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[Disopyramide].

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Arrhythmias, Cardiac↗
PubMed1999

A comparison of the binding characteristics of class I antiarrhythmic agents for human muscarinic m1-m3 receptors.

The binding characteristics of the class 1 antiarrhythmic agents, cibenzoline, disopyramide, disopyramide metabolite (the main active metabolite of disopyramide in humans), and pirmenol, for human muscarinic receptors (m1-m3) stably expressed in Chinese hamster ovary cells (CHO) were investigated by binding assay with [3H]N-methylscopolamine ([3H]NMS) as a ligand. All of these agents inhibited the specific [3H]NMS binding to membrane preparations in a concentration-dependent manner. The potencies of affinity of these agents for m1, m2, and m3 receptors (compared by IC50) were disopyramide > pirmenol > disopyramide metabolite > cibenzoline, pirmenol > cibenzoline > disopyramide > disopyramide metabolite, and disopyramide > disopyramide metabolite > pirmenol > cibenzoline, respectively. Some competition curves of cibenzoline, disopyramide, and pirmenol were shallow, and Hill coefficients of these curves differed from unity, suggesting that these agents have allosteric binding characteristics for human muscarinic receptors. The m2-selective ratios to m1 (IC50 m1/IC50 m2) and m3 (IC50 m3/IC50 m2) of cibenzoline were 4.0 and 16, and those of pirmenol were 6.5 and 43, respectively, whereas those of disopyramide and its metabolite ranged from 0.46 to 1.6, suggesting that cibenzoline and pirmenol exerted high selectivity to the m2 receptor. We conclude that (a) all class 1 antiarrhythmic agents in this study have inhibitory effects on human m1, m2, and m3 receptors, and some of those binding may show allosteric characterization; (b) disopyramide and its metabolite have similar affinity to m1 to m3 receptors; and (c) cibenzoline and pirmenol have high m2-selective ratios to m1 and m3.

Animals↗
PubMed1988

Comparative effects of three class I antiarrhythmic drugs on plateau and pacemaker currents of sheep cardiac Purkinje fibres.

The electrophysiological effects of three class I antiarrhythmic drugs, lignocaine, disopyramide, and penticainide, were compared in sheep cardiac Purkinje fibres. Action potential duration was shortened with all three drugs, the effect being small with disopyramide, moderate with penticainide, and greatest with lignocaine. Slowing down of the early phase of repolarisation was greatest with disopyramide, smaller with penticainide, and did not occur with lignocaine. Automaticity recorded in low potassium media was unaltered (disopyramide), depressed (penticainide), or stopped (lignocaine). Ionic currents were recorded in short fibres using the two microelectrode voltage clamp technique. The tetrodotoxin sensitive slow component of the sodium current was suppressed (lignocaine) or reduced (penticainide and disopyramide) and the instantaneous background potassium current slightly reduced (disopyramide more than penticainide), unaffected, or slightly increased (lignocaine). The three drugs depressed moderately and similarly the slow inward calcium current. The amplitude of the 4-aminopyridine sensitive transient outward potassium current was almost unaffected (lignocaine) or appreciably depressed (disopyramide more than penticainide). The pacemaker current was reduced greatly by lignocaine, moderately by penticainide, and slightly by disopyramide. Changes in ionic currents may explain the effects of the three drugs on action potential plateau and automaticity of sheep Purkinje fibres. It is concluded that the pronounced differences observed in the effects of these three class I antiarrhythmic drugs on pacemaker depolarisation and on initial repolarisation may justify a more discriminative subdivision of class I antiarrhythmic drugs.

Action Potentials↗
PubMed1991

Combined effects of different class I antiarrhythmic agents on maximum rate of depolarization (Vmax) of action potentials in guinea-pig papillary muscles.

The combination of two different kinds of class I antiarrhythmic agents (class Ia, Ib, or Ic) was examined with regard to their effects on the maximum rate of depolarization (Vmax) of action potentials in guinea-pig papillary muscles. The combinations of disopyramide plus lidocaine, disopyramide plus mexiletine, mexiletine plus flecainide, and disopyramide plus flecainide were employed to study their effects on use-dependent block of Vmax. All the combinations increased the percent of use-dependent block at most of the frequencies employed (0.1-3.3 Hz) as compared to the effects of the single use of either drug, but no decrease in use-dependent block was found with any of the combinations. The time courses of the development of use-dependent block by disopyramide, lidocaine, and mexiletine were best expressed by two exponential functions, whereas those by flecainide were expressed by a single exponential function. Disopyramide plus lidocaine and disopyramide plus mexiletine produced increases in the time constant of the fast component of the block (tau f), the fast fraction of the block (Af), and the ratio of the fast to the slow fraction (Af/As). Mexiletine plus flecainide increased tau f, Af, and As; whereas disopyramide plus flecainide caused no changes in the kinetic parameters of use-dependent block. These results suggest that there may be diverse modes of interaction between the drug and the Na+ channel, and the combination of two different types of the drug may sometimes provide different effects on the fast and slow components of the use-dependent block of Vmax.

Action Potentials↗
PubMed1991

Combination antiarrhythmic treatment among class Ia, Ib, and II agents for ventricular arrhythmias.

Ventricular arrhythmia suppression trials were performed to compare the efficacies and side effects of disopyramide and mexiletine used alone and in combination, and to compare the efficacies and side effects of mexiletine and propranolol used alone and in combination, in patients with chronic ventricular premature contractions (VPCs, greater than or equal to 3000 beats/day). The study on the combination of disopyramide and mexiletine included 26 patients (19 men and 7 women). Disopyramide 100 mg tid or mexiletine 150 mg tid was administered as single-drug therapy, and disopyramide 50 mg plus mexiletine 100 mg tid was administered as combination therapy. Each patient underwent Holter monitoring during four different periods: baseline, disopyramide alone, mexiletine alone, and combination therapy. The mean number of VPCs/hr at baseline was 796 +/- 522 (mean +/- SD), which was significantly decreased with all three therapies (p less than 0.01 in each) to a) 415 +/- 480 with disopyramide alone, b) 341 +/- 368 with mexiletine alone, and c) 345 +/- 408 with the combination therapy. The number of patients demonstrating a significant reduction in VPCs (greater than or equal to 75%) and the elimination of ventricular tachycardia (VT; three or more consecutive VPCs) did not differ significantly among the three therapies. The prematurity index (PI), vulnerability index (VI), and QTc tended to be aggravated by disopyramide therapy alone, but these values were corrected by combination therapy. No patients withdrew from the study due to side effects during combination therapy, although three patients withdrew from the study due to severe side effects during single-drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Intravenous administration of diltiazem in the treatment of supraventricular tachyarrhythmias.

UNLABELLED: The aim of the study was to investigate the efficacy of diltiazem bolus intravenous administration, compared to disopyramide, in the treatment of various types of paroxysmal supraventricular tachyarrhythmias. METHOD: Fifty patients (23 males, 27 females, mean age 47.7 +/- 15.2 years) with paroxysmal supraventricular tachyarrhythmia (20 with paroxysmal atrial tachycardia, 23 with paroxysmal atrial fibrillation and rapid ventricular response and 7 with atrial fluttering) were studied. Diltiazem at a dose of 0.25-0.30 mg/kg BW or disopyramide at a dose of 50 mg were given bolus IV. If conversion of the arrhythmia to sinus rhythm could not be achieved with the initial drug, the alternate was given. The order of administration of the drugs was random, independent of the type of the arrhythmia. Before and during drug administration detailed clinical examination and frequent blood pressure (BP) measurements were performed. Twenty-four hour Holter monitoring was done in all patients, starting with the administration of the antiarrhythmic drug. RESULTS: 1) Paroxysmal atrial tachycardia: diltiazem administration converted the arrhythmia to sinus rhythm in all patients while disopyramide in only 1 of 9 patients who received this drug. 2) Paroxysmal atrial fibrillation: disopyramide converted the arrhythmia in 5 patients without significant change in ventricular response in the others. Diltiazem did not convert the arrhythmia though it caused significant decrease in ventricular response (< 100 bpm) and in 1 patient an important bradycardia (45 bpm). 3) Atrial fluttering: disopyramide converted the arrhythmia to sinus rhythm in 1 patient without significant change in the ventricular response in the others. Diltiazem caused significant decrease in the ventricular response without conversion to sinus rhythm. During conversion to sinus rhythm an AV junctional rhythm of short duration (< 1 min) was noticed in 5 patients and a short pause (< 2 sec) with or without an initial premature contraction in the remaining 21. Disopyramide administration was not associated with side effects. Diltiazem administration cause small (< 20 mm Hg), transient (< 30 min) decrease of BP without symptoms with the exception of the patient with bradycardia in whom the BP decrease was significant (90/60 from 160/80 mm Hg) followed by intense symptoms which lasted for six hours. CONCLUSIONS: Diltiazem administration is extremely effective in conversion of paroxysmal atrial tachycardia to sinus rhythm. In addition it retards ventricular response in patients with atrial fibrillation and fluttering. Compared to disopyramide these effects of diltiazem are more pronounced and clinically pertinent.

Adult↗
PubMed1998

Reduced systemic availability of an antiarrhythmic drug, bidisomide, with meal co-administration: relationship with region-dependent intestinal absorption.

PURPOSE: The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related antiarrhythmic agent, disopyramide. METHODS: Bidisomide plasma levels, following oral administration and intravenous infusion in the fasted state and with various meal treatments, were determined in human subjects. A dialysis technique was employed to examine the potential for drug binding to meal homogenates. Plasma levels, following drug administration through duodenal and jejunal intestinal access ports and following various meal treatments with oral drug co-administration, were compared for bidisomide and disopyramide in a canine model. RESULTS: Bidisomide plasma AUC was significantly reduced following oral drug co-administration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooked breakfast. While intravenous bidisomide infusion in human subjects showed a statistically significant reduction in AUC 15 minutes after oral administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (-13%) was substantially smaller than the reduction (from -43% to -63%) observed with oral bidisomide meal co-administration. The percentages of bidisomide and disopyramide lost by binding to homogenates of cooked breakfast were 25.0 +/- 5.7% and 23.7 +/- 7.7%, respectively, as determined by dialysis at 4 hours. In dogs, the extent of absorption of disopyramide was comparable from oral, duodenal and mid-jejunal administration while the extent of bidisomide absorption from mid-jejunal administration was significantly lower than for oral or duodenal administration. Non-viscous liquid meals decreased Cmax but not AUC, while viscous homogenized solid meals decreased both Cmax and AUC for bidisomide with oral drug-meal co-administration. Oral non-caloric hydroxypropyl methylcellulose meals decreased bidisomide to the same extent as homogenized solid meals but did not lower disopyramide AUC. CONCLUSIONS: The significant reduction in bidisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorption and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appear to be a function of drug binding to cooked meal components over typical human upper gastrointestinal residence times. In dogs, the high-viscosity medium generated by oral co-administration of a solid meal reduced the upper intestinal absorption of bidisomide and disopyramide. Bidisomide AUC was decreased since it was well absorbed in the upper but not lower small intestine. Disopyramide AUC was not significantly affected since it was well absorbed from both regions. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar regionally-dependent absorption profiles.

Animals↗
PubMed1992

Sodium channel states control binding and unbinding behaviour of antiarrhythmic drugs in cardiac myocytes from the guinea pig.

OBJECTIVE: The aim was to investigate whether cardiac sodium channel states (rested, activated, inactivated) regulate the binding and unbinding behaviour of antiarrhythmic drugs on the receptor sites. METHODS: Single ventricular myocytes of adult guinea pig heart were obtained by an enzymatic dissociation method in the Langendorff manner. The channel state dependent blocking effects on cardiac sodium current (INa) of quinidine and disopyramide were studied under the whole cell variation of the patch clamp technique. RESULTS: 10 microM quinidine and 20 microM disopyramide produced similar levels of tonic block and use dependent block. The steady state inactivation curve (h infinity curve) was shifted parallel in the negative potential direction by quinidine (10 microM) and disopyramide (20 microM) to the same extent (-10 mV). Removal of the fast inactivation process of INa by chloramine-T did not reduce tonic and use dependent block by these drugs. Onset block study using a double pulse protocol revealed that block developments by both drugs were fitted to the sum of double exponential functions. However, time constant of fast phase of block by disopyramide was faster than that by quinidine, while slow phase was not significantly different. Definition of time courses of unbinding (recovery) at -140 mV indicated that quinidine dissociated relatively slowly as compared to disopyramide. CONCLUSIONS: Quinidine produces more potent tonic and use dependent block of INa by binding to sodium channels at both rested and inactivated states, while disopyramide has a higher affinity for activated state. Therefore, sodium channel states regulate the binding and unbinding behaviour of antiarrhythmic drugs. Furthermore, the fast inactivation process is not essential in producing tonic and use dependent block by antiarrhythmic drugs.

Action Potentials↗
PubMed1988

General pharmacological studies on N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate. 1st communication: effect on the central nervous system.

The pharmacological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent, on the central nervous system were studied in various experimental animals as compared with those of disopyramide, mexiletine and lidocaine, and the following results were obtained. 1. Acute toxicity of SUN 1165 in mice was similar to that of mexiletine, and twice as potent as compared with that of disopyramide and lidocaine. Main acute toxic symptoms of SUN 1165 were muscle relaxation, ataxia, clonic convulsions, tremor and a decrease in spontaneous activity in mice, rats and rabbits. In addition to these symptoms, vomiting in dogs was observed. These toxic symptoms were similar to those of lidocaine. In the case of disopyramide, ataxia, tremor and a decrease in spontaneous activity were observed in mice and rats. On the other hand, mexiletine caused central nervous excitatory symptoms, that is, tremor, Straub tail, clonic convulsions, jumping, running and opisthotonus in mice and rats, and vomiting in dogs. 2. SUN 1165 even at large doses (50-100 mg/kg p.o.) exerted no significant effects on the following changes: hexobarbital-induced induced hypnosis, oxotremorine-induced tremor, apomorphine-induced hypothermia, reserpine-induced ptosis and hypothermia, 5-hydroxytryptophan syndrome and fighting behavior in mice, and conditioned avoidance response in rats. 3. An ineffective dose of SUN 1165 (12.5 mg/kg p.o.) on spontaneous locomotor activity was lower than of disopyramide and lidocaine, however, higher than that of mexiletine. 4. SUN 1165 at large doses showed antagonistic action on toxic extensor seizures induced by maximal electroshock, picrotoxin, or strychnine in mice, but anticonvulsive effects of SUN 1165 were less potent than those of mexiletine and lidocaine. SUN 1165 had no effect on clonic convulsions induced by pentetrazol and pictrotoxin in mice, while both mexiletine and lidocaine prolonged the duration of clonic convulsions. 5. The muscle relaxant effect of SUN 1165 (50%-toxic dose, TD50 = 30 mg/kg p.o.) was more marked than that of lidocaine (TD50 = 92 mg/kg p.o.) on traction test in mice. However, effect of SUN 1165 (TD50 = 62 mg/kg p.o.) on motor incoordination was similar to that of disopyramide, mexiletine and lidocaine on the rotarod test in mice. 6. The analgesic effect of SUN 1165 was as weak as that of disopyramide, mexiletine and lidocaine on chemically and mechanically-induced pain response in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

General pharmacological studies on N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate. 2nd communication: effect on the peripheral nervous system and peripheral organs.

The pharmacological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent, on the peripheral nervous system and peripheral organs were studied in various laboratory animals in comparison with those of disopyramide and mexiletine, and the following results were obtained. 1. Large doses (50 or 100 mg/kg p.o.) of SUN 1165 as well as mexiletine had little effects on the pilocarpine-induced hypersalivation and the pupil size in mice. At higher concentration (10(-5) g/ml), SUN 1165 had no effects on the various spasmogen acetylcholine (ACh)-, histamine- or BaCl2-induced contractions in the isolated guinea pig ileum, tracheal smooth muscle and urinary bladder. Disopyramide caused mydriasis, inhibited the pilocarpine-induced hypersalivation at antiarrhythmic doses (10-30 mg/kg p.o.), and suppressed ACh-induced contractions in the various organs. 2. SUN 1165, like disopyramide and mexiletine, decreased the contractile amplitude and diastolic tone of the isolated rabbit ileum. SUN 1165 as well as disopyramide had no effect on the intestinal propulsion even at a large dose (100 mg/kg p.o.). Mexiletine inhibited it at antiarrhythmic doses (10-30 mg/kg p.o.). SUN 1165 only at a large dose (100 mg/kg i.d. or p.o.) inhibited volume of pepsin output in the gastric juice in pylorus-ligated rats and caused a damage to the gastric mucosa. 3. SUN 1165, like disopyramide and mexiletine, slightly potentiated the norepinephrine-induced contraction of the rat vas deferens in vitro. Moreover, SUN 1165 as well as disopyramide and mexiletine slightly potentiated the serotonin-induced contraction of the rat isolated fundus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗