ADVERSE DRUG REACTIONS. DR. SHABANA ALI. Adverse Drug Reactions (ADR). Harm associated with the use of a given medications OR Unwanted or harmful reaction experienced after the administration of a drug or combination of drugs under normal conditions of use.
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ADVERSE DRUG REACTIONS DR. SHABANA ALI
Adverse Drug Reactions (ADR) Harm associated with the use of a given medications OR • Unwanted or harmful reaction experienced after the administration of a drug or combination of drugs under normal conditions of use
ADR= significant morbidity & mortality • Range from mild reactions (drowsiness, nausea, itching& rash); disappear after discontinuation of drug OR • Severe reactions(respiratory depression, neutorpenia, hepatocellualr injury, hemorrhage, anaphylaxis
ADR most common in • Women • Elderly (>60 y old) • Very young (1-4 y) • Patients taking more than one drug
Classification of ADR • Rawlin & Thompson classification ABCD • Traditional classification A & B About 80% of ADR----Type A reactions 1) Type A Reactions a) Related to pharmacological action of drug Extensions of the principal pharmacological action of the drug • Cont.
b) Predictable Relatively easily predicted by preclinical and clinical pharmacological studies c) Common Type A reactions not serious---common d) Dose-dependent Usually dose dependent
Type A reactions (classes) i) Toxicity of overdose (Drug overdose) An adverse drug reaction caused by excessive dosing e.g., hepatic failure with dose of paracetamol Headache with antihypertensives hypoglycemia with sulfonylurea;
ii) Side Effects Nearly unavoidable secondary drug effect produced by therapeutic doses • intensity is dose dependent • Occur immediately after initially taking drug or may not appear until weeks after initiation of drug use • E.g., sedation with antihistamines
iii) Secondary Effects Secondary pharmacological effect • E.g., development of diarrhea with antibiotic therapy due to altered GIT bacterial flora • Orthostatic hypotension with a phenothiazine
iv) Drug Interactions When two drugs taken together & they effect each other’s response pharmacologically or kinetically • E.g., one drug slow metabolism of 2nd drug blood conc.= toxicity • Theophylline toxicity in presence of erythromycin
2) Type B Reactions • Unrelated to known pharmacological actions of drug • Unpredictable • Often caused by immunological & pharmacogenetic mechanisms • Unrelated to dosage • Comparatively rare & cause serious illness or death cont.
Results (more likely) in withdrawal of marketing authorization • Often not discovered until after drug is marketed • Both environmental & genetic factors = important in this reaction
Type B Reactions (classes) i) Drug Intolerance Lower threshold to normal pharmacological action of a drug e.g., tinnitus (single average dose of aspirin) ii) Hypersensitivity (immunological reaction) Immune mediated response to a drug agent in sensitized patient e.g., anaphylaxis with penicillin
iii) Pseudoallergic Reaction • Direct mast cell activation & degranulation by drugs (opiates, vancomycin & radiocontrast media) • Clinically indistinguishable form Type I hypersensitivity but not involve IgE(non immunologic reactions)
iv) Idiosyncratic Reactions • An uncommon & abnormal response to drug • Usually due to genetic abnormality • Affect drug metabolism & receptor sensitivity • Harmful even fatal, appear in low doses E.g., Anemia (hemolysis) by antioxidant drugs (G6PD deficiency) Paralysis due to succinylcholine (enzyme deficiency)
3) Type C (chronic) Reactions • Associated with long-term drug therapy • Well known and can be anticipated • Adaptation occurs = discontinuation of drug=abstinence syndrome E.g. opoids, alcohol, barbiturates
4) Type D (delayed) Reactions • Carcinogenic & teratogenic effects • Delayed in onset • Very rare Carcinogenic Effect Medication lead to cancer; take >20 y to develop Teratogenic Effect Drug- induced birth defects
Sign & Symptoms of ADR • Mild, moderate, severe or lethal • Sign & symptoms manifest soon after 1st dose or only after chronic use e.g., Allergic reactions occur soon after drug is taken usually 2nd time ( itching, rash, eruption, upper or lower airway edema with dyspnea & hypotension) Idiosyncratic reactions=any unpredicted symptom
Mechanisms of ADR Type A =non immunological, reversible with reduction of dose, non serious, extension of pharmacological effects Type B Biochemical mechanism unrelated to pharmacological Immunologic = Hypersensitivity (Type I, II, III, IV) OR Non immunologic (direct)= Pseudoallergic, idiosyncratic, intolerance
Mechanism of Type B Reactions i) Often mediated by a chemically reactive metabolite Non detoxification of metabolite Direct cytotoxicity Direct tissue damage + necrosis
ii) Bind to NA altered gene product • Bind to a larger macromolecule inducing immune response (produce Ab & bind to Ab)
Drug Hypersensitivity (allergic) Reaction • Common form of adverse response to drugs Classification (Gell & Coombs) Type I reactions (IgE-mediated) Type II reactions (cytotoxic) Type III reactions (immune complex) Type IV (delayed, cell mediated)