adverse drug reaction pharmacology

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 EventsIt 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-effectsIt 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.

Examplesa. Atropine is used as a pre-anaesthetic medication as it decreases secretion, as side-effects itcauses 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 effectIt 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 ADR1. Type A reaction (augmented reaction).

It also known as quantitative intolerance and is dose related.It depends on: a. The duration of the treatment,

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b. Total intake of the drug, c. Capacity of the drug to accumulate or gets deposited in certain tissues

2. Type B (Bizarre reaction)It is also known as qualitative intolerance.It is non-dose dependent and can occur from single dose of the drug.Two main types of type B reactions are:a. Hypersensitivity reaction.b. Idiosyncrasy.

Possible mechanism of pathogenesis of type B reactions are:I. Receptor abnormalityII. Abnormal biological system that is apparent only in the presence of the drug.III. Any pharmaceutical variation.IV. Drug-drug interaction.V. Immunological.

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.It occurs in 5-10% of the population.Only a few drugs (mol wt>10,000) are large enough to act as effective antigen or immunogens and are capable of initiating an immune response on their own.Most drugs/metabolites (hapten) must be converted to antigen by linkage to body protein.Hypersensitivity reaction can be humoral or cell mediated.

Type I: Anaphylactic reactionDrug specific antibody of IgE type combines with the Fc segment of mast cell. 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, broncho-spasm, headache, flushing, laryngeal oedema, urticaria, rash...

Treatment: Epinephrine 0.5 ml of 1:1000 IM Hydrocortisone 100-200 mg, Iv 6-8 hourly (max of 400mg/day).Chlorpheniramine 10 mg IV 6-8 hourly till pruritus and rashes decrease.Salbutamol nebuliser or IVI of aminophylline for bronchospasm.Supportive treatment.

Type II: Cytotoxic reactionDrug antibody Ig G/ Ig M complex adhere to the surface of the blood cells and cause activation of complements.It manifests as hemolytic anaemia, agranulocytosis, thrombocytopenia, collagen vascular disease.

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. It is characterised by fever, lymphadenopathy, arthralgia, myalgia, interstitial nephritis and neuropathy.

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Type IV(delayed cell mediated).The drug is bound to the surface of T-lymphocytes with production of lymphokine and cause an inflammatory response.Steven’s Johnson reaction is an example of such a reaction.

Examples of drugs that are likely to cause allergic reactionAntibiotics (Penicillin anaphylactic reaction and cephalosporin in particular), vaccines, monoclonal antibodies, insulin…

Idiosyncratic reactionIt is a functional term which does not apply to any mechanism of toxicity.Immunological phenomenon cannot be proved. It is likely to have a genetic predisposition.

Examples of idiosyncratic reactions:1. Individual with G6PD deficiency are likely to suffer from hemolytic anaemia with oxidizing agents like primaquine, sulfa drugs (sulphonamides), quinolones, metronidazole, chloroquine, high dose of vitamin C.2. Prolonged apnoea by succinylcholine in patient with atypical cholinesterase.3. Anaphylactoid reaction with aspirin.4. Chloramphenicol : bone marrow suppression and agranulocytosis.

Comparison between type A and type B reaction:

ADR Type A Type BDose relationship Present Absent Frequency More common Less commonMortality rate Lower Higher Treatment Stop/reduce dose Stop the drug at once.

NB: Anaphylactoid reaction mimicks anaphylactic reaction but it does have any immunological basis. Drugs causing anaphylactoid reaction: aspirin, paracetamol, N-acetyl-cysteine, succinylcholine, d-tubocurarine, mivacurium, iron, iodine containing contrast…

3. Type C (continuous reaction).It occurs on the long term use of a particular drug.

Examples:Analgesic nephropathy, tardive dyskinesia with prolonged use of anti-psychotics, chloroquine induced retinopathy…

4. Type D (delayed effects).Teratogenicity and carcinogenesis.

Teratogenicity

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It is the ability of a drug to induce physical malformation in the foetus when such a drug is administered to the pregnant woman. The stage of organogenesis (18-55days) is the most vulnerable period).

Examples of teratogenic drugs:Thalidomide: Was used as sedative/hypnotics and for the relief of morning sickness. It caused phocomelia, Amelia and multiple defects.Phenytoin, valproate, carbamazepine: fetal hydantoin syndrome and neural tube defects characterized by microcephaly, facial dysmorphism, limb defects (hypoplastic phalanges).Warfarin: growth retardation with nose, ears and hand defects.Tetracycline: deformed and discoloured teeth and retarded bone growth.

Carcinogenesis The female offspring of women who were exposed to stilboesterol during their child-bearing age have been shown to develop vaginal cancers.

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).Sudden withdrawal of high doses of β-blockers in hypertensive patients causes rebound increase in blood pressure (up-regulation of receptors).Abrupt stoppage of nasal decongestants following chronic use leads to rebound congestion (down regulation of receptors).

Photosensitivity These are cutaneous reactions resulting from drug induced sensitization of the skin to UV radiation. It is of two types:a. Photo-toxicity: the drug or its metabolite accumulates in the skin and absorbs the light (UVB) and cause tissue damage by a chemical reaction. It ressembles sun-burn (erythema, oedema, blistering, hyperpigmentation).Examples: Amiodarone, thiazides, fluoroquinolones, sulfones…

b. Photo-allergic reaction: it is a cell-mediated immune response and on exposure to sunlight, it gives eczematous like picture.Examples: Sulphonamides, sulfonylureas, griseofulvin, terbinafine.

Iatrogenic diseasePhysician induced disease.

Examples: 1. Steroid induced hypertension, diabetes mellitus, osteoporosis.2. Broadspectrum antibiotic induced candidiasis.3. Hydralazine/procainamide induced SLE.4. Isoniazid induced hepatitis.

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Addiction (psychological dependence).It consists of compulsive, relapsing drug use despite negative consequences and at times is triggered by cravings. It includes strong feeling of euphoria and the reward pathway is stimulated.Examples: caffeine, cocaine, tobacco…

Dependence (physical dependence)Altered physiological state produced by repeated administration of a drug such that when the drug is abruptly discontinued, characteristic withdrawal syndrome occurs.Examples: opioids, alcohol, benzodiazepines, sympathomimetics vasoconstrictors, bronchodilators.

Steven’s Johnson syndromeStevens-Johnson syndrome is an immune-complex–mediated hypersensitivity complex that typically involves the skin and the mucous membranes. It is a minor form of toxic epidermal necrolysis, with less than 10% body surface area (BSA) involved.

Etiology1. Infectious2. Drug-induced3. Malignancy-related4. Idiopathic

Drugs that are implicated:1. Antibiotics: Penicillins and sulfa drugs are prominent; ciprofloxacin has also been

reported.2. NSAIDS 3. Anticonvulsant drugs: carbamazepine, oxcarbamazepine, phenytoin, valproate,

lamotrigine.4. Modafinil (Provigil)5. Allopurinol

6. TNF-alpha antagonists (eg, infliximab, etanercept, adalimumab

7. Sertraline8. Pantoprazole9. Tramadol

Treatment1. No specific treatment.2. Symptomatic treatment in the form of fluid resuscitation, calamine lotion.3. Corticosteroid therapy.4. Immunosuppressant.

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5. Human intravenous immunoglobulin (IVIG) has been described as both treatment and prophylaxis.

Toxic Epidermal Necrolysis (TEN), Lyell’s SyndromeIt is a life-threatening dermatologic disorder characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes, resulting in exfoliation and possible sepsis and/or death.Mucous membrane involvement can result in gastrointestinal hemorrhage, respiratory failure, ocular abnormalities, and genitourinary complications.

The most commonly implicated agents include the following:1. Sulfonamide antibiotics2. Antiepileptic drugs3. Oxicam nonsteroidal anti-inflammatory drugs4. Allopurinol5. Nevirapine 6. Abacavir 7. Lamotrigine

TreatmentSame as for Steven’s Johnson syndrome.

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adverse drug reaction pharmacology

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