1. DR. SHABANA ALI

2. 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

3. 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

4. ADR most common in Women Elderly (>60 y old) Very young (1-4 y) Patients taking more than one drug

5. 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.

6. 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

7. 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;

8. 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

9. 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

10. iv) Drug Interactions When two drugs taken together & they effect each other’s response pharmacologically or kinetically E.g., one drug slow metabolism of 2 nd drug blood conc.= toxicity Theophylline toxicity in presence of erythromycin

11. 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.

12. Results (more likely ) in withdrawal of marketing authorization Often not discovered until after drug is marketed Both environmental & genetic factors = important in this reaction

13. 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

14. 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)

15. 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)

16. 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

17. 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

18. Sign & Symptoms of ADR Mild, moderate, severe or lethal Sign & symptoms manifest soon after 1 st dose or only after chronic use e.g., Allergic reactions occur soon after drug is taken usually 2 nd time ( itching, rash, eruption, upper or lower airway edema with dyspnea & hypotension) Idiosyncratic reactions=any unpredicted symptom

19. 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

20. Mechanism of Type B Reactions i) Often mediated by a chemically reactive metabolite Non detoxification of metabolite Direct cytotoxicity Direct tissue damage + necrosis

21. ii) Bind to NA altered gene product Bind to a larger macromolecule inducing immune response (produce Ab & bind to Ab)

22. 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)