ADVERSE DRUG EVENTS Gza T Terzhalmy D D

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ADVERSE DRUG EVENTS Géza T. Terézhalmy, D. D. S. , M. A. Professor and

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

Adverse Drug Events • Clinicians and patients both acknowledge the major role played by

Adverse Drug Events • Clinicians and patients both acknowledge the major role played by drugs in modern health care 12/3/2020 Terezhalmy 2

Adverse Drug Events 12/3/2020 Terezhalmy 3

Adverse Drug Events 12/3/2020 Terezhalmy 3

Adverse Drug Events • There are no “absolutely” safe biologically active therapeutic agents 12/3/2020

Adverse Drug Events • There are no “absolutely” safe biologically active therapeutic agents 12/3/2020 Terezhalmy 4

Adverse Drug Events • Therapeutic agents seldom exert their beneficial effects without also causing

Adverse Drug Events • Therapeutic agents seldom exert their beneficial effects without also causing adverse drug events 12/3/2020 Terezhalmy 5

Adverse Drug Events • OHCP should be aware of the spectrum of druginduced events

Adverse Drug Events • OHCP should be aware of the spectrum of druginduced events and should be actively involved both in monitoring for and reporting such events 12/3/2020 Terezhalmy 6

Adverse Drug Events • Etiology and epidemiology • 75 % of office visits to

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 12/3/2020 Terezhalmy 7

Adverse Drug Events • Etiology and epidemiology • The FDA has the most rigorous

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 Ø 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 12/3/2020 Terezhalmy 8

Adverse Drug Events • Etiology and epidemiology • Classification of adverse drug events •

Adverse Drug Events • Etiology and epidemiology • Classification of adverse drug events • Type A reactions Ø Associated with the administration of therapeutic dosages of a drug (exception: drug overdose) Ø Usually predictable and avoidable Ø Responsible for most adverse drug events § Overdose § Cytotoxic reactions § Drug-drug interactions § Drug-food interactions § Drug-disease interactions 12/3/2020 Terezhalmy 9

Adverse Drug Events • Etiology and epidemiology • Classification of adverse drug events •

Adverse Drug Events • Etiology and epidemiology • Classification of adverse drug events • Type B reactions Ø Generally independent of dose Ø Rarely predictable or avoidable Ø 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 12/3/2020 Terezhalmy 10

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Cytotoxic effects •

Adverse Drug Events Type 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 Ø 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 O 2 to produce free radicals 12/3/2020 Terezhalmy 11

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Two or more drugs administered at the same time or in close sequence Ø May act independently Ø May interact to or the magnitude or duration of action of one or more of the drugs Ø May interact to cause an unintended reaction • Drug-drug interactions all seem to have either a pharmacodynamic or a pharmacokinetic basis 12/3/2020 Terezhalmy 12

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms Ø 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 12/3/2020 Terezhalmy 13

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms Ø 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 12/3/2020 Terezhalmy 14

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms Ø 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 12/3/2020 Terezhalmy 15

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms Ø Chemical interactions § Drug A interacts with drug B and prevents drug B from interacting with its intended receptor § protamine sulfate vs. heparin 12/3/2020 Terezhalmy 16

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacodynamic mechanisms Ø 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 § alpha 1 -adrenergic receptor agonists down-regulate their own receptors § beta 1 -adrenergic receptor antagonists up-regulate their own receptors 12/3/2020 Terezhalmy 17

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 18

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 19

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 p. H, prevents the absorption of drug B (weak acids) § antacids absorption of acetylsalicylic acid 12/3/2020 Terezhalmy 20

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 21

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 § H 2 -receptor antagonists the plasma level of many drugs § macrolides, azole antifungal agents, ethanol (chronic use) plasma level of many drugs 12/3/2020 Terezhalmy 22

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 23

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 24

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 25

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 26

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-drug interactions • Pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 27

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-food interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-food interactions • Most known drug-food interactions appear to be associated with pharmacokinetic mechanisms Ø 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 12/3/2020 Terezhalmy 28

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-food interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-food interactions • Interactions affecting absorption Ø 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 12/3/2020 Terezhalmy 29

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-food interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-food interactions • Interactions affecting metabolism Ø Components of some nutrients can inhibit CYP 450 isoenzymes and the metabolism of some drugs § grapefruit juice the metabolism of warfarin, benzodiazepines, and calcium-channel blocking agents 12/3/2020 Terezhalmy 30

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions •

Adverse Drug Events Type 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 Ø Pharmacodynamic mechanisms Ø Pharmacokinetic mechanisms 12/3/2020 Terezhalmy 31

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms Ø Non-selective beta 1 -adrenergic receptor antagonists, prescribed for the treatment of chronic stable angina, hypertension, or cardiac arrhythmia can increase airway resistance by interacting with beta 2 -adrenergic receptors § induce asthma in susceptible patients 12/3/2020 Terezhalmy 32

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms Ø Beta 1 -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 12/3/2020 Terezhalmy 33

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms Ø Beta 1 -adrenergic receptor antagonists can adversely affect carbohydrate metabolism and inhibit epinephrinemediated hyperglycemic response to insulin § Increase the risk of hypoglycemia and mask some of its clinical manifestations in diabetic patients 12/3/2020 Terezhalmy 34

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms Ø COX-1 inhibitors block cyclooxygenase-dependent prostaglandin and thrombaxane A 2 synthesis § Exacerbate peptic ulcer disease and gastroesophageal reflux disease in susceptible patients 12/3/2020 Terezhalmy 35

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacodynamic mechanisms Ø Hypothyroidism § sensitivity to CNS depressants in susceptible patients Ø Hyperthyroidism § susceptibility to epinephrine-induced hypertension and cardiac arrhythmia 12/3/2020 Terezhalmy 36

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions •

Adverse Drug Events Type A Reactions • Etiology and epidemiology • Drug-disease interactions • Pharmacokinetic mechanisms Ø Cardiac dysfunction § metabolism and excretion of drugs Ø Hepatic dysfunction § metabolism and biliary and renal excretion of drugs Ø Renal dysfunction § hepatic metabolism and renal excretion of drugs 12/3/2020 Terezhalmy 37

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Idiosyncratic reactions •

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Idiosyncratic reactions • Drug metabolism is largely dominated by oxidation reactions catalyzed by the cytochrome P 450 enzyme system Ø 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 12/3/2020 Terezhalmy 38

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions •

Adverse Drug Events Type 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 Ø 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 Ø Most reactions occur in young or middle aged adults Ø Drug allergy is twice a frequent in women than in man 12/3/2020 Terezhalmy 39

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions •

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions • Type I (immediate) hypersensitivity 12/3/2020 Terezhalmy 40

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions •

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions • Type II (cytotoxic) hypersensitivity 12/3/2020 Terezhalmy 41

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions •

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions • Type III (immune-complex) hypersensitivity 12/3/2020 Terezhalmy 42

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions •

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Allergic/immune reactions • Type IV (delayed) hypersensitivity 12/3/2020 Terezhalmy 43

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Pseudoallergic reactions •

Adverse Drug Events Type 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 Ø Certain medications directly activate mast cells through non-Ig. E-receptor pathways and initiate the release of bioactive substances Ø Other medications block the degradation of bioactive substances Ø Still other medications, by inhibiting the action of cyclooxygenase activity, synthesis of lipoxygenasedependent leukotrienes 12/3/2020 Terezhalmy 44

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Teratogenic/developmental effects •

Adverse Drug Events Type 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 Ø Teratogenic effects depend on the accumulation of a drug or its metabolite in the fetus at critical time periods § 3 rd to 12 th week of gestation 12/3/2020 Terezhalmy 45

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Oncogenic effects •

Adverse Drug Events Type B Reactions • Etiology and epidemiology • Oncogenic effects • Primary oncogenic effects Ø Produced by certain procarcinogenic drugs, which have been converted into carcinogens by polymorphic oxidative reactions § Reactive metabolites bind covalently to DNA • Secondary oncogenic effects Ø 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 12/3/2020 Terezhalmy 46

Adverse Drug Events 12/3/2020 Terezhalmy 47

Adverse Drug Events 12/3/2020 Terezhalmy 47

Adverse Drug Events • Clinical manifestations • Type A reactions • Primary (direct effects)

Adverse Drug Events • Clinical manifestations • Type A reactions • Primary (direct effects) or secondary (indirect effects) Ø Dose dependent § Exaggerations of direct effects § Multiple concurrent “side “ effects • Type B reactions • Primary (direct effects) or secondary (indirect effects) Ø Generally independent of the dose 12/3/2020 Terezhalmy 48

Adverse Drug Events Type A Reactions • Clinical manifestations • Cytotoxic reactions 12/3/2020 Terezhalmy

Adverse Drug Events Type A Reactions • Clinical manifestations • Cytotoxic reactions 12/3/2020 Terezhalmy 49

Adverse Drug Events Type A: Cytotoxic Reactions 12/3/2020 Terezhalmy 50

Adverse Drug Events Type A: Cytotoxic Reactions 12/3/2020 Terezhalmy 50

Adverse Drug Events Type A: Cytotoxic Reactions 12/3/2020 Terezhalmy 51

Adverse Drug Events Type A: Cytotoxic Reactions 12/3/2020 Terezhalmy 51

Adverse Drug Events Type A Reactions • Clinical manifestations • Gastrointestinal disturbances • Nausea

Adverse Drug Events Type A Reactions • Clinical manifestations • Gastrointestinal disturbances • Nausea and vomiting Ø Vomiting center § Chemoreceptor trigger zone § Pharynx § Gastrointestinal tract § Cerebral cortex (emotion, olfaction, visual stimuli) § Stimulation of the vestibular apparatus § opioid-, dopaminergic (D 2)-, histaminic (H 1)-, muscarinic-, and serotonengic (5 -HT 3)-receptor agonists 12/3/2020 Terezhalmy 52

Adverse Drug Events Type A Reactions • Clinical manifestations • Gastrointestinal disturbances • Constipation

Adverse Drug Events Type A Reactions • Clinical manifestations • Gastrointestinal disturbances • Constipation Ø Diet, functional abnormalities, colonic disease, rectal problems, neurological disease, metabolic disorders, drugs § anticholinergic agents, antihistamines, antidepressants, anticonvulsants, antiparkinsonian drugs, opioid analgesics, antacids 12/3/2020 Terezhalmy 53

Adverse Drug Events Type A Reactions • Clinical manifestations • Gastrointestinal disturbances • Diarrhea

Adverse Drug Events Type A Reactions • Clinical manifestations • Gastrointestinal disturbances • Diarrhea Ø Chronic § Functional abnormalities, colonic disease, neurological disease, and metabolic disorders Ø Acute § Osmotic changes when poorly absorbable solutes are present in the intestine § Inhibition of ion transport or stimulation of ion secretion § Toxins, infection (viral, bacterial), drugs § cholinergic agents, antibacterial agents 12/3/2020 Terezhalmy 54

Adverse Drug Events Type A Reactions • Clinical manifestations • Urinary incontinence • Increased

Adverse Drug Events Type A Reactions • Clinical manifestations • Urinary incontinence • Increased urinary flow § diuretics, cholinergic agents • Overflow secondary to urinary retention § anticholinergic agents, adrenergic agonists • Increased ADH release Ø Painful stimuli, fear, anger, drugs § opioid analgesics • Decrease ADH release § alcohol 12/3/2020 Terezhalmy 55

Adverse Drug Events Type A Reactions • Clinical manifestations • Mood alterations • Depression

Adverse Drug Events Type A Reactions • Clinical manifestations • Mood alterations • Depression § beta 1 -adrenergic blocking agents, cardiac glycosides, benzodiazepines, phenothiazines, corticosteroids, • Delirium (acute confusional states) § drugs with anticholinergic properties, cardiac glycosides, opioid analgesics, benzodiazepines, other CNS depressants 12/3/2020 Terezhalmy 56

Adverse Drug Events Type A Reactions • Clinical manifestations • Cardiac dysfunction • Orthostatic

Adverse Drug Events Type A Reactions • Clinical manifestations • Cardiac dysfunction • Orthostatic hypotension § antihypertensive agents (reduce BP), psychotropic drugs (impair autonomic reflexes) • Arrhythmia § cardiac glycosides, macrolides, calcium-channel blocking agents, azoles (antifungal agents), protease inhibitors 12/3/2020 Terezhalmy 57

Adverse Drug Events Type A Reactions • Clinical manifestations • Equilibrium problems • Increased

Adverse Drug Events Type A Reactions • Clinical manifestations • Equilibrium problems • Increased risk of falls (patients with decreased vision, impaired mobility and cognition, postural hypotension, peripheral neuropathy) § drugs that impair autonomic reflexes (benzodiazepines, alcohol) 12/3/2020 Terezhalmy 58

Adverse Drug Events Type A Reactions • Clinical manifestations • Xerostomia • Diuretics •

Adverse Drug Events Type A Reactions • Clinical manifestations • Xerostomia • Diuretics • Drugs with anticholinergic activity § antihistamines, psychotropic drugs, CNS stimulants, antineoplastic agents 12/3/2020 Terezhalmy 59

Adverse Drug Events Type A Reactions: Xerostomia 12/3/2020 Terezhalmy 60

Adverse Drug Events Type A Reactions: Xerostomia 12/3/2020 Terezhalmy 60

Adverse Drug Events Type A Reactions • Clinical manifestations • Mucositis • Drugs that

Adverse Drug Events Type A Reactions • Clinical manifestations • Mucositis • Drugs that arrest the growth and maturation of normal cells § antineoplastic agents 12/3/2020 Terezhalmy 61

Adverse Drug Events Type A Reactions • Clinical manifestations • Bleeding diatheses • Drugs

Adverse Drug Events Type A Reactions • Clinical manifestations • Bleeding diatheses • Drugs that interfere with platelet function and the coagulation phase of hemostasis § COX-1 inhibitors clopedigrol, warfarin, heparin 12/3/2020 Terezhalmy 62

Adverse Drug Events Type A Reactions: Bleeding Diatheses 12/3/2020 Terezhalmy 63

Adverse Drug Events Type A Reactions: Bleeding Diatheses 12/3/2020 Terezhalmy 63

Adverse Drug Events Type A Reactions • Clinical manifestations • Bacterial infections • Drugs

Adverse Drug Events Type A Reactions • Clinical manifestations • Bacterial infections • Drugs that alter the normal flora § antibacterial agents • Drugs that cause immunosuppression § immunosuppressants 12/3/2020 Terezhalmy 64

Adverse Drug Events Type A Reactions • Clinical manifestations • Fungal infections • Drugs

Adverse Drug Events Type A Reactions • Clinical manifestations • Fungal infections • Drugs that alter the normal flora § antibacterial agents • Drugs that cause immunosuppression § immunosuppressants 12/3/2020 Terezhalmy 65

Adverse Drug Events Type A Reactions • Clinical manifestations • Viral infections • Drugs

Adverse Drug Events Type A Reactions • Clinical manifestations • Viral infections • Drugs that cause immunosuppression § immunosuppressants 12/3/2020 Terezhalmy 66

Adverse Drug Events Type A Reactions: Viral Infections 12/3/2020 Terezhalmy 67

Adverse Drug Events Type A Reactions: Viral Infections 12/3/2020 Terezhalmy 67

Adverse Drug Events Type A Reactions • Clinical manifestations • Gingival hyperplasia § phenytoin,

Adverse Drug Events Type A Reactions • Clinical manifestations • Gingival hyperplasia § phenytoin, calciumchannel blocking agents, cyclosporine 12/3/2020 Terezhalmy 68

Adverse Drug Events Type A Reactions • Clinical manifestations • Neurological complications • Oral

Adverse Drug Events Type A Reactions • Clinical manifestations • Neurological complications • Oral pain § drugs that cause mucositis and/or immunosuppression § certain antineoplastic agents (vincristine) • Tardive dyskinesia § neuroleptic agents, which alter striatal dopaminergic receptor activity • Taste alterations § drugs that affect trace metal homeostasis 12/3/2020 Terezhalmy 69

Adverse Drug Events Type A Reactions • Clinical manifestations • Inadequate nutrition § drugs

Adverse Drug Events Type A Reactions • Clinical manifestations • Inadequate nutrition § drugs that produce nausea, vomiting, diarrhea § drugs that produce mucositis, xerostomia, § drugs that are hepatotoxic 12/3/2020 Terezhalmy 70

Adverse Drug Events Type B Reactions • Clinical manifestations • Idiosyncratic reactions • An

Adverse Drug Events Type B Reactions • Clinical manifestations • Idiosyncratic reactions • An unusual reaction of any intensity observed in a small number of patients Ø Hypo-reactive patient § The drug produces its usual effect at an unexpectedly high dose Ø Hyper-reactive patient § The drug produces its usual effect at an unexpectedly low dose 12/3/2020 Terezhalmy 71

Adverse Drug Events Type B Reactions • Clinical manifestations • Allergic/ immunologic reactions •

Adverse Drug Events Type B Reactions • Clinical manifestations • Allergic/ immunologic reactions • Type I (immediate) hypersensitivity reaction 12/3/2020 Terezhalmy 72

Adverse Drug Events Type B Reactions • Clinical manifestations • Allergic/ immunologic reactions •

Adverse Drug Events Type B Reactions • Clinical manifestations • Allergic/ immunologic reactions • Type II (cytotoxic) hypersensitivity reaction 12/3/2020 Terezhalmy 73

Adverse Drug Events Type B Reactions • Clinical manifestations • Allergic/ immunologic reactions •

Adverse Drug Events Type B Reactions • Clinical manifestations • Allergic/ immunologic reactions • Type III (immunecomplex) hypersensitivity reaction 12/3/2020 Terezhalmy 74

Adverse Drug Events Type B Reactions • Clinical manifestations • Allergic/ immunologic reactions •

Adverse Drug Events Type B Reactions • Clinical manifestations • Allergic/ immunologic reactions • Type IV (delayed) hypersensitivity reaction 12/3/2020 Terezhalmy 75

Adverse Drug Events Type B Reactions • Clinical manifestations • Lichenoid mucositis § diuretics

Adverse Drug Events Type B Reactions • Clinical manifestations • Lichenoid mucositis § diuretics § beta 1 adrenergic antagonists § ACE-inhibitors § COX-1 inhibitors 12/3/2020 Terezhalmy 76

Adverse Drug Events Type B Reactions • Clinical manifestations • Erythema multiforme • Stevens-Johnson

Adverse Drug Events Type B Reactions • Clinical manifestations • Erythema multiforme • Stevens-Johnson syndrome § sulfonamides § anticonvulsive agents § COX-1 inhibitors 12/3/2020 Terezhalmy 77

Adverse Drug Events Type B Reactions: SJS 12/3/2020 Terezhalmy 78

Adverse Drug Events Type B Reactions: SJS 12/3/2020 Terezhalmy 78

Adverse Drug Events Type B Reactions • Clinical manifestations • Teratogenic effect • Drugs

Adverse Drug Events Type B Reactions • Clinical manifestations • Teratogenic effect • Drugs given during pregnancy can affect the fetus by producing lethal, toxic, or teratogenic effect ØConstricting placental vessels ØImpairing gas and nutrient exchange between fetus and mother ØProducing hypertonia resulting in anoxic injury ØIndirectly, changing the biochemical dynamics of the mother 12/3/2020 Terezhalmy 79

Adverse Drug Events Type B Reactions • Clinical manifestations • Teratogenic effect • Fetal

Adverse Drug Events Type B Reactions • Clinical manifestations • Teratogenic effect • Fetal age, drug potency, and dosage Ø < 20 days after fertilization § An all-or-nothing effect Ø 2 nd to 3 rd trimesters § Unlikely to be teratogenic § Alter growth and function of normally formed fetal organs and tissues 12/3/2020 Terezhalmy 80

Adverse Drug Events Type B Reactions • Clinical manifestations • Teratogenic effect • 3

Adverse Drug Events Type B Reactions • Clinical manifestations • Teratogenic effect • 3 rd to 8 th week Ø No measurable effect Ø Spontaneous abortion Ø Sublethal § True teratogenic effect 12/3/2020 Terezhalmy 81

Adverse Drug Events Type B Reactions: Teratogenic Effects 12/3/2020 Terezhalmy 82

Adverse Drug Events Type B Reactions: Teratogenic Effects 12/3/2020 Terezhalmy 82

Adverse Drug Events Type B Reactions • Clinical manifestations • Oncogenic effects • SCC

Adverse Drug Events Type B Reactions • Clinical manifestations • Oncogenic effects • SCC of the skin • SCC of the lips Ø 7 to 8. 1 % § vs. 0. 3 % Ø Average 42 years § vs. 60 years Ø Latency 5. 3 years 12/3/2020 Terezhalmy 83

Adverse Drug Events Type B Reactions • Clinical manifestations • Oncogenic effects • Kaposi

Adverse Drug Events Type B Reactions • Clinical manifestations • Oncogenic effects • Kaposi sarcoma Ø 5. 6 % § vs. 0. 03 -0. 07 % Ø 60 % non-visceral § Skin § Oral ( 2 %) Ø Visceral § Skin (24 %) § Oral 3 % 12/3/2020 Terezhalmy 84

Adverse Drug Events Type B Reactions • Clinical manifestations • Oncogenic effects • Lymphoproliferative

Adverse Drug Events Type B Reactions • Clinical manifestations • Oncogenic effects • Lymphoproliferative disease • Lymphomas • Leiomyoma • Leiomyosarcoma • Spindle-cell sarcoma 12/3/2020 Terezhalmy 85

Adverse Drug Events • Preventing adverse drug events • Rational approach to the pharmacological

Adverse Drug Events • Preventing adverse drug events • Rational approach to the pharmacological management of oral/odontogenic disease • • • 12/3/2020 Accurate diagnosis Critical assessment of the need for pharmacotherapy Benefits versus risks of drug therapy Individualization of drug therapy Patient education Continuous reassessment of drug therapy Terezhalmy 86

Adverse Drug Events • Diagnosing adverse drug events • Step 1 • Identify the

Adverse Drug Events • Diagnosing adverse drug events • Step 1 • Identify the drug(s) taken by the patient • Step 2 • Verify that the onset of signs and symptoms was after the initiation of pharmacological intervention • Step 3 • Determine the time interval between the initiation of drug therapy and the onset of the adverse drug event 12/3/2020 Terezhalmy 87

Adverse Drug Events • Diagnosing adverse drug events • Step 4 • Stop drug

Adverse Drug Events • Diagnosing adverse drug events • Step 4 • Stop drug therapy and monitor the patient’s status • Step 5 • If appropriate, restart drug therapy and monitor for recurrence of adverse drug event 12/3/2020 Terezhalmy 88

Adverse Drug Events • Reporting adverse drug events • An event is serious and

Adverse Drug Events • Reporting adverse drug events • An event is serious and should be reported when the patient outcome is • • • 12/3/2020 Death Life-threatening Hospitalization Disability Congenital anomaly Requires intervention to prevent permanent impairment or damage Terezhalmy 89

Adverse Drug Events • Reporting adverse drug events • FDA Form 3500 • http:

Adverse Drug Events • Reporting adverse drug events • FDA Form 3500 • http: //www. fda. gov/medwatch/report/hcp. htm Ø Complete the voluntary form 3500 online Ø Download a copy of the form § Fax it to 1 -800 -FDA-0178 OR § Mail it back using the postage-paid addressed form • Call 1 -800 -FDA-1088 to report by telephone 12/3/2020 Terezhalmy 90

Adverse Drug Events • Conclusion • ADEs evolve through the same physiological and pathological

Adverse Drug Events • Conclusion • ADEs evolve through the same physiological and pathological pathways as normal disease • Prerequisites to consider ADEs in the differential diagnosis Ø An awareness that an ever increasing number of patients are taking more and more medications (polypharmacy) Ø Recognition that many drugs will remain in the body for weeks after therapy is discontinued Ø Clinical experience Ø Familiarity with relevant literature about ADEs 12/3/2020 Terezhalmy 91

Adverse Drug Events • Conclusion • Recognize that some ADEs occur rarely and detection

Adverse Drug Events • Conclusion • Recognize that some ADEs occur rarely and detection based on clinical experience or reports in the medical literature at time is difficult if not impossible 12/3/2020 Terezhalmy 92

Adverse Drug Events • Conclusion • Timely reporting of ADEs • Saves lives •

Adverse Drug Events • Conclusion • Timely reporting of ADEs • Saves lives • Reduces morbidity • Decrease the cost of health care 12/3/2020 Terezhalmy 93

Adverse Drug Events 12/3/2020 Terezhalmy 94

Adverse Drug Events 12/3/2020 Terezhalmy 94

Adverse Drug Events 12/3/2020 Terezhalmy 95

Adverse Drug Events 12/3/2020 Terezhalmy 95

Adverse Drug Events 12/3/2020 Terezhalmy 96

Adverse Drug Events 12/3/2020 Terezhalmy 96