Professional Documents
Culture Documents
Classification
Subclass
Hydrolyz ed by Yes No
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
No No No No
Muscarinic + Nicotinic Muscarinic Nicotinic Muscarinic > Nicotinic - production of aqueous humor
Physostigmine
Binds to acetylcholinesteras e
Pyridostigmine
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
Erectile dysfunction
Atropine
Hyoscyamine Scopolamine Dicyclomine Ipratropium Flavoxate, Oxybutinin, Tropicamide Trimethapham Atracurium Doxacurium Pancuronium Tubocurarine Vecuronium Succinylcholine Sp. Drugs Dobutamine Dopamine
Semisynthetic + synthetic
- sympathetic blockade (hypotension) - para (dry mouth, blurred vision, urinary retenti on)
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
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
( 1)
INDIRECT ACTING
( 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
Local anesthesia Nasal decongestion Applies to ALL: for BPHP (Benign Prostatic Hyperplasia) Anorexic drugs (large qty: 50-100mg)? Contra: HPN Px
-Adrenergic
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
PRIMAQUINE
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
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)
EMETINES
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
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
*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)
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)
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
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)
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
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
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
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)
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
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
*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
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)
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
*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
ABACAVIR
MISCELLANEOUS ANTIVRALS
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
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
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: N/V, Bone marrow suppression, leucopenia, thrombocytopenia T: Renal failure (Nephrotoxic?!?)
OTHERS: AKYLSULFONATES
CISPLATIN / CARBOPLATIN
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
*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
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
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)
MERCAPTOPURIN E (6-MP)
AE: bone marrow suppression (dose-limiting) Hepatic dysfunction (cholestasis, jaundice, necrosis)
*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)
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
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
*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
*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
MITOMYCIN
* Against hypoxic tumor cells * Adenoca: cervix, stomach, pancreas, lung Used as combination regimen
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
*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
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
RITUXIMAB
Acute T: N/V, chills, fevers, HA Rituximab: hypersensitivity rxns, myelosuppression Trastuzumab: cardiac dysfunction (CHF)
TRASTUZUMAB
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
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:
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
*DOC: systemic infections (Blastomyces / Sporothrix) : Subcutaneous Chromoblastomycosis AU: Aspergillus, Coccidioides, Cryptococcus, Histoplasma Esophageal Candidiasis: active in some strains resistant to Fluconazole
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
*also accumulates in Keratin (PULSE DOSING) *Onychomycosis: more effective than Griseofulvin
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
*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
*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
Anticoagulants: potentiate action Pxs w/history of Gallstones: CAUTION! (inc risk of gallstones)
MISCELLANEO US
PROBUCOL
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
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
*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)
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
MISCELLANEO US
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
SYMPTOMATIC TX
BETA BLOCKERS
*Hyperthyroidism: to alleviate s/s (tremors, sweating, palpitations tachycardia) *Radiation Adjuvant: used in pxs while awaiting 131 I effects
MOA/PK/PD/RESISTANCE
DRUG INTERACTIONS
NOTES