Lorcainide

Summary

Synopsis: Lorcainide¹ is a type I antiarrhythmic drug of the local anaesthetic type. It can be given either intravenously or orally, and its pharmacokinetic properties allow relatively long (12 hours) dosing intervals with oral administration. A slowly eliminated metabolite, norlorcainide, probably contributes to the effects of orally administered lorcainide in chronically treated patients. In mainly short term studies, lorcainide has been shown to suppress ventricular ectopy in about 80% of patients treated either orally or intravenously. Preliminary evidence suggests that its efficacy in suppressing ectopy in the setting of acute myocardial infarction is comparable with that of lignocaine (lidocaine). It is of variable efficacy in preventing recurrent ventricular tachycardia and has been shown to be effective in some patients who have failed to respond to other antiarrhythmic drugs. Experience is limited in treating supraventricular arrhythmias, but initial results in patients with Wolff-Parkinson-White syndrome have been favourable.

Adverse cardiac effects are infrequent. Abnormal sinus node function may be exacerbated by lorcainide treatment, however, and bundle branch block may be precipitated in patients with pre-existing conduction system disease. Exacerbation of pre-existing arrhythmias is uncommon, and clinically important myocardial depression has not been observed. The most frequent side effect is disturbed sleep during the initiation of oral treatment, which may occur in the majority of patients but usually responds to treatment with a benzodiazepine and subsides with time.

Thus, lorcainide appears useful against a variety of arrhythmias. With its convenient dosage schedule and apparently low incidence of serious side effects it should become a useful addition to the antiarrhythmic agents available, although longer term studies are needed to confirm its continued efficacy and lack of unexpected side effects when used for long periods.

Pharmacodynamic Studies: The major effect of lorcainide on the action potential is a slowing of its maximum rate of rise, resulting in slowed conduction. The actions of lorcainide are compatible with depression of fast sodium conductance. Other observed effects include prolongation of the effective refractory period and a slight increase in action potential duration. Some depression of spontaneous pacemaker activity also occurs.

In man and animals, atrial, ventricular and AV nodal refractory periods are generally unchanged. Cardiac conduction is slowed, most prominently in the His-Purkinje system. Sinus node function is unchanged in healthy subjects but may be significantly depressed in patients with sinoatrial node dysfunction, as may infranodal conduction in patients with pre-existent bundle branch block. Retrograde and anterograde refractory periods of accessory pathways are generally prolonged.

The QRS duration is prolonged by lorcainide treatment and a log-linear relationship between QRS duration and plasma lorcainide concentrations has been demonstrated. P wave duration, P-R interval and QT_c have been slightly prolonged in some but not all studies.

Haemodynamic studies show a slight increase in heart rate after intravenous administration of lorcainide. Blood pressure and vascular resistance do not change significantly, and while there is evidence of a myocardial depressant effect, clinically important deterioration of cardiac function does not seem to occur.

Lorcainide is effective against a variety of experimental arrhythmias and its potency in raising the ventricular fibrillation threshold in isolated perfused hearts is 14 times that of lignocaine on a weight basis.

Pharmacokinetic Studies: At doses of 2 mg/kg over 10 to 20 minutes, peak lorcainide blood concentrations of up to 200 μg/L occur. Intravenously administered lorcainide undergoes rapid distribution to most tissues. The volume of distribution at steady-state is 7.5 L/kg, and lorcainide is approximately 85% protein bound. The elimination half-life is approximately 8 hours. Plasma concentrations in the ‘therapeutic range’ (about 150 to 400 μg/L) can be achieved and maintained by a 1.9 to 2.0 mg/kg intravenous ‘loading’ dose, followed by infusion of 0.18 to 0.27 mg/kg/hour.

Orally administered lorcainide undergoes first-pass hepatic elimination, an effect which can be saturated by a larger initial dose or by separating the first 2 doses by only 1 or 2 hours, thus exhibiting dose-dependent bioavailability. Elimination is almost entirely by hepatic biotransformation and is hepatic blood flow-dependent, so that cirrhosis or congestive heart failure prolongs the elimination half-life. Desired plasma concentrations can generally be achieved with dosages of 100mg 2 to 3 times daily, although there is considerable individual variation. Norlorcainide, the N-dealkylated lorcainide metabolite which has some antiarrhythmic activity, has a 27-hour half-life, and during chronic oral administration of lorcainide plasma concentrations of the metabolite are generally about double those of the parent compound.

Therapeutic Trials: A number of open studies of intravenously or orally administered lorcainide have demonstrated significant suppression of premature ventricular contractions in approximately 80% of patients. A few small placebo-controlled studies have yielded similar results, and the effectiveness of lorcainide in suppressing ventricular ectopy in patients with acute myocardial infarction appears to approximate that of lignocaine, although the latter finding is based on a single (albeit well designed) study and thus requires confirmation.

The effectiveness of lorcainide in suppressing ventricular tachycardia and occasional instances of fibrillation has been somewhat more variable. In a study of 76 patients with refractory forms of these arrhythmias, 11 were unable to take the drug because of side effects and control was attained in 29 of the remaining 65 patients. In patients with Wolff-Parkinson-White syndrome and atrial fibrillation, initial experience with lorcainide suggests that the drug is effective in slowing anterograde conduction over the accessory pathway (especially so in patients with short refractory periods), but its effect on circus-movement arrhythmias in these patients is variable.

In addition to the comparative study with lignocaine in patients with acute myocardial infarction mentioned above, a few additional comparative studies have been reported. These suggest approximate equivalence of effect between lorcainide and lignocaine (in an additional study in non-infarct patients with premature ventricular contractions), aprindine and mexiletine, although such studies may not have involved sufficient patients to identify small differences in efficacy if they existed.

Side Effects: The most troublesome side effect of oral lorcainide treatment is disturbed sleep, with insomnia and vivid dreams. This problem is most prominent during the early weeks of treatment, may occur in the majority of patients, and usually responds to treatment with a benzodiazepine. Other side effects include gastrointestinal disturbances, excessive perspiration, and dizziness. Cardiovascular side effects are uncommon, but when they occur they consist primarily of exacerbation of pre-existing sinus node dysfunction and ventricular conduction deficits. A few patients have shown aggravation of their arrhythmias following treatment with lorcainide but significant myocardial depression has not been observed.

Dosage and Administration: Lorcainide has a ‘wide’ apparent therapeutic range with considerable individual variation in the plasma concentration required for therapeutic efficacy. In addition, a wide dosage range may be required to produce any given plasma concentration in different patients. Consequently individualisation of dosage is imperative. The usual oral starting dose is 100mg twice daily (100mg 3 times daily has been recommended in some countries in patients weighing more than 75kg), but total daily doses in excess of 600mg have occasionally been used. Because of the slow accumulation of the active metabolite norlorcainide, it is advisable to increase dosages at no shorter than weekly intervals. If therapeutic levels are desired shortly after oral treatment is begun, an additional 100 to 300mg must be given either with the first dose or within an hour or two, to saturate the hepatic first-pass metabolism of lorcainide. The usual initial intravenous dose is 10 mg/min and the usual active dose 100 to 150mg. Maintenance of therapeutic levels can be achieved by continuous infusion of from 0.18 to 0.27 mg/ kg/h. Dosage may require modification in situations of altered hepatic blood flow such as cirrhosis or congestive heart failure. QRS widening may be a reasonable indication by which to determine dosage adjustments of lorcainide.