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PubMed1987

Effects of diet-induced hypokalaemia on the antiarrhythmic and electrophysiological actions of prolonged oral treatment with either amiodarone or disopyramide in the anaesthetised rat.

The potential antiarrhythmic and electrophysiological effects of prolonged oral dosing with amiodarone (20 mg/kg/day) or disopyramide (25 or 50 mg/kg b.i.d.) were compared in normokalaemic (NK) and diet-induced hypokalaemic (HK) anaesthetised rats. In NK rats, amiodarone reduced the number of electrical deaths consequent upon coronary artery ligation and prolonged action potential duration (APD50) of papillary muscle. Disopyramide conferred marked protection against arrhythmias in NK animals, prolonged APD50, reduced the maximum rate of depolarisation, and induced bradycardia. Hypokalaemia inhibited both the antiarrhythmic efficacy and these electrophysiological actions of amiodarone and disopyramide. However, prolongation of APD90 by both drugs was little affected by hypokalaemia. Amiodarone prolonged QTc both in NK and HK rats, whilst disopyramide only prolonged QTc in NK rats and only at the higher dose. It is concluded that reduced antiarrhythmic efficacy of the two drugs by hypokalaemia may be due to altered electrophysiological responses. QTc prolongation per se appears to be associated with antiarrhythmic, not arrhythmogenic, actions in this experimental model.

Amiodarone↗
PubMed1987

Stereospecific effects of disopyramide enantiomers following pretreatment of canine cardiac Purkinje fibers with verapamil and nisoldipine.

The effect of racemic disopyramide and its enantiomers on the action potential was studied in Tyrodes (4.0 mM KCL)-superfused canine cardiac Purkinje fibers. Nonstereodependent depression of action potential amplitude and phase 0 Vmax was observed in control fibers and following pretreatment with either nisoldipine or verapamil. Stereospecific effects of the enantiomers were prominent during repolarization phases of the action potential and could be modified by pretreatment with the calcium channel blocking agents. R(-) disopyramide decreased action potential duration at 90% repolarization and shortened the effective refractory period. S(+) disopyramide increased action potential duration at 90% repolarization and prolonged refractoriness. This disparate effect of the enantiomers was eliminated following pretreatment with verapamil. Stereospecific effects on repolarization persisted when fibers were pretreated with nisoldipine, a more selective calcium channel blocking agent that lacks effects on outward plateau current. The data suggest that the increase in action potential duration and refractoriness produced by disopyramide is mediated by a stereospecific inhibition of outward repolarizing current by the S(+) enantiomer.

Action Potentials↗
PubMed1988

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.

Adult↗
PubMed1991

Effects of pentisomide and E-4031 on canine atrial flutter due to reentry: a comparative study with disopyramide and propafenone.

Effects of new antiarrhythmic drugs, pentisomide [3.5 +/- 0.5 mg/kg intravenously (i.v.) n = 8], and E-4031 (5.6 +/- 1.0 micrograms/kg, n = 8), a class III drug, on atrial flutter (AF) caused by reentry were compared with those of disopyramide (1.6 +/- 0.2 mg/kg, n = 8) and propafenone (2.2 +/- 0.2 mg/kg, n = 8). AF was induced with burst atrial pacing after we made an intercaval crush in anesthetized, open-chest dogs. Termination of AF did not differ among test drugs (8 of 8 with disopyramide, 7 of 8 with propafenone, 6 of 8 with pentisomide, and 8 of 8 with E-4031). Cycle length (CL) of AF was prolonged more with propafenone (57 +/- 10%) and pentisomide (41 +/- 5%) than with E-4031 (12 +/- 3%, p less than 0.05). This was also true for increase in interatrial conduction time determined at a pacing CL of 150 ms. Increase in atrial effective refractory period (ERP) determined at a basic pacing CL of 300 ms did not differ among test drugs. Changes in CL of AF correlated significantly with those in interatrial conduction time (r = 0.84, p less than 0.001), but not with those of ERP (r = 0.10, NS). Reinitiation of AF was significantly greater in propafenone (7 of 7) and pentisomide (5 of 6) groups than in disopyramide (1 of 8) and E-4031 (0 of 8) groups (p less than 0.001). Pentisomide and E-4031 were effective in terminating canine AF due to reentry, as were disopyramide and propafenone. Reinitiation of AF was greater in dogs treated with antiarrhythmic drugs that had more prominent effects on conduction time than on ERP.

Animals↗
PubMed1983

Plasma protein binding of disopyramide by equilibrium dialysis and ultrafiltration.

An ultrafiltration technique, using Ultrafree Anticonvulsant Drug Filters, was compared to equilibrium dialysis for the determination of disopyramide plasma protein binding. Mean total recovery of drug was 92.4% for ultrafiltration compared with 98.4% for equilibrium dialysis. At initial plasma concentrations spanning the therapeutic range (2-8 micrograms/ml), the percentage binding of disopyramide was concentration dependent for both methods (78-38%). Initial experiments with ultrafiltration (1 ml of plasma) indicated a small (0.14%) but variable loss of total plasma protein in the ultrafiltrate (0.1-ml volume). In ultrafiltration, percentage binding of disopyramide was similar at 22 and 37 degrees C, whereas in equilibrium dialysis, binding was significantly (p less than 0.001) greater (1.4-2.7%) at 22 than at 37 degrees C. Percentage binding for plasma (1-ml volume), assessed at ultrafiltrate volumes of approximately 0.1 and 0.25 ml, was found to be significantly (p less than 0.05) different, but in practical terms the mean difference was less than 1% at any of the concentrations studied and was therefore of little consequence. Absolute values for percentage disopyramide bound by ultrafiltration and equilibrium dialysis were very similar, irrespective of the temperature. However, when these values were related in the usual way to the starting plasma drug concentration for ultrafiltration or to the final dialysed plasma concentration, ultrafiltration gave results that were consistently greater than those with equilibrium dialysis. Reasons for these differences and their implications are discussed.

Blood Proteins↗
PubMed1984

Evaluation of fluorescence immunoassay for total and unbound serum concentrations of disopyramide.

The accuracy of determining disopyramide concentrations in 80 serum samples by high-performance liquid chromatography (HPLC) and fluorescence immunoassay (FIA) on 2 consecutive days was similar. The precision of both methods was excellent. The interday precision of FIA was superior to HPLC at nominal concentrations of 1.5 and 3.0 mg/L, but was similar at 7.0 mg/L. Following equilibrium dialysis of 40 serum samples, the unbound concentration of disopyramide determined by a modified FIA method under-estimated by 16% the unbound concentration determined by a reference method. The discrepancy may be avoided by preparing standards in the appropriate buffer. Fluorescence of disopyramide optical isomers at similar concentrations were identical. It is concluded that FIA for determining plasma concentrations of disopyramide is accurate and precise, and may be modified to accurately determine unbound concentrations following separation of plasma water and protein.

Blood Proteins↗
PubMed1980

Pharmacokinetics of oral disopyramide phosphate in patients with renal impairment.

1 The pharmacokinetics of disopyramide were studied after the oral administration of a 300 mg dose to 11 patients with stable chronic renal impairment (creatinine clearance 2-53 ml min-1). 2 Absorption half-life and volume of distribution were similar to those seen in normal subjects. 3 Mean plasma elimination half-life in these patients was 12.7 h, which is substantially greater than that reported for normal subjects. Elimination half-life tended to increase as creatinine clearance fell, and renal clearance of disopyramide correlated significantly (r=0.814; P < 0.001) with creatinine clearance. 4 From these results, we have calculated that patients with renal impairment should be started on a dose of disopyramide 1.5 mg kg-1 thrice daily and the regimen subsequently altered according to plasma concentrations of the drug. However, further studies are needed to define the handling of the metabolites of disopyramide.

Adolescent↗
PubMed1982

A placebo-controlled study to determine the efficacy of oral disopyramide phosphate for the prophylaxis of ventricular dysrhythmias after acute myocardial infarction.

1 To evaluate oral disopyramide phosphate in the prophylaxis of dysrhythmias occurring in acute myocardial infarction (MI) patients (presenting within 12 h of symptoms, age 21-70 years), a placebo-controlled, randomized double-blind, in hospital trial was conducted. After prognostic stratification (anterior and non-anterior MI at each of 4 regional hospitals) patients were randomly assigned to receive oral disopyramide phosphate (loading dose 150, 200, or 300 mg followed 6 h later by 100, 150, or 200 mg every 6 h for patients assessed to weigh less than 55, 55-85, or greater than 85 kg, respectively or matching placebo. The primary exclusion criteria were overt heart failure, systolic BP less than 100 mmHg, significant heart block or history of urinary retention. Active drug or placebo was continued for 7 days or until (a) detection of "warning arrhythmias' requiring i.v. lignocaine intervention (greater than 5 for 7 days or until (a) detection of "warning arrhythmias' requiring i.v. lignocaine intervention (greater than 5 premature ventricular contractions (PVCs)/min, R on T PVCs, multifocal PVCs, bigeminal PVCs, ventricular tachycardia or ventricular fibrillation) or (b) onset of exclusion criteria. In addition, plasma drug concentrations were determined and 24 h electrocardiographic tapes were obtained on day 1, and on one of days 4-7 but these results are not presented here. 2 Out of 121 patients entering the trial, 101 had confirmatory ECG and enzyme changes. Of these, 9 of 47 patients receiving disopyramide phosphate required lignocaine compared to 20 of 54 receiving placebo (19% v 37%; P = 0.047). Corresponding numbers for patients discontinuing trial medication for other non-fatal complications of MI were 5 and 3, and for those dying, were 3 (2 infarct extensions and 1 massive infarction), and 0, respectively. Respective numbers discontinuing trial medication for possible drug side effects (viz. urinary retention requiring catheterization) were 6 and 1 (P = 0.031). 3 In circumstances where i.v. therapy is deemed impractical, use of oral disopyramide phosphate given prophylactically in patients with acute MI may reduce the incidence of "warning arrhythmias' by a clinically significant extent.

Adult↗
PubMed1984

Prophylaxis against ventricular arrhythmias in suspected acute myocardial infarction: a comparison of tocainide and disopyramide.

Five hundred and seventy one patients admitted to a coronary care unit with suspected acute myocardial infarction were considered for entry into a double-blind study. Two hundred and eighty-three patients were excluded, mainly because of recent treatment with beta-adrenoceptor blocking agents, life threatening arrhythmias requiring specific treatment and left ventricular failure presenting with hypotension or pulmonary oedema. Two hundred and eighty-eight entered the trial of whom 202 were subsequently confirmed to have had myocardial infarction. The effects of tocainide and disopyramide on ventricular arrhythmias were compared with placebo over the first 48 h period. The three treatments were given by a combination of intravenous infusion and oral administration. The doses used were tocainide 500 mg intravenously over 30 min plus 2800 mg orally over 48 h and disopyramide 150 mg intravenously over 30 min plus 1050 mg orally over 48 h. As judged by counts of ventricular premature beats, tocainide and disopyramide exerted a similar and significant antiarrhythmic effect. The median number of ventricular premature beats over the first 24 h of treatment was 58 on placebo compared with 30 on tocainide (P less than 0.05) and 19 on disopyramide (P less than 0.05). The corresponding figures for the second 24 h were 9, 6 and 2, respectively. There were eight deaths and three episodes of ventricular fibrillation with no significant differences between the three treatment groups. Sustained ventricular tachycardia was observed in one patient in the tocainide group.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1987

Quantitative and qualitative binding characteristics of disopyramide in serum from patients with decreased renal and hepatic function.

Protein binding of disopyramide, binding capacities, affinity constants and serum concentrations of alpha 1-acid glycoprotein (AAG) were studied in five groups of patients. A: young healthy volunteers (n = 8); B: elderly patients with minor symptoms of ischaemic heart disease (n = 9); C: patients with cirrhosis of the liver and normal values of coagulation factors (II, VII and X), albumin and immunoglobulin G (n = 8); D: patients with cirrhosis and at least two abnormal of the previously mentioned values (n = 9) and E: eleven patients with severely impaired renal function. Subfractions of AAG (Fr1, Fr2 and Fr3) were determined by affinoimmunoelectrophoresis. AAG concentration was significantly (P less than 0.005) elevated in group E patients and decreased (P less than 0.025) in group D patients. Fr2 is probably associated with the high affinity, first binding site of disopyramide to AAG. Earlier observations of a reduced qualitative binding of disopyramide in patients with cirrhosis can be explained by a significant decrease in Fr2 (P less than 0.001) in group D patients. The protein binding of disopyramide in patients with uraemia was significantly increased due to a significant (P less than 0.005) increase in AAG concentration in spite of a smaller (P less than 0.025) affinity constant. Suggestions for therapeutic drug monitoring based on total serum concentrations are given.

Adult↗
PubMed1982

Oral disopyramide dosage regimes in ischaemic heart disease.

The serum concentration/time profiles resulting from two oral disopyramide dosage regimes were studied in ten patients with ischaemic heart disease. Conventional dosing on a 6 r 8 hourly basis consistently achieved disopyramide concentrations within the accepted therapeutic range of 2-7 micrograms/ml. In contrast, a twice daily regime was associated in some patients with trough levels below the minimum effective concentration. The mean elimination half-life was 5.8 h; this does not substantiate previous reports of significantly prolonged disopyramide half-lives in patients with ischaemic heart disease. Unless significant renal impairment or cardiac failure is present, or a sustained release preparation is used, the dosage interval for oral disopyramide should not exceed 8 h.

Administration, Oral↗
PubMed1978

Electrophysiology of disopyramide in man.

The electrophysiological effects of an intravenous dose of disopyramide phosphate (2 mg per kg body weight) were studied in 17 patients. Studies were performed with the patients fasting, unpremedicated, and off all medication for three days. Blood samples for estimation of serum levels of disopyramide were collected in 15 of these patients. The effects of intravenous disopyramide were maximal at five minutes, less marked at 20 minutes, and largely gone by 30 minutes after administration of the drug. Sinus cycle length and corrected sinus node recovery time were shortened significantly. No index of atrioventricular nodal function was significantly changed. Both atrial and ventricular effective refractory periods were significantly prolonged. Further impairment of intraventricular conduction occurred in six patients with bundle branch block on electrocardiogram or prolonged HV interval. In one of two patients with Wolff-Parkinson-White syndrome, the bypass effective refractory period was prolonged. These electrophysiological changes are similar to quinidine and quinidine like drugs. It is recommended that disopyramide should be used cautiously in patients with evidence of His Purkinje system disease since it may lead to higher degrees of intraventricular block.

Adolescent↗
PubMed1987

Conversion from intravenous to oral slow-release disopyramide in acute myocardial infarction.

Twelve patients with acute myocardial infarction were given 1.5 mg/kg/5 min bolus +0.4 mg/kg/hr 6 hr IV infusion of disopyramide followed by 250 mg twice daily of a slow-release oral formulation of this drug. Plasma concentrations of total disopyramide rapidly reached steady-state within the therapeutic margins. The plasma steady-state concentrations of the major metabolite mono-N-dealkyl-disopyramide (MND) showed large intra-individual variations. There was no correlation between plasma levels of either disopyramide or MND and the occurrence of anticholinergic side effects. The drug had no significant effect on mean blood pressure, heart rate, or ECG intervals. This therapeutic regimen, including conversion from the IV form to oral slow-release tablets, could be recommended in myocardial infarction.

Adult↗
PubMed1994

Effects of disopyramide and flecainide on the kinetics of inward rectifier potassium channels in rabbit heart muscle.

1. Standard patch-clamp techniques were used to study the interaction of therapeutic concentrations of flecainide and disopyramide with single inwardly-rectifying potassium channels in cell-attached membrane patches from rabbit ventricular myocytes. 2. Under drug-free conditions, the potassium channels had a conductance of 31 +/- 2 pS (n = 13), a mean open time of 230 +/- 6 ms (n = 11) recorded at the resting cell potential, and an open probability of 0.66 +/- 0.20 (n = 39). The resting potential of the cells studied was -68.5 +/- 3.6 mV (n = 32). 3. Disopyramide did not reduce the open probability of the channel when the cell was voltage-clamped at the resting cell potential. However, disopyramide increased the mean open time of the channel, recorded at the resting cell potential, by 15% at 5 microM and by 29% at 20 microM. The action potential prolonging actions of disopyramide in therapeutic concentrations appear not to be due to blocking the inward rectifier K+ channel. 4. Flecainide (3.0 microM, but not at 0.5 microM) decreased the open probability without changing the conductance of the channel, at 3 microM (51.0 +/- 7.2%, n = 6, P = 0.03) at the resting cell potential. Flecainide increased the mean open time of the channel, recorded at the resting cell potential, by 12% at 3.0 microM. 5. We propose that flecainide stabilized the inward rectifier K+ channel in an inactivated state, without plugging the conducting pore. In addition, it appeared to bind to an open conformation of the channel,since some of the reduction in open probability could be accounted for by the lengthening of the mean open time. The changes in open-state kinetics suggest that this binding may be in the region of the activation gate.

Animals↗
PubMed1979

Intravenous disopyramide phosphate and ventricular overdrive pacing in the termination of paroxysmal ventricular tachycardia.

Both antiarrhythmic drugs and bursts of rapid ventricular pacing provide alternatives to DC cardioversion for the treatment of paroxysmal ventricular tachycardia. This report considers the individual and combined success of burst ventricular pacing and intravenous disopyramide phosphate in the tretment of 11 examples of paroxysmal ventricular tachycardia. Rapid ventricular pacing, at a rate of up to 50 beats/min faster than the tachycardia rate terminated 7 of the tachycardias. Intravenous disopyramide resulted in increased tachycardiac cycle length (342 +/- 34 ms-385 +/- 56 ms), increased QRS complex width (147 +/- 42 ms-180 +/- 41 ms) and termination of 8 the tachycardias. The remaining 3 tachycardias could be terminated by bursts of ventricular pacing following the infusion of disopyramide. Of these, 2 could not be terminated prior to disopyramide. The use of both techniques allowed the extinction of all 11 tachycardias and prevented the need to proceed to DC conversion.

Adult↗
PubMed1987

Haemodynamic effects of disopyramide using a new model of intravenous administration.

Intravenous treatment with disopyramide is usually performed by administration of a bolus injection of 150 mg given over 5 min. followed by a continuous infusion of 18-24 mg hour-1. A decrease in cardiac output is associated with this rapid bolus injection. Seven patients with ischaemic heart disease entered an open randomised cross-over trial to elucidate if an extension of the bolus injection time to 20 min. resulted in a smaller decrease in cardiac output. Cardiac index decreased significantly (P less than 0.001) in both situations, with maximum decrease observed at time 5 and 20 min., respectively (equivalent to the ending of the administration of 150 mg disopyramide). The decrease in Cardiac index (mean +/- S.E.M.) was identical in the two situations (2.56 +/- 0.23 to 1.78 +/- 0.21 l/min. X m2 (30%) and 2.66 +/- 0.17 to 1.94 +/- 0.19 l/min. X m2 (27%], respectively. Blood pressure was unchanged, while heart-rate (P less than 0.025) and preejection period index (P less than 0.005) increased significantly and to the same extent in the two situations. Significant correlations between the log free and log total serum concentration of disopyramide and the relative change in preejection period index of r = 0.840 (P less than 0.01) and 0.919 (P less than 0.01), respectively, were observed giving disopyramide over 5 min. A significant anticlockwise hysteresis was observed extending the time of administration to 20 min. As no haemodynamic advantages are achieved by the slower way of administration we would still recommend the bolus injection to be given over 5 min.

Disopyramide↗
PubMed1985

Protein binding of disopyramide--displacement by mono-N-dealkyldisopyramide and variation with source of alpha-1-acid glycoprotein.

The binding of disopyramide to human serum proteins and human alpha-1-acid glycoprotein (AAG) was determined over a wide drug concentration range. Addition of 3.7 X 10(-6) mol litre-1 mono-N-dealkyldisopyramide caused a 20-100% increase in disopyramide free fraction. The disopyramide free fraction in AAG solutions prepared from various commercially available sources of alpha-1-acid glycoprotein varied up to 2.5 fold at corresponding disopyramide concentrations. Pronounced differences in the calculated binding constants (affinity and capacity) were observed among the commercially available AAG preparations. These findings suggest that binding studies should be performed in appropriately harvested human serum or plasma to avoid possible artifacts associated with the use of commercial preparations of alpha-1-acid glycoprotein for binding studies.

Binding, Competitive↗
PubMed1983

Treatment of recurrent sustained ventricular tachycardia with mexiletine and disopyramide. Control by programmed ventricular stimulation.

Oral antiarrhythmic treatment with mexiletine and disopyramide was evaluated in 34 patients with recurrent sustained ventricular tachycardias by programmed ventricular stimulation, except in a few instances where spontaneous attacks occurred under therapy. Coronary heart disease was present in 17 patients, cardiomyopathy in 11, myocarditis in five, and mitral valve prolapse in one. Complete suppression of ventricular tachycardia was observed in three of 30 patients under mexiletine and in one of 25 patients under disopyramide. Disopyramide slowed the rate of the ventricular tachycardia considerably, while mexiletine had no such influence. For a mean of 24 months, 19 patients were maintained on either substance. Complete suppression of ventricular tachycardia during programmed stimulation predicted freedom from recurrences. Ventricular tachycardias recurred less frequently and at a slower rate in the other patients, but 31% have died. This study shows that complete suppression of ventricular tachycardia by mexiletine or disopyramide can be achieved only in a minority of patients with previously drug-resistant tachycardias.

Adult↗