1. Adverse Drug Reactions (ADRs)

Definition: Harmful or seriously unpleasant effects occurring at doses intended for therapeutic (prophylactic or diagnostic) effect which call for reduction of dose or withdrawal of the drug or indicate caution in future use of the same drug.

ADRs are broadly classified into two main types:

  • Type A (Predictable/Augmented): Dose-dependent, related to the drug's known pharmacological effects.
  • Type B (Unpredictable/Bizarre): Not dose-dependent, unrelated to the drug's known pharmacology (e.g., idiosyncrasy, allergy).

2. Side Effects (S/Es)

  • Unwanted, unavoidable pharmacological effects.
  • Occur at therapeutic doses.
  • Can be predicted from the drug's pharmacological profile.
  • Generally decrease with dose reduction.

Examples:

  • Same action as therapeutic effect: Atropine in preanesthetic medication causing dry mouth.
  • Different facet of action: Antihistamines causing sedation.
  • Therapeutic in one context, S/E in another: Codeine for cough causing constipation (can be therapeutic in traveler's diarrhea).

3. Secondary Effects

Indirect consequences of a primary drug action.

Example: Opportunistic infections due to alteration of normal flora by broad-spectrum antibiotics.

4. Toxicity vs. Intolerance

Toxicity

Direct damaging action of the drug at high doses.

Example: Liver damage from paracetamol overdose.

Intolerance

Low threshold to the normal pharmacodynamic action of a drug. Appearance of characteristic toxic effects at therapeutic doses in an individual.

5. Idiosyncrasy

Genetically determined abnormal reactivity to a chemical.

Example: Barbiturates causing excitement & mental confusion in some individuals.

6. Classification of ADRs (ABCDE)

Type A (Augmented)

  • Predictable, dose-related.
  • Due to excess of normal pharmacodynamic effects.
  • Common.
  • Examples: Postural hypotension (alpha blockers), Hypoglycemia (insulin).

Type B (Bizarre)

  • Unpredictable, not dose-related.
  • Not part of normal pharmacology.
  • Occurs in some people only.
  • Includes: Idiosyncrasy, Drug allergy.

Type C (Chronic)

  • Related to long-term exposure.
  • Examples: Analgesic nephropathy, Carcinogenesis.

Type D (Delayed)

  • Effects appear after prolonged exposure or at a critical time.
  • Example: Teratogenesis.

Type E (Ending of Use)

  • Effects of abrupt discontinuation of chronic therapy.
  • Example: Adrenal insufficiency after stopping steroids.

7. Drug Abuse, Addiction & Habituation

Drug Abuse

Use of drugs in ways not medically approved, often for euphoria or altered perception. Repetitive exposure can lead to addiction.

Drug Addiction

Compulsive drug use characterized by overwhelming involvement with the drug. Examples: Amphetamines, cocaine, cannabis, LSD.

Drug Habituation

Less intensive involvement. Withdrawal leads to mild discomfort. Examples: Tea, coffee, tobacco, social drinking.

8. Teratogenicity

Capacity of a drug to cause fetal abnormalities when given to a pregnant mother.

Stages of fetal affect:

  1. Fertilization & Implantation (Conception to ~17 days): Pregnancy failure.
  2. Organogenesis (18-55 days): Most vulnerable period for deformities.
  3. Growth & Development (56 days onwards): Developmental & functional abnormalities.

    Examples: ACE inhibitors (organ hypoplasia), NSAIDs (premature closure of ductus arteriosus).

Pregnancy Categories (A,B,C,D,X): Category X drugs have potential risks that outweigh benefits.

9. Drug-Induced (Iatrogenic) Reactions

Functional disturbances caused by a drug that persist even after the drug is withdrawn and largely eliminated.

Examples: Peptic ulcer (salicylates, corticosteroids), Parkinsonism (phenothiazines), Hepatitis (isoniazid).

10. Drug Allergy

Immunologically mediated reaction producing stereotyped symptoms unrelated to the drug's pharmacodynamic profile and largely independent of dosage.

  • Occurs in a small proportion of patients.
  • Requires prior exposure (sensitization) with a latent period of 1-2 weeks after first exposure.
  • Involves antigen (AG) and antibody (AB) production.

Types of Allergic Reactions

Type I: Anaphylactic Reaction (Humoral)

IgE mediated. Release of mediators (histamine, 5-HT, leukotrienes, prostaglandins) from mast cells.

Type II: Cytolytic Reaction (Humoral)

IgG/IgM mediated. Drug or metabolite acts as antigen on cell surfaces, leading to complement activation and cytolysis.

Type III: Arthrus Reaction (Humoral)

Circulating IgG forms immune complexes that deposit on vascular endothelium, causing destructive inflammation (e.g., serum sickness, PAN, Stevens-Johnson syndrome).

Type IV: Delayed Hypersensitivity (Cell-Mediated)

Mediated by sensitized T-lymphocytes. Develops >12 hours after exposure. Causes inflammatory responses (e.g., contact dermatitis, photosensitization).

Treatment of Drug Allergy

  • Stop the offending drug immediately.
  • Type I/Anaphylaxis: Antihistamines, adrenaline (0.5 mg IM), oxygen, glucocorticoids (hydrocortisone 100-200 mg IV).

11. Photosensitivity

Drug-induced sensitization of the skin to UV radiation.

Phototoxic

Drug accumulates in skin, absorbs light, and causes direct tissue damage (erythema, edema, hyperpigmentation).

Drugs: Nalidixic acid, fluoroquinolones, sulfonamides, phenothiazines, thiazides, amiodarone.

Photoallergic

Drug induces cell-mediated immunity (CMI), leading to papular or eczematous contact dermatitis upon sunlight exposure.

Drugs: Sulfonamides, sulfonylureas, griseofulvin, chloroquine.

12. Drug Dependence

A state arising from repeated administration that results in harm. Characterized by a desire/compulsion to continue use and withdrawal symptoms upon abrupt deprivation.

Psychological Dependence

Belief that optimal wellbeing is achieved only through the drug. Involves "liking," "craving," and "reinforcement."

Physical Dependence

Altered physiological state requiring the continued presence of the drug to maintain equilibrium. Discontinuation leads to a characteristic withdrawal syndrome.

Drugs causing physical dependence: Opioids, barbiturates, alcohol, benzodiazepines, stimulants (amphetamines, cocaine).

13. Pharmacovigilance & ADR Monitoring

Pharmacovigilance: Science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems.

ADR Monitoring Systems

  • Collect new information from reliable sources.
  • Classify and analyze the information.
  • Circulate findings and actions to all health sectors.

ADR Reporting (4 Elements)

  1. Patient
  2. A drug
  3. An adverse drug reaction
  4. Reporter of the report

Methods of Data Collection

  • Experimental Studies: Formal therapeutic trials (Phases 1-3). Detect incidence up to ~1:200.
  • Observational Studies (Pharmacoepidemiology): Cohort & case-control studies under normal use conditions.
  • Spontaneous/voluntary reporting.
  • Prescription event monitoring.
  • Record linkage systems.