Mechanisms of common and important adverse drug reactions. Jack W. Strandhoy, Ph.D.

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1 Mechanisms of common and important adverse drug reactions Jack W. Strandhoy, Ph.D.

2 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

3 Idiosyncratic Adverse Drug Reactions (or Effects) Mechanism-dependent toxicities Genetic influences Interactions: drugs, foods

4 Mechanism-dependent toxicities exaggerated effects ion disturbances cardiovascular problems

5 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

6 Interactions drugs (Rx, OTC, herbal) foods (vitamins, suppl)

7 Interactions: drugs Seldane terfenidine CYP3A4 (-) Allegra fexofenidine erythromycin Torsades de Pointes - Ventricular tacharrythmia - Prolonged QT

8 Interactions: drugs Interaction occurs esp. in patients with altered KCNE2 gene for I K r potassium channel that is important for repolarization QT also by trimethoprim-sulfamethoxazole

9 Interactions: drugs Tylenol Sinus Congestion & Pain Daytime Tamoxifen? CYP2D6 Tylenol Allergy Multi-Symptom chlorpheniramine also 2D6 antidepressants like fluoxetine

10 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

11 Genetic Influences metabolism receptors transporters HLA haplotypes Disposition, PK Effect, PD

12 Env Health Perspect

13 Genetics in ADRs metabolism: deficiency Clopidogrel (Plavix) - platelet P2Y 12 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)

14 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

15 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]

16 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

17 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

18 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

19 Pre-clinical Mechanisms Education Reporting ADRs Clinical Observations

Clinically Significant Cardiovascular. Drug Interactions. April 30, 2014 Michael A Militello, PharmD, BCPS Cardiovascular Clinical Pharmacist

Clinically Significant Cardiovascular Drug Interactions April 30, 2014 Michael A Militello, PharmD, BCPS Cardiovascular Clinical Pharmacist Introduction Drug interactions represent 3-5% of preventable