Adverse Drug Reactions

Dr. Gyanendra Raj Joshi PharmD, RPh

Terminologies

• Side effect • Toxicity • Secondary effects • Intolerance • Idiosyncrasy

Adverse Drug Reaction

• WHO definition:– A response to a drug which is noxious, unintended

and occurs at doses used in man for prophylaxis, diagnosis or therapy.

• UK Commission on Human Medicines:– An 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 the drug.

Predisposing factors

• Multiple drug therapy • Age • Gender • Concomitant disease • Race and genetic polymorphism

Severity of ADR

• Minor • Moderate • Severe • Lethal

Classification

• 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)

Type A reactions

• Exaggerated pharmacological response

• Excessive : Anticoagulants

• Unwanted : TCAs

• Withdrawal : Clonidine

• Delayed : Diethylstilbestrol

Mechanisms of Type A reactions

1. Pharmaceutical causes :– Quantity of drug– Quality of drug – Release characters

2. Pharmacokinetic causes :a. Absorption– Dosage– GI motility – First pass metabolism – Nature of gastric contents – Disease – Concomitant drugs

b. Distribution:– Regional blood flow – Plasma protein binding – Tissue binding c. Elimination :– Reduced elimination – Increased elimination – Drug Metabolism – Drug Excretion

3. Pharmacodynamic causes

Mechanism of Type B Reactions

1. Pharmaceutical Causes :– Degradation products – Non-drug components (excipients )– Synthetic by- products

2. Pharmacokinetic Causes :– Bioactivation to reactive metabolites • Tacrine: hepatotoxicity• Clozapine : agranulocytosis • Halothane : hepatotoxicity

3. Pharmacodynamic causes :a. Immunological b. Genetic c. Teratogenic

Immunological mechanismsReaction Immunological mechanism Clinical manifestation Drugs

Type I IgE mediated •Anaphylaxis Penicillin

Type II Humoral (Antibody dependent Cytotoxic) IgG /IgM

•Hemolysis •Thrombocytopenia

Methyl Dopa

Type IIIArthus reaction

Humoral Immune Complex mediatedIgG/IgM

•Serum sickness•Acute Glomerulonephritis •SLE•Vasculitis

Streptokinase

Type IVDelayed

Cell mediated injuryT cells

•Skin eruptions •Steven Johnsons syndrome •Contact dermatitis •Delayed tuberculin test

Amoxicillin

Genetic mechanisms

• G6PD deficiency • N-acetyltransferase activity

Teratogenic mechanisms

• Fertilization and implantation (upto 17 days)• Organogenesis (18-55)• Growth and development (56 onwards )

• Thalidomide • Phenytoin• Warfarin• Valproic acid • Vit A derivatives • Tetracyclines

Pregnancy category of drugs

• A• B• C• D• X

Comparison between Type A and Type B

Basis Type A Type B

Pharmacologically predictable

Yes No

Dose dependent Yes No

Incidence High Low

Morbidity High Low

Mortality Low High

Management Dose adjustment Stop drug

Detecting ADRs

• Causal attributes :– Time sequence – Withdrawal or reintroducing – Established pharmacology and toxicology

• Degrees of conviction:– Definite – Probable – Possible – Conditional – Doubtful

Pharmacovigilance

• Science and activities relating to the detection , assessment , understanding and prevention of adverse effects or any other drug related problems.

• Activities :– Post marketing surveillance /ADR monitoring – Dissemination of ADR data – Changes in labeling

Prevention of ADRs

• Avoid inappropriate use• Rational use of drugs • Past medication history • Past medical history• Drug interactions • Correct route and method • Lab tests

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