Adverse drug Reactions

Define adverse drug reactions/ effects? (ADE) Pharmacological actions of drug are 1] Beneficial effects OR 2] Adverse effects Any noxious change suspected to be due to a drug, occurs at doses normally used in man. Also named as Untoward effects, Unwanted effects, undesirable effects, adverse effects.

What are types of ADE? For simplication purpose ADEs classified as Predictable & Unpredictable AE. Predictable reactions can explained based on the mechanism of action of drug and Augmented pharmacological responses; hence they are predictable (expected) reactions or type A reactions. Unpredictable responses cannot be explained based on pharmacological mechanism. And are Bizarre. Hence called as type B responses. Although these responses are identified with certain drugs which individual will develop this reaction cannot be predicted (expected); hence the name unpredictable AE

Explain different predictable AEs Side effects: At therapeutic doses, drugs act at all sites specific to them whether we want or not. Drug actions at sites where we dont want the drug to act become side effects. Seen with therapeutic dose of drugs; Unavoidable Usually explained by drugs mechanism of action Eg: Promethazine produces sedation when used for allergy. Anti cholinergic drug produce dryness of mouth when used for urinary colic. Secondary effects: Indirect consequences of primary action of drug. Eg: Corticosteroids produce immunosuppression that can result in tuberculosis. Antibiotics can suppress colonic bacterial flora giving rise to supra infection Toxic effects: Predictable; due to overdose or with therapeutic dose used for prolonged period; exaggerated responses to drug either extension of beneficial effects or extension of side effects. The AE may be result of functional alterations ( reversible) or due to drug induced permanent damage to the organs on high dose / prolonged usage Eg: Heparin induced bleeding; Chloroquine induced retinal toxicity

Explain Type B reactions? Hypersensitivity / Allergic reactions Genetically mediated Idiosyncratic Phototoxicity

Explain Hypersensitivity reactions? Hypersensitivity / Allergic reactions: Some drug molecules, on first exposure, are recognized by host immune system as antigens resulting in either humoral / cell mediated immune reactions following subsequent exposure. There are 4 types of which the first three are mediated by antibodies and the last one cell mediated. Type 1(Immediate hypersensitivity / Anaphylactic): Drug molecule acts as antigen , Ig E antibodies are formed bind to mast cells; on subsequent exposure to drug, antigen: antibody reaction takes place on mast cell surface releasing chemical mediators. Reaction seen within minutes of second exposure to drug and can be life threatening like shock. Adrenaline + Antihistamines are drugs for type 1 ( Eg: Penicillin allergy) Type 2 (cytolytic reactions): Drug+ specific tissue protein act as antigen antibody (IgG, IgM) that bind to that particular tissue/ cell. On next exposure to drug, antigen: antibody reaction takes place on cell ( RBC, Platelet, kidney) cytolytic reaction. Within 72 hrs of exposure. Eg: methyl dopa induced hemolytic anemia Type 3 (serum sickness): IgG antibody formed circulate; subsequent exposure, (drug) antigen : antibody binds to complement, together get precipitated at the vascular endothelium inflammation tissue damage. Seen after 72 hrs of exposure. Eg: Ampicillin, NSAID induced fever, urticaria. Type 4 (delayed / Cell mediated): T cells activated release mediators inflammation tissue damage. Eg: Pneumonitis, photosensitivity sulfonamides, Gresiofulvin, Methotrexate Type 2,3,4 reactions treated with corticosteroids

Genetically mediated AEs? Some AEs due to some drugs can be explained on genetic basis. Some individuals show genetic variations in the metabolism of drug or at the level with drug action. This can give rise to unwanted effects. Predicted with certain drugs however, which patient exhibits genetic variation is not known. Genetic testing prior to starting drug treatment is the answer for this ( pharmacogenomics) which is not possible at this level. Eg: Acetylator polymorphism with Isoniazid metabolism; G-6PD deficiency induced hemolytic anemia with methotrexate.

Idiosyncratic reactions? Bizarre AE for which genetic background has not yet been identified are called as idiosyncratic reactions. Seen in minority of patients ; harmful / fatal in nature Eg: Aplastic anemia with Chloramphenicol; Thiazide induced erectile dysfunction.

Phototoxicity? Drug / metabolite accumulate in skin absorbs UV rays damage the tissue Eg:Erythema, blistering of skin with Thiazides, quinolones (Avoid exposure to sun)

Define Type C, D, E adverse reactions? Type C (Chronic): seen on prolonged drug use at therapeutic dose . Can also be toxic effects ( Corticosteroid induced Cushingoid features) Type D (Delayed)- Seen several years of stopping drug or in the progeny to the drug exposed pregnant mother. ( Anticancer drug induced carcinomas; hormone induced carcinomas in the child born to mother receiving hormones during pregnancy) Type E( End of treatment) : Withdrawal reactions seen after sudden stoppage of drug after prolonged use. ( Hypertensive crisis after withdrawal of Propranolol; acute adrenal insufficiency after stopping corticosteroids)

Drug dependence? Physical dependence Psychological dependence Drug addiction

Iatrogenic disease? These are AE that persist even after the offending drug has been withdrawn. AE persist even after the offending drug has been withdrawn. Eg: Peptic ulcer by aspirin; Parkinsonism by Antipsychotics; Diabetes by cortico steroids

Teratogenicity? Ability of the drug to cause fetal abnormalities when administered to a pregnant mother Type / severity of fetal anomalies depend on Time of gestation Drug Maternal / Fetal Blood concentration Duration of drug exposure Time of gestation drug effect Fertilization & Implantation (first 17days): All / none phenomena ( drug has no effect of fetus at all; if affected then pregnancy will not continue) A lady will not know whether she is conceived or not until this period so cant avoid drug intake also Organogenesis (18-55days): Most vulnerable period. Anatomical deformities are common if fetus is exposed to drugs. Growth & Development (>55days): Developmental & Functional anomalies common in fetus. It is wise to avoid all drugs during pregnancy unless compelling indications exist for their use regardless of the assigned pregnancy category, or presumed safety by US-FDA

How the Severity of ADR defined? Minor: No treatment or No hospital stay Moderate: Treatment or needs hospital stay Severe: Potentially life threatening; needs intensive treatment; causes permanent damage Lethal: Directly/ indirectly contributes to death of patients

Pharmacovigilance? WHO definition: Science & activities relating to the detection, assessment, understanding, and prevention of AE. Uppsala Monitoring Centre in Sweden is the International Collaborating centre