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PubMed1989

The activation gate of the sodium channel controls blockade and deblockade by disopyramide in rabbit Purkinje fibres.

1. The effect of disopyramide on the maximum upstroke velocity (Vmax) and the sodium current of rabbit cardiac Purkinje fibres was studied with the two-microelectrode voltage-clamp technique. 2. In the absence of stimulation the drug did not cause block at membrane potentials ranging from -100 to -65 mV. Use-dependent block of Vmax was most pronounced at -75 mV. At hyperpolarized membrane potentials development of use-dependent block was faster than at depolarized membrane potentials. The time course of development of use-dependent block was not significantly influenced by the duration of the depolarizing pulse. These results strongly suggest that disopyramide predominantly blocks activated sodium channels. 3. The relative decrease of the sodium current at the beginning of a 2 s depolarizing clamp to -45 mV was almost the same as at the end, implying a rapid blockade of activated sodium channels. The Hill plots were linear with slopes ranging from 0.978 to 1.08 indicating a first order reaction; the dissociation constant for activated channels was 70 microM. 4. Recovery of Vmax from use-dependent block during rest was strongly voltage-dependent, the time constant of recovery increasing upon hyperpolarization. When the fraction of charged molecules was reduced by changing the pH of the external solution, the voltage-dependence of recovery was decreased. In contrast, recovery of Vmax for a change in holding potential from -80 to -95 mV was very fast during repetitive stimulation. 5. It is concluded that disopyramide blocks the sodium channel during activation and is trapped in the channel when the activation gate closes.

Animals↗
PubMed1991

Comparison of the electrophysiological effects of Org 7797, disopyramide, mexiletine and propafenone in anaesthetized dogs with myocardial infarcts.

1. The electrophysiological effects of intravenously administered Org 7797 were compared with those of disopyramide (class Ia), mexiletine (Ib) and propafenone (Ic) in anaesthetized dogs with 5-6 day-old left ventricular myocardial infarcts. 2. Org 7797 (0.5 mg kg-1) slowed conduction at all levels of the myocardium as shown by increases in St-A, AH, HV and QRS intervals, very modestly prolonged atrial and ventricular refractory periods and slightly shortened ventricular repolarization. Sinus node recovery time was increased whilst the RR interval was unchanged. A higher dose (2 mg kg-1) prolonged RR and rendered 5 out of 8 dogs unable to follow an atrial pacing stimulus of mean cycle length 322 ms. 3. Electrophysiological changes induced by propafenone (2 mg kg-1) were qualitatively similar to those of Org 7797 (0.5 mg kg-1). 4. Electrophysiological changes induced by mexiletine (2 mg kg-1) were small or insignificant. The most noticeable effect was a modest increase in the St-A interval and a slight shortening of ventricular repolarization. A higher dose (8 mg kg-1) additionally slowed conduction in the His-Purkinje system and in the ventricular myocardium. 5. Disopyramide (2 and 5 mg kg-1) prolonged all cardiac intervals including JTc, QTc and QT during pacing and prolonged cardiac refractory periods. 6. It was concluded that the electrophysiological profile of Org 7797 is more like that of the Ic agent propafenone than that of the class Ia and Ib drugs, disopyramide and mexiletine.

Anesthetics↗
PubMed1988

Flecainide compared with a combination of digoxin and disopyramide for acute atrial arrhythmias after cardiopulmonary bypass.

Fifty six adult patients were randomised to treatment with flecainide (group 1, n = 29) or a combination of digoxin and disopyramide (group 2, n = 27) for acute atrial fibrillation and flutter after cardiac surgery. Intravenous flecainide was given as a 2 mg/kg bolus over 20 minutes followed by an infusion (0.2 mg/kg per hour) for 12 hours. Group 2 were given digoxin (0.75 mg) intravenously followed two hours later by an intravenous bolus of disopyramide (2 mg/kg) and an infusion (0.4 mg/kg per hour) for 10 hours. Within 12 hours sinus rhythm was restored in 86% of the group 1 (25 patients) and 89% of the group 2 (24 patients). The median time to reversion was significantly shorter in group 1 (80 minutes, range 30-180 minutes) than group 2 (220 minutes, range 138-523 minutes). None of the patients in group 1 and four of the patients in group 2 had transient relapses into atrial fibrillation during the 12 hours of intravenous treatment. There were five late relapses in group 1 and seven in group 2 during subsequent oral treatment. Two group 1 patients and two group 2 patients showed adverse drug effects. Intractable ventricular arrhythmias occurred after five days of oral treatment in one patient (group 1) who had poor left ventricular function, hepatic impairment, and toxic concentrations of drugs at the time of death. Flecainide was as effective as the combination of digoxin and disopyramide and it acted significantly faster and was associated with fewer relapses. Monitoring of blood concentrations of flecainide is essential in patients with poor left ventricular function and hepatic impairment.

Acute Disease↗
PubMed1980

Successful management of serious disopyramide poisoning.

A case of deliberate disopyramide overdosage is described. Circulatory collapse was treated by means of a large dose of isoprenaline, and charcoal haemoperfusion was used in an attempt to enhance the elimination of disopyramide. The suitability of this treatment regime is discussed in the light of findings from animal studies and the implications for the management of the disopyramide-poisoned patient are considered.

Adult↗
PubMed1981

Effect of disopyramide and disobutamide on conduction in perfused rabbit hearts.

The effects of disopyramide (DP) and a new antiarrhythmic agent, disobutamide (DB) on cardiac conduction were studied using His bundle recording from modified rabbit Langendorff preparations electrically driven at 3 and 4 Hz. Both disopyramide (4-16 microgram/mL) and disobutamide (1-30 microgram/ml) showed conduction throughout the atrioventricular conduction system, i.e., SA, AH, and HV intervals were increased in a dose-related manner. Conversion of the conduction time changes to percent changes indicates that disobutamide had a relatively equal effect on each part of the system whereas disopyramide exhibited significantly less effect on AV nodal conduction. Slowing of conduction in the AV node by DP was clearly related to rate. Changes in SA and HV intervals were rate related to a lesser degree. No such rate-related effect was evident with disobutamide. Block of arterial conduction occurred in two out of six hearts when the rate was increased 8 microgram/mL of DP and in three additional hearts at 16 microgram/mL. This was interpreted to indicate a change in atrial excitability such that 2 X threshold currents no longer excited the tissues. This was not observed at any concentration of DB.

Animals↗
PubMed1986

Disopyramide phosphate effects on slow and depressed fast responses.

We studied the effects of disopyramide phosphate on explanted neonatal rat ventricle cells exhibiting depressed fast responses or naturally occurring slow response action potentials together with automatic activity. Disopyramide suppressed the spontaneous activity at a concentration of 2.5 micrograms/mL with a half-maximal value of 10 micrograms/mL. Before spontaneous activity was lost, there was an increase in beating rate possibly related to membrane depolarization. In depressed fast and slow response action potentials there was an increase in action potential duration (APD) which was consistently found both at the level of the plateau and at 90% repolarization. Comparison of the APD increase observed after disopyramide treatment and that after exposure to 20 mM tetraethylammonium suggested a block of a potassium conductance as a possible cause underlying the change in APD. The Vmax values of the depressed fast response decreased at constant membrane potential and this was attributed to the local anesthetic effect of the drug. In addition, we report two novel findings: (i) a decrease of Vmax of the slow response action potentials which may be secondary to membrane depolarization, and (ii) an increase in the duration of slow action potentials, possibly caused by inhibition of a potassium conductance.

Animals↗
PubMed1982

The cardiac effects of d- and l-disopyramide in normal subjects: a noninvasive study.

Commercially available disopyramide is a racemic mixture of equal parts of dextrorotatory (d-) and levorotatory (l-) optical isomers. We studied the cardiac effects of i.v. administration of each isomer and the racemic mixture (dl-) in six normal males by digitized echocardiography, systolic time intervals and ECG. Both isomers and the racemic mixture produced equally marked dose-dependent negative inotropic effects (28.1 +/- 11.8% mean maximal reduction in fractional shortening of left ventricular dimension) and diastolic effects (28.6 +/- 24.1% mean maximal reduction in peak left ventricular filling rate). However, only the d-isomer prolonged QTc duration (by 13.6 +/- 5.2% at maximum, p less than 0.001 vs l-isomer). We conclude that disopyramide, in the doses used, produces marked adverse effects on left ventricle systolic and diastolic function in normal subjects independent of optical rotation. The production of these effects by the l-isomer without affecting QTc duration suggests different subcellular mechanisms for the myocardial depressant effects and some of the electrophysiologic effects of disopyramide.

Adult↗
PubMed1975

Electrophysiological actions of disopyramide phosphate on canine ventricular muscle and purkinje fibers.

Disopyramide phosphate is a new antiarrhythmic drug that has been shown to possess significant antiarrhythmic effects in animals and man. In the present investigation, the effects of 2, 5, and 10 mug/ml of disopyramide phosphate were studied on the electrophysiological properties of canine Purkinje fibers and ventricular muscle superfused in vitro. Transmembrane action potentials were recorded from Purkinje fibers in the region of maximum action potential duration (gate), from Purkinje fibers proximal and distal to the gate, and from ventricular muscle. Disopyramide phosphate produced a concentration-dependent decrease in the slope of phase 4 diastolic depolarization of spontaneously beating Purkinje fibers. In all electrically stimulated fibers, the drug decreased the amplitude and the maximum upstroke velocity of the action potential. This depression of phase 0 characteristics was accompanied by a decrease in conduction velocity. In Purkinje fibers located at the gate, a concentration-dependent parallel shift to the right and a depression of the maximum of the membrane responsiveness curve occurred. Effects on action potential duration were variable. Repolarization was altered so that action potentials with dissimilar durations recorded from sites proximal to, at, and distal to the gate became equal. The total action potential duration and the effective refractory period of gate Purkinje fibers were prolonged, but the change in action potential duration was always greater than the change in effective refractory period so that the ratio of the change in duration to the change in refractory period was always greater than one.

Action Potentials↗
PubMed1987

Evaluation of the vasodilator vs inotropic effect of milrinone using an animal model of left ventricular failure: reversal of disopyramide depression of the myocardium with milrinone.

Milrinone (M) has been shown to improve left ventricular (LV) performance in animal and human studies. M has strong vasodilator action, and whether increased LV performance is due primarily to vasodilation or to a direct positive inotropic effect is unclear. Ten mongrel dogs were studied. Disopyramide caused a significant and sustained decrease in LV function and was a good model for myocardial depression. At equal reduction in systemic vascular resistance (SVR), M reversed this LV depression to a significantly greater degree than nitroprusside (NP) did. At equal levels of vasodilation, M produced significantly greater improvement in indices of LV function than NP did in our model of disopyramide-induced LV failure. This suggest that its effect on LV function is not due entirely to afterload reduction, or to reflex sympathetic stimulation, but has a substantial component of direct inotropic stimulation. This study also demonstrated a reversal of disopyramide-induced LV dysfunction by M, which may be clinically useful since, as in many antiarrhythmics, myocardial depression may be a limiting factor in its use.

Animals↗
PubMed1999

Effect of disopyramide on left ventricular pressure gradient in hypertrophic obstructive cardiomyopathy in comparison with propranolol--a case report.

The effect of intravenous administration of disopyramide (total dose 100 mg, bolus 20 mg every 5 minutes) was compared with that of propranolol (total dose 10 mg, bolus 2 mg every 5 minutes) in a patient with hypertrophic obstructive cardiomyopathy. Left ventricular pressure gradient (LVPG) was assessed by continuous wave Doppler flowmetry. LVPG markedly decreased (97 to 16 mmHg), and preejection period (PEP) increased with an increase in heart rate (HR) during disopyramide injection. No changes were observed in LVPG and PEP, and a decrease occurred in HR during propranolol administration. These results indicate that disopyramide produced greater effects on the reduction of LVPG than propranolol, a negative inotropic agent, did.

Aged↗
PubMed1981

Study of an anti-arrhythmic agent, disopyramide, in delayed action form ('Ritmoforine' Retard).

A study was carried out in 10 patients with ventricular dysrhythmias to determine serum levels and effectiveness of treatment with a new delayed-action formulation of disopyramide. Patients received 1 tablet (322.5 mg disopyramide phosphate) twice daily and were monitored constantly. A therapeutically effective level of 3 mg/l was achieved in most cases after 24 hours and in 8 out of the 10 patients the levels remained reasonably stable during the 4 days of observation. It is suggested that adjustment of dosage is advisable in patients with renal dysfunction or left heart failure. Although the new formulation provided a good alternative to the standard preparation of disopyramide, which is usually given on a 4-times daily regimen, it is recommended that the standard capsules should be used during the first 24 hours of treatment to ensure that effective blood levels are achieved rapidly.

Aged↗
PubMed2004

Failure of disopyramide to improve right ventricular outflow tract obstruction after living-donor lobar lung transplantation.

Right ventricular (RV) outflow tract obstruction (RVOTO) is an uncommon complication of lung transplantation in patients with pulmonary hypertension (PH) and both medical management and surgical intervention are required. A 28-year-old female with primary PH was referred and because she did not respond to medical treatment, living-donor lobar lung transplantation was performed. The operation was successful, but dyspnea and exercise intolerance developed during rehabilitation and transthoracic echocardiography revealed RVOTO. Intravenous disopyramide during cardiac catheterization reduced the pressure gradient from 35 mmHg to 16 mmHg without decreasing RV systolic pressure. However, electrical and hemodynamic parameters were adversely affected by disopyramide and thus, after cardiac catheterization, administration of fluid and a low dose of atenolol was started, and her symptoms improved. Transthoracic echocardiography showed improvement in the RVOTO. This case suggests that disopyramide should be avoided for patients with RVOTO following lung transplantation and that other negative inotropic agents, such as beta-blockers, are more effective for relief of RVOTO.

Adult↗
PubMed1999

Disopyramide improves hypoxia in patients with tetralogy of Fallot through a negative inotropic action.

The hemodynamic and right ventricular volumetric effects of disopyramide were investigated in patients with tetralogy of Fallot (TF). Intracardiac pressure and oxygen saturation were measured, before and after intravenous administration of disopyramide (2 mg/kg) in 7 patients who had not had previous surgery. Right ventricular volume and the diameter of its outflow tract were analyzed in these 7 and in a further 4 patients with a previous shunt. Aortic oxygen saturation increased from 90.4+/-7.5 (mean+/-SD) to 94.1+/-5.5% (p<0.05) with an increase in pulmonary blood flow and pressure. The systolic pressure gradient between the main pulmonary artery and the right ventricle decreased from 59+/-8 to 42+/-9 mmHg (p<0.01). Aortic pressure fell from 77+/-5 to 67+/-4 mmHg (p<0.05). Systemic vascular resistance increased from 15.3+/-2.2 to 19.4+/-3.3 u x m2 (p<0.05). Pulmonary vascular resistance remained unchanged. The diastolic and systolic diameter indices of the right ventricular outflow tract increased from 17.8+/-3.8 to 20.5+/-3.4 and from 6.5+/-3.0 to 10.4+/-2.2 mm/m2, respectively (p<0.01), whereas the right ventricular ejection fraction decreased. Disopyramide improves systemic oxygen saturation in patients with TF through its negative inotropic action on the right ventricle.

Adolescent↗
PubMed1980

Toxic synergism of disopyramide and hyperkalemia.

A patient is presented whose electrocardiogram became remarkably abnormal and who developed hypotension while receiving disopyramide and potassium. This report documents a potassium-disopyramide synergism leading to life-threatening toxicity. These abnormalities were corrected by glucose, insulin and bicarbonate therapy, suggesting that serious disopyramide toxicity may be enhanced by hyperkalemia and reversed by lowering the serum potassium.

Aged↗
PubMed1980

Effects of intravenous disopyramide on myocardial function in patients with different degrees of cardiac failure.

The effects of intravenous disopyramide phosphate on myocardial function were evaluated by non-invasive indices of cardiac performance (systolic time intervals, STI) in 15 patients with atherosclerotic heart disease and different degrees of cardiac failure. Disopyramide (1.5 mg/Kg) was given intravenously over a period of 5 min. This drug induced in patients in I-II classes of NYHA a significant decrease of LVETc, while PEP, ICT, and PEP/LVET ratio rose significantly. STI were affected much more markedly in patients in III-IV classes of NYHA. Particularly affected were contractility indices (PEP, ICT, PEP/LVET), which were reduced significantly more in patients in III-IV classes as compares to patient in I-II classes. In contrast, LVETc, which correlates to stroke volume and cardiac output, was similarly worsened by the drug in the 2 groups of patients. Therefore, this study shows that disopyramide has relevant depressant effects on myocardial performance, simultaneously reducing stroke volume and contractility, and that the effect on contractility is more marked in patients with severe left ventricular impairment.

Arrhythmias, Cardiac↗
PubMed1980

Electrophysiologic effects of disopyramide in children.

Disopyramide has been successfully used to treat a variety of supraventricular and ventricular arrhythmias. The electrophysiologic effects of this drug were studied following diagnostic cardiac catheterization in 14 children aged 7 months to 14 years, suffering from congential heart disease. Surface EKG, intra-atrial, and His bundle electrogram as well as right atrial pacing with the use of extrastimulus technique were obtained before and after a single intravenous dose of disopyramide (2 mg/Kg, max 50 mg). The drug significantly prolonged the HV interval, effective and functional refractory periods of the atrium and the AV node. The most consistent change was the prolongation of the atrial refractory periods. The electrophysiologic effects of this drug on the conduction system have been variable and this variability has been attributed to the degree of vagal tone. The findings in this age group are similar to adults with simultaneous cholinergic blockade. This might be due to the direct depressant effects of disopyramide on the atrial and AV nodal tissue, and point to the potential usefulness of this drug in the pediatric age group.

Adolescent↗
PubMed1980

Hypoglycemic effect of disopyramide in a case of diabetes mellitus under insulin treatment.

In a 41-year-old male with diabetes mellitus well controlled with insulin (50 units/day), hypoglycemia developed after starting disopyramide treatment (200 mg/day) for correction of tachycardia. Lower levels of blood glucose and smaller amounts of urinary sugar persisted until disopyramide was withdrawn even after reducing insulin to a minimum dose of 20 units/day. The insulin requirement increased again thereafter to the original dose. These results indicate that disopyramide had a hypoglycemic effect in this patient.

Adult↗