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PubMed1990

Negative inotropic effects of disopyramide on guinea-pig papillary muscles.

1. The inhibitory effects of disopyramide on electromechanical responses were investigated in guinea-pig papillary muscles driven by electrical stimuli. Disopyramide up to 10(-5) M did not cause a negative inotropic effect, while the maximum upstroke velocity of the action potential (dV/dtmax) was significantly decreased. 2. At higher concentrations, this drug dose-dependently inhibited the contraction, and dV/dtmax was further decreased. This inhibition of contraction was accompanied by a depression of the slow action potential in partially depolarized preparations by increasing [K+]0 (26 mM). 3. In preparations pretreated with nifedipine (10(-6) M) and ryanodine (10(-6) M), the contraction was almost completely inhibited. In such preparations, ouabain (2 x 10(-6) M) markedly increased the contraction, probably through the Na(+)-Ca2+ exchange mechanism. This contraction was inhibited by disopyramide above 10(-8) M, and an almost complete inhibition was caused at 3 x 10(-5) M. 4. A similar inhibitory effect was observed on the contraction increased by the lowering of [Na+]0 (36 mM). 5. These results suggest that disopyramide at high concentrations inhibits Ca influx through slow Ca2+ channels and at low concentrations, it reduces the contraction increased through the Na(+)-Ca2+ exchange mechanism. Disopyramide had a greater effect on cardiac contractility mediated by the Na(+)-Ca2+ exchange mechanism.

Action Potentials↗
PubMed1991

Mechanisms of the anticholinergic effect of SUN 1165 in comparison with flecainide, disopyramide and quinidine in single atrial myocytes isolated from guinea-pig.

1. The mechanism of the anticholinergic effect of SUN 1165 on the acetylcholine (ACh)-induced K+ current (IK.ACh) was examined and compared with those of flecainide, disopyramide and quinidine in single atrial myocytes, in a whole-cell configuration by use of the concentration-jump technique. This technique combines an intracellular perfusion and a rapid exchange of external solution surrounding the voltage-clamped single myocyte within 2 ms. 2. In the cells loaded with guanosine-5'-triphosphate (GTP), 100 microM, the muscarinic ACh response, (IK.ACh), was mediated by GTP-binding proteins. The concentrations of the test drugs that produced a half-maximal inhibition of ACh (1 microM)-induced IK.ACh (IC50) were 29 microM for SUN 1165, 3.6 microM for flecainide, 1.7 microM for disopyramide, and 1.6 microM for quinidine. The blockade of IK.ACh by SUN 1165 and its recovery from the inhibition occurred within a few seconds. Disopyramide had a similar rapid action, while the effects of flecainide and quinidine occurred much more slowly within a few tens of seconds. 3. In cells loaded with 100 microM guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S, a nonhydrolysable GTP analogue), the K+ channel was uncoupled from the muscarinic receptors and activated irreversibly due to direct activation of GTP-binding proteins by GTP gamma S. SUN 1165 and disopyramide had a weak inhibitory effect (IC50 greater than 100 microM for both), while flecainide and quinidine depressed the GTP gamma S-induced K+ current with similar potencies to the cases of ACh-induced currents; IC50 was 5.3 microM for flecainide and 4.4 microM for quinidine. 4 These results suggest that the mechanisms underlying the anticholinergic effects of these antiarrhythmic drugs are different; disopyramide and high concentrations of SUN 1165 mainly block muscarinic ACh receptors in atrial myocytes, while flecainide and quinidine inhibit the K+ channel itself and/or GTP-binding proteins.

Acetylcholine↗
PubMed1999

Torsades de pointes ventricular tachycardia induced by clarithromycin and disopyramide in the presence of hypokalemia.

We report a 76-year-old woman who developed TdP ventricular tachycardia induced by combined use of clarithromycin and disopyramide. She had a history of myocardial infarction 5 years earlier and has taken disopyramide for supraventricular arrhythmias. In addition, she had taken clarithromycin for upper respiratory tract infection. On admission, an ECG showed prolongation of QTc interval to 0.71 seconds and self-terminating TdP occurred several times. Disopyramide was metabolized by the cytochrome enzyme CYP3A4 and clarithromycin competitively inhibits this enzyme, probably resulting in an increase in plasma concentration of disopyramide. We should consider this possibility when prescribing clarithromycin in combination with antiarrhythmic agent disopyramide.

Aged↗
PubMed1986

The pharmacokinetics and protein binding of disopyramide in pigs.

The pharmacokinetics of disopyramide were investigated in 5 pigs. Disopyramide was administered as intravenous bolus injections at different doses and as intravenous infusions at different rates. By measuring the free and total concentrations in plasma of parent compound and desisopropyldisopyramide (the main metabolite in humans) and the amounts excreted in urine it was found that disopyramide had a concentration dependent protein binding and that free and total concentrations could be described by a two-compartment model with a t1/2, beta of approximately 2 hours. The free concentrations were found to be more valuable for estimating the kinetic parameters. The total clearance of disopyramide in the pig was found to approximately 3 ml/min./kg which is about 3 times greater than in man. In contrast to humans the free clearance in the pig increased with declining concentration. Apart from this the kinetics of disopyramide in the pig were very similar to those in man. In conclusion the pig could be a relevant model for studying the pharmacokinetics in humans.

Animals↗
PubMed1987

Displacement of lidocaine from human plasma proteins by disopyramide.

Displacement from human plasma proteins of lidocaine by disopyramide was investigated in serum from nine patients receiving lidocaine treatment because of severe ventricular arrhythmias. From each patient disopyramide in concentrations of 5.9 and 14.7 mumol/l was added to three different serum concentrations of lidocaine and the displacement was examined. At a serum concentration of disopyramide of 14.7 mumol/l the percentage of unbound lidocaine increased from 30.4 +/- 0.2 to 36.3 +/- 0.2% (mean +/- S.E.M., P less than 0.001) at an average total serum concentration of lidocaine of 22.7 mumol/l. The study implies a stronger binding affinity of disopyramide than lidocaine to alpha-1-acid glycoprotein. We recommend caution when using disopyramide immediately after an infusion of lidocaine. With the dosage regimen used serum concentrations considerably above the suggested therapeutic level were achieved in the majority of patients.

Aged↗
PubMed1989

Disposition kinetics of disopyramide in human healthy volunteers described by an open three compartment model.

Disposition kinetics of disopyramide was examined in an open randomised cross-over study in 8 healthy volunteers. Disopyramide was randomly administered as a single bolus injection (150 mg) over a period of 5 min. and as an infusion (28.2) mg/h to steady state. Disposition kinetics of disopyramide were most precisely described by an open three compartment model according to Akaike's information criteria. Significant positive correlations (0.909 +/- 0.04, P less than 0.05 (injection study); 0.787 +/- 0.11, P less than 0.05 (infusion study] were observed between total serum concentrations of disopyramide and renal clearance while no significant correlation could be demonstrated between free serum concentrations and renal clearance. This implies a constant value of unbound renal clearance. The results are consistent with non linear kinetics (mainly caused by the variable free fraction of the drug), when based on total serum concentrations. The disposition of unbound disopyramide, however seems to be linear (i.e. the kinetic parameters are independent of dose) in the bolus injection study. Total elimination clearance (free and total), volume of distribution and elimination half-life were significantly higher in the steady state experiment than in the bolus injection study.

Adult↗
PubMed1978

Disopyramide phosphate: is it just another quinidine.

We compared the effects of a therapeutic concentration of disopyramide with those of quinidine and lidocaine on the action potential characteristics and on the steady-state relationship between membrane potential and the maximum rate of rise of the action potential in the same normal Purkinje fiber in which constant impalement was maintained for more than 7 h. All the drugs depressed the steady-state upstroke velocity in the following order of magnitude: quinidine greater than disopyramide greater than lidocaine. Both lidocaine and disopyramide shifted the normalized steady-state curve to more negative membrane potentials indicating a greater depression of upstroke velocity at lower membrane potentials. Quinidine did not shift this curve. Lidocaine abbreviated all phases of repolarization while both disopyramide and quinidine shortened the plateau phase and lengthened the terminal phase of the action potential. The results suggest that the actions of disopyramide on upstroke velocity resemble those of lidocaine, while its effects on action potential duration resemble those of quinidine. The actions of this drug are therefore more complex than previously assumed.

Action Potentials↗
PubMed1985

Protein binding of disopyramide and elevated alpha-1-acid glycoprotein concentrations in serum obtained from dialysis patients and renal transplant recipients.

A rapid ultrafiltration technique was used to measure the free (unbound) fraction of disopyramide in serum obtained from 14 normal volunteers, 6 chronic hemodialysis patients, and 10 renal transplant recipients. The disopyramide-free fraction varied more than tenfold at a corresponding total (free plus bound) serum disopyramide concentration of 3 micrograms/ml and was related to the concentration of an acute-phase protein, alpha-1-acid glycoprotein (AAG), in patient serum. Moreover, disopyramide-free fraction values were nearly twofold lower than normal in serum specimens obtained from those renal patients and transplant recipients with corresponding AAG serum concentrations greater than 100 mg/100 ml. AAG concentrations varied tenfold in patient serum and were on average nearly three times higher than AAG concentrations in normal volunteer serum. These findings suggested that the free fraction of disopyramide and possibly other drugs which bind extensively to AAG may be lower, and the interpatient variability in drug binding may be much more pronounced in serum obtained from hemodialysis patients and transplant recipients than previously recognized.

Adult↗
PubMed1994

Wavelength index: a predictor of the response to disopyramide in paroxysmal lone atrial fibrillation.

We investigated whether the new parameter wavelength index could predict the response to chronic disopyramide therapy in patients with paroxysmal atrial fibrillation (AF). Twenty-seven patients with AF underwent electrophysiologic studies and the wavelength index was determined before and after intravenous administration of disopyramide. Then all patients were treated with oral disopyramide for 6 months. In 17 patients, AF was eliminated (group A), while it persisted in another 10 patients (group B). The ratio of the wavelength index before and after intravenous disopyramide was higher in group A than in group B. Thus, the wavelength index proved useful for predicting the response of AF to disopyramide.

Adult↗
PubMedDate not supplied

Effects of intravenous disopyramide on coronary hemodynamics and vasodilator reserve in hypertrophic obstructive cardiomyopathy.

Disopyramide reduces the subaortic pressure gradients and improves the clinical symptoms of patients with hypertrophic obstructive cardiomyopathy. Changes in coronary hemodynamics and vasodilator reserve in response to this agent have not been evaluated in such patients. To assess the acute effects of intravenous administration of disopyramide on coronary hemodynamics, microvascular dilatory capacity, and balance between myocardial oxygen supply and demand in hypertrophic obstructive cardiomyopathy, we examined 12 patients using an intravascular Doppler catheter and spectral analysis. Intravenous disopyramide 100 mg over 10 min caused mild increases in heart rate and aortic systolic pressure and a significant fall in left ventricular systolic pressure, resulting in a 13% decrease in the product of heart rate and left ventricular systolic pressure (from 1.13 +/- 0.18 x 10(4) before disopyramide to 0.98 +/- 0.17 x 10(4) beats/min x mm Hg 10 min afterwards; p < 0.05) and a reduction in the resting peak systolic pressure gradients of the left ventricular outflow tract. There was a 14% reduction in coronary blood flow (from 93.5 +/- 13.2 to 80.3 +/- 11.6 ml/min; p < 0.05) with an increase in coronary resistance (from 0.94 +/- 0.16 to 1.23 +/- 0.21 mm Hg/ml/min; p < 0.001). The index of coronary vasodilator reserve remained unchanged. These findings suggest that intravenous disopyramide causes a coronary vasoconstrictive effect without significantly changing the coronary microvascular dilatory capacity, but this effect may not be harmful to the balance between myocardial oxygen supply and demand in patients with hypertrophic obstructive cardiomyopathy.

Adult↗
PubMed1980

The effect of concurrent oral administration of propranolol and disopyramide on cardiac function in healthy men.

Sixteen healthy men were evaluated for left ventricular performance changes and beta-blockade after therapeutic oral doses of disopyramide and propranolol administered alone and concurrently. The volunteers were randomly assigned to receive one of two drug treatment regimens that differed in the sequence and duration of administration of the drugs. Left ventricular function was assessed by echocardiographically determined ejection fraction (EF) and systolic time intervals. Beta-blockade was assessed by changes in exercise heart rate. Both disopyramide and propranolol exhibited negative inotropic activity, as evidenced by significant, although clinically inconsequential, decreases in EF and increases in the ratio of preejection period to left ventricular ejection time. The negative inotropic effects of a single 200-mg dose of disopyramide and an 80-mg dose of propranolol were comparable, while chronic disopyramide therapy (200 mg every 6 hours for 1 week) had a greater negative inotropic effect than chronic propranolol therapy (80 mg every 8 hours for 1 week). Only propranolol had beta-adrenoceptor blocking activity. When the drugs were administered concurrently, the negative inotropic effects of oral propranolol and disopyramide were neither additive nor synergistic.

Administration, Oral↗
PubMed1982

Effects of oral disopyramide phosphate on induction and sustenance of atrioventricular reentrant tachycardia incorporating retrograde accessory pathway conduction.

We performed electrophysiologic studies before and after oral administration of disopyramide phosphate, 200 mg every 6 hours, in 20 patients with atrioventricular (AV) reentrant tachycardia using a retrogradely conducting accessory pathway. Disopyramide markedly depressed retrograde accessory pathway conduction by increasing the mean ventricular paced cycle length that produced ventriculoatrial block (less than or equal to 287 +/- 4 to greater than or equal to 392 +/- 22 msec, p less than 0.01); it also depressed antegrade normal pathway AV conduction by increasing the atrial paced cycle length that produced AV block (287 +/- 9 to 328 +/- 7 msec, p less than 0.01). In 14 patients, tachycardia could not be induced or sustained after disopyramide phosphate. In 13 patients, this reflected depression of the retrograde limb with either absence of atrial echoes (nine patients) or induction of nonsustained tachycardia that terminated after the QRS complex (four patients), and in one, it reflected depression of the antegrade limb with induction of a single atrial echo not followed by a QRS response. In six patients, sustained tachycardia could still be induced after disopyramide. Oral disopyramide phosphate is effective in preventing induction of sustained AV reentrant tachycardia in most patients. This effect is achieved by depression of the retrograde limb of the reentrant circuit.

Administration, Oral↗
PubMed1982

Electrophysiologic effects of disopyramide in patients with atrioventricular nodal dysfunction.

Seventeen patients with first-degree or Mobitz I atrioventricular (AV) block and narrow QRS complexes underwent electrophysiologic drug testing before and after i.v. administration of disopyramide. Disopyramide did not significantly change the mean sinus cycle length (895 +/- 131 vs 877 +/- 119 msec), mean maximal sinus node recovery time (1134 +/- 160 vs 1133 +/- 13 msec), mean atrial effective refractory period (314 +/- 72 vs 307 +/- 54 msec), mean AV nodal conduction time (187 +/- 79 vs 180 +/- 73 msec) or the mean paced cycle length at which AV nodal Wenckebach conduction occurred (545 +/- 144 vs 497 +/- 130 msec) after disopyramide. The mean AV nodal effective refractory period decreased significantly (from 535 +/- 137 to 521 +/- 122 msec), and both infranodal conduction time and the paced ventricular cycle length producing ventriculoatrial block increased significantly (from 56 +/- 12 to 63 +/- 13 msec and from 625 +/- 158 to 655 +/- 157 msec, respectively). We conclude that i.v. disopyramide administered in a dose resulting in therapeutic blood levels showed no adverse effects on AV nodal conduction in patients with AV nodal dysfunction. In contrast, i.v. disopyramide depressed retrograde AV conduction.

Aged↗
PubMed1983

Hypoglycemia in patients receiving disopyramide phosphate.

Postmarketing drug surveillance revealed the occurrence of hypoglycemia associated with the use of disopyramide phosphate (Norpace) for the control of ventricular arrhythmias. The data obtained suggest that elderly patients or those with impaired hepatic or renal function may be more at risk of developing hypoglycemia while taking disopyramide. In a clinical study, nine healthy male volunteers were dosed with disopyramide to steady-state concentration. Comparison of the glucose levels during periods of fast, when the presence of food did not present a confounding factor, suggested that disopyramide may have a glucoregulatory effect in humans. A placebo-controlled clinical study, conducted in 11 healthy, male subjects, demonstrated that disopyramide evoked a small, but statistically significant, decrease in glucose levels during both the fed and fasted state. None of the classical signs or symptoms associated with hypoglycemia were noted during either of these clinical studies.

Aged↗
PubMedDate not supplied

Enzyme induction: rifampin-disopyramide interaction.

A 62-year-old woman with a history of supraventricular tachycardia, paroxysmal atrial tachycardia, and premature ventricular contractions was admitted with palpitations and anxiety. Previous therapy with antiarrhythmics had resulted in intolerable adverse effects or no effect on the arrhythmia. She had been taking rifampin prior to admission for acid-fast bacilli. Disopyramide was started on admission for supraventricular tachycardia. Subtherapeutic disopyramide blood concentrations were noted with concomitant administration of rifampin and disopyramide at normal doses. This case report demonstrates a possible drug interaction between these two drugs and the importance of careful monitoring. It was found that it takes three to five days after rifampin is discontinued before the enzyme induction of disopyramide disappears and disopyramide concentrations return to normal.

Cardiac Complexes, Premature↗
PubMed1997

Toxic interactions between disopyramide and propranolol in chick embryos.

The toxic interaction between disopyramide and propranolol were studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. Disopyramide with and without propranolol was injected into the air sac of a fertilized egg on the 16th day of incubation. Electrocardiograms (ECGs) were recorded 0 to 60 min after the injection. After each drug injection alone, the heart rate was not different compared with control. However, the heart rate was significantly decreased by combination with disopyramide and propranolol. In addition, arrhythmia was produced by disopyramide 1.0 mg/egg alone and in combination with propranolol. These findings indicate that the interaction between disopyramide and propranolol has a marked influence on the heart rate in chick embryos.

Animals↗
PubMed2001

Influence of the light schedule on the toxic interaction between propranolol and disopyramide in chick embryos.

The effect of the light schedule on toxic interactions between propranolol and disopyramide were studied in chick embryos. Fertilized eggs of White Leghorns were incubated under dark conditions and investigated, on two occasions, under light conditions or under dark conditions. Propranolol, with and without disopyramide, was injected into the air sac of fertilized eggs on the 16th day of incubation. Electrocardiograms (ECGs) were recorded 0 to 60 min after the injection. After the injection of propranolol with disopyramide, the heart rate was significantly decreased compared with the injection of propranolol alone under light conditions. In addition, this toxic interaction between propranolol and disopyramide was more severe under dark conditions than under light conditions. These findings indicate that manipulation of the light schedule has a marked influence on the toxic interaction between propranolol and disopyramide in chick embryos.

Adrenergic beta-Antagonists↗
PubMed1982

Electrophysiological effects of disopyramide phosphate in patients with sinus node dysfunction.

The electrophysiological effects of intravenous administration of disopyramide (1.5 mg/kg) were studied in 26 patients with sinus node dysfunction (SND). Disopyramide shortened spontaneous cycle length (SCL) in 12 patients and lengthened it in 4. Maximum sinus node recovery time (max SRT) was prolonged in 9 patients and shortened in 6. Estimated sinoatrial conduction time (SACT) was prolonged in 4 and shortened in 4 out of 10 patients in whom this measurement was possible. However, these changes were not statistically significant. Neither were there any significant changes in PA and AH intervals nor refractory periods of the AV node. HV intervals and refractory periods of the atrium at matched cycle length were significantly lengthened. Atrial echo beats and atrial premature beats disappeared in 7 of 12 patients treated with disopyramide. In all of these 7 patients atrial refractory period were increased. Thus, the disappearance of atrial echo beats and atrial premature beats was thought to be due to a prolonged atrial refractoriness. In 4 patients who had supraventricular arrhythmias without having either marked prolongation of max SRT or episodes of syncope, disopyramide was administered orally for a long term, during which these arrhythmias and symptoms disappeared and sinus rate increased. These results suggest that disopyramide is useful in patients with SND and supraventricular arrhythmias.

Arrhythmias, Cardiac↗