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 Traditional classification A&B About 80% of ADR----Type A reactions

ABCD

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 others 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 but not

form involve

Type IgE

I
(non

hypersensitivity

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)