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Adverse Drug Reactions and Drug Allergy

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ADVERSE DRUG REACTIONS (ADRs) AND DRUG ALLERGY Achara Srisodsai, Ph.D. Department of Toxicology Faculty of Pharmaceutical Sciences Khon Kaen University

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?????????????????????? ?????????????????????????????????????????????????????? ?????????????????????????????????? ADRs ???????????????????????????? ADRs ??????????? ??????????????????????????????????? ??????????????????????????????????? ??????????????????????????????????????

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ADRs Definition Classification of ADRs Mechanisms Drug allergy Characteristics Mechanisms Clinical Manifestation OVERVIEW

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THE FIRST APPEARANCE OF THALIDOMIDE 'Thalidomide Babies'

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First appeared in Germany on 1st October 1957. As a sedative with apparently remarkably few side effects. Prescribing to pregnant women to help combat morning sickness. The tests were conducted on rodents which metabolise the drug in a different way to humans. Later tests on rabbits and monkeys produced the same horrific side effects as in humans. Thalidomide

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Towards the end of the fifties, children began to be born with shocking disabilities. Probably the most renowned is Phocomelia, the name given to the flipper-like limbs which appeared on the children of women who took thalidomide. Babies effected by this tragedy were given the name 'Thalidomide Babies'.

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Why drugs can cause tragedy?

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Compound Success Rates By Stages 0 2 4 6 8 10 12 14 16 Years Discovery (2-10 Years) Preclinical Testing Laboratory and animal testing Phase I 20-80 healthy volunteers used to determine safety and dosage Phase II 100-300 patient volunteers to look for efficacy and side effects Phase III 1,000-5,000 patient volunteers used to monitor adverse reactions to long-term use FDA Review/Approval Additional post-marketing testing Compound Success Rates by Stage 5,000-10,000 screened 250 Enter preclinical testing 5 Enter clinical testing 1 Approved by the FDA Postmarketing survillence

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Limitations of premarketing clinical trials Short duration — effects that develop with chronic use or those that have a long latency period are impossible to detect. Narrow population — generally do not include special groups (e.g., children, elderly), to a large degree, and are not always representative of the population that may be exposed to the drug after approval.

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Adverse Reaction Drug Time Lag (yr) Pulmonary embolism Oral contraceptives 3 Myocardial infarction Oral contraceptives 5 Deaths from asthma Sympathomimetic aerosols 4 Jaundice Halothane 7 Colitis Lincomycin 6 Colitis Clindamycin 5 Aplastic anemia Phenylbutazone 6 Venning, GR. Br. Med. J. 286:365-368, 1983 Summary of time lags after U.S. marketing before adverse drug reactions were widely recognized

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Narrow set of indications — those for which efficacy is being studied and do not cover actual evolving use. Small size (generally include 3,000 to 4,000 subjects) — effects that occur rarely are very difficult to detect. Limitations of premarketing clinical trials

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Required sample size for detecting a rare adverse drug reaction

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ADVERSE DRUG REACTIONS (ADRs)

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WHO: Any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological functions. What is ADR?

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Excluding………. Therapeutic failures Intentional and accidental overdose Drug abuse Errors in drug administration

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Adverse Drug Events (ADEs) - ????????? ?????????????????????????????????? Risk assessment of drug - ??????????????????????????????????????????????????????????????????????? ?????????????????????????????, ???????????????????????????????????????? ????????????, ????????????????????????, ????????????????????????? Adverse Product Reaction (APR) - ?????, ?????????, ????????????

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Classification of Adverse Drug Reactions

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Classification of Adverse Drug Reactions ?????????????????????????? (Severity classification) 1. ?????????? (Mild) ?????????????????? ???????????????????????????????? ? 2.????????????? (Moderate) ????????????????????????????????????????????????????????????????????? 3. ????????? (Severe) ???????????????????????????????????????????????????????

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Serious adverse events: ????????? (fatal) ?????????? (life-threatening) ????? (disabling) ????????????????????????????????? (prolongs hospitalization) ??????????????????????????????????? (congenital anomaly) ??????????????????????????????????????????????????? (requires intervention)

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???????? (Possible) ?????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????? ????????????? - ????????? (Doubtful/ Unlikely) ???????????????????????????????????????????????????????????????????????????

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???????????????? Type A (augmented/predictable) - ????????????????????????????????????????????????????????? ???? ???????????????????????????????????????????? Type B (bizarre/unpredictable) - ???????????????????????????????????????????????????????????????????????????????????????????????????? - ??????????????????? ??????????????????????????????????????????? ?????????

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3. Type C (chronic) - ????????????????????????????????????????????????????? ???????????????????????????? ???? ??????????????? Benzodiazepines 4. Type D (delayed) - ???????????????????????????????????????????? ???? ???????????? ???? ????????????????????????????? 5. Type E (end-of-treatment) - ???????????????????????????? (withdrawal) ?????????????

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Type A (augmented/predictable) reactions Expected extensions of an individual drug’s known pharmacologic properties and are responsible for the bulk of ADEs encountered. Even though their incidence and morbidity is high, they are rarely life-threatening, although they can produce significant disability.

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Causes of Type A reactions 1. Pharmaceutical causes - Drug quantity - Drug release e.g. Osmosin® (slow release indomethacin) GI bleeding 2. Pharmacokinetic causes - Drug absorption - Drug elimination - Drug distribution - Drug metabolism 3. Pharmacodynamic causes - Drug receptors - Homeostatic mechanisms - Disease

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Drug absorption ??????????????????? ???? ??????????? digoxin ??????? atropine ?????????????????? digoxin ?????????????? (ADR?) Drug distribution Tetracycline ???????????????????????????????????????????????????????????????????????? Pharmacokinetic causes

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Drug excretion ???????? aspirin ???????????????????????? organic acid ???? urate ?????????????????? ????????????????????????? hyperuricemia Drug metabolism Paracetamol ?????????????????? ????????????? unchanged form ??????????????????????? ??????????????????????????????????? CYP2E1?????? toxic metabolite ?????????????????????

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Paracetamol Metabolism Glucuronide conjugation 50-60% Sulphate conjugation 25-35% N-acetylbenzoquinoimine (NAQI) CYP 2E1 Hepatotoxicity Glutathione conjugation GSH Mercapturic acid conjugates excreted in urine 2-4% Covalently-bound paracetamol Cell macromolecule

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Factors predisposing to pharmacological adverse drug reactions Factor Example Toxicity Mechanism Pharmaceutical Osmosin Gastrointestinal Release of high (slow release bleeding concentrations of indomethacin) active drug locally in GI Pharmacokinetic* Digoxin Digoxin toxicity Decreased elimination (nausea, arrhythmias) if renal function is impaired Pharmacodynamic Indomethacin Left ventricular Water and sodium failure retention Drug-drug TerfenadineTM Prolonged QT Inhibition of interaction* Erythromycin interval and metabolism of torsades de terfenadine by pointes erythromycin *Can affect absorption, distribution, metabolism, or excretion.

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Ways to minimize both pharmacokinetically- and pharmacodynamically-derived ADEs include Understanding the pharmacology of the drug being prescribed Monitoring drugs with a narrow therapeutic window Avoiding polypharmacy whenever possible

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Type B (bizarre/unpredictable) reactions Type B reactions include idiosyncratic reactions, immunologic or allergic reactions (e.g.anaphylaxis), and carcinogenic/teratogenic events. While uncommon, are often among the most serious and potentially life-threatening of all ADEs, and are a major cause of important drug-induced disease.

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Receptor abnormality —malignant hyperthermia with general anesthetics Mechanisms of Type B reaction Autosomal dominant genetic disorder of SM Mutation in the gene loci corresponding to skeletal muscle ryanodine receptor (RYR1), the calcium release channel of sarcoplasmic reticulum. Tachycardia, HT, severe muscle rigidity, hyperthermia

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Abnormal biological system unmasked by drug —primaquine induced haemolysis in patients deficient in glucose 6-phosphate dehydrogenase

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Genetic heterogeneity among affected individuals with over 400 variants of the enzyme identified. - The severity of the problem can vary from hemolysis even in the absence of oxidative stress to hemolysis only on exposure to mild to marked oxidant stress.

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Abnormalities in drug metabolism - Atypical pseudocholinesterase ??????????????? succinylcholine ???????? prolong apnea ????? cholinesterase ???????????????????????????????????????????????????????????????? Atypical ChE ?? affinity ??? substrate ???????? half life ??? - Polymorphism drug oxidation ???? CYP2D6 polymorphism (debrisoquine/sparteine) CYP2C19 polymorphism (Mephenyltoin)

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???????????????? Type A ??? Type B ADRs Type A Type B 1. Predictability 2. Dose-dependent 3. Incident 4. Mortality 5. Treatment 6. Pharmacological basis 7. Seriousness Yes No Yes No Common Rare No Yes Adjust dose No Yes No No Yes

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Summary points Adverse drug reactions are a common clinical problem They are diagnosed on clinical grounds from the temporal relation between the start and finish of drug treatment and the onset and offset of the reaction Pharmacological adverse reactions are generally dose-dependent, related to the pharmacokinetic properties of the drug, and resolve when the dose is reduced

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Idiosyncratic adverse reactions are not related to the known pharmacology of the drug, do not show any simple dose-response relation, and resolve only when treatment is discontinued Vigilance by clinicians in detecting, diagnosing, and reporting adverse reactions is important for continued drug safety monitoring

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???????????????????????????????????????????????????????????????????????????????????????????antibody??????? ??????????????????????????????????????????????????????????????????? Drug allergy

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????????????????????????? ?????????????????????????? ?????????????????????????????? ?????????????????? ??????????????????????????????????????? ????????????????????????????????????? ???????????????????? ?????????????????????? ???????????? Ab ???? T-lymphocyte ???????????????????????????????????????????????????????????

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??????????????????????????????????????? 1. ??????????????????????????? ??????????????????????????????????? ???????????????????????????????????????? ??????????????antibody????????????????????????????? 2. ?? Reactive metabolite ?????????????????? ?????? metabolite ???????????????????????????????????? ?????????????????????????????????? e.g. penicillin 3. ????????????????????????????????????????? ???? penicillenic acid, pennicilloic acid

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4. ???? polymerization ??????? ?????????????????????????? polymerization ???????????????????????? ?????????????????? ???? ampicillin 5. ?? contaminants or additives ?????????????????? ??????????????????????????????????? benzylpenicillin ??????????????? ???????????????? ????? pennicilloylated protein 6. ???????????????????????????????????????? ???? penicillins, cephalosporins

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Type I — Anaphylactic/ Immediate type (e.g., Penicillin, insulin urticaria or anaphylaxis) Type II — Cytotoxic type (e.g., drug-induced haemolytic anaemia or thrombocytopenia [reduced platelets]) Type III — Immune complex type (e.g., serum sickness-like drug reactions) Type IV — Cell-mediated or delayed hypersensitivity (e.g., neomycin contact dermatitis) ???????????????

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??????????????? ????????? ????????????????????????????? Ag ?????????????????? IgE ?????????????????? mast cells ??? basophils Systemic anaphylaxis, ?????, ??????????????, angioneurotic edema Type I: Anaphylactic/Immediate type

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??????????????????????????????????????????????? hemolytic anemia, thrombocytopenia, granulocytopenia Type II: Cytolytic Reactions The Fab of IgG reacts with epitopes on the host cell membrane. Phagocytes bind to the Fc portion. Phagocytes binding to the Fc portion of the IgG and discharge their lysosomes causing cell lysis.

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Type III: Immune Complex Reactions ?????????????????? IgG ???????????????????????? immune complexes ??????????????? complement ?????????????????????? ?????????????? Glomerulonephritis

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IgG ??? IgM ?????????????? antigen ????????????????????????????? immune complex ???????????????????????????????????????????????????

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??????????????????? complement ??????????????????????????????????????????????? antigen ???? ??????????????? phargocyte ?????????????????????? lysosomal enzyme ???????????????????????????????????????????????????????????? ??????????????????????????????? arthus reaction ???????????????????????????????????????? serum sickness

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Type IV: Cell-Mediated Reactions ?????????????????????????????????????????? ???? ?? macrophage ????? ?????????????????????????????????? T cells Contact dermatitis, fixed-drug eruptions

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?????????? ??????????????????????? ???????????????????????????????????????????????????????? ??????????????????? 24 ??????? ????????????????? penicillin, sulfonamide Urticaria:

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- ?????????????????????? ????? - ??????????????????????????????????????? - ???????????????????????????????????, ??????, ???? ????????? - ???????????????????????? ????????????? - ????????????????? penicillin, sulfonamide Angioedma

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- ????????????? ???????? ??????????????????????????????????????????????????????????????????????? iris ???? target ????????????????????????? - ????????????????? penicillin, sulfonamide, barbiturate, NSAIDs, phenyltoin, allopurinol Erythema multiforme:

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- ??????????????????????????? ???????????????????? ???????????????????????? ?????????????????? ???????????????????? - ????????????????? tetracyclin, sulfonamide Fixed-drug eruptions:

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- ????????????????????????????? - ????????????????? penicillin, sulfonamide, barbiturate, hydantoin, NSAIDs, phenyltoin, allopurinol Toxic Epidermal Necrolysis (TEN):

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- ???????????????????????????????? erythema multiforme ?????????????????????????????? ???????????????? ????????????? ????????? ???????????????????? ????????????? - ????????????????? penicillin, sulfonamide, barbiturate, hydantoin, NSAIDs, phenyltoin, allopurinol Steven Johnson Syndrome:

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??????????????????? ????????????: ????????????????????????????? www.who.int www.fda.gov/medwatch

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THE END

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