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PubMed1988

Facilitating influence of disopyramide on atrial flutter termination by overdrive pacing.

Long-lasting (mean 30 days) type I atrial flutter was treated with overdrive pacing in 30 patients (mean age 69 years) with organic heart disease. To evaluate the effect of pretreatment with disopyramide, the study population was divided in 3 groups of 10 patients each: group A, no disopyramide therapy; group B, intravenous disopyramide (maximum dose 250 mg in 1 hour); and group C, oral disopyramide (400 mg daily for 4 days). There were no differences in baseline cycle length of atrial flutter among the 3 groups before drugs were given. The stimulation protocol included overdrive atrial pacing up to the shortest paced cycle of 150 ms performed at a maximum of 3 atrial sites. Reversion to sinus rhythm occurred in 2 patients in group A, 7 in group B (p less than 0.01) and 5 in group C. Pacing was performed from a mean number of 2.1 sites/patient in group A, 1.2 in group B and 2.0 in group C. Atrial fibrillation occurred in 7, 3 and 4 patients, respectively. Acceleration to a faster form of atrial flutter occurred in 3, 3 and 4 patients, respectively, and reversion to sinus rhythm occurred in all patients who had intravenous disopyramide and in 1 who took the drug orally. The administration of disopyramide before overdrive pacing improved the rate of conversion to sinus rhythm and allowed an easier stimulation protocol with a lower incidence of pacing-induced atrial fibrillation. Disopyramide is beneficial when overdrive atrial pacing is performed for the treatment of long-standing atrial flutter in patients with organic heart disease.

Administration, Oral↗
PubMed1978

Some effects of disopyramide and its N-dealkylated metabolite on isolated nerve and cardiac muscle.

In animals and man the antidysrhythmic agent disopyramide in primarily metabolised by mono-N-dealkylation. The effects of disopyramide and its N-dealkylated metabolite (MIP) have been investigated using isolated cardiac and nervous tissue, and their effects have been compared with the effects of other antidysrhythmic agents. Disopyramide, d,l-propranolol and quinidine all decreased both maximum driving frequency and developed tension in electrically driven guinea pit atria. MIP and procaine amide also decreased maximum driving frequency, but had a positive intropic effect. MIP was only 4 times less active than disopyramide in decreasing maximum driving frequency. There was no evidence that either disopyramide or MIP possessed beta-adrenoceptor antagonist properties. In superfused rat sciatic nerves, it has been shown that neither disopyramide nor MIP possesses significant local anaesthetic properties. Procaine amide and lignocaine were highly active in this test. The possible contribution of MIP to the actions of disopyramide in vivo is discussed.

Action Potentials↗
PubMed1977

Efficacy of disopyramide phosphate in the treatment of refractory ventricular tachycardia.

The effects of intravenously administered disopyramide phosphate were evaluated in seven patients with refractory ventricular tachycardia. All patients had organic heart disease, including acute infarction (three patients), chronic coronary artery disease (two patients) and cardiomyopathy (two patients). The severity of the heart disease was reflected in the advanced patient age (average 64 years) and the occurrence before disopyramide therapy of cardiac arrest in five patients and congestive heart failure in all seven patients. In five patients, disopyramide was given as a bolus injection, 2 mg/kg body weight, followed by an infusion of 20 to 40 mg/hour. The final two patients received 4 mg/kg divided as a bolus injection and an infusion over 1 hour followed by a 0.4 mg/kg infusion during the next hour. Intravenous administration of disopyramide resulted in more effective electrical stability in all patients and completely eliminated ventricular tachycardia in six. Recurrence of ventricular tachycardia was prevented in six patients with subsequent long-term oral administration of disopyramide. Possible dose-related cardiac pump depression occurred in two patients, but disopyramide was otherwise well tolerated. Therefore, these data document the therapeutic efficacy of disopyramide in the treatment of refractory life-threatening ventricular tachyarrhythmias.

Aged↗
PubMed1985

Comparative study of encainide and disopyramide in chronic ventricular arrhythmias: a double-blind placebo-controlled crossover study.

Ten patients suffering from chronic premature ventricular complexes (greater than 60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia. Encainide was effective in four patients (complete suppression of premature ventricular complexes) and ineffective in five. One patient who showed a 92% reduction in the number of premature ventricular complexes developed sustained ventricular tachycardia after 24 hours of treatment. Disopyramide was effective in three patients (greater than 80% reduction in the number of premature ventricular complexes) and ineffective in seven patients. With encainide, the percent increase in PR, QRS and QT interval duration was, respectively: 32.7 (p less than 0.001), 30.8 (p less than 0.001) and 10.6% (p less than 0.01). With disopyramide this increase was not significant. Despite the variability of drug blood levels, a relation between blood levels and suppression of premature ventricular complexes on the 48 hour ambulatory electrocardiogram was found with encainide, but not with disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1983

Disopyramide kinetics in renal impairment: determinants of interindividual variability.

Disopyramide kinetics were studied in 30 patients with normal to severely impaired renal function (endogenous creatinine clearance 7.6 to 116.9 ml/min/1.73 m2) after intravenous bolus injection. Serum concentration-time curves were fitted to an open two-compartment model. There was close correlation between renal disopyramide clearance and creatinine clearance (r = 0.922). Disopyramide body clearance or elimination rate constant (kel beta) and creatinine clearance did not correlate as closely (r = 0.756 and 0.644). Volume of distribution at steady state and extrarenal clearance of disopyramide both correlated slightly positively with renal function. Disopyramide body clearance and volume of distribution, but not kel beta, were found to be dose dependent. Disopyramide kinetics in renal impairment were not sufficiently predictable from clinical data of the patient because of great interindividual variation in drug disposition and renal and extrarenal elimination. Dosage regimen must therefore be based on individual response and controlled by the clinical effect and estimates of disopyramide serum concentration.

Adult↗
PubMed2002

Cisapride reverses the anticholinergic effect of disopyramide on the isolated guinea-pig urinary bladder.

The present investigation aims to examine whether the prokinetic agent cisapride is able to reverse disopyramide's anticholinergic effect on the isolated guinea-pig urinary bladder. Acetylcholine, at concentrations ranging from 10(-7) to 10(-3) M, produced a stimulatory effect on the urinary bladder (pEC(50) value=5.1). Disopyramide competitively antagonized the contractile effect of acetylcholine with an ID(50)=4.4 x 10(-6) M. Although cisapride by itself had either no intrinsic contractile action or a modest effect on the urinary bladder, at concentrations ranging from 3 x 10(-7) to 10(-6) M, it significantly reversed the above inhibitory effect of disopyramide, and produced a parallel leftward shift of the concentration-response curve for acetylcholine in the presence of disopyramide. The pEC(50) values for acetylcholine in the presence of 3 x 10(-6) M and 10(-5) M disopyramide were 4.7 and 4.2, respectively, while in the presence of 10(-5) M disopyramide, after pretreatment with 5 x 10(-7) M cisapride, the pEC(50) value for acetylcholine was 4.6. It is concluded that cisapride is effective in reversing the anticholinergic activity of disopyramide on the isolated guinea-pig urinary bladder, probably by facilitating cholinergic neurotransmission.

Acetylcholine↗
PubMed1987

Non-competitive effects of disopyramide at the neuromuscular junction: evidence for endplate ion channel block.

The effects of disopyramide were studied at the neuromuscular junction in an attempt to elucidate the mechanism of its blocking action at this site. Disopyramide 5 X 10(-5) - 10(-3) mol litre-1 produced a concentration-dependent reduction of twitch amplitude in the indirectly stimulated chick biventer cervicis preparation, but greater concentrations were required to reduce twitches elicited directly in the presence of erabutoxin-b 1 microgram ml-1. Equieffective twitch blocking doses of either disopyramide or tubocurarine greatly reduced agonist responses to acetylcholine and carbachol, but the reduction was less for magnesium-blocked twitches. Neostigmine antagonized tubocurarine-induced, but not disopyramide-induced, blockade of twitches. Concentration-response profiles to acetylcholine and carbachol were shifted to the right in a non-parallel fashion and the maximal response was depressed by disopyramide 5 X 10(-5) - 10(-4) mol litre-1. Intracellular recording studies carried out in the cut, voltage-clamped costo-cutaneous muscle of the garter snake showed that disopyramide 5 X 10(-5) - 5 X 10(-4) mol litre-1 produced a concentration- and voltage-dependent reduction of the amplitude of neurally evoked endplate-currents (EPC) and of the time constant of decay (tau) of EPC. We conclude that disopyramide possesses a non-competitive blocking action at the neuromuscular junction, which is not reversible by anticholinesterase agents. The voltage-dependent nature of the block suggests that it is mediated via blockade of the open form of the acetylcholine-activated receptor-ion channel complex.

Animals↗
PubMedDate not supplied

Disopyramide plasma and myocardial tissue concentrations as they relate to antiarrhythmic activity.

Antiarrhythmic concentrations of disopyramide in canine plasma and myocardium were determined by gas chromatography. Ventricular tachycardia was incuded in anesthetized dogs by the intravenous administration of ouabain. Disopyramide phosphate was then administered by a two-stage continuous infusion method. A rapid infusion of disopyramide (9.08 mg/kg/hr) was administered for 30 min, followed by a slow infusion (2.18 mg/kg/hr) to maintain steady-state plasma levels of 1.98-2.21, mean +/- SEM = 2.1 +/- 0.02 microgram/ml at the end of 2 hr. Myocardial tissue levels of disopyramide at steady-state plasma levels were four times those of plasma (atrial tissue, 8.91 +/- 0.10; right ventricular free wall, 8.93 +/- 0.13; left ventricular free wall, 9.11 +/- 0.16 microgram/gm wet tissue). The intravenous administration of 80 units crystalline zinc insulin produced both hypokalemia (3.78 +/- 0.22 reduced to 2.36 +/- 0.18 mEq potassium/liter plasma) and a reappearance of ventricular tachycardia despite no change in plasma and myocardial tissue concentrations of disopyramide from those which had been effective in establishing and maintaining sinus rhythm. The observations demonstrate a relationship between plasma and myocardial disopyramide concentrations such that the former can be used in assessing patient therapy. In addition, this study suggests the important of plasma potassium in determining the therapeutic effectiveness of disopyramide.

Animals↗
PubMedDate not supplied

The stereoselective disposition of disopyramide in the dog.

The disposition of d-, 1-, and d,1-disopyramide was studied in 5 conscious dogs after intravenous administration (15 mg/kg) of each compound using a balanced crossover design. The clearance of d-disopyramide (15.4 +/- 5.10 ml/min/kg) was significantly greater than that of the l-isomer (9.45 +/- 2.52 ml/min/kg) (p < 0.001). The clearance of the d,1-mixture was intermediate between that obtained for the d- and l-isomers. The steady-state volume of distribution of the three compounds was similar (approximately 1.4 liters/kg). The elimination half-life reflected differences in clearance, being 76.4 +/- 7.30 min for d-disopyramide, 112 +/- 23.4 min for 1-disopyramide, and 97.2 +/- 15.1 min for d,1-disopyramide. The effect of general anesthesia with urethane and chloralose on the disposition of the compounds was also examined. General anesthesia decreased the clearance and increased the half-life of all three compounds. No consistent differences in the volume of distribution were observed with anesthesia as compared to control. Thus, there is stereoselective elimination of the optical isomers of disopyramide in the dog, and general anesthesia decreases the clearance of d-, 1-, and d,1-disopyramide.

Anesthesia↗
PubMedDate not supplied

Comparison of the antiarrhythmic efficacy of disopyramide and mexiletine against stimulus-induced ventricular tachycardia.

Programmed ventricular stimulation was used to assess the effect of oral disopyramide (600 mg/day), mexiletine (600--1000 mg/day), and a combination of both drugs in a randomized cross-over study on 12 patients with documented ventricular tachycardia and/or fibrillation. In two cases, all three types of treatment were ineffective in that ventricular tachycardia could still be initiated under the same conditions. In four cases, disopyramide and mexiletine alone were ineffective or the change in inducibility was only slight. However, when both drugs were administered in combination, ventricular tachycardia was more difficult to induce or was no longer inducible. In two other cases, disopyramide was the more effective drug. In the remaining four patients, all three types of treatment were similarly effective. In patients whose ventricular tachycardia remained inducible its rate decreased from 188 +/- 45 bpm (control) to 170 +/- 40 bpm on disopyramide, 172 +/- 31 bpm on mexiletine, and 146 +/- 39 bpm on disopyramide plus mexiletine. Long-term therapy was based on the results of acute testing. Seven patients received both disopyramide and mexiletine and tolerated this therapy well during a follow-up of 42 +/- 23 weeks. Two sudden deaths occurred, one possibly due to dose reduction and one in a patient in whom short bursts of ventricular tachycardia remained inducible during acute testing. We conclude that the combined administration of disopyramide and mexiletine is effective and safe in patients with ventricular tachycardia. It is tolerated without major side effects even during long-term therapy.

Adult↗
PubMedDate not supplied

Enhancement of the antiarrhythmic action of disopyramide by digoxin.

Acute antiarrhythmic testing with 200 mg of disopyramide p.o. was performed in two groups of 15 patients each, with a prevalence of ventricular premature depolarization (VPD) exceeding one per minute. Patients in the first group were not receiving cardiac glycosides; those in the second group were on maintenance therapy with oral digoxin. Systolic time intervals (STI) were recorded throughout the test in order to evaluate left ventricular performance. Plasma levels of disopyramide were measured at peak ECG changes and digoxin levels before and 2 h following administration of disopyramide. Only five patients in the first group responded with an 80% or greater reduction in VPD rate and abolition of repetitive forms. In contrast, 13 digitalized patients responded to disopyramide. Mean plasma levels of disopyramide did not differ in the two groups (1.68 and 1.78 microgram/ml, respectively). Digoxin plasma levels in no case exceeded 3 ng/ml and did not change significantly after disopyramide. Significant increases in STI and in the QTC interval were recorded only in patients of the first group. The PR interval was prolonged in both groups, but to a greater extent in patients receiving digoxin. We conclude that digitalization may prevent myocardial functional depression caused by disopyramide and enhance its antiarrhythmic action.

Adult↗
PubMedDate not supplied

Influence of disopyramide, compared with procainamide and quinidine, on isolated dog arteries in response to transmural stimulation and norepinephrine.

In helically cut strips of dog cerebral, coronary, and mesenteric arteries contracted with prostaglandin (PG) F2 alpha, disopyramide phosphate produced moderate contractions that were unaffected by phentolamine, chlorpheniramine, cinanserin, or aspirin. Procainamide and quinidine elicited only a slight contraction. Mesenteric arterial strips contracted with norepinephrine slightly contracted in response to disopyramide but significantly relaxed with procainamide and quinidine. The contractile response of mesenteric arterial strips to transmural electrical stimulation was attenuated by high concentrations (5 x 10(-5) M) of disopyramide or procainamide and by low concentrations of quinidine. Disopyramide-induced attenuation was greater in the response to high-frequency stimulation. Disopyramide at high concentrations potentiated the contractile response of mesenteric arteries to norepinephrine and tyramine, while, in contrast, procainamide and quinidine shifted the dose-response curve for norepinephrine to the right. Treatment with procainamide and quinidine, but not with disopyramide, protected alpha-adrenoceptors from persistent blockade by phenoxybenzamine; quinidine was far more effective than procainamide. It may be concluded that disopyramide possesses a nonspecific vasoconstricting action but not an alpha-adrenoceptor blocking property, whereas quinidine and procainamide show a reversible, competitive alpha-adrenoceptor antagonism. Different hemodynamic actions of these antiarrhythmics in situ appear to be related to such contrasting effects on arterial smooth muscle.

Animals↗
PubMed1994

Molecular mechanism of cibenzoline-induced anticholinergic action in single atrial myocytes: comparison with effect of disopyramide.

The anticholinergic effects of cibenzoline were examined and compared with those of disopyramide in atrial myocytes isolated from guinea pig heart. The tight-seal whole-cell voltage clamp technique was performed with a patch pipette filled with guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S). In GTP-loaded cells, both acetylcholine (ACh) and adenosine (Ado) induced a specific K channel current through GTP-binding proteins by binding to the muscarinic and Ado receptors, respectively. Both cibenzoline and disopyramide suppressed the ACh-induced K current effectively in a concentration-dependent manner. The concentrations for half-maximal inhibition of the current (EC50) caused by cibenzoline and disopyramide were 8 and 3 microM, respectively. In GTP gamma S-loaded cells, the K current was irreversibly activated because GTP binding proteins were directly elicited by GTP gamma S. Cibenzoline effectively caused a decrease in the GTP gamma S-induced K current, whereas the extent of disopyramide action on the GTP gamma S-induced K current was much less. Cibenzoline also caused significant inhibition of Ado-induced K current in GTP-loaded cells. However, the action of disopyramide was less effective in inhibiting Ado-induced K current. These results indicate that cibenzoline has less potent anticholinergic effects than disopyramide in atrial myocytes. In addition, cibenzoline effectively inhibits the muscarinic K channel itself and/or GTP-binding proteins coupled to the channel, whereas the effect of disopyramide is attributed mainly to blockade of muscarinic receptors. These findings provide novel understanding of the molecular mechanism of anticholinergic action of cibenzoline.

Animals↗
PubMed1996

Antiarrhythmic effects of optical isomers of disopyramide on canine ventricular arrhythmias.

Disopyramide is an effective class I antiarrhythmic drug and widely used for the treatment of arrhythmias, but it has anticholinergic side effects. In vitro studies demonstrated that dextrorotatory (D-) disopyramide has a stronger anticholinergic action, whereas the levorotatory (L-) isomer has a stronger Na channel blocking action. Because the antiarrhythmic mechanism of disopyramide suppressing digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmias is the drug-induced Na channel block, we examined the antiarrhythmic efficacy of D- and L-disopyramide on two arrhythmia models. On ouabain-induced ventricular tachycardia (VT), L-disopyramide 3 mg/kg decreased the arrhythmic ratio (number of ectopic beats/total heart rate), whereas the same dose of the D-isomer was ineffective and a higher dose (5 mg/kg) was needed to suppress the arrhythmia. The effective plasma concentrations (IC50) decreasing the arrhythmic ratio to 50% of the control were 5.3 and 11.3 mu g/ml for L- and D-disopyramide, respectively. We obtained similar results using 24-h two-stage coronary ligation VT. The IC50 were 8.9 and 22.2 mu g/ml for the L- and D-isomers, respectively. Our results indicate that L-disopyramide is about twice as strong an antiarrhythmic drug as the D-isomer.

Action Potentials↗
PubMed1988

Propafenone versus disopyramide for treatment of chronic symptomatic ventricular arrhythmias. A multicenter study.

The efficacy and safety of propafenone, 150 mg four times daily, were compared with those of disopyramide, 100 mg four times daily, in a randomized single-blind, cross-over study in 38 patients with symptomatic premature ventricular complexes (PVCs). The 24-hour ambulatory ECG, employed for assessing antiarrhythmic efficacy, was analyzed blindly. The median reduction in the number of PVCs was higher with propafenone than with disopyramide (91.4% vs. 63.5%, respectively, p less than 0.01). A reduction of at least 80% was achieved by propafenone in 22 (59%) and by disopyramide in 16 patients (43%) (NS). Ventricular tachycardias (VTs) were abolished by propafenone in eight out of 11, and by disopyramide in five out of nine patients with VTs (NS) a possible proarrhythmic effect was seen in three patients during disopyramide and in one patient during propafenone treatment. Micturition disturbances (p less than 0.001) and a dry mouth (p less than 0.01) were more commonly associated with disopyramide than with propafenone. In conclusion, in the given dosages, propafenone was superior to disopyramide in suppressing PVCs and had fewer side-effects.

Adult↗
PubMed1984

Anticholinergic activity in the serum of patients receiving maintenance disopyramide therapy.

The steady state serum levels of disopyramide and its metabolite, mono-N-dealkylated disopyramide (MND) were measured by gas-liquid chromatography in 40 patients receiving maintenance disopyramide treatment. The levels were mean 3.11 micrograms/ml +/- 0.28 (s.e. mean) and 0.9 micrograms/ml +/- 0.13 (s.e. mean), respectively. A radioreceptor assay was used for the quantitation of the anticholinergic activity of disopyramide and its metabolite in the same serum samples. The serum levels of anticholinergic activity varied between 0 and 6.7 ng/ml when measured as atropine equivalent (mean 1.88 +/- 0.26, s.e. mean, ng/ml). After a single oral dose of disopyramide the serum anticholinergic activity was, however, not detectable or very low. There was a significant correlation between disopyramide concentrations in serum and the serum anticholinergic activity (r = 0.655, P less than 0.001). No correlation was found between MND concentrations and the anticholinergic activity arguing against the role of MND causing antimuscarinic side effects. The affinity of MND for the muscarinic receptors in vitro was also lower than that of disopyramide.

Adult↗
PubMed1979

The effects of disopyramide phosphate on early post-coronary artery ligation dysrhythmias and on epicardial ST-segment elevation in anaesthetized dogs.

1 The antidysrhythmic, haemodynamic and metabolic effects of intravenously administered disopyramide phosphate (1 to 5 mg/kg) have been studied in greyhounds, anaesthetized with trichloroethylene. 2 In doses of 2.5 and 5.0 mg/kg, disopyramide significantly reduced the ventricular dysrhythmias that occur in the initial 30-min period following acute coronary artery ligation. None of the disopyramide-treated animals developed ventricular fibrillations. 3 The metabolic consequences of coronary artery ligation, assessed by local coronary venous sampling from the ischaemic area, were not modified by disopyramide except that K+ egress was prevented. 4 There was evidence for substantial disopyramide-induced myocardial depression (decreased cardiac output and left ventricular dP/drmax with elevated ventricular filling pressure and pulmonary oedema and shunting) and it is suggested that great care be taken when the drug is administered intravenously in conditions where cardiac function is already compromised. Disopyramide also reduced myocardial blood flow. 5 In chloralose-anaesthetized mongrel dogs, disopyramide (2.5 mg/kg) significantly reduced the ST-segment elevation (assessed from epicardial recordings) that resulted from short (3 min) coronary artery occlusions. This could indicate a reduction in the extent and severity of myocardial injury or simply reflect decreased K+ efflux (since locally administered K+ itself increased ST-segment elevation).

Animals↗
PubMed1987

The effects of external and internal application of disopyramide on the ionic currents of the squid giant axon.

1 The actions of the class I anti-arrythmic agent, disopyramide, on the ionic currents of the voltage-clamped squid axon have been investigated, by use of both extra-axonal and intra-axonal routes of application. 2 Extra-axonal application of 0.1 mM disopyramide produced no significant effects on the membrane currents. External disopyramide at 1.0 mM caused small, poorly reversible inhibition of both sodium and potassium currents. This block was use-dependent and was enhanced by use of test stimuli to more positive membrane potentials. 3 Intra-axonal application of 0.1 mM disopyramide caused a 40% reduction in the first-pulse sodium current (tonic block) and an additional use-dependent block. Analysis of first-pulse currents in terms of the Hodgkin-Huxley formalism indicated that the block resulted mainly from a reduction in the maximum available sodium conductance (gNa); there were no effects on the voltage dependence of the steady-state activation and inactivation parameters, m infinity and h infinity. 4 The use-dependent actions of disopyramide were investigated with a double voltage-clamp pulse protocol. The significant use-dependent effects of the drug were a further reduction in gNa and an increase in the time constant of inactivation (tau h). 5 Disopyramide appears to enter a blocking site in the sodium channel which is only readily accessible from the axoplasmic phase. Partition to the site depends on membrane voltage and on the state of the channel gates. Disopyramide binds at a significant rate to both open and inactivated forms of the sodium channel.

Animals↗