Adverse Drug Reactions and Drug Interactions

Adverse Drug Reaction:

Response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis and therapy (WHO) Unwanted or harmful reaction experienced after the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to drug

Type of adverse reactions:

Type A (Augmented) Type B (Bizarre) Type C (Chronic) Type D (Delayed) Type E (End of use) Type F (Therapeutic failure) Type G (Genetic/genomic)

Classification is based on Dose relatedness Time course Susceptibility

Type A ADRs intrinsic to the drug effects Type B ADRs - idiosyncratic

Predisposing factors:
Multiple drug therapy Age

1. Elderly- hypnotics, diuretics, NSAIDS, anti-hypertensives, psychotropics, digoxin 2. Adults- polypharmacy

3. Children- antiepileptics, cytotoxic agents, anesthetic gases, antibiotics (associated with hepatic failure), Na valproate 4. Neonates- chloramphenicol, morphine, antiarrhythmics Reyes syndrome - ? Hepatotoxicity Na valproate Gender Females have 1.5-1.7 folds of developing ADR than males Women are prone to develop blood dyscrasias with phenylbutazone & chloramphenicol Histaminoid reactions with neuromuscular blocking drugs Intercurrent disease Hepatic/renal disease HIV skin reactions with co-trimoxazole Critical illness Trauma Race and genetic polymorphism Drug-metabolizing enzymes (poor, extensive & ultra-rapid metabolizers) Drug receptors Drug transporters (P-gp or MDR1)

Mechanism of dose related (Type A) reactions

Different doses to produce the pharmacologic effect Different responses to a defined dose

Pharmaceutical cause -pharmaceutical aspects of a dosage form Indomethacin GI bleeding

Pharmacokinetic causes 1. Absorption reduced efficacy GI motility, gastric contents, disease, absorption in the GI tract, first-pass metabolism in liver & gut wall, concomitant drugs 2. Distribution Plasma-protein and tissue binding 3. Metabolism Enzyme induction or inhibition efficacy?? Genetic variants oxidation, hydrolysis, acetylation Drugs competing for glucoronidation Microsomal oxidation CYP2D6 or Debrisoquine hydroxylase polymorphism (5-10% Europeans) Poor metabolizers reduced first-pass Drugs metabolized includes psychiatric, neurological and cardiovascular Higher incidence of extrapyramidal symptoms seen as AE of antipsychotics metabolized by CYP2D6 CYP2C9 -CYP2C9*1/*1 normal metabolic rate for warfarin CYP2C9*3/*3 lowest metabolic clearance rate for warfarin Hydrolysis Pseudocholinesterase - Decreased activity in variants leading to suxamethonium apnea Acetylation N-acetyltransferase rapid (Japan, Canadian, half of UK) & slow acetylators Dapsone, INH, hydralazine, phenelzine, procainamide, sulfonamides Peripheral neuropathy INH, hematologic AE- dapsone, SLE procainamide & hydralazine

Glucuronidation Morphine, paracetamol, ethinylestradiol Glucuronyltransferases

4. Elimination -digoxin, ACE inhibitors, aminoglycosides antibiotics, class I anti-arrhythmic drugs (disopyramide, flecainide) and cytotoxic agents

Mechanisms of non dose-related (Type B) ADR:

Pharmaceutical causes Presence of degradation products of the active constituents Excipients Pharmacokinetic causes - P-glycoprotein / MDR1 found in the cells of gut wall, surface of hepatocytes & renal tubular cells Pharmacodynamic causes -target organs genetic, immunologic, neoplastic or teratogenic Erythrocyte glucose-6-phosphate (G6PD) deficiency Sex-linked inherited deficiency Weakened red cell membrane Hemolysis from primaquine, sulfonamides, sulfones and nitrofurantoin African type-mild, Mediterranean type-severe Drugs that should be avoided with G6PD deficiency Dapsone Niridazole Methylene blue (methylthioninium Cl) Primaquine Quinolones (ciprofloxacin, nalidixic acid, norfloxacin, ofloxacin)

Sulfonamides (Cotrimoxazole)

Hereditary methemoglobinemias Methemoglobin reductase - cyanosis

Porphyrias Inherited disorder in heme biosynthesis Abdominal and neuropsychiatric disturbances Excretion of excessive amounts of porphyrin precursors 5-ALA (aminolaevulinic) or porphobilinogen Malignant hyperthermia Rapid rise in body temperature (at least 2 C per hour) Associated with anesthetics and muscle relaxants (succinylcholine) Stiffness of skeletal muscle, hyperventilation, acidosis, hyperkalemia, increased activity of sympathetic NS outcome? Associated with a sudden release of intracellular ionized Ca Antidote: D _ _ _ _ _ _ ene

Glucocorticoid glaucoma Cholestatic jaundice induced by oral contracepitves Immunologic reasons for abnormal response Features: No relation to the unusual pharmacologic effects of the drug Delay between the 1st exposure to the drug and subsequent occurrence of the ADR Small doses may elicit the reaction once the allergy is established Reaction disappears on withdrawal Illness is often recognizable as a form of immunologic reaction

Delayed adverse effects Pigmentary retinopathy phenothiazine

Vaginal carcinoma stilbestrol Malignancy immunosuppressives and chemotherapeutic agents

Adverse effects associated with drug withdrawal Benzodiazepine withdrawal syndrome Rebound hypertension clonidine Acute adrenal insufficiency - corticosteroids

DRUG INTERACTIONS:
Occurs when the effects of one drug are changed by the presence of another drug, herbal medicine, or some environmental chemical agent Outcome Good or bad or fatal

Mechanism of drug interactions Pharmacokinetic pharmacodynamic Who are susceptible? Polypharmacy Hepatic or renal disease Long-term therapy for chronic illness Critically ill ICU patients Patients who have more than one prescribing MD Drugs with high risk of interaction Concentration dependent toxicity 1. Digoxin 2. Lithium 3. Aminoglycosides 4. Cytotoxic agents

5. Warfarin Steep dose response curve 1. Verapamil 2. Sulfonylureas 3. Levodopa Patient dependent on therapeutic effect 1. Immunosuppresives (e.g. cyclosporin, tacrolimus) 2. Glucocorticoids 3. Oral contraceptives 4. Anti-epileptics 5. Anti-arrhythmics 6. Anti-psychotics 7. Antiretrovirals Saturable hepatic metabolism 1. Phenytoin 2. Theophylline Pharmacokinetic: Absorption

1. Changes in GI pH - PPIs, H2 antagonist + weak acid, itraconazole 2. Adsorption, chelation and other complexing mechanism -tetracycline and aluminum/magnesium hydroxide - kaolin/charcoal - Colestyramine, colestipol digoxin, propranolol, warfarin levothyroxine, cyclosporin 3. Effects on GI motility Narcotics, atropine, antacids motility?

Domperidone, metoclopramide, cisapride motility? Slow motility is dis/advantageous to penicllin & levodopa Rapid motility is dis/advantageous to enteric coated tablet & griseofulvin 4. Induction or inhibition of drug transport proteins Verapamil enhances digoxin bioavailability by inhibiting P-gp Distribution - Dependent on ionic composition, lipid solubility, and protein-binding characteristics - Plasma protein binding Albumin acidic drugs (warfarin) 1 acid glycoprotein basic drugs (TCA, lidocaine, disopyramide & propranolol) Metabolism CYP3A4 in the intestinal wall grapefruit juice & felodipine & cyclosporine MAO-A in the liver & intestinal wall tranylcypromine, phenelzine & tyramine (diet) increase norepinephrine Dexamethasone R-warfarin Ciprofloxacin Imipramine Disulfiram halothane Verapamil Midazolam Tobacco smoke theophylline Cimetidine theophylline Omeprazole Diazepam Phenytoin - Nifedipine Enzyme induction Carbamazepine, barbiturates autoinduction Short-half life drugs (rifampicin) induce metabolism than long-half life drugs (phenytoin)

Chronic alcohol use, Cigarette smoking, St. Johns wort (Hypericum perforatum)

Enzyme inhibition Grapefruit juice- caution with simvastatin, tacrolimus, vardenafil Caution when given with drugs with narrow TI theophylline, phenytoin, warfarin Elimination 1. Changes in urinary pH Enhance excretion of weak acids (aspirin) at alkaline pH Enhance excretion of weak base (paracetamol) at acidic pH Strong acids and bases are not affected by pH changes 2. Changes in active renal tubular secretion - Competition with the organic anion transporters- probenecid & penicillin - NSAIDs, salicylates & methotrexate 3. Changes in renal blood flow Prostaglandins produces renal blood flow NSAIDs & lithium

4. Influence of proximal reabsorption in relation to sodium ions -Thiazide, loop diuretics & lithium decrease renal clearance of lithium Drugs excreted entirely by glomerular filtration is unlikely to be affected by other drugs 5. Biliary excretion and enterohepatic shunt Ethinylestradiol conjugates & antibiotics 6. Drug transporter proteins P-glycoprotein present in renal proximal tubule, hepatocytes, intestinal mucosa, and blood brain barrier Inhibitors- verapamil, atorvastatin

Inducers- rifampicin

Pharmacodynamic Antagonistic Flumazenil and benzodiazepines (diazepam) Salbutamol and b-blockers (propranolol) Vit K and anticoagulants Levodopa and dopamine antagonist

Additive /synergistic Antidepressants, hypnotics, antihistamines MAOI and tyramine, amphetamines, pseudoephedrine, cough & cold medicines TCA, antihistamines, phenothiazines anticholinergic TCA & epinephrine Benzodiazepines and alcohol Aspirin and warfarin ACE inhibitor, K supplement, and K sparing diuretic hyperkalemia Hydrocortisone & hydrochlorothiazide hyperglycemia & hypokalemia Diuretic-induced hypokalemia & hypomagnesemia increases risks of dysrhythmia caused by digoxin Increase risk of ototoxicity and nephrotoxicity from combination of aminoglycosides and furosemide