Pharm Phlashcards (Latest update)

Pharm Phlashcards (Latest update) Aspirin - (ASA) NSAID, Poor po metabolism, acidic, zero order elimination, cyp2c9, irreversibly binds platelets; low doses: Anti-platelet (TIAs, stroke, MI prophylaxis), intermediate doses: Analgesic; Anti-pyretic (medium to low grade fevers), high doses: Anti-inflammatory (arthritis, joint swelling); SE: gi mucosal damage, bleeding, allergic rxn, Reye's syndrome Reye's Syndrome - febrile viral illness in children under 16 + ASA = persistent vomiting/confusion --> encephalopathy, microvesicular steatosis --> coma/death Oxidation of drugs (3 components) - Flavoprotein, CYP enzyme, obligatory cofactors NADPH and O2 Phase 1 metabolism - Oxidation by CYP, sometimes reduction/hydrolysis (flavin monooxygenases - O2, NADPH, N, S, esterases, reductases, epoxide hydrolases) CYP1 (mechanism of induction) - Aryl hydrocarbons bind AHR -> forms hererodimer with ARNT -> complex binds gene promoters (DRE and XRE) Cyp1A1 - No basal expression, metabolizes carcinogens Cyp1a2 - Constitutively expressed, metabolizes carcinogens Cyp1b1 - Metabolizes carcinogens Cyp2 (mechanism of induction) - CAR binds drugs -> forms hererodimer with RXR -> binds PBREM enhancer -> transcription - lots of pharmacogenetic issues Cyp2c19 - Omeprazole, diazepam, clopidogrel NSAIDs - Cyp2c9, aspirin, ibuprofen, Naproxen, indomethacin, etc. inhibit cyclooxygenase enzymes, ↓ synthesis and release of prostaglandin which normally sensitize nocireceptors. use for pain, ↓ inflammation, acute and chronic gout; low CNS SE; no physical dependence - can combine with opioids, SE: ulcers, renal toxicity, ↓ GFR, CV toxicity, thromboembolism from unopposed TXA2; SE due to COX-1 inhibition Thalidomide - Limb malformations in nearly all fetally-exposed infants Diethylstilbesterol (DES) - Used to prevent miscarriage, caused female children to develop clear cell vaginal/cervical andenocarcinoma 15-20 years later Omeprazole - Cyp2c19, induces CYP1A2*1c and *1f -> ultrarapid metabolizers of clozapine (decreased efficacy) Diazepam - Cyp2c19, a benzodiazepine (valium) Clopidogrel - Genetics: Cyp2c19, used for mi, cva, peripheral arterial disease Cyp2d6 - Codeine, metoprolol, most antidepressants, tamoxifen, can be increased/decreased/ablated by single nucleotide polymorphism (clozapine, risperidone, olanzapine are qt liable) Codeine - Cyp2d6, prodrug that becomes morphine, natural opiate, risk for tolerance/dependence, good first line for pain, se: nausea, use caution when giving with acetaminophen Tamoxifen - Genetics: Cyp2d6, used to treat breast cancer, binds ER-alpha (nuclear receptor - not membrane limited) and competes with estrogen (which normally promotes breast cancer cell growth) Irinotecan - Treat colon cancer, inhibit topoisomerase 1, converted to sn38 metabolite that is inactivated by UGT1a1, if 7 ta repeats, UGT is low -> toxic, also can cause cholinergic toxidrome EGFR - TKR that activates RAS and pik3ca- Mutations can make tumors in lung more or less receptive to EGFR inhibitors Vemurafenib - Takes advantage of B-RAF mutations to target and treat melanomas Mutidrug resistance proteins - ATP dependent TM pumps out antibiotics share cyp3a4 substrates (abc transporter gene) Cyp2as - Steroids and nicotine (cyp2a6) Steroids - End in "sone", cyp2as, binds nuclear receptors in cell cytoplasm --> changes protein levels in cells; possibly indirect inhibition of phospholipase A2 and reduced expression of COX-2 in immune cells; ↓ both prostanoids and leukotrienes; use for RA, allergic disorders (long term management of asthma - beclamethosone, fluticasone, prednisone); accelerate lung maturation in preemies, cancer chemo (trigger apoptosis and appetite) and to reduce inflammation in gout (injections); SE: osteoporosis, Cushings, impaired wound healing, low K, impaired growth, cataracts (fewer side effects when inhaled appropriately for asthma) Cyp2e1 - Ethanol, anesthetic, sometimes acetaminophen (to toxic metabolite) Acetaminophen - Hepatotoxic at 7 grams, toxic metabolite napqi when metabolized by cyp2e1, napqi can be neutralized by GSH, like NSAIDs but no effect on inflammation, use for analgesia, antipyretic and when aspirin is contraindicated Cyp3 (mechanism of induction) - PXR binds drugs -> forms hererodimer with RXR -> binds PBREM enhancer -> transcription Cyp3a4 - Metabolizes 1/3 to 1/2 of all po drugs, main site for drug-drug interactions - terfenadine and most drugs, blocked by erythromycin and ketoconazole, irreversibly blocked by grapefruit juice in the gut Terfenadine - Cleared by cyp3a4, was an antihistamine prodrug but was cardiotoxic, now given as active drug fexofenadine Ketoconazole - Anti fungal, inhibits cyp3a4 Erythromycin - Antibiotic blocks cyp3a4, toxic prodrug, binds to HERG potassium channel -> long qt Cyp3a5 - Abundant in 10-15% of people Phase II metabolism - Conjugation - glucoronidation, sulfation. Preserved in elderly. Make drugs more polar/less active , aids in excretion Glucoronidation - Phase II metabolism by UGT, induced by AHR, CAR, and PXR, low in neonates, can lead to toxicity of irinotecan and other drugs if low Benzodiazepines - Treats anxiety/panic disorders/anti-epileptic GABA receptor agonist -> increases frequency Cl- channel opening (hyperpolarizes) -> decreases excitability of neurons, effective for status epilepticus; increased side effects in elderly, good anxiolytic and amnestic Chloramphenicol - Decreased glucoronidation and renal excretion in babies = gray baby syndrome Gilbert syndrome - Mutation variable number tandem repeats down regulates UGT promoter - causes mild hyperbilirubinemia Bilirubin - Conjugated by ugt1a1, if not causes jaundice Crigler-Naijar syndrome - Mutation = no UGT, lots of problems Sulfation - Phase II metabolism by SULTs Reactive metabolites (4 outcomes) - Inactivate: Bind water, bind glutathione (gsh) Toxic: bind protein, bind dna/rna Ethanol - Zero order metabolism, metabolized/induces cyp2e1, in beverages, gasoline, labs EtOh->acetaldehyde-> acetic acid, gives positive osmol gap, chronic use -> liver cirrhosis, cancer, pacreatitis, epilepsy Phenytoin - Protein bound, zero order elimination, cyp 2c9, anti-epileptic NA channel blocker, effective for status epilepticus, induces P450s, se: metabolic bone disease, hirsutism, neuropathy, ataxia, gingival hyperplasia Cyp2c9 - Warfarin, phenytoin, NSAIDs Theophylline - Zero order elimination, bronchodilator Methotrexate - immunosuppressant for RA, psoriasis, Crohn's, etc.; for cancer at high doses, low dose: inhibition of lymphocyte proliferation (blocks purine synthesis), high dose: folate antagonist, acidic; SE: mucosal ulceration, nausea, cytopenia, liver cirrhosis, pneumonia-like illness Propanolol - b1, b2 antagonist, use for hypertension, headache prophylaxis, angina, glaucoma, poor po metabolism, se: bronchoconstriction, cardiac failure, cold extremities, fatigue, depression, hypoglycemia Nitroglycerin - Poor po metabolism, risk for tachyphylaxis Isoproterenol - b1,b2 agonist used for heart failure and asthma (obsolete), poor po metabolism Lidocaine - Poor po metabolism, local anesthetic Morphine - Mu agonist, weak kappa, poor po metabolism, can give IV, IM, PO, rectal, subq, risk for tolerance, onset 5 min, peak 30 min, good for post MI (decrease vascular resistance), good analgesic Nicotine - Short term - ganglionic agonist, Cyp2a6, risk for tolerance, causes tachycardia, increased CO, increase BP, nausea, vomiting, decrease GI motility, diaphoresis; side effects decline with use (long term- ganglionic antagonism) Atropine - Muscarinic antagonist, anti-sludge, decrease gi motility = poor drug absorption, can use pre-op to dry secretions, treat organophospate poisoning/mushroom poisoning, se: dry, red, hot, and mad Epinephrine - Vasoconstricts (do not use in digits/penis/nose), increases duration of local anesthetic through decreased absorption, a1, a2, b1, b2 agonist, used for cardiac arrest, se hypertension, vasoconstriction, tachycardia, ventricular dysrhythmias