You are on page 1of 16

Typ e

Classification

Subclass

Sp. Drugs Ach (acetylcholine)

Hydrolyz ed by Yes No

Sp. Receptor / distinguishing feature Muscarinic + Nicotinic - Muscarinic - synthetic drug

MOA

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) Alzheimers 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 <eg ATROPINE> (IM / IV) Myasthenia gravis (Oral / IM / IV) Antidote: Curariform drug toxicity (IV) Alzheimers disease (Oral) Glaucoma + accommodative esotropia Ocular) Pediculosis (Topical) (Topical

Contra/ Side Effects

Choline Esters Bethenacol

Direct acting CReceptor Agonists Plant Alkaloids

Carbachol Muscarine Nicotine Pilocarpine Donezepil Endrophonium Neostigmine

No No No No

Muscarinic + Nicotinic Muscarinic Nicotinic Muscarinic > Nicotinic - production of aqueous humor

Mimic action of Ach

Cholinergic (C) Receptor AGONISTS

Indirect Acting (exaggerate effects of parasympa NS by Inhibiting Cholinesterase

Reversible (short acting)

Physostigmine

Binds to acetylcholinesteras e

Pyridostigmine

Irreversible (long acting) increases Ach Release

Tacrine Echothiophate Isoflurophate Malathione Cisapride Metoclopramide Potentiates vasodilative effect of Ach = penile blood flow = penile erection Extra careful in (kse vasodilators un drugs!) HPN px, Reflex tachycardia, angina, MI Indications look at handouts

Form covalent bonds w/ catalytic site cholinesterase

Other Cholinergic Receptor Agonists

Sildenafil ( a.k.a. Viagra) Tadalafil Vardenafil

Inhibition of cGMP metab by type5 Phosphodiestera se = cGMP

Erectile dysfunction

Headache Blurred vision Nasal congestion

Atropine

Belladonna alkaloids Muscarinic Receptor Antagonists

Hyoscyamine Scopolamine Dicyclomine Ipratropium Flavoxate, Oxybutinin, Tropicamide Trimethapham Atracurium Doxacurium Pancuronium Tubocurarine Vecuronium Succinylcholine Sp. Drugs Dobutamine Dopamine

Aka Buscopan - anti-spasmodic - anti-spasmodic - checks secretions - combined w/ Salbutamol = anti-asthma

Adrenergic Receptor AGONISTS Cholinergic (C) Receptor ANTAGONISTS

Semisynthetic + synthetic

Nicotinic Receptor Antagonists

Ganglionic blocking agents

- sympathetic blockade (hypotension) - para (dry mouth, blurred vision, urinary retenti on)

Blocks NN receptor @ both sympa + para ganglia

Indications: - hypertensive emergencies - neurosurgery (controlled hypotension = bloodless)

Neuromuscular Blocking agents

Non depolarizing Depolarizing

Typ e

Classification

Subclass

Pharmacologic Effects (and Receptor) Cardiac stimulation Renal vasodilation Cardiac stimulation BP Cardiac stimulation BP Bronchodilation ( 1) (D1) ( 1) ( 1) ( 1) ( 1) ( 2)

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

Notes Dobutamine, Dopamine, Epi - contraindication in HPN Px

Overall effect

Epinephrine Catecholamines

DOC for anaphylactic shock! Potency- adrenergic Rec E/Ne > isoproterenol Potency- adrenergic Rec Isoproterenol > E /NE Bronchodilati on BP

Isoproterenol DIRECT ACTING Norepinephrine Albuterol Apraclonide Clonidine Oxymetazoline Noncatecholamines Phenylephrine

Cardiac Stimulation

( 1)

AV block Bradycardia

BP Bronchodilation aqueous humor formation sympathetic outflow from CNS imidazoline) Vasoconstriction

( 1) ( 2) ( 2) ( 2 + ( 1)

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

Vasoconstriction, BP, mydriasis

( 1)

INDIRECT ACTING

Ritodrine Terbutaline Amphetamine

Bronchodilation + uterine relaxation in norepinephrine release

( 2)

MIXED ACTING

Cocaine Ephedrine Phenylpropanolami ne Pseudoephedrine Selective 1 blockers Non Selective blockers Selective 1 blockers Doxazosin Prazosin Terazosin Phenoxybenzamin e Phentolamine Acebutolol Atenolol Esmolol Metoprolol Nadolol Pindolol Timolol Propranolol Carvediol Labetalol

(X) inhibition of norepinephrine uptake Vasoconstriction ( 1)

Local anesthesia Nasal decongestion Applies to ALL: for BPHP (Benign Prostatic Hyperplasia) Anorexic drugs (large qty: 50-100mg)? Contra: HPN Px

Adrenergic Receptor ANTAGONISTS

-Adrenergic

- for HPN Pxs

Good to use bcoz effects can be limited

-Adrenergic Non Selective blockers + Adrenergic

- cheapest anti-HPN (eg. Neobloc)

- for hyperthyroidism (eg. tremors, tachycardia, irregular rates)

ANTI-PROTOZOAL GROUPS SUBGROUPS ANTICHLOROQUINE (CHL) MALARIALS

MOA/PK/PD/RESISTANCE *4-aminoquinoline derivative PK: rapidly absorbed when given orally Widely distributed to tissues (ENTER THE BBB, CROSSES PLACENTA) (+) large Vd (volume of distribution) HL: 7 days 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) 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 PK: complete absorption after oral administration,

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 AU: Amebic liver dse (with Metronidazole-resistance) Autoimmune DO (ie RA) Extra-intestinal Amebiasis: due to E. histolytica (w/ D. Furoate) * (+) TISSUE AMEBICIDE

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

DRUG INTERACTIONS

NOTES

QUININE

* (+) 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)

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 *still, may cause: GI distress, pruritus, HA & metHgb

MEFLOQUINE

*for PROPHYLAXIS in all malarious areas with chloroquine resistance

PRIMAQUINE

* (+) TISSUE SCHIZONTICIDE (Vivax, Ovale, Falciparum)

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 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 inhibiting 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 *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 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) AU: tx of the following 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) * (+) LUMINAL AMEBICIDES (2 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 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) AU: prophylaxis against Toxoplasmosis & Isospora belli infections
nd

CONTRAINDICATION: G6PD def (hematotoxic / hemolytic) Pxs predisposed to granulocytopenia (ie: SLE, RA) T: folic acid deficiency (high doses)

Sulfonamide s (Sulfodoxine )

T: GI distress, skin rashes, hemolysis, kidney damage T: Pyrimethamine + Sulfadiazine * GI irritation, glossitis, neurologic s/s (HA, insomnia, tremors, seizures) * hematotoxicity (megaloblastic anemia, thrombocytopenia) T: Pyrimethamine + Clindamycin *antibiotic-associated colitis

(+) competitive interaction with plasma protein binding sites

DRUGS FOR AMEBIASIS

METRONIDAZOLE

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: inhibit protein synthesis by blocking ribosomal movement along mRNA PK: alkaloids given parenterally *halogenated hydroxyquinoline PK: orally active luminal amebicide (acts on Trophozoites) *converted in the gut to the diloxanide freebase form (active amebicide) *aminoglycoside antibiotic

AE: GI irritation, HA, dark coloration of urine T: leucopenia, dizziness, ataxia CONTRAINDICATION: Pregnancy (may be teratogenic)

Ethanol: disulfiram-like rxns ( acetaldehyde accumulation) Coumarin: potentiation of anticoag effects

EMETINES

T (severe): GI distress, muscle weakness, cardiovascular dysfunction (arrhythmia, CHF)

IODOQUINOL

DILOXANIDE FUROATE

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

PAROMOMYCIN

DRUGS FOR PNEUMOCYSTO SIS (PCP) and TOXOPLASMOS IS

PENTAMIDINE

MOA: (~) inhibition of glycolysis; (+) selective toxicity to parasites interference with nucleic acid metabolism of protozoans and fungi PK: DO NOT cross BBB PD: aerosol pentamidine (once monthly) Daily IV or IM injection (usually for 21 days) PD: oral (double strength formulation TID) or IV

TRIMETHOPRIMSULFAMETHOXAZOLE (TMP-SMZ)

AE: occurs in 50% of AIDS pxs GI distress, rash, fever, neutropenia, thrombocytopenia

ANTIFOLATES: (see above) PYRIMETHAMINE & SULFONAMIDES ATROVAQUONE

MOA: inhibits mitochondrial electron transport & probably folate metabolism

*for mild-moderate PCP *less effective than TMP-SMZ or pentamidine but better tolerated

AE: rash, cough, N/V, diarrhea, fever, abnormal liver function test

MISCELLANEOUS AGENTS DRUGS FOR TRYPANOSOMI ASIS PENTAMIDINE (see above) MELARSOPROL

PK: used orally Poorly absorbed and should be given with food to maximize bioavailability eliminated in feces Unchanged Trimethroprim + dapsone Primaquine + clindamycin Trimetrexate + leucovorin *organic arsenical MOA: inhibits enzyme sulfhydryl groups Given parenterally (due to GI irritation) 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 *DOC: for African sleeping sickness late stage (enters CNS) T: may cause reactive encephalopathy (fatal)

NIFURTIMOX SURAMIN

*DOC: for American trypanosomiasis AU: for mucocutaneous Leishmaniasis *DOC: early hemolymphangitic stages of African trypanosomiasis (BEFORE CNS INVOLVEMENT)

T (severe): allergies, GI irritation, CNS effects T: rashes, GI distress, neurologic complications

LEISHMANIASIS

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 AGAINST NEMATODES

DRUGS ALBENDAZOLE

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

DIETHYLCARBAMAZIN E

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

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)

IVERMECTIN

MOA: intensifies GABA mediated neurotransmission (immobilization of parasites) removal by reticuloendothelial system Selective toxicity: do not pass BBB MOA: *Inhibition of microtubule assembly *blocks glucose uptake in Nematodes

DOC: Onchocerciasis (River blindness) (acts slowly than Diethylcarbamazine but fewer systemic/ocular rxns) DOC: Strongloidiasis (threadworm) AU: Filariasis DOC: Pinworm (Enterobiasis) / Whipworm (Trichuriasis)

MEBENDAZOLE

PK: < 10% of drug absorbed systematically after oral use Metabolized rapidly

DOC: (with Pyrantel Pamoate): Roundworm And combined infections: Ascarids + Hookworms AU: as back-up drug for Cestodes / Trematode infections

*CONTRAINDICATED: PREGNANCY (embryotoxic)

PIPERAZINE PYRANTEL PAMOATE

MOA: GABA receptor agonist (paralyzes parasites) 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: rapid gut absorption Metabolized by the liver (to inactive cmpds)

AU: Ascariasis DOC: (with Mebendazole): Hookworm, Pinworm, Roundworm

SE: mild GI irritation CONTRAINDICATED: SEIZURE PATIENTS AE (minor): GI distress, HA, weakness

THIABENDAZOLE

DOC: Visceral 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)

T: GI irritation, HA, dizziness, drowsiness, leucopenia, hematuria, allergic rxns (INTRAHEPATIC CHOLESTASIS), StevenJohnsons 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 Pregnancy Common AE: N/V, diarrhea, Abd cramps, dizziness, HA, phototoxicity Less frequently: pyrexia, tinnitus, proteinuria, leukopenia T: excess Cholinergic stimulation

AGAINST TREMATODES

PRAZIQUANTEL

Recall: Schistosoma sp (blood flukes) Clonorchis sinensis (liver flukes) Paragonimus westermani (lung fluke)

BITHIONOL

MOA: unknown PK: orally effective; eliminated in urine

AU: Paragonimiasis DOC: Schistosoma haematobium (BILHARZIASIS) DOC: Schistosoma mansoni

METRIFONATE

OXAMNIQUINE

*organophosphate PROdrug MOA: converted to DICHLORVOS (Cholinesterase inhibitor) Acts solely to Schistosoma haematobium (BILHARZIASIS) MOA: acts solely to Immature / Adult schistosomal forms

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) NICLOSAMIDE

MOA: uncoupling oxidative phosporylation. 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) AU: small / large intestinal flukes

Mild AE: GI distress, HA, rash, fever

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)

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 (important for viral-specific phosphorylation)

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

DRUG INTERACTIONS NOTES Notes: ACYCLOVIR 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 cause chain

termination PK: given topical, oral, IV (for severe & neonatal HSV infection) Excretion: RENAL FOSCARNET *phosphonoformate derivative MOA: inhibits viral RNA polymerase, DNA polymerase, & HIV reverse transcriptase R: point mutation in the DNA polymerase gene 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 *guanine derivative MOA: triphosphorylated to form a nucleotide that inhibits DNA polymerases of CMV & HSV (do not cause chain termination) R: changes in DNA polymerase & mutations in the gene that codes for activating viral phosphotransferase Thymidine kinase deficient HSV: also resistant to Ganciclovir 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 *Adenine analog PK: (+) rapid metabolic inactivation with marked toxic potential *DOC: for CMV Prophylaxis (including CMV retinitis) 2nd to Ganciclovir (+) good activity with Ganciclovir-resistant strains AU: Acyclovir-resistant strains of herpes that are thymine kinase-def -via inhibiting DNA polymerase T: NEPHROTOXIC (30%) Electrolyte-imbalance (++hypocalcemia) Genitourinary ulceration CNS toxicity: HA, hallucination, seizures Valacyclovir: converted to Acyclovir by hepatic metabolism; Reaches plasma level 3-5x faster than Acyclovir + longer duration of action

GANCICLOVIR

*DOC: for CMV Prophylaxis (including CMV retinitis)

T: Leukopenia, thrombocytopenia, mucositis, Hepatic dysfunction, seizures

If used with Zidovudine: -may cause severe NEUTROPENIA Other Myelosuppressant agents: -may cause severe NEUTROPENIA

CIDOFOVIR

*for CMV retinitis AU: mucocutaneous HSV infections (including Acyclovir-resitant) Genital warts

NEPHROTOXIC!!!

VIDARABINE

(+) activity against: HSV, VZV, CMV Given IV: severe HSV infections (including Acyclovirresistant) Also to prevent dissemination of VZV in immunocompromised pxs Topical: HSV Keratitis (NO EFFECT in Gental Herpes) (+) activity against: HSV-1, VZV, EBV

T: GI irritation, paresthesias, tremor, convulsions & hepatic dysfunctions *** TERATOGENIC (in animal studies)

SORIVUDINE

IDOXURIDINE TRIFLURIDINE FOMIVIRSEN

*Pyrimidine analog * still an investigational drug: 1000x more potent that Acyclovir (but still not effective for Acyclovir resistant HSV) *Pyrimidine analogs *anti-sense oligonucleotide 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 R: seen in advanced HIV pxs: several site mutations on the pol gene 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 R: associated with point mutations of the pol gene

Topical: HSV Keratitis Given IntraVitreally: CMV retinitis

TOO TOXIC FOR SYSTEMIC USE!!!

ANTI-HIV (NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS NRTIs)

ZIDOVUDINE (ZDV)

*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

Myelosuppressants: -additive BM suppression Drugs that undergo glucoronidation (Paracetamol, Benzodiazepines, Cimetidine, Sulfonamides) -inc plasma levels of ZDV Azole antifungals and Protease inhibitors: -inhibits metabolism of ZDV Rifampicin: inc clearance of ZDV

DIDANOSINE (ddI)

*commonly used: HAART regimen

T: PANCREATITIS (dose-limiting) -seen with Alcohol intake -also seen in Hypertriglyceridemia AE: Peripheral neuropathy, diarrhea, hepatic dysfunction,

Chelating agents and Food intake: decreases BA of ddI With Alcohol: (+) Pancreatitis

Complete cross-resistance with Zalcitabine (ddC) Partial resistance to Zidovudine (ZDV) PK: BA: if with food or Chelating agents Elimination: by Glomerular filtration + Active Tubular secretion ZALCITABINE (ddC) LAMIVUDINE (3TC) STAVUDINE (d4T) *pyrimidine nucleoside MOA/R: similar to other NRTIs PK: high oral BA MOA: similar to other NRTIs PK: used orally (part of HAART regimen) *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 *commonly used in combined regimens

Hyperuricemia, CNS effects

*active against HIV-1 (including ZDV-resistant strains) AU: Hepa B, HBV (12wks tx in adjuct w/ Interferon alpha) *used in HAART regimen

T: Peripheral Neuropathy (Dose-dependent) Nephrotoxic!!! Pancreatitis, esophageal ulceration, stomatitis, arthralgias AE: usually mild: GI distress, HA, insomnia, fatigue

T: Peripheral Neuropathy (Dose-dependent) Nephrotoxic!!!

ABACAVIR

*used in combination w/ ZDV + 3TC

T: Severe Hypersensitivity reactions involving multiple organ systems (lethal!)

ANTI-HIV (NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS NNRTIs) ANTI-HIV (PROTEASE INHIBITORS)

NEVIRAPINE DELAVIRDINE EFAVIRENZ

MISCELLANEOUS ANTIVRALS

TOPICAL ANTIVIRAL DRUGS

INDINAVIR RITONAVIR Other Protease inhibitors: SAQUINAVIR NELFINAVIR AMPRENAVIR AMANTADINE RIMANTADINE OSELTAMIVIR ZANAMIVIR INTERFERONS RIBAVIRIN IDOXURIDINE CYTARABINE TRIFLUOROTHYMI DINE

ANTI NEOPLASMS GROUPS SUBGROUPS ALKYLATING AGENTS (CCNS DRUGS) -react with DNA - targets: N-7 and O-6 positions of guanine -results with *DNA crosslinking *base-pair mismatching *DNA breakage NITROSOUREAS NITROGEN MUSTARDS: CHLORAMBUCIL

DRUGS CYCLOPHOSPHA MIDE

MOA/PK/PD/RESISTANCE PK: hepatic cyt p450 biotransformation 1 of breakdown product: ACROLEIN

CLINICAL USE (CU) /ALTERNATE USE (AU) *Non-Hodgkin Lymphoma * Breast / Ovarian Ca * Neuroblastoma

AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) AE: GI distress, myelosupression & alopecia *** Hemorrhagic Cystitis: due to ACROLEIN May be dec by vigorous hydration + use of MESNA (mercapt oethanesulfonate) *may also cause: cardiac dysfunction, pulmonary toxicity, SIADH AE: Bone marrow suppression (leucopenia, thrombocytopenia) AE: GI distress, myelosupression & alopecia *** marked vesicant action

DRUG INTERACTIONS

NOTES *Alkylating agents are CCNS drugs MOA: form reactive molecular species that alkylate nucleophillic groups on DNA bases (N-7 position of guanine) R: inc DNA repair dec drug permeability (+) production of trapping agents (ie thiol)

MELPHALAN MECHLORETHAMI NE

*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

*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

CARMUSTINE (BCNU) LOMUSTINE (CCNU) STREPTOZOCIN

PK: highly lipophilic Facilitates CNS entry *naturally occurring antibiotic derived from Streptomyces acromogenes *Diabetogenic agent: High affinity / toxicity to Pancreatic Beta cells PK: crosses BBB CCNS Cisplatin: used IV Distributed to most tissues Cleared in kidneys Unchanged *Platinum coordination complex MOA: enters cells by diffusion & is hydrolyzed to form an activated electrophile which alkylates DNA CCNS

AE: GI distress, myelosupression & CNS dysfxn

AE: N/V, Bone marrow suppression, leucopenia, thrombocytopenia T: Renal failure (Nephrotoxic?!?)

OTHERS: AKYLSULFONATES

CISPLATIN / CARBOPLATIN

*Testicular Ca / Bladder Ca / Lung Ca * Ovarian Ca * regimen VBC: Vinblastine, Bleomycin, Cisplatin

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

PROCARBAZINE

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: hepatically activated Given IV *alkyl-sulfonate type bifunctional alkylating agent

*Hodgkin Lymphoma: MOPP regimen (see above)

*inhibit many enzymes: MAO * Enzymes involved in Hepatic metabolism Ethanol: disulfiram-like reactions

DACARBAZINE

BUSULFAN

*sometimes used in CML * ABVD regimen (for Hodgkins Lymphoma): Adriamycin, Bleomycin, Vinblastine, Dacarbazine * Malignant Melanoma DOC: CML

T: adrenal insufficiency, pulmonary fibrosis, skin pigmentation

METHOTREXATE

MOA: substrate for + inhibitor of dihydrofolate reductase synthesis of thymidilate, purine nucleotides and AA interfering with NA and protein metabolism *formation of POLYGLUTAMATE DERIVATIVES is

*Choriocarcinoma * Breast Ca * Acute Leukemias * Hodgkins lymphoma * cutaneous T-cell lymphomas AU: used also in Rheumatic Arthritis

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 Long term use: Hepatotoxic, Pulmonary

Salicylates, NSAIDS, Sulfonamides, Sulfonylureas: - increase Methotrexate toxicity

important for cytotoxic actions PK: IV / Oral admin: good tissue distribution (except CNS) Not metabolized Clearance: dependent on RENAL functions (adequate hydration needed to prevent crystallization) 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. 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 MOA: activated by kinases AraCTP (inhibitor of DNA polymerases: inhibiting DNA chain elongatio n) R: dec uptake dec conversion to AraCTP 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 R: thymidylate synthase activity dec activation of 5-FU reduced drug sensitivity to this enzyme PK: given IV: widely distributed (even to CSF) Elimination: by metabolism *Urea analog MOA: prevents DNA synthesis by inhibiting Ribonucleotide reductase Acts on S-phase MOA: SPINDLE POISONS (M-phase) 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 *Acute leukemias * DOC: AML

infiltrates/fibrosis

ANTIMETABO LITES (CCS DRUGS) -inhibit steps in DNA biosynthesis (specific Sphase)

ANTAGONISTS OF FOLIC ACID

MERCAPTOPURIN E (6-MP)

*acute leukemias: AML, ALL * CML

AE: bone marrow suppression (dose-limiting) Hepatic dysfunction (cholestasis, jaundice, necrosis)

Allopurinol: dec metabolism of 6-MP by xanthine oxidase

*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)

PYRIMIDINES

FLUOROURACIL (5FU)

*Breast / Ovarian Ca * Head and Neck Ca * Liver / Bladder Ca

AE: GI distress, myelosupression & alopecia

HYDROXYUREA

*CML * Melanoma, Polycythemia vera, Sickle cell anemia *Vincristine: MOPP regimen (see above) * also COP (Cyclophosphamide, Oncovin (Vincristine), Prednisone) -used with or without Doxorubicin (COP-D) -Non-Hodgkins lymphoma * acute leukemia, lymphomas, Wilms, Choriocarcinoma *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, Kaposis sarcoma *used in drug combination regimens * Lung (SMALL CELL), Prostate, Testicular

AE: bone marrow suppression, leucopenia, megaloblastic anemia, thrombocytopenia N/V, diarrhea *Vincristine: does not cause serious myelosuppression * NEUROTOXIC: areflexia, peripheral neuritis, paralytic ileus *Vinblastine: GI distress, myelosupression & alopecia

PLANT ALKALOIDS (CCS drugs)

VINCA ALKALOIDS

VINBLASTINE VINCRISTINE

PODOPHYLLOTOXI NS

ETOPOSIDE TENIPOSIDE

Tenoposide is an analog MOA: inc degradation of DNA, possibly via interaction with topoisomerase II. Inhibits mitochondrial electron

AE: GI distress, myelosupression & alopecia

*CCS drugs

transport Most active in LATE S-phase to EARLY G2-phase 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 PK: given IV Metabolized in the liver Exceted: bile & urine (red color not hematuria) BLEOMYCINE *mixture of glycopeptides MOA: generates free radicals which binds to DNA, cause strand breaks, inhibiting DNA synthesis CCS drug (inhibits at G2 phase) 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: CCNS 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) *most commonly used *most used in combination drug regimens

TAXANES

PACLITAXEL DOCETAXEL

*Breast / Ovarian Ca

*Paclitaxel: neutropenia, 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

ANTIBIOTICS

ANTHRACYCLINES (CCNS drugs)

DOXORUBICIN (Adriamycin) DAUNORUBICIN

*Doxorubicin: ABVD regimen (see above) * myelomas, sarcomas * breast / endometrial / ovarian * lung, thyroid *Daunorubicin: acute leukemia *Idarubicin: AML

*component of drug regimens for Hodgkins (ABVD) and Testicular Ca (VBC or VBE) *lymphomas & Squamous cell Ca

T: PULMONARY TOXICITY (pneumonitis, fibrosis): develops slowly & dose-limiting Hypersensitivity rxns (chills, fever, anaphylaxis) Mucocutaneous rxns (alopecia, blister-formation, hyperkeratosis)

DACTINOMYCIN (Actinomycin D)

*Melanoma * Wilms tumor & Rhabdomyosarcoma: VAC regimen Vincristine, Actinomycin, Cyclophosphamide

AE: GI irritation, bone marrow suppresson & skin rxns

MITOMYCIN

* Against hypoxic tumor cells * Adenoca: cervix, stomach, pancreas, lung Used as combination regimen

T: toxic myelosuppresion Toxic: heart, lung, liver, kidney

HORMONAL ANTICANCER AGENTS

GLUCOCORTICOID S

PREDNISONE

*Hodgkins lymphoma (MOPP regimen) *Non-Hodgkins (COP regimen) *other lymphomas, acute / chronic lymphocytic leukemias *Fluoxymesterone: may be used in women w/ advanced Breast Ca *Diethylstilbesterol (estrogenic steroids): -sometimes used in Prostate Ca *Breast Ca: positive-receptor

T: adrenal suppression / insufficiency, salt retention, psychosis Metabolic effects: growth inhibition, diabetes, muscle wasting, osteoporosis

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

SEX HORMONES

SEX HORMONE ANTAGONIST

FLUOXYMESTERO NE (androgenic steroid) TAMOXIFEN

*estrogens, progestins, androgens: used in hormone-dependent ca *estrogen receptor PARTIAL agonist MOA: blocks the binding of estrogen to receptors of estrogen-sensitive cells in breast tissue *newer estrogen-receptor antagonist *Androgen-receptor antagonist *administered in CONSTANT doses as to maintain stable blood levels Leuprolide: long-acting GnRH analog

*have activity in Progetin-RESISTANT Endometrial Ca BUT may activate Estrogen receptor in endometrial cells = hyperplasia + neoplasia T: hot flushes, vaginal bleeding, HYPERcalcemia, ocular dynfunction & peripheral edema

GnRH ANALOGS

TOREMIFENE FLUTAMIDE LEUPROLIDE GOSERELIN NAFARELIN

*advanced Breast 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: AROMATASE INHIBITOR MISCELLANEOU S ANTICANCER AGENTS ANASTROZOLE LETROZOLE ASPARAGINASE MITOXANTRONE ALPHAINTERFERONS

inhibit release of Pituitary LH / FSH *Advanced Breast Ca *T-cell Auxotrophic Ca (leukemia/lymphomas) *combination regimens: Refractory acute leukemia, Breast Ca *Hairy cell leukemia * CML (early stage) * T-cell lymphomas T: nausea, diarrhea, hot flushes, bone marrow & back pain, dyspnea, peripheral edema AE: severe hypersensitivity rxns, acute pancreatitis, bleeding T: GI effects, myelosuppression, cardiac arrythmias T: myelossuppression, neurologic dysfunction

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 suppresant Antiviral actions *MAB to a surface protein in Hodgkins lymphoma *MAB to surface protein in Breast Ca that OVEREXPRESS the HER-2 protein

INTERFERONS (INF) MONOCLONAL ANTIBODIES

RITUXIMAB

*used in combination for low grade lymphomas

Acute T: N/V, chills, fevers, HA Rituximab: hypersensitivity rxns, myelosuppression Trastuzumab: cardiac dysfunction (CHF)

TRASTUZUMAB

ANTI-FUNGALS GROUP SUB-GROUPS / DRUGS SYSTEMIC AMPHOTERICIN B ANTIFUNGAL S

MOA/PK/PD/RESISTANCE *polyene (amphipathic both lipo/hydrophillic) antibiotic related to Nystatin 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 MOA: FUNGICIDAL EFFECT: effects on the permeability & transport properties Bind to Ergosterol cause artificial pores (same w/ Nystatin) R: dec lever or structural change in membrane ergosterol *pyrimidine antimetabolite related to 5-Fluorouracil (anticancer) PK: effective ORALLY Widely distributed to most tissues (INCLUDING CNS) Eliminated: intact in urine Dose reduced in patients with Renal impairment MOA: accumulated in fungal cells by membrane PERMEASE & converted by Cytosine Deaminase to 5-FU (Selective toxicity) 5-FU: thymidylate synthase inhibitor R: occur rapidly, dec activity in permease & deaminase ***Resistance dec when given with Amphotericin B PK: Oral bioavailability is variable (normal gastric acidity reqd) Distributed to most body tissues except

CLINICAL USE (CU) /ALTERNATE USE (AU) *most important drug available for systemic mycosis * FUNGICIDAL * has the WIDEST ANTIFUNGAL SPECTRUM * Aspergillus, Candida albicans (systemic), Cryptococcus, Histoplasma, Mucor, Blastomycosis, Coccidiodomycosis * Fungal Meningitis: INTRATHECAL administration AU: Sporotrichosis, Leishmaniasis

AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) *Infusion related: AE (by IV): fever, chills, vomiting, muscle spasm, shock-like fall in BP PREmedication to prevent s/s: antihistamines, antipyretics, 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 T: in prolonged high plasma levels (REVERSIBLE): bone marrow depression, alopecia, liver (similar to AE from 5-FU) dysfunction, N/V

DRUG INTERACTIONS Magnesium: Renal tubular acidosis

NOTES

FLUCYTOSINE

*narrow antifungal spectrum * Candidiasis: with Amphotericin B * Cryptococcal meningitis * limited to tx w/ Amphotericin B: Cryptococcus neoformans (Cryptoco ccal meningitis) -possibly some systemic Candidal infections

AZOLES:

*used for long-term prophylaxis in Neutropenic pxs (resistance occurs)

AE: vomiting, diarrhea, rash, sometimes hepatotoxic

Fluconazole Liver metabolism (except Fluconazole) **Fluconazole: good CNS penetration **Fluconazole: eliminated by KIDNEYS, largely Unchanged **Fluconazole: water soluble (unlike others: lipid soluble) MOA: interfere the fungal cell membrane permeability by inhibiting the synthesis of Ergosterol (act on 14 demethylation of Lanosterol, catalyzed by cyt p450) KETOCONAZOL E 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 *DOC: initial and secondary PROPHYLAXIS against CRYPTOCOCCAL MENINGITIS (and Naegleria fowleri) ITRACONAZOL E

PULSE DOSING: for DERMATOPHYTES -Itraconazole (effective in Onychomycoses) - drug persists in nails for months - also possible in Fluconazole / Terbinafine

*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

FLUCONAZOLE

*equivalent to Amphotericin B in Candidemia

*DOC: systemic infections (Blastomyces / Sporothrix) : Subcutaneous Chromoblastomycosis AU: Aspergillus, Coccidioides, Cryptococcus, Histoplasma Esophageal Candidiasis: active in some strains resistant to Fluconazole

SUPERFICIAL ANTIFUNGAL S (SYSTEMIC)

VORICONAZOLE GRISEOFULVIN

*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

*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

Coumarin: enhance metabolism dec anticoagulant effect

TERBINAFINE AZOLES (see above) NYSTATINS

*also accumulates in Keratin (PULSE DOSING) *Onychomycosis: more effective than Griseofulvin

AE: GI upsets, rash, HA, taste disturbances

SUPERFICIAL ANTIFUNGAL S (TOPICAL) ANTI-HYPERLIPIDEMICS GROUP SUB-GROUPS / DRUGS BILE ACID CHOLESTYRAMINE SEQUESTRAN COLESTIPOL TS (RESINS)

*polyene antibiotic related to Amphotericin B MOA: disrupts fungal membranes by binding to Ergosterol PK: NOT ABSORBED in GI tract MOA/PK/PD/RESISTANCE *bile acid binding resins: promotes excretion of bile salts by forming an insoluble complex in SI 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)

*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

CLINICAL USE (CU) /ALTERNATE USE (AU) *for HYPERCHOLESTEROLEMIA * Cholestasis / Bile Acid accumulation Type IIa (Familial hypercholesterolemia), IIb (Familial combined hyperlipidemia)

AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) T: BLOATEDNESS, CONSTIPATION, UNPLEASANT GRITTY TASTE

DRUG INTERACTIONS / NOTES Impaired () absorption: *Vitamin K / Dietary folates (fat soluble) * Digitalis * Thiazides * Warfarin * Pravastatin * Fluvastatin 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.)

STATINS ATORVASTATIN CERIVASTATIN FLUVASTATIN PRAVASTATIN

*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 PK: metabolized by Cyt P450 system PRODRUGS Nicotinic Acid MOA: directly reduces secretion/production of VLDL resulting to dec LDL inc clearance of VLDL by lipoprotein lipase inc HDL dec serum triglyceride concentration *ligands for PPAR- protein: regulates transcription of genes involved in lipid metabolism - (Peroxisome Proliferator Activated Receptor-Alpha) MOA: inc activity of lipoprotein lipase enhanced clearance of triglyceride-rich lipoproteins dec hepatic secretion/production of VLDL, ( LDL: HDL) dec serum triglycerides MOA: lowers serum cholesterol by inc LDL catabolism

* 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)

*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

VITAMIN

LOVASTATIN SIMVASTATIN NIACIN

*wider spectrum of use Type IIa (Familial hypercholesterolemia), IIb (Familial combined hyperlipidemia), III (Familial dysbetalipoproteinemia), IV (Familial hypertriglyceridemia), V (Familial Mixed Hypertriglyceridemia) Type IIb (Familial combined hyperlipidemia), III (Familial dysbetalipoproteinemia), IV (Familial hypertriglyceridemia), V (Familial Mixed Hypertriglyceridemia) *usually combined with other antihyperlipidemics

*Intense CUTANEOUS FLUSHING (prevented by pretreated with Aspirin / NSAIDS) AE: dose-dependent nausea and abdominal discomfort, pruritus, moderate of liver enzymes, may be hepatotoxic AE: NAUSEA, skin rashes (Gemfibrozil), GI distress, gas Some pxs: dec WBC / Hct T (Clofibrates): GI and Hepatobiliary neoplasms

decreases circulating FIBRINOGEN increases TISSUE PLASMINOGEN ACTIVATOR (TPA) Carbohydrate tolerance: may be moderately impaired

FIBRATES

GEMFIBROZIL FENOFIBRATES CLOFIBRATES (more toxic)

Anticoagulants: potentiate action Pxs w/history of Gallstones: CAUTION! (inc risk of gallstones)

MISCELLANEO US

PROBUCOL

Type IIa (Familial hypercholesterolemia)

T: PROLONGED QT (Arrythmias), Eosinophilia

THYROID DRUGS GROUP DRUGS T3 LIOTHYRONINE LIOTRIX (most toxic: T4:T3 = 4:1)

MOA/PK/PD/RESISTANCE *10x more potent than T4 PK: absorbed in small intestines (SI) PD: HL (2days) T3 PD: HL (7days) T4 (more bound, less active, longer

CLINICAL USE (CU) /ALTERNATE USE (AU) *Myxedema coma: medical emergency due to severe, long-standing hypothyroidism

AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) T: THYROTOXICOSIS Cardiac effects (palpitations, arrythmias)

DRUG INTERACTIONS Cholestyramine (resins) & Al (OH)3: -decreases absorption of T3 and /or T4

NOTES

HL) T4 (considered to be a prohormone) LEVOTHYROXINE SODIUM *pregnant hypothyroid women: higher T4 dose needed -estrogen increases TBG production

-hypothermia, respiratory depression, unconsciousness *Hypothyroidism: due to prolonged duration of action -to prevent Cretinism (in hypothyroid NB, given after birth) *after Thyroid Ca: to suppress TSH *GRAVES DISEASE *Radiation Adjuvant: used in pxs while awaiting 131 I effects *prior to surgery: to prevent thyroid storm PTU: for hyperthyroidism in pregnant and nursing women T: Transient leucopenia Fever, skin rash, itching, joint pains, Hypothyroidism

Estrogen: TBG (more protein to bind to T4) Glucocorticoids: conversion of T4 T3

ANTITHYROID S

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 PK: 80% bound to serum proteins (highly protein bound that it cant pass through placenta, less concentration in breastmilk) Shorter HL: 1-2 hrs PK: less protein bound HL: 5-6 hrs MOA: inhibits RELEASE of T3 / T4 from the thyroid gland Acutely inhibits IODINATION of TG (WolffChaikoff effect) Lugols: 5% iodine + 10% Potassium iodide Iodine component is reduced Iodide in the SI prior to absorption *Emits both and rays MOA: rays: specifically destroys thyroid parenchyma / cells PK: crosses the placenta + found in breastmilk HL: 8 days
131

METHIMAZOLE IODIDE LUGOLS SOLN. POTASSIUM IODIDE

*same with above * less Agranulocytosis seen (0.12%) *GRAVES DISEASE *Radiation Adjuvant: used in pxs while awaiting 131 I effects *prior to surgery: to prevent thyroid storm Potassium Iodide (AU): for SPOROTRICHOSIS 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)

RADIOACTIVE IODIDE (delayed onset of effects)

123

Hyperthyroidism -Hyperthyroidism in elderly with cardiac dse - DOC: persistent / recurrent Graves dse (despite Sx/meds) - Toxic nodular goiter *** use restricted to pxs older than 30yo For Diagnostic thyroid scanning ***rarely used now

*Emits / x-rays HL: 13 hrs MOA: competitively inhibits IODIDE TRANSPORT mechanism in thyroid follicular cells High doses: inhibits TG IODINATION

IONIC INHIBITORS

THIOCYANATE PERCHLORATE

Perchlorate: FATAL APLASTIC ANEMIA

MISCELLANEO US

IOPANOIC ACID SODIUM IPODATE

MOA: inhibits PERIPHERAL CONVERSION T4 T3 Suppress conversion of T4 T3 via 5deiodinase (liver, kidney, peripheral tissue) MOA: blocks both B1 / B2 receptors in tissues

*short term treatments of hyperthyroid states

SYMPTOMATIC TX

BETA BLOCKERS

*Hyperthyroidism: to alleviate s/s (tremors, sweating, palpitations tachycardia) *Radiation Adjuvant: used in pxs while awaiting 131 I effects

ANTI-MICROBIALS GROUP DRUGS

MOA/PK/PD/RESISTANCE

CLINICAL USE (CU) /ALTERNATE USE (AU)

AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD)

DRUG INTERACTIONS

NOTES