SC-36602, a new antiarrhythmic agent: comparison of its cardiovascular profile with that of other antiarrhythmic drugs

The cardiovascular profile of SC-36602, a new class 1A/1B antiarrhythmic agent, was compared to those of disopyramide, lidocaine, mexiletine, flecainide, encainide, lorcainide, and quinidine. These drugs were compared at their respective canine antiarrhythmic doses in a hemodynamic evaluation using anesthetized dogs. In another test using anesthetized dogs, the cardiovascular effects of cumulative doses of SC-36602 were assessed. The direct negative inotropic potential of each drug was also determined using isolated cat papillary muscles. In the hemodynamic study, SC-36602 and quinidine did not cause significant myocardial depression, measured as a decrease in the maximal first derivative of the left ventricular pressure. (Heart rate and diastolic filling pressure were not controlled in order to mimic clinical conditions). SC-36602, mexiletine, flecainide, and quinidine increased heart rate. SC-36602 and mexiletine caused a small increase in mean arterial pressure, whereas disopyramide and quinidine decreased it. Disopyramide was the only drug studied that increased left ventricular end-diastolic pressure. SC-36602, quinidine, and mexiletine increased index of cardiac effort. Disopyramide caused a decrease in the latter. Disopyramide, flecainide, encainide, and lorcainide lengthened the ECG intervals. Cumulative intravenous doses of SC-36602 up to 50 mg/kg produced significant decreases in mean arterial pressure, increases in heart rate, and increases in P-R and QRS intervals of the ECG relative to placebo-matched controls. SC-36602 had the least direct negative inotropic action of the drugs studied, as measured in isolated papillary muscles. These data suggest SC-36602, when compared to the other antiarrhythmic drugs studied, has the least amount of hemodynamic side-effects at its antiarrhythmic dose.     

Canine plasma concentration-cardiovascular effect relationships for bidisomide,a new antiarrhythmic drug,and disopyramide,cibenzoline, and propafenone

Bidisomide (SC-40230) is a unique new antiarrhythmic agent. In this study the canine intravenous (i.v.) antiarrhythmic doses of bidisomide (9 ± 1 mg/kg), disopyramide (8 ± 1 mg/kg), cibenzoline (8 ± 2 mg/kg), and propafenone (6 ± 0.5 mg/kg) were established in a 24 h coronary ligation ventricular arrhythmia model. Based on the canine therapeutic doses of the four agents, three cumulative i.v. doses (load/maintenance infusions) of each of these drugs and placebo were then studied in normal anesthetized dogs to evaluate their general cardiovascular effects. Propafenone (0.7–3.0 μg/ml plasma concentration) caused potent reductions in cardiac output and increases in QRS duration relative to the other agents. Cibenzoline (0.9–7.0 μg/ml) and disopyramide (1.4–12.9 μg/ml), at matched plasma concentrations, caused very similar cardiac output reductions, but cibenzoline caused nearly double the QRS increase. Bidisomide (1.9–16.1 μg/ml) had the least potent effects on cardiac output and QRS duration. All four drugs increased PR and QT in addition to QRS, but only disopyramide and propafenone increased JT (QT-QRS). These experiments suggest that the antiarrhythmic plasma concentrations of bidisomide, in contrast to those of selected reference agents, do not cause prominent ventricular conduction slowing or prolongation of ventricular repolarization, and in addition, cause only modest hemodynamic effects in normal dogs. © 1995 Wiley-Liss, Inc.     

Pharmacodynamics and pharmacokinetics of disopyramide phosphate

Based on pharmacodynamic and pharmacokinetic studies in 42 patients with paroxysmal and extrasystolic abnormalities of the rhythm it was established that disopyramide phosphate (ritmilen) is an effective antiarrhythmic agent for atrial fibrillation paroxysms. The drug exerts negative, chronotropic, dromotropic and inotropic effects, especially upon intravenous injections for removal of atrial fibrillatin paroxysms. Ritmilen moderately reduces the blood pressure. When used for removal of atrial fibrillation paroxysms ritmilen is effective in doses of 1.2-1.7 mg/kg intravenously and in doses of 2.5-3.8 mg/kg per os. In patients with chronic ventricular premature heart beat the single effective drug doses amount to 0.61-1.7 mg/kg. After oral use the ritmilen concentration in blood plasma is lower than after intravenous use in adequate doses. No relationship has been found between the drug antiarrhythmic effect and blood plasma concentration.     

Assessment of drug effects on spontaneous and induced ventricular arrhythmias in a 24-h canine infarction model

The antiarrhythmic efficacy of encainide, sotalol, flecainide and disopyramide was evaluated in anesthetized dogs subjected to 2-stage total occlusion of the left anterior descending coronary artery. Utilization of this canine model, while anesthetized, permitted the assessment of drug effects not only on uni- and/or multi-focal ectopic ventricular arrhythmias, but also on dysrhythmias associated with aberrant conduction or reentrant excitation pathways. The former was assessed by quantification of ectopic-to-total beat ratios while the later was determined by subjecting the animal to provocative stimuli which produced repetitive ventricular responses. At the cumulative i.v. doses studied, encainide (0.5-4 mg/kg), flecainide (1-8 mg/kg) and disopyramide (0.3-10 mg/kg), but not sotalol (2-8 mg/kg), effectively suppressed ventricular ectopic activity in a dose-related manner. In contrast, sotalol was highly effective in preventing the induction of reentrant ventricular tachyarrhythmias. Disopyramide was only modestly active, while flecainide and encainide had the least favorable profiles of effect in suppressing re-entry arrhythmias in this model. Based on these observations, the anesthetized Harris dog appears to represent a useful two-faceted in vivo model for use in the evaluation of potential antiarrhythmic agents.     

Comparison of anticholinergic effects of cibenzoline, disopyramide, and atropine.

The anticholinergic effects of cibenzoline, disopyramide, and atropine were compared on experimental models. Using inhibition of specific binding of 3H-quinuclidinyl benzylate (3H-QNB) in rat heart and cerebral cortex, Ki values were 15.8 +/- 1.6, 12 +/- 3.5, and 0.013 +/- 0.001 microM, respectively, for heart membranes and 31.6 +/- 1.5, 7.8 +/- 1.3, and 0.006 +/- 0.001 microM, respectively, for cerebral cortex membranes. In isolated guinea pig ileum, disopyramide was about 15 times more anticholinergic than cibenzoline but about 900 times less so than atropine. In anesthetized dogs, the three drugs administered by intravenous bolus reduced bradycardia caused by vagal stimulation. The effect of cibenzoline at 7 mg/kg i.v. (double the antiarrhythmic dose) was approximately the same as that of disopyramide at 2.5 mg/kg (half the antiarrhythmic dose). The drugs were infused for 1 h at 0.17 mg/kg/h for atropine, 11.6 mg/kg/h for disopyramide, and 5.5 mg/kg/h for cibenzoline. The maximal inhibition of the vagal stimulation was 98, 95, and 52%, respectively, for the three drugs. In nonanesthetized dogs, inhibition of the vagal-tone-induced tachycardia reached 33 +/- 4, 134 +/- 20, and 206 +/- 19% for cibenzoline, disopyramide and atropine, respectively. These results show cibenzoline to exert less potent anticholinergic effects than disopyramide.     

Comparative hemodynamic effects of Org 7797, flecainide, and propafenone in anesthetized pigs with developing myocardial infarcts.

The hemodynamic effects of a new Ic antiarrhythmic agent (Org 7797) were compared with those of flecainide and propafenone in anesthetized pigs with developing myocardial infarcts. One hour after acute coronary artery occlusion, the only significant hemodynamic effect of an intravenous (i.v.) dose of Org 7797 (0.5 mg/kg) known to prevent ischemia-induced ventricular fibrillation (VF) in dogs was a decrease in heart rate (HR) (of 3%) while cardiac output (CO), stroke volume (SV), and left ventricular (LV) dP/dtP-1 were unchanged. At four times this dose, the only sustained and significant responses to Org 7797 were decreased CO and bradycardia, whereas decreases in arterial and LV pressures (BP and LVP) and LVdP/dtP-1 were transient. In contrast, a therapeutic dose of flecainide (2 mg/kg) induced sustained reductions in CO, SV, LVdP/dtP-1, and LVP whereas a similar (therapeutic) dose of propafenone decreased LVP, reduced CO partly as a result of bradycardia and decreased LVdP/dtP-1 but not sufficiently to decrease SV. Two electrical deaths occurred in each of the propafenone (n = 6) and flecainide (n = 7) groups, but arrhythmic deaths did not occur in Org 7797- or saline-treated animals. We conclude that Org 7797 in therapeutic doses, unlike propafenone and especially flecainide, is not cardiodepressant in animals whose cardiac function is already compromised. In addition, there was no evidence of proarrhythmogenicity at the doses of Org 7797 used.     

Hemodynamic effects of penticainide (CM 7857), a novel class I antiarrhythmic drug--comparison with disopyramide

Penticainide (CM 7857) is a new class I antiarrhythmic agent, which has been shown to suppress ventricular arrhythmias by a specific effect on repolarization, shortening the action potential duration. To assess acute hemodynamic effects of penticainide and to compare them to those of disopyramide, 20 patients with normal left ventricular function were studied by simultaneous left and right heart catheterization before as well as 5 and 30 min after intravenous drug administration (1.5 mg/kg for both compounds) in a randomized fashion. After penticainide, a maximal negative inotropic effect was noted at the end of the 5 min infusion, as reflected by reductions in stroke index and parameters of contractility despite increases in vascular resistances. These changes returned to baseline after 30 min except for ejection fraction, which was still lower than at baseline. After disopyramide, similar hemodynamic drug effects were observed that were greater than after penticainide, leading to a moderate tachycardia immediately after drug infusion. In addition, all parameters of contractility as well as stroke index were still significantly reduced 30 min after disopyramide, but not after penticainide. Thus, the hemodynamic profiles of both drugs tested were similar, but the negative inotropic effect of penticainide was less marked and of shorter duration than that of disopyramide in an equipotent antiarrhythmic dose. Penticainide may therefore be used in treatment of acute ventricular arrhythmias, but it should be administered with caution in patients with depressed left ventricular function.     

Impact of stereoselectivity on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs

Many antiarrhythmic drugs introduced into the market during the past three decades have a chiral centre in their structure and are marketed as racemates. Most of these agents, including disopyramide, encainide, flecainide, mexiletine, propafenone and tocainide, belong to class I antiarrhythmics, whereas verapamil is a class IV antiarrhythmic agent. Except for encainide and flecainide, there is substantial stereoselectivity in one or more of the pharmacological actions of chiral antiarrhythmics, with the activity of enantiomers differing by as much as 100-fold or more for some of these drugs. The absorption of chiral antiarrhythmics appears to be nonstereoselective. However, their distribution, metabolism and renal excretion usually favour one enantiomer versus the other. In terms of distribution, plasma protein binding is stereoselective for most of these drugs, resulting in up to two-fold differences between the enantiomers in their unbound fractions in plasma and volume of distribution. For disopyramide, stereoselective plasma protein binding is further complicated by nonlinearity in the binding at therapeutic concentrations. Hepatic metabolism plays a significant role in the elimination of these antiarrhythmics, accounting for >90% of the elimination of mexiletine, propafenone and verapamil. Additionally, in most cases, significant stereoselectivity is observed in different pathways of metabolism of these drugs. For some drugs, such as propafenone and verapamil, the stereoselectivity in metabolism is further complicated by nonlinearity in one or more of the metabolic pathways. Further, the metabolism of a number of chiral antiarrhythmics, such as mexiletine, propafenone, encainide and flecainide, cosegregates with debrisoquine/sparteine hydroxylation phenotype. Therefore, it is not surprising that a wide interindividual variability exists in the metabolism of these drugs. Excretion of the unchanged enantiomers in urine is an important pathway for the elimination of disopyramide, flecainide and tocainide. The renal clearances of both disopyramide and flecainide exceed the filtration rate for these drugs, suggesting the involvement of active tubular secretion. However, the stereoselectivity in the renal clearance of these drugs, if any, is minimal. Similarly, there is no stereoselectivity in the renal clearance of tocainide, a drug that undergoes tubular reabsorption in addition to glomerular filtration. Overall, substantial stereoselectivity has been observed in both the pharmacokinetics and pharmacodynamics of chiral antiarrhythmic agents. Because the effects of these drugs are related to their plasma concentrations, this information is of special clinical relevance.     

Rapid infusions of bidisomide or disopyramide in conscious dogs: effect of myocardial infarction on acute tolerability.

The acute tolerability of rapid infusions of bidisomide or disopyramide was evaluated in normal conscious dogs and in conscious dogs 48 h after the creation of myocardial infarctions (MIs). Both drugs were given in total doses of 15 mg/kg (1.5 x the canine antiarrhythmic dose for each drug). Bidisomide was well tolerated at infusion rates of 3, 5, 11, and 15 mg/kg/min by normal dogs. Disopyramide was well tolerated, except for anticholinergic effects, by normal dogs given infusions at rates of 1.5 and 3 mg/kg/min. Disopyramide caused a ventricular arrhythmia at 4.5 mg/kg/min in one dog, however. Bidisomide (15 mg/kg/min) was well tolerated and antiarrhythmic in dogs with infarctions. Disopyramide (3 and 4.5 mg/kg/min) was lethal in dogs that had myocardial infarctions. A 1 mg/kg/min infusion rate of disopyramide was antiarrhythmic and well tolerated, except for anticholinergic effects, in the post-MI dogs. Both drugs prolonged the ECG lead II P duration, PR interval (bidisomide more so than disopyramide), and QRS duration. Both bidisomide and disopyramide shifted the mean electrical axis of the QRS complex from a right axis deviation to the normal range in dogs with infarctions. The data indicated that the desired cardiac electropharmacologic effects of bidisomide can be achieved in a 1 min infusion. Normal dogs, and especially dogs with infarctions, revealed the potential hazards of rapidly infusing disopyramide.     

Acute haemodynamic effects of ibopamine and dopamine on isovolumic relaxation

The effects of intraduodenal ibopamine (a new orally active inotropic agent claimed to have haemodynamic effects similar to dopamine) on isovolumic relaxation were monitored for 90 min in eight closed-chest anaesthetized dogs. Dopamine and epinine (ibopamine active metabolite) were also infused at graded doses. After 15 min, ibopamine (12 mg/kg) shortened the time constant of isovolumic relaxation, and increased stroke volume and mean aortic pressure. Peak positive dP/dt increased significantly only 10 min later. Heart rate did not change. Dopamine (10 micrograms/kg per min) similarly reduced the time constant, and increased stroke volume, mean aortic pressure, peak positive dP/dt and heart rate. Epinine (10 micrograms/kg per min) caused similar changes in peak positive dP/dt, stroke volume, mean aortic pressure, and accelerated time constant without raising the heart rate. Ibopamine and epinine therefore significantly improved the isovolumic relaxation phase, like dopamine, without however affecting the heart rate.     

Comparison of the in vivo hemodynamic effects of the antiarrhythmic agents vernakalant and flecainide in a rat hindlimb perfusion model

A series of in vivo experiments were conducted to compare the hemodynamic actions of vernakalant (a novel, relatively atrial selective, antiarrhythmic drug) to flecainide after infusion into the peripheral vasculature. Anesthetized rats were surgically prepared to have an extracorporeal perfusion circuit whereby blood in the abdominal aorta (distal to the renal arteries) was diverted to a constant flow pump and returned to the abdominal aorta at the same level allowing measurement of hindlimb vascular resistance. The effects of cumulative, ascending doses of intravenous vernakalant and flecainide on vascular resistance, after arterial pressures, and heart rate were measured. Blood samples were drawn following each dose to determine drug plasma concentrations. Vernakalant had no significant vasomotor effects on peripheral or systemic vasculature. In contrast, flecainide decreased peripheral vascular resistance (15% at 0.8 μg/mL) and systemic pressures (32% mean arterial pressure at 0.8 μg/mL) in a dose-dependent manner. At therapeutic plasma concentrations, vernakalant (1 μg/mL) had little effect on heart rate (-24 beats/min) or QRS intervals (+3.4 msec), whereas flecainide (0.8 μg/mL) significantly decreased heart rate (55 beats/min) and increased QRS intervals (9.9 msec). In conclusion, vernakalant did not have negative hemodynamic effects at therapeutic plasma concentrations in a rat hindlimb perfusion model.     

Electrophysiologic, antiarrhythmic, and cardioprotective effects of N-[3,5 dichlorophenyl] 4-[4-hydroxy-2-methoxy-phenyl] piperazine carboxamidine dihydrochloride (RS-87337)

N-[3,5-Dichlorophenyl] 4-[4-hydroxy-2-methoxy-phenyl] piperazine carboxamidine dihydrochloride (RS-87337) is a chemically novel antiarrhythmic agent with an electrophysiologic profile characteristic of both class III and class Ia compounds as defined by Vaughan-Williams and Campbell. In isolated superfused guinea pig papillary muscles, RS-87337 (0.1-10 microM) prolonged the duration of the action potential (class III effect) and at higher concentrations (10-30 microM) reduced the maximum rate of membrane depolarisation (class I effect). The rate of onset and of recovery from the latter activity was similar to that of disopyramide, between that of lignocaine and flecainide, which allowed its placement in subclass Ia. When perfused into isolated working rat hearts, RS-87337 (10-1,000 nM) reduced the incidence of ventricular fibrillation that followed coronary artery reperfusion and in anaesthetised rats [RS-87337, 1-5 mg/kg intravenously (i.v.)] enabled more animals to survive the tachycardia, fibrillation, and mortality produced by a similar procedure. In conscious dogs, i.v. (3-10 mg/kg) and oral (15-60 mg/kg) doses of RS-87337 reduced the number of the ectopic electrocardiogram (ECG) complexes observed 24 h after a two-stage coronary ligation. In anaesthetised dogs with paced hearts, i.v. doses of RS-87337 (0.02-5.0 mg/kg) reduced the elevated ECG S-T segment evoked by brief coronary artery occlusion without altering baseline haemodynamic values. We assume that the class III and Ia effects of RS-87337 made an important contribution to the compound's antiarrhythmic and cardioprotective effects.     

Antiarrhythmic effects of pilsicainide hydrochloride and effects on cardiac function and ECG in dogs: comparison with disopyramide

Antiarrhythmic effects and cardiovascular effects of pilsicainide hydrochloride were compared with those of disopyramide in a canine model of coronary ligation-induced ventricular arrhythmias and anesthetized dogs. Pilsicainide (1.25, 2.5 and 5 mg/kg) and disopyramide (2.5 and 5 mg/kg) decreased the arrhythmic ratio ?(ventricular arrhythmias/total heart rate) x 100? dose-dependently. Pilsicainide at 2.5 and 5 mg/kg and disopyramide at 5 mg/kg suppressed ventricular arrhythmias more than 50%. The effective dose of pilsicainide was lower than that of disopyramide, but the effective plasma concentration of pilsicainide was between 3 and 8 micrograms/ml, which was almost the same as that of disopyramide. In anesthetized dogs, both drugs decreased LV dP/dt max in almost the same concentration-dependent manner. PQ-interval was prolonged by pilsicainide, but not by disopyramide. QRS and QTc were prolonged by both drugs in a concentration-dependent manner. However, the prolongation of QTc by disopyramide was provoked at lower plasma concentrations than by pilsicainide. Because the excessive prolongation of QTc lead to the lethal arrhythmias such as torsades de pointes, pilsicainide may be useful as an injectable antiarrhythmic agent superior to disopyramide.     

General pharmacology of diprafenone,a new class lc antiarrhythmic agent,and 5-hydroxydiprafenone,an active metabolite

This study compareo the effects of diprafenone, a new class lc antiarrhythmic agent, and 5-hydroxydiprafenone (5-OHDP), an active metabolite of diprafenone, to standard class l antiarrhythmic agents (propafenone, flecainide, or lidocaine), in several pharmacologic models, to ascertain the potential for side effects relative to the currently available class l antiarrhythmic agents. Diprafenone and propafenone decreased blood pressure and heart rate in anesthetized rabbits at 3 and 7 mg/kg, i.v., respectively. Neuromuscular transmission in rabbit gastrocnemius muscle was partially (38%) inhibited after 3 mg/kg of diprafenone and 7 mg/kg of propafenone. Diprafenone and 5-OHDP (10^?4M), but not lidocaine, inhibited aggregation of human platelets evoked by sodium arachidonate and adenosine diphosphate. Diprafenone, fleoainide, and 5-OHDP (10^?4M) inhibited the contractile responses of guinea pig vas deferens to norepinephrine and spontaneous and bradykinin-evoked contractions of the guinea pig uteri. Diprafenone and 5-OHDP, but not flecainide, relaxed rabbit bronchial smooth muscle contracted by acetylcholine. Diprafenone, 5-OHDP and propafenone (10^?5M and 10^?4M) also depressed the contractile responses of canine mesenteric arteries to transmural nerve stimulation. Thus, high concentrations of diprafenone (10^?5M and 10^?4M) depress smooth muscle and neural function. The depressant effects occur with 4ndash;40 times the antiarrhythmic concentration of diprafenone and are shared by propafenone and, in part, by 5-OHDP and flecainide. It is unlikely that major peripheral side effects will occur with therapeutic doses of diprafenone in man.     

Pirmenol hydrochloride (CI-845): antiarrhythmic profile in coronary artery ligated conscious dogs

The antiarrhythmic profile of CI-845 (pirmenol hydrochloride) was assessed in conscious, coronary artery ligated dogs. In single-dose studies in these arrhythmic dogs, CI-845 administered by the intravenous, intranuscular, and oral routes was highly effective in restoring normal sinus rhythm. A 2.5 mg/kg dose was effective against the arrhythmias occurring on the second day after ligation, while 5 mg/kg was effective against the higher-rate arhythmias of the first day after ligation. The reference agents ajmaline, aprindine, disopyramide, lidocaine, mexiletine, procainamide, and quinidine were also tested, and in this model, CI-845 had greater efficacy, a longer duration of activity, and/or a wider safety margin. In slow rate intravenous infusion studies, 1-2 mg/kg/hr of CI-845 maintained near total arrhythmia conversion in first-day postligation dogs. Rapid rate intravenous infusion studies (10 mg/kg/hr) demonstrated a good correlation between the CI-845 dose, plasma level, and arrhythmia conversion, as well as a wide margin of safety. Mean conversions to 80% normal rhythm were achieved at 2.5 mg/kg, with associated plasma levels of 0.8 +/- 0.1 micron/ml, while first sings or gross toxicity occurred at 21.7 +/- 2.4 mg/kg at plasma levels of 6.2 +/- 0.4 micron/ml. There were minimal effects on cardiac conduction and blood pressure even at large doses. In drug interaction studies, CI-845 was safe and effective in combination with disopyramide, lidocaine, procainamide, propranolol, and quinidine. The results clearly show CI-845 to be an orally effective, long-acting antiarrhythmic agent with a favorable margin of safety in the coronary artery ligated dog model.     

Characterization of a new oral antiarrhythmic drug,flecainide (R818)

Flecainide is a local anaesthetic with five times the potency of procaine on frog nerve, with a longer duration of action. It reduces the maximum rate of depolarisation in cardiac muscle at low concentration, both in solutions containing 5.6 mM KCl and 2.8 mM KCl. It has no anti-sympathetic effects, nor does it antagonise the positive inotropic action of calcium on cardiac muscle. Flecainide prolonged the duration of the action potential at 90% repolarisation. In guinea-pigs anaesthetised with urethane does of 5 mg/kg of flecainide significantly increased the amount of ouabain necessary to induce heart block and ventricular arrhythmias. Flecainide 15 mg/kg caused abnormal ventricular conduction and death in this preparation, but in pithed rats doses of 30 mg/kg of flecainide caused no abnormalities in the electrocardiogram. Flecainide is a class 1 antiarrhythmic drug, with very little negative inotropic or chronotropic action.     

BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents

BW A256C (5(3)-amino-6-(2,3-dichlorophenyl)-2,3(2,5)-dihydro-3(5)-imino-2 -isopropyl-1,2,4-triazine) is a novel class 1 antiarrhythmic agent designed to combine the features of potency with reduced central nervous system penetration. BW A256C reduced the maximum rate of depolarization of guinea-pig ventricle and dog Purkinje fibres in vitro (EC50, 2.2 X 10(-6) M and 1.8 X 10(-6) M, respectively), being significantly more potent than quinidine, lidocaine, disopyramide and flecainide. BW A256C was also more potent than these agents at inhibiting aconitine-induced arrhythmias in anaesthetized rats; however, unlike these agents, BW A256C was devoid of hypotensive activity at antiarrhythmic doses. In anaesthetized dogs, intravenous administration of BW A256C (0.25-1 mg kg-1) caused a dose-dependent suppression of ventricular arrhythmias that occurred on reperfusion of an occluded coronary artery. In conscious dogs, intravenous infusion (total dose, 1.5 mg kg-1) or oral administration of BW A256C (1.25-5 mg kg-1) caused dose-dependent suppression of the ventricular ectopic activity that occurred following 20-24 h of permanent coronary artery ligation. In the conscious dog, BW A256C was approximately 7 times more potent and was also longer acting than flecainide. Administration of BW A256C was not associated with any evidence of peripheral or CNS toxicity. However, plasma levels 3-4 times greater than the antiarrhythmic levels were associated with a proarrhythmic activity.     

Coupling interval-related effects of class I antiarrhythmic drugs, mexiletine, cibenzoline and disopyramide, on ventricular activation in canine myocardial infarction.

Time-dependent inhibition of sodium channels by class I antiarrhythmic drugs has been observed in isolated cardiac muscles or cells. We examined coupling interval-related effects of class I antiarrhythmic drugs, mexiletine, cibenzoline and disopyramide, on ventricular activation in canine infarcted myocardium. A ventricular stimulation with various coupling intervals was applied to the right ventricle, and activation delays (time intervals between the initiation of a deflection and the final rapid deflection of a bipolar electrocardiogram) of infarcted and normal zones were measured. The premature stimulation produced a delayed activation and in some animals, caused reentrant beats. Mexiletine (3 and 10 mg/kg), cibenzoline (1 and 4 mg/kg) and disopyramide (1 and 4 mg/kg) further enhanced or blocked the delayed activation. The effects of these drugs were more marked at shorter coupling intervals, although cibenzoline and disopyramide showed significant effects also at long coupling intervals. The effect of these drugs on the activation in the normal zone was less than that in the infarcted zone. In conclusion, mexiletine, cibenzoline and disopyramide showed a coupling interval-related depression of delayed activation in infarcted myocardium, which may be a reflection of their time-dependent inhibition of sodium channels.     

Chronotropic, inotropic, dromotropic and coronary vasodilator effects of bisaramil, a new class I antiarrhythmic drug, assessed using canine isolated, blood-perfused heart preparations.

The cardiovascular effects of a new class I antiarrhythmic drug, bisaramil, were examined using canine isolated, blood-perfused heart preparations. Bisaramil exerted negative chronotropic, inotropic and dromotropic effects as well as coronary vasodilator action, which are qualitatively the same as those of classical class I drugs. The selectivity of bisaramil for the intraventricular conduction vs the other cardiac variables was compared with that of disopyramide and flecainide. Bisaramil was the most selective for intraventricular conduction, while it was the least selective for ventricular muscle contraction. We conclude that bisaramil may become a useful antiarrhythmic drug with less cardiac adverse effects.     

Comparative haemodynamic effects of lidocaine, mexiletine, and disopyramide

The effect of intravenous boluses of lidocaine (5 mg/kg), mexiletine (3.5 mg/kg), and disopyramide (5 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance, left ventricular end-diastolic pressure, and peak rate of change of left ventricular pressure (peak LV dP/dt) were assessed in the conscious rabbit. Plasma levels for the three drugs corresponded to the human therapeutic range 3 min after administration. All three drugs had negative inotropic effects and reduced HR. Lidocaine reduced peak LV dP/dt by 26%, mexiletine by 41%, and disopyramide by 53%. The three drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: disopyramide caused a 21% fall in CO, associated with a significant vasoconstriction; mexiletine did not lower CO, as it caused a substantial vasodilation; and lidocaine did not produce any substantial change in either CO or vascular resistance. Cardiac autonomic blockade did not alter these changes. These results confirm that disopyramide has a marked cardiodepressant effect, and demonstrate that, although lidocaine depresses myocardial contractility in the conscious rabbit, it has little effect on other haemodynamic parameters. The experiments also show that mexiletine is a more profound negative inotrope than lidocaine, but that, as it produces a significant fall in MAP and thus a reduction in afterload, the CO is maintained.