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Pharmacology 2060A/B midterm summary.doc

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Pharmacology 2060A/B
Angela Nissen

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St. John’s Wort: natural health product Kanamycin and glucose are P molecules Lithium treats bipolar disorder Preclinical testing: in cultured cells, experimental animals. Evaluate biological effects, pharmacokinetics, toxicity Clinical trial application: submitted to Health Canada prior to human studies Phase I clinical trial: 20-100 healthy volunteers. Evaluation of pharmacokinetics and pharmacodynamics Phase II clinical trial: 300-500 patients w/disorder. Therapeutic effectiveness, side effects and dosing information Phase III clinical trial: 500-5000patients w/disorder. Therapeutic effectiveness, long term side effects New Drug Submission (NDS) submitted to Health Canada; details therapeutic effectiveness & safety. If approved, health Canada issues a Notice of Compliance (NOC) and a Drug Information Number (DIN) to market drug Phase IV clinical trial: post marketing surveillance; monitor efficacy and safety of drug Oral drug → stomach → small intestine → portal vein → liver (metabolism) → systemic circulation → tissues Liver → gall bladder via bile duct → large intestine → fecal excretion (secondary) Parenteral injection; absorbed from injection site into systemic circulation, bypasses liver. Tight jxns prevent molecules b/w cells SER metabolizes drugs, carbohydrates and steroids. RER synthesizes p- Small compounds <200 through channels/pores (selective). Ions mostly, not every small ion can pass through a channel, depends on charge Specific transport p- move drugs. Uptake transporters: intestinal absorption, renal excretion and reaching target action site inside cell Efflux transporters: intestine, placenta, kidney and at BBB Aspirin: weak acid. Amphetamine: weak base Nitroglycerine for angina sublingually Albumin: for lipophilic acidic drug. Alpha 1 acid glycoprotein: for hydrophilic basic drug Ethanol: example of zero order kinetics metabolism CYP: (12) families of drug metabolizing phase 1 enzymes, oxidize drugs. Malnutrition ↓ CYP activity CYP3A4 metabolizes 50% of currently marketed drugs Liver, kidney diseases, inflammation and infection decrease CYP activity Phase 2 metabolic enzymes (fraction of drugs metabolized split evenly among UGTs, SULTs, GSTs, NATs) 1. UDP-glucoronosyltansferases (UGTs): in SER. Catalyze transfer of a glucuronic acid (sugar) to a drug, making it more P, easily excreted. 19 UGT enzymes 2. Sulfotransferases (SULTs): cytosol, catalyze transfer of a sulfate group to a hydroxyl group of drug, more P. 11 SULT enzymes 3. Glutathione S Transferases (GSTs): cytosolic or microsomal, catalyze transfer of a glutathione molecule to a reactive/toxic drug → less toxic. 20 GST enzymes a. Glutathione(GSH) is an intracellular antioxidant 4. N-acetyltransferases (NATs): cytosol, catalyze transfer of an acetyl group from acetyl CoA to a drug, making it more water soluble. 2 NAT enzymes (1 & 2) a. Subject to genetic polymorphisms → drug response variability. 5. Thionpurine Metytransferase (TPMT): cytosolic, catalyze transfer of a methyl group from S-adenosylmethionine to a drug a. Subject to genetic polymorphisms (variability), has effect on drug safety Phase 1 SNPs: CYP2C9: metabolizes the anticoagulant drug warfarin. SNP results in decreased enzyme activity, therefore, patients with SNP in CYP2C9 require lower dose of warfarin CYP2D6: metabolizes codeine to morphine (more potent). Has many genetic SNPs that can result in 4 phenotypes 1) Ultra-rapid metabolizer: significantly increased CYP2D6 activity; more morphine, good pain relief but side effects of morphine. Possess multiple copies of the CYP2D6 gene 2) Extensive metabolizer: normal enzymatic activity 3) Intermediate metabolizer: reduced metabolic activity 4) Poor metabolizers: have no metabolic activity, inadequate pain relief Phase 2 SNPs: UGT1A1: glucuronidates the anti-cancer compound SN-38 (the active metabolite of irinotecan). SNPs in UGT1A1 decrease its activity. Increased diarrhea and bone marrow suppression (side effects from drug) NAT2: acetylates the drug isoniazid (treats TB), caffeine and cancer causing chemicals. 23 different SNPs in NAT2 gene. Patients classified as rapid or slow acetylators based on genotype Slow acetylators more susceptible to isoniazid toxicity, higher risk for cancer Dopamine: agonist drug causes different effects depending on the dose. Low dose to dopamine receptor: renal artery vasodilation, increased renal BF, increased urinary output Moderate dose to B1 adrenergic receptor: increased CO High dose to alpha adrenergic receptor: renal artery vasoconstriction, decreased renal BF, decreased urinary output Antagonists Beta blockers: block binding of endogenous E to beta 1 receptors in the heart, slows HR Anti-histamine: block binding of histamine to H1 histamine receptors in the nasal mucosa, prevents allergy symptoms Gastric acid reducers: block binding of histamine to H2 histamine receptors in the gut, decrease gastric acid secretion into stomach Opioid receptor blockers: block binding of opioids to opiate receptors, used in treating opiate overdose Rosuvastatin: higher [] in Asians, therefore need lower dose Smoking induces drug metabolizing enzymes Antihistamines block H1 histamine receptor to prevent vasodilation (runny nose, watery eyes), therefore get vasoconstriction (no allergy symptoms). Side effects b/c antihistamines bind in brain (drowsiness, dry mouth and urinary retention). Allergic rxns: penicillins, sulfonamindes, nonsteroidal anti-inflammatory drugs (NSAID) Blood test determines if person is at risk for idiosyncratic rxn due to genetic polymorphisms for the drugs warfarin (blood thinner metabolized by CYP2C9) and 6-mercaptopurine (metabolized by thiopurine methyltransferase TPMT) Examples of genetic polymorphisms that cause idiosyncratic rxns: • CYP2C9: approx. 15% Caucasians have a polymorphism that decreases metabolism • CYP2D6: 10% Caucasian and African American are poor metabolizers therefore don’t experience pain relief with codeine (a pro-drug metabolized by CYP2D6 to morphine) • Thiopurine methyltransferase (TPMT): 10% patients have decreased activity, 0.3% have no activity. Treatment with thiopurine drugs in patients with low or absent TPMT → life threatening bone marrow suppression • OATP1B1 (uptake drug transporter in the liver; drugs from blood into liver). 15% Asian and Caucasian patients have a polymorphism that decreases fxn. ∴ increase in plasma drug concentration. This polymorphism causes myopathy (muscle toxicity) in patients taking statin drugs. • Glucose 6-phosphate dehydrogenase deficiency (G6
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