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PubMed2000

Potentially fatal interaction between azithromycin and disopyramide.

A patient on disopyramide developed disopyramide toxicity when treated concurrently with azithromycin. Evidence of toxicity included an elevated serum disopyramide level and ventricular tachycardia requiring cardioversion. The azalide antibiotic presumably inhibited dealkylation of disopyramide to its major metabolite, mono-N-dealkyldisopyramide. Physicians should avoid using azithromycin in patients on disopyramide. If this drug combination is unavoidable, disopyramide levels must be closely monitored.

Adult↗
PubMed1985

Kinetics of disopyramide after intravenous infusion to patients with myocardial infarction and heart failure.

Total body clearance, half-life and volume of distribution of disopyramide (Norpace, Searle G.D.) was measured during a six to eight hour infusion to steady state in twenty four patients with either congestive heart failure or acute myocardial infarction and compared to eleven patients without these diseases. All patients were given a bolus injection of 150 mg disopyramide followed by a continuous infusion of 18-24 mg per hour. Serum concentration of disopyramide and its main dealkylated metabolite were determined by HPLC. The clearance in patients without myocardial infarction or congestive heart failure was 1.71 +/- 0.60 ml/min./kg (mean +/- S.D.), not significantly different from those who had either myocardial infarction, congestive heart failure or both. Half-life was 798 min. in patients without heart failure, not significantly different from the values in the other groups. The ratio between disopyramide and its metabolite varied between 3 to 10. Twenty-six % of the steady state serum concentrations of disopyramide were outside the recommended therapeutic range (2-5 micrograms/ml), but no adverse haemodynamic effects were observed in any of the patients. The suggested dosage regimen of disopyramide seems to result in a satisfactory response.

Aged↗
PubMed1988

Elimination kinetics and urinary excretion of disopyramide in human healthy volunteers.

Elimination kinetics and the renal handling of disopyramide was examined in 8 healthy volunteers. Approximately 50% of the administered disopyramide undergoes hepatic metabolism (metabolic clearance = 116.1 +/- 42.2 ml/min.), while the rest is excreted by the kidneys (renal clearance = 101.9 +/- 21.6 ml/min.). Total renal excretion rate of disopyramide was 0.676 +/- 0.188 mumol/min. and 0.258 +/- 0.029 mumol/min. was excreted by glomerular filtration leaving a net tubular secretion of 60% of the total renal elimination. A significant positive correlation was observed between total serum concentrations and renal clearance values of disopyramide while no significant correlation could be obtained between serum concentrations of the unbound drug and renal clearance values of disopyramide, implying a constant value of unbound renal clearance. Hepatic blood flow was significantly (P less than 0.005) decreased following disopyramide infusion.

Adult↗
PubMed1983

Selective blockade of retrograde fast pathway by intravenous disopyramide in paroxysmal supraventricular tachycardia mediated by dual atrioventricular nodal pathways.

Electrophysiological effects of 2 to 2.5 mg/kg iv disopyramide were studied in 10 patients with dual nodal pathways who used a slow pathway for anterograde and a fast pathway for retrograde conduction during paroxysmal supraventricular tachycardia (mean cycle length 308.5 +/- 37 ms; range 260-370 ms). Disopyramide terminated the tachycardia in six cases by production of ventriculoatrial block in five and by sinus overdrive in one. In the remaining four patients cycle length of the paroxysmal supraventricular tachycardia increased significantly from 270 +/- 8 ms to 377.5 +/- 28 ms. In all 10 patients disopyramide depressed retrograde fast pathway conduction manifest by an increase in mean ventricular paced cycle length producing ventriculoatrial block from less than or equal to 296.5 +/- 25 ms to 358 +/- 60 ms, and increase in retrograde fast pathway effective refractory period from less than or equal to 246 +/- 34 ms to 325 +/- 36 ms; the drug abolished ventriculoatrial conduction in two cases. Anterograde slow pathway and fast pathway conduction properties were unchanged after disopyramide (atrial paced cycle length producing AH block 292 +/- 30 to 306.5 +/- 30 ms; effective refractory period of anterograde fast pathway less than or equal to 274 +/- 56 to 284 +/- 44 ms, before and after the drug, respectively) suggesting that anterograde conduction was not crucial either for sustainment or for failure to initiate paroxysmal supraventricular tachycardia after the drug. Paroxysmal supraventricular tachycardia could not be reinduced in six cases after disopyramide. In the other four the ventricular paced cycle lengths producing ventriculoatrial block (318 +/- 41 ms) and effective refractory period of retrograde fast pathway (320 +/- 28 ms) were shorter than the cycle length of reinduced paroxysmal supraventricular tachycardia (367.5 +/- 35 ms) allowing perpetuation of the tachycardia. We conclude that disopyramide breaks atrioventricular nodal re-entrant tachycardia by specific blockade of the retrograde fast pathway though the effect on anterograde atrioventricular nodal conduction is variable.

Adult↗
PubMed1985

Disopyramide induced second and third degree atrioventricular block in patients with bifascicular block. An acute stress test to predict atrioventricular block progression.

Syncopal attacks in patients with bifascicular block may be due to both ventricular tachyarrhythmias and intermittent atrioventricular block in addition to non-cardiac causes and lead to antiarrhythmic treatment with drugs or pacemaker or both. The acute electrophysiological effect of intravenous disopyramide 2 mg/kg body weight given over five minutes on the His-Purkinje system was assessed in 27 patients with chronic bifascicular block undergoing evaluation for permanent pacemaker treatment. The predictive value of this pharmacological stress test as regards the development of atrioventricular block during follow up was analysed. The HV interval increased (mean 43%) and the QRS duration was prolonged (mean 24%). Intrahisian or infrahisian second or third degree atrioventricular block occurred in 14 patients after disopyramide administration, requiring temporary pacing in four of them. Before the electrophysiological study 15 of the 27 patients had had at least two syncopal attacks of suspected cardiac origin but no evidence of second or third degree atrioventricular block. Second or third degree atrioventricular block was subsequently recorded in five of these 15 patients during a mean of two years follow up. The sensitivity, specificity, and predictive value of second or third degree atrioventricular block produced by disopyramide administration including subsequent atrial pacing--a positive disopyramide test--as regards later development of atrioventricular block were 80%, 90%, and 80% respectively. Intravenous administration of disopyramide to patients with bifascicular block and syncopal attacks of suspected cardiac origin may provoke atrioventricular block and asystole requiring immediate temporary pacing. Furthermore, a positive disopyramide test seems to have a significant value in predicting the later development of atrioventricular block.

Adult↗
PubMed1978

The electrophysiological effects of disopyramide phosphate on canine ventricular muscle and Purkinje fibers in normal and low potassium.

We studied the effect of lowering the extracellular potassium concentration ([K+]o) on the electrophysiological actions of disopyramide phosphate, a new antiarrhythmic drug. At low [K+]o, therapeutic concentrations of disopyramide phosphate caused significantly less depression of action potential amplitude and maximum upstroke velocity of both Purkinje fiber and ventricular muscle action potentials. The drug shifted the membrane responsiveness curve along the voltage axis to more negative membrane potentials regardless of [K+]o. However, a greater shift occurred when [K+]o was normal. Disopyramide phosphate prolonged both action potential duration and effective refractory period in all fibers but there was consistently greater prolongation of these parameters at low [K+]o. More importantly, disopyramide phosphate altered repolarization time course of action potentials in such a way that action potentials with dissimilar durations throughout the ventricular conducting system became more equal. The drug was less effective in decreasing this disparity in action potential durations throughout the ventricles in the presence of low [K+]o. These modifications of the electrophysiological actions of disopyramide by low [K+]o suggest that a therapeutic concentration of disopyramide might have less of an antiarrhythmic effect in the presence of hypokalemia.

Action Potentials↗
PubMed1989

Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers.

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. Vmax was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of Vmax depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on Vmax. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on Vmax but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 +/- 535 ms and 15.7 +/- 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when Vmax depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.

Action Potentials↗
PubMed1993

Disopyramide blocks pancreatic ATP-sensitive K+ channels and enhances insulin release.

An antiarrhythmic agent, disopyramide, was found to enhance the insulin secretory capacity of Wistar rat pancreatic islets with a half-maximal concentration of 23.3 microM. Employing a patch-clamp technique, disopyramide was found to inhibit ATP-sensitive K+ (KATP) channel activity in rat pancreatic beta-cells in primary culture without altering the unitary conductance. Half-maximal inhibition was achieved by the addition of 3.6 microM disopyramide to the intracellular bathing solution in the inside-out mode, 11.0 microM to the extracellular bathing solution in the outside-out mode, and 87.4 microM in the cell-attached mode. The binding of [3H]glibenclamide to pancreatic islets was inhibited by unlabeled glibenclamide but not by unlabeled disopyramide. Based on these observations, it is concluded that disopyramide blocks pancreatic KATP channels via binding to a site(s) distinct from the sulfonylurea receptor. This effect may be causatively involved in disopyramide-induced hypoglycemia.

Adenosine Triphosphate↗
PubMed1979

Electrophysiological effects of disopyramide in patients with bundle branch block.

Electrophysiological studies were performed in 22 patients with intraventricular conduction delay before and after intravenous infusion of disopyramide (Norpace), 2 mg/kg. Mean control maximal sinus node recovery time (1039 +/- 187 msec), atrioventricular nodal conduction time (113 +/- 28 msec), and atrioventricular nodal effective refractory periods (349 +/- 67 msec) did not change significantly after administration of disopyramide (1073 +/- 284 msec, 112 +/- 31 msec, and 342 +/- 42 msec, respectively). Mean spontaneous cycle length (756 +/- 146 msec) decreased significantly 5 minutes after disopyramide (717 +/- 124 msec) (p less than 0.05), but not after 30 minutes (734 +/- 142 msec). A small but statistically significant (p less than 0.05) increase occurred after disopyramide in the mean atrial effective refractory period (259 +/- 51 to 280 +/- 53 msec), ventricular effective refractory period (253 +/- 23 to 275 +/- 33 msec), as well as the relative refractory period of the ventricular specialized conduction system (six patients) 433 +/- 78 to 479 +/- 62 msec). Although mean control infranodal conduction time (67 +/- 35 msec) increased 5 minutes after disopyramide (79 +/- 41 msec) (p less than 0.001) (18%), no spontaneous episodes of second-degree or third-degree atrioventricular block were observed. In six patients with premature ventricular depolarizations (greater than or equal to 1/min), the arrhythmia was totally abolished in four, markedly reduced in one, and remained unchanged in one. Disopyramide resulted in significant prolongation of infranodal conduction time as well as in atrial and ventricular refractoriness, but nevertheless appears to be safe in patients with bundle branch block.

Atrioventricular Node↗
PubMed1979

Electrophysiologic effects of disopyramide phosphate on sinus node function in patients with sinus node dysfunction.

The electrophysiologic effects of intravenously administered disopyramide (2 mg/kg) on three parameters of sinus node function were examined in 16 symptomatic patients with sinus node dysfunction. Based on their ECG data before study, patients were subdivided into group A (n = 8), those with sinus pauses and/or sinoatrial (SA) exit block; and group B (n = 8), those with sinus bradycardia. Disopyramide shortened spontaneous cycle length in 10 of 16 patients and lengthened it in six--markedly so (91%) in one patient. Estimated SA conduction time decreased in seven of 14 patients and increased in seven. Two patients developed second degree SA exit block after disopyramide. Maximum sinus node recovery time was prolonged by disopyramide in 11 of 16 patients and markedly so in four. For the group as a whole there was no significant difference in spontaneous cycle length, maximum sinus node recovery time or estimated SA conduction time. P-wave and QRS durations and H-V intervals were significantly lengthened by disopyramide. Marked depression of the three parameters of sinus node function occurred in three group A patients and in one group B patient who had persistent severe sinus bradycardia. These four patients also had secondary pauses after termination of rapid atrial pacing under control conditions. Disopyramide should be administered cautiously to patients with sinus node dysfunction, particularly those with sinus pauses, SA exit block or secondary pauses.

Adult↗
PubMed1981

Effects of oral disopyramide phosphate on induction of paroxysmal supraventricular tachycardia.

The effects of oral disopyramide phosphate on laboratory induction of paroxysmal supraventricular tachycardia (PSVT) were studied in 16 patients with clinical PSVT. After control electrophysiologic study to determine the inducibility and mechanism of PSVT, patients were given 200-300 mg (275 +/- 45 mg, mean +/- SD) of disopyramide for three to five doses over 24 hours and were then restudied. All patients had inducible, sustained PSVT during the control study. After disopyramide, PSVT was noninducible in eight patients (50%), including six of nine with atrioventricular nodal reentrance and two of seven with atrioventricular reentrance; inducible but nonsustained in two (12.5%) (both with atrioventricular reentrance); and inducible and sustained in six (37.5%). The benefit of disopyramide seemed predominantly to reflect depression of conduction in the retrograde limb of the circus movements, although effects upon the antegrade limb were also observed. In the eight patients with inducible PSVT before and after disopyramide, tachycardia cycle length increased from 348 +/- 33 to 404 +/- 29 msec (mean +/- SEM) (p less than 0.001). These results suggest that disopyramide would be effective in preventing recurrence of clinical PSVT in selected patients.

Administration, Oral↗
PubMed1984

Comparative effect of disopyramide and ethmozine in suppressing complex ventricular arrhythmias by use of a double-blind, placebo-controlled, longitudinal crossover design.

This placebo-controlled, double-blind, longitudinal crossover study compares the efficacy of disopyramide and ethmozine, a new investigational drug, in suppressing frequent (40 or more per hour) ventricular premature depolarizations (VPDs) in 27 patients completing a 37 day protocol. Although both drugs significantly reduced VPDs relative to placebo, ethmozine was a superior antiarrhythmic drug in ach9eving near-total abolition of VPDs (30% of patients), which was never observed during disopyramide dosing (p less than .05). At the 80% VPD reduction level, ethmozine was effective in 56% of all patients compared with an effectiveness in only 22% of patients during disopyramide therapy (p less than .05). The mean peak plasma level of ethmozine was 0.66 +/- 0.8 micrograms/ml, which significantly fell to a trough level of 0.1 +/- 0.08 micrograms/ml (p less than .001). Mean peak and trough plasma levels of disopyramide exhibited less fluctuation (2.6 +/- 0.9 micrograms/ml vs 2.2 +/- 0.9 micrograms/ml). Ethmozine had no effect on the QT interval, whereas disopyramide prolonged it significantly. Importantly, while disopyramide produced serious side effects in 30% of patients, ethmozine was well tolerated with no statistically significant side effects compared with placebo.

Adult↗
PubMed1989

Anti-cholinergic effects of quinidine, disopyramide, and procainamide in isolated atrial myocytes: mediation by different molecular mechanisms.

Effects of quinidine, disopyramide, and procainamide on the acetylcholine (ACh)-induced K+ channel current were examined in single atrial cells, using the tight-seal, whole-cell clamp technique. The pipette solution contained guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3-thiotriphosphate) (GTP-gamma S, a nonhydrolysable GTP analogue). In GTP-loaded cells, not only ACh but also adenosine induced a specific K+ channel current via GTP-binding proteins (G) by activating muscarinic ACh or adenosine receptors. Quinidine and disopyramide depressed the ACh-induced K+ current quite effectively. Procainamide had a weak inhibitory effect. Quinidine also depressed adenosine-induced K+ current, while the effect of disopyramide on adenosine-induced current was much smaller than that on ACh-induced current. In GTP-gamma S-loaded cells, the K+ channel was uncoupled from the receptors and was activated irreversibly, probably due to direct activation of G proteins by GTP-gamma S. Quinidine depressed the GTP-gamma S-induced K+ current just as in the cases of ACh- and adenosine-induced currents of GTP-loaded cells. Disopyramide had only a weak inhibitory effect and procainamide showed no effect. From these results, it is strongly suggested that the major mechanisms underlying the anti-cholinergic effects of quinidine, disopyramide, and procainamide are different; quinidine may inhibit the muscarinic K+ channel itself and/or G proteins, while disopyramide and high doses of procainamide may mainly block functions of muscarinic ACh receptors in atrial myocytes.

Animals↗
PubMed2003

Inhibitory effect of erythromycin on potassium currents in rat ventricular myocytes in comparison with disopyramide.

Disopyramide, a class Ia antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (I(K)) and transient outward current (I(to)), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10-100 microM) and erythromycin (100 microM) led to increases in the APD at 90% repolarization level. Disopyramide reduced I(K) (IC50 = 37.2 +/- 0.17 microM) and I(to) (IC50 = 20.9 +/- 0.13 microM) while erythromycin reduced I(K) (IC50 = 60.1 +/- 0.29 microM) but not I(to). The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.

Action Potentials↗
PubMed2005

Toxic interactions between fluconazole and disopyramide in chick embryos.

The present study evaluated the effect of fluconazole on the heart, as well as and the toxic interactions between fluconazole and disopyramide in chick embryos. Chick embryos have been widely used in pharmacologic and toxicologic experiments for evaluating drug action. Fertilized eggs of White Leghorns were incubated and investigated. Fluconazole 0.4 mg/egg, 0.8 mg/egg, 1.2 mg/egg alone or disopyramide 0.3 mg/egg alone was injected into the air sac of each fertilized egg. And fluconazole 0.4 mg/egg with disopyramide 0.3 mg/egg was injected into the air sac of each fertilized egg. Electrocardiograms (ECGs) were recorded 0 to 60 min after the drug injection, and heart rate was determined from ECG wave cycles. Changes in heart rate were expressed as mean-percent changes of the drug-treated groups to the matched control. After the administration of fluconazole 0.4 mg/egg alone, the heart rate did not differ compared with that of the controls. However, the heart rate was significantly decreased with the administration of fluconazole 0.8 mg/egg and 1.2 mg/egg. The heart rate was also significantly decreased by the administration of fluconazole 0.4 mg/egg together with disopyramide 0.3 mg/egg. In addition, an arrhythmia was produced by fluconazole and disopyramide. These findings indicate that the interaction between fluconazole and disopyramide has a marked influence on the heart rate in chick embryos.

Animals↗
PubMed1981

Combined effect of verapamil and disopyramide on induction of circus movement tachycardia in patients with pre-excitation.

By means of intracardiac recordings and programmed electrical stimulation of the heart, the combination effect of verapamil and disopyramide on induction of circus movement tachycardia was studied in 8 patients with anomalous extranodal atrioventricular (A-V) pathway. In 4 of 6 patients who manifested reproducible circus movement tachycardia, verapamil, 0.2 mg/kg intravenously administered, prevented the induction of tachycardia by increasing the A-V nodal refractoriness. Disopyramide in a dose of 2 mg/kg was injected 30 minutes after the start of verapamil administration, when prolongation of the A-V nodal conduction time (A-H interval) had continued in most of the patients. Disopyramide lengthened the effective refractory period of the anomalous pathway in all patients in whom this could be determined. The A-H interval, which had been prolonged by verapamil, was shortened in 4 patients and about unchanged in the remaining 4. After addition of disopyramide, sustained tachycardia could be induced in 2 patients who had lost the ability of initiating circus movement tachycardia after verapamil administration. Thus, disopyramide, when administered together with verapamil, may block the effect of verapamil on the A-V node by its anticholinergic action. A concomitant prescription of disopyramide with verapamil in expectation of the depression of both the anomalous pathway and the A-V node may have an untoward outcome.

Adolescent↗
PubMed1982

Electrophysiological effects of disopyramide on hypoxic rabbit ventricular muscle.

Intracellular microelectrode recording techniques were used to elucidate the mechanism of the antiarrhythmic action of disopyramide in an isolated rabbit ventricular muscle perfused by hypoxic Tyrode's solution. Hypoxia induced no significant changes of the resting membrane potential or action potential amplitude but decreased the maximum upstroke velocity of the action potential (dV/dt max) and shortened the action potential duration and the effective refractory period. Disopyramide in a dose of 5 microgram/ml induced a significant decrease of resting membrane potential and action potential amplitude of hypoxic muscle while it did not alter these parameters in oxygenated muscle. Disopyramide depressed dV/dt max in hypoxic muscle as well as in oxygenated muscle. However, there was much greater depression in hypoxic cells. After disopyramide, action potential duration at the 90% level of repolarization and the effective refractory period were prolonged in both hypoxic and oxygenated ventricular muscle. However, disopyramide lengthened the effective refractory period of hypoxic muscle to a much greater degree than that of oxygenated muscle. This resulted in a decrease of disparity in refractoriness. The above differential effects of disopyramide in oxygenated and hypoxic tissue may account for its effectiveness in postinfarction re-entrant arrhythmias.

Action Potentials↗
PubMedDate not supplied

The effects of urine pH and plasma protein binding on the renal clearance of disopyramide.

To ascertain whether the renal clearance of disopyramide (pKa = 8.36) is affected by urine pH, the disposition kinetics of disopyramide were compared during excretion of acidic and alkaline urine following both single dose intravenous (2mg/kg) and oral (5 mg/kg) administration to 4 healthy male volunteers. No significant difference was observed in the plasma concentration-time curve of disopyramide. The mean 72 hour recovery of disopyramide and its N-deisopropyl metabolite (MND) in urine was 55.1 and 20.3% of the dose respectively, with no apparent difference between the two routes of administration or pH of urine. Renal clearance of disopyramide was found to vary with time, which is partly the result of a concentration dependent change in plasma protein binding. The unbound fraction of drug in plasma varied from 0.32 to 0.72 between 0.4 to 4microgram/ml concentration. However, time-dependent change in renal clearance of disopyramide persists even after correction for plasma protein binding.

Administration, Oral↗