Acta cardiologica. Supplementum最新文献

Intravenous mexiletine (250 mg in 10 min) given to patients at the acute stage of a myocardial infarction was responsible of a mild decrease of the left ventricular function; two of our patients presented bradycardia with hypotension, immediately corrected by atropine (i.v.). Adverse hemodynamic effects are seldom reported after oral administration.

The hemodynamic and electrocardiographic effects of intravenous injections of mexiletine in progressively increased doses, starting from 1.5 and 3 mg, have been studied in two series of 8 and 6 dogs anaesthetized with pentobarbital. The analysis of the results showed that absence of change in aortic pressure, heart rate and output when the minimal doses are injected, is due to the interaction of opposite effects: a direct depressing effect on the myocardial contractility, and a sympathic reflex stimulation secondary to a peripheral vasodilation. The comparison of hemodynamic, electrocardiographic and toxic effects of mexiletine with those produced by other antiarrhythmics showed that mexiletine placed itself among the better tolerated antiarrhythmics during the administration of progressively increasing doses.

This paper consists of a review of some of the most important papers which have recently been devoted to mexiletine. The electrophysiological effects of the drug in normal subjects and in patients with abnormal impulse formation or conduction are described. The results of open studies related to the clinical effects of mexiletine administered intravenously or orally are briefly reported. The efficacy of the drug on ventricular rhythm disorders is then discussed on the basis of data provided by several controlled double-blind studies. The possible role of mexiletine as a protection against sudden death following myocardial infarction is envisaged. The side-effects which were described by the different investigators are listed.

Mexiletine is effective in abolishing experimentally induced cardiac arrhythmias and belongs to the Vaughan-Williams Class I group of antiarrhythmic agents. It depresses the maximum rate of depolarisation with little or no modification of resting potentials or the duration of action potentials. When given intravenously mexiletine redistributes rapidly from plasma to tissues after a single intravenous injection. Therapeutic plasma concentrations lie in the region of 1-2 mcg/ml and in order to achieve these concentrations rapidly an initial loading dose is desirable. After oral administration it is rapidly and well adsorbed. An initial oral loading dose is advisable to achieve constant adequate plasma concentrations. The prior administration of opiates may delay oral absorption but this is compensated for by a larger initial loading dose. The half-life may vary under certain circumstances and lies in the region of 10-16 hours. Some 10-15% is excreted unchanged in the urine within 72 hours of oral administration. Mexiletine is largely metabolised in the liver and although there is some renal excretion with pH dependent tubular reabsorption, in clinical practice this has not presented any major problems.

Although pharmacodynamic factors are very important in regard to the need for dose adaptation of mexiletine, pharmacokinetic factors also play a role. Pharmacokinetic variability for mexiletine is mainly due to interindividual differences in biotransformation rate in patients with normal hepatic function. Whether the existence of a compromised renal, hepatic or cardiac function alters dosage requirements is not clear. Oral administration of three times 250 mg daily is probably a good starting dose but adaptation will be necessary in many patients. The need for a loading dose depends on the urgency of the situation. For the intravenous administration a loading dose is always necessary. A regimen consisting of 100 to 250 mg mexiletine over 10 minutes, followed by 200 mg over 1 hour has been proposed. This is then followed by a continuous infusion of 0.5-2.5 mg/min. Pharmacodynamic variations notwithstanding, it is of interest to obtain plasma levels of mexiletine within the range of 1-2 microgram/ml.