Type Classification Subclass Sp. Drugs Hydrolyzed by

Sp. Receptor / distinguishing feature

MOA Clinical Use (Administration) Contra/ Side Effects

Chol

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Direct acting C-Receptor Agonists

Choline EstersAch (acetylcholine) Yes Muscarinic + Nicotinic

Mimic action of Ach

Miosis during ophthalmic surgery (Intraocular)

Bethenacol No - Muscarinic- synthetic drug

Coronary Angiography (Intracoronary)Post-op or post-partum urinary retention (Oral / SQ)

Plant Alkaloids

Carbachol No Muscarinic + Nicotinic Glaucoma (Topical Ocular)Miosis during ophthalmic surgery (Intraocular)

Muscarine No MuscarinicNicotine No Nicotinic Smoking cessation programs (Oral / transdermal)

Pilocarpine No Muscarinic > Nicotinic- production of aqueous humor

Glaucoma (Topical Ocular)Xerostomia – dryness of the mouth (Oral)

Indirect Acting … (exaggerate effects of parasympa NS by

Inhibiting Cholinesterase

Reversible …(short acting)

Donezepil

Binds to acetylcholinesterase

Alzheimer’s Disease (Oral)Endrophonium Myasthenia gravis – diagnosis (IV)

NeostigmineMyasthenia gravis, post-op urinary retentionand post-op abdominal (Oral / IV / SQ)distention

Physostigmine

Antidote: Curariform drug toxicity (IV)Glaucoma (Topical Ocular)Reversal of CNS effects of anti-muscarinic <eg ATROPINE> (IM / IV)

PyridostigmineMyasthenia gravis (Oral / IM / IV)Antidote: Curariform drug toxicity (IV)Alzheimer’s disease (Oral)

Tacrine

Irreversible …(long acting)

Echothiophate Form covalent bonds w/ catalytic site cholinesterase

Glaucoma + accommodative esotropia (Topical Ocular)IsoflurophateMalathione Pediculosis (Topical)

increases Ach Release CisaprideMetoclopramide

Other Cholinergic Receptor Agonists

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

Potentiates vasodilative effect of Ach= penile blood flow= penile erection

Extra careful in… (kse vasodilators un drugs!) HPN px, Reflex tachycardia, angina, MI

Inhibition of cGMP metab by type5 Phosphodiesterase

= cGMP

Erectile dysfunction

HeadacheBlurred visionNasal congestion

Chol

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NTA

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Muscarinic Receptor Antagonists

Belladonna alkaloids

Atropine Indications… look at handouts…

Hyoscyamine Aka Buscopan- anti-spasmodic

Scopolamine

Semisynthetic + synthetic

Dicyclomine - anti-spasmodic

Ipratropium - checks secretions- combined w/ Salbutamol = anti-asthma

Flavoxate, Oxybutinin, Tropicamide

Nicotinic Receptor Antagonists

Ganglionic blocking agents

Trimethapham - sympathetic blockade (hypotension)- para … (dry mouth, blurred vision, urinary retention)

Blocks NN receptor @ both sympa + para ganglia

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

NeuromuscularBlocking agents

Non depolarizing

AtracuriumDoxacuriumPancuroniumTubocurarineVecuronium

Depolarizing Succinylcholine

Type Classification Subclass Sp. Drugs Pharmacologic Effects (and Receptor) Clinical Use (Administration) Notes Overall effect

Adre

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DIRECT ACTING…

Catecholamines

Dobutamine Cardiac stimulation (1) Shock and heart failureDobutamine, Dopamine, Epi… - contraindication in HPN Px

Bronchodilation BP

DopamineRenal vasodilation (D1) Cardiac stimulation (1) BP (1)

Shock and heart failure

EpinephrineCardiac stimulation (1) BP (1)Bronchodilation (2)

Anaphylactic shock, cardiac arrest, ventricular fibrillation, reduction in bleeding during surgery, and prolongation of the action of local anesthetics

DOC for anaphylactic shock!

Isoproterenol Cardiac Stimulation (1)AV blockBradycardia

Potency- adrenergic Rec E/Ne > isoproterenol

Potency- adrenergic Rec Isoproterenol > E /NE

Norepinephrine BP (1)Hypotension + shock

Non-catecholamines

Albuterol Bronchodilation (2) AsthmaApraclonide aqueous humor formation ( 2) Chronic open-angle glaucomaClonidine sympathetic outflow from CNS ( 2 + imidazoline) Chronic hypertensionOxymetazoline Vasoconstriction ( 1) Nasal + ocular decongestion

Phenylephrine Vasoconstriction, BP, mydriasis ( 1)

Nasal decongestionOcular decongestionMydriasisMaintenance of BP during surgery Tx of neurogenic shock

RitodrineBronchodilation + uterine relaxation (2) Asthma + premature labor

Terbutaline

INDIRECT ACTING…Amphetamine in norepinephrine release CNS effectsCocaine (X) inhibition of norepinephrine uptake Local anesthesia

MIXED ACTING…Ephedrine

Vasoconstriction ( 1) Nasal decongestionAnorexic drugs (large qty: 50-100mg)? Contra: HPN PxPhenylpropanolamine

Pseudoephedrine

Adre

nerg

ic R

ecep

tor -Adrenergic…

Selective 1 blockers

DoxazosinPrazosinTerazosin - for HPN Pxs

Applies to ALL: for BPHP (Benign Prostatic Hyperplasia)

Good to use bcoz effects can be limited

Non – Selective blockers

PhenoxybenzaminePhentolamine

-Adrenergic… Selective 1 blockers AcebutololAtenololEsmololMetoprolol - cheapest anti-HPN (eg. Neobloc)

ANTA

GO

NIS

TS Non – Selective blockers

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

+ Adrenergic… CarvediolLabetalol

ANTI-PROTOZOALGROUPS SUBGROUPS MOA/PK/PD/RESISTANCE CLINICAL USE (CU) /ALTERNATE USE (AU) AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS NOTESANTI-MALARIALS CHLOROQUINE (CHL) *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

*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

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

QUININE *principal alkaloid derived from the bark of the Cinchona treePK: 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)

* (+) 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

MEFLOQUINE *synthetic 4-quinoline derivative chemically related to QuininePK: given orally (due to local irritation) with variable absorptionMOA: unknown

*for PROPHYLAXIS in all malarious areas with chloroquine resistance T: less toxic than quinineAE: GI distress, skin rash, HA, dizziness

CONTRAINDICATION: Pregnancy Epilepsy

PRIMAQUINE *synthetic-8-aminoquinolinePK: complete absorption after oral administration, followed by extensive metabolism

MOA: forms QUINOLINE-QUINONE metabolites – acts as cellular oxidants

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

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

CONTRAINDICATION: G6PD def (hematotoxic / hemolytic) Pxs predisposed to granulocytopenia (ie: SLE, RA)

ANTI-FOLATE DRUGS*Pyrimethamine*Sulfadoxine*Dapsone*Proguanil (short HL – 12-16hrs; bioactivated to Cycloguanil)

Pyrimethamine MOA: (together w/Cycloguanil): selective inhibitors of protozoan dihydrofolate reductase

***(+) synergistic antimalarial effects with Sulfodoxine – (+) sequential blockade of 2 steps in FA synthesis

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

T: folic acid deficiency (high doses)

Sulfonamides(Sulfodoxine)

MOA: act as anti-metabollite of PABA and block folic acid synthesis (in certain protozoans) by inhibiting dihydropteroate synthase

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

* (+) TISSUE AMEBICIDESDOC: severe intestinal wall dse and hepatic abscess and other extraintestinal amebic dse (luminal / extraluminal)

AE: GI irritation, HA, dark coloration of urineT: leucopenia, dizziness, ataxia

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

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

AU: tx of the following Trichomoniasis, Giardiasis, Gardnerella vaginalis infection, anaerobic

bacteria (Bacteroides fragilis, Clostridium difficile)

CONTRAINDICATION: Pregnancy (may be teratogenic)

EMETINES MOA: inhibit protein synthesis by blocking ribosomal movement along mRNA

PK: alkaloids given parenterally

* (+) TISSUE AMEBICIDES* used as back-up drugs for severe intestinal or hepatic amebiasis in hospitalized patients

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

IODOQUINOL *halogenated hydroxyquinoline

PK: orally active luminal amebicide (acts on Trophozoites)

* (+) LUMINAL AMEBICIDES

AU: alternative drug for mild-severe intestinal infections

AE: common but usually mild (GI)T (systemic absorption after high doses): Thyroid enlargement, neurotoxic (peripheral neuropathy, visual

dysfunction)DILOXANIDE FUROATE *converted in the gut to the diloxanide freebase form (active

amebicide)* (+) LUMINAL AMEBICIDES* DOC: asymptomatic amebiasis (cyst-passers)

T: mild, usually restricted to GI s/s

CONTRAINDICATION: Lactating mothers Infants < 2months age

PAROMOMYCIN *aminoglycoside antibiotic * (+) LUMINAL AMEBICIDES (2nd line w/ D. Furoate)*AU: some effects on Cryptosporidiosis (AIDS)*sometimes used with Tetracycline (Doxycycline) in mild intestinal dse

*common adverse GI effectsT (systemic absorption): HA, dizziness, rashes, arthralgia

DRUGS FOR PNEUMOCYSTOSIS(PCP)andTOXOPLASMOSIS

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)

*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)

TRIMETHOPRIM-SULFAMETHOXAZOLE (TMP-SMZ)

PD: oral (double strength formulation TID) or IV *PROPHYLAXIS (FIRST CHOICE) for PCP – AIDS px (CD4 < 200cells/ul)* choice of treatment for PCP (Pnemocystosis Pneumonia)

AU: prophylaxis against Toxoplasmosis & Isospora belli infections

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

ANTIFOLATES: (see above)PYRIMETHAMINE & SULFONAMIDESATROVAQUONE MOA: inhibits mitochondrial electron transport & probably

folate metabolism

PK: used orally Poorly absorbed and should be given with food to maximize bioavailability eliminated in feces Unchanged

*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 Trimethroprim + dapsonePrimaquine + clindamycinTrimetrexate + leucovorin

DRUGS FOR TRYPANOSOMIASIS

PENTAMIDINE (see above)MELARSOPROL *organic arsenical

MOA: inhibits enzyme sulfhydryl groups Given parenterally (due to GI irritation)

PK: enters the CNS (passes BBB)

*DOC: for African sleeping sickness – late stage (enters CNS) T: may cause reactive encephalopathy (fatal)

NIFURTIMOX *nitrofurazone derivativeMOA: inhibits trypanothione reductase (unique to parasite)

*DOC: for American trypanosomiasis

AU: for mucocutaneous Leishmaniasis

T (severe): allergies, GI irritation, CNS effects

SURAMIN *polyanionic cmpd MOA: unclear but may involve inhibition of enzymes required for energy metabolism

PK: given parenterally

*DOC: early hemolymphangitic stages of African trypanosomiasis (BEFORE CNS INVOLVEMENT)

AU: alternative to Ivermectin (Onchocerciasis: with Diethylcarbamazine)

T: rashes, GI distress, neurologic complications

LEISHMANIASIS 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-HELMINTHSGROUP DRUGS MOA/PK/PD/RESISTANCE CLINICAL USE (CU) /ALTERNATE USE (AU) AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS NOTESAGAINST NEMATODES

ALBENDAZOLE MOA: blocks glucose uptake in both larval / adult parasites ↓ dec ATP formed subsequent parasite immobilization Inhibition of microtubule assembly

*wide antihelminthic spectrumAU: alternative drug for larva migrans, ascariasisInfections: roundworm, whipworm, hookworm, pinworm, threadworm Also active in PORK TAPEWORM (larval stage)

*few toxic effects in short coursesT (prolonged use): REVERSIBLE leucopenia, alopecia, changes in liver enzymesLong-term animal toxicity: bone marrow suppression, Fetal toxicity

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)

DIETHYLCARBAMAZINE MOA: immobilizes microfilariae (increases susceptibility to host defense) ↑inc susceptibility of microfilaria to phagocytosis

PK: rapidly absorbed in gut, excreted in urine

DOC: Filariasis

AU: (**in combination with Suramin) – Onchocerciasis Loa loa Ascariasis Topical pulmonary eosinophilia

AE: HA, malaise, weakness, anorexiaRxns 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

IVERMECTIN MOA: ↑ intensifies GABA mediated neurotransmission (immobilization of parasites) removal by reticuloendothelial system Selective toxicity: do not pass BBB

DOC: Onchocerciasis (River blindness)(acts slowly than Diethylcarbamazine but fewer systemic/ocular rxns)

DOC: Strongloidiasis (threadworm)AU: Filariasis

*Single dose oral tx: may cause MAZZOTTI RXN(usually short duration: controlled by Antihistamines Or NSAIDS)

*Antihistamines*NSAIDS -both to ↓ Mazzotti rxns

MEBENDAZOLE MOA: *Inhibition of microtubule assembly *blocks glucose uptake in Nematodes

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

DOC: Pinworm (Enterobiasis) / Whipworm (Trichuriasis)DOC: (with Pyrantel Pamoate): Roundworm And combined infections: Ascarids + Hookworms

AU: as back-up drug for Cestodes / Trematode infections

AE: limited to GI irritation

*CONTRAINDICATED: PREGNANCY (embryotoxic)

PIPERAZINE MOA: GABA receptor agonist (paralyzes parasites) Paralyzed roundworms are expelled alive via Normal peristalsis (YAK!!!) AU: Ascariasis

SE: mild GI irritationCONTRAINDICATED: SEIZURE PATIENTS

PYRANTEL PAMOATE *congener: Oxantel PamoateMOA: inhibits Cholinesterases & stimulates Nicotinic receptors present at NMJ of nematodes (initial contraction of muscles depolarization-induced paralysis)

PK: poorly absorbed when given orally

DOC: (with Mebendazole): Hookworm, Pinworm, Roundworm AE (minor): GI distress, HA, weakness

THIABENDAZOLE *structural congener of MebendazoleMOA: Inhibition of microtubule assembly

PK: rapidly absorbed in the gut Metabolized by hepatic enzymes (+) Immunorestorative / Anti-inflammatory actions in the host

DOC: Visceral larva migrans

AU: for treatment of: Strongyloidiasis (Threadworm), Cutaneous larva migrans: DOC

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

AGAINST TREMATODES

PRAZIQUANTEL 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)

*wide spectrum: Trematodes + CestodesDOC: Schistosomiasis (all species) Clonorchiasis / Paragonimiasis

AU: DOC (with Niclosamide): Cestodes (all common tapeworms) Cysticercosis

Common AE: HA, dizziness, malaiseLess frequently: GI irritation, skin rash, fever

CONTRAINDICATED: OCULAR CYSTICERCOSIS Pregnancy

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

BITHIONOL MOA: unknown

PK: orally effective; eliminated in urine

DOC: Fascioliasis (sheep liver fluke)

AU: Paragonimiasis

Common AE: N/V, diarrhea, Abd cramps, dizziness, HA, phototoxicityLess frequently: pyrexia, tinnitus, proteinuria, leukopenia

METRIFONATE *organophosphate PROdrugMOA: converted to DICHLORVOS (Cholinesterase inhibitor) Acts solely to Schistosoma haematobium (BILHARZIASIS)

DOC: Schistosoma haematobium (BILHARZIASIS)T: excess Cholinergic stimulation

OXAMNIQUINE MOA: acts solely to Immature / Adult schistosomal forms DOC: Schistosoma mansoni AE: DIZZINESS, HA, GI irritation, pruritus

Rxns due to proteins of dying filariae: -eosinophilia, urticaria, pulmonary infiltrates

CONTRAINDICATED: PREGNANCY, SEIZURESAGAINST PRAZIQUANTEL (see above) Recall:

CESTODES 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)

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

ANTI-VIRALSGROUP DRUGS MOA/PK/PD/RESISTANCE CLINICAL USE (CU) /ALTERNATE USE (AU) AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS NOTESANTIHERPETIC DRUGS ACYCLOVIR

(ACYCLOGUANOSINE)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)

PK: given topical, oral, IV (for severe & neonatal HSV infection) Excretion: RENAL

*DOC: for HSV / VZV* Mucocutaneous and Genital Herpes*for Prophylaxis in AIDS / Immunocompromised pxs

AE: generally well tolerated but may cause GI distress, HA

T (parenteral): delirium, tremor, seizures, hypotension NEPHROTOXIC!*** NO noted toxicity on bone marrow

Notes: ACYCLOVIR CONGENERSFamciclovir: 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

Valacyclovir: converted to Acyclovir by hepatic metabolism; Reaches plasma level 3-5x faster than Acyclovir + longer duration of action

FOSCARNET *phosphonoformate derivativeMOA: 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

*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

GANCICLOVIR *guanine derivativeMOA: 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

*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 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

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

NEPHROTOXIC!!!

VIDARABINE *Adenine analogPK: (+) rapid metabolic inactivation with marked toxic potential

(+) activity against: HSV, VZV, CMVGiven IV: severe HSV infections (including Acyclovir-resistant) Also to prevent dissemination of VZV in immunocompromised pxs

Topical: HSV Keratitis (NO EFFECT in Gental Herpes)

T: GI irritation, paresthesias, tremor, convulsions & hepatic dysfunctions

*** TERATOGENIC (in animal studies)

SORIVUDINE *Pyrimidine analog* still an investigational drug: 1000x more potent that Acyclovir (but still not effective for Acyclovir resistant HSV)

(+) activity against: HSV-1, VZV, EBV

IDOXURIDINETRIFLURIDINE

*Pyrimidine analogs Topical: HSV Keratitis TOO TOXIC FOR SYSTEMIC USE!!!

FOMIVIRSEN *anti-sense oligonucleotideMOA: binds to mRNA of CMV inhibiting early protein synthesis

Given IntraVitreally: CMV retinitis

ANTI-HIV (NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS - NRTIs)

ZIDOVUDINE (ZDV) *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)

*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

Elimination: Hepatic metabolism to glucoronides + Renal excretion HL: 1-3 hrs

Azole antifungals and Protease inhibitors: -inhibits metabolism of ZDV

Rifampicin: ↑inc clearance of ZDVDIDANOSINE (ddI) *Deoxyadenosine analog

MOA: activated by host kinases triphosphate form inhibits reverse transcriptase + causes chain termination

R: associated with point mutations of the pol gene 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

*commonly used: HAART regimen T: PANCREATITIS (dose-limiting) -seen with Alcohol intake -also seen in Hypertriglyceridemia

AE: Peripheral neuropathy, diarrhea, hepatic dysfunction, Hyperuricemia, CNS effects

Chelating agents and Food intake: ↓ decreases BA of ddI

With Alcohol: (+) Pancreatitis

ZALCITABINE (ddC) *pyrimidine nucleosideMOA/R: similar to other NRTIs

PK: high oral BA

*commonly used in combined regimens T: Peripheral Neuropathy (Dose-dependent) Nephrotoxic!!! Pancreatitis, esophageal ulceration, stomatitis, arthralgias

LAMIVUDINE (3TC) MOA: similar to other NRTIs

PK: used orally (part of HAART regimen)

*active against HIV-1 (including ZDV-resistant strains)

AU: Hepa B, HBV (12wks tx in adjuct w/ Interferon alpha)

AE: usually mild: GI distress, HA, insomnia, fatigue

STAVUDINE (d4T) *thymidine analogPK: good oral BA, penetrates most tissues (CROSSES BBB)

R: may be due to Stavudine alone or could have Cross-resistance

*used in HAART regimen T: Peripheral Neuropathy (Dose-dependent) Nephrotoxic!!!

ABACAVIR *guanosine analogPK: good oral BA Metabolism: via Alcohol dehydrogenase and Glucuronosyltransferase

*used in combination w/ ZDV + 3TC T: Severe Hypersensitivity reactions involving multiple organ systems (lethal!)

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

NEVIRAPINEDELAVIRDINEEFAVIRENZ

ANTI-HIV(PROTEASE INHIBITORS)

INDINAVIRRITONAVIROther Protease inhibitors:SAQUINAVIRNELFINAVIRAMPRENAVIR

MISCELLANEOUS ANTIVRALS

AMANTADINERIMANTADINEOSELTAMIVIRZANAMIVIRINTERFERONSRIBAVIRIN

TOPICAL ANTIVIRAL DRUGS

IDOXURIDINE

CYTARABINETRIFLUOROTHYMIDINE

ANTI NEOPLASMSGROUPS SUBGROUPS DRUGS MOA/PK/PD/RESISTANCE CLINICAL USE (CU) /ALTERNATE USE (AU) AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS NOTESALKYLATING AGENTS (CCNS DRUGS)

-react with DNA- targets: N-7 and O-6 positions of guanine-results with *DNA cross-linking*base-pair mismatching*DNA breakage

NITROGEN MUSTARDS: CHLORAMBUCIL

CYCLOPHOSPHAMIDE PK: hepatic cyt p450 biotransformation 1 of breakdown product: ACROLEIN

*Non-Hodgkin Lymphoma* Breast / Ovarian Ca* Neuroblastoma

AE: GI distress, myelosupression & alopecia *** Hemorrhagic Cystitis: due to ACROLEIN May be ↓ dec by vigorous hydration + use of MESNA (mercaptoethanesulfonate)

*may also cause: cardiac dysfunction, pulmonary toxicity, SIADH

*Alkylating agents are CCNS drugsMOA: 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 *Phenylalanine derivative of nitrogen mustard that cross links strands of DNA and RNA

*Ovarian Ca, Multiple Myeloma AE: Bone marrow suppression (leucopenia, thrombocytopenia)

MECHLORETHAMINE MOA/PK: spontaneously converted to a reactive cytotoxic product in the body

*Hodgkin Lymphoma: MOPP regimen(Mechlorethamine, Oncovin (Vincristine), Procarbazine, Prednisone)-MAINSTAY of drug tx for st III-IV-replaced for initial therapy by ABVD regimen

AE: GI distress, myelosupression & alopecia *** marked vesicant action

NITROSOUREAS CARMUSTINE (BCNU)LOMUSTINE (CCNU)

PK: highly lipophilic Facilitates CNS entry

*used as ADJUNCTS for tx of BRAIN TUMORS AE: GI distress, myelosupression & CNS dysfxn

STREPTOZOCIN *naturally occurring antibiotic derived from Streptomyces acromogenes*Diabetogenic agent: High affinity / toxicity to Pancreatic Beta cells

PK: crosses BBB CCNS

*Pancreatic Carcinoma* Insulinomas

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

OTHERS: AKYLSULFONATES

CISPLATIN / CARBOPLATIN

Cisplatin: used IV Distributed to most tissues Cleared in kidneys Unchanged

*Platinum coordination complexMOA: enters cells by diffusion & is hydrolyzed to form an activated electrophile which alkylates DNA CCNS

*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

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

*Hodgkin Lymphoma: MOPP regimen(see above)

(+) myelosuppressant(+) LEUKEMOGENICAE: GI Irritation, CNS dysfxn, peripheral neuropathy, skin rxns

*inhibit many enzymes: MAO * Enzymes involved in Hepatic metabolism

Ethanol: disulfiram-like reactions

DACARBAZINE MOA: thought to inhibit DNA / RNA synthesis via formation of Carbonium ions

PK: hepatically activated Given IV

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

T: adrenal insufficiency, pulmonary fibrosis, skin pigmentation

BUSULFAN *alkyl-sulfonate type bifunctional alkylating agent DOC: CML AE: GI distress, myelosupression & alopecia Skin rash, phototoxicity, flu-like syndromeT (high doses): Pulmonary fibrosis, seizures, hepatic veno- occlusive disease

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 important for cytotoxic actions

PK: IV / Oral admin: good tissue distribution

*Choriocarcinoma* Breast Ca* Acute Leukemias* Hodgkins lymphoma* cutaneous T-cell lymphomas

AU: used also in Rheumatic Arthritis

(+) 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 infiltrates/fibrosis

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

(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

ANTIMETABOLITES(CCS DRUGS)-inhibit steps in DNA biosynthesis (specific S-phase)

ANTAGONISTS OF FOLIC ACID

MERCAPTOPURINE (6-MP)

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

*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 S-phase* (+) IMMUNOSUPPRESSANT ACTIONS

PURINES THIOGUANINE (6-TG)*cytosine arabinoside* most specific to S-phase

MOA: activated by kinases AraCTP(inhibitor of DNA polymerases: inhibiting DNA chain elongation)

R: ↓ dec uptake ↓ dec conversion to AraCTP

PK: parenterally via Slow IV infusion May reach appreciable levels to CSF Eliminated: via Hepatic Metabolism

*Acute leukemias* DOC: AML

AE: GI irritation, myelosupression, stomatitisT: Neurotoxic (high doses: Cerebellar dysfxn, peripheral neuritis)

CYTARABINE (ARA-C)

PYRIMIDINES FLUOROURACIL (5-FU) 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

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

AE: GI distress, myelosupression & alopecia

HYDROXYUREA *Urea analogMOA: prevents DNA synthesis by inhibiting Ribonucleotide reductase Acts on S-phase

*CML* Melanoma, Polycythemia vera, Sickle cell anemia

AE: bone marrow suppression, leucopenia, megaloblastic anemia, thrombocytopenia N/V, diarrhea

PLANT ALKALOIDS(CCS drugs)

VINCA ALKALOIDS VINBLASTINEVINCRISTINE

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

*Vincristine: MOPP regimen (see above)* also COP (Cyclophosphamide, Oncovin (Vincristine), Prednisone) -used with or without Doxorubicin (COP-D) -Non-Hodgkins lymphoma* acute leukemia, lymphomas, Wilm’s, 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, Kaposi’s sarcoma

*Vincristine: does not cause serious myelosuppression* NEUROTOXIC: areflexia, peripheral neuritis, paralytic ileus

*Vinblastine: GI distress, myelosupression & alopecia

PODOPHYLLOTOXINS ETOPOSIDETENIPOSIDE

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

*used in drug combination regimens* Lung (SMALL CELL), Prostate, Testicular

AE: GI distress, myelosupression & alopecia *CCS drugs

TAXANES PACLITAXELDOCETAXEL

MOA: “SPINDLE POISONS” Prevents DISassembly of microtubules into tubulin monomers

PK: given IV

*Breast / Ovarian Ca *Paclitaxel: neutropenia, thrombocytopenia, peripheral neuropathy (high incidence), hypersensitivity rxns (possible during infusion)

*Docetaxel: neurotoxicity, bone marrow depressionANTIBIOTICS ANTHRACYCLINES

(CCNS drugs)DOXORUBICIN(Adriamycin)DAUNORUBICIN

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)

*Doxorubicin: ABVD regimen (see above)* myelomas, sarcomas* breast / endometrial / ovarian* lung, thyroid

*Daunorubicin: acute leukemia

*Idarubicin: AML

AE: GI distress, myelosupression & severe alopeciaT: ** CARDIOTOXIC: abn ECG arrhythmia slow-developing cardiomyopathy CHF ** Dexrazoxane: given to counteract cardiotoxicity (free radical scavenger) ** Liposomal formulation of Doxorubicin: less cardiotoxic

BLEOMYCINE *mixture of glycopeptidesMOA: 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

*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)

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

*Melanoma* Wilm’s tumor & Rhabdomyosarcoma: VAC regimen Vincristine, Actinomycin, Cyclophosphamide

AE: GI irritation, bone marrow suppresson & skin rxns

MITOMYCIN 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)

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

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

HORMONAL ANTICANCER AGENTS

GLUCOCORTICOIDS PREDNISONE *most commonly used*most used in combination drug regimens

*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

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 FLUOXYMESTERONE(androgenic steroid)

*estrogens, progestins, androgens: used in hormone-dependent ca

*Fluoxymesterone: may be used in women w/ advanced Breast Ca*Diethylstilbesterol (estrogenic steroids): -sometimes used in Prostate Ca

SEX HORMONE ANTAGONIST

TAMOXIFEN *estrogen receptor PARTIAL agonistMOA: blocks the binding of estrogen to receptors of estrogen-sensitive cells in breast tissue

*Breast Ca: positive-receptor *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

TOREMIFENE *newer estrogen-receptor antagonist *advanced Breast CaFLUTAMIDE *Androgen-receptor antagonist *Prostate Ca AE: gynecomastia, hot flushes, hepatic dysfunction

GnRH ANALOGS LEUPROLIDEGOSERELINNAFARELIN

*administered in CONSTANT doses as to maintain stable blood levelsLeuprolide: long-acting GnRH analog

MOA: inhibit release of Pituitary LH / FSH

*effective as Diethylstibesterol: Prostate Ca(with fewer AE)

Leuprolide (T): bone pains, gynecomastia, hematuria, impotence, testicular atrophy

AROMATASE INHIBITOR

ANASTROZOLELETROZOLE

MOA: inhibit Aromatase (enz that catalyzes conversion of Androstenedione Estrone)

*Advanced Breast Ca T: nausea, diarrhea, hot flushes, bone marrow & back pain, dyspnea, peripheral edema

MISCELLANEOUS ANTICANCER AGENTS

ASPARAGINASE MOA: depletes serum Asparagine (needed for growth) Given IV

*T-cell Auxotrophic Ca (leukemia/lymphomas) AE: severe hypersensitivity rxns, acute pancreatitis, bleeding

MITOXANTRONE *anthracine cmpdMOA: acts via alkylation of DNA bases

*combination regimens: Refractory acute leukemia, Breast Ca

T: GI effects, myelosuppression, cardiac arrythmias

ALPHA-INTERFERONS *endogenous glycoproteins with antineoplastic Immunosuppresant Antiviral actions

*Hairy cell leukemia* CML (early stage)* T-cell lymphomas

T: myelossuppression, neurologic dysfunction

INTERFERONS (INF) RITUXIMAB *MAB to a surface protein in Hodgkins lymphoma *used in combination for low grade lymphomas Acute T: N/V, chills, fevers, HA

Rituximab: hypersensitivity rxns, myelosuppressionTrastuzumab: cardiac dysfunction (CHF)

MONOCLONAL ANTIBODIES

TRASTUZUMAB *MAB to surface protein in Breast Ca that OVEREXPRESS the HER-2 protein

ANTI-FUNGALSGROUP SUB-GROUPS / DRUGS MOA/PK/PD/RESISTANCE CLINICAL USE (CU) /ALTERNATE USE (AU) AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS NOTESSYSTEMIC ANTIFUNGALS

AMPHOTERICIN B *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

*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

*Infusion related: AE (by IV): fever, chills, vomiting, muscle spasm, shock-like fall in BP PREmedication to prevent s/s: antihistamines, antipyretics, Meperidine, 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

Magnesium: Renal tubular acidosis

FLUCYTOSINE *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

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

T: in prolonged high plasma levels (REVERSIBLE): bone marrow depression, alopecia, liver (similar to AE from 5-FU) dysfunction, N/V

AZOLES: PK: Oral bioavailability is variable (normal gastric acidity req’d) Distributed to most body tissues except 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 14α demethylation of Lanosterol, catalyzed by cyt p450)

R: changes in sensitivity of the target enzymes

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

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

AE: vomiting, diarrhea, rash, sometimes hepatotoxic

KETOCONAZOLE 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

*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 *DOC: Candidiasis (Oropharyngeal / Esophageal), Coccidioidomycosis Single-oral dose in Vaginal Candidiasis

*DOC: initial and secondary PROPHYLAXIS against CRYPTOCOCCAL MENINGITIS (and Naegleria fowleri)

*equivalent to Amphotericin B in Candidemia

ITRACONAZOLE *DOC: systemic infections (Blastomyces / Sporothrix) : Subcutaneous Chromoblastomycosis

AU: Aspergillus, Coccidioides, Cryptococcus, Histoplasma

Esophageal Candidiasis: active in some strains resistant to Fluconazole

VORICONAZOLE *new azole with wider spectrum than ItraconazoleSUPERFICIALANTIFUNGALS(SYSTEMIC)

GRISEOFULVIN 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

*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 MOA: inhibits fungal enzyme, SQUALENE EPOXIDASE FUNGICIDAL

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

AE: GI upsets, rash, HA, taste disturbances

AZOLES (see above)SUPERFICIALANTIFUNGALS(TOPICAL)

NYSTATINS *polyene antibiotic related to Amphotericin BMOA: disrupts fungal membranes by binding to ErgosterolPK: NOT ABSORBED in GI tract

*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

ANTI-HYPERLIPIDEMICSGROUP SUB-GROUPS / DRUGS MOA/PK/PD/RESISTANCE CLINICAL USE (CU) /ALTERNATE USE (AU) AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS / NOTESBILE ACID SEQUESTRANTS (RESINS)

CHOLESTYRAMINECOLESTIPOL

*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)

*Pxs w/ Familial hyperlipidemia: can ↑ inc VLDL

*for HYPERCHOLESTEROLEMIA* Cholestasis / Bile Acid accumulation

Type IIa (Familial hypercholesterolemia), IIb (Familial combined hyperlipidemia)

T: BLOATEDNESS, CONSTIPATION, UNPLEASANT GRITTY TASTE

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”ATORVASTATINCERIVASTATINFLUVASTATINPRAVASTATIN

MOA: REVERSIBLE and COMPETITIVELY inhibit HMG-CoA 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

*↓ 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

LOVASTATINSIMVASTATIN

PRODRUGS

VITAMIN NIACIN “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

*wider spectrum of useType IIa (Familial hypercholesterolemia), IIb (Familial combined hyperlipidemia), III (Familial dysbetalipoproteinemia), IV (Familial hypertriglyceridemia), V (Familial Mixed Hypertriglyceridemia)

*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)

Carbohydrate tolerance: may be moderately impaired

FIBRATES GEMFIBROZILFENOFIBRATESCLOFIBRATES (more toxic)

*ligands for PPAR-α 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

Type IIb (Familial combined hyperlipidemia), III (Familial dysbetalipoproteinemia), IV (Familial hypertriglyceridemia), V (Familial Mixed Hypertriglyceridemia)

*usually combined with other antihyperlipidemics

AE: NAUSEA, skin rashes (Gemfibrozil), GI distress, gas Some pxs: ↓dec WBC / Hct

T (Clofibrates): GI and Hepatobiliary neoplasms

Anticoagulants: ↑ potentiate action

Pxs w/history of Gallstones: CAUTION! (↑inc risk of gallstones)

MISCELLANEOUS PROBUCOL MOA: ↓ lowers serum cholesterol by ↑ inc LDL catabolism Type IIa (Familial hypercholesterolemia) T: PROLONGED QT (Arrythmias), Eosinophilia

THYROID DRUGSGROUP DRUGS MOA/PK/PD/RESISTANCE CLINICAL USE (CU) /ALTERNATE USE (AU) AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS NOTEST3 LIOTHYRONINE

LIOTRIX (most toxic: T4:T3 = 4:1)

*10x more potent than T4PK: absorbed in small intestines (SI)PD: HL (2days) – T3PD: HL (7days) – T4 (more bound, less active, longer HL)

*pregnant hypothyroid women: higher ↑ T4 dose needed -estrogen ↑increases TBG production

*Myxedema coma: medical emergency due to severe, long-standing hypothyroidism -hypothermia, respiratory depression, unconsciousness

T: THYROTOXICOSIS Cardiac effects (palpitations, arrythmias)

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

Estrogen: ↑ TBG (more protein to bind to T4)

Glucocorticoids: ↓ conversion of T4 T3

T4 (considered to be a prohormone)

LEVOTHYROXINE SODIUM

*Hypothyroidism: due to prolonged duration of action -to prevent Cretinism (in hypothyroid NB, given after birth)

*after Thyroid Ca: to suppress TSH

ANTITHYROIDS

PROPYLTHIOURACIL

MOA: INHIBITS THYROID PEROXIDASE thereby preventing iodination of tyrosyl residues of TG and coupling of Iodotyrosine residues

*GRAVE’S 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*The only drug that INHIBITS PERIPHERAL DEIODINATION OF T4 T3

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

T: Transient leucopenia Fever, skin rash, itching, joint pains, Hypothyroidism

METHIMAZOLE PK: less protein bound HL: 5-6 hrs

*same with above* less Agranulocytosis seen (0.12%)

IODIDE LUGOL’S SOL’N.POTASSIUM IODIDE

MOA: inhibits RELEASE of T3 / T4 from the thyroid gland Acutely inhibits IODINATION of TG (Wolff-Chaikoff effect)

Lugol’s: 5% iodine + 10% Potassium iodide Iodine component is reduced Iodide in the SI prior to absorption

*GRAVE’S 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)

RADIOACTIVE IODIDE(delayed onset of effects)

123 I *Emits both β and γ raysMOA: β rays: specifically destroys thyroid parenchyma / cells

PK: crosses the placenta + found in breastmilk HL: 8 days

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

T: high incidence of delayed Hypothyroidism

CONTRAINDICATIONS: Pregnancy, Nursing mothers, coexisting severe ophthalmopathy (may exacerbate condition)

131 I *Emits γ / x-rays HL: 13 hrs

For Diagnostic thyroid scanning

IONIC INHIBITORS THIOCYANATEPERCHLORATE

MOA: competitively inhibits IODIDE TRANSPORT mechanism in thyroid follicular cells

High doses: inhibits TG IODINATION

***rarely used now Perchlorate: FATAL APLASTIC ANEMIA

MISCELLANEOUS IOPANOIC ACIDSODIUM IPODATE

MOA: inhibits PERIPHERAL CONVERSION T4 T3 Suppress conversion of T4 T3 via 5’deiodinase (liver, kidney, peripheral tissue)

*short term treatments of hyperthyroid states

SYMPTOMATIC TX BETA BLOCKERS MOA: blocks both B1 / B2 receptors in tissues *Hyperthyroidism: to alleviate s/s (tremors, sweating, palpitations tachycardia)

*Radiation Adjuvant: used in pxs while awaiting 131 I effects

ANTI-MICROBIALSGROUP DRUGS MOA/PK/PD/RESISTANCE CLINICAL USE (CU) /ALTERNATE USE (AU) AE/SE/TOXICITY (T)/ ALTERNATIVE DRUG (AD) DRUG INTERACTIONS NOTES