* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Mechanisms of common and important adverse drug reactions
Survey
Document related concepts
Compounding wikipedia , lookup
Toxicodynamics wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Discovery and development of proton pump inhibitors wikipedia , lookup
Orphan drug wikipedia , lookup
Drug design wikipedia , lookup
Drug discovery wikipedia , lookup
Theralizumab wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Prescription costs wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Pharmacognosy wikipedia , lookup
Psychopharmacology wikipedia , lookup
Neuropharmacology wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Transcript
Mechanisms of common and important adverse drug reactions Jack W. Strandhoy, Ph.D. Drug Safety Pharmacovigilance • Paracelsus: “All substances are poisons…dose differentiates” • Toxicology – adverse effects of chemicals, incl drugs, on living organisms. ↑doses. • Pharmacovigilance – concerns detection, assessment, understanding, prevention of adverse events with medicines in nl doses • Adverse Drug Reactions – noxious and unintended; at normal therapeutic doses – Affect 2 million / yr in US; 100,000 deaths / yr Idiosyncratic Adverse Drug Reactions (or Effects) Mechanism-dependent toxicities Genetic influences Interactions: drugs, foods Mechanism-dependent toxicities • exaggerated effects • ion disturbances • cardiovascular problems Mechanism-dependent toxicities • An exaggeration of the expected pharmacological effect • Hyperkalemia – ACEI, ARB, K-sparing diuretics; complicated by ↓renal fx, acidosis, diabetes … • Cardiovascular risks – – COX-2 inhibitors (rofecoxib) – ↑ stroke and MI – Immediate release Ca blockers - ↓↓BP • HTN, proteinuria – cediranib for cancer. VEGF-R tyr kinase inhibitor. Titrate to dose • Bleeding, coughing, GI ulcers, infection risk, CNS effects … Interactions • drugs (Rx, OTC, herbal) • foods (vitamins, suppl) Interactions: drugs Seldane terfenidine CYP3A4 (-) Allegra fexofenidine erythromycin Torsades de Pointes - Ventricular tacharrythmia - Prolonged QT Interactions: drugs • Interaction occurs esp. in patients with altered KCNE2 gene for IK r potassium channel that is important for repolarization • ↑QT also by trimethoprim-sulfamethoxazole Interactions: drugs Tylenol Sinus Congestion & Pain Daytime Tamoxifen ? Tylenol Allergy Multi-Symptom CYP2D6 chlorpheniramine • also 2D6↓ antidepressants like fluoxetine Interactions: foods • Grapefruit juice – irreversibly inhibits CYP3A4 on GI mucosa – Consequence is ↑drug absorption – Cyclosporine, some statins • Ca+2, GI transit time may ↓ absorption of some drugs – Tetracyclines, ciprofloxacin Genetic Influences • • • • metabolism Disposition, PK receptors transporters Effect, PD HLA haplotypes Env Health Perspect Genetics in ADRs metabolism: deficiency • Clopidogrel (Plavix) - ↓platelet P2Y12 receptor binding of ADP • Prodrug, activated by CYP2C19 • Loss of function = 2C19*2 allele – Greater risk of thrombi, MI, stroke • PPIs may also ↓2C19 (esp.omeprazole) but ↓ risk of GI bleeding (esp. pantoprazole) – Ray et al., Ann Int Med (2010) Genetics in ADRs metabolism: surplus • Azathioprine, 6-MP detoxified by thiopurine S-methyltransferase (TPMT) • Genetic ↓ TPMT → toxicity, pancytopenia • Kits available for genotyping TPMT • Dose adjustments in pts can be life-saving Genetics in ADRs metabolism, receptors • Warfarin (Coumadin) – anticoagulant antagonist of vit. K • Wide variability in dosing, to effect measured by INR • Pharmacogenomic variability in CYP2C9 and VKORC1 [receptor] Genetics in ADRs transporters • Pravastatin, simvastatin – myopathy risk ↑ with variant of organic anion transporter polypeptide (OATP), SLC01B1 – More severe rhabdomyolysis may also be linked but is very rare • P-glycoprotein variant ↑digoxin bioavailability; p-gp also site of drug interactions Genetics in ADRs HLA haplotypes • Carbamazepine (Tegretol) – used for seizures, trigeminal neuralgia, etc. – HLA B*1502 associated with propensity for severe toxic epidermal necrolysis and Stevens-Johnson syndrome – Mechanism unknown • Aspirin hypersensitivity – associated with HLAs and altered AA metabolism to leucotrienes – HLA DPB1*0301; HLA DB1*0609 Opportunities for teaching drug safety in the curriculum • Explaining ADRs and drug interactions illustrates PK/PD mechanisms of drugs • Vigilance in drug safety improves clinical observational skills • Predictive modeling of ADRs requires laboratory skills and sagacity • Population-based data supports EBM, regulatory and cost-saving decisions • Learners will better identify, predict, report, model and prevent ADRs Pre-clinical Mechanisms Education Reporting ADRs Clinical Observations