain drugs (broadspectrum antibiotics, corticosteroids, or im m unosuppressants). Bu dding yeast cells an d pseu dohyph ae of Candida albicans, th e m ost com m on Candida species causing can didiasis, can be detected by m icroscop ic exam in at ion of biologic sp ecim en s. C. albicans is sen sit ive to m ost an t ifu ngal drugs, bu t for gen ital can didiasis, a top ical or oral azole d erivat ive or top ical nystat in is th e

rst-lin e t reat m en t . Oral an d top ical th erap ies

are th erapeut ically equivalen t . A Nyst at in is e ect ive again st Candida sp ecies, bu t it is u sed on ly topically becau se of its toxicit y. B, D, E Th ese agen ts are n ot an t ifu ngal drugs. F Griseofulvin is n ot e ect ive again st C. albicans.

Learning objective: Outline the pharm acotherapy of system ic candidiasis. 8. E Th e pat ien t’s sign s, sym ptom s, an d x-ray suggest a system ic m ycosis. Lab resu lts con rm th e d iagn osis of system ic can didiasis, w h ich accou n t s for abou t 80%of m ajor system ic fu ngal in fect ion s. Am ph otericin B, an t ifu ngal azoles, an d ech in ocan din s are rst-lin e agen t s for system ic can didiasis. A−D All of th ese fungal in fect ion s are paired w ith th e ap propriate t reat m en t , bu t th ey do n ot p rodu ce ch lam ydosp ores in blood cu lt ures.

470


Learning objective: Explain the mechanism of action of ucytosine.

toxoplasm osis, cr yptococcosis is th e m ost com m on cen t ral

9. C Flu cytosin e is accu m u lated in fu ngal cells an d is conver ted

n er vous system infection associated w ith AIDS. Cryptococcus

by a cytosin e deam in ase to 5- uorouracil (select ivit y occurs

neoform ans is a yeast th at is ch aracterized by a th ick poly-

becau se m am m alian cells do n ot accu m u late an d d o n ot de-

sacch arid e cap su le. Du ring in fect ion , th e capsu lar p olysac-

am in ate

u cytosin e). Flu orou racil is in t u rn m et abolized to

ch ar id e is d issolved in sp in al u id an d can be d etected by

5-deoxy u orou ridylic acid, a p oten t in h ibitor of thym idylate

an agglu t in at ion test t h at is d iagn ost ic of cr yptococcosis.

syn th et ase, th e en zym e resp on sible for conver t ing deoxyu -

C. neoform an s is sen sit ive to am p h oter icin B,

ridin e m on op h osp h ate to deoxyth im idin e m on op h osp h ate.

an d an t ifungal azoles. Th e curren t t reat m en t recom m en ded

Th is red u ces t h e availabilit y of t hym idylic acid , im p air in g

for acu te cr yptococcal m en ingit is is am p h oter icin B p lu s

DNA syn t h esis. Th e d r ug is n ot u sed alon e bu t is given to -

u cytosin e. Syn ergism bet w een t h e t w o d r ugs h as been

geth er w ith it racon azole in ch rom oblastom ycosis to avoid

dem on st rated in vit ro an d in vivo. It m ay be related to en -

th e developm en t of resist an ce.

h anced pen etration of ucytosine through the am photericin -

A, B Flu orou racil an d cyt arabin e can in h ibit DNA syn th esis

u cytosin e,

dam aged fu ngal cell m em bran e.

in m am m alian cells but are n ot accum ulated in fungal cells

A−C Th ese agen ts are n ot an t ifungal drugs.

an d th erefore are devoid of an t ifu ngal act ivit y.

E, F Th ese an t ifungal drugs are n ot e ect ive again st C.

D−F Th ese an t ifungal drugs do n ot in h ibit DNA syn th esis.

Learning objective: Identify the drug used to treat m eningeal coccidioidomycosis.

neoform ans.

Learning objective: Identify the drug used to treat candiduria. 12. B Th e pat ien t is su ering from can diduria, a con dit ion often

10. D Th e p at ien t’ sign s an d sym ptom s suggest th e diagn osis of

related to th e placem en t of an in dw elling urin ar y cath eter,

m en ingit is, an d th e lab resu lt s con rm th at th e m an w as

especially if the patient is taking broad-spectrum antibiotics,

su ering from m en ingeal coccidioidom ycosis. Th e in fect ion

as in th is case. Eradicat ion of Candida in th e urin e in cludes

is cau sed by Coccidioides im m it is, a soil m old th at lives in

th e rem oval of th e cath eter an d an an t ifu ngal t reat m en t .

sem iarid region s of th e globe, in clu ding th e sou th w estern

Treat m en t opt ion s in clu d e am p h oter icin B,

Un ited States. In h alat ion of th e arth rosp ores leads to a pri-

an d an ech in ocan din su ch as caspofu ngin . How ever, in th is

m ar y in fect ion th at is asym ptom at ic in 60% of in divid u als.

p at ien t , am p h otericin B, w h ich directly dam ages ren al t u -

Others develop a ulike self-lim ited illness called valley fever

bu les, is con t rain dicated becau se of ch ron ic ren al dysfu n c-

or desert rheum atism . Follow ing inhalation, the arthrospores

t ion . Ech in ocan d in s are th e n ew est class of an t ifu ngal drugs.

form sph erules th at con tain en dospores. In biologic speci-

Th ey act by in h ibit ing th e syn th esis of β-glu can , an essen t ial

m en s, th ese sph eru les are diagn ost ic of C. im m it is in fect ion .

con st it uen t of th e fungal cell w all. Th eir an t ifu ngal spect ru m

In less th an 1% of in dividuals, a secon dar y or dissem in ated

is lim ited to Candida an d Aspergillus species. Ech in ocan d in s

in fect ion evolves w ith in a year after th e prim ar y on e. Th is

are ap proved for t reat m en t of m u cocu t an eou s or dissem i-

secon dar y in fect ion is often life-th reaten ing an d can a ect

n ated can didiasis.

u con azole,

m any p ar ts of th e body an d t issu es, bu t th e m ost frequ en t


are th e bon e, join t s, an d m en inges. Un t reated m en ingit is is

C, D Piperacillin an d m et ron idazole are n ot an t ifungal

alw ays fat al. C. im m it is is sen sit ive to am ph otericin B an d an t ifungal azoles. Flu con azole is th e rst-lin e agen t for m en ingeal coc-

d rugs. E Th ough an an t ifu ngal drug, griseofulvin is n ot e ect ive again st C. albicans.

cidioidom ycosis. It easily crosses the blood−brain barrier, and cerebrospin al uid con cen t rat ion s are 50 to 90% of plasm a con cen t rat ion s. A It racon azole is e ect ive again st C. im m it is, bu t pen et rat ion in to th e brain is n egligible. B, C Th ese an t ifu ngal drugs are n ot e ect ive again st C. im m it is. E, F Th ese agen t s are n ot an t ifungal drugs.

Learning objective: Recognize the adverse e ect s of am photericin B. 13. A Th e lab resu lt s in d icate t h at t h e p at ien t w as su er in g from ren al in su

cien cy. Am p h otericin B is th e drug of

ch oice for m any system ic m ycoses, bu t it can cause seriou s, d ose-depen den t ren al dysfun ct ion d ue to direct dam age of ren al t ubules. Azotem ia, ren al t ubular acidosis, an d K+ w asting are th e m ost prom in en t sym ptom s.

Learning objective: Outline the pharm acotherapy of cryptococcal meningitis. 11. D Th e p at ien t ’s h istor y, sign s an d sym ptom s, an d lab resu lt s suggest th e diagn osis of cr yptococcal m en ingit is. After

B−D Th ese an t ifu ngal drugs do n ot cau se ren al toxicit y. E, F Th ese agen ts are n eph rotoxic but are n ot an t ifungal drugs.

Answers and Explanations: VIII-5 Antifungal Drugs 471 Learning objective: Identify the site of action of terbina ne.

opport un ist ic m ycosis of th e gen it al t ract in w om en t aking

14. C Tin ea m an u s is a cu t an eou s m ycosis cau sed by derm ato-

oral contraceptives. Other predisposing factors are pregnancy,

p hytes th at in fect on ly th e super cial, kerat in ized t issu es.

m enstruation, diabetes m ellitus, and use of broad- spectrum

Th ese fu ngi are probably rest ricted to th e n onviable, kerat i-

antibiotics, corticosteroids, or im m unosuppressive d r ugs.

n ized t issues (st rat um corn eum , h airs, n ails) because m ost

Bu d ding yeast cells an d p seu d ohyp h ae of Candida albicans,

are u n able to grow at 37°C (98.6°F). Derm atophytoses can be

th e m ost com m on Candida species causing can didiasis, can

t reated locally w ith several an t ifu ngal drugs, bu t a rst-lin e

be d etected by m icroscopic exam in at ion of biologic sp eci-

agen t for system ic t reat m en t is terbin a n e. Th e d r ug h as

m en s. Local th erapy of vu lvovagin al can didiasis in clu des

good oral bioavailabilit y an d is dep osited in n ew ly form ed

azoles an d nystat in . Cu re rates for u n com plicated vu lvovagi-

kerat in ized t issu es, w h ere it exer t s it s an t ifu ngal act ion .

n al can didiasis are 80 to 95% w ith topical or oral azoles an d

A, B, D, E See correct an sw er exp lan at ion . F Terbin a n e can be deposited in th e h air sh aft , w h ere it can cu re t in ea capit is, bu t in th is case, th e fu ngu s is in th e

70 to 90% w ith nystat in . A, B, D−F All of th ese m ycoses are in correctly p aired w ith th e app ropriate th erap eu t ic agen t .

skin’s st rat u m corn eu m , n ot in th e h air.

Learning objective: Identify the drug used to treat mycoses due to Trichophyton tonsurans.

Learning objective: Identify the drug used to treat invasive pulm onary aspergillosis. 18. D Fu ngi of th e gen u s Aspergillus u su ally coexist w ith m an

15. C Th e m icroscopic exam in at ion of th e h air suggest s th e diag-

in h arm less sym biosis. In sp ecial circum st an ces, h ow ever,

n osis of “black dots” t in ea capit is, a skin m ycosis cau sed by

som e sp ecies m ay p lay an opp or t u n ist ic role in produ cing

T. tonsurans. Cut an eous m ycoses are caused by fungi (m ain ly

d isease in h u m an s. Pat ien t s w ith ch em oth erapy-in du ced

derm atophytes) th at in fect on ly th e su per cial kerat in ized

n eut ropen ia or im paired im m un e respon ses from any cause

t issu es. Derm atophytes are sen sit ive to terbin a n e, an t ifu n -

are at h igh risk for invasive p u lm on ar y aspergillosis, as in

gal azoles, griseofu lvin , an d am p h otericin B, bu t th e rst t w o

th is case. Recen t st u dies in dicate th at th e isolat ion of asper-

are agen t s of ch oice in cut an eous m ycoses because th ey are

gilli in bron ch oalveolar lavage u id correlates st rongly w ith

dep osited in n ew ly form ing skin , w h ere th ey bin d to kerat in ,

histologic evidence of parenchym al invasion. The disease m ust

protect ing th e skin from th e in fect ion . Griseofu lvin is less

be t reated aggressively w ith am ph otericin B or voricon azole,

frequ en tly u sed today becau se of it s toxicit y.

w h ich m ost exper ts n ow con sider a rst-lin e agen t . Despite

A, B, D Th ese agen ts are n ot an t ifu ngal drugs. E Am p h oter icin B is on ly u sed top ically for cu t an eou s m ycoses. F Flu cytosin e is a system ic an t ifu ngal d r ug bu t is n ot effect ive again st derm atophytes.

t reat m en t , th e m or talit y rate rem ain s h igh (30−90%). A Flu cytosin e is e ect ive in vit ro again st Aspergillus sp ecies bu t is n ot clin ically e ect ive in case of invasive asp ergillosis. B, C Th ese an t ifungal drugs are n ot e ect ive again st Aspergillus species.

Learning objective: Describe the use of glucocorticoids to prevent amphotericin B−related infusion reaction. 16. D Th e in t raven ou s adm in ist rat ion of am p h otericin B can cau se an in fu sion react ion w ith fever, ch ills, m u scle spasm s, h eadach e, vom it ing, an d hypoten sion . Prem edicat ion w ith

E Nyst at in is too toxic for paren teral adm in ist rat ion an d is on ly u sed top ically.

Learning objective: Explain the m echanism of antifungal action of terbina ne.

n onsteroidal antiin am m atory drugs, antihistam ines, or glu-

19. C Terbin a n e is an an t ifu n gal d r ug t h at in h ibit s fu n gal

cocor t icoid s can alleviate t h e syn d rom e. Th e cau se of t h is

squ alen e epoxidase, th e en zym e th at catalyzes th e conver-

react ion is st ill u n cer t ain , bu t h ist am in e an d p rost aglan d in

sion of lan osterol in to ergosterol. Th e in h ibit ion leads to th e

release seem s to be involved.

accu m u lat ion of squ alen e, w h ich is toxic to derm atophytes.


Th e drug is d ep osited in kerat in ized t issu e an d is u sed in th e t reat m en t of derm atop hytoses, m ain ly onych om ycosis. Th e

Learning objective: Outline the pharm acological therapy of genital candidiasis. 17. C The patient’s sym ptom s and lab results suggest that she w as su ering from vu lvovagin al can didiasis, th e m ost com m on

drug is fungicidal and is therefore m ore e ective than griseofu lvin , w h ich is fu ngist at ic. A, B, D, E See correct an sw er exp lan at ion .

472


Learning objective: Identify the drug used to treat dissem inated histoplasmosis.

fou n d ver y large di eren ces bet w een th e leth al dose of lipo-

20. A Th e fact th at un in ucleated, en capsulated m icroorgan ism s

clin ical im provem en t obtain ed w ith th e liposom al veh icles

are fou n d in t racellu larly suggest s an in fect ion w ith Histoplasm a capsulat um . Oth er in t racellu lar m icroorgan ism s are eith er m u lt in u cleate, su ch as blastom yces, or n ot en capsu lated, su ch as th e in t racellu lar st age of several path ogen ic protozoa. In fect ion w ith H. capsulat um is ext rem ely com -

som al form u lat ion s an d th ose of regu lar form u lat ion s, th e is, at best , m od erate. A Decreased interactions w ith other drugs could occur, but th is is n ot th e m ain advan tage of liposom al preparat ion s. B Am p h otericin B is th e act ive m olecu le, an d th e an t ifu n gal act ivit y spect ru m is th e sam e.

m on . In th e vast m ajorit y of cases, it is subclin ical, or it m ay

D Th e clearan ce of lip osom al p rep arat ion s can be d e-

m an ifest it self as a m ild, self-lim ited pn eum on ia. Progressive

creased or in creased , bu t t h is is n ot t h e reason for t h eir

dissem in ated h istop lasm osis u su ally occu rs in peop le w ith

advan t age over th e regular p reparat ion .

su ppressed cell-m ediated im m un it y, esp ecially if th ey are from en dem ic areas (Mississip p i River valleys an d th e Carib bean basin ), as in t h is case. Most laborator y

E In test in al absor pt ion of all am p h oter icin B for m u lat ion s is n egligible.

n d in gs are

10 t im es above n orm al. Progressive dissem in ated h istoplas-

Learning objective: Outline the therapy for severe invasive candidiasis.

m osis h as a h igh fatalit y rate. Am ph otericin B rem ain s th e

23. D Becau se of it s broad spect rum of fungicidal act ivit y, am -

rst-lin e agen t , but m ild cases can be t reated in it ially w ith

p h otericin B rem ain s th e rst-lin e agen t for n early all severe

n on speci c, but th e lact ate dehydrogen ase level can reach

paren teral azoles.

fu ngal in fect ion s. Du e to toxicit y, th e drug is often u sed in i-


t ially to rap idly redu ce fu ngal load an d th en is rep laced by an oth er less toxic an t ifu ngal agen t , as in th is case.

Learning objective: Describe griseofulvin-induced photosensitivit y. 21. D Th e locat ion of th e fungal in fect ion suggest s th at th e pa-

A−C, E, F All of t h ese p airs in clu d e at least on e d r ug t h at is n ot e ect ive again st system ic can didiasis.

t ien t w as m ost likely su er in g from t in ea barbae, a d er m agen u s. Griseofu lvin an d terbin a n e are th e agen t s of ch oice.

Learning objective: Explain the m echanism of resistance to uconazole.

Griseofulvin can cause both a ph ototoxic an d a ph otoallergic

24. C Fu ngal resistan ce to dr ugs in th e azole class ten ds to occu r

react ion in sun -exposed areas. Oth er an t ifungal drugs th at

gradu ally over th e cou rse of p rolonged drug th erapy. In Can-

can cau se p h otosen sit ivit y e ects are an t ifu ngal azoles.

dida in fect ion s, resistan ce occu rs by w ay of m u tat ion s in th e

tophytosis m ost often caused by fungi of th e Trichophyton

A−C Th ese an t ifungal drugs are n ot e ect ive again st derm atophytosis, an d th ey do n ot cau se ph otosen sit ivit y. E, F Th ese an t ibiot ics can cau se ph otosen sit ivit y but are n ot e ect ive again st fungal in fect ion s.

gen e th at en codes for an en zym e of th e P-450 system . Th ese m ut at ion s preven t th e azole drug from bin ding an d in h ibiting th e en zym e. Developm en t of resist an ce to on e azole in th is w ay con fers resistan ce to all drugs in th e class. A, B, D−F Th ese act ion s are n ot involved in th e m ycobacte-

Learning objective: Explain the m ain advantage of liposom al preparations of am photericin B.

rial resist an ce to u con azole.

22. C In liposom al preparat ion s of am ph otericin B, th e drug is

ANTIFUNGAL DRUGS Answ er key

con t ain ed in side lipid deliver y veh icles. Th e drug bin ds to th e lipids of th ese veh icles w ith an a

n it y th at is low er th an

th at for fu ngal ergosterol bu t h igh er th an th at for h u m an ch olesterol. Th us, th e drug is m ore likely to be delivered to fu ngi th an to h u m an cells. Moreover, som e fu ngi con t ain lip ases th at can liberate free am ph otericin B directly at th e site of in fect ion . Th erefore, th e lip osom al p reparat ion s allow a redu ct ion of toxicit y; th at is, th ey im p rove th e th erap eu t ic index of the drug. However, although laboratory experim ents

1. 2. 3. 4. 5.

B A B B C

6. 7. 8. 9. 10.

E C E C D

11. 12. 13. 14. 15.

D B A C C

16. 17. 18. 19. 20. 21. 22. 23. 24.

D C D C A D C D C

Answers and Explanations: VIII-6 Antiviral Drugs 473

Answers and Explanations: VIII-6 Antiviral Drugs Questions 1−3

an d reduces th e frequen cy of react ivat ion episodes. Acyclovir

1. F

m ust be act ivated by ph osph or ylat ion , th en th e t riph osph ate

2. C

com poun d com pet it ively in h ibit s viral DNA polym erase, th us

3. E

blocking DNA syn th esis. Tran script ion is th erefore in h ibited. A, B, D−F See correct an sw er exp lan at ion .

Learning objective: Describe the m echanism of action of raltegravir.

Learning objective: Explain the mechanism of action of gancyclovir.

4. E Raltegravir is an in tegrase in h ibitor. Drugs from th is class

8. C Gan ciclovir and acyclovir are nucleoside analogues that m ust

block th e t ran sfer of reverse-t ran scribed HIV DNA in to th e

be p h osph or ylated rst by viru s-speci c en zym es. Both drugs

ch rom osom es of h ost cells, th us preven t ing th e

n al step of

are p h osp h or ylated by a viral t hym id in e kin ase in h er p es

proviru s in tegrat ion . It is u sed m ain ly w h en st an dard an t iret-

sim plex virus (HSV)−in fected cells. Gan ciclovir is also ph os-

roviral th erapy is n ot e ect ive for a given pat ien t , as in th is

ph or ylated by a sp eci c viral p h osp h ot ran sferase in cytom eg-

case.

alovirus (CMV)−in fected cells. Th is explain s w hy both drugs

A Th is drug is a reverse t ran script ase in h ibitor.

are act ive again st HSV, but on ly gan ciclovir is e ect ive again st

B−D Th ese drugs are protease in h ibitors.

CMV. A Foscarn et is used in CMV ret in it is, bu t it does n ot requ ire

Learning objective: Explain the reason for a ritonavir−lopinavir combination. 5. E Riton avir is a pow erful in h ibitor of th e CYP3A4 en zym es. Even w h en given in su bth erapeu t ic doses, th e d rug in h ibit s th e m etabolism of lopin avir w ith a result an t in crease of lopin avir plasm a levels. Th is p erm it s low er or less frequ en t dosing w ith greater tolerabilit y. Th erefore, in th is com bin ation, ritonavir is m ainly acting as a pharm acokinetic enhancer, an d for th is reason it is curren tly given m ain ly in associat ion w ith an oth er protease in h ibitor.

act ivat ion by ph osph or ylat ion . B, D Ribavirin an d acyclovir h ave n o act ivit y again st CMV in fect ion s. E, F Vidarabin e an d zid ovu din e are n u cleosid e an alogu es t h at m u st be p h osp h or ylated to becom e act ive. How ever, for t h ese d r ugs, p h osp h or ylat ion is car r ied ou t by h ost cell en zym es on ly, an d th ese drugs are n ot e ect ive again st CMV.

Learning objective: Outline the prophylactic use of neuram inidase inhibitors. 9. E Vaccin at ion plus ch em oprophylaxis again st in uen za is ad-


visable for residen t s of n u rsing h om es or oth er ch ron ic care

Learning objective: Describe the adverse e ect s of protease inhibitors. 6. E Most protease in h ibitors can cause a Cush ing-like syn drom e w ith cen t ral obesit y, dorsocer vical fat en largem en t (bu alo h um p), an d periph eral w ast ing. Th e syn drom e is related to an im pairm en t of glu cose an d lip id m et abolism (hyp erlip idem ia an d hyperglycem ia w ith in sulin resistan ce are com m on ) an d m ay a ect up to 50% of pat ien t s receiving protease in h ibitors for several m on th s. A−D These antiretroviral drugs do not cause a Cushing-like syn d rom e.

h igh -risk pat ien t s, as in th is case. Oselt am ivir an d zan am ivir are in h ibitors of n euram in idases produced by in uen za A an d B viruses. Th ese en zym es cleave sialic acid residu es from cell su rfaces, th u s p rom ot ing th e release of n ew ly form ed viru s from th e su rface of in fected cells. Both drugs cau se a sign i can t redu ct ion of th e sym ptom s of in u en za A an d B an d are th erefore preferable to am an t adin e, w h ich is e ect ive on ly again st in u en za A. Resist an ce to n eu ram in idase in h ibitors w as un com m on u n t il recen tly, bu t n ow rates of resistan ce to oseltam ivir am ong H1N1 virus (a subt ype of in uenza A) have risen abruptly an d dram at ically.

Learning objective: Identify which step of the viral growth cycle is inhibited by acyclovir. 7. C Th e prescribed dr ug w as m ost likely acyclovir, a

facilit ies an d p erson n el w h o h ave exten sive con t act s w ith

rst-lin e

agen t for h erp es gen it alis. Oral th erapy sp eeds u p th e h ealing

A−D, F Th ese d r ugs are n ot e ect ive again st in u en za vir u ses.

474


Learning objective: Describe the adverse e ect s of acyclovir.

in th e h ost cells th at con t ribu te to viral resistan ce th rough

10. B Th e p at ien t w as m ost likely su ering from h erp es sim p lex

di eren t m ech an ism s, in clu ding in h ibit ion of viral p en et ra-

virus (HSV) pn eum on ia, a disease th at a ects prim arily im -

tion and uncoating, synthesis of viral DNA and RNA, and viral

m u n ocom p rom ised an d elderly p eop le. Acyclovir is a

assem bly an d release.

rst-

lin e agen t for HSV in fect ion . More th an 90% of acyclovir is elim in ated u n ch anged by t h e kid n eys, an d n ep h rotoxic ef-

A−C, E, F Th ese an t iviral drugs are n ot e ect ive again st HBV.

fect s can occur w ith paren teral adm in ist rat ion as a result of cr ystallizat ion of th e drug w ith in th e n ep h ron . Acyclovir h as

Learning objective: Explain the mechanism of action of foscarnet.

low solu bilit y in u rin e. Low u rin e volum e associated w ith

13. D Foscar n et is an in organ ic pyrop h osp h ate an alogu e t h at

volum e con t ract ion m ay con t ribu te to cr yst allu ria, w h ich in

in h ibit s viral DNA p olym erase, RNA p olym erase, an d HIV

t u rn can lead to azotem ia, ren al t u bu lar obst ru ct ion , ren al

reverse t ran scr ipt ase direct ly w ith ou t requ ir in g act ivat ion

failure, an d death . Cr ystalluria is m ore likely to occur du ring

by p h osp h or ylat ion . Th e d r ug, given on ly by in t raven ou s

ad m in ist rat ion of large p aren teral d oses, as in t h is case.

inject ion , is e ect ive in th e t reat m en t of cytom egalovirus

Ren al failu re is m ore likely in t h is p at ien t becau se of h is

(CMV) in fect ion s, in cluding ret in it is, colit is, an d esoph agit is.

ren al in su

It is often given togeth er w ith gan ciclovir because it h as

cien cy (see creat in in e levels).

A, C−F Acyclovir h as n o sign i can t toxicit y on th e bon e m arrow, liver, or p an creas.

been sh ow n th at th e com bin at ion is su p erior to eith er agen t alon e in d elaying th e progression of ret in it is. Adverse e ect s can be severe, an d ren al im p airm en t m ay occu r in u p to 30%

Learning objective: Explain the mechanism of action of amantadine.

of pat ien t s. A−C, E, F None of these drugs are e ective in CMV retinitis.

11. D Am an t adin e an d rim an tadin e are adam an tan e d erivat ives Th ey act by p reven t ing u n coat ing of th e viru s on ce it is fu sed

Learning objective: Explain why antiviral drugs cannot prevent recurrence of viral diseases.

in to h ost cell m em bran es. Th ese drugs can reduce th e sever-

14. C Herpes viruses replicate in th e skin or m ucous m em bran es

it y of sym ptom s an d th e durat ion of illn ess an d are m ain ly

at th e in it ial site of in fect ion , th en m igrate u p th e n eu ron

u sed in elderly pat ien t s or in th ose w ith un derlying diseases,

an d becom e laten t in th e sen sor y ganglion cells. Th e viru s

as in th e p resen t case Th e dr ugs h ave n o e ect on in u en za

can be react ivated from th e laten t st ate by a variet y of fac-

B an d C vir u ses or p arain u en za vir u ses. Un for t u n ately,

tors, in clu d ing su n ligh t , h or m on al ch anges, t rau m a, st ress,

m ore t h an 90% of circu lat in g in u en za A vir u ses are n ow

an d fever. Up on react ivat ion , t h e vir u s m igrates d ow n t h e

resist an t to adam an tan e derivat ives.

n euron an d replicates in th e skin , causing lesion s. No cur-

app roved for both p rop hylaxis an d th erapy of in u en za A.

A−C, E, F Th ese an t iviral drugs are n ot act ive again st in u en za viru ses.

ren t ly available an t iviral d r ugs can at t ack vir u ses d u r ing laten cy; th ey act on ly on act ively replicat ing viruses. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Outline the use of interferon alfa-2a in viral hepatitis B.

Learning objective: Outline the therapeutic uses of lam ivudine.

12. D Th e ch ron ic occu rren ce of jau n dice in a you ng p at ien t is

15. F Lam ivudin e is th e

rst n ucleoside an alogue approved by

suggest ive of h epat it is, an d th e p resen ce of h ep at it is B su r-

th e U.S. Food an d Drug Adm in ist rat ion for u se in pat ien ts

face an t igen (HBsAG) in serum is diagn ost ic for h epat it is B

w it h h ep at it is B vir u s (HBV). It in h ibit s HBV DNA p oly-

virus (HBV) in fect ion . Approxim ately 5% of th e w orld’s pop -

m erase an d HIV reverse t ran script ase by com pet ing w ith

u lat ion is in fected w ith HBV. Th e m ost prom in en t risk fac-

d eoxycyt idin e t rip h osph ate for in corp orat ion in to th e viral

tors associated w ith th e disease are sexual con t act s (> 50%)

DNA. Lam ivudin e is an e ect ive agen t for pat ien ts w ith

an d injected drug u se (15%). Su bclin ical in fect ion s are com -

ch ron ic h epat it is B. It can su ppress HBV DNA to un detect-

m on , bu t 25% of carriers develop ch ron ic act ive h ep at it is.

able levels in abou t 40% of pat ien ts an d can n orm alize liver

Worldw ide, on e m illion death s a year are at t ribu ted to HBV-

t ran sam in ase in u p to 75% of p at ien t s. Un for t u n ately, resis-

related diseases, in cluding h epatocellular carcin om a. Drugs

t an ce is a p roblem , develop ing in u p to 70% of p at ien t s after

for th e t reat m en t of ch ron ic h epat it is B in clu de in terferon s,

5 years of th erapy.

adefovir, en tecavir, ten ofovir, an d lam ivu d in e. Th ese drugs

A−E Th ese an t iviral drugs are n ot e ect ive again st HBV.

are on ly m od erately e ect ive in t reat ing th e disease. Rem ission m ay be su stain ed, bu t in m any pat ien ts, viral replica-

Learning objective: Explain the mechanism of action of maraviroc.

t ion reapp ears follow ing cessat ion of th erapy. In terferon s

16. D Maraviroc bin d s to th e h ost protein CCR5 receptor, on e of

are cytokines that possess antiviral, im m unom odulating, and

th e t w o ch em okin e receptors n ecessar y for en t ran ce of HIV

antiproliferative actions. They induce over t wo dozen protein s

in to CD4+ cells. Th is blocks th e fusion of viral an d cellu lar

Answers and Explanations: VIII-6 Antiviral Drugs 475 m em bran es, preven t ing viral en t r y. It h as been sh ow n th at

Learning objective: Explain the m echanism of action of entecavir.

abou t 50% of pat ien t s in w h om at least t w o an t iviral regi-

20. A En tecavir is a guan osin e derivat ive th at in h ibits h epat it is B

m en s h ad failed w ere in fected w ith R5 HIV-1. Because m ar-

vir u s (HBV) DNA p olym erase. Th e d r ug is m ore e ect ive

aviroc is act ive exclu sively again st HIV st rain s th at u se CCR5

th an lam ivu din e again st h ep at it is B an d is h igh ly e ect ive in

bu t n ot again st oth er HIV st rain s, t rop ism test ing sh ou ld be

lam ivu din e-resistan t st rain s. Clin ical resist an ce to en tecavir

perform ed before st art ing a t reat m en t w ith th is drug, as in

is ver y rare (< 1% at 4 years).

th is case.

B−F Th ese en zym es are n ot in h ibited by en tecavir.

A Ribavirin is n ot an an t iret roviral agen t . B En fuvirt ide is an en t r y in h ibitor bu t t arget s a gp41 su b un it of th e viral envelope. C Didan osin e is a reverse t ran script ase in h ibitor. E, F In din avir an d at azan avir are protease in h ibitors.

Learning objective: Identify the drug that act s by inhibiting reverse transcriptase. 17. E Lam ivu din e is a reverse t ran script ase in h ibitor. Reverse

Learning objective: Explain the m echanism of action of enfuvirtide. 21. A En fuvir t ide in h ibits HIV-1 en t r y in to th e h ost cell by bin ding to th e gp41 su bun it of th e viral envelop e glycoprotein , p reven t ing t h e con for m at ion al ch anges requ ired for t h e fu sion of viral an d cellu lar m em bran es. It h as n o act ivit y again st HIV-2. B−F See correct an sw er explan at ion .

t ran script ase is an en zym e speci c to ret roviru ses th at u ses viral RNA to m ake a com p lem en t ar y single-st ran d ed DNA copy. Th e copy is t h en d u p licated to for m t h e d ou blest ran ded proviral DNA, w h ich m igrates in to th e n u cleu s an d becom es in tegrated w ith th e gen et ic m aterial of th e h ost cell. All reverse t ran scriptase in h ibitors can block th e in it ial p h ase of viral rep licat ion . In th is w ay, th ey can p reven t th e in fect ion of n ew cells, but th ey do n ot a ect ch ron ically in fected cells in w h ich th e HIV gen om e is already in tegrated in to th e h ost gen om e. A−D Th ese dr ugs d o n ot a ect reverse t ran scr ipt ase act ivit y.

Learning objective: Explain the m ost com m on reason of failure of acyclovir therapy. 18. C Acyclovir resistan ce is th e m ost com m on cause of failure of acyclovir th erapy. Acyclovir-resist an t st rain s of th e h erpes sim p lex an d varicella zoster viru ses arise ch ie y from m u tat ion s in th e thym idin e kin ase gen e th at resu lt in lit tle or n o p rodu ct ion of th e en zym e. Because viral thym idin e kin ase is essen t ial for conversion of acyclovir to act ive derivat ives, resistan ce to th e drug en su es. Resist an t st rain s are m ost com m on ly reported in severely im m u n ocom p rom ised p at ien t s receiving an exten ded course of th e drug, as in th is case. A, B, D, E None of these enzym es are involved in the m ech an ism of act ion of acyclovir.

Learning objective: Outline the prophylactic uses of palivizum ab. 19. E Palivizu m ab is a h u m an ized m on oclon al an t ibody th at bin ds to th e A an t igen site on th e F su rface p rotein of resp irator y syn cyt ial virus (RSV). It is approved for th e preven t ion of RSV in fect ion in h igh -risk in fan t s an d ch ildren , such as th ose w ith p u lm on ar y dysp lasia, as in th is case. A−D, F These drugs are not e ective against RSV infection.

Learning objective: Identify the steps of the HIV growth cycle speci cally a ected by nucleoside reverse transcriptase inhibitors and protease inhibitors. 22. E Lam ivudine and stavudine are nucleoside reverse transcrip t ase in h ibitors (NRTIs). Th ey block th e reverse t ran script ion of RNA in to DNA. At azan avir is a p rotease in h ibitor t h at blocks t h e p roteolyt ic cleavage of im m at u re bu d d in g p art icles, t h u s p reven t in g t h e assem bly of st r u ct u ral p rotein s arou n d gen om ic RNA to form a n u cleocapsid. A−D At least one of these t w o steps is not a ected by NRTIs or protease in h ibitors.

Learning objective: Explain the m echanism of action of acyclovir. 23. B Dr ugs for varicella zoster viru s (VZV) in fect ion in clude acyclovir, fam ciclovir, an d pen ciclovir. Th ese dr ugs are act ivated by p h osp h or ylat ion , cat alyzed by th e viru s-speci c thym idin e kin ase in in fected cells. Th e t rip h osph ate derivat ives are p oten t in h ibitors of both viral DNA an d m am m alian DNA polym erase. How ever, viral DNA polym erase is m ore sen sit ive to in h ibit ion th an th e DNA p olym erase of th e h ost cell. A, C−F Th ese en zym es are n ot in h ibited by acyclovir.

Learning objective: Explain the mechanism of action of oseltamivir. 24. A Oseltam ivir an d zan am ivir are in h ibitors of n eu ram in idase, an en zym e produ ced by in u en za A an d B viru ses. Th e en zym e cleaves sialic acid residu es from cell su rfaces, p rom ot ing th e release of n ew ly form ed viru s from th e su rface of in fected cells. By blocking th e en zym e, th ese drugs in h ibit virus release from th e in fected cells. B−E See correct an sw er explan at ion .

476


Learning objective: Describe the adverse e ect s of ganciclovir.

A Adefovir is used for viral h epat it is.

25. A Gan ciclovir is a dr ug of ch oice for cytom egaloviru s (CMV)

B−D Lopin avir, n evirapin e, an d zidovu din e are u sed for

in fect ion s. Th e dose-lim it ing toxicit y of both zidovudin e an d gan ciclovir is bon e m arrow su p pression ; th erefore, an em ia

HIV in fect ion . F Zan am ivir is used for in u en za.

an d n eu t rop en ia can be p redicted from th e con cu rren t ad B, C Ret in al detach m en t an d cat aract s are adverse e ects

Learning objective: Outline the highly active antiretroviral therapy (HAART) for AIDS.

of gan ciclovir th at can occur follow ing in t ravit real adm in is-

28. E HAARTs are prescribed to m any HIV-posit ive pat ien t s even

t rat ion of th e drug for CMV ret in it is. Th ey do n ot occu r w h en

before th ey develop sym ptom s of AIDS. Th ese th erap ies h ave

th e drug is adm in istered in t raven ou sly for system ic an t i-

d ram at ically altered t h e n at u ral p rogression of in fect ion

CMV th erapy.

an d sign i can tly im p roved th e qu alit y of life of m any HIV-

m in ist rat ion of gan ciclovir an d zidovu din e.

D Sexual dysfun ct ion is n ot an adverse e ect of th e drugs th e p at ien t h as been receiving. E Hyperglycem ia can occur after prolonged adm in ist rat ion of p rotease in h ibitors su ch as at azan avir, bu t it d oes n ot occur w ith gan ciclovir. F Lact ic acidosis h as been reported w ith th e use of n ucle-

in fected p at ien ts. HAART usu ally in clu des t w o n ucleoside reverse t ran script ase in h ibitors (NRTIs; e.g., zidovudin e an d d idan osin e), p lus a p rotease in h ibitor (e.g., at azan avir) or a n on n ucleoside reverse t ran script ase in h ibitor (NNRTI). A−D All of th ese drug com bin at ion s in clude at least on e d rug th at is n ot an an t iret roviral agen t .

oside reverse transcriptase inhibitors such as zidovudine and d idan osin e, but it is does n ot occur w ith gan ciclovir.

Learning objective: Outline the antiretroviral therapy to prevent mother-to-infant HIV transmission during pregnancy.

Learning objective: Describe the adverse e ects com m on to zalcitabine and stavudine.

29. D It is kn ow n th at HIV can be t ran sm it ted to th e fet u s or

26. D Periph eral n eu rop athy is a dose-lim it ing adverse e ect of

h as been sh ow n th at cert ain an t iret roviral drugs, w h en

both zalcitabin e an d stavu din e, w h ich can occu r in u p to 30%

given to th e m oth er an d to th e n ew born du ring th e p erin at al

of pat ien t s. It is slow ly reversible upon th e prom pt discon -

p eriod, can p reven t th e t ran sm ission of HIV. Zidovudin e,

t in u at ion of th e drug.

given for 6 w eeks before deliver y, w as used in th e p ast , bu t

A Neph rolith iasis is a poten t ial adverse e ect of in din avir, n ot of zalcitabin e an d stavudin e. B Myelosu p p ression is a t yp ical adverse e ect of zid ovu d in e. Zalcit abin e an d st avu d in e ver y rarely cau se m yelosu p p ression . C Zalcit abin e an d st avu din e easily en ter th e cen t ral n ervous system , bu t h allucin at ion s are n ot reported. E Altered body fat dist ribut ion is a t ypical adverse e ect of p rotease in h ibitors. Zalcitabin e an d st avudin e do n ot cau se th is e ect .

n ew bor n du r ing p regn an cy, d eliver y, or breast feeding. It

recen tly it h as been foun d th at n evirapin e is m ore conven ien t , as a single dose of th e drug is e ect ive w h en adm in istered to w om en at th e on set of labor an d follow ed by an oral d ose to th e n eon ate w ith in 3 days after th e deliver y. A A h igh ly e ect ive an t iret roviral th erapy (HAART) usu ally in clu des m ore th an on e drug. B A single dose of an an t iret roviral drug can n ot preven t AIDS. C Nevirapin e is n ot an oxytocic drug. Moreover, oxytocic d rugs are given after th e deliver y, n ot at th e on set of labor. E Preven t ion of n ew born respirator y dist ress syn drom e is

Learning objective: Outline the therapeutic uses of tri uridine.

u su ally ach ieved w ith glu cocor t icoid an ten at al th erapy.

27. E Herpes sim plex kerat it is is a com m on ocular disorder an d St ates. Th e illn ess is u su ally t reated topically, an d t ri u ridin e

Learning objective: Identify the antiretroviral drug that does not need phosphorylation to become active.

eye drops 8 or 9 t im es daily are e ect ive in m ost cases. Th e

30. A Th e h igh ly act ive an t iret roviral t h erapy (HAART) can be

d rug is ph osp h or ylated in t racellularly by h ost cell en zym es

n on n u cleosid e based , t h at is, on e n on n u cleosid e reverse

an d th en com petes w ith thym id in e t riph osph ate for in cor-

t ran script ase in h ibitor (NNRTI) p lu s t w o n u cleoside reverse

p orat ion by th e viral DNA p olym erase, th u s in h ibit ing th e

t ran script ase in h ibitor (NRTIs). Efaviren z is an NNRTI. Un like

enzym e. Incorporation into both viral and host DNA prevents

NRTIs, n o NNRTIs requ ire p h osph or ylat ion to be act ivated.

on e of th e m ost frequen t cau ses of blin dn ess in th e Un ited

its system ic use. Th e drug is n ot e ect ive again st h erpes zoster keratitis. Another pharm acotherapy used occasionally for h erpes sim plex kerat it is is oral acyclovir, especially for recu rren t in fect ion .

B Foscarn et does n ot require ph osph or ylat ion to be act ivated, bu t it is n ot an an t iret roviral drug. C−F Because th ese drugs are NRTIs, th ey required ph osp h or ylat ion to becom e act ive.

Answers and Explanations: VIII-6 Antiviral Drugs 477 Learning objective: Describe the main adverse e ects of abacavir. 31. D Th e pat ien t w as m ost likely su ering from a hyp ersen si-

Learning objective: Identify the protease inhibitor with the m ost pronounced inhibitory e ect on CYP3A4.

t ivit y react ion to abacavir. Th is is a m u lt iorgan system ic ill-

34. D All of th e an t iret roviral protease in h ibitors are subst rates

n ess th at occurs in up to 8% of HIV-in fected pat ien t s w h o

an d in h ibitors of CYP3A4, w ith riton avir h aving th e m ost

in it iate th erapy w ith abacavir. Abacavir hypersen sit ivit y re-

p ron ou n ced in h ibitor y e ect an d saquin avir th e least . As a

act ion can cau se life-th reaten ing com p licat ion s if abacavir is

result , th ere is a h uge poten t ial for drug−drug in teract ion s

continued despite progressive sym ptom s. In addition, am ong

w ith oth er an t iret roviral agen ts an d oth er com m on ly used

p erson s w h o h ave experien ced th e abacavir hypersen sit ivit y

m edicat ion s. Th is poten t ial is also exp loited th erap eu t ically

reaction, subsequent rechallenge w ith abacavir follow ing dis-

in th e m arketed riton avir−lop in avir com bin at ion . Riton avir

con t in uat ion can cause an im m ediate an d poten t ially fat al

act s as a p h arm acokin et ic en h an cer by in h ibit ing lop in avir

react ion .

m etabolism .

A, E Th ese d r ugs ver y rarely cau se hyp ersen sit ivit y react ion s.

A−C, E Th ese drugs h ave n o clin ically sign i can t in h ibitor y e ect on CYP3A4.

B, C, F Th ese drugs are n ot act ive again st HIV.

Learning objective: Outline the therapeutic uses of foscarnet. Learning objective: Outline the therapeutic uses of acyclovir.

35. A Herp et ic t rach eobron ch it is h as been docu m en ted in both

32. B Th e m oth er’s h istor y (several episod es of gen ital h erp es)

im m u n ocom prom ised an d im m u n ocom p eten t in dividuals.

an d t h e p at ien t ’s sign s (p rem at u r it y, resp irator y d ist ress,

Norm al h ost s t yp ically are eld erly in dividu als. Early detec-

an d cu t an eou s vesicles) suggest t h at t h e baby w as su er in g

t ion of h erpet ic t rach eobron ch it is app ears crit ical so th at

from con gen it al h er p es, a d isease t h at a ect s abou t 1 in

acyclovir, w h ich is a drug of rst ch oice for h erp es sim p lex

3000 live bir t h s an d is acqu ired , in m ost cases, d u r in g p as-

virus (HSV) in fect ion s, can be given du ring th e t im e of peak

sage th rough th e bir th can al. Th e diagn osis is con rm ed by

viral replicat ion , w h ich ten ds to coin cide w ith sym ptom at ic

the

n d in g of d en d r it ic kerat it is, w h ich is p at h ogn om on ic

clin ical illn ess. Th e m ost com m on cau se of failu re of acy-

of h erpet ic keratoconju n ct ivit is. An t ih erpes d rugs in clu de

clovir th erapy is th e presen ce of thym idin e kin ase−d e cien t

acyclovir, several acyclovir congen ers, foscarn et , gan ciclovir,

st rain s of HSV. Becau se acyclovir m u st be p h osph or ylated

cidofovir, and tri uridine. Acyclovir is still the rst-line agent

by a viral thym idin e kin ase to becom e a n ucleot ide an alogue

for system ic t reat m en t . Foscarn et an d cidofovir can be used

th at in h ibit s viral DNA p olym erase, th ese st rain s are acyclo-

for acyclovir-resist an t st rain s. Tri uridin e can be used topi-

vir-resist an t . In th is case, foscarn et , w h ich directly in h ibit s

cally to m an age kerat it is.

viral DNA polym erase, represen t s a useful altern at ive.

A, C Atazan avir an d zidovu din e are an t iret roviral d rugs u sed on ly in HIV in fect ion . D−F Th ese drugs are n ot an t iviral agen t s.

B−D At azan avir, am an t adin e, an d zidovudin e are n ot act ive again st HSV. E Tri uridin e is e ect ive again st HSV, bu t it is ver y toxic an d th erefore is on ly u sed topically.

Learning objective: Identify the step of viral growth cycle blocked by atazanavir. 33. E Du ring th e late st age of th e HIV grow th cycle, th e gen e

Learning objective: Explain the main reason for a triple therapy in HIV infection.

p rodu cts becom e im m at u re budding part icles. Th e im m a-

36. C Th e p r im ar y goal of h igh ly act ive an t iret roviral t h erapy is

t u re core (n on in fect iou s) is cleaved in to sm aller in fect iou s

to d elay t h e em ergen ce of resist an ce, as m u t at ion s con fer-

p ar t icles by viral aspar tate protease. At azan avir is a protease

r in g resist an ce to on e d r ug d o n ot n ecessar ily con fer resis-

in h ibitor th at blocks th e proteolyt ic cleavage, preven t ing

t an ce to oth er drugs. An ad dit ion al ben e t of th e com bin at ion

viral m at urat ion . Un like oth er protease in h ibitors, it does

t h erapy is to d ecrease t h e r isk of toxicit y associated w it h

n ot appear to be associated w ith th e im pairm en t of glucose

any on e of th e agen ts, as th e drugs h ave di eren t toxicit y

an d lip id m etabolism .

p ro les.

A−D, F Non e of t h ese step s are a ected by p rotease in h ibitors.

A Th ere are n o drugs able to kill n on replicat ing viruses. B, D Th is can occur in rare cases but is n ot th e purpose of th e com bin at ion th erapy. E An t iviral drugs u su ally h ave n o e ect on oppor t un ist ic in fect ion s, w h ich are prim arily bacterial in fect ion s.

478


Learning objective: Describe the m ost serious adverse e ect of didanosine.

p at ien t s presen t ing such react ion s. Efaviren z can cau se skin

37. C Th e pat ien t’s sign s, sym ptom s, an d lab tests in dicate th at

rash es in up to 28% of pat ien ts. Becau se th e pat ien t w as tak-

sh e w as m ost likely su ering from acu te pan creat it is, th e

ing both drugs, th ere is a h igh probabilit y th at an er yth em a-

m ost seriou s adverse e ect associated w ith didan osin e th er-

tous skin rash m igh t occu r.

apy. Th e e ect is dose-depen den t an d can occur in u p to 7%

an d er yt h em atou s skin rash occu rs in abou t on e h alf of

B Efaviren z can cau se psych ot ic sym ptom s, but th e frequ en cy of such adverse e ects is exceedingly low.

of pat ien t s on an t iret roviral th erapy w ith th is drug. A, B, D Th e risk of acu te pan creat it is w ith th ese drugs is

C−E Th e risk of th ese adverse e ect s is n egligible.

n egligible.

Learning objective: Outline the therapeutic uses of ganciclovir.

E, F Th ese drugs are n ot an t iret roviral agen t s.

40. C Hem orrh agic ret in it is in an AIDS pat ien t suggest s th e diag-

Learning objective: Outline the therapeutic uses of acyclovir.

n osis of cytom egalovirus (CMV) ret in it is, w h ich accoun t s for

38. E Th e p at ien t’s sign s an d sym ptom s suggested th e p resu m p -

m ore th an 75% of CMV en d-organ disease in HIV-posit ive

t ive diagn osis of bacterial m en ingit is, bu t th e lack of e

cacy

p at ien ts. Treat m en t opt ion s for CMV ret in it is in clude gan ci-

of an t ibiot ic t h erapy an d t h e n egat ive cerebrosp in al

u id

clovir, foscarn et , an d cidofovir. Th ese drugs are adm in istered

resu lt raised t h e su sp icion of h er p es sim p lex vir u s (HSV)

in t raven ou sly or by in t raocular inject ion s. Fom ivirsen is an -

en cep h alit is, th e m ost com m on sp oradic viral in fect ion of

oth er drug used for CMV ret in it is an d is adm in istered on ly

th e cen t ral n er vou s system . Acyclovir is th e

by in t raocular inject ion .

for HSV in fect ion , an d th e e

rst-lin e agen t

cacy of th erapy con rm s th at

th e p at ien t w as su ering from h erp es en cep h alit is.

A, B, D These antiviral drugs are not used for CMV retinitis. E, F Th ese drugs are n ot an t iviral agen ts.

A See correct an sw er explan at ion . B, C Th ese diseases are rare in pat ien ts w ith ou t HIV an d

ANTIVIRAL DRUGS Answ er key

can n ot be cu red w ith an t iviral drugs. D Cytom egalovirus (CMV) in fect ion occurs m ain ly in im m u n ocom p rom ised pat ien ts or is congen ital, an d acyclovir is n ot act ive again st CMV.

Learning objective: Describe the m ost likely adverse e ect of the concurrent adm inistration of abacavir and efavirenz. 39. A Abacavir an d efaviren z can frequen tly cau se skin rash es. Abacavir can cause allergic react ion s in up to 8% of pat ien ts,

1. 2. 3. 4. 5.

F C E E E

6. 7. 8. 9. 10.

E C C E B

11. 12. 13. 14. 15.

D D D C F

16. 17. 18. 19. 20.

D E C E A

21. 22. 23. 24. 25.

A E B A A

26. 27. 28. 29. 30.

D E E D A

31. 32. 33. 34. 35.

D B E D A

36. 37. 38. 39. 40.

C C E A C

Answers and Explanations: VIII-7 Antiprotozoal Drugs Questions 1−5 1. A

Learning objective: Identify the species and stages of Plasmodium that can be killed by me oquine.

2. F

7. E Me oqu in e is a blood sch izon t icid e t h at is m od erately ef-

3. E

fect ive again st gam etocytes, except t h ose of Plasm odium

4. H

falciparum . It h as n o e ect on p rim ar y t issu e sch izon ts or

5. M

hyp n ozoites. Me oqu in e is especially u sefu l as a ch em oprop hylact ic agen t for t ravelers in areas th at are ch loroqu in e-

Learning objective: Explain the mechanism of action of chloroquine. 6. E Malarial p arasites grow in h ost er yth rocytes by ingest ing

resistan t , as in th is case. A−D, F See correct an sw er explan at ion .

h em oglobin , a process th at gen erates free radicals an d h em e u n react ive m alarial pigm en t called h em ozoin . Ch loroquin e

Learning objective: Explain the m echanism of plasm odial resistance to chloroquine.

in h ibit s plasm odial h em e polym erase, th e en zym e th at po-

8. C Ch loroqu in e acts by being accu m u lated in th e food vacu ole,

lym erizes h em e in to h em ozoin , an d th e bu ild u p of free h em e

w h ere it in h ibits h em e polym erase. Resist an t st rain s are able

cau ses th e death of parasites.

to e

as h igh ly react ive by-p rod u ct s. Hem e p olym er izes in to an


u x th e drug by an act ive pum p m ech an ism an d release

Answers and Explanations: VIII-7 Antiprotozoal Drugs 479 t h e d r ug at least 40 t im es faster t h an sen sit ive st rain s,

P. falciparum , bu t t h e ad d it ion of p rogu an il m arked ly re-

t h ereby ren d er ing t h e d r ug in e ect ive. Ch loroqu in e resist -

du ces th is resistan ce.

an ce is m ain t ain ed t h rough ou t t h e w h ole life cycle an d is transferred to the progeny. Cross-resistance has been dem on-

A, B, D, E In th ese drug com bin at ion s, at least on e drug is n ot act ive again st P. falciparum .

st rated w ith oth er 4-am in o qu in olin es bu t n ot to qu in in e, m e oquin e, or an t ifolates. A, B, D, E See correct an sw er exp lan at ion .

Learning objective: Identify the appropriate antiam ebic drug for a patient su ering from epilepsy. 12. D Th e pat ien t’s sym ptom s an d lab test s in dicate th at sh e w as

Learning objective: Identify the enzym e defect that can cause hemolytic anemia in a patient receiving primaquine.

su er ing from am ebic dysen ter y. Becau se t h e p at ien t ap -

9. E Th e pat ien t’s h istor y an d lab tests in dicate th at h e w as su f-

com puted tom ography scan ), a lu m in al am ebicide is appro-

fering from h em olyt ic an em ia. Th e disorder w as m ost likely

p riate. Parom om ycin is a secon d-lin e lu m in al am ebicide. In

t riggered by prim aqu in e in a p erson w ith a gen et ically in -

t h is p at ien t , h ow ever, m et ron idazole is relat ively con t rain -

duced glucose-6-phosphate dehydrogenase de ciency (G6PD),

d icated becau se of ep ilep sy (t h e d r ug is relat ively con t ra-

an X-lin ked disorder. Over 100 m u tan t form s of th e en zym e

in dicated in pat ien ts w ith any n eurologic disorder).

p aren tly h ad n o ext rain test in al am ebiasis (see th e n egat ive

h ave been iden t i ed, but th e m ost com m on on e is th e drug-


sen sit ive variet y. Th e en zym e defect occu rs in abou t 10% of

B Ch loroquin e is e ect ive on ly again st liver am ebiasis.

Am erican Black m ales. Hem olysis a ect s th e older red blood

C, E, F Th ese drugs are n ot e ect ive again st Entam oeba

cells (RBCs) after exposu re to drugs th at produce peroxide

histolyt ica.

an d cau ses oxidat ion of RBC m em bran es. A vast array of in cluding prim aqu in e an d oth er an t im alarial drugs (ch loro-

Learning objective: Explain the m olecular m echanism of action of pyrimetham ine.

qu in e, qu in in e). Th e d egree of h em olyt ic an em ia var ies

13. E Th e pat ien t m ost likely received a su lfadiazin e−pyrim eth -

greatly. Jau n d ice, ret iculocytosis, an d leukocytosis are com -

am in e com bin at ion th at rep resen t s th e st an dard th erapy for

m on , as in th is case.

toxoplasm osis. Pyrim eth am in e select ively in h ibit s protozoal

d rugs can in duce h em olysis in people w ith G6PD de cien cy,


d ihydrofolate red uct ase, a key en zym e for folate biosyn th esis in th e p arasite. Th is in t u rn leads to failu re in DNA syn -

Learning objective: Describe the em ergency treatm ent for falciparum m alaria.

th esis an d n u clear division . A−D See correct an sw er explan at ion .

10. A Th e h istor y an d th e sign s of th e pat ien t , togeth er w ith th e cip aru m m alaria. Becau se in fect ion s w ith Plasm odium falci-

Learning objective: identify the drug active against the late exoerythrocytic stage of Plasmodium vivax and P. ovale.

parum in n on im m un e p at ien t s can progress rapid ly to a fat al

14. A Prim aqu in e is th e on ly agen t able to preven t relap se of in -

outcom e, th erapy sh ou ld be in it iated prom ptly. Artem isin -

fect ion due to th e late exoer yth rocyt ic st age of P. vivax an d

based com bin at ion th erapy is cu rren tly th e stan dard t reat-

P. ovale. It is th erefore com m on ly given to ach ieve a radical

m en t for severe falcipar u m m alaria. Artesu n ate is given for

cu re of vivax or ovale m alaria.

lab result s, in dicate th at sh e w as m ost likely a ected by fal-

3 days, follow ed by a 7-d ay oral cou rse of d oxycyclin e or


clin dam ycin . Ar tem isin d er ivat ives are ver y rap id ly act in g blood sch izon t icid es again st all h u m an m alar ia p arasites. Th e m ech an ism of an t im alarial act ivit y of ar tem isin s is st ill u n cer t ain but likely results from th e product ion of toxic free radicals. B−E See correct an sw er explan at ion .

Learning objective: Identify the drugs used for antim alarial prophylaxis in people visiting areas with chloroquine-resistant Plasmodium falciparum. 11. C Atovaqu on e−progu an il com bin at ion (Malaron e) is a stan d ard p rop hylact ic regim en for ch loroqu in e-resist an t P. falciparum . Resist an ce to atovaqu on e alon e d evelop s easily in

Learning objective: Explain the m echanism of action of m etronidazole. 15. D Th e w om an w as m ost likely su ering from t rich om on iasis, a p rotozoal in fect ion of th e vagin a th at m ay be asym p tom at ic or m ay cau se in am m ator y disorders in th e gen ital t ract . Met ron idazole is a

rst-lin e agen t for t rich om on iasis.

It s m ech an ism of act ion m ost likely involves dam age of protozoal DNA th rough th e form at ion of a h igh ly react ive n it ro radical an ion . Th erapy m ust in clude sex part n ers in order to avoid rein fect ion . A−C, E Th ese an t ibiot ics are n ot e ect ive again st Trichom onas vaginalis.

480


Learning objective: Outline the pharm acotherapy in the case of leishm aniasis.

su ering from giardiasis. Metronidazole w ould be the drug of

16. B Th e pat ien t’s h istor y, sign s, an d lab tests in dicate th at sh e

becau se sh e is an alcoh olic. Con cu rren t alcoh ol con su m pt ion

w as m ost likely su er in g from cu t an eou s leish m an iasis.

w ith m et ron idazole causes a disu l ram -like e ect th at can

Leishm ania t ropica is th e cau sat ive agen t in sou t h er n Eu -

be dan gerou s (p sych ot ic react ion s h ave been rep or ted in

rop e. Dr ugs of ch oice for leish m an iasis in clu d e an t im ony

alcoh olics receiving m et ron idazole). Parom om ycin is act ive

com p ou n d s (e.g., sod iu m st iboglu con ate), p en t am id in e,

again st Giardia lam blia an d can be a useful opt ion w h en

am p h otericin B, an d cer tain azoles (it racon azole). Sodiu m

m et ron idazole is con t rain dicated, as in th is case.

ch oice for th is disease but is con t rain dicated in th is pat ien t

st iboglu con ate is th e classic th erapy for all sp ecies of Leish-


m ania. Resistan ce to th e d rug h as led to failu re of th is th er-

C−F Th ese drugs are n ot e ect ive again st giardiasis.

apy in In dia bu t n ot in oth er p ar ts of th e w orld. A, C−F These drugs are not e ective against leishm aniasis.

Learning objective: Outline the pharmacotherapy of extraintestinal amebiasis.

Learning objective: Describe the prophylactic use of m e oquine in people visiting areas with chloroquine-resistant Plasmodium falciparum. 20. D Resistan ce to ch loroquin e is n ow ver y com m on in m any

17. A Th e pat ien t’s sym ptom s an d lab test s in dicate th at h e w as

areas of Africa. Me oqu in e h as st rong sch izon t icidal act ivit y

m ost likely su ering from an am ebic abscess p resu m ably lo-

an d is e ect ive again st m any ch loroqu in e-resist an t st rain s

cated on th e gu t w all (am ebom a). For ext rain test in al am ebi-

of P. falciparum an d ot h er m alar ia sp ecies. Ot h er regim en s

asis, m et ron idazole is th e drug of ch oice. A lu m in al am ebicide

for m alar ia ch em op rop hyla xis in region s w it h m u lt id r ug-

su ch as iodoqu in ol or parom om ycin m u st be given con com -

resistan t st rain s of P. falciparum are doxycyclin e an d atova-

itan tly to eradicate th e in fect ion .

qu on e−progu an il (Malaron e).

B−F In t h ese d r ug com bin at ion s, at least on e of t h e d r ugs is n ot act ive again st Entam oeba histolyt ica.

A Prim aquin e is th e on ly an t im alarial drug act ive again st th e hypn ozoite stages of P. vivax an d P. ovale. Becau se of th is, som e exp er ts advocate th e u se of th e drug after t ravel to an

Learning objective: Outline the pharm acotherapy of congenital toxoplasm osis. 18. B Toxoplasm a gondii is a sm all in t racellular protozoan th at can in fect peop le w orldw ide. Asym ptom at ic in fect ion s are com m on in im m un ocom peten t in dividuals, but th e disease can be life-th reaten ing in n ew born s. A com bin at ion of su lfadiazin e an d pyrim eth am in e represen t s th e t reat m en t of ch oice for toxoplasm a in fect ion . Th e t reat m en t m ust be con t in u ed for 1 year. Treat m en t of in fan t s w ith ou t su bst an t ial

en dem ic area to m arkedly dim in ish th e risk of relap se. B Met ron idazole is n ot act ive again st plasm odia. C, E Ch em oprophylaxis w ith th ese drugs is n ot recom m en ded because of frequ en t resist an ce. F Alth ough m ost ch loroquin e-resist an t st rain s of P. falciparum are sen sit ive to quin in e, th e drug is n ot used for prophylaxis becau se of its toxicit y.

Learning objective: Describe the adverse e ects of chloroquine.

n eurologic disease at bir th using pyrim eth am in e an d sul-

21. B Th e p at ien t w as m ost likely t reated w ith ch loroqu in e, a

fadiazin e h as resulted in n orm al cogn it ive, n eurologic, an d

qu in olin e derivat ive th at is a rst-lin e agen t for Plasm odium

au ditor y ou tcom es for all pat ien ts. Treat m en t of in fan t s w h o

vivax an d P. ovale in fect ion s. All qu in olin es can p rolong th e

h ad m oderate or severe n eurologic disease at birth h as re-

QT in ter val on an elect rocardiogram , in creasing th e risk of

su lted in n orm al n eu rologic an d/or cogn it ive ou tcom es for

torsades de poin tes. Th e arrhyth m ia is rare, bu t it s occur-

m ore th an 72% of pat ien ts. Th e best altern at ive th erapy for

ren ce m ay be in creased in p at ien t s already at r isk becau se

p at ien ts in toleran t to su lfon am ides is clin dam ycin an d pyri-

of a con com it an t d isease, as in t h is case (see t h e p at ien t ’s

m eth am in e. Altern at ive th erap ies are t rim eth op rim −su lfa-

an orexia).

m eth oxazole, azith rom ycin , an d doxycyclin e. A, C−E Th ese drug com bin at ion s are n ot e ect ive again st T. gondii.

A Quin in e can cause torsades de poin tes but is n ot used to t reat P. vivax in fect ion becau se ch loroqu in e is m ore e ect ive an d less toxic. E, F Th ese an t im alarial drugs h ave a n egligible risk of tor-

Learning objective: Identify the appropriate pharm acotherapy for an alcoholic person su ering from giardiasis. 19. A Th e p at ien t’s sym ptom s an d lab test resu lt s (h eart-sh ap ed t rop h ozoites w ith fou r pairs of agella) in dicate th at sh e w as

sades de poin tes. C, D Th ese drugs are n ot e ect ive again st m alaria.

Answers and Explanations: VIII-8 Anthelm intic Drugs 481 Learning objective: Describe the adverse e ect of m etronidazole 22. D Th e pat ien t’s h istor y an d sym ptom s in dicate th at sh e w as m ost likely su ering from oral can did iasis du e to m et ron idazole, a

rst-lin e agen t for am ebiasis. Th e drug can cau se a

d isru pt ion of th e n orm al biologic ora, favoring th e ap pearan ce of opp or t u n ist ic in fect ion s.

ANTIPROTOZOAL DRUGS Answ er key 1. 2. 3. 4. 5.

A F E H M

6. 7. 8. 9. 10.

E E C E A

11. 12. 13. 14. 15.

A, B Th ese an t iam ebic d r ugs h ave a ver y low r isk of

C D E A D

16. 17. 18. 19. 20. 21. 22.

B A B A D B D

can didiasis. C, E, F Th ese drugs are n ot e ect ive again st Entam oeba species.

Answers and Explanations: VIII-8 Anthelm intic Drugs Questions 1−5

A Met ron idazole is e ect ive again st Dracunculus m edinensis on ly.

1. A 2. E

B Diethylcarbam azin e is e ect ive again st lariasis on ly.

3. D

C Iverm ect in is ver y e ect ive again st St rongyloides stercora-

4. C

lis bu t is far less e ect ive th an m eben dazole again st Ascaris

5. E

lum bricoides an d Trichuris t richiura. D Praziquan tel is used to kill t rem atodes an d cestodes.

Learning objective: Explain the anthelm intic m echanism of action of iverm ectin. 6. D St rongyloidiasis is en dem ic th rough out th e t ropics an d su b -

Learning objective: Identify the drug used in case of Wuchereria bancrofti infection.

t rop ics, in clu ding ru ral areas of th e sou th ern Un ited St ates.

8. E W uchereria bancroft i in fect ion a ect s 120 m illion people

Iverm ect in in du ces paralysis of w orm m usculat ure by act i-

w orldw ide each year. More th an 26 m illion cases of th is in fec-

vat ing a fam ily of glu tam ate-gated Cl− ch an n els th at are fou n d

t ion are hyd rocele. In d ia bears th e greatest bu rden of th is dis-

on ly in inver tebrates. Th is cau ses a slow an d ir reversible

ease, w ith m ore th an 550 m illion people at risk. In fect ion

open ing of th e ch an n els, leading to a long-last ing hyperpolar-

often leads to m icro larem ia w ith ou t over t clin ical m an ifes-

izat ion of n eu ron s or m u scle cells. Iverm ect in also act ivates

tations. How ever, acute in am m ator y lariasis can occur w ith

(d irect ly or in d irect ly) gam m a-am in obu t yr ic acid (GABA)−

fever an d in am m at ion of lym ph n odes, as in th is case. Gen i-

gated Cl− ch an n els, w h ich leads to th e sam e hyperpolarizing

tals an d low er ext rem it ies are m ost com m on ly a ected. Di-

act ion . Th e u lt im ate e ect is th e p aralysis of th e w orm . Th e

ethylcarbam azin e is th e rst-lin e agen t for lariasis in fect ion .

d rug, given for 1 or 2 days, is h igh ly act ive again st St rongyloi-

It kills both m icro lariae and adult worm s, but adults are killed

des stercoralis. Th e dr ug does n ot cross th e blood−brain bar-

m ore slow ly, often requ iring repeated courses of t reat m en t .

rier, so it can n ot a ect GABA n eu rot ran sm ission in th e h u m an

A−D Th ese drugs are n ot act ive again st W. bancroft i.

cen t ral n er vous system . A−C, E See correct an sw er explan at ion .

Learning objective: Identify the drug used to treat enterobiasis. 9. E Th e p at ien t’s sign s an d lab exam in dicate th at h e w as m ost

Learning objective: Outline the appropriate pharm acotherapy for mixed nematode infections.

likely su ering from en terobiasis, w h ich is th e m ost com m on

7. E Com bin ed in fect ion s w ith t w o or even th ree di eren t n em -

an n u al in cid en ce of 42 m illion . Meben dazole is a

h elm in th ic in fect ion in th e Un ited St ates, w ith an est im ated rst -lin e

atode sp ecies are n ot except ion al in p eople w ith in ad equ ate

agen t again st p inw or m in fect ion , an d a sin gle d ose, rep eated

person al hygien e living in a poor san itat ion area, as in th is

after 2 w eeks, u su ally erad icates t h e in fect ion . Th e d r ug h as

case. Meben dazole is a drug of ch oice for rou n dw orm an d

an oral bioavailabilit y of less t h an 10%, so it is n early free of

w h ipw orm in fect ion an d is an altern at ive drug for th read-

adverse e ects.

w orm in fect ion . It is th erefore th e m ost ap p rop riate drug in th is case.

A−D, F Th ese dr ugs are n ot act ive again st Enterobius verm icularis.

482


Learning objective: Outline the appropriate therapy for schistosom iasis. 10. A Th e pat ien t’s h istor y an d lab exam (eggs w ith a lateral

A, B Diethylcarbam azin e an d p raziqu an tel are n ot act ive again st on ch ocerciasis. D, E Fluconazole and m etronidazole are not anthelm intics.

spin e) suggest th at Schistosom a m ansoni w as th e m ost likely o en ding path ogen . Th is w orm is th e on ly sch istosom a spe-

Learning objective: Identify the drug used to treat paragonimiasis.

cies presen t in th e Western Hem isph ere (Brazil, Ven ezu ela,

14. E Th e p at ien t’s h istor y an d lab exam in dicate th at sh e w as

an d som e Car ibbean islan d s). Hu m an s are in fected from

m ost likely su ering from an in fect ion by Paragonim us w es-

cercariae p resen t in fresh w ater. Acu te sch istosom iasis m ay

term ani (orien tal lung uke), a disease caused by ingest ion

occur 2 to 4 w eeks after exposure an d presen ts m ost of th e

of raw or poorly cooked crust acean s in fected w ith en cysted

sign s an d sym ptom s sh ow ed by th e pat ien t . Praziqu an tel is

cercar iae. Th e in fect ion is en d em ic in Jap an , Korea, Ch in a,

th e

an d Taiw an , w h ere peop le eat u n dercooked fresh w ater crabs

rst-lin e agen t for t reat m en t of m ost t rem atode in fec-

t ion s, in clu ding sch istosom iasis. B−F Th ese h elm in t h s are in cor rect ly m atch ed w it h t h e e ect ive drug.

or cray sh . Th e eggs of th e h elm in th are large (80−100 m illim icron s) an d op erculated. Th e in fect ion a ect s th e lu ng, as in th is case. Praziquan tel is e ect ive for m ost t rem atod e an d cestode in fect ion s, an d a 2-day course provides 90 to 100%

Learning objective: Explain the anthelm intic m echanism of action of praziquantel.

cu re rates for pu lm on ar y p aragon im iasis.

11. D Diphyllobothrium lat um is a t ap ew or m fou n d m ain ly in

in fect ion s.

A−D Th ese an th elm in t ics are n ot act ive again st t rem atode

t h e n orth ern tem p erate region s w h ere fresh w ater sh are a m ajor p or t ion of th e d iet . Many fresh w ater sh sp ecies con -

Learning objective: Identify the drug used to treat ascariasis.

st it u te th e in term ediate h ost of th e parasite. Praziqu an tel is

15. B Th e p at ien t ’s sign s in d icate t h at sh e w as m ost likely su f-

a drug of ch oice for dip hylloboth riasis. It is th ough t to act by

fer in g from an in fect ion w it h Ascaris lum bricoides, on e of

en h an cin g calciu m in u x, t h u s in creasin g w or m m u scu lar

t h e m ost com m on an d cosm op olitan h elm in th ic diseases.

act ivit y follow ed by con t ract ion an d spast ic p aralysis.

Ben zim idazoles such as m eben dazole an d alben dazole are


rst -lin e agen t s for t h is d isease. Meben dazole, given for 3 con secu t ive days, ach ieves a cu re rate of 90 to 100% for

Learning objective: Explain the anthelm intic m echanism of action of m ebendazole.

ascariasis. A, C−F See correct an sw er explan at ion .

12. F Trichuris t richiura (w h ipw orm ) is a parasite w ith cosm opolit an d ist ribu t ion , alth ough it is m ore com m on in w arm ,

Learning objective: Describe the adverse e ects of iverm ectin.

m oist region s. Th e in fect ion is u su ally asym ptom at ic, bu t

16. A Th e p at ien t’s h istor y, sign s, an d sym ptom s suggest h e w as

h eavy in fect ion can cau se abd om in al p ain , an orexia, an d

m ost likely su er in g from a Mazzot t i-like react ion , a syn -

diarrh ea an d m ay ret ard grow th . Meben dazole, alben dazole,

d rom e d ue to killing of m icro lariae by iverm ect in . Th e drug

an d t h iaben d azole are ben zim idazole d er ivat ives m ain ly

d oes n ot kill adu lt w orm s bu t a ect s d eveloping lar vae an d

act ive again st n em atodes. Th ese drugs produ ce m any bio-

kills m icro lariae in th e w orm u terus, m arkedly decreasing

ch em ical ch anges in w orm cells, but th e m ain act ion seem s

m icro larial cou n t s in th e skin an d oth er t issu es. Th e reac-

to be in h ibit ion of m icrot u bu le p olym er izat ion by bin d in g

t ion is u su ally m ild an d lasts ju st a few days. Rarely, a m ore

to β-t ubulin . Th e m icrot ubular system of th e h ost cells is un -

severe react ion can occu r, as in th is case. An t ih istam in es an d

a ected. Th e in h ibit ion of t ubulin polym erizat ion disrupts

n on steroidal an t iin am m ator y drugs u sually can con t rol th e

n em atode m ot ilit y an d DNA replicat ion , leading to im m obi-

syn drom e. Glu cocor t icoid s are in dicated for th e m ost severe

lizat ion an d th e death of th e w orm .

cases.


B, C Praziqu an tel an d m eben dazole are n ot act ive again st on ch ocerciasis.

Learning objective: Identify the drug to be used in case of onchocerciasis.

D−F Ketoconazole, am photericin B, and m e oquine are not an th elm in t ics.

13. C Th e p at ien t’s ocu lar sign s an d th e skin biop sy in dicate th at Onchocerca volvulus. Th e in fect ion cau ses a ch ron ic skin dis-

Learning objective: Identify the drug used to treat cystic hydatid disease.

ease an d eye lesion s th at m ay lead to blin dn ess (on ch ocerci-

17. E Th e p at ien t’s exam s in dicate th at h e w as m ost likely su f-

asis is also called river blin dn ess). Iverm ect in is th e drug of

fering from cyst ic hydat id disease due to Echinococcus gran-

ch oice for on ch ocerciasis given as a single oral dose on ce or

ulosus. Th is t yp e of in fect ion occurs in sh eep -raising areas

t w ice a year.

of m any part s of th e w orld. Alben dazole is th e t reat m en t of

sh e w as su ering from a larial in fect ion , m ost likely du e to

Answers and Explanations: VIII-8 Anthelm intic Drugs 483 ch oice for m edical th erapy of th e disease. It provides on ly a

dep olarizing n eu rom u scu lar blocking agen t in h elm in th s.

m odest cu re rate w h en used alon e, but it is a u seful adjun ct

These actions cause extensive depolarization of the helm inth

t reat m en t in th e p reop erat ive p eriod to redu ce th e risk of

m uscle m em brane, producing tension of the helm inth’s m us-

dissem in ated in fect ion resu lt ing from sp illage of th e cyst

cles that causes paralysis of the w orm s. Then norm al peristal-

con ten t s at th e t im e of su rger y or during aspirat ion .

sis causes expulsion of the parasites from the gastrointestin al

C, D Th e an t h elm in t ic d r ugs iver m ect in an d d iet hylcarbam azin e are n ot act ive again st ech in ococcosis. A, B, F Met ron idazole an d ch loroqu in e are n ot an t h elm intics.

t ract . B, C Th e an th elm in t ics praziquan tel an d diethylcarbam azin e are n ot act ive again st Enterobius verm icularis. D, E Metronidazole and

uconazole are not anthelm intics.

Learning objective: Identify the drug used to treat taeniasis.

Learning objective: Describe the adverse e ects of m ebendazole.

18. C Th e h istor y an d sign s of th e pat ien t , togeth er w ith th e lab

21. A Th e p at ien t ’s sym ptom s an d laborator y valu es in d icate

results, in dicate th at h e w as su ering from t aen iasis m ost

t h at sh e w as m ost likely su er in g from an acu te h ep ato -

likely due to Taenia saginata (u n like Taenia solium , T. sagi-

cellu lar injur y. Th e inju r y arose con cu rren tly w ith sign s an d

nata proglot t id s can em erge by m ean s of th eir ow n m ot ilit y

sym ptom s of hyp ersen sit ivit y (rash an d fever) w ith in days

th rough th e an u s an d dep osit th e eggs in th e perian al re-

of st art ing a secon d course of m eben dazole. Th is pat tern is

gion ). Praziqu an tel is cu rren tly a drug of ch oice for m ost ces-

t ypical of a drug-in du ced allergic react ion , im m un oallergic

tode an d trem atode infection s. A single dose results in n early

h ep at it is in t h is case. Th e d isease u su ally resolves rap id ly

100% cu re rates for T. solium , T. saginata, an d Diphylloboth-

w h en t h e o en d ing d r ug is w it h d raw n . Th e gran u lom as

rium lat um .

fou n d on liver biopsy re ect th e gen eralized hypersen sit iv-

A, B Th e an th elm in t ics iverm ect in an d ar tem isin are n ot act ive again st cestodes. D−F Met ron idazole, am ph otericin B, an d

it y, an d sim ilar gran u lom as are likely to be fou n d in oth er organ s. In test in al absorpt ion of m eben dazole is quite low

ucon azole are

n ot an th elm in t ics.

(oral bioavailabilit y is less th an 10%), an d dose-related adverse e ects are rare. Alth ough allergic react ion s to m eben dazole are also rare, th ey can occu r, as in th is case.

Learning objective: Outline the appropriate therapy for ancylostom iasis.

th elm in t ic drugs p raziqu an tel an d diethylcarbam azin e are

19. E Th e p at ien t ’s sign s an d lab resu lt s in d icate t h at h e w as

n ot used to t reat ascariasis.

su ering from a ch ron ic h elm in th ic in fect ion (see th e th in -

B, C Most drugs can cause allergic react ion s, but th e an -

D, E Metronidazole and

uconazole are not anthelm intics.

sh elled oval eggs) du e to a w orm able to cau se iron de cien cy an em ia. Hook w orm s su ch as Necator am ericanus

Learning objective: Describe the adverse e ects of praziquantel.

at tach to th e in test in al villi an d suck blood. Th ey p eriodi-

22. D Th e pat ien t’s sym ptom s in dicate th at h e w as m ost likely

cally m ove from on e place of th e in test in al w all to an oth er to

su ering from adverse e ect s of praziqu an tel. Th is drug is

su ck blood from di eren t villi. Becau se th ey locally inject

th e

an t icoagu lan t com p ou n ds, th e arteriole bleeds for a w h ile,

t ion s. Alth ough seriou s adverse e ects of th e drug are rare,

so occu lt blood is fou n d in th e stools. Meben dazole is th e

m in or adverse e ect s are com m on an d u su ally su bside in 1

d rug of ch oice for an cylostom iasis. A cu re rate of m ore th an

or 2 days.

99% h as been reported after a cou rse of t w o tablet s daily for 3 days. A−D, F In fect ion w ith th ese h elm in th s rarely causes an em ia, and they are incorrectly m atched w ith the e ective drug.

rst-lin e agen t for m ost t rem atode an d cestod e in fec-

A−C Th e an th elm in t ic drugs diethylcarbam azin e, iverm ect in , an d pyran tel p am oate are n ot u sed again st cestode in fect ion s. E, F Met ron idazole an d m icon azole are n ot an th elm in t ics.

Learning objective: Outline the therapeutic uses of pyrantel pam oate. 20. A W h en a dr ug th erapy is n ot e ect ive, an altern at ive t reatm en t is ap p rop riate. Pyran tel pam oate is a broad-spect ru m an th elm in t ic th at is h igh ly e ect ive for th e t reat m en t of en terobiasis an d ascar iasis. Pyran tel act ion s are n eit h er verm icidal n or ovicidal. Th e drug in h ibits ch olin esterase an d act ivates n icot in ic acet ylch olin e receptors, th u s act ing as a

ANTHELMINTIC DRUGS Answ er key 1. 2. 3. 4. 5.

A E D C E

6. 7. 8. 9. 10.

D E E E A

11. 12. 13. 14. 15.

D F C E B

16. 17. 18. 19. 20. 21. 22.

A E C E A A D

484


Answers and Explanations: VIII-9 Antineoplastic Drugs Questions 1−4 1. B

Learning objective: Explain why carmustine and other nitrosoureas are used to treat brain tumors.

2. E

7. B Car m u st in e belongs to t h e n it rosou reas grou p of d r ugs.

3. D

Th ese alkylat in g agen t s h ave a h igh lip op h ilicit y t h at facili-

4. F

tates th eir en t r y in to th e brain . In fact , th eir con cen t rat ion in th e cerebrospin al uid is 15 to 70% of th e con cu rren t plasm a

Learning objective: Outline the anticancer use of trastuzum ab.

valu es. Becau se of th is, n it rosoureas are th e m ain ch em oth er-

5. C Trast u zu m ab is a m on oclon al an t ibody again st a su rface

apeut ic agen ts used in th e t reat m en t of brain t u m ors.

protein called h u m an ep iderm al grow th factor receptor 2 (HER-2), w h ich m ay be overexpressed in prim ar y breast carcin om a. Th e drug bin ds w ith h igh a

n it y to th is receptor,

th us preven t ing th e bin ding of HER to th e sam e receptor. In th is w ay, t um or grow th is in h ibited. Trast u zu m ab is used in HER-2 p osit ive, m etastasized breast can cer, alon e or in com bin at ion w ith paclit axel. A, B, D−F Th ese d r ugs are n ot u sed in breast can cer

A Nit rosoureas are alkylat ing agen t s th at act ually can kill both n eoplast ic an d n on n eoplast ic cells. C Carm u st in e act u ally can cau se en cep h alop athy w h en given in h igh d oses. D Th e am in e p u m p is sp eci c for m on oam in es. Nit ro sou reas are n ot m on oam in es. E Th e h alf-life of carm ust in e is act ually sh or t , about 15 to 30 m in u tes.

ch em oth erapy.

Learning objective: Explain the concept of rescue therapy in anticancer drug treatment.

Learning objective: Explain the m echanism of anticancer action of doxorubicin. 8. A Doxor u bicin is an an t h racyclin e an t ibiot ic, t h u s t h e A in

6. E Rescue th erapy is a st rategy aim ed at alleviat ing som e ad-

t h e ABVD acronym ; altern at ively, th e A m ay be con sidered to

verse e ect s of an t ican cer ch em oth erapy by th e use of drugs

stan d for Adriam ycin , a bran d n am e for doxoru bicin . Th ese

th at can “rescue” th e n orm al cells exposed to th e an t ican cer

anticancer drugs likely act w ith m ultiple m echanism s, includ-

drug. Leu covorin (form yl tet rahydrofolate, also called folin ic

ing in tercalat ion bet w een adjacen t base p airs of DNA, th u s

acid) is accum u lated m ore readily by n orm al cells th an by

cau sing blockad e of DNA rep licat ion ; blockade of top oisom er-

n eoplast ic cells. Th e adm in ist rat ion of th is drug result s in res-

ase II, th e en zym e th at cat alyzes DNA repair (it breaks an d

cu e of th e n orm al cells, as th e drug byp asses th e t w o step s in

then reseals DNA strands); and generation of free radicals that

th e purin e syn th esis th at are blocked by m eth ot rexate (i.e.,

can oxidize DNA bases. The end result of these m ultiple m ech-

folate to dihydrofolate an d dihydrofolate to tet rahydrofolate).

an ism s is cell apoptosis.

A Log kill is a r u le t h at st ates t h at a given d ose of an an t i-

B Th is is th e m ech an ism of act ion of taxan es.

can cer d r ug kills a con st an t p rop or t ion of t h e t u m or cell

C Th is is th e m ech an ism of act ion of vin ca alkaloids.

popu lat ion .

D Th is is th e m ech an ism of act ion of alkylat ing drugs.

B Recr uit m en t refers to a st rategy th at involves in it ial use

E Th is is th e m ech an ism of act ion of m eth ot rexate.

of cell cycle n on speci c (CCNS) an t ican cer dr ugs to ach ieve a sign i can t cell kill. Th is kill “en rolls” p reviou sly rest ing cells

Learning objective: Describe the adverse e ects of doxorubicin.

in th e G0 ph ase of th e cell cycle. At th is stage, cell cycle speci c

9. B In th e CHOP acronym , C st an ds for cyclop h osp h am ide; H for

(CCS) an t ican cer drugs are given . Becau se th ese drugs are ac-

hydroxydau n oru bicin , w h ich is an oth er n am e for doxoru bi-

t ive again st d ividing cells, m axim al cell kill m ay be ach ieved.

cin ; O is for On covin , w h ich is a bran d n am e for vin crist in e;

C Pu lsing is a st rategy th at involves cycles of t reat m en t w ith

an d P is for predn ison e or predn isolon e. Th e CHOP regim en

ver y h igh doses of an an t ican cer drug. Bet w een cycles, n orm al

h as been con sidered th e best t reat m en t for th e in it ial th erapy

cells can recover from th e cytotoxic e ect s of th e drug.

of pat ien t s w ith di u se n on -Hodgkin lym ph om a. Recen tly, it

D Com bin at ion th erapy is th e rule in an t ican cer t reat m en t

h as been sh ow n th at th e com bin at ion of CHOP w ith rit u x-

an d is usually don e w ith drugs h aving di eren t m ech an ism s

im ab can im prove respon se rates, disease-free su r vivals, an d

of act ion an d (w h en possible) di eren t toxic e ect s.

overall su r vivals com pared w ith CHOP ch em oth erapy alon e.

Answers and Explanations: VIII-9 Antineoplastic Drugs 485 Th e sign s an d sym ptom s of th e pat ien t suggest th e diag-

w ith in th e rst few w eeks of th erapy. Are exia is com m on in

n osis of cardiac failu re. An th racyclin es (doxorubicin , daun o-

p at ien ts t reated w ith h igh cu m ulat ive doses. Vin ca alkaloids

ru bicin , idar u bicin , etc.) are th e an t ican cer drugs th at h ave

h ave cer tain toxicit ies in com m on (i.e., n ausea an d vom it ing,

th e h igh est risk of cardiac toxicit y. Th ey can cau se a dose-

diarrhea, alopecia), but other adverse e ects di er. Vincristine

depen den t dilated cardiom yopathy associated w ith a p oten -

cau ses a dose-lim it ing n eu rotoxicit y bu t is a m ild m yelosu p -

t ially fat al cardiac failu re. Th is toxicit y app ears to resu lt from

pressant, w hereas vinblastine causes negligible neurotoxicit y

increased production of free radicals w ithin the myocardium .

bu t gives rise to a severe, dose-lim it ing m yelosu p p ression .

A, C−E Th ese d r ugs h ave a low (cyclop h osp h am id e) or n egligible r isk of card iac toxicit y. Ot h er an t ican cer d r ugs t h at can cau se card iac toxicit y are

B−E Th e risk of periph eral n europathy w ith th ese drugs is n egligible.

u orou racil, p aclit a xel,

an d t rast u zu m ab.

Learning objective: Describe the local adverse e ect s of m echlorethamine given intravenously.

Learning objective: Outline the chem otherapy for rem issioninduction of acute lymphoblastic leukem ia.

14. D Th e MOPP acronym is derived from : M for m u st argen , also

10. C Th e pat ien t’s bon e m arrow biopsy con rm ed th e diagn osis

for vin cr ist in e; P for p rocarbazin e; an d P for p red n ison e.

of acute lym ph oblast ic leukem ia. A com bin at ion of vin cris-

Mech loretham in e is an alkylating agen t. All alkylating agents

t in e an d p redn ison e (p lu s asparagin ase) is a cu rren t th erapy

are st rongly cytotoxic an d can dam age t issues at th e site of

of ch oice to in du ce rem ission , as n on e of th ese agen t s is m y-

inject ion . Th is is because th ey can form covalen t bon ds w ith

elosuppressive to n orm al bon e m arrow elem en ts. Over 90%

m any cell con st it uen t s, leading to cell death .

of ch ildren en ter com plete rem ission w ith th is t reat m en t . A Th is com bin at ion is curren tly used for lung an d test icu-

kn ow n as m ech loret h am in e; O for On covin , a bran d n am e

A−C Predn ison e, vin crist in e, an d procarbazin e are devoid of vesican t proper t ies.

lar can cers. B Th is com bin at ion is cu rren tly u sed for p rost ate can cer.

Learning objective: Explain the mechanism of action of cytarabine.

D Th ese drugs are used to t reat breast can cer.

15. B Th e st an dard t reat m en t for acu te m yelogen ou s leu kem ia

E Th is com bin at ion is curren tly used for h ead an d n eck can cers.

in clu des rem ission th erapy w ith an an th racyclin e an d cytarabin e. Cyt arabin e is act ivated to a com p ou n d th at is in corp orated at th e term in al posit ion of a grow ing DNA ch ain , th us

Learning objective: Explain the m echanism of cancer resistance to uorouracil. 11. A Flu orou racil is a p rod r ug t h at is conver ted w it h in cells

im pairing elongat ion of DNA st ran ds. A Th is is th e m ech an ism of act ion of etoposide C Th is is th e m ech an ism of act ion of pen tost at in

to u oro-deoxyuridin e-m on oph osph ate, w h ich in h ibits thy-

D Th is is th e m ech an ism of act ion of vin ca alkaloids

m idylate syn th ase, th us causing a “thym in eless death ” of

E Th is is th e m ech an ism of act ion of t axan es

cells. A decreased abilit y of can cer cells to ph osph or ylate pyrim idin es p reven t s th e act ivat ion of th e p rodrug, th u s cau sing drug resist an ce. B−E All th ese m ech an ism s w ould decrease, n ot in crease, th e resist an ce to uorouracil.

Learning objective: Explain the m echanism of action of dactinomycin. 16. D Dact in om ycin is a cytotoxic an th racyclin e an t ibiot ic. Th e m ain m ech an ism of an t ican cer act ion of t h ese d r ugs in volves bin ding to double-h elical DNA, th us preven t ing DNA

Learning objective: Outline the therapeutic uses of cisplatin.

tran scription. Th e action is sim ilar to th at of alkylating drugs,

12. D Test icu lar can cer is th e m ost com m on m align an cy in m en

bu t an th racyclin es bin d dou ble-h elical DNA by in tercalat ion

bet w een ages 15 an d 35 years. Th e x-ray an d com pu ted to-

n ot by alkylat ion . Dact in om ycin is u sed m ain ly in W ilm s

m ograp hy resu lts in dicate m etastat ic test icu lar can cer, an d

t u m or, a kid n ey t u m or t h at is t h e m ost com m on in t ra-

the patient should receive system ic chem otherapy. The com -

abdom in al t u m or of ch ild h ood an d accou n ts for abou t 6% of

bin at ion of cisplat in , etop oside an d bleom ycin com m on ly

all ch ildh ood m align an cies.

con t rols th e t um or long term an d is w idely u sed today.

A Th is is th e m ech an ism of act ion of alkylat ing drugs.

A Carm ust in e is m ain ly used for brain t u m ors.

B Th is is th e m ech an ism of act ion of m eth ot rexate.

B, C, E Meth ot rexate, cyt arabin e, an d m ercaptop u rin e are

C This is the m echan ism of action of pyrim idine analogues.

m ain ly u sed for h em atologic m align an cies.

E Th e form at ion , n ot th e in h ibit ion , of free radicals is on e of th e post ulated m ech an ism s of act ion of som e an t ican cer

Learning objective: Describe the adverse e ect s of vincristine. 13. A Th e pat ien t’s paresth esias an d loss of re exes are sign s of vin crist in e p eriph eral n europathy, w h ich often appears

d rugs, in clu ding doxoru bicin an d bleom ycin . F Th is is th e m ech an ism of act ion of im at in ib.

486


Learning objective: Explain the m echanism of action of cyclophospham ide.

Learning objective: Describe the adverse e ects of bleomycin. 20. E Th e p at ien t w as at risk for several processes th at cou ld pro-

17. A Cycloph osph am ide is an alkylat ing agen t . Th ese drugs act

d uce h is sym ptom s, but th e exam resu lt s ru led ou t bacterial

by in t ram olecular cyclizat ion to form eith er an ethylen ei-

in fect ion s an d th e progression of lym p h om a. Th erefore, pu l-

m on iu m or a carbon iu m ion w h ich are st rongly elect rop h ilic

m on ar y toxicit y resu lt ing from on e or m ore of th e drugs h e

(i.e., elect ron at t ract ing). Th ese in term ed iates can alkylate,

received is th e m ost likely hypoth esis. Am ong th e an t ican cer

th at is th ey can t ran sfer alkyl grou p s to variou s cellu lar con -

d rugs, bleom ycin m ost com m on ly causes pulm on ar y toxic-

st it u en t s by form at ion of covalen t bon ds w ith n u cleop h ile

it y, m ain ly in terst it ial pn eu m on it is follow ed by pu lm on ar y

(i.e., elect ron don or) grou p s of th ese con st it u en t s. Alkylat ion

brosis. Th e m or t alit y associated w ith bleom ycin pu lm o-

of gu an in e of a sin gle st ran d of t h e DNA m olecu le resu lt s in m iscoding or in depurin at ion by excision of guan in e residu es. Alkylat ion of gu an in es in both st ran ds of th e DNA m olecu le resu lt s in cross-lin king, w h ich app ears to be of m ajor im port an ce to th e cytotoxic act ion of alkylat ing agen ts.

n ar y toxicit y is ver y h igh (about 50%). A Cyclop h osph am ide m ay cau se p ulm on ar y toxicit y, bu t th e risk is m u ch low er th an th at of bleom ycin . B−D Th e risk of pulm on ar y toxicit y w ith th ese drugs is ver y low.

B Th is is th e m ech an ism s of act ion of cyt arabin e. C Th is is th e m ech an ism s of act ion of uorouracil.

Learning objective: Describe the adverse e ects of cisplatin.

D Th is is th e m ech an ism s of act ion of topoisom erase

21. D Th e pat ien t’s lab resu lt s suggest th e diagn osis of ren al fail-

in h ibitors.

u re. Cisplat in is th e an t ican cer drug w ith th e h igh est risk of

E Th is is th e m ech an ism s of act ion of vin ca alkaloids.

n eph rotoxicit y, an d hyp om agn esem ia is th e m ost com m on elect rolyte abn or m alit y cau sed by cisp lat in . How ever, t h e

Learning objective: Explain the mechanism of action of paclitaxel.

rou t in e u se of hyd rat ion an d d iu resis h as largely red u ced

18. C Alth ough aden ocarcin om a of th e lung is less sen sit ive th an

cisp lat in -in duced n ep h rotoxicit y.

sm all cell lung can cer to ch em oth erapy, com bin at ion th erapy can im prove su r vival. A w idely u sed

A−C, E Th ese drugs ver y rarely cau se n eph rotoxicit y.

rst-lin e regim en

(e.g., paclitaxel). Taxan es bin d to t u bulin an d in h ibit s t ubulin

Learning objective: Explain the m echanism of action of m ercaptopurine.

depolym erization, thus preven ting m icrotubule disassem bly.

22. F Main ten an ce th erapy of acute lym ph oblast ic leukem ia is

A, B, D−F Th ese d rugs are n ot u sed for lu ng can cer an d th ey

u su ally perform ed for 2½ to 3 years after rem ission , sin ce

in cludes a plat in um com poun d (e.g., cisplat in ), an d a taxan e

d o n ot bin d to t ubulin .

early trials have show n that w ithout m aintenance, m ost children w ill relapse w ith in 1 or 2 m on th s. Im p ressive im prove-

Learning objective: Explain the mechanism of action of etoposide.

m en ts in d isease-free su r vival an d cu re rates are ach ieved

19. C Sm all cell lu n g carcin om a is on e of t h e fou r m ain t yp es

w it h var iou s m ain ten an ce regim en s. Met h ot rexate an d

of lu ng can cer an d accou n ts for 15 to 20% of p rim ar y lu ng

m ercaptopu rin e are th e drugs m ost often in clu ded in th ese

t u m ors. Becau se sm all cell lu ng carcin om a dissem in ates

regim en s. Mercaptopu rin e is an an t im et abolite an t ican cer

early in th e disease, surger y is alm ost n ever in dicated. Most

d rugs th at is in act ive in its paren t form an d m ust be m etab -

chem otherapeutic regim ens include high-dose cisplatin w ith

olized by the enzym e hypoxanthine-guanine phosphoribosyl

etoposide. Etoposide in h ibits topoisom erase II, on e of th e

t ran sferase in to th e m on op h osp h ate n u cleot ide 6-th ioin os-

en zym es t h at reseals d ou ble-st ran d ed DNA breaks. As a

in ic acid, w h ich in t urn in h ibit s several en zym es of de n ovo

resu lt , DNA breaks accu m u late an d lead to cell d eat h . It is

p urin e n u cleot ide biosyn th esis. Th e m on op h osp h ate form

w or t h n ot in g t h at qu in olon es are also able to in h ibit to -

is even t u ally t ran sform ed in to th e t rip h osp h ate form w h ich

p oisom erase II. How ever, qu in olon es in h ibit on ly th e bacte-

can get in corp orated in to both DNA an d RNA, blocking DNA

rial cell en zym e an d are th erefore h arm less to eu kar yot ic

an d RNA syn th esis.

cells, w h ereas etoposide in h ibits on ly eu kar yot ic cell en -


zym es an d are th erefore devoid of an t ibacterial act ivit y. B Th is is th e m ech an ism of act ion of uorouracil.

Learning objective: Identify the drug to be used to treat colon cancer.


23. E Because of signi cant relapse rate in patients w ith extensive

A Th is is th e m ech an ism of act ion of m eth ot rexate.

E Th is is th e m ech an ism of act ion of t axan es.

colon can cer, adjuvan t th erapy is usually perform ed in th ose p at ien ts w h o u n der w en t poten t ially cu rat ive su rger y. It h as been show n that this therapy im proves disease-free sur vival. The currently used adjuvant chem otherapy regim ens contain

Answers and Explanations: VIII-9 Antineoplastic Drugs 487 uorouracil an d leucovorin . Oth er dr ugs th at can be used in com bin at ion s in clude oxaliplat in an d capecit abin e. A−D Th ese drugs are all cell cycle speci c an d are m ain ly used in t u m ors w ith a h igh grow th fract ion . Curren tly, th ey

m yeloid leukem ia is cyt arabin e. For rem ission th erapy, cytarabin e is cu rren tly u sed togeth er w ith an an th racyclin e. A−C, E Th ese drugs are n ot curren tly u sed for rem ission th erapy of acute m yelogen ous leukem ia.

are n ot used to t reat colon can cer, a t um or w ith low grow th

Learning objective: Explain the m eaning of the “log kill” rule in anticancer chemotherapy.

fract ion .

Learning objective: Describe the e ect of anticancer chem otherapy on blood cells.

28. B Th e th erapeut ic st rategy adopted in th is case is based on

24. D Th e decrease of periph eral blood cells after can cer ch em o-

an t ican cer drug w ill kill a con st an t p roport ion (n ot a con -

th erapy depen ds u p on th e life sp an of th at cell lin e. Th e life

st an t n u m ber) of t h e t u m or cell p op u lat ion as w ell as of

span of gran u locytes, on ce released from th e bon e m arrow,

sen sit ive n orm al cell populat ion s. In oth er w ords, killing by

is 4 to 5 h ou rs in t h e blood an d an ot h er 4 or 5 days in t h e

an t ican cer dr ugs is a rst order process, an d th e cu r ve repre-

t issu es. Platelet s su r vive abou t 10 d ays. Th erefore m yelo -

sen t ing th e n u m ber of killed cells w ith in creasing dose of an

su p p ression

an t ican cer drug is an exp on en t ial cu r ve. Th is cu r ve can be

rst resu lt s in gran u locytop en ia follow ed by

th rom bocytop en ia

th e “log kill” ru le. Th is ru le states th at a given dose of an

t ran sfor m ed in to a st raigh t lin e by p lot t in g t h e logar it h m

A Lym ph ocytes con t in ually circu late th rough out th e body an d h ave life span s of w eeks, m on th s or even years.

of th e n u m ber of killed cells again st th e dose. Rem em bering th at th e logarith m is th e expon en t requ ired to produ ce a

B See correct an sw er exp lan at ion .

given n u m ber, it follow s th at 1 is th e log of 10 1 , 2 is th e log of

C Mon ocytes, on ce in th e t issues, becom e m acroph ages

10 2 (th at is 100), 3 is th e log of 10 3 (th at is 1000) an d so on .

an d can live for m on th s or even years. E Er yth rocytes h ave a life span of abou t 120 days

Th erefore if a popu lat ion of 10 3 t u m or cells is redu ced to 10 2 t u m or cells it can be said th at it is redu ced by 1 log. Th is m ean s th at 900 cells are killed by th e drug, resu lt ing in a 90%

Learning objective: Identify the pairs of drugs m ost frequently used to treat di use ovarian cancer.

decrease of cell n u m ber. Accordingly, a 2 log decrease m ean s

25. E Ovarian can cer is th e

fth m ost com m on cau se of can cer

th e cells are killed, an d so on . Usu ally a 2 log decrease is th e

an d can cer death in w om en . Becau se th e can cer is relat ively

st rategy m ost often u sed, as a h igh er decrease w ou ld p ro-

asym ptom at ic, it u su ally h as exten ded beyon d th e p elvis at

du ce un acceptable toxicit y to h ealthy d ividing cells.

th e t im e of diagn osis. Ch em oth erapy is th erefore in dicated

th at 99% of th e cells are killed, a 3 log decrease th at 99.9% of


after su rger y. Cisp lat in or carbop lat in p lu s p aclit a xel are rst-lin e regim en s m ost com m on ly u sed in ovarian can cer. A−D Th ese drugs are n ot used to t reat ovarian can cer.

Learning objective: Describe the adverse e ects of cisplatin. 29. E Ototoxicit y, ch aracter ized by a p rogressive h ear in g loss, com m on ly occu rs w it h cisp lat in an d ap p ears to be m ore

Learning objective: Identify the drug to be used as a m ethotrexate antidote.

p ron ou n ced in ch ild ren . It m ost likely resu lt s from a d irect

26. E Leu covorin can be given to cou n teract th e adverse e ects

icit y is quest ion able an d seem s substan t ial on ly w ith early

th at m eth ot rexate h as on n orm al cells. Leu covorin (form yl

cessat ion of cisp lat in . Ototoxicit y d oes n ot ap p ear to be as-

tet rahyd rofolate, also called folin ic acid) is accu m u lated

sociated w it h ot h er p lat in u m an alogu es (carbop lat in an d

m ore read ily by n or m al cells t h an by n eop last ic cells. Th e

oxalip lat in ).

adm in ist rat ion of th is drug resu lt s in rescu e of th e n orm al

toxic e ect on t h e coch lea. Th e reversibilit y of t h is ototox-

A−D Th e risk of ototoxicit y w ith th ese drugs is n egligible.

cells, becau se th e drug bypasses th e step in th e purin e syn th esis th at is blocked by m eth ot rexate (i.e., dihyd rofolate to tet rahydrofolate). A−D See correct an sw er explan at ion .

Learning objective: Identify the anticancer drug that act s in the G2 phase of the tumor cell cycle. 30. B Bleom ycin is th e on ly cytotoxic an t ibiot ic th at is cell cycle speci c (CCS). It h as been sh ow n th at th e dr ug cau ses accu -

Learning objective: Identify the drug to be used to treat acute myelogenous leukem ia.

m u lat ion of cells in th e G2 ph ase of th e cell cycle.

27. D Th e blood exam an d th e bon e m arrow biopsy are con sis-

th e ABVD acronym st an ds for Adriam ycin , a bran d n am e for

ten t w ith th e diagn osis of acute m yelogen ous leukem ia. Th is leu kem ia prim arily a ect s adu lt s (th e in ciden ce in creases w ith age) an d is ch aracterized by th e n eoplast ic proliferat ion of m yeloblast s. Th e single m ost act ive agen t for acu te

A, D Th ese drugs are cell cycle n on sp eci c (CCNS). Th e A in doxoru bicin . C Vin blast in e is CCS but acts in th e M p h ase of th e cell cycle.

488


Learning objective: Describe the adverse e ect s of cyclophospham ide.

th at on th e

31. F Th e p at ien t p resen ted w it h gross h em at u r ia, w h ich can

im port an t factor in uen cing th e frequ en cy of n au sea an d

be eith er pain less or p ain fu l. W h ereas th e form er can h ave

vom it ing is th e em etogen ic poten t ial of th e drug. Am ong th e

m any cau ses, pain fu l h em at u ria is u su ally du e to in am m a-

drugs adm in istered to th is pat ien t , cyclop h osp h am id e an d

tor y disease of th e urogen it al t ract (cyst it is an d prostat it is),

doxoru bicin are h igh ly em etogen ic, w h ereas th e em etogen ic

renal infarction, or nephrolith iasis. Renal infarction an d renal

poten t ial of vin crist in e is low. Cor t icosteroids, by con t rast ,

calcu li are u n u su al in a ver y you ng ch ild . Cyclop h osp h am ide

are e ect ive an t iem et ics m ain ly in ch em oth erapy-in du ced

can cau se bladd er m u cosa edem a, u lcerat ion s, an d m in or to

nausea and vom iting, but the basis for this e ect is unknow n.

rst day of ch em oth erapy, n ausea is p resen t in

abou t 50% an d vom it ing in about 25% of pat ien t s. Th e m ost

severe h em orrh age. Th is toxicit y is believed to be du e to m e-

A−D All of t h ese listed adverse e ect s can occu r (n eu rop -

tabolites of cyclophospham ide, including chlorethylaziridine

athy w ith vin crist in e, h em orrh agic cyst it is, an d, rarely, pu l-

an d acrolein , w h ich are form ed by h epat ic m icrosom es an d

m on ar y

excreted in th e urin e. Th ey can con cen t rate in th e bladder

failure w ith doxor ubicin ), but th ey are m u ch less frequen t

an d cau se m u cosal dam age. Th e in cid en ce of h em or rh agic

th an n ausea an d vom it ing an d are n ot acute adverse e ects.

brosis w ith cycloph osph am ide, congest ive h ear t

cyst it is from cyclop h osp h am id e ad m in istered at conven t ion al d oses is u n kn ow n , bu t in pat ien ts receiving h igh -dose regim en s, it is about 10%. A−C Adverse e ect s of t h ese d r ugs d o n ot in clu de n eph rotoxicit y. D, E Cisplatin and, ver y rarely, doxorubicin can cause nephrotoxicit y, but h em orrhagic cystitis has n ot been reported.

Learning objective: Explain the m olecular m echanism of action of methotrexate. 35. A Methotrexate is a folic acid antagonist that inhibits dihydrofolate redu ct ase, th e en zym e respon sible for th e reduct ion of d ihyd rofolate to tet rahyd rofolate. Th e d r ug is biot ran sfor m ed in t racellu larly to p olyglu t am ated d er ivat ives t h at are select ively retain ed w ith in can cer cells an d h ave a h igh er

Learning objective: Outline the therapeutic uses of m ethotrexate in lymphoblastic leukem ia.

in h ibitor y e ect on th e en zym e. Th e in h ibit ion of dihydrofo-

32. A Th e blood test an d th e bon e m arrow biop sy are con sisten t

late, w h ich is a on e-carbon u n it carrier. Th ese on e-carbon

w ith th e diagn osis of acute lym ph oblast ic leukem ia. Before

un its are u sed in th e syn th esis of p u rin es, w h ich in t u rn are

cen t ral n er vous system (CNS) preven t ive th erapy w as rou-

essen t ial for th e syn th esis of DNA an d RNA.

late red u ct ase leads to decreased syn th esis of tet rahyd rofo-

t in e, th e CNS w as th e m ost com m on site of leu kem ic relapse

B Th is is th e m ech an ism of act ion of cytarabin e.

in ch ildren w ith acute lym p h oblast ic leukem ia. Today, pre-

C Th is is th e m ech an ism of act ion of topotecan .

ven t ive th erapy is perform ed w ith in t racran ial irradiat ion

D Th is is th e m ech an ism of act ion of bleom ycin .

an d in t rath ecal ad m in ist rat ion of an t ican cer drugs. Meth o-

E Th is is th e m ech an ism of act ion of vin ca alkaloids.

t rexate w ith or w ith ou t cytarabin e an d cor t icosteroids is th e m ost com m on drug adm in istered in t rath ecally to preven t relapse.

Learning objective: Outline the pharm acotherapy of chronic myelogenous leukemia.

B−F Th ese drugs are n ot curren tly used to t reat acu te lym -

36. A Th e w h ite blood cell cou n t an d th e presen ce of th e Ph ila-

p h oblast ic leu kem ia an d are n ot adm in istered in t rath ecally.

d elp h ia ch rom osom e con r m t h e d iagn osis of ch ron ic m yelogen ou s leu kem ia. Th e d isease, w h ich is associated w it h

Learning objective: Explain the mechanism of action of bleomycin.

th e Ph iladelp h ia ch rom osom e in over 90%of cases, is ch arac-

33. A Bleom ycin bin d s to DNA. Th e bleom ycin −DNA com p lex

terized by in creased gran ulocytes in periph eral blood an d

redu ces m olecular oxygen to free oxygen radicals, w h ich in

often in creased platelet s in early stages, as in th is case. Th e

t u rn cau ses DNA fragm en tat ion .

goal of ch em oth erapy in n ew ly diagn osed p at ien t s w ith ver y

B Th is is th e m ech an ism of act ion of vin ca alkaloids.

h igh leu kocyte cou n ts is to redu ce leukocytosis an d its asso-

C Th is is th e m ech an ism of act ion of u orou racil.

ciated sym ptom s. Hydroxyu rea is st ill th e m ost com m on


agen t u sed for in it ial leu cocyte redu ct ion . How ever, in terfer-

E Th is is th e m ech an ism of act ion of m eth ot rexate.

on -alfa an d im at in ib give bet ter result s in term s of rem ission an d 5-year su r vival.

Learning objective: Describe the adverse e ect s of anticancer combination chem otherapy. 34. E Nausea an d vom it ing are am ong th e m ost com m on com plications of chem otherapy adm inistration . It has been show n

B, C Th ese drugs are h em atopoiet ic grow th factors. D−F Th ese an t ican cer dr ugs are n ot used in ch ron ic m yelogen ou s leukem ia.

Answers and Explanations: VIII-9 Antineoplastic Drugs 489 Learning objective: Explain the m echanism of action of asparaginase.

• In creased DNA repair, du e to in creased act ivit y of to-

37. B Asp aragin ase is an en zym e t h at hyd rolyzes circu lat in g

A DNA repair is increased, not decreased, in cases of m ulti-

asp aragin e. Becau se t u m or cells in acu te lym ph oblast ic leu kem ia h ave ver y low levels of asp aragin e syn th et ase, th ey require an exogen ous source of asparagin e for grow th . As-

poisom erase en zym es d rug resist an ce. B−D Th ese m ech an ism s can explain resist an ce to single d rugs bu t can n ot accou n t for m ult idrug resistan ce.

p aragin ase depletes th e exist ing su pply of asparagin e, in h ib cells can syn th esize asparagin e an d are th erefore less sus-

Learning objective: Identify the drug used as an antidote against cyclophosphamide.

cept ible to th e cytotoxic act ion of asparagin ase. An in creased

41. C Cyclop h osp h am ide can cau se h em orrh agic cyst it is, w h ich

asparagin e syn th et ase act ivit y of t u m or cells is th e cau se of

seem s to be du e m ain ly to acrolein , an act ive m et abolite th at

resistan ce to asparagin ase.

is excreted in h igh con cen t rat ion in th e urin e. Preven t ion

it ing protein syn th esis in th e t um or cells. In con t rast , n orm al

A, C−F All of th ese drugs can be u sed in acu te lym ph oblas-

con sist s of providing adequate in t raven ous hydrat ion an d

t ic leu kem ia, bu t th ey h ave di eren t m ech an ism s of act ion .

adm inistration of 2-m ercaptoethane sulfonate (MESNA). This agen t con tain s a free th iol group th at can n eu t ralize acrolein

Learning objective: Identify the drug used concom itantly to increase the cytotoxic activit y of uorouracil. 38. C Fluorou racil is converted in cells to

uorodeoxyuridin e

m on op h osp h ate, w h ich in h ibits thym idylate syn th ase an d

in th e bladder. MESNA can p reven t th e bladder toxicit y com p letely, so it s u se is th e cu rren t st an dard of care. A, B, D, E Non e of th ese d rugs can p reven t cyclop h osp h am ide-in d u ced h em orrh agic cyst it is.

cau ses a “thym in eless death ” of cells. Leu covorin is 5-form ylt ion of a redu ced folate (i.e., leu covorin ), th e form at ion of a

Learning objective: Identify the appropriate combination chemotherapy for chronic lymphocytic leukemia.

stable com p lex bet w een th e act ive

u orou racil m et abolite,

42. E Th e lab resu lt s suggest th at th e p at ien t w as su ering from

th e redu ced folate, an d th e en zym e thym idylate syn th ase is

ch ron ic lym ph ocyt ic leukem ia, th e m ost com m on form of

favored, th us in creasing th e cytotoxicit y of uorouracil.

leukem ia in adu lt s over age 50, w h ich occu rs t w ice as often

tet rahydrofolate. By in creasing th e in t racellular con cen t ra-

A Folic acid is n ot a reduced folate an d does n ot in crease th e form at ion of th e st able com plex d escribed above. B, D−F See correct an sw er explan at ion .

in m en as in w om en . Th e disease is h igh risk w h en lym p h ocytosis is accom pan ied by an em ia an d th rom bocytopen ia, as in th is case. In th e past , ch loram bucil w ith or w ith out p red n ison e h ad been th e st an dard in it ial t reat m en t of ch ron ic

Learning objective: Describe the procedure to prevent cisplatininduced nephrotoxicit y.

lym p h ocyt ic leu kem ia, bu t today

39. B Cisplat in can cause n eph rotoxicit y, but th is adverse e ect

n ison e can be useful in elderly pat ien t s w ith an em ia an d

h as been largely abrogated by vigorou s pret reat m en t w ith hydrat ion an d adm in ist rat ion of diu ret ics. Loop diu ret ics are requ ired in p at ien t s w it h com p rom ised card iac reser ve, as

u darabin e gives bet ter

results. However, th e com bin ation of chloram bucil an d predth rom bocytop en ia, as in th is case. A−D Th ese an t ican cer drug com bin at ion s are n ot used in case of ch ron ic lym p h ocyt ic leu kem ia.

in th is case. A, C−E See correct an sw er explan at ion .

Learning objective: Identify the anticancer drug that act s by form ing both inter- and intrastrand cross-links in DNA m olecules.

Learning objective: Explain the m echanism of m ultidrug resistance in cancer chem otherapy.

43. D Cisplat in is th e protot ype of plat in u m an alogu es. Th ese

40. E An t in eoplast ic drug resistan ce can develop to a single dr ug

used for treatm en t of ovarian , head and neck, bladder, esoph -

or to a var iet y of d r ugs of d i eren t st r u ct u res after t h e ex-

agu s, lu ng, an d colon can cers. Plat in u m an alogu es are act i-

p osure to a single agen t .

vated in sid e cells, yield in g p osit ively ch arged an d h igh ly

Mu lt idrug resist an ce is m ost likely du e to • In creased e

u x of th e drug from th e cells, due to in -

creased exp ression of a n orm al gen e th at en codes for a cell surface t ran spor ter glycoprotein (P-170) th at uses th e en ergy of aden osin e t riph osp h ate (ATP) to exp el a variet y of foreign m olecules. Th is is th e m ost com m on m ech an ism of m ult idrug resist an ce.

d rugs h ave broad an t in eop last ic act ivit y an d are cu rren tly

react ive m olecules. Th ese m olecules can react w ith various sites on DNA, form ing both inter- and in trastran d cross-links, w h ich in t urn block DNA replicat ion . A−C, E See correct an sw er explan at ion .

490


Learning objective: Describe the adverse e ect s of bleomycin.

Learning objective: Outline the therapeutic uses of etoposide.

44. E Am ong th e ch em oth erapeut ic drugs, bleom ycin h as th e

48. F Th e p at ien t ’s sym ptom s an d t h e bron ch ial biop sy are

h igh est risk of pulm on ar y toxicit y. It can cause an in terst it ial

con sisten t w it h t h e d iagn osis of a sm all-cell lu ng can cer.

p n eum on it is follow ed by pulm on ar y

brosis. Th e d isease

Alth ough th e risk of developing any t ype of lung can cer in -

is ver y serious an d is leth al in about 50% of cases. Th e m ain

creases w ith cigaret te sm oking, th e relat ive risk of sm all-cell

factor associated w it h t h e d evelop m en t of p u lm on ar y tox-

lung can cer is am ong th e h igh est . Th e cells of th ese can cers,

icit y is t h e cu m u lat ive d ose of bleom ycin . Th e h igh er t h e

also called “oat cell” carcin om as, con t ain a scan t y am ou n t

cu m ulat ive dose, th e h igh er th e risk.

of cytop lasm an d rarely h ave n u cleoli. Th ese m align an cies,

A Acute leukem ias h ave been associated w ith can cer ch e-

w h ich are of n euroen docrin e origin , m ay cause a variet y of

m oth erapy, but ch ron ic m yelogen ous leukem ia is n ot related

paraneoplastic syndrom es due to the syn th esis and secretion

to th e previous use of an t ican cer drugs.

of h orm on es such as adren ocort icot ropic h orm on e (ACTH)

B−D Th e dr ugs taken by th e pat ien t do n ot in crease th e risk of th ese diseases.

an d seroton in . Sm all-cell lu ng can cers carr y a poor progn osis becau se th ey m et ast asize early an d are already spread at th e t im e of diagn osis. Etoposid e, given togeth er w ith a plat i-

Learning objective: Identify the drug to be used for m aintenance therapy in acute lymphoblastic leukemia.

n um com poun d, h as been sh ow n to sign i can tly im prove

45. C Main ten an ce th erapy of acute lym ph oblast ic leukem ia is

A−C Ison iazid, ceft azidim e, an d st reptom ycin are an t im i-

u su ally perform ed for 2½ to 3 years after rem ission because early trials have show n that w ithout m aintenance, m ost children w ill relapse w ith in 1 or 2 m on th s. Im p ressive im prove-

su r vival an d is cu rren tly a drug of ch oice in th is disease. crobial agen ts an d are th erefore of n o valu e in lu ng can cer. D, E Asparagin ase an d cyt arabin e are n ot used in sm allcell lung can cer.

m en ts in d isease-free su r vival an d cu re rates are ach ieved w ith various m ain ten an ce regim en s. Meth ot rexate an d m er-

Learning objective: Outline the therapeutic uses of im atinib.

captop u rin e are th e drugs m ost often in clu ded in th ese reg-

49. F Im at in ib is th e p rotot yp e of a n ew class of an t ican cer

im en s. Mercaptopurin e is e ect ive an d w ell tolerated orally

agen t s called t yrosin e kin ase in h ibitors. Th ese drugs sp eci -

w h en adm in istered daily.

cally in h ibit th e t yrosin e kin ase act ivit y of BCR-ABL (break-

A, B, D, E All of th ese are cell cycle−n on sp eci c an t ican cer

p oin t clu ster region −Abelson m urin e leukem ia), th e fu sion

d rugs, an d th ey are n ot curren tly used in post in du ct ion reg-

p roduct of th e Ph iladelph ia ch rom osom e. BCR-ABL is a con -

im en s for acute lym ph oblast ic leukem ia.

st it u t ively act ive p rotein kin ase su p p or t in g cell p roliferat ion ; in h ibit ion of th e en zym e by im at in ib blocks th e kin ase

Learning objective: Explain the m echanism of action of vinca alkaloids.

act ivit y an d dow n st ream act ivat ion of cellu lar p roliferat ion .

46. A Vincristine an d vinblastine are vinca alkaloids. These drugs

p ress t h e en zym e bu t do n ot a ect n or m al cells. Th ey are

Tyrosin e kin ase in h ibitors cau se ap optosis in cells t h at ex-

bin d sp eci cally to β-t u bu lin , th e st r u ct u ral protein s th at

cu r ren t ly

form m icrotubules, and block β-tubulin polym erization w ith

m ia. Th ey are n ot cu rat ive bu t can prolong su r vival an d can

α -tubulin, thus preventing m icrotubule assem bly. In this w ay,

ach ieve a com p lete h em atologic rem ission .

th ey cau se an arrest of th e m itot ic cycle in m et ap h ase. B−E See correct an sw er explan at ion .

rst -lin e agen t s in ch ron ic m yelogen ou s leu ke-

A−E Th ese an t ican cer drugs are n ot used in ch ron ic m yelogen ou s leukem ia.

Learning objective: Describe the adverse e ect s of paclitaxel.

Learning objective: Describe the adverse e ects of asparaginase.

47. C Paclitaxel is th e protot ype of taxan e derivat ives. Periph eral

50. E Asp aragin ase is an en zym e th at catalyzes th e hydrolysis of

n europathy is a com m on adverse e ect of taxan es, a ect ing

p lasm a asparagin e to asp ar t ic acid an d am m on ia. Because it

m ore th an 50% of pat ien ts u n der t reat m en t . Th e e ect is

is a foreign protein , it h as an t igen ic propert ies, an d hyper-

d ose-depen den t an d cum ulat ive.

sen sit ivit y react ion s are com m on (u p to 20%). Th ey are u su -

A, B Th e risk of th ese adverse e ects is ver y low. D, E Paclitaxel causes a profoun d m yelosuppression , w h ich in t urn in creases th e risk of oppor t un ist ic in fect ion s. Th ese in clu d e can d id iasis, cr yptosp or id iosis, cr yptococcosis, an d Mycobacterium avium -int racellulare in fect ion , bu t u r in ar y t ract in fect ion s an d t u bercu losis h ave n ot been rep or ted .

ally m ild, but fatal anaphylactic reactions have been reported. A−D Th e risk of th ese adverse e ects after asparagin ase adm in ist rat ion is n egligible.

Answers and Explanations: VIII-9 Antineoplastic Drugs 491 ANTINEOPLASTIC DRUGS Answ er key 1. 2. 3. 4. 5.

B E D F C

6. 7. 8. 9. 10.

E B A B C

11. 12. 13. 14. 15.

A D A D B

16. 17. 18. 19. 20.

D A C C E

21. 22. 23. 24. 25.

D F E D E

26. 27. 28. 29. 30.

E D B E B

31. 32. 33. 34. 35.

F A A E A

36. 37. 38. 39. 40.

A B C B E

41. 42. 43. 44. 45.

C E D E C

46. 47. 48. 49. 50.

A C F F E

Pharmacology Test Prep 1500 USMLE-Style Questions & Answers First Edition,None Edition 2014 {PRG}

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