ADVERSE DRUG REACTIONS

Undesired effects of drugs occurring

under normal conditions of use

Remedy often proves worse than the

disease (William Pens)

SIGNIFICANCE
A

major cause of morbidity and

mortality

Account

for 5% of acute medical

emergencies

10

to 20 % of hospitalized patients
suffer from an ADR

CLASSIFICATION / TYPES
Type

A (Augmented):

Predictable
dose-related*
pharmacodynamic effects e.g:

hypoglycemia

with antidiabetics
hypokalemia with diuretics

*Poisons in small doses are the best medicines and useful

medicines in too large doses are poisons (William Withering)

 Type

B (Bizarre):

Unrelated

to dose and pharmacodynamics

of the drug
Generally unpredictable
Have genetic basis e.g:
Idiosyncrasies
allergies

Type C:

Associated with long term use e.g:

Type D:

Delayed reactions e.g:

analgesic nephropathy
tardive dyskinesia

carcinogenesis
teratogenesis

Type E:

End-of-use reactions e.g

adrenal insufficiency on steroid withdrawal
angina on stoppage of blockers

CAUSES OF ADVERSE DRUG REACTIONS

Inappropriate use of drugs

Cured yesterday of my disease, died last night of my
physician (Mathew Prior)
When you can cure by a regimen, avoid having recourse to
medicine and when you can effect a cure by means of a simple
medicine, avoid employing a compound one (Rhazes)

Inadequately monitored use

Drug-drug interactions
Self-medication
Inadequately evaluated and irrational drugs

RECOGNITION OF ADRS

when an unexpected event takes place

for which there is no obvious cause
occurs in a patient taking a drug
possibility must always be considered
that it is drug-caused

ESTABLISHMENT OF
CAUSE-EFFECT RELATIONSHIP

DEFINITE: (Postural hypotension)

Reasonable time relationship with drug
administration
Event corresponds with known
pharmacological properties of the drug
Event ceases on stopping the drug
Event returns on restarting the drug

POSSIBLE: (tremors)
Time relationship reasonable
Event corresponds with known
pharmacological properties of the drug
Could have resulted from patients
disease or other drugs

CONDITIONAL: (hemolytic anemia)

Time relationship reasonable
Event DOES NOT correspond with known
pharmacological properties of the drug
Event NOT reasonably explained by
patients disease
DOUBTFUL: (rash)
Events not meeting the above criteria

FACTORS THAT PREDISPOSE TO ADR

Related to the patient:

Age of the patient

Ability to metabolize & excrete the drug

Underlying disease

Genetic factors

Pregnancy and lactation

FACTORS THAT PREDISPOSE TO ADR

Drug-Related

Chemical nature
Nature of metabolites
Pharmacodynamic profile
Dose
Age of the drug
Route of administration
Concurrent therapy

DRUG EVALUATION FOR ADR

Preclinical Evaluation (Animal studies)

Acute toxicity studies

Subacute toxicity studies

Chronic toxicity studies

Studies for mutagenesis/ carcinogenesis

Studies for teratogenesis

DRUG EVALUATION FOR ADR

Clinical evaluation
Phase-1 (Clinical pharmacology studies)
Limited sample size (20-50)
Healthy volunteers (or selected patients)
Pharmacokinetic studies
Pharmacodynamic studies for efficacy & safety

DRUG EVALUATION FOR ADR

Phase-2 (Clinical investigation)

Conducted on patients
Larger sample size (50-300)
Pharmacokinetic studies
Pharmacodynamic studies for efficacy & safety

DRUG EVALUATION FOR ADR

Phase-3 (Formal therapeutic trials)

Larger scale trials in patients

Randomized/controlled
Efficacy & safety on a larger scale
Comparison with other drugs

DRUG EVALUATION FOR ADR

Phase-4 (Post-marketing surveillance)

Surveillance for efficacy & safety

Comparison with other drugs

STRATEGIES FOR PREVENTION OF ADR

Availability of safe and quality drugs

Rational use of drugs
p-drug concept, individualization of therapy
Continued medical education
It is an absolute obligation on doctors to use only
those drugs about which they have troubled to inform
themselves

Role of regulators