ADVERSE EFFECTS OF DRUGS (ADR) Introduction: Any unwanted, undesirable response resulting from the administration of a particular drug

ug at doses normally used. Range from mild- side effects (no need to stop medication) to severe including death.

Groups of drugs more likely to produce ADR Antibiotics Anticoagulants Digoxin Diuretics Hypoglycemic agents NSAIDs

Classification of ADRs 1- Type A: (Dose dependent Augmented, predictable) reactions 2- Type B: (Dose independent, Bizarre reaction)- Unpredictable reactions. 3 subordinate types are: 3- Type C: (Continuous) reactions due to long term use, e.g., analgesic nephropathy with phenacetin, osteoporosis with corticosteroids. 4- Type D: (Delayed) effects, e.g., teratogenesis, carcinogenesis. 5- Type E: (Ending of use) reactions, where discontinuation is too abrupt, e.g., rebound adrenocortical insufficiency, blockers causing rebound hypertension, withdrawal syndrome with opioids, sedatives, hypnotics

Differences between type 1 and type 2 reactions Type A Predictable, occurs in all if certain dose is exceeded. Dose dependent Incidence is high Morbidity- high Mortality- low Adjust dose to treat Examples: Insulin hypoglycemia Warfarin hemorrhage Type B Not predictable, occurs only in some. Not dose-related, not correlated with pharmacological action. Incidence low Morbidity- low Mortality is high Stop the drug Examples: Allergic reactions: anaphylaxis (penicillin), aplastic anemia (chloramphenicol), drug fever (sulfonamides), serum sickness, etc. Idiosyncratic reactions: hemolysis with G6PD deficiency, acute porphyria: with barbiturate; malignant hyperthermia- succinylcholine

Predisposing factors: 1. Age. 2. Sex 3. Enzyme abnormalities 4. Protein binding displacement 5. Liver Diseases 6. Renal Diseases 7. Route of administration 8. Immunological responses 9. Polypharmacy

Predisposing factors: 1- Age (Adverse reactions are seen at extremes of age): a- Drugs given in first 3 months of pregnancy, during the period of organogenesis, may cause congenital abnormalities and are called teratogenic. Examples: Thalidomide Phenytoin Valproate Warfarin Estrogens Phocomelia Cleft palate, hare lip Spina-bifida Microcephaly Ca of vagina in offspring

b- After the period of organogenesis: affect the growth or function in fetus. Examples: Impaired bone growth and discoloration of teeth and susceptibility to caries- Tetracyclines. Severe jaundice or kernicterus by long acting sulphonamides (displacement of bilirubin from protein binding sites) c- At the time of Labour: Fetal distress syndrome, respiratory depression with analgesics, sedatives, hypnotics and anesthetics. d- Neonate, infant, and children: 1- Neonate, infant: Deficiency of Drug metabolizing enzymes in a new born (4-6 weeks), especially in premature. Gray baby syndrome with Chloramphenicol due to decrease glucuronidation and decrease renal function. Kernicterus with Sulphonamides and aspirin. Paradoxical effect with phenobarbitone. Tooth discoloration with tetracycline. 2- Older children (1-8 years):

e- Old age: 1- Sedatives (phenobarbitone, benzodiazepines), and hypnotics may produce confusional states due to reduced metabolism and age related changes in sensitivity of CNS. 2- Digoxin toxicity: Decrease GFR and accumulation of drug with age. Factors which lead to increased incidence of adverse reactions: 2- Sex Women more susceptible to toxic effects of : Digoxin Heparin Captopril Chloramphenicol-2X aplastic anemia Phenylbutazone- 3 X agranuloctytosis. Decrease in weight Decrease in GFR Decrease in blood flow to vital organs Decrease in protein binding capacity Decrease in metabolism Less efficient homeostatic mechanism Increased tendency to be on multiple drug regimens.

3- Renal Diseases: Accumulation of drugs, eliminated in urine, occurs in renal impairment producing adverse effects, e.g. Ototoxicity and nephrotoxicity with aminoglycoside. Digoxin toxicity. Lithium toxicity.

4- Route of administration Intra-arterial injection of thiopentone leads to tissue necrosis. Intrathecal dose of penicillin G is one hundredth less than intramuscular dose. May produce encephalopathy.

5- Enzyme abnormalities: A- Inherited (Genetic): Examples: 1- Deficiency of pseudoChE or presence of atypical ChE leading to prolonged apnoea with succinylcholine. 2- Deficiency of N-acetyltransferase results in altered acetylation of INH, procainamide, hydralazine, sulphonamides. Slow acetylators of INH may develop polyneuritis and fast acetylators may develop hepatic toxicity. 3- Deficiency of G6PD - may lead to hemolysis by drugs like primaquine, quinine, sulphonamides, nitrofurantoin, chloramphenicol and by food products like fava beans. 4- Deficiency of Erythrocyte diaphorase (methemoglobin reductase) methemoglobinemia by sulphonamides and nitrites. B- Acquired: 1- Enzyme induction: It leads to increased inactivation of drugs and endogenous products. Enzyme inducer Phenobarbitone Phenytoin Drug affected Warfarin Vitamin D Result Decrease anticoagulant effect Osteomalacia or rickets

2- Enzyme Inhibition: Administration of MAOI may produce Cheese death with certain food stuffs containing tyramine (chicken liver, cheese, wine, meat, Yeast) Cimetidine - inhibitor of microsomal MFO-leads to adverse drug interactions with many drugs. Allopurinol may increase toxicity of mercaptopurine, azathioprine. Chloramphenicol- inc. toxicity of phenytoin. Erythromycin, ciprofloxacin inc toxicity of theophylline.

6- Polypharmacy: multiple drugs. The more number of drugs prescribed more likelihood of adverse drug interactions.

7- Protein binding displacement Long acting sulfonamides may displace tolbutamide producing severe hypoglycemia. Sulphonamide may displace bilirubin in fetus or neonate and produce kernicterus. Important only if protein binding is more than 80% and if the VD of displaced drug is low. 8- Liver Diseases a- Drugs like frusemide (by producing hypokalemia); narcotics may precipitate hepatic encephalopathy in patients with liver disease. b- Slow metabolism of drugs like corticosteroids, narcotic analgesics, barbiturates, phenothiazines. c- Drugs may produce liver disease. Examples: Hepatocellular jaundice: Paracetamol, halothane. Fatty liver and hepatic encephalopathy - Aspirin (Reye's Syndrome) Cirrhosis - Vitamin A Fibrosis - Methotrexate Hepatocellular carcinoma and adenoma - Sex hormones, oral contraceptives. 9- Immunological responses: a- Type I: Hypersensitivity and anaphylactic reaction with penicillin. b- Type II: Hemolysis with -methyldopa. c- Type III: Serum sickness with streptokinase. d- Type IV: Delayed skin reaction (skin eruption with amoxicillin).