Adverse drug reactions (ADRs) remain a major health issue worldwide. They affect the treating outcomes, increase the admission rate to hospitals, increase the morbidity and mortality, increase the cost of therapy, affect the quality of life, and affect the patient satisfaction of health care. This chapter aims to discuss the ADRs-related issues, such as history, types, causes, management and reporting of ADRs, as well as highlight the challenges of ADRs and their reporting in the developing countries, and provide recommendations to overcome the challenges in order to improve practices in the developing countries.

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 2nd 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 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

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)