Adverse Drug Reaction

Unnikrishnan M KAdditional Prof in Pharmacology,

Manipal College of Pharmaceutical Sciences,

Manipal 576 104

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 tobl 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

• [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