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PubMed1993

Relative bioavailability of two disopyramide capsules in humans based on total, unbound, and unbound enantiomer concentrations.

The relative bioavailability of two 100-mg disopyramide formulations which showed almost an 8- to 10-fold difference in their dissolution rates at pH 1.2 and 6.8 was determined in eight healthy subjects using a randomized block design. Although no significant differences in relative bioavailability were observed between the two formulations when based on the total disopyramide concentration, an almost 30 per cent difference in the extent of bioavailability was observed when assessed in terms of the unbound (+/-)- and (-)-disopyramide concentration, due probably to stereoselective nonlinear plasma protein binding. This suggests that unbound enantiomer parameters would be more sensitive to differences in bioavailability between two disopyramide formulations. Therefore, the type of concentration used would be an important factor for precise evaluation of the relative bioavailability of racemic drugs.

Adult↗
PubMed1979

Disopyramide kinetics in patients with acute myocardial infarction.

The kinetic behavior of disopyramide was studied in 20 patients with suspected myocardial infarction: in 13 of these, the diagnosis was subsequently confirmed. All received a 400-mg oral loading dose of disopyramide base followed by an oral maintenance regimen of either 100 or 200 mg 4 times daily. The elimination half-life (t1/2beta) was longer (p less than 0.05) in patients with confirmed infarction than in patients with unconfirmed infarction [38.0 +/- 3.7 hr (mean +/- SEM) compared to 24.3 +/- 0.8 hr, and 21.2 +/- 2.1 hr compared to 7.2 +/- 2.4 hr for the 100- and 200-mg maintenance dose regimens, respectively]. The t1/2beta was dose dependent for infarct and noninfarct patients. Two of the patients with confirmed infarction failed to reach trough plasma levels equal to or exceeding the lower end of the manufacturer's recommended therapeutic range (3.3 mug/ml) during the study. For the remaining 11 patients the time taken to achieve trough plasma levels of 3.3 mug/ml varied from 18 to 170 hr; hence plasma disopyramide concentration in these patients was suboptimal at a time when the risk of arrhythmias is high. Modification of existing oral loading dose regimens is therefore required for optimization of oral disopyramide therapy.

Administration, Oral↗
PubMed1997

Enantiomer separation of disopyramide with capillary electrophoresis using various cyclodextrins.

Enantiomers of disopyramide display different biological actions, and therefore chiral selective analysis is necessary. Fifteen different cyclodextrins (CDs) and CD derivatives were tested as capillary electrophoresis (CE) additives for the chiral separation of disopyramide. Eleven types of CDs showed chiral recognition features and four types had a baseline or close to baseline separation. The best resolution (Rs = 3.0) was with 15 mM carboxymethylated beta-CD (pH 4.9). A sharp decrease in the selectivity of gamma-phosphate (gamma-PhoCD) was observed in the pH range of 2-3, indicating a structural change of gamma-PhoCD. The enantiomers of disopyramide were separated in its ionized as well as neutral forms using acidic substituted CDs. The results show that the size of the CD cavity can not be used as a guide to estimate chiral separations, suggesting a more complex separation mechanism of these CDs towards disopyramide.

Cyclodextrins↗
PubMed1994

Bioavailability of total and unbound disopyramide: implications for clinical use of the immediate and controlled-release dosage forms.

This study further characterized the impact of concentration-dependent protein binding on the bioavailability and clinical use of the immediate-release (IR) and controlled-release (CR) dosage forms of disopyramide after single doses and during steady-state conditions in ten healthy volunteers. Consistent with the clinical use of these products, steady state has incorporated an IR to CR conversion step. Side effects and electrocardiographic actions were quantitated using a visual analog scale and serial Holter monitor recordings, respectively. Significant decreases resulted in area under the curve for total disopyramide between single dose and steady state: IR, 47.8 +/- 13.6 versus 33.0 +/- 6.4 mg/Lxh (P < .05); and CR, 46.9 +/- 9.5 versus 31.7 +/- 5.9 mg/Lxh (P < .05). In contrast, there were no differences in area under the curve for unbound disopyramide between phases or products. During conversion, the mean IR peak significantly decreased (P < .05) to the nadir before the first CR dose for total (37%) and unbound (60%) concentrations. There were no major differences in change in QT interval or side effects detected between products or phases. These findings indicate that, because of concentration-dependent protein binding, unbound, not total, concentrations should be used to estimate the bioavailability of disopyramide. Also, although the previously recommended conversion method (first CR dose 6 hours after the last IR dose) should provide an adequate transition in most, an alternative method (combined first CR with last IR dose) is indicated in select patients.

Adolescent↗
PubMed1975

Linear relationships between plasma binding and lipophilicity of disopyramide derivatives.

The extent of plasma binding and the partition coefficient of disopyramide and 20 disopyramide derivatives were determined. Structural variations on the four functional groups around the tetrahedral carbon in the disopyramide molecule was found to influence both parameters to varying degrees. Three linear equations were developed to correlate the observed effects, depending on the type of chemical modification. The linear correlation between drug-plasma interaction and lipophilic character was analyzed theoretically. A simple model was derived to relate quantitatively the variation in the extent of plasma binding to the change in lipophilicity of disopyramide derivatives.

Arrhythmias, Cardiac↗
PubMed1984

Binding of disopyramide to alpha 1-acid glycoprotein in plasma measured by competitive equilibrium dialysis.

A modification of equilibrium dialysis in which alpha 1-acid glycoprotein and plasma compete directly for disopyramide has been used in conjunction with binding curves to measure the extent of the alpha 1-acid glycoprotein-disopyramide interaction. At concentrations in the therapeutic range, 80-90% of disopyramide was bound to alpha 1-acid glycoprotein for plasma from each of six healthy adults. Also, equilibrium dialysis data are presented, indicating that pH does not influence the binding of disopyramide within the therapeutic range.

Dialysis↗
PubMed1992

Effect of disopyramide on left ventricular diastolic function in patients with hypertrophic cardiomyopathy: comparison with diltiazem.

Left ventricular diastolic function before and after the administration of disopyramide (100 mg) or diltiazem (30 mg) was assessed in 10 patients with nonobstructive type hypertrophic cardiomyopathy. Left ventricular diastolic function was assessed by Doppler echocardiography. The peak early (E) and late (A) diastolic flow velocities and E/A ratio (E/A) were measured. Three hours after the administration of disopyramide, blood pressure did not significantly change, but heart rate was decreased significantly (p less than 0.01). Disopyramide increased the E velocity and E/A ratio from 43.8 +/- 15.0 cm/sec to 51.3 +/- 16.1 cm/sec and from 0.71 +/- 0.20 to 1.00 +/- 0.24 (each p less than 0.01), respectively, and decreased the A velocity from 63.9 +/- 18.5 cm/sec to 52.1 +/- 14.9 cm/sec (p less than 0.01). Diltiazem increased the E velocity and E/A ratio from 42.8 +/- 12.5 cm/sec to 46.4 +/- 13.4 cm/sec (p less than 0.05) and from 0.74 +/- 0.21 to 0.96 +/- 0.28 (p less than 0.01), respectively, and decreased the A velocity from 60.6 +/- 16.4 cm/sec to 50.2 +/- 15.6 cm/sec (p less than 0.01). These results indicate that disopyramide improved left ventricular diastolic filling in hypertrophic cardiomyopathy, and its effect was similar to that of diltiazem.

Adult↗
PubMed1986

Disopyramide in acute myocardial infarction: problems with changing pharmacokinetics.

In the acute phase of myocardial infarction it is recognized that serum disopyramide concentrations may be lower than expected. This has generally been attributed to reduced oral bioavailability. This report describes data obtained routinely from 6 patients with acute myocardial infarction and cardiac dysrhythmias treated initially with intravenous disopyramide. Serum disopyramide concentrations were consistently lower than expected, on average by 2.6 micrograms/ml. This was interpreted as being due to relatively high drug clearance, calculated as 6.7 +/- 1.5 l/h, compared to expected values of 3-4 l/h. Dosage schedules determined on the basis of the acute phase pharmacokinetics subsequently produced higher than predicted concentrations at later times on average by 2.8 micrograms/ml. Clearance at this time was calculated to be 3.1 +/- 0.6 l/h. Thus even with intravenous disopyramide therapy there are problems with changing pharmacokinetic parameters after myocardial infarction.

Aged↗
PubMed1983

Prajmalium bitartrate in chronic ventricular arrhythmias: comparison with disopyramide.

24-h ECG recordings were used to assess the efficacy of prajmalium bitartrate (PB) in reducing the incidence and the severity of premature ventricular complexes (PVCs), and to compare its antiarrhythmic action with that of Disopyramide. 13 patients with frequent PVCs were distributed randomly into 2 groups. The first group of 7 patients received PB 80 mg/day for 4 days as their first treatment, and disopyramide 400 mg/day for a further 4 days as the second therapy. The succession of the drugs was reversed in the other group of 6 patients. Analysis of the Holter recordings showed that PB and disopyramide reduced PVC frequency to a similar extent as compared to the corresponding wash-out period, viz. by 56.7% (p less than 0.05) and 62.1% (p less than 0.01), respectively. Thus, PB appears to be an effective antiarrhythmic drug and comparable to disopyramide. It may be used to prevent premature ventricular complexes and runs of ventricular tachycardia.

Adult↗
PubMed1986

Efficacy of and adverse effects of disopyramide. Comparison of capsules, controlled release tablets and placebo in patients with chronic ventricular arrhythmias.

The efficacy of disopyramide compared to placebo for exercise induced ventricular arrhythmias was tested in a double-blind randomized controlled clinical trial with cross-over design in 14 patients with coronary heart disease. Disopyramide was given as ordinary capsules (q.i.d.) or as a slow release preparation (b.i.d.) in a total dose of 600 mg per day. The placebo preparations were identical looking capsules and tablets. Each treatment period lasted one week. Efficacy was assessed by a standardized exercise test on a bicycle ergometer and a 6-h Holter monitoring at the end of each period. Plasma levels of disopyramide, measured in conjunction with exercise test, fell within therapeutic range, with a mean value of 7.9 and 8.9 mumol/l for capsules and slow release tablets, respectively. Disopyramide gave a marked and significant reduction of ventricular ectopic beats both at rest and during and after exercise. There was also a significant decrease in the number of ectopic beats recorded on tape during treatment periods compared to during placebo periods. There were no differences between the two preparations with respect to antiarrhythmic effect. Only mild side-effects, mainly mild anticholinergic symptoms, similar for both preparations were reported. No significant cardiovascular changes (heart rate and blood pressure response) were observed.

Aged↗
PubMed1985

Atenolol inhibits the elimination of disopyramide.

The effect of atenolol on the total elimination of disopyramide and its main dealkylated metabolite was studied in 6 patients and 3 volunteers. During administration of 50 mg atenolol b.i.d. the clearance of disopyramide decreased significantly (p less than 0.02) from 1.90 +/- 0.71 (mean +/- SD) to 1.59 +/- 0.68 ml/kg/min, while its half-life, concentration of the metabolite, and the volume of distribution remained unchanged. The reduction in the clearance of disopyramide by atenolol might contribute to the alleged pharmacodynamic interaction between disopyramide and beta-blocking drugs.

Adult↗
PubMed1993

Kinetics of interaction of disopyramide with the cardiac sodium channel: fast dissociation from open channels at normal rest potentials.

Block of cardiac sodium channels is enhanced by repetitive depolarization. It is not clear whether the changes in drug binding result from a change in affinity that is dependent on voltage or on the actual state of the channel. This question was examined in rabbit ventricular myocytes by analyzing the kinetics of block of single sodium channel currents with normal gating kinetics or channels with inactivation and deactivation slowed by pyrethrin toxins. At -20 and -40 mV, disopyramide 100 microM blocked the unmodified channel. Mean open time decreased 45 and 34% at -20 and -40 mV during exposure to disopyramide. Exposure of cells to the pyrethrin toxins deltamethrin or fenvalrate caused at least a tenfold increase in mean open time, and prominent tail currents could be recorded at the normal resting potential. The association rate constant of disopyramide for the normal and modified channel at -20 mV was similar, approximately 10 x 10(6)/M/sec. During exposure to disopyramide, changes in open and closed times and in open channel noise at -80 and -100 mV are consistent with fast block and unblocking events at these potentials. This contrasts with the slow unbinding of drug from resting channels at similar potentials. We conclude that the sodium channel state is a critical determinant of drug binding and unbinding kinetics.

Animals↗
PubMed2005

Atrial pacing failure following termination of atrial fibrillation by acute administration of disopyramide phosphate.

Atrial pacing failure occurred after termination of atrial fibrillation by acute administration of disopyramide phosphate in a 71-year-old woman implanted with an AAI pacemaker for sick sinus syndrome. The atrial pacing threshold showed an 810% increase; however, the serum concentration of disopyramide corresponded to therapeutic level. Infusion of the same dose of disopyramide phosphate used during the period of atrial pacing rhythm did not increase the atrial pacing threshold. In the present patient, we supposed that atrial pacing failure did not occur by the effect of disopyramide alone, but rather was a reciprocal action in response to atrial fibrillation.

Aged↗
PubMed1983

Concurrent use of quinidine and disopyramide: evaluation of serum concentrations and electrocardiographic effects.

The effects of concurrent disopyramide phosphate and quinidine sulfate therapy were studied in 16 normal healthy adults. No adverse effects serious enough to warrant discontinuation of therapy were observed. There was a small but significant increase in disopyramide serum concentration when concurrent quinidine therapy was given and a small decrease in quinidine serum concentration when disopyramide was added. No significant change in elimination half-life was seen for either drug. Both drugs produced prolongation of the corrected QT interval. This QT prolongation was greater for quinidine than for disopyramide.

Adult↗
PubMed1983

Safety of multiple bolus loading of intravenous disopyramide.

Although a single intravenous bolus of disopyramide is an effective antiarrhythmic, side effects occur in some patients. We tested the safety of multiple bolus loading for intravenous disopyramide in 10 patients with frequent premature ventricular beats. Concurrent with a 1.0 mg/kg/hr infusion, a bolus of 0.5 mg/kg of disopyramide was given over 5 minutes. Up to three additional boluses were given 5 minutes after the first bolus unless a 50% reduction in premature ventricular beats or side effects occurred. The infusion was continued for 3 hours and was then decreased to 0.4 mg/kg/hr for 15 hours. All patients had a 50% reduction in premature ventricular beats and attained therapeutic blood levels. Three patients with a history of controlled congestive heart failure developed either hypotension or pulmonary edema. Hypotension and pulmonary edema following intravenous disopyramide is more related to the pharmacology of the drug than to the loading scheme employed.

Adult↗
PubMed1984

A double-blind, crossover comparison of flecainide acetate and disopyramide phosphate in the treatment of ventricular premature complexes.

The efficacy and safety of flecainide, 200 mg twice daily, was compared with disopyramide, 150 mg 4 times daily, in a randomized, double-blind, crossover study in 25 patients (19 men and 6 women, aged 20 to 71 years, mean 52.5) with more than 1,000 ventricular premature complexes (VPCs) in a pretrial 24-hour Holter monitoring screen. Each 14-day active treatment period was preceded and followed by a 7-day placebo period. Ambulatory ECGs were recorded at the end of each study week and analyzed blindly. Average VPCs recorded during each of the 2 active periods were compared with average VPCs in the placebo periods. Twenty-two of 25 patients attained therapeutic plasma levels of both drugs. The occurrence of VPCs was significantly less during flecainide than during disopyramide treatment, 92 and 39%, respectively (p less than 0.01). Complex arrhythmic events were significantly more suppressed with flecainide than with disopyramide. No difference was observed between the 2 drugs in the incidence or severity of reported side effects. PQ, QRS and QT intervals increased beyond normal limits on both drugs in some patients, significantly more with flecainide than with disopyramide. The JT interval did not change or decrease; hence, all changes in the QT interval were attributable to a widening of the QRS complex. Neither drug showed any significant effect on blood pressure or heart rate. Flecainide may be a well-tolerated and valuable alternative to currently available antiarrhythmic agents.

Adult↗
PubMed1987

Antiarrhythmic efficacy of Ethmozine (moricizine HCl) compared with disopyramide and propranolol.

In the investigation of new antiarrhythmic drugs, comparative trials with clinically available antiarrhythmic agents provide a perspective from which to judge the new investigational agent. Two clinical investigations of moricizine HCl, each using a placebo-controlled, double-blind, crossover design, are summarized. In the first study, 18 patients with greater than or equal to 30 ventricular premature complexes (VPCs) per hour (mean 369 +/- 95) were given propranolol (120 mg daily) compared with moricizine HCl (816 +/- 103 mg daily). Propranolol suppressed 38% of VPCs in the study group, moricizine HCl, 81% of VPCs, and the combination of both drugs, 87%. Moricizine HCl was more effective than propranolol in suppressing VPCs at all individual levels greater than 70% (p less than 0.05, McNemar's test). The combination of moricizine HCl and propranolol was well tolerated. The second investigation used a placebo-controlled, double-blind, crossover design to compare the efficacy of disopyramide (600 mg daily) and moricizine HCl (800 mg daily) in 27 patients. Patients had greater than or equal to 40 VPCs/hr on a 24-hour ambulatory electrocardiogram. During moricizine HCl administration, the mean VPC frequency decreased from 524 to 151 VPCs/hr (71.2% reduction). In contrast, disopyramide reduced VPC frequency from 535 to 253 VPCs/hr (52.8% reduction) and demonstrated significantly greater side effects (p less than 0.05). Moricizine HCl was more effective than disopyramide in suppressing VPCs at all individual percent reduction levels greater than 70% (p less than 0.05, McNemar's test). Moricizine HCl was more effective in suppressing VPCs than either disopyramide or propranolol, with significantly fewer side effects.

Adult↗
PubMed1988

Disopyramide in hypertrophic cardiomyopathy. I. Hemodynamic assessment after intravenous administration.

The hemodynamic effects of intravenous disopyramide were determined in 43 patients with hypertrophic cardiomyopathy and pressure gradients at rest (resting obstruction). The basal subaortic pressure gradient decreased in all patients by a mean of 61 mm Hg (range 16 to 123); in 35 patients the gradient was abolished (less than 20 mm Hg). The reduction in pressure gradient was achieved through a decrease in left ventricular systolic pressure, from 178 to 135 mm Hg (p less than 0.0001), and a rise in aortic systolic pressure, from 105 to 123 mm Hg (p less than 0.0001). Left ventricular ejection time was reduced from 326 to 273 ms (p less than 0.0001). Left ventricular end-diastolic pressure decreased from 19 to 16 mm Hg (p less than 0.0001). In a subgroup of 13 patients, cardiac output was unchanged after disopyramide, despite a prolongation of the pre-ejection period from 104 to 137 ms (p less than 0.0001) indicating a decrease in contractility. The maintenance of cardiac output, despite a decrease in contractility, may reflect a decrease in mitral regurgitation resulting from the reduction of systolic anterior motion of the mitral valve by disopyramide. These results indicate that disopyramide produces predictably favorable hemodynamic effects in patients with hypertrophic cardiomyopathy and resting obstruction to left ventricular outflow.

Adolescent↗