Katzung Summary

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DRUGS THAT ACT IN THE CENTRA NER!"US S#STE$ ANTIDE%RESSANTS A&t'depressa&ts

Subclass

$echa&'sm E((ects o( Act'o&

Cl'&'cal %harmaco)'&et'cs* Appl'cat'o&s To+'c't'es* I&teract'o&s

Select',e seroto&'& reupta)e '&h'b'tors SSRIs Fluoxetine ,italopra& Escitalopra& .aroxetine Sertraline

Highly se selective blockade of serotonin transporter (SERT) little effect on norepinephrine transporter (NET)

cute increase of serotonergic synaptic activity slo!er changes in several signaling path!ays and neurotrophic activity

"a#or depression depression$$ anxiety disorders panic disorder obsessive% co&pulsive disorder post% trau&atic stress disorder peri&enopausal vaso&otor sy&pto&s eating disorder (buli&ia)

Half%lives fro& '* h oral activity Toxicity: Toxicity: +ell +ell tolerated but cause sexual dysfunction Interactions: So&e ,-. inhibition (fluoxetine /01$ 234 fluvoxa&ine '/4 paroxetine /01)

Fluvoxamine: Similar to above but approved only for obsessive-co obsessive-compulsive mpulsive behavior Seroto&'&-&orep'&ephr'&e Seroto&'&-&o rep'&ephr'&e reupta)e '&h'b'tors SNRIs 0uloxetine 5enlafaxine

"oderately selective blockade of NET and SERT

cute increase in serotonergic and adrenergic synaptic activity

"a#or depression depression$$ chronic pain disorders fibro&yalgia$ peri&enopausal

Toxicity: nticholinergic$ Toxicity: nticholinergic$ sedation$ hypertensio hypertension n (venlafaxine) Interactions: So&e ,-./01 inhibition (duloxetine$

Subclass



other!ise like sy&pto&s desvenlafaxine) SSR6s Desvenlafaxine: Desmethyl metabolite of venlafaxine, metabolism is by phase II rather than CY phase I Tr'c/cl'c a&t'depressa&ts TCAs 6&ipra&ine "any others 0-HT1 A&tago&'sts Nefa7odone Tra7odone Tetrac/cl'cs* u&'c/cl'c 8upropion &oxapine "aprotiline "irta7apine $o&oam'&e o+'dase '&h'b'tors $A"Is .henel7ine Tranylcypro&ine Selegiline

DRUGS USED 2"R $"!E$ENT DIS"RDERS Drugs Used (or $o,eme&t D'sorders

Subclass



e,odopa a&d comb'&at'o&s 9evodopa

Transported in into the central nervous syste& (,NS) and converted to dopa&ine (!hich does not enter the ,NS)4 also converted to dopa&ine in the periphery

&eliorates all sy&pto&s of .arkinson:s disease and causes significant peripheral dopa&inergic effects (see text)

.arkinson:s disease; "ost efficacious therapy but not al!ays used as the first drug due to develop&entt of develop&en disabling response fluctuations over ti&e

h effect Toxicity: ?astrointestinal upset$ arrhyth&ias$ dyskinesias$ on%off and !earing%off pheno&ena$ behaviorall disturbances behaviora Interactions: @se !ith carbidopa greatly di&inishes reAuired dosage use !ith ,<"T or "<%8 inhibitors prolongs duration of effectB

!evodopa " carbidopa #Sinemet$: Carbidopa inhibits peripheral metabolism of levodopa to dopamine and reduces re%uired dosa&e and toxicity' Carbidopa does not enter C(SB C(S B !evodopa " carbidopa " entacapone #Stalevo$: )ntacapone is a catechol-< catechol-<-methyltransferase #C*+T$ inhibitor #see belo$ Dopam'&e ago&'sts .ra .r a&i &ipe pex xole

0ir ire ect ag agoni nist st at at 02 receptors$ nonergot

Reduces sy&pto&s of parkinsonis& s&ooths out fluctuations in levodopa response

.arkinson:s disease; ,an be used as initial therapy also effective in on%off pheno&enon

h effect Toxicity: Nausea Toxicity: Nausea and vo&iting$ postural hypotension$$ dyskinesias hypotension

opinirole: Similar to pramipexole. noner&ot. relatively pure D / a&onist

/romocriptine: )r&ot derivative. potent a&onist at D/ receptors. more toxic than pramipexole or /romocriptine: ropinirole

0pomorphine: (oner&ot. subcutaneous 0pomorphine: subcutaneous route useful for rescue rescue treatment in levodopa-induced levodopa-induced dys1inesia. hi&h incidence of nausea and vomitin&

Subclass



$o&oam'&e o+'dase $A" '&h'b'tors Rasagiline

6nhibits "<%8 selectively$ higher doses also inhibit "<%

6ncreases dopa&ine stores in neurons4 &ay have neuroprotective effects

.arkinson:s disease4 ad#unctive to levodopa4 s&ooths levodopa response

Sele&iline: !i1e rasa&iline, ad3unctive use ith levodopa. may be less potent than rasa&iline in +T-induced par1insonism C"$T '&h'b'tors Entacapone

6nhibits ,<"T in Reduces periphery does &etabolis& of not enter ,NS levodopa and prolongs its action

.arkinson:s disease

Tolcapone: !i1e entacapone but enters C(S' Some evidence of hepatotoxicity, elevation of liver en4ymes' A&t'muscar'&'c age&ts 8en7tropine

ntagonist at " receptors in basal ganglia

Reduces tre&or .arkinson:s and rigidity disease little effect on bradykinesia

/iperiden, orphenadrine, procyclidine, trihexyphenidyl: Similar antimuscarinic a&ents ith C(S effects Drugs used '& Hu&t'>o&3s d'sease Tetrabena7ine$ 0eplete a&ine reserpine trans&itters$ especially dopa&ine$ fro& nerve endings

Reduce chorea severity

Huntington:s disease other applications$ see ,hapter ''

5aloperidol, other neuroleptics: Sometimes helpful Drugs used '& Tourette3s s/&drome Haloperidol

8locks central 0/ Reduces vocal

Tourette:s

Subclass



receptors

syndro&e other applications$ see ,hapter /C

and &otor tic freAuency$ severity

other dyskinesias sedation

Clonidine: )ffective in 6 789 of patients. see Chapter  for basic pharmacolo&y henothia4ines, ben4odia4epines, carbama4epine: Sometimes of value

SEDATI!E-H#%N"TICS Sedat',e-H/p&ot'cs

Subclass a&d E+amples



4e&5od'a5ep'&es lpra7ola&

8ind to specific ?8 receptor ,hlordia7epoxide subunits at central nervous ,lora7epate syste& (,NS) neuronal ,lona7epa& synapses facilitating 0ia7epa& ?8%&ediated chloride ion Esta7ola& channel opening enhance Flura7epa& &e&brane hyperpolari7ation 9ora7epa& "ida7ola&
0ose%dependent depressant effects on the ,NS including sedation and relief of anxiety$ a&nesia$ hypnosis$ anesthesia$ co&a and respiratory depression

cute anxiety states panic attacks generali7ed anxiety disorder inso&nia and other sleep disorders relaxation of skeletal &uscle anesthesia (ad#unctive) sei7ure disorders

Half%lives fro& /3D h oral activity Hepatic &etabolis&so&e active &etabolites Toxicity: Extensions of ,NS depressant effects dependence liability Interactions: dditive ,NS depression !ith ethanol and &any other drugs




4e&5od'a5ep'&e a&tago&'st Flu&a7enil

ntagonist at ben7odia7epine binding sites on the ?8 receptor

8locks actions "anage&ent of of ben7odia7epine ben7odia7epines overdose and 7olpide& but not other sedative% hypnotic drugs

65$ short half%life Toxicity: gitation$ confusion possible !ithdra!al sy&pto&s in ben7odia7epine dependence

4arb'turates &obarbital

8ind to specific ?8 receptor 8utabarbital subunits at ,NS neuronal "ephobarbital synapses facilitating .entobarbital ?8%&ediated chloride ion .henobarbital channel opening enhance Secobarbital &e&brane Newer h/p&ot'cs hyperpolari7ation Es7opiclone Ialeplon

0ose%dependent depressant effects on the ,NS including sedation and relief of anxiety a&nesia hypnosis anesthesia co&a and respiratory depression steeper dose% 8ind selectively response Rapid onset of to a subgroup of relationship hypnosis !ith ?8 receptors$ than fe! a&nestic ben7odia7epines acting like effects or day%

ben7odia7epines to enhance $elato&'& receptor ago&'st &e&brane hyperpolari7ation Ra&elteon ctivates "T' and "T/ receptors in Iolpide& suprachias&atic nuclei in the ,NS

after psycho&otor depression or so&nolence Rapid onset of sleep !ith &ini&al rebound inso&nia or !ithdra!al sy&pto&s

nesthesia (thiopental) inso&nia (secobarbital) sei7ure disorders (phenobarbital)

Half%lives fro& 31D h oral activity hepatic &etabolis& phenobarbital /DG renal eli&ination Toxicity: Extensions of ,NS depressant effects dependence liability  ben7odia7epines Interactions: dditive ,NS depression !ith ethanol and &any other drugs induction of hepatic drug% &etaboli7ing en7y&es

Sleep disorders$ especially those characteri7ed by difficulty in falling asleep

0-HT-receptor ago&'st 8uspirone

"echanis& uncertain; .artial agonist at %HT receptors but

Slo! onset ('/ ?enerali7ed !eeks) of anxiety states anxiolytic effects &ini&al


$echa&'sm E((ects o( Act'o& affinity for 0/ receptors also possible


psycho&otor i&pair&entno additive ,NS depression !ith sedative% hypnotic drugs

gastrointestinal distress Interactions: ,-.23 inducers and inhibitors

ANTI%S#CH"TIC DRUGS 6 ITHIU$ A&t'ps/chot'c Drugs 6 'th'um

Subclass



%he&oth'a5'&es ,hlorpro&a7ine 8lockade of 0/ receptors  Fluphena7ine HT/ receptors Thiorida7ine Th'o+a&the&e Thiothixene

4ut/rophe&o&e

%Receptor

.sychiatric; schi7ophrenia blockade (fluphena7ine (alleviate positive sy&pto&s)$ least) &uscarinic (")% bipolar disorder (&anic phase) receptor blockade nonpsychiatric; antie&esis$ (especially chlorpro&a7ine preoperative and thiorida7ine) sedation H'%receptor (proða7ine) pruritus blockade (chlorpro&a7ine$ thiothixene) central nervous syste& (,NS) depression (sedation) decreased sei7ure threshold T prolongation (thiorida7ine)

Subclass

Haloperidol



8lockade of 0/ receptors  HT/ receptors

So&e blockade$ but &ini&al " receptor blockade and &uch less sedation than the phenothia7ines

Schi7ophrenia (alleviates positive sy&pto&s)$ bipolar disorder (&anic phase)$ Huntington:s chorea$ Tourette:s syndro&e

No significant antagonistic actions on autono&ic nervous syste& receptors or specific ,NS receptors no sedative effects

8ipolar affective disorder prophylactic use can prevent &ood s!ings bet!een &ania and depression

At/p'cal a&t'ps/chot'cs ripipra7ole ,lo7apine
"echanis& of action uncertain suppresses inositol signaling and inhibits glycogen synthase kinase% 2 (?SJ%2)$ a &ultifunctional protein kinase

Newer age&ts (or b'polar d'sorder ,arba&a7epine 9a&otrigine 5alproic acid

DRUGS USED S7EETA $USCE REA8ANTS Drugs Used

Subclass



Depolar'5'&g &euromuscular bloc)'&g age&t Succinylcholine

gonist at nicotinic acetylcholine (,h) receptors$ especially at neuro&uscular #unctions depolari7es &ay sti&ulate ganglionic nicotinic ,h and cardiac &uscarinic ,h receptors

6nitial depolari7ation causes transient contractions$ follo!ed by prolonged flaccid paralysis depolari7ation is then follo!ed by repolari7ation that is also acco&panied by paralysis

.lace&ent of tracheal tube at start of anesthetic procedure rarely$ control of &uscle contractions in status epilepticus

Rapid &etabolis& by plas&a cholinesterase nor&al duration$ = &in Toxicities: rrhyth&ias hyperkale&ia transient increased intra%abdo&inal$ intraocular pressure postoperative &uscle pain

.revents depolari7ation by ,h$ causes flaccid paralysis can cause hista&ine release !ith hypotension !eak block of cardiac &uscarinic ,h receptors

.rolonged relaxation for surgical procedures superseded by ne!er nondepolari7ing agents

Renal excretion duration$ =3D1D &in Toxicities: Hista&ine release hypotension prolonged apnea

9ike tubocurarine but lacks hista&ine

.rolonged relaxation of surgical

Not dependent on renal or hepatic function duration$ =/3 &in Toxicities:

No&depolar'5'&g &euromuscular bloc)'&g age&ts d-Tubocurarine

,isatracuriu&

,o&petitive antagonist at n,h receptors$ especially at neuro&uscular #unctions

Si&ilar to tubocurarine

Subclass



release and procedures .rolonged apnea but less anti&uscarinic relaxation of toxic than atracuriu& effects respiratory &uscles to facilitate &echanical ventilation in intensive care unit Rocuroniu&

Si&ilar to cisatracuriu&

9ike 9ike cisatracuriu& cisatracuriu& useful in patients but slight !ith renal anti&uscarinic i&pair&ent effect

Hepatic &etabolis& duration$ =/D2 &in Toxicities: 9ike cisatracuriu&

+ivacurium: apid onset, short duration #8;<8 min$. metaboli4ed by plasma cholinesterase =ecuronium: Intermediate duration. metaboli4ed in liver Ce&trall/ act'&g spasmol/t'c drugs 8aclofen

?88 agonist$ facilitates spinal inhibition of &otor neurons

,ycloben7aprine .oorly understood inhibition of &uscle stretch reflex in spinal cord

.re% and postsynaptic inhibition of &otor output

Severe spasticity due to cerebral palsy$ &ulitple sclerosis$ stroke

Reduction in cute spas& due hyperactive to &uscle in#ury &uscle infla&&ation reflexes anti&uscarinic effects

Hepatic &etabolis& duration$ =31 h Toxicities: Strong anti&uscarinic effects

Chlorphenesin, methocarbamol, orphenadrine, others: !i1e cycloben4aprine ith varyin& de&rees of antimuscarinic effect 0ia7epa&

Ti7anidine

Facilitates ?8ergic trans&ission in central nervous syste& (see ,hapter //)

%drenoceptor

/

6ncreases interneuron inhibition of pri&ary &otor afferents in spinal cord central sedation

,hronic spas& due to cerebral palsy$ stroke$ spinal cord in#ury acute spas& due to &uscle in#ury

Hepatic &etabolis& duration$ ='//3 h Toxicities: See ,hapter //

.resynaptic

Spas& due to

Renal and hepatic

Subclass



agonist in the spinal cord

and postsynaptic inhibition of reflex &otor output

&ultiple sclerosis$ stroke$ a&yotrophic lateral sclerosis

eli&ination duration$ 21 h Toxicities: +eakness$ sedation hypotension

Reduces actin% &yosin interaction !eakens skeletal &uscle contraction

65; "alignant hyperther&ia
65$ oral duration$ 31 h Toxicities: "uscle !eakness

D'rect-act'&g muscle rela+a&ts 0antrolene

8locks RyR' ,a/K%release channels in the sarcoplas&ic reticulu& of skeletal &uscle

ANTISEI9URE DRUGS A&t'se'5ure Drugs

Subclass

$echa&'s %harmaco)'&et' Cl'&'cal To+'c't'es* m o( cs Appl'cat'o& I&teract'o&s Act'o& s

C/cl'c ure'des .henytoin$ fosphenytoin

8locks high% freAuency firing of neurons through action on voltage% gated (5?) NaK channels decreases synaptic release of gluta&ate

bsorption is for&ulation dependent highly bound to plas&a proteins no active &etabolites dose% dependent eli&ination$ t 'L/ '/21 h fosphenytoin is for 65$ 6" routes

?enerali7ed tonic%clonic sei7ures$ partial sei7ures

Toxicity: 0iplopia$ ataxia$ gingival hyperplasia$ hirsutis&$ neuropathy Interactions: .henobarbi tal$ carba&a7epine$ isonia7id$ felba&ate$ oxcarba7epine$ topira&ate$ fluoxetine$ flucona7ole$ digoxin$ Auinidine$ cyclosporine$ steroids$ oral contraceptives$ others

.ri&idone

Si&ilar to phenytoin but converted to

+ell absorbed orally not highly bound to

?enerali7ed tonic%clonic sei7ures$ partial

Toxicity: Sedation$ cognitive issues$ ataxia$

Subclass

$echa&'s %harmaco)'&et' Cl'&'cal To+'c't'es* m o( cs Appl'cat'o& I&teract'o&s Act'o& s phenobarbital

.henobarbital Enhances phasic ?8 receptor responses reduces excitatory synaptic responses

Ethosuxi&ide Reduces lo! threshold ,a/K currents (T% type)

plas&a proteins peak sei7ures concentrations in /1 h t 'L/ 'D/ h t!o active &etabolites (phenobarbital and phenylethyl&alona&ide)

hyperactivity Interactions: Si&ilar to phenobarbital

Nearly co&plete absorption not significantly bound to plas&a proteins peak concentrations in M to 3 h no active &etabolites t 'L/ varies fro& * to '/ h

?enerali7ed tonic%clonic sei7ures$ partial sei7ures$ &yoclonic sei7ures$ generali7ed sei7ures$ neonatal sei7ures$ status epilepticus

Toxicity: Sedation$ cognitive issues$ ataxia$ hyperactivity Interactions: 5alproate$ carba&a7epine$ felba&ate$ phenytoin$ cyclosporine$ felodipine$ la&otrigine$ nifedipine$ ni&odipine$ steroids$ theophylline$ verapa&il$ others

+ell absorbed orally$ !ith peak levels in 2* h not protein%bound co&pletely &etaboli7ed to inactive co£s t 'L/ typically 3D h

bsence sei7ures Toxicity: Nausea$ headache$ di77iness$ hyperactivity Interactions: 5alproate$ phenobarbital$ phenytoin$ carba&a7epine$ rifa&picin

+ell absorbed orally$ !ith peak levels in 1> h no significant protein binding &etaboli7ed in part to active 'D%''% epoxide t 'L/ of parent ranges fro& >'/ h in treated patients to 21 h in nor&al sub#ects


Tr'c/cl'cs ,arba&a7epi 8locks high% ne freAuency firing of neurons through action on 5? NaK channels decreases synaptic release of gluta&ate

Toxicity: Nausea$ diplopia$ ataxia$ hyponatre&ia$ headache Interactions: .henytoin$ carba&a7epine$ valproate$ fluoxetine$ verapa&il$ &acrolide antibiotics$ isonia7id$ propoxyphene$ dana7ol$ phenobarbital$ pri&idone$ &any others

*xcarba4epine: Similar to carbama4epine. shorter half-life but active metabolite ith lon&er duration and feer interactions reported

Subclass

$echa&'s %harmaco)'&et' Cl'&'cal To+'c't'es* m o( cs Appl'cat'o& I&teract'o&s Act'o& s

4e&5od'a5ep'&es 0ia7epa&

.otentiates ?8  responses

+ell absorbed orally Status rectal ad&inistration epilepticus$ gives peak sei7ure clusters concentration in =' h !ith CDG bioavailability 65 for status epilepticus highly protein%bound extensively &etaboli7ed to several active &etabolites t 'L/ =/ d

Toxicity: Sedation Interactions: "ini&al

,lona7epa&

s for dia7epa&

>DG bioavailability extensively &etaboli7ed but no active &etabolites t 'L/ /DD h

Toxicity: Si&ilar to dia7epa& Interactions: "ini&al

bsence sei7ures$ &yoclonic sei7ures$ infantile spas&s

!ora4epam: Similar to dia4epam Cloba4am: Indications include absence sei4ures, myoclonic sei4ures, infantile spasms GA4A der',at',es ?abapentin

0ecreases excitatory trans&ission by acting on 5? ,a/K channels presynaptically ( / subunit)

8ioavailability DG$ decreasing !ith increasing doses not bound to plas&a proteins not &etaboli7ed t 'L/ 1> h

?enerali7ed tonic%clonic sei7ures$ partial sei7ures$ generali7ed sei7ures

Toxicity: So&nolence$ di77iness$ ataxia Interactions: "ini&al

.regabalin

s for gabapentin

+ell absorbed orally not bound to plas&a proteins not &etaboli7ed t 'L/ 1* h

.artial sei7ures

Toxicity: So&nolence$ di77iness$ ataxia Interactions: "ini&al

5igabatrin

6rreversibly *DG bioavailable not inhibits ?8% bound to plas&a transa&inase proteins not &etaboli7ed$ t 'L/ * h

.artial sei7ures$ infantile spas&s

Toxicity: 0ro!siness$ di77iness$ psychosis$ visual field loss Interactions: "ini&al

Subclass

$echa&'s %harmaco)'&et' Cl'&'cal To+'c't'es* m o( cs Appl'cat'o& I&teract'o&s Act'o& s (not relevant because of &echanis& of action)

$'scella&eous 5alproate

8locks high% freAuency firing of neurons &odifies a&ino acid &etabolis&

+ell absorbed fro& several for&ulations highly bound to plas&a proteins extensively &etaboli7ed t 'L/ C'1 h

?enerali7ed tonic%clonic sei7ures$ partial sei7ures$ generali7ed sei7ures$ absence sei7ures$ &yoclonic sei7ures

Toxicity ; Nausea$ tre&or$ !eight gain$ hair loss$ teratogenic$ hepatotoxic Interactions; .henobarbital$ phenytoin$ carba&a7epine$ la&otrigine$ felba&ate$ rifa&pin$ ethosuxi&ide$ pri&idone

9a&otrigine

.rolongs inactivation of 5?%NaK channels acts presynaptically on 5?%,a/K channels$ decreasing gluta&ate release

+ell absorbed orally no significant protein binding extensively &etaboli7ed$ but no active &etabolites t 'L/ /2 h

?enerali7ed tonic%clonic sei7ures$ generali7ed sei7ures$ partial sei7ures$ generali7ed sei7ures$ absence sei7ures

Toxicity ; 0i77iness$ headache$ diplopia$ rash Interactions; 5alproate$ carba&a7epine$ oxcarba7epine$ phenytoin$ phenobarbital$ pri&idone$ succini&ides$ sertraline$ topira&ate

9evetiraceta &

ction on synaptic protein S5/

+ell absorbed orally not bound to plas&a proteins &etaboli7ed to 2 inactive &etabolites t 'L/ 1'' h

?enerali7ed tonic%clonic sei7ures$ partial sei7ures$ generali7ed sei7ures

Toxicity ; Nervousness$ di77iness$ depression$ sei7ures Interactions; .henobarbital$ phenytoin$ carba&a7epine$ pri&idone

Tiagabine

8locks ?8 reuptake in forebrain by selective blockade of ?T%'

+ell absorbed highly bound to plas&a proteins extensively &etaboli7ed$ but no active &etabolites t 'L/ 3> h

.artial sei7ures

Toxicity ; Nervousness$ di77iness$ depression$ sei7ures Interactions; .henobarbital$ phenytoin$ carba&a7epine$ pri&idone

Topira&ate

"ultiple actions on

+ell absorbed not

?enerali7ed tonic%clonic

Toxicity ; So&nolence$ cognitive slo!ing$

Subclass

$echa&'s %harmaco)'&et' Cl'&'cal To+'c't'es* m o( cs Appl'cat'o& I&teract'o&s Act'o& s synaptic function$ probably via actions on phosphorylatio n

bound to plas&a proteins extensively &etaboli7ed$ but 3DG excreted unchanged in the urine no active &etabolites t 'L/ /D h$ but decreases !ith conco&itant drugs

sei7ures$ partial sei7ures$ generali7ed sei7ures$ absence sei7ures$ &igraine

confusion$ paresthesias Interactions; .henytoin$ carba&a7epine$ oral contraceptives$ la&otrigine$ lithiu&

Ionisa&ide

8locks high% freAuency firing via action on 5? NaK channels

pproxi&ately *DG bioavailable orally &ini&ally bound to plas&a proteins DG &etaboli7ed t 'L/ D*D h

?enerali7ed tonic%clonic sei7ures$ partial sei7ures$ &yoclonic sei7ures

Toxicity ; 0ro!siness$ cognitive i&pair&ent$ confusion$ poor concentration Interactions; "ini&al

9acosa&ide

Enhances slo! +ell absorbed &ini&al inactivation of protein binding one NaK channels &a#or nonactive blocks effect of &etabolite t 'L/ '/'3 h neurotrophins (via ,R".%/)


Toxicity ; 0i77iness$ headache$ nausea s&all increase in .R interval Interactions; "ini&al

DRUGS USED 2"R "CA ANESTHESIA Drugs Used (or ocal A&esthes'a

Subclass $echa&'sm o( Act'o&

E((ects

Cl'&'cal Appl'cat'o&s

%harmaco)'&et'cs* To+'c't'es

Slo!s$ then blocks action potential propagation

Short%duration procedures epidural$ spinal anesthesia

.arenteral duration 2D1D &in /1 h !ith epinephrine Toxicity: ,NS excitation

Sa&e as lidocaine

9onger%duration procedures

.arenteral duration /3 h Toxicity: ,NS excitation cardiovascular collapse

Am'des 9idocaine

8lockade of sodiu& channels

8upivacaine Sa&e as lidocaine

Subclass $echa&'sm o( Act'o&

E((ects

Cl'&'cal Appl'cat'o&s

%harmaco)'&et'cs* To+'c't'es

rilocaine, ropivacaine, mepivacaine, levobupivacaine: !i1e bupivacaine Esters .rocaine

9ike lidocaine

9ike lidocaine 5ery short procedures

.arenteral duration '2D &in 2DCD &in !ith epinephrine Toxicity: 9ike lidocaine

,ocaine

Sa&e as above also has sy&patho&i&etic effects

Sa&e as above

Topical or parenteral duration '/ h Toxicity: ,NS excitation$ convulsions$ cardiac arrhyth&ias$ hypertension$ stroke

.rocedures reAuiring high surface activity and vasoconstriction

Tetracaine: >sed for spinal, epidural anesthesia. duration <;? h

"%I"IDS* "%I"ID SU4STITUTES* AND "%I"ID ANTAG"NISTS "p'o'ds* "p'o'd Subst'tutes* a&d "p'o'd A&tago&'sts

Subclass


Cl'&'cal %harmaco)'&et'cs* Appl'cat'o&s To+'c't'es

Stro&g op'o'd ago&'sts "orphine "ethadone Fentanyl

Strong % receptor agonists variable affinity for and receptors

nalgesia relief of anxiety sedation slo!ed gastrointestinal transit

Severe pain ad#unct in anesthesia (fentanyl$ &orphine) pul&onary ede&a (&orphine only) &aintenance in rehabilitation progra&s (ðadone only)

First%pass effect duration '3 h except ðadone$ 31 h Toxicity: Respiratory depression severe constipation addiction liability convulsions

5ydromorphone, oxymorphone: !i1e morphine in efficacy, but hi&her potency +eperidine: Stron& a&onist ith anticholiner&ic effects Sufentanil, alfentanil, remifentanil: !i1e f entanyl but shorter durations of action %art'al ago&'sts

Subclass ,odeine Hydrocodone



9ess efficacious than &orphine can antagoni7e strong agonists

9ike strong agonists !eaker effects

"ild%&oderate pain cough (codeine)

9ike strong agonists$ toxicity dependent on genetic variation of &etabolis&

9ike strong agonists but can antagoni7e their effects also reduces craving for alcohol

"oderate pain so&e &aintenance rehabilitation progra&s

9ong duration of action 3 > h &ay precipitate abstinence syndro&e

$'+ed op'o'd ago&'st-a& ago&'st-a&tago&'sts tago&'sts 8uprenorphine

Nalbuphine

.arti tial al agonist antagonist

gonist antagonist

Si&ilar to "oderate pai pain n buprenorphine

9ike bu buprenorphine

A&t'tuss',es 0extro&e 0ext roðor thorphan phan .oorly .oorly Reduces cough cute debilitating 2D1D &in duration understood but reflex cough Toxicity: "ini&al !hen strong and taken as directed partial agonists are also effective Codeine, levopropoxyphene: Similar to dextromethor dextromethorphan phan "p'o'd a&tago&'sts Naloxone

ntagonist at $ $ and receptors

Rapidly
0urati 0ura tion on '/ '/ h (&a (&ay y have have to be repeated !hen treating overdose) Toxicity: .recipitates Toxicity: .recipitates abstinence syndro&e in dependent users

(altrexone, nalmefene: !i1e naloxone but lon&er durations of action #8" h$. naltrexone is used in maintenance pro&rams and can bloc1 heroin effects for up to @A h 0lvimopan, methylnaltrexone methylnaltrexone bromide: otent anta&onists ith poor entry entry into the central nervous system. can be used to treat severe opioid-induced constipation constipation ithout precipitatin& an abstinence syndrome "ther a&alges'cs used '& moderate pa'& Tra&adol

"ixed effects; !eak agonist$

nalgesia

"oderate pa pain 0uration 31 h Toxicity: ad#unct to opioids

Subclass



&oderate SERT inhibitor$ !eak NET inhibitor

in chronic pain syndro&es

Sei7ures

NET$ norepinephrine reuptake transporter4 SERT$ serotonin reuptake transporterB

DRUGS USED T" TREAT DE%ENDENCE AND ADDICTI"N Drugs Used to Treat Depe&de&ce a&d Add'ct'o&

Subclass


Cl'&'cal %harmaco)'&et'cs* Appl'cat'o& To+'c't'es* I&teract'o&s

"p'o'd receptor a&tago&'st Naloxone

Nonselective antagonist of opioid receptors

Reverses the
Effectt &uch Effec &uch short shorter er tha than n &orphine ('/ h)$ therefore several in#ections reAuired

Naltrexone

ntagonist of opioid receptors

8locks effects of illicit opioids

Treat&ent of alcoholis&

Half%life = 3 h

cute effects si&ilar to &orphine (see text)

Substitution High oral bioavailability therapy for opioid half%life highly variable addicts a&ong individuals (range 3 '2D h) Toxicity: Respiratory depression$ constipation$ &iosis$ tolerance$ dependence$ and !ithdra!al sy&pto&s

S/&thet'c op'o'd "ethadone

Slo!%acting agonist of % opioid receptor

%art'al -op'o'd receptor ago&'st 8uprenor 8upr enorphine phine .artial .artial agonist agonist at ttenuates acute %opioid effects of receptors &orphine

N'cot'&'c receptor part'al ago&'st

9ong half%life (3D h) for&ulated together !ith naloxone to avoid illicit 65 in#ections

Subclass

5arenicline


Cl'&'cal %harmaco)'&et'cs* Appl'cat'o& To+'c't'es* I&teract'o&s

.artial agonist of of
S&oking cessation

Toxicity: Nausea and Toxicity: Nausea vo&iting$ convulsions$ psychiatric changes

Cytisine: (atural analo& #extracted from laburnum floers$ of varenicline 4e&5od'a5ep'&es
.ositive &odulators of the ?8 receptors$ increase freAuency of channel opening

Enhances ?8ergic synaptic trans&ission4 attenuates !ithdra!al sy&pto&s (tre&or$ hallucinations$ anxiety) in alcoholics prevents !ithdra!al sei7ures

0eliri 0el iriu& u& tre&e tre&ens ns Half%l Half%life ife 3' 3' h phar&acokinetics not affected by decreased liver function

!ora4epam: 0lternate to oxa4epam ith similar properties N-meth/l-D-aspartate N$DA ca& c a&pr pros osat ate e

ntago nta goni nist st of of "ay interfere N"0 gluta&ate !ith for&s of receptors synaptic plasticity that depend on N"0 receptors

Treat&ent of alcoholis& effective only in co&bination !ith counseling

llergic reactions$ arrhyth&ia$ and lo! or high blood pressure$ headaches$ inso&nia$ and i&potence hallucinations$ particularly in elderly patients

pproved in @S and Europe to treat obesity S&oking cessation is an

"a#or depression$ including increased risk of suicide

Ca&&ab'&o'd Ca&&ab'&o 'd receptor ago&'st Ri&onabant

,8' receptor agonist

0ecreases neurotrans&itter release at ?8ergic and gluta&atergic

Subclass

$echa&'sm E((ects o( Act'o& synapses

Cl'&'cal %harmaco)'&et'cs* Appl'cat'o& To+'c't'es* I&teract'o&s off%label indication

AUT"N"$IC DRUGS DRUGS USED 2"R CH"IN"$I$ETIC E22ECTS Drugs Used (or Chol'&om'met'c E((ects

Subclass

$echa&'sm o( Act'o&

E((ects

Cl'&'cal %harmaco)'&et'cs Appl'cat'o& * To+'c't'es* s I&teract'o&s

ctivates "' through "2 receptors in all peripheral tissues causes increased secretion$ s&ooth &uscle contraction (except vascular s&ooth &uscle relaxes)$ and changes in heart rate

.ostoperative and neurogenic ileus and urinary retention

D'rect-act'&g chol'&e esters 8ethanechol

"uscarinic agonist negligible effect at nicotinic receptors

Carbachol: (onselective muscarinic and nicotinic a&onist. otherise similar to bethanechol. used topically almost exclusively for &laucoma D'rect-act'&g muscar'&'c al)alo'ds or s/&thet'cs .ilocarpine

9ike bethanechol$ partial agonist

9ike bethanechol ?lauco&a4 S#Pgren:s syndro&e

Cevimeline: Synthetic + 2-selective. similar to pilocarpine

Subclass

$echa&'sm o( Act'o&

E((ects


ctivates autono&ic postganglionic neurons (both sy&pathetic and parasy&pathetic) and skeletal &uscle neuro&uscular end plates enters ,NS and activates NN receptors

"edical use in
D'rect-act'&g &'cot'&'c ago&'sts Nicotine

gonist at both NN and N" receptors

=arenicline: Selective partial a&onist at cessation

@ < nicotinic receptors. used exclusively for smo1in&

Short-act'&g chol'&esterase '&h'b'tor Edrophoniu& lcohol$ binds briefly to active site of acetylcholinesteras e (,hE) and prevents access of acetylcholine (,h)

&plifies all 0iagnosis and actions of ,h acute treat&ent of increases &yasthenia gravis parasy&patheti c activity and so&atic neuro&uscular trans&ission

.arenteral Auaternary a&ine does not enter ,NS Toxicity: .arasy&patho&i&etic excess Interactions: dditive !ith parasy&patho&i&etics

I&termed'ate-act'&g chol'&esterase '&h'b'tors Neostig&ine

For&s covalent bond !ith ,hE$ but hydroly7ed and released

9ike edrophoniu&$ but longer% acting

"yasthenia gravis postoperative and neurogenic ileus and urinary retention

yridosti&mine: !i1e neosti&mine, but lon&er-actin& #@;B h$. used in myasthenia hysosti&mine: !i1e neosti&mine, but natural al1aloid tertiary amine. enters C(S o&g-act'&g chol'&esterase '&h'b'tors Echothiophat

9ike neostig&ine$

9ike

Topical only Toxicity:

Subclass

$echa&'sm o( Act'o&

E((ects

e

but released &ore slo!ly

neostig&ine$ but longer% acting

Cl'&'cal %harmaco)'&et'cs Appl'cat'o& * To+'c't'es* s I&teract'o&s used in glauco&a

8ro! ache$ uveitis$ blurred vision

+alathion: Insecticide, relatively safe for mammals and birds because metaboli4ed by other en4ymes to inactive products. some medical use as ectoparasiticide arathion, others: Insecticide, dan&erous for all animals. toxicity important because of a&ricultural use and exposure of farm or1ers #see text$ Sarin, others: (erve &as, used exclusively in arfare and terrorism

DRUGS :ITH ANTICH"INERGIC ACTI"NS Drugs w'th A&t'chol'&erg'c Act'o&s

Subclass $echa&'sm E((ects o( Act'o&


$ot'o& s'c)&ess drugs Scopola&ine @nkno!n &echanis& in ,NS

Reduces vertigo$ postoperative nausea

.revention of &otion sickness and postoperative nausea and vo&iting

Transder&al patch used for &otion sickness 6" in#ection for postoperative use Toxicity: Tachycardia$ blurred vision$ xerosto&ia$ deliriu& Interactions; +ith other anti&uscarinics

Gastro'&test'&al d'sorders 0icyclo&ine ,o&petitive Reduces 6rritable bo!el antagonis& at "2 s&ooth &uscle syndro&e$ &inor receptors and secretory diarrhea activity of gut

5yoscyamine: !on&er duration of action

vailable in oral and parenteral for&s short t 'L/ but action lasts up to 1 hours Toxicity: Tachycardia$ confusion$ urinary retention$ increased intraocular pressure Interactions; +ith other anti&uscarinics



lycopyrrolate: Similar to dicyclomine "phthalmolog/ tropine

,o&petitive ,auses antagonis& at all &ydriasis and " receptors cycloplegia

Retinal exa&ination4 prevention of synechiae after surgery

@sed as drops long (1 days) action Toxicity: 6ncreased intraocular pressure in closed%angle glauco&a Interactions; +ith other anti&uscarinics

Scopolamine: Faster onset of action than atropine 5omatropine: Shorter duration of action #<;<@ h$ Cyclopentolate: Shorter duration of action #?;B h$ Tropicamide: Shortest duration of action #7;B8 min$ Resp'rator/ asthma* C"%D 6pratropiu&

,o&petitive$ nonselective antagonist at " receptors

Reduces or prevents bronchospas&

.revention and relief of acute episodes of bronchospas&

erosol canister$ up to Aid Toxicity: Qerosto&ia$ cough Interactions; +ith other anti&uscarinics

Tiotropium: !on&er duration of action. used %d Ur'&ar/
Nonselective &uscarinic antagonist

Reduces @rge incontinence4 detrusor postoperative s&ooth &uscle spas&s tone$ spas&s

Darifenacin, solifenacin, and tolterodine: Tertiary amines ith somehat &reater selectivity for + ? receptors Trospium: Euaternary amine ith less C(S effect Chol'&erg'c po'so&'&g tropine

Nonselective co&petitive antagonist at all

8locks &uscarinic excess at

"andatory 6ntravenous infusion until antidote for severe anti&uscarinic signs appear cholinesterase


.ralidoxi&e


&uscarinic receptors in ,NS and periphery

exocrine inhibitor poisoning continue as long as necessary glands$ heart$ Toxicity: 6nsignificant as long s&ooth &uscle as ,hE inhibition continues

5ery high affinity for phosphorus ato& but does not enter ,NS

Regenerates active ,hE4 can relieve skeletal &uscle end plate block

@sual antidote for early%stage (3> h) cholinesterase inhibitor poisoning

6ntravenous every 31 h Toxicity: ,an cause &uscle !eakness in overdose

S#$%ATH"$I$ETIC DRUGS S/mpathom'met'c Drugs

Subclass

;



Ago&'sts

"idodrine

ctivates phospholipase ,$ resulting in increased intracellular calciu& and vasoconstriction

5ascular s&ooth

henylephrine: Can be used I= for short-term maintenance of / in acute hypotension and intranasally to produce local vasoconstriction as a decon&estant 1

Ago&'sts

,lonidine

6nhibits adenylyl cyclase and interacts !ith other intracellular path!ays

5asoconstriction is &asked by central sy&patholytic effect$ !hich lo!ers 8.

Hypertension


Ti4anidine: >sed as a muscle relaxant 0praclonidine and brimonidine: >sed in &laucoma to reduce intraocular pressure Ago&'sts

;

0obuta&ine'

ctivates .ositive inotropic ,ardiogenic 65 reAuires dose titration to adenylyl cyclase$ effect shock$ acute heart desired effect increasing failure &yocardial contractility

Ago&'sts

1

lbuterol

See other

ctivates adenylyl cyclase

8ronchial s&ooth &uscle dilation

sth&a

6nhalation duration 31 h Toxicity: Tre&or$ tachycardia

a&onists in Chapter <8

<

Dopam'&e D; Ago&'sts Fenoldopa&

ctivates adenylyl cyclase

5ascular s&ooth Hypertension &uscle relaxation

ReAuires dose titration to desired effect

Restores dopa&ine actions in the central nervous syste&

D1 Ago&'sts 8ro&ocriptine 6nhibits adenylyl cyclase and interacts !ith other intracellular path!ays

.arkinson:s disease$ prolactine&ia

See other D< a&onists in Chapters
'

0obuta&ine has other actions in addition to

%agonist effectB See text for detailsB

'

S#$%ATHETIC ANTAG"NISTS

S/mpathet'c A&tago&'sts

Subclass


Cl'&'cal %harmaco)'&et'cs Appl'cat'o&s * To+'c't'es* I&teract'o&s

Alpha-adre&oceptor a&tago&'sts .henoxyben7a&in 6rreversibly e blocks ' and indirect baroreflex activation

hentolamine: ' and pheochromocytoma

.ra7osin

/

9o!ers blood pressure (8.) but heart rate (HR) rises due to baroreflex activation

.heochro&ocyto& a high catechola&ine states

6rreversible blocker half% life  ' day Toxicity:
anta&onist. half-life about @7 min after I= in3ection. used to treat

/

8lock

$ but not 9o!er 8.

'

/

0oxa7osin

Hypertension benign prostatic hyperplasia

9arger depressor effect !ith first dose &ay cause orthostatic hypotension

Tera7osin Ta&sulosin

-ohi&bine

9abetalol (see carvedilol section belo!)

' 8lockade Ta&sulosin is 8enign prostatic slightly selective &ay relax hyperplasia for ' prostatic s&ooth &uscles &ore than vascular s&ooth &uscle

8locks / elicits Raises 8. and "ale erectile increased central HR dysfunction sy&pathetic hypotension activity increased norepinephrine release

"ay cause anxiety excess pressor effect if norepinephrine transporter is blocked



'

block

4eta-adre&oceptor a&tago&'sts

9o!ers 8. !ith li&ited HR increase

Hypertension

Subclass

.ropranolol

$echa&'sm E((ects o( Act'o& 8lock ' and receptors

/

Nadolol Ti&olol "etoprolol

8lock



'

/

tenolol lprenolol

Cl'&'cal %harmaco)'&et'cs Appl'cat'o&s * To+'c't'es* I&teract'o&s

9o!er HR and Hypertension 8. reduce angina pectoris renin arrhyth&ias &igraine hyperthyroidis&

9o!er HR and ngina pectoris 8. reduce hypertension renin &ay be arrhyth&ias safer in asth&a

8radycardia fatigue vivid drea&s cold hands

6ncreases peripheral resistance

Toxicity: sth&a provocation

8etaxolol Nebivolol 8utoxa&ine'

.indolol cebutolol ,arteolol

8locks

'

$

/



'



/

'

$ !ith

9o!ers 8. intrinsic &odestly sy&patho&i&eti lo!er HR c (partial agonist) effect

No clinical indication

Hypertension
8opindolol'

,eliprolol'

.enbutolol ,arvedilol

block

9ong half%life

Heart failure

6ntravenous use half%life

Rapid control of 8. .arenteral only Toxicity: and arrhyth&ias$ 8radycardia hypotension

"edroxalol '

8ucindolol' (see labetalol above)

Es&olol



'

/

Subclass

$echa&'sm E((ects o( Act'o& = 'D &in

Cl'&'cal %harmaco)'&et'cs Appl'cat'o&s * To+'c't'es* I&teract'o&s thyrotoxicosis and &yocardial ische&ia intraoperatively

T/ros'&e h/dro+/lase '&h'b'tor "etyrosine

8locks tyrosine hydroxylase reduces synthesis of dopa&ine$ norepinephrine$ and epinephrine

9o!ers 8. in .heochro&ocyto& Extrapyra&idal sy&pto&s central a orthostatic hypotension nervous crystalluria syste& &ay elicit extrapyra&ida l effects (due to lo! dopa&ine)

CARDI"!ASCUAR-RENA DRUGS DRUGS USED IN H#%ERTENSI"N Drugs Used '& H/perte&s'o&

Subclass


Cl'&'cal %harmaco)'&et'cs* Appl'cat'o& To+'c't'es* s I&teract'o&s

D'uret'cs Thia7ides; 8lock NaL,l Hydrochlorothia7ide transporter in renal distal convoluted tubule

Reduce blood Hypertension$ volu&e plus &ild heart failure poorly understood vascular effects

9oop diuretics; Furose&ide

9ike thia7ides Severe greater efficacy hypertension$ heart failure

8lock NaLJL/,l transporter in renal loop of Henle

See ,hapter '

Subclass


S pironolactone

8lock aldosterone receptor in renal collecting tubule

Eplerenone


6ncrease Na ldosteronis&$ and decrease J heart failure$ excretion hypertension poorly understood reduction in heart failure &ortality

S/mpathopleg'cs* centrally acting ,lonidine$ ðyldopa

ctivate / adrenoceptors

Reduce central sy&pathetic outflo! reduce norepinephrine release fro& noradrenergic nerve endings

Hypertension clonidine also used in !ithdra!al fro& abused drugs

S/mpathet'c &er,e term'&al bloc)ers Reserpine

8locks vesicular a&ine transporter in noradrenergic nerves and depletes trans&itter stores

Reduce all sy&pathetic effects$ especially cardiovascular$ and reduce blood pressure

Hypertension but rarely used

?uanethidine

6nterferes !ith a&ine release and replaces norepinephrine in vesicles

Sa&e as reserpine

Sa&e as reserpine

?uanethidine; Severe orthostatic hypotension sexual dysfunction

4loc)ers .ra7osin Tera7osin 0oxa7osin

4loc)ers

Selectively block .revent Hypertension sy&pathetic benign prostatic ' adrenoceptors vasoconstriction hyperplasia reduce prostatic s&ooth &uscle tone

Subclass


"etoprolol$ others 8lock ' receptors4 ,arvedilol carvedilol also blocks receptors

.revent sy&pathetic cardiac sti&ulation reduce renin secretion

Cl'&'cal %harmaco)'&et'cs* Appl'cat'o& To+'c't'es* s I&teract'o&s Hypertension heart failure

See ,hapter 'D

ropranolol: (onselective prototype bloc1er 0tenolol: =ery idely used -selective bloc1er. claimed to have reduced central nervous system toxicity !asod'lators 5erapa&il 0iltia7e&

Nonselective block of 9%type calciu& channels

Nifedipine

8lock vascular calciu& &lodipine$ other channels  dihydropyridines cardiac calciu& channels Hydrala7ine

,auses nitric oxide release

"inoxidil

"etabolite opens J channels in vascular s&ooth &uscle

Reduce cardiac Hypertension$ rate and output angina$ reduce arrhyth&ias vascular resistance

See ,hapter '/

Reduce vascular resistance

Hypertension

See ,hapter '/

5asodilation reduce vascular resistance arterioles &ore sensitive than veins reflex tachycardia

Hypertension
"inoxidil; Hypertrichosis

%are&teral age&ts Nitroprusside

Releases nitric oxide

Fenoldopa&

ctivates 0' receptors

.o!erful vasodilation

Hypertensive e&ergencies

.arenteral short duration Toxicity: Excessive hypotension$ shock

Subclass

0ia7oxide



A&g'ote&s'&-co&,ert'&g e&5/me ACE '&h'b'tors ,aptopril$ &any others

6nhibit angiotensin converting en7y&e

Reduce Hypertension angiotensin 66 heart failure$ levels reduce diabetes vasoconstriction and aldosterone secretion increase bradykinin

Sa&e as ,E inhibitors but no increase in bradykinin

Hypertension heart failure

Hypertension

A&g'ote&s'& receptor bloc)ers 9osartan$ &any others

8lock T' angiotensin receptors

Re&'& '&h'b'tor liskiren

6nhibits en7y&e Reduces activity of renin angiotensin 6 and 66 and aldosterone

DRUGS USED IN ANGINA %ECT"RIS Drugs Used '& A&g'&a %ector's

Subclass



Releases nitric oxide in s&ooth &uscle$ !hich

ngina; Sublingual 5ery high first%pass effect$ so for& for acute sublingual dose is &uch episodes oral and s&aller than oral high lipid

N'trates Nitroglycerin

S&ooth &uscle relaxation$

Subclass



activates guanylyl cyclase and increases c?".

transder&al for&s for prophylaxis 65 for& for acute coronary syndro&e

especially in vessels other s&ooth &uscle is relaxed but not as &arkedly vasodilation decreases venous return and heart si7e &ay increase coronary flo! in so&e areas and in variant angina

solubility ensures rapid absorption Toxicity:
Isosorbide dinitrate: =ery similar to nitro&lycerin, sli&htly lon&er duration of action Isosorbide mononitrate: 0ctive metabolite of the dinitrate. used orally for prophylaxis 4eta bloc)ers .ropranolol

Nonselective co&petitive antagonist at adrenoceptors

0tenolol, metoprolol, others:

0ecreased heart rate$ cardiac output$ and blood pressure decreases &yocardial oxygen de&and

.rophylaxis of angina for other applications$ see ,hapters 'D$ ''$ and '2

-Selective bloc1ers, less ris1 of bronchospasm, but still si&nificant



See Chapters 8 and  for other bloc1ers and their applications Calc'um cha&&el bloc)ers 5erapa&il$ diltia7e&

Nonselective block of 9%type calciu& channels in vessels and heart

Reduced vascular resistance$ cardiac rate$ and cardiac force results in decreased

.rophylaxis of angina$ hypertension$ others

h Toxicity: trioventricular block$ acute heart failure4 constipation$ ede&a Interactions: dditive !ith other cardiac depressants and hypotensive drugs

Subclass



oxygen de&and Nifedipine (a 8lock of vascular dihydropyridine) 9%type calciu& channels  cardiac channels

9ike .rophylaxis of verapa&il and angina$ diltia7e&4 less hypertension cardiac effect

*ther dihydropyridines: !i1e nifedipine but sloer onset and lon&er duration #up to < h or lon&er$ $'scella&eous Ranola7ine

6nhibits late sodiu& current in heart also &ay &odify fatty acid oxidation

Reduces .rophylaxis of cardiac angina oxygen de&and fatty acid oxidation &odification &ay i&prove efficiency of cardiac oxygen utili7ation

h Toxicity: T interval prolongation$ nausea$ constipation$ di77iness Interactions: 6nhibitors of ,-.2 increase ranola7ine concentration and duration of action

Ivabradine: Investi&ational inhibitor of sinoatrial pacema1er. reduction of heart rate reduces oxy&en demand

DRUGS USED IN HEART 2AIURE Drugs Used '& Heart 2a'lure

Subclass


Cl'&'cal Appl'cat'o &s

%harmaco)'&et'c s* To+'c't'es* I&teract'o&s

9oop diuretic; 0ecreases Na,l and J,l reabsorption in thick ascending

cute and chronic heart failure severe hypertension e de&atous

D'uret'cs Furose&ide

6ncreased excretion of salt and !ater reduces cardiac preload and afterload reduces

Subclass




li&b of the loop of Henle in the nephron (see ,hapter ')

pul&onary and peripheral ede&a

conditions

sulfona&ide allergy

Sa&e as furose&ide$ but less efficacious

"ild chronic failure &ild% &oderate hypertension hypercalciuria

Hydrochlorothia7i 0ecreases Na,l de reabsorption in the distal convoluted tubule

Three other loop diuretics: /umetanide and torsemide similar to furosemide. ethacrynic acid not a sulfonamide +any other thia4ides: 0ll basically similar to hydrochlorothia4ide, differin& only in pharmaco1inetics Aldostero&e a&tago&'sts Spironolactone

8lock cytoplas&ic aldosterone receptors in collecting tubules of nephron possible &e&brane effect

6ncreased salt and !ater excretion reduces re&odeling reduces &ortality

,hronic heart failure aldosteronis& (cirrhosis$ adrenal tu&or) hypertension

)plerenone: Similar to spironolactone. more selective antialdosterone effect. no si&nificant antiandro&en action A&g'ote&s'& a&tago&'sts A&g'ote&s'&co&,ert'&g e&5/me ACE '&h'b'tors< ,aptopril

6nhibits ,E rteriolar and reduces 66 venous dilation for&ation by reduces aldosterone inhibiting secretion increases conversion of 6 cardiac output to ll reduces cardiac re&odeling

,hronic heart failure hypertension diabetic renal disease

Subclass




A&g'ote&s'& receptor bloc)ers AR4s<

ntagoni7e 66 effects at T' receptors

9ike ,E inhibitors used in patients intolerant to ,E inhibitors

h Toxicity: Hyperkale&ia4 angioneurotic ede&a Interactions: dditive !ith other angiotensin antagonists

,hronic heart failure; To slo! progression reduce &ortality in &oderate and severe heart failure &any other indications in ,hapter 'DB

9ike ,E inhibitors

9osartan )nalapril, many other 0C) inhibitors: !i1e captopril Candesartan, many other 0/s: !i1e losartan 4eta bloc)ers ,arvedilol

,o&petitively blocks ' receptors (see ,hapter 'D)

Slo!s heart rate reduces blood pressure poorly understood effects reduces heart failure &ortality

+etoprolol, bisoprolol: Select &roup of bloc1ers that reduce heart failure mortality Card'ac Gl/cos'de 0igoxin

NaK$JK T.ase inhibition results in reduced ,a/K expulsion and increased ,a/K stored in sarcoplas&ic reticulu&

6ncreases cardiac contractility cardiac parasy&patho&i&e tic effect (slo!ed sinus heart rate$ slo!ed atrioventricular conduction)

,hronic sy&pto&atic heart failure rapid ventricular rate in atrial fibrillation

Releases nitric oxide (N<) activates guanylyl cyclase (see ,hapter '/)

5enodilation reduces preload and ventricular stretch

cute and chronic heart failure angina

!asod'lators !e&od'lators; 6sosorbide dinitrate

Subclass



%harmaco)'&et'c s* To+'c't'es* I&teract'o&s phosphodiesterase type  inhibitors

Arter'olar d'lators< Hydrala7ine Comb'&ed arter'olar a&d ,e&od'lator< Nitroprusside 4eta-adre&oceptor ago&'sts 0obuta&ine

8eta'selective agonist increases c". synthesis

6ncreases cardiac cute contractility$ output deco&pensated heart failure inter&ittent therapy in chronic failure reduces sy&pto&s

65 only duration a fe! &inutes Toxicity: rrhyth&iasB Interactions: dditive !ith other sy&patho&i&etics

0opa&ine

0opa&ine receptor agonist higher doses activate and adrenoceptors

6ncreases renal blood flo! higher doses increase cardiac force and blood pressure

cute deco&pensated heart failure shock

65 only duration a fe! &inutes Toxicity: rrhyth&ias Interactions: dditive !ith sy&patho&i&etics

.hosphodiestera se type 2 inhibitors decrease c". breakdo!n

5asodilators lo!er peripheral vascular resistance also increase cardiac contractility

cute 65 only duration 21 h deco&pensated Toxicity: rrhyth&ias heart failure Interactions: dditive !ith other arrhyth&ogenic agents

5asodilation diuresis

cute 65 only duration '> deco&pensated &inutes Toxicity: Renal failure da&age$ hypotension

4'p/r'd'&es 6na&rinone$ &ilrinone

Natr'uret'c %ept'de Nesiritide

ctivates 8N. receptors$ increases c?".

ANTIARRH#TH$IC DRUGS A&t'arrh/thm'c Drugs

Subclass



Class IA .rocaina&ide 6Na (pri&ary) and Slo!s 6Jr (secondary) conduction blockade velocity and pace&aker rate prolongs action potential duration and dissociates fro& 6Na channel !ith inter&ediate kinetics direct depressant effects on sinoatrial (S) and atrioventricular (5) nodes

"ost atrial and ventricular arrhyth&ias drug of second choice for &ost sustained ventricular arrhyth&ias associated !ith acute &yocardial infarction

Disopyramide: Similar to procainamide but si&nificant antimuscarinic effects. may precipitate heart failure Euinidine: Similar to procainamide but more toxic #cinchonism, torsade$. rarely used Class ;4 9idocaine

Sodiu& channel (6Na) blockade

8locks activated and inactivated channels !ith fast kinetics does not prolong and &ay shorten action potential

Ter&inate ventricular tachycardias and prevent ventricular fibrillation after cardioversion

65 first%pass hepatic &etabolis& reduce dose in patients !ith heart failure or liver disease Toxicity: Neurologic sy&pto&s

+exiletine: *rally active con&ener of lidocaine. used in ventricular arrhythmias, chronic pain syndromes

Subclass



Sodiu& c hannel (6Na) blockade

Supraventricular
Class ;C Flecainide

0issociates fro& channel !ith slo! kinetics no change in action potential duration

ropafenone: *rally active, ea1 -bloc1in& activity. supraventricular arrhythmias. hepatic metabolism +orici4ine: henothia4ine derivative, orally active. ventricular arrhythmias, proarrhythmic' Githdran in >S0' Class 1 .ropranolol

%drenoceptor blockade

0irect &e&brane effects (sodiu& channel block) and prolongation of action potential duration slo!s S node auto&aticity and 5 nodal conduction velocity

trial arrhyth&ias
)smolol: Short-actin&, I= only. used for intraoperative and other acute arrhythmias Class = &iodarone

8locks 6Jr$ 6Na$ 6,a%9 channels$ adrenoceptors

.rolongs action potential duration and T interval slo!s heart rate and 5 node conduction lo! incidence of torsade de pointes

Serious ventricular arrhyth&ias and supraventricular arrhyth&ias

Subclass


Cl'&'cal %harmaco)'&et'cs* Appl'cat'o&s To+'c't'es* I&teract'o&s Interactions: "any$ based on ,-. &etabolis&

0ofetilide

6Jr block

.rolongs action potential$ effective refractory period

"aintenance or restoration of sinus rhyth& in atrial fibrillation

Sotalol: -0drener&ic bloc1er, direct action potential prolon&ation properties, use for ventricular arrhythmias, atrial fibrillation Ibutilide: otassium channel bloc1er, may activate inard current. I= use for conversion in atrial flutter and fibrillation Dronedarone: Investi&ational amiodarone derivative. multichannel actions, reduces mortality in patients ith atrial fibrillation =erna1alant: Investi&ational, multichannel actions in atria, prolon&s atrial refractoriness, effective in atrial fibrillation Class > 5erapa&il

,alciu& channel Slo!s S node Supraventricular (6,a%9 type) auto&aticity and tachycardias blockade 5 nodal conduction velocity decreases cardiac contractility reduces blood pressure

Diltia4em: )%uivalent to verapamil $'scella&eous denosine

ctivates in!ard 5ery brief$ .aroxys&al rectifier 6J usually co&plete supraventricular blocks 6,a 5 blockade tachycardias

"agnesiu&

.oorly understood interacts !ith NaK$JK T.ase$

Nor&ali7es or increases plas&a "g/K

65 only duration 'D' Toxicity: Flushing$ chest tightness$ di77iness Interactions: "ini&al

Torsade de pointes 65 duration dependent on digitalis%induced dosage Toxicity: "uscle arrhyth&ias !eakness in overdose

Subclass



JK and ,a/K channels

.otassiu&

6ncreases JK per&eability$ JK currents

Slo!s ectopic pace&akers slo!s conduction velocity in heart

0igitalis%induced arrhyth&ias arrhyth&ias associated !ith hypokale&ia

DIURETIC AGENTS D'uret'c Age&ts

Subclass

$echa&'s m o( Act'o&

E((ects


Carbo&'c a&h/drase '&h'b'tors ceta7ola&ide$ others

6nhibition of the en7y&e prevents dehydration of H/,<2 and hydration of ,
Reduces ?lauco&a$ reabsorption of &ountain H,<2 in the sickness$ ede&a kidney$ !ith alkalosis causing self% li&ited diuresis hyperchlore&i c &etabolic acidosis reduces body pH$ reduces intraocular pressure

'/ h Toxicity: "etabolic acidosis$ renal stones$ hypera&&one&ia in cirrhotics

/rin4olamide, dor4olamide: Topical for &laucoma oop d'uret'cs Furose&ide

6nhibition of the NaLJL/,l transporter in the ascending

"arked increase in Na,l excretion$

.ul&onary ede&a$ peripheral ede&a$

Subclass


E((ects


li&b of Henle:s loop

so&e J !asting$ hypokale&ic &etabolic alkalosis$ increased urine ,a and "g

hypertension$ acute hypercalce&ia or hyperkale&ia$ acute renal failure$ anion overdose

/umetanide, torsemide: Sulfonamide loop a&ents li1e f urosemide )thacrynic acid: (ot a sulfonamide but has typical loop activity and some uricosuric action Th'a5'des Hydrochlorothia7id e

6nhibition of the NaL,l transporter in the distal convoluted tubule

"odest increase in Na,l excretion so&e J !asting hypokale&ic &etabolic alkalosis decreased urine ,a

Hypertension$ &ild heart failure$ nephrolithiasis$ nephrogenic diabetes insipidus

'/ h Toxicity: Hypokale&ic &etabolic alkalosis$ hyperurice&ia$ hyperglyce&ia$ hyponatre&ia

+etola4one: opular for use ith loop a&ents for syner&istic effects Chlorothia4ide: *nly parenteral thia4ide available #I= ) %otass'um-spar'&g d'uret'cs Spironolactone

.har&acologic antagonist of aldosterone !eak antagonis& of androgen receptors

Reduces Na retention and J !asting in kidney poorly understood antagonis& of aldosterone in heart and vessels

ldosteronis& fro& any cause hypokale&ia due to other diuretics post&yocardial infarction

Slo! onset and offset of effect duration /33> h Toxicity: Hyperkale&ia$ gyneco&astia (spironolactone$ not eplerenone) additive interaction !ith other J% retaining drugs

&iloride

8locks epithelial sodiu& channels in collecting tubules

Reduces Na retention and J !asting increases lithiu&

Hypokale&ia
Subclass


E((ects


clearance )plerenone: !i1e spironolactone, more selective for aldosterone receptor Triamterene: +echanism li1e amiloride, much less potent, more toxic "smot'c d'uret'cs "annitol

.hysical os&otic effect on tissue !ater distribution because it is retained in the vascular co&part&ent

"arked increase in urine flo!$ reduced brain volu&e$ decreased intraocular pressure$ initial hyponatre&ia$ then hypernatre&ia

Renal failure due to increased solute load (rhabdo&yolysis$ che&otherapy)$ increased intracranial pressure$ glauco&a

ntagonist at 5'a and 5/ 0H receptors

Reduces !ater Hyponatre&ia reabsorption$ increases plas&a Na concentration

65 ad&inistration Toxicity: Nausea$ vo&iting$ headache

"ther Age&ts ,onivaptan

65
DRUGS USED IN ASTH$A Drugs Used '& Asthma

Subclass

$echa&'sm o( Act'o&

E((ects


Selective agonist

.ro&pt$ efficacious bronchodilation

sth&a$ chronic obstructive pul&onary disease (,<.0) drug of choice in acute asth&atic

4eta ago&'sts lbuterol

/

erosol inhalation duration several hours also available for nebuli7er and parenteral use Toxicity ; Tre&or$ tachycardia overdose; arrhyth&ias

Subclass

$echa&'sm o( Act'o&

E((ects

Cl'&'cal %harmaco)'&et'cs* Appl'cat'o&s To+'c't'es bronchospas&

Sal&eterol

Selective agonist

/

Slo! onset$ pri&arily preventive action4 potentiates corticosteroid effects

sth&a prophylaxis

erosol inhalation duration '//3 h Toxicity ; Tre&or$ tachycardia$ overdose; arrhyth&ias

+etaproterenol, terbutaline: Similar to al buterol. terbutaline available as an oral dru& Formoterol: Similar to salmeterol Epinephrine

6soproterenol

Nonselective and 8ronchodilation agonist plus all other sy&patho&i&etic effects on cardiovascular and other organ syste&s (see ,hapter C) and

'

agonist

/

naphylaxis$ asth&a$ others (see ,hapter C) rarely used for asth&a ( /% selective agents preferred)

erosol$ nebuli7er$ or parenteral see ,hapter C

8ronchodilation plus po!erful cardiovascular effects

sth&a$ but /% selective agents preferred

erosol$ nebuli7er$ or parenteral see ,hapter C

Reduces &ediators of infla&&ation po!erful prophylaxis of exacerbations

sth&a ad#unct in ,<.0

erosol duration hours Toxicity ; 9i&ited by aerosol application candidal infection$ vocal cord changes

Cort'costero'ds* '&haled Fluticasone

lters gene expression

/eclomethasone, budesonide, flunisolide, others: Similar to fluticasone Cort'costero'ds* s/stem'c .rednisone

9ike fluticasone

9ike fluticasone

sth&a ad#unct in ,<.0

+ethylprednisolone: arenteral a&ent li1e prednisone Stab'l'5ers o( mast a&d other cells

Subclass

$echa&'sm o( Act'o&

E((ects


,ro&olyn$ nedocro&il

lters function of delayed chloride channels inhibits infla&&atory cell activation

.revents acute bronchospas&

sth&a (other routes used for ocular$ nasal$ and gastrointestinal allergy)

erosol duration 1> h Toxicity ; ,ough not absorbed so other toxicities are &ini&al

$eth/l+a&th'&es Theophylline @ncertain phosphodiesterase inhibition adenosine receptor antagonist

8ronchodilation$ sth&a$ ,<.0 cardiac sti&ulation$ increased skeletal &uscle strength (diaphrag&)

'/ h but extended%release preparations often used Toxicity ; "ultiple (see text)

eu)otr'e&e a&tago&'sts "ontelukast$ 8lock leukotriene 7afirlukast 03 receptors

8lock air!ay response to exercise and antigen challenge

.rophylaxis of
Hileuton: Inhibits lipoxy&enase, reduces synthesis of leu1otrienes IgE a&t'bod/ <&ali7u&ab

Hu&ani7ed 6gE antibody reduces circulating 6gE

Reduces freAuency of asth&a exacerbations

Severe asth&a inadeAuately controlled by above agents

.arenteral duration /3 d Toxicity ; 6n#ection site reactions (anaphylaxis extre&ely rare)

A%%ENDI8< !ACCINES* I$$UNE G"4UINS* 6 "THER C"$%E8 4I""GIC %R"DUCTS< INTR"DUCTI"N 5accines and related biologic products constitute an i&portant group of agents that bridge the disciplines of &icrobiology$ infectious diseases$ i&&unology$ and i&&unophar&acologyB  list of the &ost i&portant preparations is provided hereB The reader !ho reAuires &ore co&plete infor&ation is referred to the sources listed at the end of this appendixB

ACTI!E I$$UNI9ATI"N ctive i&&uni7ation consists of the ad&inistration of antigen to the host to induce for&ation of antibodies and cell%&ediated i&&unityB 6&&uni7ation is practiced to induce protection against &any infectious agents and &ay utili7e either inactivated (killed) &aterials or live attenuated agents (Table ')B 0esirable features of the ideal i&&unogen include co&plete prevention of disease$ prevention of the carrier state$ production of prolonged i&&unity !ith a &ini&u& of i&&uni7ations$ absence of toxicity$ and suitability for &ass i&&uni7ation (eg$ cheap and easy to ad&inister)B ctive i&&uni7ation is generally preferable to passive i&&uni7ationin &ost cases because higher antibody levels are sustained for longer periods of ti&e$ reAuiring less freAuent i&&uni7ation$ and in so&e cases because of the develop&ent of concurrent cell%&ediated i&&unityB Ho!ever$ active i&&uni7ation reAuires ti&e to develop and is therefore generally inactive at the ti&e of a specific exposure (eg$ for parenteral exposure to hepatitis 8$ concurrent hepatitis 8 6g? passive antibodies and active i&&uni7ation are given to prevent illness)B

Table A?; $ater'als Commo&l/ Used (or Act',e Immu&'5at'o& '& the U&'ted States. ;

!acc'&e

T/pe o( Age&t

Route o( %r'mar/ 4ooster1 I&d'cat'o& Adm'&'strat'o Immu&'5at'o s & &

0iphtheria% tetanus acellular pertussis (0Ta.)

Toxoids and inactivated bacterial co&ponents

6ntra&uscular

See Table /

None

5aemophilus influen4ae type b con#ugate (Hib)

8acterial polysaccharid e con#ugated to protein

6ntra&uscular

Not 'B For all reco&&ende children d /B splenia and other at%risk conditions

Hepatitis 

6nactivated virus

6ntra&uscular

t 1'/ &onths for long%ter& i&&unity

For all children

'B Travelers to hepatitis  ende&ic areas /B Ho&osexual and bisexual &en 2B 6llicit drug users 3B ,hronic liver disease or clotting factor disorders B .ersons !ith occupational risk for infection 1B .ersons living in$ or relocating to$ ende&ic areas *B Household and sexual contacts of individuals !ith acute hepatitis 

Hepatitis 8

6nactive viral

6ntra&uscular

Three doses at D$

Not routinely 'B For all

!acc'&e

T/pe o( Age&t


antigen$ reco&binant

(subcutaneous in#ection is acceptable in individuals !ith bleeding disorders)

'$ and 1 &onths (see Table / for childhood schedule)

reco&&ende infants d /B .readolescents$ adolescents$ and young adults 2B .ersons !ith occupational$ lifestyle$ or environ&ental risk 3B He&ophiliacs B .ersons !ith end%stage renal disease or chronic liver disease 1B .ostexposure prophylaxis

Hu&an 5irus%like 6ntra&uscular papillo&aviru particles of s (H.5) the &a#or capsid protein

Three doses at D$ /$ and 1 &onths

6nfluen7a$ inactivated

6nactivated virus or viral co&ponents

6ntra&uscular

None

ll fe&ales bet!een C and /1 years of age

'B dults D years /B .ersons !ith high%risk conditions (eg$ asth&a) 2B Health care !orkers and others in contact !ith high%risk groups

!acc'&e

T/pe o( Age&t

Route o( %r'mar/ 4ooster1 I&d'cat'o& Adm'&'strat'o Immu&'5at'o s & & 3B Residents of nursing ho&es and other residential chronic care facilities B ll children aged 1 &onths to '> years 1B Healthy persons age 'C3C !ho desire protection against influen7a *B +o&en !ho !ill be pregnant during the influen7a season

6nfluen7a$ live attenuated

9ive virus

6ntranasal

Split dose in each -early !ith nostrilB ,hildren current age > !ho are vaccine receiving influen7a vaccine for the first ti&e should receive t!o doses ad&inistered 1'D !eeks apart

Healthy persons age 'C3C !ho desire protection against influen7aB "ay be substituted for inactivated vaccine in healthy children /'> years

"easles

9ive virus

Subcutaneous

T!o doses at least ' &onth apart

'B dults and adolescents born after 'C1 !ithout a history of &easles or live virus

None

!acc'&e

T/pe o( Age&t

Route o( %r'mar/ 4ooster1 I&d'cat'o& Adm'&'strat'o Immu&'5at'o s & & vaccination on or after their first birthday /B .ostexposure prophylaxis in uni&&uni7ed persons

"easles% &u&ps% rubella (""R)

9ive virus

"eningococc al con#ugate vaccine

8acterial 6ntra&uscular polysaccharid es con#ugated to diphtheria toxoid

8acterial polysaccharid es of serotypes L,L-L+%'2

"eningococc al polysaccharid e vaccine

Subcutaneous

See Table /

None

'B For all children /B dults born after 'C1

Subcutaneous

@nkno!n

'B ll adolescents /B .referred over polysaccharide vaccine in persons age '' years

Every 2 years if there is continuing high risk of exposure

'B "ilitary recruits /B Travelers to areas !ith hyperende&ic or epide&ic &eningococcal disease 2B 6ndividuals !ith asplenia$ co&ple&ent deficiency$ or properdin deficiency 3B ,ontrol of outbreaks in closed or se&iclosed

!acc'&e

T/pe o( Age&t

Route o( %r'mar/ 4ooster1 I&d'cat'o& Adm'&'strat'o Immu&'5at'o s & & populations B ,ollege fresh&en !ho live in dor&itories 1B "icrobiologists !ho are routinely exposed to isolates of (eisseria menin&itidis

"u&ps

9ive virus

Subcutaneous

None

dults born after 'C1 !ithout a history of &u&ps or live virus vaccination on or after their first birthday

.neu&ococca 8acterial 6ntra&uscular or l con#ugate polysaccharid subcutaneous vaccine es con#ugated to protein

See Table /

None

For all children

.neu&ococca l polysaccharid e vaccine

8acterial polysaccharid es of /2 serotypes

6ntra&uscular or subcutaneous

Repeat after 'B dults 1  years in years patients at /B .ersons at high risk increased risk for pneu&ococcal disease or its co&plications

.oliovirus vaccine$ inactivated (6.5)

6nactivated viruses of all three serotypes

Subcutaneous

See Table / for childhood scheduleB dults; T!o doses 3> !eeks apart$ and a third dose 1'/

'B For all children /B .reviously unvaccinated adults at

!acc'&e

Rabies

T/pe o( Age&t

6nactivated virus


6ntra&uscular (6")

&onths after the second

exposure

%ree+posure< Three doses at days D$ *$ and /' or />

Serologic testing every 1 &onths to / years in persons at high risk

%oste+posure< Five%doses at days D$ 2$ *$ '3$ and />

increased risk for occupational or travel exposure to polioviruses 'B %ree+posure prophylaxis in persons at risk for contact !ith rabies virus /B %oste+posure prophylaxis (ad&inister !ith rabies i&&une globulin)

Rotavirus

9ive virus

See Table /

None

For all infantsB The series of 2 doses should be initiated by age '/ !eeks and co&pleted by age 2/ !eeks

Rubella

9ive virus

Subcutaneous

days apart)

None

dults born after 'C1 !ithout a history of rubella or live virus vaccination on or after their first birthday

Tetanus% diphtheria (Td or 0T)2

Toxoids

6ntra&uscular

T!o doses 3> Every 'D !eeks apart$ and a years or a third dose 1'/ single &onths after the booster at second age D

'B ll adults /B .ostexposure prophylaxis if   years has passed since

!acc'&e

T/pe o( Age&t

Route o( %r'mar/ 4ooster1 I&d'cat'o& Adm'&'strat'o Immu&'5at'o s & & last dose

Tetanus$ diphtheria$ pertussis (Tdap)

Toxoids and inactivated bacterial co&ponents

6ntra&uscular

Substitute ' dose of Tdap for Td in patients 'C13 years of age

Typhoid$ Ty/'a oral

9ive bacteria

Four doses Four doses ad&inistered every every  other day years

Risk of exposure to typhoid fever

Typhoid$ 5i 8acterial capsular polysaccharid polysaccharid e e

6ntra&uscular

Risk of exposure to typhoid fever

5aricella

Subcutaneous

T!o doses 3> @nkno!n !eeks apart in persons past their '2th birthday (see Table / for childhood schedule)

9ive virus

None

Every / years

ll adults  1 years

'B For all children /B .ersons past their '2th birthday !ithout a history of varicella infection or i&&uni7ation 2B .ostexposure prophylaxis in susceptible persons

-ello! fever

9ive virus

Subcutaneous

'B 9aboratory personnel !ho &ay be exposed to yello! fever virus /B Travelers to areas !here yello! fever occurs

Ioster

9ive virus

Subcutaneous

None

ll adults 1D

!acc'&e

T/pe o( Age&t

Route o( %r'mar/ 4ooster1 I&d'cat'o& Adm'&'strat'o Immu&'5at'o s & & years of age

'

0osages for the specific product$ including variations for age$ are best obtained fro& the &anufacturer:s package insertB /

2

Td is tetanus and diphtheria toxoids for use in persons * years of age (contains less diphtheria toxoid than 0.T and 0T)B 0T is tetanus and diphtheria toxoids for use in persons  * years of age (contains the sa&e a&ount of diphtheria toxoid as 0.T)B ,urrent reco&&endations for routine active i&&uni7ation of children are given in Table /B

Table A?1 Recomme&ded Rout'&e Ch'ldhood Immu&'5at'o& Schedule.

Age

Immu&'5at'o&

Comme&ts

8irth to / &onths

Hepatitis 8 vaccine (H85)

I&(a&ts bor& to sero&egat',e mothers< d&inistration should begin at birth$ !ith the second dose ad&inistered at least 3 !eeks after the first doseB I&(a&ts bor& to seropos't',e mothers< Should receive the first dose !ithin '/ hours after birth (!ith hepatitis 8 i&&une globulin)$ the second dose at '/ &onths of age$ and the third dose at 1 &onths of ageB

/ &onths

0iphtheria and tetanus toxoids and acellular pertussis vaccine (0Ta.)$ inactivated poliovirus vaccine (6.5)$ 5aemophilus influen4ae type b con#ugate vaccine (Hib)$' pneu&ococcal con#ugate vaccine (.,5)$ rotavirus vaccine (Rota)

'3 &onths

H85

3 &onths

0Ta.$ Hib$' 6.5$ .,5$ Rota

1 &onths

0Ta.$ Hib$' .,5$ Rota

1'> &onths

H85$ 6.5$ influen7a

The second dose should be given at least 3 !eeks after the first doseB

The third dose of H85 should be given at least '1 !eeks after the first dose and at

Age

Immu&'5at'o&

Comme&ts least > !eeks after the second dose$ but not before age 1 &onthsB 6nfluen7a vaccine should be ad&inistered annually to children aged 1 &onths to '> yearsB

'/' &onths

"easles%&u&ps%rubella vaccine (""R)$ Hib$' .,5

'/'> &onths

0Ta. at ''> &onths$ varicella vaccine

0Ta. &ay be given as early as age '/ &onthsB 5aricella vaccine is reco&&ended at any visit after the first birthday for susceptible childrenB The second dose should be ad&inistered at age 31 yearsB

'//2 &onths

Hepatitis  vaccine

T!o doses 1 &onths apartB

31 years

0Ta. 6.5$ ""R$ varicella vaccine

The second dose of ""R should be routinely ad&inistered at 31 years of age but &ay be given during any visit if at least 3 !eeks have elapsed since ad&inistration of the first doseB The second dose should be given no later than age '''/ yearsB

'''/ years

Tetanus$ diphtheria$ pertussis (Tdap) vaccine$ Three doses of H.5 should be ad&inistered hu&an papillo&avirus vaccine (H.5)$ to fe&ales at D$ /$ and 1 &onthsB &eningococcal con#ugate vaccine

'

Three Hib con#ugate vaccines are available for use; (a) oligosaccharide con#ugate Hib vaccine (Hb<,)$ (b) polyribosylribitol phosphate%tetanus toxoid con#ugate (.R.%T)$ and (c) 5aemophilus influen4ae type b con#ugate vaccine (&eningococcal protein con#ugate) (.R.%<".)B ,hildren i&&uni7ed !ith .R.%<". at / and 3 &onths of age do not reAuire a dose at 1 &onths of ageB dapted fro& ""+R "orb "ortal +kly Rep /DD>4*;%'B

%ASSI!E I$$UNI9ATI"N .assive i&&uni7ation consists of transfer of i&&unity to a host using prefor&ed i&&unologic productsB Fro& a practical standpoint$ only i&&unoglobulins have been used for passive i&&uni7ation$ since passive ad&inistration of cellular co&ponents of the i&&une syste& has been technically difficult and associated !ith graft%versus%host reactionsB .roducts of the cellular i&&une syste& (eg$ interferons) have also been used in the therapy of a !ide variety of he&atologic and infectious diseases (see ,hapter 1)B .assive i&&uni7ation !ith antibodies &ay be acco&plished !ith either ani&al or hu&an i&&unoglobulins in varying degrees of purityB These &ay contain relatively high titers of antibodies directed against a specific antigen or$ as is true for pooled i&&une globulin$ &ay si&ply contain antibodies found in &ost of the populationB .assive i&&uni7ation is useful for (') individuals unable to

for& antibodies (eg$ congenital aga&&aglobuline&ia)4 (/) prevention of disease !hen ti&e does not per&it active i&&uni7ation (eg$ postexposure)4 (2) for treat&ent of certain diseases nor&ally prevented by i&&uni7ation (eg$ tetanus)4 and (3) for treat&ent of conditions for !hich active i&&uni7ation is unavailable or i&practical (eg$ snakebite)B ,o&plications fro& ad&inistration of human i&&unoglobulins are rareB The in#ections &ay be &oderately painful and rarely a sterile abscess &ay occur at the in#ection siteB Transient hypotension and pruritus occasionally occur !ith the ad&inistration of intravenous i&&une globulin (656?) products$ but generally are &ildB 6ndividuals !ith certain i&&unoglobulin deficiency states (6g deficiency$ etc) &ay occasionally develop hypersensitivity reactions to i&&une globulin that &ay li&it therapyB ,onventional i&&une globulin contains aggregates of 6g?4 it !ill cause severe reactions if given intravenouslyB Ho!ever$ if the passively ad&inistered antibodies are derived fro& animal sera$ hypersensitivity reactions ranging fro& anaphylaxis to seru& sickness &ay occurB Highly purified i&&unoglobulins$ especially fro& rodents or lago&orphs$ are the least likely to cause reactionsB To avoid anaphylactic reactions$ tests for hypersensitivity to the ani&al seru& &ust be perfor&edB 6f an alternative preparation is not available and ad&inistration of the specific antibody is dee&ed essential$ desensiti7ation can be carried outB ntibodies derived fro& hu&an seru& not only avoid the risk of hypersensitivity reactions but also have a &uch longer half%life in hu&ans (about /2 days for 6g? antibodies) than those fro& ani&al sources (* days or less)B ,onseAuently$ &uch s&aller doses of hu&an antibody can be ad&inistered to provide therapeutic concentrations for several !eeksB These advantages point to the desirability of using hu&an antibodies for passive protection !henever possibleB "aterials available for passive i&&uni7ation are su&&ari7ed in Table 2B

Table A?= $ater'als A,a'lable (or %ass',e Immu&'5at'o&. ;

I&d'cat'o&

%roduct

Dosage

Comme&ts

8lack !ido! spider bite

ntivenin #!atrodectus
For persons !ith hypertensive cardiovascular disease or age  '1 or  1D yearsB

8one &arro! transplantation

6&&une globulin (intravenous 65)/

DD &gLkg 65 on days * and / prior to transplantation and then once !eekly through day CD after transplantationB

.rophylaxis to decrease the risk of infection$ interstitial pneu&onia$ and acute graft% versus%host disease in adults undergoing bone &arro! transplantationB

8otulis&

8otulis& antitoxin$ eAuine

,onsult the ,0,B2

Treat&ent and prophylaxis of botulis&B vailable fro& the ,0,B2 Ten to /D percent incidence of seru& reactionsB

,hronic

6&&une globulin (65)/

3DD &gLkg 65 every 23

,99 patients !ith

I&d'cat'o&

%roduct

ly&phocytic leuke&ia (,99)

Dosage

Comme&ts

!eeksB 0osage should be hypoga&&aglobuline&ia ad#usted up!ard if bacterial and a history of at least one infections occurB serious bacterial infectionB

,yto&egalovirus (,"5)

,yto&egalovirus i&&une globulin (65)

,onsult the &anufacturer:s dosing reco&&endationsB

.rophylaxis of ,"5 infection in bone &arro!$ kidney$ liver$ lung$ pancreas$ heart transplant recipientsB

0iphtheria

0iphtheria antitoxin$ eAuine

/D$DDD'/D$DDD units 65 or Early treat&ent of 6" depending on the respiratory diphtheriaB severity and duration of vailable fro& the ,0,B2 illnessB naphylactic reactions in *G of adults and seru& reactions in 'DG of adultsB

Hepatitis 

6&&une globulin (intra&uscular 6")

%ree+posure proph/la+'s< DBD/ &9L kg 6" for anticipated risk of 2 &onths$ DBD1 &9Lkg for anticipated risk of  2 &onths$ repeated every 3 1 &onths for continued exposureB

.reexposure and postexposure hepatitis  prophylaxisB The availability of hepatitis  vaccine has greatly reduced the need for preexposure prophylaxisB

%oste+posure< DBD/ &9Lkg 6" as soon as possible after exposure up to / !eeksB Hepatitis 8

Hepatitis 8 i&&une globulin (H86?)

DBD1 &9Lkg 6" as soon as possible after exposure up to ' !eek for percutaneous exposure or / !eeks for sexual exposureB DB &9 6" !ithin '/ hours after birth for perinatal exposureB

.ostexposure prophylaxis in noni&&une persons follo!ing percutaneous$ &ucosal$ sexual$ or perinatal exposureB Hepatitis 8 vaccine should also be ad&inisteredB

H65%infected children


3DD &gLkg 65 every /> daysB

H65%infected children !ith recurrent serious bacterial infections or hypoga&&aglobuline&iaB

Ja!asaki disease


3DD &gLkg 65 daily for 3 consecutive days !ithin 3 days after the onset of illnessB  single dose of /

Effective in the prevention of coronary aneurys&sB For use in patients !ho &eet strict criteria for Ja!asaki

I&d'cat'o&

"easles

%roduct

6&&une globulin (6")

Dosage

Comme&ts

gLkg 65 over 'D hours is also effectiveB

diseaseB

Normal hosts< DB/ &9Lkg .ostexposure prophylaxis 6"B (!ithin 1 days after exposure) in noni&&une Immu&ocomprom'sed contacts of acute casesB hosts< DB &9Lkg 6" (&axi&u& ' &9 for all patients)B

6diopathic 6&&une globulin (65)/ thro&bocytopenic purpura (6T.)

,onsult the &anufacturer:s dosing reco&&endations for the specific product being usedB

Response in children !ith 6T. is greater than in adultsB ,orticosteroids are the treat&ent of choice in adults$ except for severe pregnancy%associated 6T.B

.ri&ary 6&&une globulin (65)/ i&&unodeficiency disorders

,onsult the &anufacturer:s dosing reco&&endations for the specific product being usedB

.ri&ary i&&unodeficiency disorders include specific antibody deficiencies (eg$ Q% linked aga&&aglobuline&ia) and co&bined deficiencies (eg$ severe co&bined i&&unodeficiencies)B

Rabies

Rabies i&&une globulin

/D 6@LkgB The full dose should be infiltrated around the !ound and any re&aining volu&e should be given 6" at an anato&ic site distant fro& vaccine ad&inistrationB

.ostexposure rabies prophylaxis in persons not previously i&&uni7ed !ith rabies vaccineB "ust be co&bined !ith rabies vaccineB

Respiratory syncytial virus (RS5)

.alivi7u&ab

' &gLkg 6" once prior to the beginning of the RS5 season and once &onthly until the end of the seasonB

For use in infants and children younger than /3 &onths !ith chronic lung disease or a history of pre&ature birth ( 2 !eeks: gestation)B

Rubella

6&&une globulin (6")

DB &9Lkg 6"B

Noni&&une pregnant !o&en exposed to rubella !ho !ill not consider therapeutic abortionB d&inistration does not prevent rubella in the fetus of an exposed &otherB

I&d'cat'o&

%roduct

Dosage

Comme&ts

Snake bite (coral snake)

ntivenin #+icrurus fulvius$, eAuine

t least 2 vials (2DD &9) 65 initially !ithin 3 hours after the biteB dditional doses &ay be reAuiredB

Neutrali7es veno& of eastern coral snake and Texas coral snakeB Seru& sickness occurs in al&ost all patients !ho receive  * vialsB

Snake bite (pit vipers)

ntivenin (,rotalidae) polyvalent$ eAuine

The entire dose should be given !ithin 3 hours after the bite by the 65 or 6" route (' vial U 'D &9); "ini&al enveno&ation; /3 vials "oderate enveno&ation; C vials Severe enveno&ation; 'D ' vials dditional doses &ay be reAuiredB

Neutrali7es the veno& of rattlesnakes$ copperheads$ cotton&ouths$ !ater &occasins$ and tropical and siatic crotalidsB Seru& sickness occurs in al&ost all patients !ho receive  * vialsB

ntivenin (,rotalidae) polyvalent i&&une Fab$ ovine

n initial dose of 31 vials should be infused intravenously over ' hourB The dose should be repeated if initial control is not achievedB fter initial control$ / vials should be given every 1 hours for up to 2 dosesB

For the &anage&ent of &ini&al to &oderate North &erican crotalid enveno&ationB

Tetanus i&&une globulin

%oste+posure proph/la+'s< /D units 6"B For severe !ounds or !hen there has been a delay in ad&inistration$ DD units is reco&&endedB

Treat&ent of tetanus and postexposure prophylaxis of nonclean$ non&inor !ounds in inadeAuately i&&uni7ed persons (less than t!o doses of tetanus toxoid or less than three doses if !ound is &ore than /3 hours old)B

Tetanus

Treatme&t< 2DDD1DDD units 6"B 5accinia

5accinia i&&une globulin

,onsult the ,0,B2

Treat&ent of severe reactions to vaccinia vaccination$ including ec7e&a vaccinatu&$ vaccinia necrosu&$ and ocular vacciniaB vailable fro& the ,0,B2

5aricella

5aricella%7oster i&&une globulin

:e'ght )g

%oste+posure proph/la+'s (preferably !ithin 3> hours

Dose u&'ts

I&d'cat'o&

%roduct

Dosage 'D

Comme&ts '/ 6"

'DB'/D

/D 6"

/DB'2D

2* 6"

2DB'3D

DD 6"

3D

but no later than !ithin C1 hours after exposure) in susceptible i&&unoco&pro&ised hosts$ selected pregnant !o&en$ and perinatally exposed ne!bornsB

1/ 6"

'

.assive i&&unotherapy or i&&unoprophylaxis should al!ays be ad&inistered as soon as possible after exposureB .rior to the ad&inistration of ani&al sera$ patients should be Auestioned and tested for hypersensitivityB /

See the follo!ing references for an analysis of additional uses of intravenously ad&inistered i&&une globulin; Ratko T et al; Reco&&endations for off%label use of intravenously ad&inistered i&&unoglobulin preparationsB V" 'CC4/*2;'>14 and Feasby T et al; ?uidelines on the use of intravenous i&&une globulin for neurologic conditionsB Transfus "ed Rev /DD*4/'(/ Suppl ')S*B 2

,enters for 0isease ,ontrol and .revention$ 3D3%12C%21*D during !eekday business hours4 **D%3>>% *'DD during nights$ !eekends$ and holidays (e&ergency reAuests only)B

EGA IA4IIT# 2"R UNT":ARD REACTI"NS 6t is the physician:s responsibility to infor& the patient of the risk of i&&uni7ation and to use vaccines and antisera in an appropriate &annerB This &ay reAuire skin testing to assess the risk of an unto!ard reactionB So&e of the risks previously described are$ ho!ever$ currently unavoidable4 on the balance$ the patient and society are clearly better off accepting the risks for routinely ad&inistered i&&unogens (eg$ influen7a and tetanus vaccines)B "anufacturers should be held legally accountable for failure to adhere to existing standards for production of biologicalsB Ho!ever$ in the present li tigious at&osphere of the @S$ the filing of large liability clai&s by the statistically inevitable victi&s of good public health practice has caused &any &anufacturers to abandon efforts to develop and produce lo!%profit but &edically valuable therapeutic agents such as vaccinesB Since the use and sale of these products are sub#ect to careful revie! and approval by govern&ent bodies such as the Surgeon ?eneral:s dvisory ,o&&ittee on 6&&uni7ation .ractices and the F0$ Ostrict product liabilityO (liability !ithout fault) &ay be an inappropriate legal standard to apply !hen rare reactions to biologicals$ produced and ad&inistered according to govern&ent guidelines$ are involvedB

REC"$$ENDED I$$UNI9ATI"N "2 ADUTS 2"R TRA!E Every adult$ !hether traveling or not$ should be i&&uni7ed !ith tetanus toxoid and should also be fully i&&uni7ed against polio&yelitis$ &easles (for those born after 'C1)$ and diphtheriaB 6n addition$ every traveler &ust fulfill the i&&uni7ation reAuire&ents of the health authorities of the countries to be visitedB These are listed in 5ealth Information for International Travel $ available fro& the Superintendent of 0ocu&ents$ @nited States ?overn&ent .rinting

Katzung Summary

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