Adverse Drug Reactions (ADR)

Adverse Drug Reactions (ADR)

• Adverse drug reactions (ADR) are unintended and undesired effects of drugs used for prevention, diagnosis, or treatment of disease.
• Antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and psychotropic drugs are commonly incriminated for ADRs.
• ADRs may develop as a result of an unwanted known property of the drug (predictable) or as a consequence of drug intolerance/idiosyncrasy (unpredictable).
• Sometimes, ADRs represent a manifestation of an immunological phenomenon, i.e., allergic drug reactions.
• ADRs are encountered in certain population groups, for example, the elderly, females, patients suffering immune deficiency (including AIDS patients or those receiving immunosuppressive therapy).

Severity of ADRs

• Minor ADRs require no treatment.
• Moderate ADRs require treatment.
• Severe ADRs are life threatening or cause permanent damage.
• Lethal ADRs lead to death.

Classification of ADRs

• Type A (Augmented & Predictable): related to the pharmacological actions or metabolism of the drug, include side effects, drug toxicity and drug interactions.
• Type B (Bizarre or unpredictable): They do not have an allergic pathogenesis and include idiosyncratic drug reactions, exacerbation of a pre-existing condition.
• Type C (Immunologically mediated): They develop as a consequence of previous exposure to the drug with resultant allergy.
• A number of drugs induce allergic reactions, including antibiotics, anticonvulsants, heparin, insulin, protamine etc.

Type A ADRs Examples

• Side effects are unwanted, but unavoidable pharmacodynamic effects that occur at therapeutic doses.
• Side effects occur with almost all drugs, are generally not serious, are predictable and can be ameliorated by dose reduction.
• Gastritis by Aspirin and throbbing headache by Nitroglycerine are examples of side effects.
• Toxic effects: Drug toxicity develops as a consequence of the gradual accumulation of a drug or its metabolite, which may occur due to over dosage or prolonged drug use.
• The CNS, CVS, kidney, liver, lung, skin & blood – forming organs are commonly damaged by toxic effects of a drug.
• Poisoning: Life – threatening effects by severe damage to a vital function by a chemical, poison or large dose of a drug.
• Drug interactions develop when one drug alters the pharmacological efficacy of another that is given concurrently.
• Drug interactions is of particular importance in the elderly, the immunosuppressed, and in those patients receiving multiple medications.

Type B ADRs Examples

• Idiosyncratic reactions (drug intolerance): a genetically abnormal reactivity to a drug, that represent the effects of abnormal or altered hepatic drug metabolism.
• Hydralazine may cause lupus erythematosus, but the risk is greatly increased in patients who metabolize the drug slowly.
• Exacerbation of a pre-existing condition.
• Lithium, beta blockers, antimalarial drugs, NSAIDs, and tetracycline may precipitate, aggravate, or induce a psoriatic eruption.

Type C ADRs Examples

• Drug allergy (hypersensitivity): Drug allergy is immunologically mediated (Antigen – antibody reaction).

Types of Allergic Reactions

• Type – I hypersensitivity (IgE-mediated): The release of histamine and other chemical mediators from tissue-fixed mast cells results in increased vascular permeability with development of edema in the dermis or deeper tissues.
• Treatment with Penicillin causes urticaria, serum – based vaccines, Lignocaine, and vitamin B, etc are all examples.
• Penicillin is the most common cause of anaphylaxis.
• Other causes include foods, stings, anesthetics, muscle relaxants, antibiotics, and allergenic extracts.
• Immune complex-associated type 3 reactions: Vascular endothelium is inflamed and expressed as urticaria, serum sickness, and leukocytoclastic (allergic) vasculitis.
• The disease manifests a week or more after exposure to the drug, by which time sufficient circulating antibody has been generated to result in immune complexes.
• Their deposition in the tissues or within blood vessel walls is accompanied by complement fixation and resultant acute inflammatory reaction.
• Delayed hypersensitivity reactions are T-lymphocyte mediated and exemplified in acute allergic contact dermatitis.
• Certain drugs may directly bind T-cell receptors and major histocompatibility complex (MHC) molecules and trigger the release of cytokines which recruit specific leukocytes.

Other ADRs

• Photosensitivity: a drug induced cutaneous reaction in sun light (UV radiation).
• Ciprofloxacin, carbamazepine, chloroquine, dapsone, sulphonamides, thiazide diuretics can cause photosensitive reactions.
• latrogenicity: an ADR is caused by the the mistake of a Physician
• Parkinsonism due to antipsychotic drugs, and Peptic ulcer due to NSAIDs are examples of latrogenicity
• Teratogenicity: If prescribed during pregnancy, some drugs can damage the fetus. Tetracyclines cause malformation of bones, and antithyroid drugs can cause fetal goitre.
• Carcinogenicity: Cancer may be caused by anticancer drugs & Estrogen.
• Mutagenicity: Certain drugs may cause mutation leading to genetic abnormalities.
• Anticancer drugs, and stilbesterol (an estrogen) are examples of mutagenicity.

Drug Dependence

• Drug dependence is a compulsion to take a drug.
• Dependence can be psychological or physical.
• Psychological dependence: is caused by CNS stimulants, like Amphetamine, Tobacco, Marijuana (Cannabis), Cocaine, LSD.
• Physical dependence: is caused by CNS depressants, it means the continuous presence of the drug is required for normal physiological functions of the body. Examples alcohol, and opioids such as heroin, benzodiazepines
• Drug addiction: There is a tendency to ↑ dose: Alcohol.
• Habituation: There is no tendency to ↑ drug dose: Tea, Coffee.
• Abuse: Self – medication.
• Reinforcement: Wish to repeat: inhaled & injected addicting drugs.

Pharmacovigilance

• WHO definition: Pharmacovigilance is the science & activities of detecting, assessing & preventing adverse effects or any other drug related problem.