piperidines and norlorcainide

Twenty-eight subjects underwent evaluation of drug toxicity and antiarrhythmic efficacy with oral and intravenous lorcainide. Lorcainide, a new type 1C antiarrhythmic drug, has an active metabolite, norlorcainide, which accumulates after oral but not significantly after intravenous administration. Group 1 consisted of 14 subjects who received intravenous lorcainide with an initial bolus of 2 mg/kg at a rate of 2 mg/min followed by 0.14 mg/min or 200 mg/24 hours. The lorcainide level after bolus was 0.432 micrograms/ml and fell to 0.178 micrograms/ml at 4 to 6 hours despite constant drug infusion. Prior work has demonstrated no detectable norlorcainide levels after intravenous infusion. Group II consisted of 14 subjects who received oral lorcainide, 100 mg orally every 8 hours. Mean lorcainide levels were 0.287 micrograms/ml and mean norlorcainide levels were 0.377 micrograms/ml. Only 2 of 12 subjects in group I experienced headache, dizziness, or sleep disturbance, compared to 12 of 14 subjects in group II (p less than 0.01). Intravenous lorcainide has a lower incidence of central nervous system side effects than oral lorcainide. These effects may be attributable to the accumulation of the norlorcainide metabolite with oral therapy.

Topics: Administration, Oral; Adolescent; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Central Nervous System; Female; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Monitoring, Physiologic; Piperidines

The effects of lorcainide and its metabolite norlorcainide on the maximal rate of depolarization (Vmax) were compared at different rates of stimulation and at various membrane potentials in ventricular muscle preparations of guinea-pig heart. A standard microelectrode technique was used. The results show that lorcainide and norlorcainide exerted qualitatively similar effects; they both depressed Vmax in a frequency- and potential-dependent way. The following quantitative differences were found: lorcainide was about 50% more potent in depressing Vmax; this difference in potency was observed at 1 and 2 Hz stimulation rates; the block by lorcainide was clearly potential-dependent; in the case of norlorcainide this effect was weak; the onset and removal of block were about twice as fast with lorcainide; the block per action potential was greater with lorcainide. The electrophysiological effects were decreased in the presence of alpha 1-acid glycoprotein, though to a similar extent with both drugs. Taking into account the difference in potency found in the present experiments and the difference in plasma concentration described in the literature, it is concluded that the parent drug and its metabolite both contribute to about the same extent to the in vivo effect of oral treatment with lorcainide.

Topics: Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Blood Proteins; Electric Stimulation; Guinea Pigs; Heart; In Vitro Techniques; Kinetics; Membrane Potentials; Piperidines; Protein Binding

Thirty-eight patients with prior history of cardiac arrest underwent programmed electrical stimulation (PES) studies and serial drug testing. Lorcainide was tested acutely in all 38 patients and prevented ventricular tachycardia (VT) or ventricular fibrillation (VF) induction in 14 patients and failed in 24 (efficacy rate 37%). Procainamide had failed clinically (cardiac arrest or breakthrough VT) in 16 patients, seven patients had previously severe adverse side effects, and thus only 15 were tested on procainamide at PES testing with seven protected. Following initial studies, 14 patients were started on lorcainide oral therapy and 24 on other therapy determined effective at PES testing (N-acetylprocainamide-two, flecainide-nine, bethanidine-three, slow-release procainamide hydrochloride-three, quinidine-two, cibenzoline-one, amiodarone-four). After 29 +/- 7 months follow-up, three are alive on lorcainide therapy, five discontinued therapy due to side effects; six died--three sudden deaths (33%) and two cardiac deaths (both myocardial infarctions). Twenty out of 24 patients are alive who were started on PES predicted effective therapy other than lorcainide; four died--three sudden deaths (13%) and one cardiac nonsudden death. Antiarrhythmic therapy guided by PES studies gives overall encouraging results in a cardiac arrest group of patients. Lorcainide, however, is not tolerated well and affords less protection against a sudden death recurrence than is noted in a population on other antiarrhythmic therapy predicted effective at PES testing.

Topics: Arrhythmias, Cardiac; Benzeneacetamides; Blood Pressure; Cardiac Pacing, Artificial; Electrocardiography; Female; Heart Arrest; Humans; Male; Middle Aged; Piperidines; Procainamide; Recurrence

Chronic premature ventricular complexes (PVCs) have been effectively suppressed by oral lorcainide as reported in previous short-term studies. The plasma level-effect relation of lorcainide may be affected by the possible cardioactivity of norlorcainide, a metabolite that accumulates after repeated oral doses. This study evaluated the long-term efficacy of lorcainide in suppressing chronic symptomatic PVCs, and examined the relation of arrhythmia suppression to plasma concentrations of lorcainide and norlorcainide. Fourteen patients were treated with lorcainide, 200 to 400 mg/day, 12 of whom achieved nearly complete suppression of arrhythmias after treatment for 1 year. Chronic lorcainide treatment was well tolerated; no patient discontinued treatment because of adverse effects. Lorcainide and norlorcainide plasma concentrations remained stable after the first week of therapy. Antiarrhythmic activity persisted throughout the year. Upon drug withdrawal, the mean lorcainide washout half-life was 14.3 +/- 3.7 hours and the mean norlorcainide washout half-life was 31.9 +/- 8.9 hours. The return of arrhythmias occurred well after the lorcainide plasma concentration had decreased to subtherapeutic levels, suggesting an antiarrhythmic effect of norlorcainide. Thus, long-term lorcainide therapy is effective in treating chronic symptomatic PVCs and is well tolerated by most patients. The metabolite norlorcainide appears to have antiarrhythmic activity independent of lorcainide.

Topics: Benzeneacetamides; Cardiac Complexes, Premature; Electrocardiography; Female; Half-Life; Heart Ventricles; Humans; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Lorcainide is an antiarrhythmic drug with unusual pharmacokinetics and an active metabolite, norlorcainide, which complicate oral drug loading. In order to characterize the accumulation of lorcainide and norlorcainide and to define the onset of antiarrhythmic action during lorcainide loading, 9 patients with frequent ventricular ectopic beats were studied. During lorcainide loading with 100 mg orally twice daily, frequent ambulatory electrocardiographic recordings were monitored and blood samples for drug concentrations were determined. There was a 10-fold range of intersubject variation in plasma concentrations. Despite a half-life of only 8.9 +/- 2.3 hours, lorcainide did not reach steady state until after 4.5 days of therapy. Norlorcainide had a half-life of 26.5 +/- 7.2 hours and was estimated to come to steady state after 7 to 10 days. There was considerable intersubject variation in time of onset of antiarrhythmic response (2 to more than 4.5 days) and a 4- to 5-fold range of intersubject variation in threshold therapeutic plasma concentration (lorcainide 40 to 200 ng/ml, norlorcainide 80 to 300 ng/ml). These observations suggest that lorcainide should be started at low doses and the dose should not be increased more frequently than once a week.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Complexes, Premature; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Kinetics; Male; Middle Aged; Piperidines; Sleep Wake Disorders; Time Factors

Lorcainide disposition kinetics were studied after intravenous and oral administration to patients with ventricular arrhythmias. After intravenous doses ranging from 100 to 200 mg, blood samples were drawn and plasma was analyzed for lorcainide concentration by high-pressure liquid chromatography. A three-compartment model was used to fit the data. The model-independent calculated values for clearance, steady-state volume of distribution, and terminal half-life were 14.4 +/- 3.28 ml/min/kg, 6.33 +/- 2.23 l/kg, and 7.8 +/- 2.2 hr. After nine doses of oral lorcainide (100 mg every 12 hr) blood samples were drawn and analyzed for lorcainide and its active metabolite, norlorcainide. The lorcainide and norlorcainide half-lifes were 9.6 +/- 2.8 and 26.8 +/- 8.2 hr. Mean steady-state level of norlorcainide was 2.2 +/- 0.9 times the level of lorcainide. The data suggest that the clearance of lorcainide decreases with time during long-term dosing.

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Female; Half-Life; Humans; Injections, Intravenous; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Topics: Anti-Arrhythmia Agents; Benzeneacetamides; Chromatography, High Pressure Liquid; Humans; Piperidines

Topics: Benzeneacetamides; Chromatography, High Pressure Liquid; Humans; Piperidines; Reference Values