ADVERSE DRUG REACTIONS
DR T R RAMANUJAM M.D., C.MI.Biol (Lond)
INTRODUCTION
DEFINITION OF A.D.R AND DRUG INTERACTIONS
CLASSIFICATION OF ADVERSE DRUG REACTIONS
ADR DUE TO DRUG INTERACTIONS
CRITERIA FOR DRUG REACTIONS
CLASSIFICATION OF ADVERSE DRUG REACTIONS
a) . Dose related (dose dependent which are augmented or extension effects) occurs in all patients which may vary from patient to patient and are specific for the drug. Some are exaggeration of therapeutic (EX: myocardial conduction defects with beta blockers in hypertensive patients) or unrelated to the pharmacological or therapeutic effects viz., Ototoxicity of aminoglycosidies.
Dose related ADR may occur because of the variations in the pharmaceutical, pharmacokinetic, pharmacogenetic or pharmacodynamic properties of the drug (s). The reactions are more common with drugs having low margin of safety i.e., the ratio between effective dose and toxic dose is very narrow. Warfarin sodium, Quindine, Digitalis, aminoglycosides, oral contraceptives, antihypertensives, cytotoxics and immunosuppressive agents are classical examples with low margin of safety.
i) Pharmaceutical Variation:
Example Phenytoin toxicity was enhanced in Australia in 1960 when the expedient of phenytoin was changed from calcium sulphate to lactose which resulted the undue increase in the bioavailability of the active drug.
Change in formulation characteristics can alter drug influence in the body.
ii) Pharmacogenetic Variation:
Acylation process INH, hydralazine, procaineamide and sulfas metabolism is influenced by genetic type of the drug enzyme Viz, rapid or slow acylators. The drug toxicity is enhanced in slow acylators.
Hydroxylation Debrisoquin, dilantin and phenformin metabolism can be altered.
Red cell membrane enzyme (g 6 PD def) may result in haemolytic anemia with Dapsone, Furadantin, phenacetin, sulfas, primaquin, phenylbutazone etc.,
Malignant hyperthermia precipitated by halothane, succinylcholine, methoxyflourane (fatal reaction genetically mediated).
iii). Pharmacokinetic Variation:
Hepatocellular dysfunction as in hepatitis reduce the clearance of dilantin, theophylline, warfarin, opioids, proporanolol, labetalol, largactil. Renal dysfunction enhanced toxicity of digitalis, aminoglycoside, allopurinol, cephalosporins, Li and amphoterecin B etc.
iv). Pharmacodynamic Variation:
Hepatic disease may influence pharmaco dynamic response to drugs. Drugs like oral anticoagulants, NSAIDS, by inhibiting clotting may cause bleeding and phenothazines, opiates precipitate hepatic encephalopathy.
Sodium and water retention can be enhanced by carbenoxobne carbamazepine phenylbutazone (NSAIDS), steroids etc., similarly hypokalemia and hypercalcemia produced by thiazines can increase the digitalis toxicity and also hypokalemia reduce the effectiveness of lignocaine, procaineamide, quinidine, and disopyramide etc.
b). Non-dose related ( or dose independent) occurs only in small number of patients.
i).Immunological reactions: (durg allergy / hypersensitivity)
No relation to pharmacological effects and there is always delay between the first and subsequent exposure to the drug and usually reaction disappears on withdrawal of the offending agents and reappears when the offending agent is administered.
Factors like macromolecular drug proteins form hapten, atopic conditions of the patient or the presence of incidental disease like infectious mononucleosis may precipitate allergic type of ADR.
For example hydrallazine causes systemic lupus erythema like syndrome in patients with HLA Dr 4 tissue type and ampicillin causes rashes in patients with Infectious mononucleosis.
Mechanisms & types of Immunological reactions:
Type I Anaphylaxis (Urticaria & angioedema) involving IGE with resulting mediators like histamine, SRS A etc., Penicillins, sulfas, Amphoterecin B etc.
Type II Cytotoxic (thrombcytopenia and hemolytic anemia) involving circulating Ab IGM, IGA resulting in the activation of complement and cell lysis.
Thrombopenia: Quinine, Quindine, Rifadin, Chlorpropamide, metronidazole.
Haemolytic anemia: Penicillins, rifadin, furans, quinidine.
Type III Immunocomplex involving IgG resulting in the activation of complement and damage to capillary endothelium serum sickness. ATS, penicillins, aminoglycosides, sulfas, antithyroid drugs.
Type IV Cell mediated or delayed hypersensitivity contact dermatitis. Local anesthetic ointments, antihistamine creams topical antimicrobials etc.
Few of the allergic manifestations & drugs implicated:
Drug Fever: Penicillins, sulfas, dilantin, hydraliazine, chloramphenicol, aminoglycosides, quinidine.
Rashes:
Toxic erythema penicillins, sulfas, phenylbutazone urticaria sulfas aspirin, codeine, phenecetin.
Erythema multiforme ( Stevens Johnson's Syndrome); penicillins, sulfas, barbiturates, phenothiazines, NSAIDS dilantin.
Erythema nodosum: sulfas, sulfones, oral contraceptives, Cutaneous vasculities: sulfas, phenylbutazone, dilantin purpura
Non-thrombopenic: steroids, meprobamate, sulfas
Exfoliative dermatitis: Gold, Phenylbutazone
Photosensitivity: Sulfas, demecolcycline, largactil, Quinolones Fixed drug eruptions (FDE) sulfas, tetracyclines, barbiturates phenolphthalein etc.
Toxic epidermal necrolysis (TEN): Dilantin, sulfas, Gold tetracycline, allopurinol etc.
Connective Tissue disease: SLE hydrallazine, sulfas, procaineamide.
Pharmacogenetic variations ( Include Idiosyncratic Reactions):
Heinz body hemolytic anemia sulfas, sulfones, primaquine, INH, phenylbutazone.
Acute porphyria: Barbiturates, meprobamate.
c). Long term effects causing ADR:
1. Due to Adaptive changes physical dependence by narcotic analgesics.
Tardive dyskinesia associated with long term neuroleptic therapy for schizophrenia.
2. Due to Rebound phenomenon: Narcotic analgesics, alcohol, benzodiazepines producing withdrawal syndrome.
More important ones are those produced by clonidine withdrawal rebound hypertension.
Withdrawal of beta blockers in hypertension leading to rebound cardiac ischemia and rebound hypercoagulability is noted in patients receiving portwine to counter act heparin overdose.
3. Other Long terms effects: Chloroquine induced corneal deposits and pigmentary retinopathy especially in patients receiving concomitant pronbenecid therapy.
4. Delayed effects causing ADR:
(i) Carcinogenesis: Uterine endometrial carcinoma with post menopausal estrogen replacement therapy vaginal adenocarcinoma of the female off spring whose mother received estrogen for threatened abortion. Benign liver tumors with oral contraceptives.
Impaired fertility reversible sulfasalazine, furans pargylin, antimalarials.
Irreversible chlorambucil, cyclophosphamide
Teratogenesis: Drug interfering with growth and development of the fetus during I trimester.
Androgens, methotrezate, steroids, tetracyclines, Warfarin, Dilantin, alcohol, clofibrate etc.
During last trimester drugs causing adverse effects include aspirin, aminoglycosides, anti-thyroid, oral-anticoagulants, etc.
Adverse effects due to drugs excreted in breast milk: Antineoplastics, antithyroids, INH, Quinolones, oral contraceptives, sulfas beta blockers, xanthine, Diazepam, Ergotamine etc.
