Typ e
Classification
Subclass
Sp. Drugs
Hydrolyz ed by
Sp. Receptor / distinguishing feature
Ach (acetylcholine)
Yes
Muscarinic + Nicotinic
Bethenacol
No
- Muscarinic - synthetic drug
Carbachol
No
Muscarinic + Nicotinic
Muscarine
No
Muscarinic
Nicotine
No
Nicotinic
Pilocarpine
No
Muscarinic > Nicotinic - production of aqueous humor
Choline Esters
Direct acting CReceptor Agonists Plant Alkaloids
Mimic action of Ach
Donezepil
S T S I N O G A
r o t p e c e R ) C ( c i g r e n i l o h C
MOA
Endrophonium
Neostigmine
Indirect Acting … (exaggerate effects of parasympa NS by
Reversible … (short acting)
Binds to acetylcholinesteras e
Physostigmine
Inhibiting Cholinesterase Pyridostigmine
Irreversible … (long acting) increases Ach Release
Other Cholinergic Receptor Agonists
Tacrine Echothiophate Isoflurophate
Form covalent bonds w/ catalytic site cholinesterase
Malathione
Contra/ Side Effects
Clinical Use (Administration) Miosis during ophthalmic surgery (Intraocular) Coronary Angiography (Intracoronary) Post-op or post-partum urinary retention (Oral / SQ) Glaucoma (Topical Ocular) Miosis during ophthalmic surgery (Intraocular) Smoking cessation programs (Oral / transdermal) Glaucoma (Topical Ocular) Xerostomia – dryness of the mouth (Oral) Alzheimer’s Disease (Oral) Myasthenia gravis – diagnosis (IV) Myasthenia gravis, post-op urinary retention and post-op abdominal (Oral / IV / SQ) distention Antidote: Curariform drug toxicity (IV) Glaucoma (Topical Ocular) Reversal of CNS effects of anti-muscarinic (IM / IV) Myasthenia gravis (Oral / IM / IV) Antidote: Curariform drug toxicity (IV) Alzheimer’s disease (Oral) Glaucoma + accommodative esotropia Ocular) Pediculosis (Topical)
(Topical
Cisapride Metoclopramide
Sildenafil ( a.k.a. Viagra) Tadalafil Vardenafil
Atropine
Potentiates vasodilative vasodilative effect of Ach = penile blood flow = penile erection Extra careful in… (kse vasodilators un drugs!) HPN px, Reflex tachycardia, tachycardia, angina, Indications… look at handouts…
Inhibition of cGMP of cGMP metab by type5 Phosphodiestera se MI
=
cGMP
Erectile dysfunction
Headache Blurred vision Nasal congestion
Belladonna alkaloids
S T S I N O G A T N A
r o t p e c e R ) C ( c i g r e n i Typ l o e h C S
Muscarinic Receptor Antagonists
Nicotinic Receptor Antagonists
Neuromuscular Blocking agents
Semisynthetic + synthetic
Ganglionic blocking agents
Non depolarizing
Depolarizing
Classification
Subclass
T S I N O G A
Hyoscyamine Scopolamine Dicyclomine Ipratropium
- anti-spasmodic - checks secretions - combined w/ Salbutamol = anti-asthma
Flavoxate, Oxybutinin, Tropicamide Trimethapham
- sympathetic blockade (hypotension) - para … (dry mouth, blurred vision, urinary retenti on)
Blocks NN receptor @ both sympa + para ganglia
Sp. Drugs
Pharmacologic Effects (and Receptor)
Dobutamine
Cardiac stimulation Renal vasodilation Cardiac stimulation BP
(β 1) (D1) (β 1) (α 1)
Cardiac stimulation BP Bronchodilation
(β 1) (α 1) (β 2)
Epinephrine Catecholamines
d A
Indications: - hypertensive emergencies - neurosurgery (controlled hypotension = “bloodless”)
Atracurium Doxacurium Pancuronium Tubocurarine Vecuronium Succinylcholine
Dopamine
r o t p e c e R c i g r e n e r
Aka Buscopan - anti-spasmodic
Clinical Use (Administration) Shock and heart failure Shock and heart failure Anaphylactic shock , cardiac arrest, ventricular fibrillation, reduction in bleeding during surgery, and prolongation of the action of local anesthetics
Cardiac Stimulation
(β 1)
AV block Bradycardia
DIRECT ACTING… Norepinephrine Albuterol Apraclonide
BP
(α 1)
Oxymetazoline
Bronchodilation aqueous humor formation sympathetic outflow from CNS imidazoline) Vasoconstriction
Phenylephrine
Vasoconstriction,
Clonidine
(β 2) (α 2) (α 2 + (α 1)
Noncatecholamines
Ritodrine Terbutaline Amphetamine
BP, mydriasis
Bronchodilation + uterine relaxation in norepinephrine release
(α 1)
(β 2)
Hypotension + shock Asthma Chronic open-angle glaucoma Chronic hypertension Nasal + ocular decongestion Nasal decongestion Ocular decongestion Mydriasis Maintenance of BP during surgery Tx of neurogenic shock Asthma + premature labor CNS effects
Overall effect
Dobutamine, Dopamine, Epi… - contraindication in HPN Px
DOC for anaphylactic shock!
adrenergic PotencyRec E/Ne > isoproterenol Isoproterenol
INDIRECT ACTING…
Notes
adrenergic PotencyRec Isoproterenol > E /NE
Bronchodilati on BP
Cocaine Ephedrine Phenylpropanolami ne Pseudoephedrine
MIXED ACTING…
S T S I N O G A T N A
r o t p e c e R c i g r e n e r d A
Selective blockers
1
-Adrenergic… Non – Selective blockers Selective blockers
1
-Adrenergic… Non – Selective blockers
+
Adrenergic…
ANTI-PROTOZOAL GROUPS SUBGROUPS ANTICH LO RO QUI NE (CH L) MALARIALS
QUININE
MEFLOQUINE
PRIMAQUINE
(X) inhibition of norepinephrine uptake Vasoconstriction
Doxazosin Prazosin Terazosin
- for HPN Pxs
Phenoxybenzamin e Phentolamine Acebutolol Atenolol Esmolol Metoprolol
- cheapest anti-HPN (eg. Neobloc)
Nadolol Pindolol Timolol Propranolol
Local anesthesia Nasal decongestion
(α 1)
Applies to ALL: for BPHP (Benign Prostatic Hyperplasia)
Anorexic drugs (large qty: 50-100mg)?
Contra: HPN Px
Good to use bcoz effects can be limited
- for hyperthyroidism (eg. tremors, tachycardia, irregular rates)
Carvediol Labetalol
MOA/PK/PD/RESISTANCE *4 -a mi noq ui no li ne der iva ti ve PK: rapidly absorbed when given orally Widely distributed to tissues (ENTER THE BBB, CROSSES PLACENTA) (+) large Vd (volume of distribution) HL: 7 days
CLINICAL USE (CU) /ALTERNATE USE (AU) *DOC: acute attacks of non-falciparum & sensitive falciparum malaria (ALL 4 TYPES MALARIA, as long as no resistance) * as chemosuppresant / PROPHYLAXIS (except falciparum resistant areas) * (+) BLOOD SCHIZONTICIDE
MOA: (1) DNA intercalation (2) prevents polymerization of the Hgb breakdown product heme into hemozoin (intracellular heme accumulation is toxic to the parasite) (3) CHL is a weak base: buffer intracellular pH (inhibits cellular invasion by parasites)
AU: Amebic liver dse (with Metronidazole-resistance) Autoimmune DO (ie RA) Extra-intestinal Amebiasis: due to E. histolytica (w/ D. Furoate) * (+) TISSUE AMEBICIDE
R: ability of the resistant parasite to expel drug via membrane P-glycoprotein pump *principal alkaloid derived from the bark of the Cinchona tree PK: rapidly absorbed orally Long HL: given weekly Metabolized before renal excretion Severe infections: possible IV administration (using Quinidine – dextrorotatory stereoisomer of Quinine) MOA: complexes with dsDNA to prevent strand separation, resulting in blocking of DNA replication and transcription to RNA (same as Chloroquine) *synthetic 4-quinoline derivative chemically related to Quinine PK: given orally (due to local irritation) with variable absorption MOA: unknown *synthetic-8-aminoquinoline
* (+) BLOOD SCHIZONTICIDE * (+) GAMETOCIDE (P. vivax / P. Ovale) * DOC for Chloroquine-resistant / multidrug resistant: P.falciparum - used in combination with FANSIDAR * sometimes used with Doxycycline: to shorten duration of therapy and ↓ dec/limit toxicity * NOT USED AS ROUTINE FOR PROPHYLAXIS AU: nocturnal leg cramps Babesiosis (w/ Clindamycin)
*for PROPHYLAXIS in all malarious areas with chloroquine resistance
* (+) TISSUE SCHIZONTICIDE (Vivax, Ovale,
AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) T: low doses: GI irritation, skin rash, HA High doses: severe skin lesions, peripheral neuropathies, myocardial depression, hypotension, retinal damage, auditory impairment, toxic psychosis *may precipitate porphyria attacks * CROSSES PLACENTA! CONTRAINDICATION: Pregnancy Porphyria G6PD def Psoriasis
T: (+) CINCHONISM GI distress, HA, vertigo, blurred vision, tinnitus Severe overdose: disturbances in cardiac conduction (+)BLACKWATER FEVER (intravascular hemolysis): rare sometimes fatal in quinine-sensitized persons * CATEGORY X
CONTRAINDICATION: G6PD def (hematotoxic / hemolytic) Pregnancy T: less toxic than quinine AE: GI distress, skin rash, HA, dizziness CONTRAINDICATION: Pregnancy Epilepsy *usually well tolerated
DRUG INTERACTIONS
NOTES
followed by extensive metabolism MOA: forms QUINOLINE-QUINONE metabolites – acts as cellular oxidants
ANTI-FOLATE DRUGS *Pyrimethamine *Sulfadoxine *Dapsone *Proguanil (short HL – 12-16hrs; bioactivated to Cycloguanil)
Pyrimethami ne
Sulfonamide s (Sulfodoxine )
MOA: (together w/Cycloguanil): selective inhibitors of protozoan dihydrofolate reductase ***(+) synergistic antimalarial effects with Sulfodoxine – (+) sequential blockade of 2 steps in FA synthesis MOA: act as anti-metabollite of PABA and block folic acid synthesis (in certain protozoans) by i nhibiting dihydropteroate synthase
* (+) GAMETOCIDE (ALL 4 species) * CU: to eradicate liver stages of P.vivax/ovale and should be used in conjunction with blood schizonticide *(+) after initial tx with Chloroquine, 14d tx with Primaquine follows as a standard Pyrithemine + Sulfodoxine: FANSIDAR Tx of chloroquine-resistant forms of this species Onset of action is slow
CONTRAINDICATION: G6PD def (hematotoxic / hemolytic) Pxs predisposed to granulocytopenia (ie: SLE, RA) T: folic acid deficiency (high doses)
*many strains are now resistant to antifolates (not the 1st line of tx) *not used as prophylaxis AU: Pyrimethamine + Sulfadiazine Acts by sequential blockade of 2 steps in FA synthesis Against Toxoplasma gondii Prophylaxis of choice: Toxoplasmosis Alternative drug to TMP-SMZ or Pentamidine as prophylaxis: Pneumocystis Pneumonia (AIDS) Active toxoplasmosis: daily for 3-4wks with folinic acid Toxoplasma encephalitis (AIDS): high dose tx daily for at least 6 weeks
T: GI distress, skin rashes, hemolysis, kidney damage
(+) competitive interaction with plasma protein binding sites
T: Pyrimethamine + Sulfadiazine * GI irritation, glossitis, neurologic s/s (HA, insomnia, tremors, seizures) * hematotoxicity (megaloblastic anemia, thrombocytopenia) T: Pyrimethamine + Clindamycin *antibiotic-associated colitis
AU: Pyrimethamine + Clindamycin Used if allergic to sulfates * (+) TISSUE AMEBICIDES DOC: severe intestinal wall dse and hepatic abscess and other extraintestinal amebic dse (luminal / extraluminal)
DRUGS FOR AMEBIASIS
METRONIDAZOLE
EMETINES
IODOQUINOL
D IL OX AN ID E F UR OA TE
DRUGS FOR PNEUMOCYSTO SIS (PCP) and TOXOPLASMOS IS
PK: effective orally Widely distributed to tissues Elimination: hepatic metabolism MOA: acts as an electron-acceptor to deprive cells of required reducing equivalents Antimicrobial activity: from the formation of chemically reactive species which interact with DNA and proteins MOA: i nhibit protein synthesis by blocking ribosomal movement along mRNA PK: alkaloids given parenterally *halogenated hydroxyquinoline PK: orally active luminal amebicide (acts on Trophozoites) * co nv er te d i n t he gu t t o t he di l ox an id e f re eb as e form (active amebicide)
P AR OMO MY CIN
*a mi nog ly co si de a nti bio ti c
PENTAMIDINE
MOA: (~) inhibition of glycolysi s; (+) selective toxicity to parasites interference with nucleic acid metabolism of protozoans and fungi PK: DO NOT cross BBB
TRIMETHOPRIMSULFAMETHOXAZOLE (TMP-SMZ)
PD: aerosol pentamidine (once monthly) Daily IV or IM injection (usually for 21 days) PD: oral (double strength formulation TID) or IV
AU: tx of the following
AE: GI irritation, HA, dark coloration of urine T: leucopenia, dizziness, ataxia CONTRAINDICATION: Pregnancy (may be teratogenic)
Trichomoniasis, Giardiasis, Gardnerella vaginalis infection, anaerobic bacteria (Bacteroides fragilis, Clostridium difficile) * (+) TISSUE AMEBICIDES * used as back-up drugs for severe intestinal or hepatic amebiasis in hospitalized patients
* (+) LUMINAL AMEBICIDES AU: alternative drug for mild-severe intestinal infections * (+) LUMINAL AMEBICIDES * DOC: asymptomatic amebiasis (cyst-passers) * (+) LU MI NAL A MEBI CI DES (2nd line w/ D. Furoate) *AU: some effects on Cryptosporidiosis (AIDS) *sometimes used with Tetracycline (Doxycycline) in mild intestinal dse *As prophylaxis (aerosol) although TMP-SMX is preferred *Active Pneumocystosis (HIV pxs): IV/IM given for 21days
T (severe): GI distress, muscle weakness, cardiovascular dysfunction (arrhythmia, CHF)
AE: common but usually mild (GI) T (systemic absorption after high doses): Thyroid enlargement, neurotoxic (peripheral neuropathy, visual dysfunction) T: mild, usually restricted to GI s/s
CONTRAINDICATION: Lactating mothers Infants < 2months age *common adverse GI effects T (systemic absorption): HA, dizziness, rashes, arthralgia
AU: as treatment for Trypanosomiasis @ hemolymphatic stages (T.gambiense, T.rhodesiense) Not used in later stages – do not cross BBB Also used as treatment for kala-azar (visceral leishmaniasis)
*PROPHYLAXIS (FIRST CHOICE) for PCP – AIDS px (CD4 < 200cells/ul) * choice of treatment for PCP (Pnemocystosis Pneumonia)
AE: occurs in 50% of AIDS pxs GI distress, rash, fever, neutropenia, thrombocytopenia
AU: prophylaxis against Toxoplasmosis & Isospora belli infections ANTIFOLATES: (see above) PYRIMETHAMINE & SULFONAMIDES ATROVAQUONE
MOA: inhibits mitochondrial el ectr on transport & probably folate metabolism
*for mild-moderate PCP *less effective than TMP-SMZ or pentamidine but better
AE: rash, cough, N/V, diarrhea, fever, abnormal liver function test
Ethanol: disulfiram-like rxns (↑ acetaldehyde accumulation) Coumarin: potentiation of anticoag effects
PK: used orally Poorly absorbed and should be given with food to maximize bioavailability eliminated in feces Unchanged T ri me th ro pr im + da ps on e Primaquine + clindamycin Trimetrexate + leucovorin
M IS CE LL AN EO US AG EN TS
DRUGS FOR TRYPANOSOMI ASIS
PENTAMIDINE (see above) MELARSOPROL
PK: enters the CNS (passes BBB) *nitrofurazone derivative MOA: inhibits trypanothione reductase (unique to parasite) *polyanionic cmpd MOA: unclear but may involve inhibition of enzymes required for energy metabolism
NIFURTIMOX
SURAMIN
LEISHMANIASIS
*organic arsenical MOA: inhibits enzyme sulfhydryl groups Given parenterally (due to GI irritation)
*DOC: for African sleeping sickness – late stage (enters CNS)
T: may cause reactive encephalopathy (fatal)
*DOC: for American trypanosomiasis
T (severe): allergies, GI irritation, CNS effects
AU: for mucocutaneous Leishmaniasis *DOC: early hemolymphangitic stages of African trypanosomiasis (BEFORE CNS INVOLVEMENT)
T: rashes, GI distress, neurologic complications
PK: given parenterally AU: alternative to Ivermectin (Onchocerciasis: with Diethylcarbamazine) Sodium stibogluconate (PENTAVALENT ANTIMONY): primary drug for all forms of disease MOA: kill parasites by inhibition of glycolysis or effects on nucleic acid metabolism
DOC:
Cutaneous Mucocutaneous Visceral
Alternative drugs: Pentamidine (Visceral leismaniasis) Metronidazole (Cutaneous leishmaniasis) Amphotericin B (Mucocutaneous leishmaniasis)
ANTI-HELMINTHS GROUP DRUGS AGAINST ALBENDAZOLE NEMATODES
DIETHYLCARBAMAZIN E
MOA/PK/PD/RESISTANCE MOA: blocks glucose uptake in both larval / adult parasites ↓ dec ATP formed subsequent parasite immobilization Inhibition of microtubule assembly MOA: immobilizes microfilariae (increases susceptibility to host defense) ↑inc susceptibility of microfilaria to phagocytosis PK: rapidly absorbed in gut, excreted in urine
IVERMECTIN
MOA: ↑ intensifies GABA mediated neurotransmission (immobilization of parasites) removal by reticuloendothelial system Selective toxicity: do not pass BBB
MEBENDAZOLE
MOA:
*Inhibition of microtubule assembly
CLINICAL USE (CU) /ALTERNATE USE (AU) *wide antihelminthic spectrum AU: alternative drug for larva migrans, ascariasis Infections: roundworm, whipworm, hookworm, pinworm, threadworm Also active in PORK TAPEWORM (larval stage) DOC: Filariasis AU: (**in combination with Suramin) – Onchocerciasis Loa loa Ascariasis Topical pulmonary eosinophilia
DOC: Onchoce rciasis (River blindness) (acts slowly than Diethylcarbamazine but fewer systemic/ocular rxns) DOC: Strongloidiasis (threadworm) AU: Filariasis DOC: Pinworm (Enterobiasis) / Whipworm
AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS *few toxic effects in short courses T (prolonged use): REVERSIBLE leucopenia, alopecia, changes in liver enzymes Long-term animal toxicity: bone marrow suppression, Fetal toxicity AE: HA, malaise, weakness, anorexia Rxns due to proteins of dying filariae: -fever, rashes, ocular damage, joint/muscle pain,lymphangitis Onchocerciasis: MAZZOTTI REACTION - skin reaction that occurs in humans when the microfilariae of Onchocerca volvulus in cutaneous sites are killed by the administration of diethylcarbamazine - hypotension, pyrexia, respiratory distress, prostration, intense itching, skin rashes, enlarged and tender LNs *Single dose oral tx: may cause MAZZOTTI *Antihistamines RXN *NSAIDS (usually short duration: controlled by -both to ↓ Mazzotti Antihistamines rxns Or NSAIDS) AE: limited to GI irritation
NOTES Recall: Enterobius vermicularis (pinworm) Trichuris trichiura (whipworm) Ascaris lumbricoides (roundworm) Anclostoma / Necator sp (hoowkorms) Strongyloides stercoralis (threadworm) Tissue nematodes: Ancylostoma sp (cutaneous larva migrans) Wuchereria bancrofti (filariasis)
PK: < 10% of drug absorbed systematically after oral use Metabolized rapidly
DOC: (with Pyrantel Pamoate): Roundworm And combined infections: Ascarids + Hookworms
*CONTRAINDICATED: (embryotoxic)
PREGNANCY
AU: as back-up drug for Cestodes / Trematode infections P IP ER AZ IN E
PYRANTEL PAMOATE
THIABENDAZOLE
AGAINST TREMATODES
PRAZIQUANTEL
M OA : G A BA r ec ep to r ag on is t (p ar al yz es pa ra si te s) Paralyzed roundworms are expelled alive via Normal peristalsis (YAK!!!) *congener: Oxantel Pamoate MOA: inhibits Cholinesterases & stimulates Nicotinic receptors present at NMJ of nematodes (initial contraction of muscles depolarization-induced paralysis) PK: poorly absorbed when given orally *structural congener of Mebendazole MOA: Inhibition of microtubule assembly PK: rapidly absorbed in the gut Metabolized by hepatic enzymes (+) Immunorestorative / Anti-inflammatory actions in the host MOA: ↑inc permeability to Ca++ initial marked contractions paralysis Followed by vacuolization parasite death Active against immature / adult schistosomal forms PK:
BITHIONOL
rapid gut absorption Metabolized by the liver (to inactive cmpds)
ME TRIF ON AT E
O XA MN IQ UI NE
DOC: (with Mebendazole): Hookworm, Pinworm, Roundworm
DOC: Vi sceral larva migrans AU: for treatment of: Strongyloidiasis (Threadworm), Cutaneous larva migrans: DOC
*wide spectrum: Trematodes + Cestodes DOC: Schistosomiasis (all species) Clonorchiasis / Paragonimiasis AU: DOC (with Niclosamide): Cestodes (all common tapeworms) Cysticercosis DOC: Fascioliasis (sheep liver fluke)
MOA: unknown PK: orally effective;
AU: Ascariasis
eliminated in urine
*or ga no pho sph at e P RO dr ug MOA: converted to DICHLORVOS (Cholinesterase inhibitor) Acts solely to Schistosoma haematobium (BILHARZIASIS) M OA : a c t s s ol el y to I mm at ur e / Ad ul t sc hi st os om al f or ms
AU: Paragonimiasis
SE: mild GI irritation CONTRAINDICA TED: SEIZURE PATIENTS AE (minor): GI distress, HA, weakness
T: GI irritation, HA, dizziness, drowsiness, leucopenia, hematuria, allergic rxns (INTRAHEPATIC CHOLESTASIS), Steven Johnson’s syndrome Rxns due to proteins of dying filariae: -fever, chills, rashes, lymphadenopathy Common AE: HA, dizziness, malaise Less frequently: GI irritation, skin rash, fever CONTRAINDICATED: CYSTICERCOSIS
OCULAR
Recall: Schistosoma sp (blood flukes) Clonorchis sinensis (liver flukes) Paragonimus westermani (lung fluke)
Pregnancy
Common AE: N/V, diarrhea, Abd cramps, dizziness, HA, phototoxicity Less frequently: pyrexia, tinnitus, proteinuria, leukopenia T: excess Cholinergic stimulation
DOC: Schist osoma haematobium (BILHARZIASIS)
DOC: Schisto soma mansoni
AE: DIZZINESS,
HA, GI irritation, pruritus
Rxns due to proteins of dying filariae: -eosinophilia, urticaria, pulmonary infiltrates CONTRAINDICATED: PREGNANCY, SEIZURES AGAINST CESTODES
PRAZIQUANTEL (see above) N IC LO SA MI DE
M OA : u n co up li ng o xi da ti ve p ho sp or yl at io n. Activating ATPases Scoleces and cestode segments are killed BUT NOT OVA
DOC (with Praziquantel): beef, pork, fish tapeworms *not effective in Cysticercosis (Mebendazole / Praziquantel used) * not effective in hydatid dse (Albendazole used)
Mild AE: GI distress, HA, rash, fever
AU: small / large intestinal flukes
ANTI-VIRALS GROUP ANTIHERPETIC DRUGS
DRUGS ACYCLOVIR (ACYCLOGUANOSI NE)
MOA/PK/PD/RESISTANCE MOA: activated to form Acyclovir triphosphate: competitive substrate for DNA polymerase leading to chain termination incorporation into viral DNA R (TK -- strains): involve changes in viral DNA polymerase: lack thymidine kinase
CLINICAL USE (CU) /ALTERNATE USE (AU) *DOC: for HSV / VZV * Mucocutaneous and Genital Herpes *for Prophylaxis in AIDS / Immunocompromised pxs
AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) AE: generally well tolerated but may cause GI distress, HA T (parenteral): delirium, tremor, seizures, hypotension NEPHROTOXIC! *** NO noted toxicity on bone marrow
Recall: Taenia saginata (beef tapeworm) Taenia solium (pork tapework, can cause cysticerci in brains / eyes) Diphyllobothrium latum (fish tapeworm) Echinococcus granulosus (dog tapeworm, causes hydatid cysts in liver, lungs, brain)
DRUG INTERACTIONS NOTES Notes: ACYCLOVI R CONGENERS Famciclovir: prodrug that is converted to Penciclovir (by FIRST PASS) Orally (for genital herpes / herpes zoster) Penciclovir: also undergoes viral thymidine kinase activation triphosphate form also inhibits DNA polymerase but DO NOT
termination PK: given topical, oral, IV (for severe & neonatal HSV infection) Excretion: RENAL
F OS CA RN ET
G AN CI CL OV IR
Valacyclovir: converted to Acyclovir by hepatic metabolism; Reaches plasma level 3-5x faster than Acyclovir + longer duration of action
* ph os ph on of or ma te d er iv at iv e MOA: inhibits viral RNA polymerase, DNA polymerase, & HIV reverse transcriptase
*DOC: for CMV Prophylaxis (including CMV retinitis) – 2nd to Ganciclovir (+) good activity with Ganciclovir-resistant strains
R: point mutation in the DNA polymerase gene
AU: Acyclovir-resistant strains of herpes that are thymine kinase-def -via inhibiting DNA polymerase
PK: given IV; good penetrance to tissues (CROSSES BBB) Up to 1/3 of dose deposited into bone Elimination: Renal – in proportion to Creatinine clearance * gu an in e d er iv at iv e MOA: triphosphorylated to form a nucleotide that inhibits DNA polymerases of CMV & HSV (do not cause chain termination)
*DOC: for CMV Prophylaxis (including CMV retinitis)
T: NEPHROTOXIC (30%) Electrolyte-imbalance (++hypocalcemia) Genitourinary ulceration CNS toxicity: HA, hallucination, seizures
T: Leukopenia, thrombocytopenia, mucositis, Hepatic dysfunction, seizures
If used with Zidovudine: -may cause severe NEUTROPENIA Other Myelosuppressant agents: -may cause severe NEUTROPENIA
R: changes in DNA polymerase & mutations in the gene that codes for activating viral phosphotransferase Thymidine kinase deficient HSV: also resistant to Ganciclovir
CIDOFOVIR
V ID ARA BIN E
S OR IV UD IN E
IDOXURIDINE TRIFLURIDINE F OM IV IR SE N
ANTI-HIV (NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS NRTIs)
ZIDOVUDINE (ZDV)
PK: given IV; good penetrance to tissues (CROSSES BBB and EYES) Oral Bioavailability is <10% (Oral prep used for maintenance) Elimination: Renal – in proportion to Creatinine clearance MOA / PK: activated exclusively by host cell kinases and inhibits DNA polymerases of HSV, CMV, Adenovirus, Papillomavirus given topical, IV, or IntraVitreal injections Elimination: Renal – in proportion to Creatinine clearance R: mutations in the DNA polymerase gene *A de ni ne ana lo g PK: (+) rapid metabolic inactivation with marked toxic potential
* Py ri mi di ne a na lo g * still an investigational drug: 1000x more potent that Acyclovir (but still not effective for Acyclovir resistant HSV) *Pyrimidine analogs * an ti -s en se o li go nu cl eo ti de MOA: binds to mRNA of CMV inhibiting early protein synthesis *formerly called: Azidothymidine (AZT) MOA: nucleoside phosphorylated by host kinases to form a nucleotide that both inhibits reverse transcriptase of HIV-1 and HIV-2 DNA chain termination
*for CMV retinitis
NEPHROTOXIC!!!
AU: mucocutaneous HSV infections (including Acyclovir-resitant) Genital warts
(+) activity against: HSV, VZV, CMV Given IV: severe HSV infections (including Acyclovirresistant) Also to prevent dissemination of VZV in immunocompromised pxs
T: GI irritation, paresthesias, tremor, convulsions & hepatic dysfunctions *** TERATOGENIC (in animal studies)
Topical: HSV Keratitis (NO EFFECT in Gental Herpes) (+) activity against: HSV-1, VZV, EBV
Topical: HSV Keratitis
TOO TOXIC FOR SYSTEMIC USE!!!
Given IntraVitreally: CMV retinitis
*commonly used: HAART regimen DOC: Prophylaxis for HIV infection (ie. Accidental needlesticks) Prophylaxis against Vertical HIV infection (mother fetus)
T: Bone marrow suppression (anemia, neutropenia) GI distress, thrombocytopenia, HA, myalgia, acute cholestatic hepatitis, agitation, insomnia
Drugs that undergo glucoronidation (Paracetamol, Benzodiazepines, Cimetidine, Sulfonamides) -↑inc plasma levels of ZDV
R: seen in advanced HIV pxs: several site mutations on the pol gene
DIDANOSINE (ddI)
PK: orally active (60% BA): well distributed to tissues (CROSSES BBB) Elimination: Hepatic metabolism to glucoronides + Renal excretion HL: 1-3 hrs *Deoxyadenosine analog MOA: activated by host kinases triphosphate form inhibits reverse transcriptase + causes chain termination
Myelosuppressants: -additive BM suppression
Azole antifungals and Protease inhibitors: -inhibits metabolism of ZDV Rifampicin: ↑inc clearance of ZDV
*commonly used: HAART regimen
T: PANCREATITIS (dose-limiting) -seen with Alcohol intake -also seen in Hypertriglyceridemia
Chelating agents and Food intake: ↓ decreases BA of ddI With Alcohol: (+) Pancreatitis
AE: Peripheral neuropathy, diarrhea, hepatic
Complete cross-resistance with Zalcitabine (ddC) Partial resistance to Zidovudine (ZDV)
Hyperuricemia, CNS effects
PK:
↓ BA: if with food or Chelating agents Elimination: by Glomerular filtration + Active Tubular secretion ZALCITABINE (ddC)
LAMIVUDINE (3TC)
*pyrimidine nucleoside MOA/R: similar to other NRTIs PK: high oral BA MOA: similar to other NRTIs PK: used orally (part of HAART regimen)
STAVUDINE (d4T)
ABACAVIR
ANTI-HIV (NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS – NNRTIs) ANTI-HIV (PROTEASE INHIBITORS)
MISCELLANEOUS ANTIVRALS
TOPICAL ANTIVIRAL DRUGS
NEVIRAPINE DELAVIRDINE EFAVIRENZ
INDINAVIR RITONAVIR Other Protease inhibitors: SAQUINAVIR NELFINAVIR AMPRENAVIR AMANTADINE RIMANTADINE OSELTAMIVIR ZANAMIVIR INTERFERONS RIBAVIRIN IDOXURIDINE CYTARABINE TRIFLUOROTHYMI DINE
*thymidine analog PK: good oral BA, penetrates most tissues (CROSSES BBB) R: may be due to Stavudine alone or could have Crossresistance *guanosine analog PK: good oral BA Metabolism: via Alcohol dehydrogenase and Glucuronosyltransferase
* co mm on ly us ed in co mb in ed re gi me ns
*active against HIV-1 (including ZDV-resistant strains) AU: Hepa B, HBV (12wks tx in adjuct w/ Interferon alpha) *used in HAART regimen
* us ed in c om bi na ti on w / Z DV + 3 TC
T : P er ip he ra l N eu ro pa th y ( Do se -d ep en de nt ) Nephrotoxic!!! Pancreatitis, esophageal ulceration, stomatitis, arthralgias AE: usually mild: GI distress, HA, insomnia, fatigue
T: Peripheral Neuropathy (Dose-dependent) Nephrotoxic!!!
T : S ev er e H yp er se ns it iv it y r ea ct io ns in vo lv in g mu lt ip le organ systems (lethal!)
ANTI NEOPLASMS GROUPS SUBGROUPS ALKYLATING AGENTS (CCNS DRUGS)
NITROGEN MUSTARDS: CHLORAMBUCIL
-react with DNA - targets: N-7 and O-6 positions of guanine -results with *DNA crosslinking *base-pair mismatching *DNA breakage
DRUGS
MOA/PK/PD/RESISTANCE
CYCLOPHOSPHA MIDE
PK: hepatic cyt p450 biotransformation 1 of breakdown product: ACROLEIN
MELPHALAN
*Phenylalanine derivative of nitrogen mustard that cross links strands of DNA and RNA MOA/PK: spontaneously converted to a reactive cytotoxic product in the body
MECHLORETHAMI NE
N IT RO SO UR EA S
OTHERS: AKYLSULFONATES
C AR MU ST IN E (BCNU) LOMUSTINE (CCNU) STREPTOZOCIN
CISPLATIN / CARBOPLATIN
PK: highly lipophilic Facilitates CNS entry
*naturally occurring antibiotic derived from Streptomycesacromogenes *Diabetogenic agent: High affinity / toxicity to Pancreatic Beta cells PK: crosses BBB CCNS Cisplatin: used IV Distributed to most tissues Cleared in kidneys Unchanged
CLINICAL USE (CU) /ALTERNATE USE (AU) *Non-Hodgkin Lymphoma * Breast / Ovarian Ca * Neuroblastoma
*Ovarian Ca,
Multiple Myeloma
*Hodgkin Lymphoma: MOPP regimen (Mechlorethamine, Oncovin (Vincristine), Procarbazine, Prednisone) -MAINSTAY of drug tx for st III-IV -replaced for initial therapy by ABVD regimen *used as ADJUNCTS for tx of BRAIN TUMORS
*Pancreatic Carcinoma * Insulinomas
*Testicular Ca / Bladder Ca / Lung Ca * Ovarian Ca * regimen VBC: Vinblastine, Bleomycin, Cisplatin
*Platinum coordination complex MOA: enters cells by diffusion & is hydrolyzed to form an activated electrophile which alkylates DNA CCNS PROCARBAZINE
DACARBAZINE
MOA: reactive agent that forms Hydrogen Peroxide generates free radicals DNA strand scission PK: orally active Penetrates to most tissues (ie: CSF) Eliminated: via Hepatic metabolism MOA: thought to inhibit DNA / RNA synthesis via formation of Carbonium ions PK:
B US UL FA N
METHOTREXATE
hepatically activated Given IV * al ky l- su lf on at e ty pe b if un ct io na l al ky la ti ng agent
MOA: substrate for + inhibitor of dihydrofolate reductase ↓ synthesis of thymidilate, purine nucleotides and AA interfering with NA and protein metabolism
*Hodgkin Lymphoma: MOPP regimen (see above)
AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD)
DRUG INTERACTIONS
*Alkylating agents are CCNS drugs MOA: form reactive molecular species that alkylate nucleophillic groups on DNA bases (N-7 position of guanine)
*may also cause: cardiac dysfunction, pulmonary toxicity, SIADH AE: Bone marrow suppression (leucopenia, thrombocytopenia) AE: GI distress, myelosupression & alopecia *** marked vesicant action
R: ↑ inc DNA repair ↓dec drug permeability (+) production of trapping agents (ie thiol)
AE: GI distress, myelosupression & CNS dysfxn
AE: N/V, Bone marrow suppression, leucopenia, thrombocytopenia T: Renal failure (Nephrotoxic?!?)
Cisplatin: GI distress, mild hematotoxicity Neurotoxic (peripheral neuritis, Acoustic nerve damage- OTOTOXIC) Nephrotoxic (↓ reduced by Mannitol + Forced hydration) Carboplatin: less nephrotoxic Less likely to cause tinnitus + hearing loss ↑ greater myelosuppression (+) myelosuppressant (+) LEUKEMOGENIC AE: GI Irritation, CNS dysfxn, peripheral neuropathy, skin rxns
*inhibit many enzymes: MAO * Enzymes involved in Hepatic metabolism Ethanol: disulfiram-like reactions
*sometimes used in CML * ABVD regimen (for Hodgkins Lymphoma): Adriamycin, Bleomycin, Vinblastine, Dacarbazine * Malignant Melanoma DOC: CML
*Choriocarcinoma * Breast Ca * Acute Leukemias * Hodgkins lymphoma * cutaneous T-cell lymphomas AU: used also in Rheumatic
NOTES
AE: GI distress, myelosupression & alopecia *** Hemorrhagic Cystitis: due to ACROLEIN May be ↓ dec by vigorous hydration + use of MESNA (mercapt oethanesulfonate)
T: adrenal insufficiency, pulmonary fibrosis, skin pigmentation
AE: GI distress, myelosupression & alopecia Skin rash, phototoxicity, flu-like syndrome T (high doses): Pulmonary fibrosis, seizures, hepatic venoocclusive disease (+) ABORTIFACIENT T: bone marrow, suppression, skin and GI mucosa (mucositis) Toxicity in normal cells may be reduced with administration of folinic acid (Leucovorin): ***LEUCOVORIN RESCUE
Salicylates, NSAIDS, Sulfonamides, Sulfonylureas: - ↑↑↑ increase Methotrexate toxicity
important for cytotoxic actions
infiltrates/fibrosis
PK: IV / Oral admin: good tissue distribution (except CNS) Not metabolized Clearance: dependent on RENAL functions (adequate hydration needed to prevent crystallization)
ANTIMETABO LITES (CCS DRUGS) -inhibit steps in DNA biosynthesis (specific Sphase)
ANTAGONISTS OF FOLIC ACID
MERCAPTOPURIN E (6-MP)
R: ↓ drug accumulation Changes in drug sensitivity or activity of dihydrofolate reductase ↓ formation of polyglutamate MOA: activated by HGPRT-ase to toxic nucleotides (6-thioinosinic acid) that inhibit several enzyme involved in purine metab.
*acute leukemias: AML, ALL * CML
AE: bone marrow suppression (dose-limiting) Hepatic dysfunction (cholestasis, jaundice, necrosis)
oxidase
R: ↓ dec activity of HGPRT-ase ↑ inc production of alkaline phosphatases (inactivates the toxic nucleotides) PK: low oral bioavailability due to FIRST PASS metabolism by hepatic enzymes PURINES
THIOGUANINE (6TG) CYTARABINE (ARA-C)
*cytosine arabinoside * most specific to S-phase
Allopurinol: ↓dec metabolism of 6-MP by xanthine
*Acute leukemias * DOC: AML
*structurally similar to endogenous compounds * CCS drugs: primarily acting on Sphase * (+) IMMUNOSUPPRESSANT ACTIONS
AE: GI irritation, myelosupression, stomatitis T: Neurotoxic (high doses: Cerebellar dysfxn, peripheral neuritis)
MOA: activated by kinases AraCTP (inhibitor of DNA polymerases: inhibiting DNA chain elongatio n) R: ↓ dec uptake ↓ dec conversion to AraCTP
P YRI MI DIN ES
F LUOR OURA CI L ( 5FU)
PK: parenterally via Slow IV infusion May reach appreciable levels to CSF Eliminated: via Hepatic Metabolism MOA: biotransformed to 5-FdUMP: inhibits thymydilate synthase “thymineless death” of cells
*Breast / Ovarian Ca * Head and Neck Ca * Liver / Bladder Ca
AE: GI distress, myelosupression & alopecia
*CML * Melanoma, Polycythemia vera, Sickle cell anemia
AE: bone marrow suppression, leucopenia, megaloblastic anemia, thrombocytopenia N/V, diarrhea
*Vincristine: MOPP regimen (see above) * also COP (Cyclophosphamide, Oncovin (Vincristine), Prednisone) -used with or without Doxorubicin (COP-D) -Non-Hodgkinslymphoma * acute leukemia, lymphomas, Wilm’s, Choriocarcinoma
*Vincristine: does not cause serious myelosuppression * NEUROTOXIC: areflexia, peripheral neuritis, paralytic ileus
R: ↑ thymidylate synthase activity ↓ dec activation of 5-FU ↓ reduced drug sensitivity to this enzyme
H YD RO XY UR EA
PLANT ALKALOIDS (CCS drugs)
VINCA ALKALOIDS
VINBLASTINE VINCRISTINE
PK: given IV: widely distributed (even to CSF) Elimination: by metabolism * Ur ea a na lo g MOA: prevents DNA synthesis by inhibiting Ribonucleotide reductase Acts on S-phase MOA: “SPINDLE POISONS” (M-ph ase) Prevents assembly of tubulin dimmers into microtubules, blocking formation of mitotic spindles R: ↑ inc efflux of drugs from tumor cells via membrane drug transporter PK: given parenterally Penetrate most tissues (EXCEPT CSF) Clearance: biliary excretion
PODOPHYLLOTOXI NS
ETOPOSIDE TENIPOSIDE
Tenoposide is an analog MOA: ↑inc degradation of DNA, possibly via interaction with topoisomerase II.
*Vinblastine: ABVD regimen (Adriamycin (Doxorubicin), Bleomycin, Vinblastine, Dacarbazine) -equally effective to MOPP -Hodgkins lymphoma -less likely to cause sterility and 2o malignancies (leukemia) -if neoplasm becomes resistant, may be alternated w/ MOPP * other lymphomas, neuroblastoma, testicular ca, Kaposi’s sarcoma *used in drug combination regimens * Lung (SMALL CELL), Prostate, Testicular
*Vinblastine: GI distress, myelosupression & alopecia
AE: GI distress, myelosupression & alopecia
*CCS drugs
transport Most active in LATE S-phase to EARLY G2-phase
A NT IB IO TI CS
TAXANES
PACLITAXEL DOCETAXEL
A NT HR AC YC LI NE S (CCNS drugs)
DOXORUBICIN (Adriamycin) DAUNORUBICIN
B LE OM YC IN E
DACTINOMYCIN (Actinomycin D)
MITOMYCIN
HORMONAL ANTICANCER AGENTS
GLUCOCORTICOID S
S EX H OR MO NE S
SEX HORMONE ANTAGONIST
P RE DN IS ON E
PK: well absorbed after oral administration Distributed to most tissues Elimination: mainly via kidneys (dose reduction if w/renal impaired) MOA: “SPINDLE POISONS” Prevents DISassembly of microtubules into tubulin monomers PK: given IV MOA: intercalate between base pairs Inhibit topoisomerase II Generate free radicals Block synthesis of DNA / RNA and causes DNA strand scission Membrane disruption occurs
*Breast / Ovarian Ca
*Doxorubicin: ABVD regimen (see above) * myelomas, sarcomas * breast / endometrial / ovarian * lung, thyroid *Daunorubicin: acute leukemia
PK: given IV Metabolized in the liver Exceted: bile & urine (red color – not hematuria)
*Idarubicin: AML
* mi xt ur e o f g ly co pe pt id es MOA: generates free radicals which binds to DNA, cause strand breaks, inhibiting DNA synthesis CCS drug (inhibits at G2 phase)
*component of drug regimens for Hodgkins (ABVD) and Testicular Ca (VBC or VBE) *lymphomas & Squamous cell Ca
PK: given parenterally INactivated by Aminopeptidases Clearance: some renal clearance of intact drug MOA / PK: CCNS drug Binds to dsDNA & inhibits DNA-dependent RNA synthesis Also causes ssDNA breaks possibly through free radicals or inhibition of topoisomerase II Must be given Parenterally Excretion: intact drug + metabolites excreted in bile MOA / PK: C CNS drug Metabolized by liver enzymes to form an alkylating agent which cross-links DNA (inhibiting DNA synthesis) Given IV Clearance: via hepatic metabolism (rapidly cleared) * mo st c om mo nl y u se d *most used in combination drug regimens
F LU OX YM ES TE RO NE (androgenic steroid) TA MO XI FE N
*estrogens, progestins, androgens: used in hormone-dependent ca
TOREMI FE NE FLUTAMIDE L EU PR OL ID E GOSERELIN NAFARELIN
*ne we r e str oge n- re ce pt or anta gon is t *Androgen-receptor antagonist *administered in CONSTANT doses as to maintain stable blood levels Leuprolide: long-acting GnRH analog
* es tr og en r ec ep to r P AR TI AL a go ni st MOA: blocks the binding of estrogen to receptors of estrogen-sensitive cells in breast tissue
*Melanoma * Wilm’s tumor & Rhabdomyosarcoma: VAC regimen Vincristine, Actinomycin, Cyclophosphamide
*Paclitaxel: n eutropenia, thrombocytopenia, peripheral neuropathy (high incidence), hypersensitivity rxns (possible during infusion) *Docetaxel: neurotoxicity, bone marrow depression AE: GI distress, myelosupression & severe alopecia T: **CARDIOTOXIC : abn ECG arrhythmia slow-developing cardiomyopathy CHF ** Dexrazoxane: given to counteract cardiotoxicity (free radical scavenger) ** Liposomal formulation of Doxorubicin: less cardiotoxic
T: PULMONARY TOXICITY (pneumonitis, fibrosis): develops slowly & dose-limiting Hypersensitivity rxns (chills, fever, anaphylaxis) Mucocutaneous rxns (alopecia, blister-formation, hyperkeratosis)
AE: GI irritation, bone marrow suppresson & skin rxns
* Against hypoxic tumor cells * Adenoca: cervix, stomach, pancreas, lung Used as combination regimen
T: toxic myelosuppresion Toxic: heart, lung, liver, kidney
*Hodgkins lymphoma (MOPP regimen) *Non-Hodgkins (COP regimen) *other lymphomas, acute / chronic lymphocytic leukemias
T: adrenal suppression / insufficiency, salt retention, psychosis Metabolic effects: growth inhibition, diabetes, muscle wasting, osteoporosis
*Fluoxymesterone: may be used in women w/ advanced Breast Ca *Diethylstilbesterol (estrogenic steroids): -sometimes used in Prostate Ca * Br ea st C a: p os it iv e- re ce pt or
* ha ve a ct iv it y in P ro ge ti n- RE SI ST AN T En do me tr ia l Ca BUT may activate Estrogen receptor in endometrial cells = hyperplasia + neoplasia T: hot flushes, vaginal bleeding, HYPERcalcemia, ocular dynfunction & peripheral edema
G nR H A NA LO GS
*a dva nc ed Br ea st Ca *Prostate Ca *effective as Diethylstibesterol: Prostate Ca (with fewer AE)
AE: gynecomastia, hot flushes, hepatic dysfunction Leuprolide (T): bone pains, gynecomastia, hematuria, impotence, testicular atrophy
MOA: GLUCOCORTICOIDS (in general) -bind to intracellular glucocorticoid receptors in T cells & induce expresson of glucocorticoid responsive genes. -results in suppression of cellular growth & proliferation as well as induction of apoptosis
MOA: AROMATASE INHIBITOR MISCELLANEOU S ANTICANCER AGENTS
ANASTROZOLE LETROZOLE ASPARAGINASE
MITOXANTRONE
ALPHAINTERFERONS
inhibit release of Pituitary LH / FSH
MOA: inhibit Aromatase (enz that catalyzes conversion of Androstenedione Estrone) MOA: depletes serum Asparagine (needed for growth) Given IV *anthracine cmpd MOA: acts via alkylation of DNA bases *endogenous glycoproteins with antineoplastic Immuno
*Advanced Br east Ca
T: nausea, diarrhea, hot f lushes, bone marrow & back pain, dyspnea, peripheral edema AE: severe hypersensitivity rxns, acute pancreatitis, bleeding
*T-cell Auxotrophic Ca (leukemia/lymphomas) *combination regimens: Refractory acute leukemia, Breast Ca *Hairy cell leukemia * CML (early stage) * T-cell lymphomas
T: GI effects, myelosuppression, cardiac arrythmias
T: myelossuppression, neurologic dysfunction
suppresant
INTERFERONS (INF)
R IT UX IM AB
Antiviral actions * MA B t o a s ur fa ce p ro te in i n H od gk in s lymphoma
*used in combination for low grade lymphomas
Acute T: N/V, chills, fevers, HA Rituximab: hypersensitivity rxns, myelosuppression Trastuzumab: cardiac dysfunction (CHF)
MONOCLONAL ANTIBODIES
ANTI-FUNGALS GROUP SYSTEMIC ANTIFUNGAL S
SUB-GROUPS / DRUGS AMPHOTERICIN B
TRASTUZUMAB
*MAB to surface protein in Breast Ca that OVEREXPRESS the HER-2 protein
MOA/PK/PD/RESISTANCE
CLINICAL USE (CU) /ALTERNATE USE (AU)
AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD)
DRUG INTERACTIONS
*polyene (amphipathic – both lipo/hydrophillic) antibiotic related to Nystatin
*most important drug available for systemic mycosis * FUNGICIDAL * has the WIDEST ANTIFUNGAL SPECTRUM * Aspergillus, Candida albicans (systemic), Cryptococcus, Histoplasma, Mucor, Blastomycosis, Coccidiodomycosis
*Infusion related: AE (by IV): fever, chills, vomiting, muscle spasm, shock-like fall in BP PREmedication to prevent s/s: antihistamines,antipyretics,
Magnesium: Renal tubular acidosis
PK: poorly absorbed from GI tract Given IV (colloidal / lipid suspension) Widely distributed (EXCEPT CNS – DO NOT CROSS BBB) Elimination: slow hepatic metabolism HL: ~ 2 weeks Excretion: small fraction of drug excreted in urine AMPHOTERICIN B IS NOT DIALYZABLE
* Fungal Meningitis: INTRATHECAL administration AU: Sporotrichosis, Leishmaniasis
MOA: FUNGICIDAL EFFECT: effects on the permeability & transport properties Bind to Ergosterol cause artificial pores (same w/ Nystatin)
FLUCYTOSINE
R: ↓ dec lever or structural change in membrane ergosterol *pyrimidine antimetabolite related to 5-Fluorouracil (anticancer) PK: effectiv e ORALLY Widely distributed to most tissues (INCLUDING CNS) Eliminated: intact in urine Dose reduced in patients with Renal impairment
Me peridine, glucocorticoids * Hypokalemia, Anemia *Dose-limiting: ↓ dec glomerular filtration Renal tubular acidosis (with Magnesium) Anemia (↓dec formation of erythropoietin) NEPHROTOXIC (dose-limiting): ↓dose reduction possible w/Flucytosine (applicable to some infections) Controlled by giving Liposomal formulations
*NEUROTOXIC: risk taken if given via INTRATHECAL administration May cause seizures & neurologic damage *narrow antifungal spectrum T: in prolonged high plasma levels (REVERSIBLE): bone marrow depression, alopecia, liver * Candidiasis: with Amphotericin B * Cryptococcal meningitis (similar to AE from 5-FU) dysfunction, N/V * limited to tx w/ Amphotericin B: Cryptococcus neoformans (Cryptoco ccal meningitis) -possibly some systemic Candidal infections
MOA: accumulated in fungal cells by membrane PERMEASE & converted by Cytosine Deaminase to 5-FU (Selective toxicity) 5-FU: thymidylate synthase inhibitor
A ZO LE S:
R: occur rapidly, ↓ dec activity in permease & deaminase ***Resistance ↓ dec when given with Amphotericin B P K: O ra l b io av ai l ab il it y i s v ar ia bl e ( no rm al g as tr ic acidity req’d)
*used for long-term prophylaxis in Neutropenic pxs
AE: vomiting, diarrhea, rash, sometimes hepatotoxic
NOTES
Fluconazole Liver metabolism (except Fluconazole) **Fluconazole: good CNS penetration **Fluconazole: eliminated by KIDNEYS, largely Unchanged **Fluconazole: water soluble (unlike others: lipid soluble)
PULSE DOSING: for DERMATOPHYTES -Itraconazole (effective in Onychomycoses) - drug persists in nails for months - also possible in Fluconazole / Terbinafine
MOA: interfere the fungal cell membrane permeability by inhibiting the synthesis of Ergosterol (act on 14α demethylation of Lanosterol, catalyzed by cyt p450)
KETOCONAZOL E
FLUCONAZOLE
R: changes in sensitivity of the target enzymes MOA: inhibits Cyt P450 isozyme disrupting permeability of cell membrane (less selective compared to new azoles) PK: DO NOT PENETRATE BBB Absorption: better at low pH Highly bound to plasma proteins *DOC: Candidiasis (Oropharyngeal / Esophageal), Coccidioidomycosis Single-oral dose in Vaginal Candidiasis
*narrow antifungal spectrum * used as back-up drug for systemic infections (Blastomyces, Coccidioides, Histoplasma) *chronic mucocutaneous candidiasis *orally given: Dermatophytes
Interferes synthesis of: Adrenal and Gonadal steroids (gynecomastia, menstrual irregularities, infertility)
↑↑ Increase Plasma levels: Anticoagulants, Cyclosporine, Oral hypoglycemic, Phenytoin Cisapride: life-threatening CARDIOTOXICITY Food / Antacids / H2 blockers: ↓ absorption
*equivalent to Amphotericin B in Candidemia
*DOC: initial and secondary PROPHYLAXIS against CRYPTOCOCCAL MENINGITIS (and Naegleria fowleri) ITRACONAZOL
*DOC: systemic infections (Blastomyces / Sporothrix) : Subcutaneous Chromoblastomycosis
E
AU: Aspergillus, Coccidioides, Cryptococcus, Histoplasma Esophageal Candidiasis: active in some strains resistant to Fluconazole SUPERFICIAL ANTIFUNGAL S (SYSTEMIC)
VORICONAZOLE GRISEOFULVIN
TERBINAFINE
AZOLES (see above) SUPERFICIAL N YS TA TI NS ANTIFUNGAL S (TOPICAL) ANTI-HYPERLIPIDEMICS GROUP SUB-GROUPS / DRUGS BILE ACID CHOLESTYRAMINE SEQUESTRAN COLESTIPOL TS (RESINS)
*new azole with wider spectrum than Itraconazole MOA: interferes with Microtubule function in Dermatophytes May also inhibit the synthesis & polymerization of nucleic acids PK: Oral absorption depends on the physical state of the drug (ultramicrosize: more absorbed) Absorption is aided by HIGH-FAT FOODS Distributed to Stratum corneum binds to Keratin Elimination: Biliary excretion MOA: inhibits fungal enzyme, SQUALENE EPOXIDASE FUNGICIDAL
* po ly en e a nt ib io ti c r el at ed to Am ph ot er ic in B MOA: disrupts fungal membranes by binding to Ergosterol PK: NOT ABSORBED in GI tract
*severe dermatophytoses of the skin, hair, nails * FUNGISTATIC * effects are slow (needs 6 months tx before results)
AE: HA, mental confusion, GI irritation, photosensitivity, changes in liver functions, bone marrow suppression
*also accumulates in Keratin (PULSE DOSING) *Onychomycosis: more effective than Griseofulvin
AE: GI upsets, rash, HA, taste disturbances
*TOPICAL: local candida infections * ORAL: “gargle & swish & swallow” for oral and GI fungi
Other TOPICAL antifungal: (Azoles) Miconazole / Clotrimazole (Non-azoles) Haloprogin, Tolnaftate, Undecylenic acid
Coumarin: ↑enhance metabolism ↓dec anticoagulant effect
MOA/PK/PD/RESISTANCE
CLINICAL USE (CU) /ALTERNATE USE (AU)
AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD)
DRUG INTERACTIONS / NOTES
*bile acid binding resins: promotes excretion of bile salts by forming an insoluble complex in SI
*for HYPERCHOLESTEROLEMIA * Cholestasis / Bile Acid accumulation
T: BLOATEDNESS, CONSTIPATION, UNPLEASANT GRITTY TASTE
Impaired (↓) absorption: *Vitamin K / Dietary folates (fat soluble) * Digitalis * Thiazides * Warfarin * Pravastatin * Fluvastatin
MOA: divert hepatic cholesterol to synthesis of new bile acids ↓ reducing cholesterol availability for production of plasma lipids (+) compensatory increase in high affinity LDL receptors (liver) Effects: cause modest ↓ reduction in LDL cholesterol (little effect on HDL, cholesterol or triglycerides)
Type IIa (Familial hypercholesterolemia), IIb (Familial combined hyperlipidemia)
Combination therapy with Statins: -interfere with the absorption - Statins must be given 1hour before or 4hours after Resins
HMG-COA REDUCTASE (rate limiting enzyme: cholesterol syn.)
VITAMIN
FIBRATES
MISCELLANEO US
“STATINS” ATORVASTATIN CERIVASTATIN FLUVASTATIN PRAVASTATIN
LOVASTATIN SIMVASTATIN NIACIN
GEMFIBROZIL FENOFIBRATES CLOFIBRATES (more toxic)
P RO BU CO L
THYROID DRUGS GROUP DRUGS T3 LIOTHYRONINE LIOTRIX (most toxic: T4:T3 = 4:1)
*Pxs w/ Familial hyperlipidemia: can ↑ inc VLDL MOA: REVERSIBLE and COMPETITIVELY inhibit HMGCoA Reductase (catalyzes HMG-CoA Mevalonate) ↑ inc LDL receptors in liver ↑ inc catabolism of LDL ↑ inc clearance of VLDL remnants (IDL) and LDL
*↓ reduce LDL levels dramtically (esp when combined with other drugs) * ↓ reduce the risk of coronary events & mortality in IHD pxs * Atorvastatin: higher efficacy, ↓↓↓ triglycerides more Type IIa (Familial hypercholesterolemia), IIb (Familial combined hyperlipidemia)
PK: metabolize d by Cyt P450 system PRODRUGS “Nicotinic Acid” *wider spectrum of use MOA: directly ↓ reduces secretion/production of Type IIa (Familial hypercholesterolemia), VLDL resulting IIb (Familial combined hyperlipidemia), to ↓ dec LDL III (Familial dysbetalipoproteinemia), ↑ inc clearance of VLDL by li poprotein lipase IV (Familial hypertriglyceridemia), ↑ inc HDL V (Familial Mixed Hypertriglyceridemia) ↓ dec serum triglyceride concentration *ligands for PPAR-α protein: regulates transcription of Type IIb (Familial combined hyperlipidemia), genes involved in lipid metabolism III (Familial dysbetalipoproteinemia), - (Peroxisome Proliferator Activated IV (Familial hypertriglyceridemia), Receptor-Alpha) V (Familial Mixed Hypertriglyceridemia) MOA: ↑ inc activity of lipoprotein lipase ↑enhanced clearance of triglyceride-rich *usually combined with other antihyperlipidemics lipoproteins ↓dec hepatic secretion/production of VLDL, (↓ LDL: ↑HDL) ↓dec serum triglycerides M OA : ↓ l ow er s s er um c ho le st er ol b y ↑ i nc L DL Ty pe I Ia ( Fa mi li al h yp er ch ol es te ro le mi a) catabolism
MOA/PK/PD/RESISTANCE *10x more potent than T4 PK: absorbed in small intestines (SI) PD: HL (2days) – T3
CLINICAL USE (CU) /ALTERNATE USE (AU) *Myxedema coma: medical emergency due to severe, long-standing
*well-tolerated * mild elevations of serum aminotransferases (common but not assoc w/liver dse) * ↑inc in creatinine kinase (skeletal mm): ~10% patients CONTRAINDICATION: Pregnancy (TERATOGENIC), Nursing mothers, Hepatic dse (relative CI: may have more severe rxns), Children
Drugs / Foods that INHIBIT Cyt P450 (ie: grapefruit juice) -↑ risk for HEPATOTOXICITY - Myopathy Gemfibrozil, Niacin, Cyclosporin, Erythromycin -myalgia, myositis, and/or rhabdomyolysis
*Intense CUTANEOUS FLUSHING (prevented by pretreated with Aspirin / NSAIDS) AE: dose-dependent nausea and abdominal discomfort, pruritus, moderate ↑ of liver enzymes, may be hepatotoxic
↓ decreases circulating FIBRINOGEN ↑ increases TISSUE PLASMINOGEN ACTIVATOR (TPA)
AE: NAUSEA, skin rashes (Gemfibrozil), GI distress, gas Some pxs: ↓dec WBC / Hct
Anticoagulants: ↑ potentiate action
T (Clofibrates): GI and Hepatobiliary neoplasms
Carbohydrate tolerance: may be moderately impaired
Pxs w/history of Gallstones: CAUTION! (↑inc risk of gallstones)
T : P RO LO NG ED Q T ( Ar ry th mi as ), E os ino ph il ia
AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) T: THYROTOXICOSIS Cardiac effects (palpitations, arrythmias)
DRUG INTERACTIONS Cholestyramine (resins) & Al (OH)3: -decreases absorption of T3
NOTES
HL) T4 (considered to be a prohormone)
LEVOTHYROXINE SODIUM
ANTITHYROID S
M ET HI MA ZO LE
RADIOACTIVE IODIDE (delayed onset of effects)
LUGOL’S SOL’N. POTASSIUM IODIDE
123
PTU: for hyperthyroidism in pregnant and nursing women
PK: 80% bound to serum proteins (highly protein bound that it can’t pass through placenta, less concentration in breastmilk) Shorter HL: 1-2 hrs P K: l e s s p ro te in b ou nd HL: 5-6 hrs
I
THIOCYANATE PERCHLORATE
*GRAVE’S DISEASE *Radiation Adjuvant: used in pxs while awaiting 131 I effects *prior to surgery: to prevent thyroid storm
Lugol’s: 5% iodine + 10% Potassium iodide Iodine component is reduced Iodide in the SI prior to absorption *Emits both β and γ rays MOA: β rays: specifically destroys thyroid parenchyma / cells
Potassium Iodide (AU): for SPOROTRICHOSIS
Hyperthyroidism -Hyperthyroidism in elderly with cardiac dse - DOC: persistent / recurrent Grave’s dse (despite Sx/meds) - Toxic nodular goiter *** use restricted to pxs older than 30yo
*Emits γ / x-rays HL: 13 hrs
For Diagnostic thyroid scanning
MOA: competitively inhibits IODIDE TRANSPORT mechanism in thyroid follicular cells
***rarely used now
High doses: inhibits TG IODINATION MISCELLANEO US
IOPANOIC ACID SODIUM IPODATE
MOA: inhibits PERIPHERAL CONVERSION T4 Suppress conversion of T4 T3 via 5’deiodinase (liver, kidney, peripheral tissue)
SYMPTOMATIC TX
B ET A BL OC KE RS
M OA : b lo ck s bo th B1 / B2 r ec ep to rs i n t is su es
Glucocorticoids: ↓ conversion of T4 T3
T3
T: Transient leucopenia Fever, skin rash, itching, joint pains, Hypothyroidism
*same with above * less Agranulocytosis seen (0.12%)
MOA: inhibits RELEASE of T3 / T4 from the thyroid gland Acutely inhibits IODINATION of TG (WolffChaikoff effect)
PK: crosses the placenta + found in breastmilk HL: 8 days 131
IONIC INHIBITORS
I
Estrogen: ↑ TBG (more protein to bind to T4)
*after Thyroid Ca: to suppress TSH *GRAVE’S DISEASE *Radiation Adjuvant: used in pxs while awaiting 131 I effects *prior to surgery: to prevent thyroid storm
MOA: INHIBITS THYROID PEROXIDASE thereby preventing iodination of tyrosyl residues of TG and coupling of Iodotyrosine residues *The only drug that INHIBITS PERIPHERAL DEIODINATION OF T4 T3 PROPYLTHIOURACI L
IODIDE
-hypothermia, respiratory depression, unconsciousness *Hypothyroidism: due to prolonged duration of action -to prevent Cretinism (in hypothyroid NB, given after birth)
*pregnant hypothyroid women: higher ↑ T4 dose needed -estrogen ↑increases TBG production
*short term treatments of hyperthyroid states
* Hy pe rt hy ro id is m: t o a ll ev ia te s /s ( tr em or s, sweating, palpitations tachycardia) *Radiation Adjuvant: used in pxs while awaiting 131 I effects
ACUTE T:
ANGIOEDEMA Swelling of the larynx, cutaneous hges, Serum sickness s/s (fever, arthralgia, lymphadenopathy, eosinophilia)
CHRONIC T (IODISM): Brassy tastes & burning in mouth, sore teeth/gums, ↑salivation, coryza, sneezing, swelling of the lids, skin lesions, respiratory problems *** Iodine-induced hypothyroidism in euthyroid pxs (with previous hx of thyroid DO) T: high incidence of delayed Hypothyroidism CONTRAINDICATIONS: Pregnancy, Nursing mothers, coexisting severe ophthalmopathy (may exacerbate condition)
Perchlorate: FATAL APLASTIC ANEMIA
ANTI-MICROBIALS GROUP DRUGS
MOA/PK/PD/RESISTANCE
CLINICAL USE (CU) /ALTERNATE USE (AU)
AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD)
DRUG INTERACTIONS
NOTES
