The Comparative Antiarrhythmic Actions of Lidocaine and its Quarternary Derivative, Methyl Lidocaine

Abstract

SUMMARYLidocaine has proved to be an effective antiarrhythmic agent in the management of ventricular arrhythmias subsequent to acute myocardial infarction. Lidocaine's short duration of action and its propensity for producing central nervous system (CNS) stimulation suggest that a safer and more effective therapeutic agent, based on a modification of the lidocaine structure, might be found. The quaternary ammonium compound, methyl lidocaine, was synthesized and its actions in experimentally-induced arrhythrnias were studied and compared to those of lidocaine. The antiarrhythmic effects of lidocaine and methyl lidocaine were examined in the anesthetized dog against ouabain-induced ventricular tachycardia and in conscious animals with ventricular tachycardia 48 hours after two-stage ligation of the anterior descending coronary artery. Both pharmacological agents were capable of reversing digitalis-induced arrhythmias and restoring normal sinus rhythm in animals 48 hours after surgical ligation of the anterior descending coronary artery, but methyl lidocaine remained effective for a significantly longer period and its continual administration was not associated with signs of CNS toxicity. In experiments designed to determine the electrical fibrillation threshold, both drugs were able to reduce the vulnerability to ventricular fibrillation but the time course of action for each drug differed. Lidocaine had an immediate effect of increasing the ventricular fibrillation threshold whereas the peak effect of methyl lidocaine was delayed and the increase in the fibrillation threshold lasted longer. This study con-

Electrophysiologic and Antiarrhythmic Actions of Sulphinpyrazone and Its Sulfide Metabolite G25671

“…It is noteworthy that the increases in the 'nonischemic' VFT value (+24%) and in the ventricular excitation threshold (+36%) in the latter study [Raeder et al, 1982] do not differ markedly from the small increases in these parameters noted with sul-phinpyrazone in the present study. Increases of this magnitude, particularly for the ven tricular fibrillation thresholds, were not found to be statistically significant by analy sis of variance in this study, and do not com pare favorably with the increases in VFT pro duced by reference standards such as Iidocaine [Kniffen et al, 1974], bretylium [Kniffen et al, 1975] and various beta-adrenergic receptor antagonists [Patterson and Lucchcsi, 1983] which have been evaluated in this laboratory using identical methods.…”

A Preclinical Study ofEO-122, a New Lidocaine- Like Antiarrhythmic Drug

“…No special effort was made at this stage to optimize the absorption of EO-122, but it has been demonstrated that more than 80% of the ingested dose could be accounted for in the circulation of healthy dogs. But whereas the antiarrhythmic effect of a 100 mg/kg oral dose of tocainide was shown to last 0.25 to 5 hours when treatment was given 48 hours postligation, that of an oral dose of EO-122 in the range of [15][16][17][18][19][20] mg/kg lasted about 20 minutes when treatment was given 24 hours after ligation and 2 hours when given 48 hours postligation. Thus the relatively short t1f2 of EO-122 with respect to tocainide is not necessarily a shortcoming when oral medication is called for, since it appears to be partly compensated for by the higher potency of EO-22.…”

“…The effect of EO-122 on normal hearts was determined by administering the compound as a bolus IV injection to 5 conscious, healthy mongrel dogs of both sexes weighing [15][16][17][18][19][20] kg. In the animals lead II of the ECG was monitored for as long as 2 hours after injection.…”

Antiarrhythmic and Arrhythmogenic Actions of Methyl Lidocaine during the Recovery Phase after Canine Myocardial Infarction

“…Both compounds termi nate ouabain-induced ventricular ectopia [Kniffen et al 1974] and spontaneous multi form ventricular rhythms present 24 or 28 h after experimental anterior descending coro nary artery occlusion [Gillis et al, 1973;Kniffen et al, 1974], Both compounds in crease the electrical threshold for the induc tion of ventricular fibrillation in the anesthe tized dog [Kniffen et al, 1974]. The quater nary compound, however, may possess ma jor therapeutic advantages.…”