Adverse Drug Reaction Unnikrishnan M K Additional Prof in Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Introduction Defn: Undesirable effect at normal dose: – trivial OR serious Or fatal Requires –Treatment –  in dosing –Discontinuation –Caution in future Occurrence –immediately or after prolonged use –or after termination –Mild ADRs common, [incidence 10-25%] –  with polypharmacy Acceptability: linked to Therap. Use; Risk Benefit Ratio

Type A: Predictable & Type B Unpredictable Type A: Response qualitatively normal but quantitatively abnormal Common, less serious, dose related, corrected by dose adjustment include side effect, toxic effect, withdrawal Type B: Because of patient peculiarities; Eg. Allergy, idiosyncrasy Dose related; uncommon; Serious  withdrawal of drug required Not always predictable / preventable

Severity of ADR: Minor/ moderate/ severe/ lethal Minor : no need of therapy, antidote, or hospitalization Moderate : requires drug change, specific treatment, hospitalization Severe: Potentially life threatening; permanent damage, and prolonged hospitalisation. Lethal: Directly or indirectly leads to death

Prevention of ADR: [cannot be totally avoided; only minimized] [1] Avoid inappropriate drugs in the context of clinical condition [2] Use right dose, route, frequency based on patient variables [3] Elicit medication history; consider untoward incidents [4] Elicit history of allergies [  in patients with allergic diseases] [5] Rule out drug interactions [6] Adopt right technique: Eg slow iv injection of aminophylline [7] Carry out appropriate monitoring [Eg PT with warfarin; Li levels]

Types of ADRs viz Side effect; Secondary effect; Toxic effect [1] Side Effects : unavoidable, predictable,  dose  amelioration Occurs as Extension of the same therapeutic effect: Eg. –Atropine as antisecretory in preanesthetic medication  dry mouth Occurs as a distinctly different effect: Eg. –Promethazine as antiallergic  sedation –Estrogen as antiovulatory  nausea Side effect exploited for a therapeutic use: Eg –Codeine [antitussive] constipating action used in diarrhoea –Sulfonylureas [tested as antibacterials] were found to  bl glucose

Secondary Effects & Toxic Effects [2] Secondary effects: Indirect effect of therapy –Eg. Iintestinal microflora killed by tetracycline  superinfection –Corticosteroids   immunity  activation of latent tuberculosis [3] Toxic effects: [Overdose or prolonged use] –Atropine  delirium ; –Paracetamol  hepatic necrosis –Barbiturates  coma; –Morphine  respiratory failure

Intolerance and Idiosyncrasy [4] Intolerance: –Opposite of tolerance:  sensitivity to low doses –few doses of carbamazepine  ataxia [ defective movement/gait] –single dose of triflupromazine  muscular dystonia [5] Idiosyncrasy: genetically determined atypical / bizarre effect –Barbiturate  excitement & mental confusion –Quinine  cramps, diarrhoea, purpura, asthma, vascular collapse

Drug allergy: [ or hypersensitivity] [6] Drug allergy: [ or hypersensitivity] –Immunologically mediated –Independent of dose –Occurs in a small proportion; –Prior sensitization required –1-2 weeks required after first dose –Drug acts as an antigen or Hapten –Chemically related drugs may show cross sensitivity –Same drug can cause diff allergic reactions in diff individuals

Drug allergy: continued.. Variable time course: Sensitive people may later tolerate drug Type I: urticaria, angioedema, asthma, anaphylactic shock Type II : Thrombocytopenia, agranulocytosis, aplastic anemia, SLE Type III: Arthralgia, lymphadenopathy, Steven Johnson Synd. Type IV: contact dermatitis, fever, photosensitisation Eg: penicillin, sulfonamides, carbamazepine, methyldopa

[7]Photosensitivity: [phototoxic & photoallergic] Phototoxic : Drug accumulates in skin  absorbs light  photochemical reaction  photobiological reaction  tissue damage [Eg erythema, edema, blistering etc] Eg tetracyclines Photoallergic: drug  cell mediated immune response  contact dermatitis on exposure to light. Eg sulfonamides, griseofulvin etc.

ADRs continued.. [8]Drug Dependence : Psychological: (Habituation) & Physical dependence: with withdrawal symptoms [9]Teratogenicity : Drug use in pregnancy affects offspring Eg Thalidomide  phocomelia; phenytoin  cleft palate [10 ]Carcinogenicity & mutagenicity : Anticancer drugs, estrogens [11] Drug induced deseases, Iatrogenic diseases : Salicylates  peptic ulcer; Phenothiazines  parkinsonism; INH  hepatitis