ADVERSE DRUG REACTION

FEB 2014

ADVERSE DRUG REACTION
Adverse Drug Reaction (ADR) It is a response to a drug that is “noxious and unintended and which occurs in doses normally used for the treatment, prophylaxis or diagnosis of disease or in the modification of physiological function”. (WHO). Adverse Events It refers to any adverse effects that occur while the patient is taking a given drug. It is not necessary that the event was a response related to the drug. Side-effects It is any effect caused by a drug other than the intended therapeutic effect whether it is beneficial, neutral or harmful. It can be based on the same therapeutic effect of the drug. Examples a. Atropine is used as a pre-anaesthetic medication as it decreases secretion, as side-effects it causes dryness of mouth. b. Codeine is used as an analgesic or cough suppressant, as side-effects leads to constipation. This adverse effect is beneficial; it allows codeine to be used as an anti-diarrheal medication. c. Minoxidil is an arterial vasodilator. It was first used to treat hypertension and was found to cause hirsutism as side-effect. This side-effect explains the use of topical minoxidil in treating alopecia. Toxic effect It refers to the direct cell damaging (eg paracetamol on the liver) action of the drug often when used at high dose. All drugs are toxic in overdose. Overdose can be: 1. Absolute: acute high dose of the drug is administered as in suicidal attempt or by accident. 2. Relative: the therapeutic dose of the drug is used but it may turn out toxic because of underlying abnormalities in the patient. Examples: a. Paracetamol at a dose of 4g /day therapeutic dose can lead to fulminant liver failure in a patient suffering from alcohol liver disease. b. When gentamicin is given to a patient with pre-existing renal impairment, ototoxicity is more likely to occur. Types of ADR 1. Type A reaction (augmented reaction). It also known as quantitative intolerance and is dose related. It depends on: a. The duration of the treatment, b. Total intake of the drug, 1

Drug-drug interaction. myalgia. agranulocytosis. thrombocytopenia. It is characterised by fever. Chlorpheniramine 10 mg IV 6-8 hourly till pruritus and rashes decrease. laryngeal oedema. 2 . Salbutamol nebuliser or IVI of aminophylline for bronchospasm. Supportive treatment. collagen vascular disease. Treatment: Epinephrine 0. Type III Immune complex vasculitis (serum sickness/ Arthus reaction) Drug antibody complex precipitates on the vascular wall and activates complement and ultimately triggers an inflammatory response. b. broncho-spasm. lymphadenopathy. urticaria. Type I: Anaphylactic reaction Drug specific antibody of IgE type combines with the Fc segment of mast cell. Immunological. interstitial nephritis and neuropathy. flushing. It manifests as hemolytic anaemia. Idiosyncrasy. IV. Capacity of the drug to accumulate or gets deposited in certain tissues 2. Only a few drugs (mol wt>10.. Hypersensitivity reactions (drug allergy) Drug allergy is an immunologically mediated reaction producing symptoms which are unrelated to the pharmacological effects and doses of the drug. Iv 6-8 hourly (max of 400mg/day).000) are large enough to act as effective antigen or immunogens and are capable of initiating an immune response on their own. V. arthralgia.ADVERSE DRUG REACTION FEB 2014 c. III. Hypersensitivity reaction can be humoral or cell mediated. It is non-dose dependent and can occur from single dose of the drug. Two main types of type B reactions are: a. headache. Type B (Bizarre reaction) It is also known as qualitative intolerance. Most drugs/metabolites (hapten) must be converted to antigen by linkage to body protein. Receptor abnormality II. rash..5 ml of 1:1000 IM Hydrocortisone 100-200 mg. Type II: Cytotoxic reaction Drug antibody Ig G/ Ig M complex adhere to the surface of the blood cells and cause activation of complements. Any pharmaceutical variation. Possible mechanism of pathogenesis of type B reactions are: I. Upon re-exposure to the antigen. degranulation of the mast cell occurs with release of histamine and other mediators which leads to manifestation like hypotension. Hypersensitivity reaction. It occurs in 5-10% of the population. Abnormal biological system that is apparent only in the presence of the drug.

It is likely to have a genetic predisposition. 4. Individual with G6PD deficiency are likely to suffer from hemolytic anaemia with oxidizing agents like primaquine. The stage of organogenesis (18-55days) is the most vulnerable period). Teratogenicity It is the ability of a drug to induce physical malformation in the foetus when such a drug is administered to the pregnant woman. sulfa drugs (sulphonamides). Comparison between type A and type B reaction: ADR Dose relationship Frequency Mortality rate Treatment Type A Present More common Lower Stop/reduce dose Type B Absent Less common Higher Stop the drug at once. 3. Type D (delayed effects). Teratogenicity and carcinogenesis. mivacurium.ADVERSE DRUG REACTION FEB 2014 Type IV(delayed cell mediated). vaccines. dtubocurarine. succinylcholine. chloroquine. insulin… Idiosyncratic reaction It is a functional term which does not apply to any mechanism of toxicity. quinolones. It occurs on the long term use of a particular drug. Examples of idiosyncratic reactions: 1. Anaphylactoid reaction with aspirin. Examples: Analgesic nephropathy. metronidazole. Steven’s Johnson reaction is an example of such a reaction. monoclonal antibodies. Chloramphenicol : bone marrow suppression and agranulocytosis. Type C (continuous reaction). N-acetyl-cysteine. iodine containing contrast… 3. chloroquine induced retinopathy… 4. NB: Anaphylactoid reaction mimicks anaphylactic reaction but it does have any immunological basis. Examples of drugs that are likely to cause allergic reaction Antibiotics (Penicillin anaphylactic reaction and cephalosporin in particular). 2. tardive dyskinesia with prolonged use of anti-psychotics. high dose of vitamin C. Immunological phenomenon cannot be proved. The drug is bound to the surface of T-lymphocytes with production of lymphokine and cause an inflammatory response. Prolonged apnoea by succinylcholine in patient with atypical cholinesterase. paracetamol. 3 . iron. Drugs causing anaphylactoid reaction: aspirin.

Hydralazine/procainamide induced SLE. Photosensitivity These are cutaneous reactions resulting from drug induced sensitization of the skin to UV radiation. limb defects (hypoplastic phalanges). terbinafine. Phenytoin. it gives eczematous like picture. Carcinogenesis The female offspring of women who were exposed to stilboesterol during their child-bearing age have been shown to develop vaginal cancers. 2. Type E (ending of use) Example : Acute adrenal crisis will occur upon abrupt discontinuation of a corticosteroid in a patient who was treatment for more than 3 weeks with a corticosteroid (suppression of HPA axis). Examples: Amiodarone. oedema. carbamazepine: fetal hydantoin syndrome and neural tube defects characterized by microcephaly.ADVERSE DRUG REACTION FEB 2014 Examples of teratogenic drugs: Thalidomide: Was used as sedative/hypnotics and for the relief of morning sickness. Steroid induced hypertension. Sudden withdrawal of high doses of β-blockers in hypertensive patients causes rebound increase in blood pressure (up-regulation of receptors). facial dysmorphism. Photo-toxicity: the drug or its metabolite accumulates in the skin and absorbs the light (UVB) and cause tissue damage by a chemical reaction. fluoroquinolones. It ressembles sun-burn (erythema. 3. sulfonylureas. Iatrogenic disease Physician induced disease. osteoporosis. blistering. hyperpigmentation). Warfarin: growth retardation with nose. It caused phocomelia. diabetes mellitus. thiazides. Broadspectrum antibiotic induced candidiasis. sulfones… b. Examples: 1. Abrupt stoppage of nasal decongestants following chronic use leads to rebound congestion (down regulation of receptors). Tetracycline: deformed and discoloured teeth and retarded bone growth. Examples: Sulphonamides. 4 . Photo-allergic reaction: it is a cell-mediated immune response and on exposure to sunlight. It is of two types: a. ears and hand defects. Amelia and multiple defects. Isoniazid induced hepatitis. 4. griseofulvin. valproate.

with less than 10% body surface area (BSA) involved. oxcarbamazepine. Corticosteroid therapy. NSAIDS 3. Examples: caffeine. Pantoprazole 9. 2. sympathomimetics vasoconstrictors. Examples: opioids. It is a minor form of toxic epidermal necrolysis. characteristic withdrawal syndrome occurs. No specific treatment. Symptomatic treatment in the form of fluid resuscitation. Tramadol Treatment 1. Idiopathic Drugs that are implicated: 1. ciprofloxacin has also been reported. relapsing drug use despite negative consequences and at times is triggered by cravings. 2. lamotrigine. 3. Steven’s Johnson syndrome Stevens-Johnson syndrome is an immune-complex–mediated hypersensitivity complex that typically involves the skin and the mucous membranes. Allopurinol 6. etanercept. Anticonvulsant drugs: carbamazepine. TNF-alpha antagonists (eg. bronchodilators. It consists of compulsive. Drug-induced 3. 5. Human intravenous immunoglobulin (IVIG) has been described as both treatment and prophylaxis. It includes strong feeling of euphoria and the reward pathway is stimulated. 4. tobacco… Dependence (physical dependence) Altered physiological state produced by repeated administration of a drug such that when the drug is abruptly discontinued. valproate. Etiology 1. infliximab. Immunosuppressant. cocaine.ADVERSE DRUG REACTION FEB 2014 Addiction (psychological dependence). adalimumab 7. Malignancy-related 4. Antibiotics: Penicillins and sulfa drugs are prominent. Modafinil (Provigil) 5. benzodiazepines. Infectious 2. calamine lotion. Sertraline 8. 4. phenytoin. alcohol. 5 .

Lamotrigine Treatment Same as for Steven’s Johnson syndrome. Lyell’s Syndrome It is a life-threatening dermatologic disorder characterized by widespread erythema. Nevirapine 6. and genitourinary complications. resulting in exfoliation and possible sepsis and/or death. Sulfonamide antibiotics 2. Antiepileptic drugs 3. Allopurinol 5. Oxicam nonsteroidal anti-inflammatory drugs 4. and bullous detachment of the epidermis and mucous membranes. respiratory failure. ocular abnormalities. 6 .ADVERSE DRUG REACTION FEB 2014 Toxic Epidermal Necrolysis (TEN). Abacavir 7. Mucous membrane involvement can result in gastrointestinal hemorrhage. The most commonly implicated agents include the following: 1. necrosis.