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Adverse Drug Reaction: Muhammad Faisal Nadeem
Adverse Drug Reaction: Muhammad Faisal Nadeem
Introduction
Defn: an unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug
Requires
Treatment in dosing Discontinuation Caution in future
Occurrence
immediately or after prolonged use or after termination Mild ADRs common, [incidence 10-25%] with polypharmacy
Type A: Response qualitatively normal but quantitatively abnormal Common, less serious, dose related, corrected by dose adjustment include side effect, toxic effect, withdrawal Type B: Because of patient peculiarities; Eg. Allergy, idiosyncrasy Dose related; uncommon; Serious withdrawal of drug required Not always predictable / preventable
Type B No No
Low Low High STOP
Yes Yes
High High Low Dosage adjustment
Type C These reactions are associated with long-term drug therapy e.g. Benzodiazepine dependence and Analgesic nephropathy. They are well known and can be anticipated. Type D reactions These reactions refer to carcinogenic and teratogenic effects. These reactions are delayed in onset
Type E
End of dose effect for example abrupt cessation of corticosteroids produces acute adrenal insufficiency and stoppage of propranolol can produce rebound effect
Type F
Failure of therapy. OCP failure when on antitubercular therapy
Severity of ADR:
Minor: no need of therapy, antidote, or hospitalization Moderate: requires drug change , specific treatment, hospitalization Severe: Potentially life threatening; permanent damage, and prolonged hospitalization. Lethal: Directly or indirectly leads to death
Predisposing factors
Multiple drug therapy Age 1. Elderly- hypnotics, diuretics, NSAIDS, antihypertensives, psychotropics, digoxin 2. Adults- polypharmacy 3. Children- antiepileptics, cytotoxic agents, anesthetic gases, antibiotics (associated with hepatic failure), Neonates- chloramphenicol, morphine, antiarrhythmics Hepatotoxicity Na valproate
Predisposing factors
Race and genetic polymorphism - Drug-metabolizing enzymes (poor, extensive & ultra-rapid metabolizers) - Drug receptors - Drug transporters (P-gp or MDR1)
Pharmacokinetics
Absorption 2. Adsorption, chelation and other complexing mechanism -tetracycline and aluminum/magnesium hydroxide - kaolin/charcoal - Colestyramine, colestipol digoxin, propranolol, warfarin levothyroxine, cyclosporin
Pharmacokinetics
Absorption 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
Pharmacokinetics
Absorption 4. induction or inhibition of drug transport proteins Verapamil enhances digoxin bioavailability by inhibiting P-gp
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
Microsomal oxidation
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
Pharmacokinetics
Metabolism CYP3A4 in the intestinal wall grapefruit juice & felodipine & cyclosporine MAO-A in the liver & intestinal wall tranylcypromine, phenelzine & tyramine (diet) increase norepinephrine
Pharmacokinetics
Metabolism Enzyme induction Carbamazepine, barbiturates autoinduction Short-half life drugs (rifampicin) induce metabolism than long-half life drugs (phenytoin)
Pharmacokinetics
Metabolism Enzyme induction Chronic alcohol use, Cigarette smoking, St. Johns wort (Hypericum perforatum)
Pharmacokinetics
Metabolism Enzyme inhibition Grapefruit juice- caution with simvastatin, tacrolimus, vardenafil Caution when given with drugs with narrow TI theophylline, phenytoin, warfarin
Phamacokinetics
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
Phamacokinetics
Elimination 2. Changes in active renal tubular secretion -competition with the organic anion transporters- probenecid & penicillin - NSAIDs, salicylates & methotrexate
Phamacokinetics
Elimination 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
Phamacokinetics
Elimination Drugs excreted entirely by glomerular filtration is unlikely to be affected by other drugs
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?
Malignant hyperthermia
Associated with a sudden release of intracellular ionized Ca Antidote: D _ _ _ _ _ _ ene
Prevention of ADR:
[1] Avoid inappropriate drugs in the context of clinical condition [2] Use right dose, route, frequency based on patient variables [3] Elicit medication history; consider untoward incidents [4] Elicit history of allergies [in patients with allergic diseases] [5] Rule out drug interactions [6] Adopt right technique: Eg slow iv injection of aminophylline [7] Carry out appropriate monitoring [Eg PT with warfarin; Li levels]
Types of ADRs
[1] Side Effects: unavoidable, predictable, dose amelioration Occurs as Extension of the same therapeutic effect: Eg.
Atropine as antisecretory in preanesthetic medication dry mouth
EVALUATION
AIRWAY BREATHING CIRCULATION DEGREE OF CONSCIOUSNESS HISTORY OF EXPOSURE/ INGESTION PHYSICAL EXAMINATION GASTRIC LAVAGE INDUCTION OF EMESIS CONTRAINDICATIONS TO EMESIS ACTIVATED CHARCOAL OTHER DECONTAMINATION
DECONTAMINATION
SUPPORTIVE CARE
RESPIRATORY CARDIOVASCULAR CNS
DIAGNOSTIC STUDIES
BLOOD TESTS ECG X RAYS SPECIFIC DRUG LEVELS
ENHANCING ELIMINATION
ACTIVATED CHARCOAL FORCED ALKALINE DIURESIS HAEMODIALYSIS/PERFUSION
ANTIDOTES
Organophosphates atropine, oximes Morphine naloxone Benzodiazepines flumazenil Paracetamol N- acetyl cysteine
[4] Intolerance:
Opposite of tolerance: sensitivity to low doses few doses of carbamazepine ataxia [ defective movement/gait] single dose of triflupromazine muscular dystonia
continued..
Type I: urticaria, angioedema, asthma, anaphylactic shock Type II: Thrombocytopenia, agranulocytosis, aplastic anemia, SLE Type III: Arthralgia, lymphadenopathy, Steven Johnson Synd. Type IV: contact dermatitis, fever, photosensitisation Eg: penicillin, sulfonamides, carbamazepine, methyldopa
[7]Photosensitivity:
Phototoxic: Drug accumulates in skin absorbs light photochemical reaction photobiological reaction tissue damage [Eg erythema, edema, blistering etc] Eg tetracyclines Photoallergic: drug cell mediated immune response contact dermatitis on exposure to light. Eg sulfonamides, griseofulvin etc.
[9]Teratogenicity: Drug use in pregnancy affects offspring Eg Thalidomide phocomelia; phenytoin cleft palate
[11] Drug induced deseases, Iatrogenic diseases : Salicylates peptic ulcer; Phenothiazines parkinsonism; INH hepatitis
12. Drug withdrawal reaction Propranolol hypertension Acute adrenal insufficiency following withdrawal of corticosteroids
Pharmacodynamic
Antagonistic - Flumazenil and benzodiazepines (diazepam) - Salbutamol and b-blockers (propranolol) - Vit K and anticoagulants - Levodopa and dopamine antagonist
Pharmacodynamics
Additive /synergistic - antidepressants, hypnotics, antihistamines - MAOI and tyramine, amphetamines, pseudoephedrine, cough & cold medicines - TCA, antihistamines, phenothiazines anticholinergic - TCA & epinephrine
Pharmacodynamics
Additive /synergistic - Benzodiazepines and alcohol - Aspirin and warfarin - ACE inhibitor, K supplement, and K sparing diuretic hyperkalemia - Hydrocortisone & hydrochlorothiazide hyperglycemia & hypokalemia
Pharmacodynamics
Additive /synergistic - Diuretic-induced hypokalemia & hypomagnesemia increases risks of dysrhythmia caused by digoxin - Increase risk of ototoxicity and nephrotoxicity from combination of aminoglycosides and furosemide