, Volume 17, Issue 3, pp 161-181

Mexiletine: A Review of its Pharmacological Properties and Therapeutic Efficacy in Arrhythmias

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Summary

Synopsis: Mexiletine2 is a new local anaesthetic antiarrhythmic agent whose chemical structure and electrophysiological properties closely resemble those of lignocaine although its anticonvulsant and pharmacokinetic properties differ from that drug. Unlike lignocaine (lidocaine) it is active following oral administration with a plasma half-life varying between 8 and 20 hours so that it can be administered twice or three times daily to sustain therapeutic plasma levels. The drug is effective when given intravenously or by the oral route in controlling ventricular arrhythmias especially following acute myocardial infarction but the side effects are greater during parenteral administration. Side effects during chronic oral therapy with mexiletine have not posed a serious problem. Mexiletine has the pharmacodynamic and pharmacokinetic properties of an agent suitable for the chronic oral prophylaxis of serious ventricular arrhythmias in patients with ischaemic heart disease.

Animal Pharmacology: In isolated cardiac tissues, therapeutically relevant concentrations of mexiletine reduce the maximal rate of depolarisation of the action potential so that conduction velocity is slowed, excitability threshold is increased and effective refractory period lengthened without a significant change in the resting membrane potential or the spontaneous frequency of the sinoatrial node. The effective refractory period is shortened but not to a greater extent than the action potential duration so that the ratio of the effective period to the action potential duration is increased by mexiletine. There are no data on the effects of the drug in damaged or ischaemic isolated myocardial tissues. In intact animals, mexiletine increases the fibrillation threshold of the ischaemic myocardium and reverses ventricular tachyarrhythmias resulting from ouabain intoxication or coronary ligation. The drug has insignificant effects on the autonomic nervous system.

Human Pharmacology: Acute intravenous administration of mexiletine in patients produces little change in atrial refractoriness, sinus node automaticity or recovery time but in the sick sinus syndrome severe bradycardia or prolonged recovery time may become apparent. In patients with normal conduction, shortening of the AV and His-Purkinje refractoriness may be seen; however, AV and His-Purkinje conduction are both delayed in patients with pre-existing disease. The effects of mexiletine on anomalous tracts in the heart are not consistent but deserve further study. The haemodynamic actions of intravenous mexiletine are comparable to those of lignocaine with minimal depressant effects in patients with normal or moderately impaired ventricular function.

Pharmacokinetics: The pharmacokinetic profile of mexiletine is characterised by high systemic availability (88 %) following oral ingestion, with peak levels being attained in 2 to 4 hours; the plasma half-life in healthy volunteers is about 12 hours and approximately 18 hours in patients with acute myocardial infarction in whom the concomitant administration of narcotic analgesics retards gastric emptying. The metabolism of mexiletine is not completely understood but occurs largely in the liver, with only 10 % appearing unchanged in the urine. The renal clearance of the drug is increased by urinary acidosis. About 70 % of serum mexiletine is protein bound. Therapeutic concentrations of mexiletine (0.75 to 2.0ug/ml) are usually maintained by daily oral doses of 600 to 1000mg administered in divided dosage schedules 8-to 12-hourly.

Therapeutic Trials: Although intravenously administered mexiletine is often effective in reverting ventricular tachyarrhythmias, the main therapeutic utility of the drug is in the chronic oral prophylaxis of ventricular arrhythmias, especially in the survivors of acute myocardial infarction as indicated by a number of trials in which the efficacy of mexiletine proved comparable to that of procainamide. In one study the drug was found to be a more acceptable antiarrhythmic agent than procainamide, producing somewhat better suppression of ventricular ectopic beats and complex ventricular arrhythmias. Trials designed to test the efficacy of mexiletine in reducing the incidence of sudden death in the survivors of acute infarction are awaited.

Side Effects: In common with lignocaine, mexiletine has minimal negative inotropic propensity but following rapid intravenous injection, especially of large doses, bradycardia, hypotension and AV block may occur. Long term studies with mexiletine have demonstrated excellent patient compliance, sustained efficacy and relative freedom from side effects. Only in a small number of patients had adverse effects been reported; these are of central nervous system origin, including tremors, nystagmus, diplopia, dizziness, dysarthria, paraesthesia, ataxia and confusion. Gastrointestinal reactions have been uncommon and positive antinuclear factors and thrombocytopenia are rare.

Dosage and Administration: When therapeutic blood levels of mexiletine must be rapidly achieved and maintained, as in acute arrhythmias, a combination of a bolus intravenous injection of 150 to 250mg administered over 2 to 5 minutes, followed by a loading infusion of 250mg over 30 minutes, then 250mg over 2.5 hours and 500mg over 8 hours, has been used. A maintenance infusion of 500 to 1000mg over 24 hours then follows. Such a regimen must be applied judiciously, especially in acutely ill and elderly patients. Alternatively, therapeutic plasma levels may be rapidly attained with an oral loading dose of 600mg.

For prophylactic oral administration, 200 to 300mg 8-hourly produced a therapeutic plasma concentration (0.75 to 2μg/ml) in two-thirds of patients.

Mexilitine may be used concomitantly with digoxin and β-adrenoceptor blocking drugs, but not with other local anaesthetic type antiarrhythmic drugs. Since the depressant electrophysiological effects of the drug are more pronounced in patients with sick sinus syndrome, unstable AV block and severe bradycardia, these conditions are contraindications to the use of the drug. The safety of the drug in advanced cardiac failure is not defined but merits study.

Supported in part by grants from the American Heart Association-Greater Los Angeles Affiliate, and by the National Institutes of Health (HL 23970), Bethesda, Maryland, and the Medical Research Service of the Veterans Administration.
Mexitil (Boehringer Ingelheim).