C. Chlorpheniramine maleate
Pharmacology
Chlorpheniramine maleate, an alkylamine derivative, is a sedating antihistamine that causes a moderate degree of sedation; it also has antimuscarinic activity. Chlorpheniramine maleate diminishes or abolishes the major actions of histamine in the body by competitive, reversible blockade of histamine H1-receptor sites on tissues; it does not inactivate histamine or prevent its synthesis, nor, in most cases, its release. Histamine H1 receptors are responsible for vasodilation, increased capillary permeability, flare and itch reactions in the skin, and to some extent for contraction of smooth muscle in the bronchi and gastrointestinal tract.
Chlorpheniramine is a racemic mixture; the dextrorotatory isomer, dexchlorpheniramine, has approximately twice the activity of Chlorpheniramine by weight.
Pharmacokinietics
Chlorpheniramine maleate is absorbed relatively slowly from the gastrointestinal tract, peak plasma concentrations occurring about 2.5 to 6 hours after administration by mouth. Bioavailability is low, values of 25 to 50% having been reported. Chlorpheniramine appears to undergo considerable first-pass metabolism. About 70% of Chlorpheniramine in the circulation is bound to plasma proteins. There is wide inter-individual variation in the pharmacokinetics of Chlorpheniramine; values ranging from 2 to 43 hours have been reported for the half-life. Chlorpheniramine is widely distributed in the body, including passage into the CNS.
Chlorpheniramine maleate is extensively metabolized. Metabolites include desmethyl- and didesmethylchlorpheniramine. Unchanged drug and metabolites are excreted primarily in the urine; excretion is dependent on urinary pH and flow rate: Only trace amounts have been found in the feces.
A duration of action of 4 to 6 hours has been reported; this is shorter than may be predicted from pharmacokinetic parameters.
More rapid and extensive absorption, faster clearance, and a shorter half-life have been reported in children.
Uses and administration
Chlorpheniramine maleate is used for symptomatic relief of allergic conditions including urticaria and angioedema, rhinitis, and conjunctivitis, and in pruritic skin disorders. It is common ingredient of compound preparations for symptomatic treatment of coughs and common cold.
Chlorpheniramine maleate is given by mouth in doses of 4 mg every 4 to 6 hours up to a maximum of 24 mg daily. Doses for children are: 1 to 2 years, 1 mg twice daily; 2 to 5 years, 1 mg every 4 to 6 hours (maximum 6 mg daily); 6 to 12 years, 2 mg every 4 to 6 hours (maximum 12 mg daily).
Adverse effects and treatment
The most common side-effect of the sedating antihistamines in CNS depression, with effects varying from slight drowsiness to deep sleep, and including lassitude, dizziness, and in coordination (although paradoxical stimulation may occasionally occur, especially at high doses in children or the elderly). These sedative effects, when they occur, may diminish after a few days of treatment.
Other side effects include headache, psychomotor impairment, and antimuscarinic effects, such as dry mouth, thickened respiratory-tract secretions, blurred vision, urinary difficulty or retention, constipation, and increased gastric reflux.
Occasional gastrointestinal side-effects include nausea, vomiting, diarrhea, or epigastric pain.
Palpitaions and arrhythmias have been reported.
Blood disorders, including agranulocytosis, leucopenia, haemolytic anaemia, and thrombocytopenia, although rare, have been reported.
Other adverse effects include convulsions, sweating, myalgia, paraesthesias, extrapyramidal effects, tremor, sleep disturbances, depression, confusion, tinnitus, hypotension, and hair loss.
Exfoliative dermatitis may develop.
Overdosage
Overdosage with sedating antihistamines is associated with antimuscarinic, extrapyramidal, and CNS effects. When CNS stimulation predominates over CNS depression, which is more likely in children or the elderly, it causes ataxia, excitement, tremors, psychoses, hallucinations, and convulsions; hyperpyrexia may also occur. Deepening coma and cardiorespiratory collapse may follow. In adults, CNS depression is more common with drowsiness, coma, and convulsions, progressing to respiratory failure and cardiovascular collapse.
Treatment of overdosage: treatment is symptomatic and supportive.
Precautions
Drowsiness is a major problem with the chlorpheniramine and those affected should not drive or operate machinery; alcohol should be avoided.
Because of its antimuscarinic actions chlorpheniramine should be used with care in conditions such as angle-closure glaucoma, urinary retention, prostatic hyperplasia, or pyloroduodenal obstruction.
Occasional reports of convulsions in patients taking chlorpheniramine also calls for caution in patients with epilepsy.
The dosage reduction may be necessary in renal impairment.
Chlorpheniramine should not be given to neonates owing to its increased susceptibility to antimuscarinic effects. Elderly patients are also more susceptible to many of the adverse effects of chlorpheniramine and, in particular, its inappropriate use for postural giddiness should be avoided.
Interactions
Chlorpheniramine may enhance the sedative effects of CNS depressants including alcohol, barbiturates, hypnotics, opioid analgesics, anxiolytic sedatives, and antipsychotics.
Chlorpheniramine has an additive antimuscarinic action with other antimuscarinic drugs, such as atropine and some antidepressants (both tricyclics and MAOIs).
Chlorpheniramine may suppress the cutaneous histamine response to allergen extracts and should be stopped several days before skin testing.
Chlorpheniramine might have delayed the hepatic metabolism of phenytoin thereby increasing the plasma concentrations.