SynopsisAs a member of the class Ib antiarrhythmic drugs mexiletine's primary mechanism of action is blocking fast sodium channels, reducing the phase 0 maximal upstroke velocity of the action potential. It increases the ratio of effective refractory period to action potential duration, but has little effect on conductivity. Unlike quinidine it does not prolong QRS and QT (QTc) intervals.In the dosage range 600 to 900mg daily mexiletine effectively suppresses premature ventricular contractions (PVCs) in 25% to 79% of patients, with or without underlying cardiac disease. In comparative studies the response rate was comparable to that with quinidine or disopyramide. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial. More importantly, mexiletine abolishes spontaneous or inducible ventricular tachycardia or fibrillation in the short term in 20% to 50% of patients with refractory arrhythmias. Arrhythmia suppression is maintained in 57% to over 80% of these early therapeutic successes in the long term, with mexiletine alone or in combination with another antiarrhythmic drug. As with other antiarrhythmic drugs, there is no substantial evidence that administration of mexiletine after acute myocardial infarction improves long term prognosis.Although the incidence of adverse effects associated with mexiletine is high, the majority are minor gastrointestinal or neurological effects which can be adequately controlled through dosage adjustment. Furthermore, mexiletine has minimal effects on haemodynamic variables, or on cardiac function in patients with or without pre-existing deterioration of left ventricular function, and it appears to have a low proarrhythmic potential. Thus, while the therapeutic efficacy of mexiletine for the prevention or suppression of symptomatic ventricular arrhythmias may be no greater than that of other antiarrhythmic drugs, and less than that of some (e.g. amiodarone), it is effective in a significant proportion of patients refractory to other treatments and can be administered without causing adverse haemodynamic effects to patients with complicating factors such as acute myocardial infarction or congestive heart failure.Pharmacodynamic PropertiesMexiletine is an orally active class Ib antiarrhythmic drug. It blocks the fast sodium channel, reducing the rate of depolarisation of the cardiac action potential. In preclinical studies it enhanced the threshold of excitability, decreased conduction velocity and shortened the effective refractory period, but most importantly it increased the ratio of effective refractory period to action potential duration. Clinical studies show little influence of mexiletine on atrial refractoriness or AV nodal function. There are reports of lengthening of the ratio of His-bundle to ventricular muscle conduction time in patients with impaired conduction, but this has not been confirmed in other studies. The electrophysiological effects of mexiletine are more pronounced in diseased (e.g. ischaemic) than healthy tissue, and in patients with conduction disorders than in healthy volunteers. Both preclinical and clinical studies have demonstrated additive or synergistic electrophysiological effects with the combination of mexiletine and quinidine. Mexiletine, unlike quinidine has no significant effect on QRS duration, PR interval or QTc interval.Mexiletine has a minimal effect on haemodynamic variables. There is evidence of a minor negative inotropic effect in healthy volunteers receiving acute administration of mexiletine 3 mg/kg intravenously or 200mg four times daily orally. This effect is equivalent to that with propafenone but less than that with disopyramide. However, radionuclide ventriculography revealed that acute or long term oral therapy with mexiletine (up to 1200mg daily) had no significant effect on cardiac function in patients with ventricular arrhythmias whether or not they had pre-existing impairment of ventricular function.Pharmacokinetic StudiesAfter intravenous administration of mexiletine there is extensive tissue uptake with an initial rapid and subsequent slow distribution phase. The volume of distribution is over 600L in healthy subjects. The bioavailability after oral administration in healthy volunteers is about 90%. Peak plasma concentrations are achieved in 2 to 4 hours and there is a linear dose-plasma concentration relationship in the dose range 100 to 600mg. With multiple oral administration steady-state is achieved after 4 or 5 days with no evidence of accumulation.There is extensive hepatic metabolism of mexiletine to inactive metabolites, and only about 8 to 15% of an administered dose is eliminated unchanged in the urine. At physiological pH the elimination half-life has been reported in the range 7.5 to 11.3 hours, but this is prolonged in the presence of alkaline urine. A sustained release formulation of mexiletine (360mg capsules) has equivalent bioavailability to the standard preparation but produces lower peak plasma concentrations at 4 to 6 hours after administration and maintains higher trough concentrations.Patients with recent acute myocardial infarction (AMI) have delayed absorption of mexiletine. They also have an increased volume of distribution and prolonged elimination. In contrast there is very little variation in the pharmacokinetics of mexiletine in patients with renal disease, even those on dialysis, or in elderly patients. Patients with hepatic disease may have a markedly prolonged elimination half-life and reduced rate of clearance of mexiletine, resulting in plasma concentrations above the therapeutic range of 0.5 to 2 mg/L in some.Therapeutic UseFor suppression of premature ventricular complexes (PVCs) in patients with or without underlying cardiac disease, orally administered mexiletine, usually at dosages in the range 600 to 900mg daily for < 1 to 12 weeks, produces response rates in the range 25% to 79%. The wide variation in response results from the variations in definition of response, trial population, study design, dosage and duration of treatment. Mexiletine 600mg daily for 2 weeks produced ≥ 75% PVC suppression in 72 to 82% of 144 patients in a placebo-controlled crossover trial. In a large comparative, parallel design study mexiletine 600 to 1200mg daily and quinidine 800 to 1600mg daily for 12 weeks, each in about 245 patients, produced ≥ 70% PVC suppression in 31% and 32% of patients, respectively. Other small parallel design studies revealed response rates of 54 to 69% with mexiletine, similar to those with quinidine. In short term crossover studies involving small numbers of patients mexiletine 300 to 1000mg daily consistently produced more strictly defined response rates (≥ 75% to ≥ 90% PVC suppression) of about 30%, which were comparable with the response rate to disopyramide 300 to 800mg daily but less than that with propafenone 900mg daily or intravenous lidocaine (lignocaine) 20mg then 2.75 mg/min. PVC suppression by mexiletine is similar in patients with or without organic heart disease. Controlled trials have shown that sustained release mexiletine 360mg twice daily produces equivalent PVC suppression to conventional mexiletine 200mg 3 or 4 times daily.Mexiletine (usually 600 to 900mg daily) abolished spontaneous or inducible VT or VF in the short term in 10% to 20% of patients with refractory arrhythmias in most studies which employed programmed electrical stimulation (PES). The response rate and tolerability can be improved with the addition of a class Ia antiarrhythmic drug or amiodarone, although further controlled trials are necessary to delineate the role of mexiletine in combination with other antiarrhythmic drugs. Long term maintenance therapy with mexiletine 600 to 900mg daily in patients whose refractory ventricular arrhythmias responded to initial treatment prevented arrhythmia recurrence in 57% to over 80% for periods of up to 6 years. Sustained therapeutic response is more predictable when initial success is defined, and mexiletine dosage determined by PES than ambulatory ECG monitoring. However, between 20% and 40% of patients might be expected to have arrhythmia recurrence or develop intolerable adverse effects during mexiletine maintenance therapy.Intravenous and/or oral administration of mexiletine is effective at suppressing ventricular arrhythmias complicating the early or late stages of AMI. Despite this mexiletine did not reduce mortality. In fact, medium term mortality (3 to 12 months) was slightly higher with mexiletine than with placebo. Any benefit on long term prognosis after AMI has yet to be proven, either with mexiletine or other class I antiarrhythmic drugs, and in view of the preliminary findings of the Cardiac Arrhythmia Suppression Trial, routine prophylactic PVC suppression cannot be recommended in asymptomatic or mildly symptomatic patients.Adverse EffectsThere is a particularly high incidence of adverse effects after acute intravenous administration of mexiletine. With lower initial doses or oral administration the incidence can be reduced, but adverse effects are still reported in 43 to 88% of patients receiving long term maintenance therapy. Nevertheless, most are not serious and can be controlled by dosage reductions or administration with food. In the largest placebo-controlled trial, including over 250 patients per treatment group, the overall incidence of adverse effects was over 80% in each group, but there were significantly more reports of tremor, loss of consciousness, nausea and constipation with mexiletine than with placebo, and more withdrawals or dosage reductions for adverse effects. Gastrointestinal disturbance and neurological side effects are the most frequently reported adverse effects with mexiletine. Such symptoms occurred more frequently with mexiletine than quinidine in one study: upper gastrointestinal distress in 38%vs22% of patients, tremor in 12%vs2% and coordination problems in 11%vs1%. Diarrhoea occurred more frequently with quinidine (7%vs35%).Adverse effects to mexiletine are dose-related and reversible following treatment withdrawal. In many patients they can be controlled by dosage reduction and/or administration with food. Administering mexiletine at lower dosages in combination with other antiarrhythmic drugs may also improve tolerability.The potential to aggravate or induce arrhythmias is a characteristic of antiarrhythmic drugs. The frequency of proarrhythmia with mexiletine appears to be relatively low.Drug InteractionsIn contrast with some other antiarrhythmic drugs, mexiletine has no significant effect on plasma digoxin concentrations. Drugs which interfere with hepatic function such as rifampicin and phenytoin may influence the rate of metabolism and excretion of mexiletine, although cimetidine - which can be of benefit for reducing the incidence of gastrointestinal disturbance with mexiletine - has no significant effect on its pharmacokinetics.Mexiletine appears to reduce the rate of clearance of methylxanthines, and there have been reports of theophylline toxicity and enhanced proarrhythmic effects in patients receiving mexiletine and theophylline concurrently.Dosage and AdministrationThe therapeutic serum concentration range for mexiletine is between 0.5 and 2.0 mg/L. Thus, careful dosage titration is necessary to establish the optimum dosage in each individual. The usual oral dosage is between 200 and 300mg three times daily administered with food, and the maximum recommended daily dosage is 1200mg. A more rapid onset of action can be achieved with an initial loading dose of 400mg orally, or by commencing therapy with an intravenous infusion.The sustained release formulation, containing 360mg of mexiletine, can be administered twice daily but this regimen allows little flexibility for dosage titration.Particular care is required during dosage titration in patients with AMI or hepatic disease in view of the influence of these conditions on the pharmacokinetics of mexiletine.