Definitions

Epidemiology Predisposing

Causes
Types

Factors

Classification

Drugs

causing ADRs

Recognition & Detection Establishment of Cause-effect relationship Management of ADRs Evaluation for ADRs during drug development Strategies for prevention of ADRs

Adverse Drug Reaction (ADR)

Response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function Excludes therapeutic failures, overdose, drug abuse, noncompliance, and medication errors

A major cause of morbidity and mortality Most common iatrogenic illness, complicating 5 to 15 % of therapeutic drug courses Account for 5% of acute medical emergencies 3 to 6 % of all hospitalizations are due to an ADR 10 to 20 % of hospitalized patients suffer from an ADR 4th to 6th leading cause of death among hospitalized patients* 30 to 60 % are preventable

98,000 people die each year as a result of medical errors

Age (children and elderly) Female gender Polypharmacy Multiple co-morbid conditions Inappropriate medication prescribing, use, or monitoring Renal insufficiency

Liver disease Alcoholism HIV infection Herpes infection Prior history of ADRs Extent (dose) and duration of exposure Genetic predisposition

 Inappropriate

use of drugs Inadequately monitored use Drug-drug interactions Self-medication Inadequately evaluated and irrational drugs

Type A: Augmented

Dose-related effects Normal pharmacological effect of the drug Often predictable Toxic effect or side effect Examples:
postural hypotension in a patient on antihypertensive medication digoxin toxicity hypoglycemia with anti-diabetics hypokalemia with diuretics heart block with propranolol dry mouth with anticholinergics

Type B: Bizzare
Effects related to abnormal interaction between

patient and drug Non-dose related Unrelated to normal pharmacodynamics of the drug Generally unpredictable, have genetic basis
Idiosyncratic / Allergic e.g. malignant hyperthermia Immunological e.g. rash associated with Penicillin use

Type C: Continuous or Chronic Delayed

Dose & Time related

Related to cumulative drug use

Associated with long-term use Examples:

NSAID induced nephropathy ocular toxicity with antimalarials tardive dyskinesia

Type D: Delayed
Delayed effect

Apparent only sometime after use of drug

Delayed reactions such as carcinogenesis and

teratogenesis Examples: Thalidomide during first trimester Phocomelia limb effects

Type E: End-of-use
Withdrawal

Related to discontinuation which is too abrupt

Examples:

Addisonian crisis after steroid withdrawal Angina pectoris after stopping -blockers

Mild Does not affect patients day-to-day activity Moderate Affects patients day-to-day activity to some extent Severe Adversely affects patients day-to-day activity

Non-serious Serious o Death / Results in death o Life-threatening o Require hospitalization / Prolongation of existing hospitalization o Cause permanent disability o Cause congenital anomalies o Require intervention to prevent any of the above

 Antibiotics Antineoplastics Anticoagulants

Cardiovascular drugs
Hypoglycemics Antihypertensives

NSAID/Analgesics
Diagnostic agents CNS drugs

 Antineoplastics* Anticoagulants Cardiovascular drugs*

Hypoglycemics
Antihypertensives NSAID/Analgesics

*Account for 69% of all fatal ADRs

Diagnostic agents
CNS drugs*

The possibility of an ADR must be considered when an unexpected event occurs in a patient taking a drug, for which there is no obvious cause

Subjective report:
Patient complaint

Objective report:
Direct observation of event Abnormal findings

Physical exam Laboratory test Diagnostic procedure

Type A reactions: Reduction in dose or withdrawal of medication altogether Type B reactions: Uncommon, unpredictable, high morbidity & mortality First step: immediate withdrawal If mild: no further intervention If moderate to severe: antihistamines + steroids + adrenaline Type C and D reactions: Irreversible/partially reversible by withdrawal by the time it is detected Type E reactions: Re-introduction and more gradual withdrawal

Pre-clinical Evaluation (Animal Studies)

Acute toxicity studies Sub-acute toxicity studies Chronic toxicity studies Studies for mutagenesis/carcinogenesis

Studies for teratogenesis

Clinical Evaluation (1/4)

Phase-1 (Clinical Pharmacology Studies) Limited sample size (20-50) Healthy Volunteers (or selected patients) Pharmacokinetic studies Pharmacodynamic studies for efficacy & safety

Clinical Evaluation (2/4)

Phase-2 (Clinical investigation) Conducted on patients Larger sample size (50-300) Pharmacokinetic studies Pharmacodynamic studies for efficacy & safety

Clinical Evaluation (3/4)

Phase-3 (Formal therapeutic trials) Large scale trials in patients Randomized / controlled Efficacy & safety on a larger scale Comparison with other drugs

Clinical Evaluation (4/4)

Phase-4 (Post-marketing surveillance) Surveillance for efficacy & safety Comparison with other drugs

Availability of safe and quality drugs Rational use of drugs Individualization of therapy (p-drug concept) 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 Health Authorities