1. ADVERSE DRUG EVENTS Géza T. Terézhalmy, D.D.S., M.A. Professor and Dean Emeritus School of Dental Medicine Case Western Reserve University Cleveland, Ohio

2. Adverse Drug Events • Clinicians and patients both acknowledge the major role played by drugs in modern health care Terezhalmy

3. Adverse Drug Events Terezhalmy

4. Adverse Drug Events • There are no “absolutely” safe biologically active therapeutic agents Terezhalmy

5. Adverse Drug Events • Therapeutic agents seldom exert their beneficial effects without also causing adverse drug events Terezhalmy

6. Adverse Drug Events • OHCP should be aware of the spectrum of drug-induced events and should be actively involved both in monitoring for and reporting such events Terezhalmy

7. Adverse Drug Events • Etiology and epidemiology • 75 % of office visits to general medical practitioners and internists are associated with the initiation or continuation of pharmacotherapy • 3 to 11 % of hospital admissions are attributed to adverse drug events • 0.3 to 44 % of hospitalizations are complicated by adverse drug events Terezhalmy

8. Adverse Drug Events • Etiology and epidemiology • The FDA has the most rigorous approval requirements in the world • Clinical trials cannot and are not expected to uncover every potential adverse drug event • Pre-marketing study populations generally include 3,000 to 4,000 subjects • Only adverse events, which occur more frequently than 1 in 1,000 will be observed • Detecting an adverse event with a incidence of 1 in 10,000 would require a study population of 30,000 Terezhalmy

9. Adverse Drug Events • Etiology and epidemiology • Classification of adverse drug events • Type A reactions • Associated with the administration of therapeutic dosages of a drug (exception: drug overdose) • Usually predictable and avoidable • Responsible for most adverse drug events • Overdose • Cytotoxic reactions • Drug-drug interactions • Drug-food interactions • Drug-disease interactions Terezhalmy

10. Adverse Drug Events • Etiology and epidemiology • Classification of adverse drug events • Type B reactions • Generally independent of dose • Rarely predictable or avoidable • While they are uncommon, they are often among the most serious and potentially life threatening • Idiosyncratic reactions • Immunologic/allergic reactions • Pseudo-allergic reactions • Teratogenic effects • Oncogenic effects Terezhalmy

11. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Cytotoxic effects • Formation of unstable or reactive metabolites related to some abnormality that interferes with normal metabolism and/or excretion of a drug • Two mechanisms • Oxidative pathway: the formation of electrophilic compounds, which bind covalently with cellular macromolecules • Reductive pathway: gives rise to intermediate compounds with an excess of electrons, which interact with O2 to produce free radicals Terezhalmy

12. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Two or more drugs administered at the same time or in close sequence • May act independently • May interact to  or  the magnitude or duration of action of one or more of the drugs • May interact to cause an unintended reaction • Drug-drug interactions all seem to have either a pharmacodynamic or a pharmacokinetic basis Terezhalmy

13. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms • The intended or expected effect produced by a given plasma level of drug A is altered in the presence of drug B • Pharmacological drug-drug interactions • Physiological drug-drug interactions • Chemical drug-drug interactions • Drug-related receptor alterations Terezhalmy

14. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms • Pharmacological drug-drug interactions • Drug A and drug B compete for the same receptor site and as a function of their respective concentrations either produce (an agonist) or prevent (an antagonist) an effect respectively • opioids vs. naloxone • acetylcholine vs. atropine • epinephrine vs. adrenergic receptor blocking agents Terezhalmy

15. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms • Physiological interactions • Drug A and drug B interact with different receptor sites and either enhance each other’s action or produce an opposing effect via different cellular mechanisms • cholinergic agents vs diazepam • epinephrine vs. lidocaine • epinephrine vs. histamine Terezhalmy

16. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms • Chemical interactions • Drug A interacts with drug B and prevents drug B from interacting with its intended receptor • protamine sulfate vs. heparin Terezhalmy

17. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms • Drug-related receptor alterations • Drug A, when administered chronically, may either  or  the number of its own receptors or alter the adaptability of its receptors to physiological events • alpha1-adrenergic receptor agonists down-regulate their own receptors • beta1-adrenergic receptor antagonists up-regulate their own receptors Terezhalmy

18. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Following concomitant administration, drug A may  or  the plasma level of drug B • Interactions affecting absorption • Interactions affecting distribution • Interactions affecting metabolism • Interactions affecting renal excretion • Interactions affecting biliary excretion Terezhalmy

19. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting absorption • Drug A, by causing vasoconstriction, interferes with the systemic absorption of drug B • epinephrine  the systemic absorption of lidocaine • Drug A, by forming a complex with drug B, interferes with the systemic absorption of drug B • calcium  the systemic absorption of tetracycline Terezhalmy

20. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting absorption • Drug A, by delaying gastric emptying, delays the systemic absorption of drug B, which is absorbed primarily in the small intestine • opioids delay the absorption of acetaminophen • Drug A, by elevating gastric pH, prevents the absorption of drug B (weak acids) • antacids  absorption of acetylsalicylic acid Terezhalmy

21. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting distribution • Drug A ( a weak acid), by competing for plasma protein binding with drug B,  the plasma level of drug B • acetylsalicylic acid  the plasma level of many drugs Terezhalmy

22. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting metabolism • Drug A, by  or  hepatic microsomal enzyme activity responsible for the metabolism of drug B,  or  plasma level of drug B respectively • H2-receptor antagonists  the plasma level of many drugs • macrolides, azole antifungal agents, ethanol (chronic use)  plasma level of many drugs Terezhalmy

23. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting metabolism • Drug A, by  hepatic non-microsomal enzyme activity responsible for the metabolism of drug B,  the plasma level of drug B • MAO-inhibitors  the plasma level of benzodiazepines Terezhalmy

24. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting metabolism • Drug A, by inhibiting the enzyme acetaldehyde dehydrogenize, interferes with the further metabolism of intermediate metabolites (oxidation products) of drug B • disulfuram and metronidazole interfere with the metabolism of ethanol Terezhalmy

25. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting renal excretion • Drug A, which competes with drug B for the same excretory transport mechanisms in the proximal tubules,  the plasma level of drug B • acetylsalicylic acid and probenecid  the plasma level of penicillin and other weak acids Terezhalmy

26. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting renal excretion • Drug A, by alkalizing the urine,  the plasma level of drug B • sodium bicarbonate  the plasma level of weak acids • Drug A, by acidifying the urine,  the plasma level of drug B • ammonium chloride  the plasma level of weak bases Terezhalmy

27. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms • Interactions affecting biliary excretion • Drug A, by increasing bile flow and the synthesis of proteins, which function in biliary conjugation mechanisms,  the plasma level of drug B • Phenobarbital  the plasma level of many drugs • Drug A binds drug B, which undergoes extensive hepatic recirculation,  the plasma level of drug B • activated charcoal and cholestyramine  the plasma level of many drugs Terezhalmy

28. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-food interactions • Most known drug-food interactions appear to be associated with pharmacokinetic mechanisms • Interactions affecting absorption • Nutrients may act as a mechanical barrier that prevents drug access to mucosal surfaces and  the rate of absorption of some drugs • Nutrients with high fatty acid content may actually  the rate of absorption of drugs with high lipid solubility Terezhalmy

29. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-food interactions • Interactions affecting absorption • Chemical interactions between a drug and food component can result in the formation of inactive complexes and  the absorption of the drug • calcium  the absorption of tetracyclines • ferrous or ferric salts  the absorption of tetracyclines and fluoroquinolones • zinc  the absorption of fluoroquinolones Terezhalmy

30. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-food interactions • Interactions affecting metabolism • Components of some nutrients can inhibit CYP450 isoenzymes and  the metabolism of some drugs • grapefruit juice  the metabolism of warfarin, benzodiazepines, and calcium-channel blocking agents Terezhalmy

31. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-disease interactions • A drug prescribed for the treatment of one disease can adversely affect a different condition that has been generally well controlled • Pharmacodynamic mechanisms • Pharmacokinetic mechanisms Terezhalmy

32. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms • Non-selective beta1-adrenergic receptor antagonists, prescribed for the treatment of chronic stable angina, hypertension, or cardiac arrhythmia can increase airway resistance by interacting with beta2-adrenergic receptors • induce asthma in susceptible patients Terezhalmy

33. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms • Beta1-adrenergic receptor antagonists and calcium-channel blocking agents prescribed for the treatment of chronic stable angina, hypertension, or cardiac arrhythmia interacting with their own receptors • precipitate cardiac complications secondary to negative inotropism (decreased contractility), decreased nodal conductance, and peripheral vasodilatation (cardiac steal syndrome) in susceptible patients Terezhalmy

34. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms • Beta1-adrenergic receptor antagonists can adversely affect carbohydrate metabolism and inhibit epinephrine-mediated hyperglycemic response to insulin • Increase the risk of hypoglycemia and mask some of its clinical manifestations in diabetic patients Terezhalmy

35. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms • COX-1 inhibitors block cyclooxygenase-dependent prostaglandin and thrombaxane A2 synthesis • Exacerbate peptic ulcer disease and gastroesophageal reflux disease in susceptible patients Terezhalmy

36. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms • Hypothyroidism •  sensitivity to CNS depressants in susceptible patients • Hyperthyroidism •  susceptibility to epinephrine-induced hypertension and cardiac arrhythmia Terezhalmy

37. Adverse Drug EventsType A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacokinetic mechanisms • Cardiac dysfunction •  metabolism and excretion of drugs • Hepatic dysfunction •  metabolism and biliary and renal excretion of drugs • Renal dysfunction •  hepatic metabolism and renal excretion of drugs Terezhalmy

38. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Idiosyncratic reactions • Drug metabolism is largely dominated by oxidation reactions catalyzed by the cytochrome P450 enzyme system • Genetic polymorphism is the primary factor responsible for inter-individual variability in response to drugs • Therapeutic consequences • intrinsic characteristics of the drug • importance of the deficient metabolic pathway • existence of alternative pathways Terezhalmy

39. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Allergic/immune reactions • In susceptible patients alkylation and/or oxidation of cellular macromolecules by drug metabolites can lead to the production of immunogens • Not related to the dose administered • Specificity to a given agent • Transferability by antibodies or lymphocytes • Recurrence when re-exposure to the offending drug occurs • Most reactions occur in young or middle aged adults • Drug allergy is twice a frequent in women than in man Terezhalmy

40. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Allergic/immune reactions • Type I (immediate) hypersensitivity Terezhalmy

41. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Allergic/immune reactions • Type II (cytotoxic) hypersensitivity Terezhalmy

42. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Allergic/immune reactions • Type III (immune-complex) hypersensitivity Terezhalmy

43. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Allergic/immune reactions • Type IV (delayed) hypersensitivity Terezhalmy

44. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Pseudoallergic reactions • Cannot be explained on an immunologic basis • Occur in patients who had no prior exposure to the drug • Certain medications directly activate mast cells through non-IgE-receptor pathways and initiate the release of bioactive substances • Other medications block the degradation of bioactive substances • Still other medications, by inhibiting the action of cyclooxygenase activity,  synthesis of lipoxygenase-dependent leukotrienes Terezhalmy

45. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Teratogenic/developmental effects • Teratogens are substances capable of causing physical or functional defects in the fetus in the absence of toxic effects in the mother • Teratogenic effects depend on the accumulation of a drug or its metabolite in the fetus at critical time periods • 3rd to 12th week of gestation Terezhalmy

46. Adverse Drug EventsType B Reactions • Etiology and epidemiology • Oncogenic effects • Primary oncogenic effects • Produced by certain procarcinogenic drugs, which have been converted into carcinogens by polymorphic oxidative reactions • Reactive metabolites bind covalently to DNA • Secondary oncogenic effects • Therapeutic immunosuppression in the presence of infection with oncogenic viruses • HBV, HCV, CMV, HSV, HPV, and EMV • Pattern of cancer is different than in the general population Terezhalmy

47. Adverse Drug Events Terezhalmy

48. Adverse Drug Events • Clinical manifestations • Type A reactions • Primary (direct effects) or secondary (indirect effects) • Dose dependent • Exaggerations of direct effects • Multiple concurrent “side “ effects • Type B reactions • Primary (direct effects) or secondary (indirect effects) • Generally independent of the dose Terezhalmy

49. Adverse Drug EventsType A Reactions • Clinical manifestations • Cytotoxic reactions Terezhalmy

50. Adverse Drug EventsType A: Cytotoxic Reactions Terezhalmy