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

ABCD

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 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 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)