Class IB Antiarrhythmic Agent Research Articles

Aprindine blocks the sodium current in guinea-pig ventricular myocytes.

Aprindine is a class Ib antiarrhythmic agent. We studied effects of aprindine (3 mumol/l) on the Na+ current using whole cell voltage clamp (tip resistance = 0.5 M omega, [Na]i ando = 10 mmol/l at 18 degrees C). Aprindine revealed tonic block (Kdrest = 37.7 mumol/l, Kdi = 0.74 mumol/l; n = 4). Aprindine, shifted inactivation curve to hyperpolarizing direction by 11.4 +/- 3.5 mV (n = 4) without changes in slope factor. In the presence of 3 mumol/l aprindine, aprindine showed phasic block, i.e., duration-dependent block at 2 Hz (64% +/- 3% at 1.5 ms, 82% +/- 6% at 20 ms, 93% +/- 7% at 200 ms; n = 4). Short single prepulse also produced aprindine-induced phasic block (12% at 1.5 ms, 22% at 100 ms; n = 2). After removal of fast inactivation of Na+ current by 3 mmol/l tosylchloramide sodium, aprindine revealed phasic block, independent of holding potential. The recovery time constant from aprindine-induced phasic block was 4.8 s at holding potential = -100 mV and 5.0 s at holding potential = -140 mV. This use-dependent block of aprindine had pH dependency. Under acidic condition (pH 6.0), 3 mumol/l aprindine showed smaller use-dependent block (14% +/- 7% at 2 Hz; n = 4) comparing with either at pH 7.4 (68% +/- 13%; n = 4) or at pH 8.0 (90% +/- 12%; n = 4). The results suggest that aprindine could bind to the receptor via activation process through channel pore, resulting in decrease of Na+ current, and egress from the receptor through the lipid bilayer. These effects might be attenuated under acidic condition due to changes in intracellular ratio of charged to neutralized form of drug molecule.

Antiarrhythmic actions of tocainide in canine models of previous myocardial infarction

The antiarrhythmic and antifibrillatory efficacies of the class IB antiarrhythmic agent tocainide were characterized in conscious dogs in the early subacute phase of anterior myocardial infarction (48 hours after infarction) and in anesthetized dogs with ventricular tachyarrhythmias that were inducible by programmed stimulation more chronically (10.8 ± 1.0 days) after anterior myocardial infarction. The frequency of spontaneous premature ventricular complexes in the early subacute postinfarction phase was reduced significantly from 48.4% ± 10.5% to 8.2% ± 5.0% of total complexes ( p < 0.01) by the cumulative intravenous administration of 10 mg/kg tocainide. In the late postinfarction setting, the intravenous administration of tocainide (6 mg/kg intravenous loading dose + 100 μg/kg/min intravenous maintenance infusion) suppressed the initiation of ventricular tachyarrhythmias by programmed stimulation in 5 of 12 animals that were tested and slowed the rate of tachycardia in 3 additional animals. However, the incidence of ventricular fibrillation and of the total number of arrhythmia-related deaths that resulted from the occurrence of a secondary ischemic insult in the presence of previous infarction did not differ significantly between tocainide (75% [9 of 12] incidence of both ventricular fibrillation and of total number of arrhythmia-related deaths) and saline-vehicle control groups (80% [12 of 15] incidence of ventricular fibrillation; 93,3% [14 of 15] incidence of total number of arrhythmia-related deaths). These findings suggest that although class I agents such as tocainide may be efficacious in the suppression of spontaneous premature ventricular complexes and ventricular arrhythmias immediately after myocardial infarction, they may be of limited value in the prevention of malignant ischemic arrhythmias that occur later after myocardial infarction.

Efficacy and tolerance of the new class IB antiarrhythmic barucainide: An intravenous dose-finding study

Barucainide is a new class IB antiarrhythmic agent that was studied for efficacy and safety after intravenous administration in patients with severe ventricular arrhythmias. All patients received 80 mg/hr barucainide intravenously for 7 hours or until ventricular arrhythmias were suppressed by greater than 90%. In responders a maintenance dose was given for 24 hours, aimed to achieve steady-state conditions. At baseline and during the treatment and washout periods 24-hour Holter recordings were performed. In addition, electrocardiogram, blood pressure, and plasma concentration of barucainide were measured. In 9 of 12 patients dose titration was effective (mean dose, 185 mg). In six of nine patients arrhythmia suppression persisted during maintenance therapy (mean dose, 18 mg/hr). Plasma concentrations correlated with given doses, rather than with antiarrhythmic efficacy. During the washout period, five patients required more than 12 hours for recurrence of arrhythmias. Treatment was stopped in one patient because of proarrhythmia; one patient had moderate heat sensations. Thus barucainide is a potent class IB agent, with a favorable side effect profile.

Barucainide, a novel class Ib antiarrhythmic agent with a slow kinetic property: Electrophysiologic observations in isolated canine and rabbit cardiac muscle

Electrophysiologic effects of barucainide hydrochloride on the transmembrane potentials of isolated canine and rabbit cardiac muscle were investigated by means of a standard microelectrode technique. Barucainide (10(-6) to 3.0 x 10(-5) mol/L) produced concentration-dependent inhibition of the maximum upstroke velocity (Vmax) in canine Purkinje fibers and ventricular muscle. Tonic block of Vmax was small and negligible. Barucainide produced marked use-dependent block (UDB). The onset rate of UDB and the speed of recovery from UDB were comparable to those of disopyramide. The recovery time constant was 8.0 +/- 0.8 seconds. Membrane depolarization induced by high concentrations of potassium enhanced the inhibitory action of barucainide on Vmax. The enhancement of tonic block was much greater than that of UDB indicating a selective effectiveness of the drug in pathologically depolarized tissues. Barucainide produced marked shortening of the action potential duration (APD), which indicates that barucainide exerts class Ib antiarrhythmic effects. Such shortening effects on the APD were not affected by pretreatment with 1 mmol/L cobalt or with 0.5 mmol/L 4-aminopyridine. In contrast, barucainide had no marked effects on the APD in the presence of 4.0 x 10(-5) mol/L lidocaine, although it produced almost the same extent of Vmax inhibition as did barucainide alone. Frequency of the pacemaker activity in the rabbit sinoatrial tissue and of the automaticity at normal resting potential in Purkinje fibers enhanced by 2.0 X 10(-6) mol/L isoproterenol were significantly suppressed by barucainide. However, barucainide up to 3.0 x 10(-5) mol/L failed to suppress the firing frequency of the abnormal automaticity in canine Purkinje fibers induced by 5 mmol/L barium. These overall findings indicate that barucainide is a novel class Ib antiarrhythmic agent which, unlike other Ib agents, has a slow kinetic property. However, the precise significance of this unique electrophysiologic feature with respect to the antiarrhythmic action of the drug is not known but provides the basis for understanding the relationship of electrophysiologic effects of barucainide in vitro and its potential antiarrhythmic actions in experimental animals and in humans.

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Electrophysiological Effects of GYKI-23 107, a New Antiarrhythmic Compound, in Isolated Rabbit and Canine Cardiac Preparations

The cellular cardiac electrophysiological effects of GYKI-23 107 (1-/2,6-dimethylamino/-2-dimethylaminopropane dihydrochloride), a new investigational antiarrhythmic drug, were studied in rabbit and canine ventricular muscle and Purkinje fibers. For comparison, mexiletine was used. GYKI-23 107, like mexiletine, did not affect the resting membrane potential and slightly reduced the action potential amplitude in both fiber types. The time for repolarization was shortened, but the ratio of effective refractory period to action potential duration was increased by both drugs. The maximum rate of depolarization (Vmax) was depressed by the drugs in a frequency-dependent ("use-dependent") manner. GYKI-23 107 slowed the recovery kinetics of Vmax in the canine ventricular muscle (Tc = 229.9 +/- 5.6 ms; n = 7) and Purkinje fiber (Tc = 149.6 +/- 33.8 ms; n = 7) in the same way as mexiletine. The kinetics of restitution of action potential duration during premature and postmature stimulation were slowed to similar degrees in the presence of both GYKI-23 107 and mexiletine in canine Purkinje fibers. It is concluded that, on the basis of its cardiac cellular electrophysiological effects, GYKI-23 107 can be categorized as a class Ib antiarrhythmic agent.

Effects of Tocainide Enantiomers on Experimental Arrhythmias Produced by Programmed Electrical Stimulation

Summary: The enantiomers of tocainide, a Class Ib antiarrhythmic agent, have recently been shown to exhibit differences in antiarrhythmic activity and pharmacokinetic characteristics. The present study examined the antiarrhythmic and electrophysiological effects of SR tocainide, S tocainide, and R tocainide on arrhythmias in a conscious canine arrhythmia model and compared the results with placebo. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious dogs, 7-30 days after coronary artery ligation. Each treatment was assessed for its ability to abolish sustained ventricular tachycardia, prevent nonsustained ventricular tachycardia, and protect against death (ventricular fibrillation), in groups of six dogs. In the placebo group, arrhythmias in four of six dogs remained unchanged, and two dogs died. SR tocainide prevented the arrhythmia in three of six dogs (mean effective dose, 21.3 mg/kg), one remained unchanged, and two died. S tocainide prevented the arrhythmia in four of six dogs (mean effective dose, 7.1 mg/kg), one remained unchanged, and one died (p < 0.05 compared with placebo). R tocainide prevented the arrhythmia in five of six dogs (mean effective dose, 9.0 mg/kg), one remained unchanged, and none died (p < 0.01 compared with placebo). PR intervals, QRS durations, and corrected QT intervals were unaffected by any treatment and there was no change in effective or functional refractory periods. These results indicate that the enantiomers of tocainide are more effective than the racemic mixture in abolishing ventricular arrhythmias and in preventing death in this model; no additive antiarrhythmic effect occurs with the racemic mixture, and adverse effects may be potentiated.

Effects of Tocainide Enantiomers on Experimental Arrhythmias Produced by Programmed Electrical Stimulation

The enantiomers of tocainide, a Class Ib antiarrhythmic agent, have recently been shown to exhibit differences in antiarrhythmic activity and pharmacokinetic characteristics. The present study examined the antiarrhythmic and electrophysiological effects of SR tocainide, S tocainide, and R tocainide on arrhythmias in a conscious canine arrhythmia model and compared the results with placebo. Using up to three extrastimuli, programmed electrical stimulation was performed in conscious dogs, 7-30 days after coronary artery ligation. Each treatment was assessed for its ability to abolish sustained ventricular tachycardia, prevent nonsustained ventricular tachycardia, and protect against death (ventricular fibrillation), in groups of six dogs. In the placebo group, arrhythmias in four of six dogs remained unchanged, and two dogs died. SR tocainide prevented the arrhythmia in three of six dogs (mean effective dose, 21.3 mg/kg), one remained unchanged, and two died. S tocainide prevented the arrhythmia in four of six dogs (mean effective dose, 7.1 mg/kg), one remained unchanged, and one died (p less than 0.05 compared with placebo). R tocainide prevented the arrhythmia in five of six dogs (mean effective dose, 9.0 mg/kg), one remained unchanged, and none died (p less than 0.01 compared with placebo). PR intervals, QRS durations, and corrected QT intervals were unaffected by any treatment and there was no change in effective or functional refractory periods. These results indicate that the enantiomers of tocainide are more effective than the racemic mixture in abolishing ventricular arrhythmias and in preventing death in this model; no additive antiarrhythmic effect occurs with the racemic mixture, and adverse effects may be potentiated.

Effects of procainamide and lidocaine on electrically inducible ventricular tachycardia studied with programmed ventricular stimulation in post myocardial infarction.

The effects of procainamide and lidocaine, representative of class IA and IB antiarrhythmic agents, on electrically inducible ventricular tachycardia (VT) were studied using programmed ventricular stimulation in 47 post myocardial infarction patients at an average of 1.5 months after the onset. The mean doses of administered procainamide and lidocaine were 1050 mg and 161 mg, and their mean plasma concentrations were 7.5 micrograms/ml and 3.1 micrograms/ml respectively. The induction of sustained VT was suppressed in 15 of 29 patients (52%) by procainamide, but in none by lidocaine. The induction of nonsustained VT was suppressed in 6 of 18 patients (33%) by procainamide, and in 1 of 8 patients (13%) by lidocaine. The efficacy rate of procainamide was significantly higher than that of lidocaine in suppression of VT induction (21/47 vs 1/14 p less than 0.01). Procainamide significantly prolonged the effective refractory period of the right ventricle as well as the HV and QRS interval, however lidocaine did not affect them significantly. On the other hand, the worsening effect which changed nonsustained VT inducible in the baseline into sustained VT inducible post drug administration was demonstrated in 8 of 18 procainamide cases (44%), and in 3 of 8 lidocaine cases (38%). Between the procainamide effective and ineffective or worsening patients, there were no differences found in the electrophysiologic variables either in the baseline or post procainamide administration. We concluded that procainamide was more effective than lidocaine for the prevention of potential life-threatening VT induction in post myocardial infarction patients, although its efficacy was considerably limited, and to confirm the effectiveness and exclude the worsening effects of the class IA and IB antiarrhythmic agents, drug testing using programmed ventricular stimulation appeared to be valuable.

Clinical significance of vanghan williams classification for treatment of ventricular tachycardia. Study of class IA and IB antiarrhythmic agents.

Ninety-eight cases of ventricular tachycardia (VT) were studied using clinical electrophysiological (EP)-pharmacological assessment to compare the efficacy of class IA (disopyramide-DP, procainamide-PA) and class IB (mexiletine-Mex, Lidocaine-Lid, aprindine-AP) agents available in Japan, and to evaluate the clinical significance of class subdivisions for the treatment of VT. In assessing the efficacy of drugs, we evaluated their ability to prevent and terminate induced sustained VT as well as their ability to suppress spontaneous premature ventricular beats (VPB). I. EP properties: DP significantly extended QTc, ERPRV, and the coupling interval by which VT or repetitive ventricular response (RVR) was induced. On the other hand, Mex and AP had no effect. Although no significant extension of QRS width was found, the significant extension of the interval from extrastimulus to the first induced VT or RVR complex by the three drugs indicates that all have suppressive effects on conduction velocity within the reentry circuit. II. Correspondence of preventive effects was 67% for DP and PA (class IA), 54% for Mex and Lid (class IB), 55% for DP and Mex, 27% for AP and Mex, and 25% for AP and DP. Correspondence of terminating effect was 85% for DP and PA, 80% for DP and AP, 77% for DP and Mex, 75% for Mex and Lid, and 63% for Mex and AP. For suppression of spontaneous VPB's, correspondence rate was 100% for DP and PA, 39% for DP and Mex, 64% for Mex and Lid, 61% for Mex and AP, and 69% for DP and AP.(ABSTRACT TRUNCATED AT 250 WORDS)

Tocainide pharmacokinetics during continuous ambulatory peritoneal dialysis

Tocainide hydrochloride is a class IB antiarrhythmic agent that has a long duration of action and a narrow therapeutic to toxic ratio. Although tocainide resembles lidocaine structurally, it differs in potency, lipophilicity, metabolism and pharmacokinetic profile. Tocainide is almost completely absorbed after oral administration and has a bioavailability approaching 100%. 1 It is both metabolized and excreted unchanged by the kidney. The metabolites do not exert cardioprotective or cardiotoxic effects. 2 In patients with normal renal function, the biologic half-life of tocainide is about 15 hours. 1 However, in patients with end-stage renal disease, the half-life is prolonged to approximately 23 hours. 3 Hemodialysis removes about 25% of tocainide from the body, decreasing the half-life to about 5 hours. 3 Nonrenal elimination of tocainide in end-stage renal disease appears unaffected. 3 The effect of continuous ambulatory peritoneal dialysis (CAPD) on the elimination of tocainide is unknown. This study examined selected tocainide pharmacokinetic variables in patients undergoing routine CAPD.

Efficacy of class Ib (lidocaine-like) antiarrhythmic agents for prevention of sustained ventricular tachycardia secondary to coronary artery disease

The effects of lidocaine, tocainide and mexiletine were examined in 17 patients with coronary artery disease and chronic, recurrent, sustained ventricular tachycardia (VT) or ventricular fibrillation and inducible VT. Eleven patients presented with sustained VT; 6 patients had had an episode of sudden death from which they had been resuscitated. All patients were refractory to conventional antiarrhythmic agents. Lidocaine prevented induction of VT in only 3 patients (18%). Tocainide prevented induction of VT in only 1 lidocaine-responsive patient. Mexiletine prevented VT induction in 1 patient who had responded to lidocaine but not tocainide. Neither tocainide nor mexiletine was effective in preventing induction of VT in any patient who did not respond to lidocaine. Lidocaine terminated VT in 3 patients, but this did not predict noninducibility with lidocaine, tocainide or mexiletine. Cycle length of VT was prolonged slightly by lidocaine (control 311 ± 14 ms, lidocaine 361 ± 26 ms, p < 0.05), tocainide (344 ± 16 ms, p < 0.05) and mexiletine (371 ± 27 ms, mean ± standard error of the mean, p < 0.05). Thus, class lb agents are infrequently effective in preventing induction of VT in this group of patients, electrophysiologic inefficacy of lidocaine is highly predictive of continued inducibility with tocainide and mexiletine, and termination of VT with lidocaine does not correlate with its ability to prevent VT induction.

Mexiletine: Its Role in the Management of Chronic Ventricular Arrhythmias

Mexiletine is a class IB anti arrhythmic agent structurally similar to lidocaine but with the advantage of a high bioavailability and relatively long half‐life, making it useful for long‐term oral therapy of ventricular arrhythmias. Mexiletine can be used orally or intravenously. Orally, it has a high bioavailability, reaching peak plasma concentration between 2 and 4 hours after administration. The steady‐state therapeutic plasma concentration ranges from 0.5 to 2.5 fig/ml. These levels are obtained by doses of 200–300 mg every 6–8 hours. It is mostly metabolized by the liver and its metabolism and excretion are not significantly affected by renal failure. Mexiletine has very few deleterious drug interactions; more importantly, it does not affect digoxin blood levels. Its efficacy in controlling ventricular arrhythmias has been widely studied. The reported success rate varies from 84% to 52%. In our study of patients with symptomatic and refractory ventricular arrhythmias, the success rate with mexiletine was 55% initially and 33% at one year. Mexiletine appears to be most useful in combination with other anti arrhythmic agents such as propranolol, quinidine, procainamide, or amiodarone. Mexiletine has very few cardiac side effects. It was found not to have significant negative inotropic effects even in patients with congestive heart failure. Its major side effects, however, include gastric intolerance. Other less common side effects include central nervous system manifestations. Like all other antiarrhythmics, it can potentially aggravate ventricular arrhythmias in about 10% of patients but in most cases the proarrhythmic effect is not Clin cally significant.

Efficacy of the antidepressant iprindole against experimental arrhythmias

The antiarrhythmic activity of iprindole was compared to that of imipramine in a variety of experimental arrhythmia models. Iprindole at 20 mg/kg i.v. showed efficacy in reverting ouabain- and aconitine-induced arrhythmias in pentobarbital anesthetized dogs, and at 15–30 mg/kg i.v. reduced the severity of the ventricular arrhythmias following acute coronary artery occlusion in anesthetized pigs. Imipramine (5–10 mg/kg i.v.) was also effective in reverting ouabain- and aconitine-induced arrhythmias, but appeared to exacerbate arrhythmias during coronary occlusion. In microelectrode experiments on isolated dog Purkinje fibers, iprindole reduced maximal upstroke velocity (V̇ max) and action potential duration (characteristics of Class Ib antiarrhythmic agents) at concentrations greater than 1 μg/ml. Significant decreases in V̇ max occurred at lower iprindole concentrations when membrane potential was reduced by increasing external potassium from 4 to 10 mM, suggesting that electrical activity in depolarized cells may be selectively suppressed by iprindole. The present data indicate that iprindole may exert beneficial therapeutic effects in the treatment of cardiac arrhythmias, mediated, at least in part, through a Class I mechanism of action.