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PubMedDate not supplied

Effects of etafenone and antiarrhythmic drugs on Na and Ca channels of guinea pig atrial muscle.

Since Ca-mediated electrophysiological phenomena seem to be important in the generation of various arrhythmias, we quantitatively compared the effects of quinidine, disopyramide, procainamide, lidocaine, propranolol, and etafenone, a new coronary vasodilator with antiarrhythmic properties, on Na and Ca channels in normal and depolarized guinea pig atria. The maximum rate of rise of the normal action potential and the amplitude of the depolarized, Ca-mediated action potential were measured to examine the Na and Ca channel activity, respectively. In both preparations, the contractile force was determined concomitantly in order to establish the role of Ca influx in the inotropic effects of the drugs. All six drugs suppressed the Na channel, the effect being strongest with etafenone, followed in order by quinidine, propranolol, disopyramide, lidocaine, and procainamide. Only quinidine, disopyramide, and propranolol suppressed the Ca channel and only in concentrations higher than those required to block the Na channel. Etafenone and procainamide decreased Ca influx, while lidocaine had no effect on it. The negative inotropic effects of propranolol and disopyramide may be due to decreases in Ca influx, but the order drugs seem to have other mechanisms for their inotropic effects.

Action Potentials↗
PubMed1989

Electrophysiologic effects of Org 7797, a new steroidal antiarrhythmic agent: comparison with class 1a, 1b, and 1c drugs.

The in vitro electrophysiologic effects of a new class I steroidal antiarrhythmic agent, Org 7797 (2-10 microM) were evaluated in porcine ventricular and Purkinje tissue using conventional microelectrode techniques. Org 7797-induced decreases in Vmax were both frequency- and voltage-dependent. Both the rate of onset and the time course of decay of sodium channel block were slow and similar to those obtained with the 1c drug propafenone. The kinetics of block by lignocaine (1b) were fast whereas those of disopyramide (1a) were intermediate. Rate constants (determined at 1.0 Hz) were 0.187, 0.078, and 0.074 for disopyramide, propafenone, and Org 7797, respectively, in concentrations giving approximately equivalent decreases in Vmax. Onset block with lignocaine was too fast to measure. The effective refractory period (ERP) was prolonged to a greater extent by lignocaine and disopyramide than by propafenone or Org 7797, but the increase in ERP in response to disopyramide resulted largely from prolongation of action potential duration (APD). The effects of Org 7797 on ERP relative to APD were more similar to those of propafenone. We conclude that Org 7797 is a class 1c agent.

Action Potentials↗
PubMed1992

Voltage-dependent modification of Vmax recovery from use-dependent block by pirmenol in guinea pig papillary muscles: comparison with other class I drugs.

Voltage-dependent modification of Vmax (the maximum upstroke velocity of the action potential) recovery from use-dependent block (UDB) by pirmenol was examined and compared with those observed with other Class I drugs using standard microelectrode techniques. A partial depolarization of the resting membrane by increasing extracellular potassium concentration ([K+]o) from 4 to 8 mM potentiated UDB at 2 Hz stimulation by any of the following drugs: pirmenol (10 microM), disopyramide (20 microM), pentisomide (50 microM), quinidine (20 microM), mexiletine (30 microM), and flecainide (5 microM). The recovery time constants from UDB of quinidine and mexiletine were prolonged and that of flecainide was unchanged in 8 mM [K+]o. However, the recovery time constant from UDB of pirmenol was shortened in high K+ solution, as observed with disopyramide and pentisomide. Thus, disopyramide and its analogues, including pirmenol, show a voltage dependency of recovery process, which is different from those of other class Ia, Ib, and Ic drugs. The main unblocking pathway of disopyramide and its analogues from sodium channels during diastolic interval may be different from that of other Class I drugs.

Action Potentials↗
PubMed1993

Antiarrhythmic agents act differently on the activation phase of the ACh-response in guinea-pig atrial myocytes.

1. Anti-acetylcholine effects of pilsicainide, flecainide, disopyramide and propafenone on the acetylcholine (ACh)-induced K+ current (IK.ACh) were examined in dissociated guinea-pig atrial myocytes under whole-cell voltage clamp by the use of the 'concentration-clamp' technique. 2. The IK.ACh was activated with a latency of about 100 ms after 1 microM ACh application and desensitized to a steady-state level. The latent period and the time to peak response were shortened with increasing ACh concentration. 3. The values of half-maximal inhibition (IC50) on the peak and steady state responses were 25 and 25 microM for pilsicainide, 1.7 and 2.0 microM for disopyramide, 19 and 2.0 microM for flecainide and 0.7 and 0.2 microM for propafenone, respectively. 4. Pilsicainide and disopyramide increased the latent period and the time to peak of IK.ACh in a concentration-dependent manner. Flecainide and propafenone did not change the latent period, but shortened the time to peak and hastened the decay of IK.ACh in a voltage-independent manner. 5. The results suggest that the mechanisms underlying the anti-acetylcholine effect of antiarrhythmic drugs are different among these drugs: i.e., pilsicainide and disopyramide mainly block the muscarinic ACh receptors while flecainide and propafenone inhibit the K+ channel itself as open channel blockers.

Acetylcholine↗
PubMed1989

Mechanisms of termination of reentrant atrial arrhythmias by class I and class III antiarrhythmic agents.

We studied atrial flutter due to circus movement in chronically instrumented conscious dogs to identify the mechanism by which class I and class III antiarrhythmic drugs terminate reentrant excitation. We used a crossover experimental design administering five class I agents and one class III agent, by intravenous bolus followed by intravenous infusion. The class I agents other than lidocaine were almost uniformly effective in terminating the arrhythmia (disopyramide in six of seven dogs, propafenone in six of six, flecainide in seven of seven, and SC-40230 in seven of seven). Termination was preceded by a marked increase in cycle length (ranging from +78% with propafenone to +55% with disopyramide), but with the exception of disopyramide, class I agents did not significantly shorten the excitable gap. With disopyramide the gap decreased from 49 +/- 3% to 28 +/- 3% of the cycle length. With no class I agent did the wavelength of effective refractoriness increase to approach the cycle length of the arrhythmia. Lidocaine, used as a negative control, terminated the reentry in one dog with modest prolongation of the cycle length. Terminations with class I agents correlated with depression of conduction rather than prolongation of refractoriness. In contrast with class I agents, D-sotalol prolonged the cycle length minimally (+10%) and terminated the arrhythmia in six of seven dogs. It decreased the excitable gap from 42 +/- 4% to 26 +/- 6% of the cycle, but it still did not cause the wavelength of effective refractoriness to equal the cycle length. Terminations by D-sotalol seemed to result from either failure of the lateral boundaries of the circus path or reflection within the path.

Animals↗
PubMed2003

Comparison of the effect of class IA antiarrhythmic drugs on transmembrane potassium currents in rabbit ventricular myocytes.

BACKGROUND: The blockade of cardiac transmembrane potassium channels, which is commonly seen with various antiarrhythmic drugs, plays an important role in their mechanism of action. We studied and compared the less-explored effects of three Class IA antiarrhythmics on the transient outward current (I(to)) and on the inward rectifier (I(kl)), ATP sensitive (I(KATP)), and delayed rectifier (I(K)) potassium currents in rabbit ventricular myocytes. METHODS AND RESULTS: Transmembrane currents were measured by applying the whole-cell configuration of the patch-clamp technique at 37 degrees C in myocytes enzymatically isolated from rabbit ventricular preparations. Quinidine (10 microM), disopyramide (10 microM), and procainamide (50 microM) were studied at concentrations close to or exceeding the therapeutic plasma level. All studied drugs significantly decreased the amplitude of I(KATP) (activated by 50 microM pinacidil) and I(K) currents. None of them influenced significantly I(kl). The amplitude of I(to) was decreased by quinidine and disopyramide but was not considerably altered by procainamide. The fast inactivation of I(to) was not changed by procainamide and was significantly accelerated by quinidine and disopyramide. CONCLUSION: Although quinidine, disopyramide, and procainamide are all classified as Class IA antiarrhythmics, these drugs had different effects on various potassium currents, which may partially explain their distinct effect on repolarization in various cardiac tissues and on cardiac arrhythmias in clinical settings.

Adenosine Triphosphate↗
PubMed1985

Usefulness of invasive and non-invasive electrophysiologic studies in the selection of antiarrhythmic drugs for the patients with paroxysmal supraventricular tachyarrhythmia.

A comparison of the effects of several antiarrhythmic agents was made in a study of 70 patients - 15 with manifest Wolff-Parkinson-White (WPW) syndrome, 17 with concealed WPW syndrome, 18 with AV nodal re-entrant tachycardia, 14 with paroxysmal atrial fibrillation and 6 with paroxysmal atrial flutter - employing intracardiac stimulation and esophageal pacing. For the termination of paroxysmal supraventricular tachycardia, intravenous administration of verapamil or aprindine was more effective than that of disopyramide or procainamide. In AV nodal re-entrant tachycardia, verapamil was the most effective for termination. In the manifest WPW syndrome, disopyramide or aprindine was indicated especially for patients with the accessory pathways of the short antegrade refractory period, because these drugs lengthened the refractory period of the accessory pathways. For the purpose of converting atrial fibrillation or flutter to the sinus rhythm, type IA drugs such as disopyramide were indicated. However, verapamil was effective for slowing down the ventricular rate in atrial fibrillation or flutter except in cases of manifest WPW syndrome. A 6-month follow-up study showed that oral administration of verapamil was also useful for putting a stop to the attacks in 24 out of 32 patients with paroxysmal supraventricular tachycardia, while oral disopyramide prevented the recurrence of atrial fibrillation in only 4 of 10 patients.

Administration, Oral↗
PubMed1986

Effects of four antiarrhythmic drugs on the induction and termination of paroxysmal supraventricular tachycardia.

The electrophysiological effects of antiarrhythmic drugs were tested in 36 patients with recurrent paroxysmal supraventricular tachycardia (PSVT), 25 of whom had accessory pathway reentrant tachycardia (APRT) and 11 A-V nodal reentrant tachycardia (AVNRT; 10 of the slow-fast type one of the fast-slow type). The test drugs were procainamide (used in 19 patients), verapamil (in 27), disopyramide (in 31), and propranolol (in 15). The drugs were tested for their ability to terminate episodes of PSVT as well as to inhibit their induction. Procainamide had an inhibitory effect on APRT in nine of 12 patients (75%) and terminated episodes of APRT in seven of 11 patients (63.6%); in all of them V-A block was responsible for the termination. In four of six patients (66.7%) with slow-fast AVNRT and in one patient with fast-slow AVNRT, inhibition of the induction of tachycardia attacks was noted after procainamide. Termination of AVNRT was seen in the same number of patients. Verapamil inhibited the induction of APRT in 12 of 18 patients (66.7%) and terminated episodes of APRT in 10 of 16 patients (62.5%), all by A-V block. In six of eight patients (75%) with slow-fast AVNRT, inhibition of the induction as well as termination of tachycardia were noted after verapamil. Disopyramide had an inhibitory effect on APRT in seven of 23 patients (30.4%) and terminated APRT in five of 21 patients (23.8%) by V-A block, while AVNRT (all slow-fast type) was terminated in only one of eight patients (12.5%) by disopyramide. Disopyramide was less effective than previously reported. This could be attributed to a relatively low dosage and slow infusion speed. Propranolol inhibited the induction of APRT and terminated episodes of APRT in only one of 10 patients (10%). In two of four patients (50%) with slow-fast AVNRT, an inhibitory effect by propranolol was noted, but termination was seen in only one patients.

Adolescent↗
PubMed1986

[Electrophysiological effects of bunaftine, an antiarrhythmic drug, on action potential characteristics in ventricular muscle preparations].

The electrophysiological effects of bunaftine were studied using the glass microelectrode technique. Bunaftine at 1, 5 and 10 mg/l produced a concentration-dependent depression of the maximum rate of rise of the action potential in guinea pig papillary muscle preparations without affecting the resting membrane potential and the action potential amplitude. The action potential duration (APD50, APD90) was significantly prolonged by the treatment with 1 and 5 mg/l bunaftine, while it was not changed by the treatment with 10 mg/l. The absolute refractory period (ARP) was also prolonged dose-dependently by the treatment of bunaftine; It was excessively prolonged (177% of control) at the concentration of 10 mg/l. Disopyramide produced similar electrophysiological changes to those of bunaftine except for the prolongation of ARP. ARP/APD90 ratio was significantly increased by bunaftine, but not by disopyramide. These electrophysiological effects of bunaftine and disopyramide observed in guinea pig ventricular preparations were similarly found in canine ventricular muscle preparations. These results indicate that the electrophysiological characteristics of bunaftine are similar to those of disopyramide in that the most prominent effect was the prolongation of ARP.

Action Potentials↗
PubMed1991

Binding profiles of class I antiarrhythmic agents to cardiac muscarinic receptors: competitive and allosteric interactions with the receptors and their pharmacological significance.

The binding profiles of the class I antiarrhythmic agents disopyramide, pirmenol and pentisomide (CM7857) to cardiac muscarinic receptors were characterized by the binding assay using [3H]-N-methyl scopolamine ([3H]NMS) as a ligand and their anti-muscarinic actions were investigated functionally in left atrial preparations. All the agents displaced the specific binding of 200 pM [3H]NMS from guinea pig left atrial membranes. Computer-assisted analysis indicated that pirmenol interacted with a single class of binding sites, but the displacement curves of disopyramide and pentisomide were shallow and best fitted to a two-site model. When the concentration of [3H]NMS was increased to 1 nM, the displacement curve of pirmenol was best fitted to a two-site model. In higher concentrations, these agents inhibited the dissociation of [3H]NMS initiated by 1 microM atropine in a concentration-dependent manner, thus revealing allosteric interactions. Two enantiomers of pirmenol possessed qualitatively the same binding properties as the racemate. In guinea pig left atria, disopyramide, pirmenol and pentisomide shifted the concentration-response curves for the negative inotropic effect of carbachol in a parallel manner. The slopes of Schild plot were not significantly different from unity, indicating that they act as a competitive antagonist of cardiac muscarinic receptors. Excellent correlation between the high affinity pKi values and the pA2 values was established for the antiarrhythmic agents. These findings suggest that disopyramide, pirmenol and pentisomide all interact with cardiac muscarinic receptors in both a competitive fashion and an allosteric one. The dual mode of the interaction with cardiac muscarinic receptors seems to be independent of their chiralities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

[Gated blood pool imaging in the diagnosis and management of arrhythmia].

The usefulness of multigated cardiac blood pool imaging in evaluating left ventricular function and ventricular activation was studied in patients with cardiac arrhythmias. Subjects consisted of 12 patients with the Wolff-Parkinson-White (WPW) syndrome; 20 with ventricular premature contractions (VPC); 21 with various modes of artificial pacemakers; and two normal controls. Phase analysis was useful in localizing the bypass tract in patients with the WPW syndrome. In four patients with the WPW syndrome and five with VVI pacing, the phase difference between the posterolateral wall of the left ventricle (LV) and the right ventricular apex correlated significantly with the activation time difference between these two regions as assessed by endocardial electrograms (r = 0.94, p less than 0.001). Images of VPC were obtained using the bad beat rejection program in an ADAC computer system. The origin of VPCs evaluated by phase image coincided with results of standard 12-lead electrograms. It was in the right ventricle in four patients, the LV in one, and probably in the interventricular septum in one. The LV ejection fraction (LVEF) decreased significantly (p less than 0.001) after the injection of lidocaine (-3.7%) or disopyramide (-6.2%). The percent reduction in LVEF was significantly greater with disopyramide than with lidocaine (-15.1 vs -11.2%). The plasma concentration of disopyramide was higher in four patients with organic heart diseases than in 11 without. There was a significant correlation between the percent reduction in LVEF and the disopyramide plasma concentrations (r = -0.62, p less than 0.001). The influence of the pacing mode and exercise on LV function was studied in 21 patients with artificial pacemakers. In the VDD and DDD modes, end-diastolic volume (EDV) and cardiac output (CO) decreased after converting to VVI mode. CO increased markedly to approximately 250% of the control value in the VDD and DDD, and moderately in the VVI and AAI modes during ergometer exercise. In conclusion, multigated cardiac pool imaging is considered useful in diagnosing and managing patients with cardiac arrhythmias.

Arrhythmias, Cardiac↗
PubMed1988

[Effect of class I anti-arrhythmia agents on the signal-averaged ECG].

This study was designed to determine which parameters in the signal-averaged ECG are subject to the influence of class I antiarrhythmic agents and whether the effects on these parameters differ with respect to the various subgroups of agents within the class I antiarrhythmics. For this purpose, disopyramide was chosen as representative of class Ia, tocainide Ib and flecainide Ic. A total of 23 patients, twelve with coronary artery disease and eleven with dilated cardiomyopathy and high grade ventricular arrhythmics, received randomized and single-blind, placebo-controlled high single oral doses of 300 mg disopyramide, 800 mg tocainide and 300 mg flecainide with a washout period of five half-times of the antecedent drug prior to the subsequent agent. Before and two hours after the respective drugs the signal-averaged ECG was recorded. The position of the electrodes was unchanged throughout the study. A total of 142 recordings were performed. Computerized calculation of the duration and mean voltage of the entire filtered QRS complex and the voltage during the last 40 and 50 ms, respectively, was carried out according to the method of Simson. Additionally, according to a modification by Karbenn, the duration and voltage of late potentials were analyzed. In the baseline signal-averaged ECG, 13 of 23 patients (57%) had late potentials. Of the 18 patients who received disopyramide, ten had late potentials before and after the drug. In seven, late potentials were not present either before or after the drug. In one patient with a negative finding at baseline, late potentials were observed after disopyramide. There was a significant increase in the duration (p less than 0.001) as well as a decrease in the voltage of the entire filtered QRS-complex (p less than 0.01) and the voltage during the last 40 and 50 ms, respectively (p less than 0.05). Late potentials were present before and after tocainide in nine of 18 patients (50%) who received this drug. In the remaining 50%, late potentials were not observed either before or after the drug. Comparison of mean values before and two hours after 800 mg tocainide showed no significant changes for duration or voltage of the entire filtered QRS-complex nor for the voltage during the last 40 and 50 ms, respectively. Before and after flecainide, eight of 17 patients had late potentials (47%).(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Arrhythmia Agents↗
PubMed1975

[The effect of drugs on "sino-atrial conduction time" and on sinus-node automaticity in man].

The effect of atropine, propafenone, and disopyramide on sinus node automaticity and "sino-atrial conduction" was tested in normal patients and patients with the sick sinus-syndrome. "Sino-atrial conduction time" was estimated indirectly by the extrastimulus technique. Atropine (n = 11) caused a significant increase in heart rate in all patients. The sinus node recovery time was shortened in 10 patients. "Sino-atrial conduction time" decreased on an average 35% (P less than 0.01). Three patients with a sick sinus-syndrome demonstrated a change of the pattern of the postextrasystolic pauses indicating great improvement in sino-atrial conduction. Propafenone (n = 10) led to a significant prolongation of the sinus node recovery time by 17% and of the "sino-atrial conduction time" by 27%. Disopyramide (n = 8) had no significant influence on heart rate and "sino-atrial conduction time". Sinus node recovery time was not changed in 6 patients. However, in two patients with a sick sinus-syndrome a dangerous prolongation of the sinus node recovery time after application of disopyramide occurred. The results indicate that atropine enhances sinus node function and sino-atrial conduction. On the other hand, propafenone and disopyramide exert either a depressant influence on sinus node automaticity or on sino-atrial conduction.

Atropine↗
PubMed1983

[Effects of lorcainide, a new antiarrhythmic agent, on experimental cardiac arrhythmias].

Antiarrhythmic actions of lorcainide were compared with those of disopyramide on different types of arrhythmias in animal models. It was shown in dogs that lorcainide and disopyramide were approximately equipotent against the arrhythmias following coronary occlusion. In guinea pigs, lorcainide was less effective than disopyramide against the ouabain-induced arrhythmia. Both drugs showed a weak protective action against the aconitine-induced ventricular arrhythmias, but had no effect on the cardiac arrest. In the arrhythmias induced by the application of acetylcholine on the right auricle of guinea pigs, the disappearance of P-waves and the disturbance of R-R intervals were inhibited by disopyramide, but lorcainide had no influence on these events; both prevented the atrial fibrillation induced by acetylcholine application. Both drugs by themselves induced ventricular arrhythmias in guinea pigs.

Acetylcholine↗
PubMed1989

Cardioprotective effects of various class I antiarrhythmic drugs in canine hearts.

This study was designed to clarify the cardioprotective effects of various class I antiarrhythmic drugs, i.e., aprindine, disopyramide, flecainide, lidocaine, mexiletine, pentisomide and propafenone, on the ischemic heart. Sixty-one adult mongrel dogs were classified into eight groups according to premedication: 1) control group, physiologic saline solution was administered intravenously 25 min before left anterior descending coronary artery ligation; 2) aprindine group, 3 mg/kg body weight of aprindine intravenously; 3) disopyramide group, 2 mg/kg of disopyramide intravenously; 4) flecainide group, 2 mg/kg of flecainide intravenously followed by drip infusion of 100 micrograms/kg per min; 5) lidocaine group, 2 mg/kg of lidocaine intravenously followed by drip infusion of 100 micrograms/kg per min; 6) mexiletine group, 3 mg/kg per min of mexiletine intravenously followed by drip infusion of 15 micrograms/kg per min; 7) pentisomide group, 5 mg/kg intravenously; and 8) propafenone group, 2 mg/kg intravenously. Arterial blood pressure and electrocardiogram were monitored throughout the experiment. Two hours after coronary occlusion, the heart was excised. Myocardial mitochondria were prepared and mitochondrial function (the respiratory control index and the rate of oxygen consumption in state III) was measured polarographically. Fractionation of myocardial tissues was performed and the lysosomal enzyme (N-acetyl-beta-glucosaminidase and beta-glucuronidase) activities among fractions were measured. No significant hemodynamic changes were observed compared with the control group except for those in the disopyramide and flecainide groups; that is, decrease in heart rate without changes in blood pressure compared with the control group was observed. All antiarrhythmic drugs effectively prevented the development of ventricular arrhythmias associated with ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosaminidase↗
PubMed1999

Effects of AH-1058, a new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents.

AH-1058 is a newly synthesized antiarrhythmic agent. We investigated the antiarrhythmic and electrophysiological effects of AH-1058 in experimental arrhythmia models and isolated cardiomyocytes. In the ouabain-induced arrhythmia model of the guinea pig, pretreatment with AH-1058 (0.1-0.3 mg/kg, i.v.) delayed the appearance of premature ventricular complex (PVC) and ventricular fibrillation (VF) induced by intravenous infusion of ouabain. However, disopyramide (10 mg/kg, i.v.) delayed only that of PVC, and verapamil (1 mg/kg, i.v.) failed to affect the ouabain-induced ventricular arrhythmias. In the reperfusion-induced arrhythmia model of the rat, in which 5-min coronary occlusion and 10-min reperfusion were produced, AH-1058 (0.1-0.3 mg/kg, i.v.) inhibited the incidence of both ventricular tachycardia (VT) and VF, whereas disopyramide (5 mg/kg, i.v.) inhibited only reperfusion-induced VF. On the other hand, a higher dose of AH-1058 (1 mg/kg, i.v.) did not affect the aconitine-induced arrhythmias in rats, which were inhibited by disopyramide (5 mg/kg, i.v.). We also confirmed oral activity of AH-1058 in the reperfusion-induced arrhythmia model of the rat. AH-1058, at doses of 2-4 mg/kg, dose-dependently inhibited VT and VF. Electrophysiological experiments with patch-clamp techniques revealed that AH-1058 potently suppressed the L-type Ca2+ currents in isolated cardiomyocytes of the guinea pig. These results suggest that AH-1058 is a potent antiarrhythmic drug having a Ca2+ channel-blocking action. The antiarrhythmic profile of AH-1058 is different from that of disopyramide and verapamil.

Aconitine↗
PubMed2002

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.

Absorption↗
PubMed1993

Importance of pharmacokinetic and physicochemical data in the discovery and development of novel anti-arrhythmic drugs.

1. The importance of pharmacokinetics and physicochemical data in the discovery and development of a new mono-cationic antiarrhythmic agent, bidisomide (pKa 9.3), structurally related to the di-cationic anti-arrhythmic disobutamide (pKa of 8.6 and 10.2) and a mono-cationic drug disopyramide (pKa 10.4), is described. 2. In man, the di-cationic disobutamide was slowly eliminated with a mean terminal phase half-life of 54 +/- 18 h, a value > 7 times longer than disopyramide. The long terminal phase half-life of disobutamide is attributed to high accumulation of the drug in the tissues, a phenomenon attributed to the di-cationic nature. 3. Structural modification of disobutamide resulted in the mono-cationic agent bidisomide, designed to minimize drug accumulation in the tissues. Human studies with bidisomide confirmed that the terminal phase elimination of this drug was much faster than that of disobutamide, with a half-life of about 11h. The absolute bioavailability of bidisomide was 45-62% which is lower than that of disopyramide (60-90%). 4. Unlike disopyramide, absorption of bidisomide was complex, characterized by a lag period (0.75-1.5 h) before absorption, followed by occurrence of two peaks in the plasma concentration-time curves. 5. The characteristic double peaks found with bidisomide was attributed to two rapid absorption sites of the drug in the gastrointestinal tract.

Adolescent↗