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Adverse drug reaction

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Adverse drug reaction

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Adverse drug reaction

  1. 1. Adverse Drug ReactionReaction Dr. Deepak K Gupta
  2. 2. Definition - WHO “Any response to a drug which is noxious,“Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy.” facebook.com/notesdental
  3. 3. Classification of Adverse Drug Reaction (ADR) 1. DOSE-RELATED ADVERSE DRUG REACTIONS a) PHARMACEUTICAL VARIATION b) PHARMACOKINETIC VARIATION c) PHARMACODYNAMIC VARIATION 2. NON-DOSE RELATED ADVERSE DRUG REACTIONS a) IMMUNOLOGICAL REACTIONS b) PSEUDO ALLERGIC REACTIONS c) PHARMACOGENETIC VARIATIONc) PHARMACOGENETIC VARIATION 3. Long-term adverse drug reactions a) ADAPTIVE CHANGES b) REBOUND PHENOMENON 4. Delayed adverse drug reactions a) CARCINOGENESIS b) EFFECTS CONCERNED WITH REPRODUCTION a) Impaired infertility b) Teratogenesis c) Drugs in breast milk facebook.com/notesdental
  4. 4. Classification of ADRs.... Wills and brown • Type A (Augmented) • Type B (Bizarre) • Type C (Chemical) • Type D (Delayed) • Type E (Exit/End of treatment)• Type E (Exit/End of treatment) • Type F (Familial) • Type G (Genotoxicity) • Type H (Hypersensitivity) • Type U (Un classified) facebook.com/notesdental
  5. 5. Dose related adverse reactions • This has led to the concept of the THERAPEUTIC INDEX, or the TOXIC:THERAPEUTIC RATIO. • This indicate the margin between the therapeutic dose and the toxic dose. • The bigger the ratio, the better. • Examples of drugs with a low TOXIC:THERPEUTIC• Examples of drugs with a low TOXIC:THERPEUTIC RATIO - Anticoagulants (warfarin, heparin), Hypoglycemic drugs (insulin, sulfonylurea), Antiarrythmic drugs (lidocaine, amiodarone) • It can occur because of variations in the – Pharmaceutical, – Pharmacokinetic, – Pharmacodynamic properties of a drug facebook.com/notesdental
  6. 6. PHARMACEUTICAL VARIATION • ADR occur because of – alterations in the systemic availability of a formulation EX: Phenytoin Intoxication – presence of a contaminant EX: Pyrogens or even– presence of a contaminant EX: Pyrogens or even Bacteria in intravenous formulations. – Out of date formulations (expiry date) - degradation products. EX: out-dated Tetracycline can cause Fanconi’s Syndrome. facebook.com/notesdental
  7. 7. PHARMACOKINETIC VARIATION • There is much variation among normal individuals in the rate of elimination of drugs. • This variation is most marked for drugs that are cleared by hepatic metabolism.are cleared by hepatic metabolism. • It is determined by several factors, which may be – GENETIC – ENVIRONMENTAL – HEPATIC. facebook.com/notesdental
  8. 8. GENETIC • Acetylation – Depending on genetics individuals are Fast and Slow acetylators. – Ex: Isoniazid, Hydralazine, Procainamide, Dapsone, Some sulfonamides. – Increased incidence of PERIPHERAL NEUROPATHY is observed in slow acetylators of Isoniazid • Oxidation – Oxidation also shows genetic variability. – There are individuals with impaired oxidation and with normal oxidation. – Impaired oxidation ones are called as POOR METBOLIZERS and the ones with– Impaired oxidation ones are called as POOR METBOLIZERS and the ones with normal are called EXTENSIVE METABOLIZERS • Succinylcholine hydrolysis: – Succinylcholine is hydrolyzed by PSEUDOCHOLINESTRASE. – In some individuals pseudocholinestrase is abnormal and does not metabolize succinylcholine rapidly. – In such cases drug persist in blood and continue to produce neuro muscular blockade for several hours. This result in respiratory paralysis called SCOLINE APNOEA. facebook.com/notesdental
  9. 9. Hepatic Disease • Hepatocellular dysfunction, as in several hepatitis or advanced cirrhosis, can reduce the clearance of drugs like phenytoin, theophylline and warfarin. • A reduction in hepatic blood flow, as in heart failure, can reduce the hepatic clearance of drugs that have an high extraction ratio for e.g. propranolol, morphine and pethidine.extraction ratio for e.g. propranolol, morphine and pethidine. • Reduced production of plasma proteins (for e.g. albumin) by the liver in cirrhosis can lead to reduced protein binding of drugs. • Hepatic congestion and reduced liver blood flow may impair the metabolism of some drugs (e.g. Lidocaine). facebook.com/notesdental
  10. 10. Renal Disease • If a drug or active metabolite is excreted by glomerular filtration or tubular secretion, it will accumulate in renal insufficiency and toxicity will occur.toxicity will occur. • Poor renal perfusion may result in reduced renal elimination (e.g. Procainamide). facebook.com/notesdental
  11. 11. Cardiac Disease • Cardiac failure, particularly congestive cardiac failure, can alter the pharmacokinetic properties of drugs by several mechanisms • Impaired absorption, due to intestinal mucosal edemaedema • Poor splanchnic circulation, can alter the efficacy of some oral diuretic, such as FUROSEMIDE • Reduction in the apparent volumes of distribution of some cardio active drugs e.g. Procainamide, Lidocaine, Quinidine facebook.com/notesdental
  12. 12. PHARMACODYNAMIC VARIATION • Various factors influences body’s reaction on drugs. It may be due to – Hepatic Disease • Reduced blood clotting• Reduced blood clotting • Hepatic encephalopathy • Sodium and water retention – Altered fluid and electrolyte balance facebook.com/notesdental
  13. 13. Hepatic Disease • Hepatic disease can alter pharmacodynamic responses to drugs in several ways; • Reduced Blood Clotting: – In cirrhosis and acute hepatitis, production of clotting factor is impaired and patients bleed more readily. – Drugs that impair blood clotting, homeostasis, or that predispose to bleeding by causing gastric ulceration should be avoided or used with care – Ex: Anticoagulants and NSAIDS. • Hepatic Encephalopathy: – In patients with, or on the border line of, hepatic encephalopathy, the brain is more sensitive to the effects of drugs with sedative actions. – If such drugs are used, coma can result. – Opioids , other Narcotic Analgesics and Barbiturates. • Sodium and Water Retention • In hepatic cirrhosis, sodium and water retention can be exacerbated by certain drugs. • NSAIDS, Corticosteroids, Carbamazepine and formulations containing large amount of sodium. facebook.com/notesdental
  14. 14. Altered Fluid and electrolyte balance • The pharmacodynamic effects of some drugs are altered by changes in fluid and electrolyte balance. Example:Example: – The toxic effect of cardiac glycosides are potentiated by both Hypokalaemia and Hypercalcaemia. – The Class1 of Antiarrhythmic drugs such as Quinidine, Procainamide and Disopyramide are more arrhythmogenic if there is hypokalaemia. facebook.com/notesdental
  15. 15. NON-DOSE RELATED ADVERSE DRUG REACTIONS • It may proceed in either of this procedure a) IMMUNOLOGICAL REACTIONS b) PSEUDO ALLERGIC REACTIONS c) PHARMACOGENETIC VARIATIONc) PHARMACOGENETIC VARIATION facebook.com/notesdental
  16. 16. IMMUNOLOGICAL REACTIONS • There is no relationship to the usual pharmacological effects of the drug; • There is often a delay between the first exposure to the drug and the occurrence of the subsequent adverse reaction;and the occurrence of the subsequent adverse reaction; • There is no formal dose-response curve; • The illness is often recognizable as a form of immunological reaction like rash, serum sickness, urticaria etc facebook.com/notesdental
  17. 17. IMMUNOLOGICAL REACTIONS • Factors involved in drug allergy are: Drug and Patients THE DRUG: – Macromolecules such as PROTEINS (vaccines and enzymes such as streptokinase), POLYPEPTIDES (insulin and dextrans) can themselves be immunogenic.dextrans) can themselves be immunogenic. THE PATIENTS: • There are genetic factors that make some patients more likely to develop allergic reactions than others: • A history of allergic disorders • HLA status(antigens on human lymphocytes) facebook.com/notesdental
  18. 18. PHARMACOGENETIC VARIATION • It may involve • Red cell enzyme defects • Porphyria • Malignant hyperthermia facebook.com/notesdental
  19. 19. RED CELL ENZYME DEFECTS • Unusual drug reaction occur in individuals whose erythrocytes are deficient in any one of three different but functionally related enzymes.enzymes. • Glucose-6-phosphate dehydrogenase • Glutathione reductase • Methaemoglobin reductase facebook.com/notesdental
  20. 20. Porphyria • Porphyrias constitute a group of disorders of haem- biosynthesis. • Different types of porphyrias are: Acute intermittent porphyrias Variegate porphyriaVariegate porphyria Porphyria cutanea tarda Erythropoietic Porphyria • Each type of Porphyria is associated with a different abnormality of an enzyme in haem-biosynthetic pathway. • Drugs to be avoided in porphyria : Barbiturates, Dapsone, Chloramphenicol, Diclofenac etc. facebook.com/notesdental
  21. 21. Malignant hyperthermia • It is an autosomal dominant generic disorder of skeletal muscles that occurs in susceptible individuals undergoing General Anesthesia with inhaled agents (halogenated) and muscle relaxants like Succinylcholine.relaxants like Succinylcholine. • This rare condition of uncontrolled release of calcium by sarcoplasmic reticulum of skeletal muscles leads to muscles spasm, hyperthermia and autonomic liability. • Dantrolene is indicated in life threatening situations. facebook.com/notesdental
  22. 22. Long Term Effect • Adaptive changes – Examples include development of tolerance to and physical dependence on the NARCOTIC ANALGESICS and the occurrence of TARDIVE DYSKINESIA in some patients receiving long term neuroleptic drug therapy for schizophrenia. • Rebound and withdrawal phenomena – During long term therapy sudden withdrawal of the drug– During long term therapy sudden withdrawal of the drug can result in rebound reactions. Examples : – Barbiturates - restlessness , mental confusion and convulsions. – β-adrenoceptors antagonists - rebound tachycardia which can precipitate myocardial ischemia. – Corticosteroids - adrenal insufficiency. facebook.com/notesdental
  23. 23. Delayed adverse drug reactions • It involves a) CARCINOGENESIS a) Hormonal b) Gene toxicityb) Gene toxicity c) Suppression of immune response b) EFFECTS CONCERNED WITH REPRODUCTION a) Impaired infertility b) Teratogenesis c) Drugs in breast milk facebook.com/notesdental
  24. 24. • There are three major mechanisms of carcinogenesis: Hormonal:  Incidence of VAGINAL ADENOCARCINOMA is increased in daughters of women who have taken  Incidence of VAGINAL ADENOCARCINOMA is increased in daughters of women who have taken STILBOESTROL during pregnancy for the treatment of threatened abortions.  Increased risk of BREAST CANCERS is about 50% and woman taking HORMONE REPLACEMENT THERAPY (HRT) for more than five years. facebook.com/notesdental
  25. 25. Gene Toxicity • Occurs when certain molecules bind to nuclear DNA and produce changes in gene expressions. Examples: – BLADDER CANCER in patient taking long term CYCLOPHOSPHAMIDECYCLOPHOSPHAMIDE – Carcinomas of RENAL PELVIS associated with PHENACETIN abuse. – Non lymphocytic LEUKEMIA in patients receiving ALKYLATING AGENTS such as melphalan, chlorambucil etc. facebook.com/notesdental
  26. 26. Suppression of immune responses • Patients taking immunosuppressive drugs such as AZATHIOPRINE with CORTICOSTEROIDS have increased risk of developing LYMPHOMAS.developing LYMPHOMAS. facebook.com/notesdental
  27. 27. EFFECTS CONCERNED WITH REPRODUCTION: Impaired Fertility • Cytotoxic drugs can cause female infertility through ovarian failure with amenorrhea. • Male fertility can be reduced by impairment of spermatozoal production or function and can be eithereither – REVERSIBLE IMPAIRMENT can be caused by sulfasalazine, nitrofurantoin, MAO inhibitors and antimalarial drugs; – IRREVERSIBLE IMPAIRMENT, due to azospermia, can be caused by cytotoxic drugs, such as alkylating agents cyclophosphamide and chlorambucil. facebook.com/notesdental
  28. 28. EFFECTS CONCERNED WITH REPRODUCTION: Teratogenesis • Teratogenesis occurs when a drug taken during early stages of pregnancy causes a developmental abnormality in a fetus. • Drugs can affect fetus at 3 stages: – FERTILIZATION AND IMPLANTATION  Conception to 17 days  Failure of pregnancy which often goes unnoticed. – ORGANOGENESIS– ORGANOGENESIS • 18 to 55 days of gestation • Most vulnerable period, deformities are produced – GROWTH AND DEVELOPMENT • 55 days onwards • development and functional abnormalities can occur • ACE inhibitors can cause HYPOPLASIA of organs • NSAIDs may induce PREMATURE CLOSURE OF DUCTUS ARTERIOSUS • Different teratogenic drugs are: Thalidomide, Methotrexate, Warfarin, Phenytoin, Phenobarbitone, Valproate Sod.,Lithium, etc. facebook.com/notesdental
  29. 29. Factors predisposing to ADRS • Drug Related Factors • Dose • Dosage form and delivery system • Interactions between drugs • Patient Related Factors • Age - Geriatrics• Age - Geriatrics • Age – Pediatrics • Concurrent diseases • Hepatic disease • Renal disease • Other diseases • Genetic factors • Gender • Nutrition facebook.com/notesdental
  30. 30. Prevention of ADR • Avoid all inappropriate use of drugs • Use appropriate dose, route & frequency • Consider previous history of Drug reaction • Rule out possibilities of Drug interference• Rule out possibilities of Drug interference • Carry appropriate laboratory monitoring facebook.com/notesdental
  31. 31. Clinical Manifestation of ADR • Side Effects – Unwanted, unavoidable pharmacological effects occurring at therapeutic doses of drug – predicted from pharmacological effects of drug – Ex: Atropine – dryness in mouth, Promethazine – sedation • Secondary Effects – Indirect consequences of primary action of drug– Indirect consequences of primary action of drug – Ex: Tetracycline – super infections • Toxic Effects – Result of excessive pharmacological action of drug due to over dosage or prolonged use – Ex: Morphine – respiratory depression, Amino glycosides – ototoxicity • Untoward effects – Occurs at therapeutic dose but if severe necessitate cessation of treatment – Vomiting and diarrhea with Para-amino salicylic acid facebook.com/notesdental
  32. 32. Clinical Manifestation of ADR • Idiosyncrasy – Genetically determined abnormal reaction to a drug or chemical – Salicylates and sulfonamides produce haemolysis in individuals whose RBC lack glucose-6-phosphate dehydrogenase • Drug allergy – Immunologically mediated reactions producing symptoms which are– Immunologically mediated reactions producing symptoms which are unrelated to pharmacodynamic profile of drug independent to dose • Photosensitivity – Drug or its metabolite accumulates in the skin, absorb light and undergo photochemical reaction to cause local tissue damage • Tetracycline, fluoroquinolones, sulfonamides facebook.com/notesdental
  33. 33. References • Basic & Clinical Pharmacology Bertram G. Katzung Twelfth Edition • Essential of medical pharmacology - K.D. Tripathi 6th edition Lippincott - Modern Pharmacology With Clinical• Lippincott - Modern Pharmacology With Clinical Applications 6E • Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann, Thieme 2000) facebook.com/notesdental
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Adverse drug reaction

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