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A patient who suffered from severe decrease of accommodation and pupillary dilatation following the systemic use of disopyramide is described. The ocular side effects when this drug is used in large doses result from its anticholinergic action.
Disopyramide has been shown in conditions of cholinergic blockade to have a depressant effect upon sinus node automaticity and the atrial refractoriness. It also prolongs atrioventricular conduction and increases atrioventricular refractoriness. These effects may often be masked in vivo by the anticholinergic effects of the drug.
A 59-year-old man presented with atrial flutter and a 2:1 atrioventricular response, which, after intravenous disopyramide, became 1:1. A mechanism of slowed atrial flutter rate and improved atrioventricular nodal conduction, similar to that recognised with quinidine, is suggested.
A case is reported where the use of i.v. disopyramide for a supraventricular tachycardia resulted in a more serious ventricular dysrhythmia giving hypotension and this probably contributed to the development of a myocardial infarction. Attention is drawn to the possible risk.
A case of fatal torsade de pointes in a 53 year old patient treated with disopyramide is described. The arrhythmia followed the development of acute hepatocellular dysfunction and may have been due to failure of the liver to efficiently degrade the drug to its metabolites.
In voltage-clamp studies of atrial myocytes exposed to disopyramide or quinidine, pulse-train stimulation revealed use-dependent block that increased with increased pulse amplitude. Use-dependent block also became negligible at hyperpolarized holding potentials (< -150 mV), consistent with either rapid unbinding at the holding potential or trapping of the drug in a drug-complexed rest conformation followed by rapid unbinding during the next channel opening event. To explore the unbinding properties of hypothetically different rest-blocked conformations, we exposed cells to a postdepolarization "conditioning" potential after channels had become fully inactivated so as to vary the transition to different hypothetical rest-blocked channels. Pulse-train stimulation from -130 to -30 mV generated only a small amount of use-dependent block. Inserting a 120-ms subthreshold (e.g., -100 mV) postdepolarization conditioning potential before return to -130 mV increased use-dependent block. The fraction of steady-state block exhibited a bell-shaped dependence on the conditioning potential. These results are consistent with the existence of a mixture of rest-blocked channel conformations, each having direct access to the blocked-inactivated state. These intermediate rest conformations display radically different drug unbinding rates.
AIMS: We evaluated the clinical pharmacokinetics of a sustained-release preparation of disopyramide phosphate (DSR) and its effects on supraventricular arrhythmias in hemodialysis patients. METHODS: Eight hemodialysis patients with either paroxysmal supraventricular tachycardia (PSVT) or PSVT plus paroxysmal atrial fibrillation (Paf) were given 150 mg of DSR 2 h before each hemodialysis. The frequency of PSVT, the duration of Paf before and 2 weeks after starting DSR and the blood concentration of the drug were evaluated. RESULTS: There was no significant difference between serum levels of DSR before and after hemodialysis. The frequency of PSVT and the duration of Paf were significantly reduced by the therapy. Side effects and electrocardiographic abnormalities did not appear during the period. CONCLUSION: We conclude that hemodialysis does not remove DSR, and that a single dose of 150 mg of DSR given 2 h before hemodialysis is safe and sufficient to reduce the incidence of supraventricular arrhythmias.
The contribution of hydrophobicity of different types of detergents to disopyramide uptake by rat small intestinal brush-border membrane vesicles was studied in relation to their membrane lipid fluidity and the physicochemical parameters of the detergents, i.e., hydrophile-lipophile balance (HLB). Span-, Tween-type detergents or glycerol esters at non-solubilizing concentrations (0.01-0.05% (w/v)) decreased the extent of maximum uptake of the drug in the presence of outward H(+)-gradient, but not in the absence of the gradient. The fluorescence anisotropy of the vesicles using diphenylhexatriene (DPH), as reflected by its incorporation into the membrane inner lipid layer, decreased with the addition of all detergents used. In contrast, that of the vesicles using trimethylammoniumphenyl phenylhexatriene (TMA-DPH), which reflected its incorporation into the membrane outer lipid layer, increased depending on the concentration of Tween-type detergents except for Tween 81 and Tween 85, glycerol esters (MO-500, MO-750, ML-500 and ML-750); it decreased with the addition of Span-type detergents, Tween 81 and glycerol ester (MO-310). Therefore, the membrane lipid fluidity change of the outer leaflet, rather than the inner lipophilic domain, of the membrane vesicles caused by the detergents was found to be dependent on the hydrophobicity, but not on the type of detergent. This seems to correlate with the inhibitory effects on the facilitated uptake of the drug by the membrane vesicles.
There were remarkable differences in the serum total and unbound concentrations of disopyramide (DP) and mono-N-dealkyldisopyramide (MND), the major metabolite of DP, among patients with arrhythmias. Serum levels of alpha 1-acid glycoprotein (AAG) also varied among the same patients. To predict the unbound DP concentrations, we have obtained the serum concentration-time curves of unbound DP in these patients by means of total DP concentration, DP pharmacokinetic parameters, AAG levels and dissociation constants of DP and MND at specific AAG binding sites. In patients with normal AAG levels, the theoretical values of unbound DP were in good agreement with the measured concentrations. On the other hand, in patients with high AAG levels, the theoretical values could be obtained by correcting the calculated values using both AAG levels of each patient and the equation correlating the unbound DP fraction to AAG concentrations. These findings indicate that patient AAG levels can provide valuable information permitting the rapid estimation of unbound DP concentrations, the pharmacologically active fraction, and the development of effective DP dosage regimens.
The oxidative metabolism of disopyramide (DIS) enantiomers to mono-N-dealkyldisopyramide in mouse hepatic microsomes was studied in vitro. When (R-)-DIS was used as a substrate Lineweaver-Bulk plot was a single line with the apparent Km value of 0.23 mM and Vmax value of 1.05 nmol/mg protein/min. When S(+)-DIS was used as a substrate the plot was biphasic, and two apparent Km values (Km1 = 0.04 and Km2 = 0.77, mM) and two Vmax values (Vmax1 = 0.58 and Vmax2 = 1.53, nmol/mg protein/min) were obtained. When racemic DIS was used as a substrate the plot was also biphasic, while the plot observed at the lower concentration region was shifted to the upper region in comparison with that estimated from the sum of the individual N-dealkylase activities of each enantiomer. These results suggest that the N-dealkylation of R(-)-DIS is carried out by very limited cytochrome P-450 isozyme(s), but that of S(+)-DIS is carried out by multiple cytochrome P-450 isozymes; that is, N-dealkylations of R(-)- and S(+)-DIS are involved in the different cytochrome P-450 isozymes each other, particularly at relatively higher concentration of the substrates.
The mechanism involved in the renal excretion of disopyramide (DPM) is still incompletely understood. The purpose of this study was to examine the renal handling of DPM and the interactions between DPM and several organic anionic or cationic drugs related to the renal tubular secretion, using the renal clearance and renal cortical slices uptake techniques in rats. The clearance ratio of DPM was greater than that of glomerular filtration and this suggests the tubular secretion of DPM. The clearance ratio of DPM did not change after infusion of either anionic drugs (p-aminohippurate and probenecid) or a cationic drug (cimetidine). The results of time and concentration-dependent experiments using renal cortical slices demonstrated that DPM was accumulated against a concentration gradient by a saturable process. Inhibition of uptake by 2,4-dinitrophenol and cyanide indicated an energy dependence. DPM uptake was considerably inhibited by the cationic drugs, cimetidine and quinine, suggesting that DPM was transported by the cation transport mechanism. Probenecid, a competitor for the anion transport mechanism, moderately inhibited DPM uptake.
A 14-year-old boy with mid-ventricular hypertrophic obstructive cardiomyopathy (MVHOCM) first presented at the age of 10 years with severe chest pain. Two-dimensional echocardiography disclosed marked hypertrophy at the mid-portion of the ventricular septum, and left ventriculography showed an hourglass appearance at systole. He was initially treated with propranolol, but the chest pain and dyspnea on exertion worsened at the age of 12 years. After disopyramide was started, the chest pain disappeared and the degree of the pressure gradient at the mid-ventricular level was reduced. There was also significant improvement on a 123I beta-methyliodophenyl pentadecaonic acid (BMIPP) myocardial scintigram.
Acute ligation of proximal left coronary artery was performed on forty male Sprague-Dawley rats. Five min later, occlusion was released in order to evaluate the effectiveness of the 3 antiarrhythmic drugs in eliminating reperfusion ventricular arrhythmias. The drugs evaluated were moricizine (5 mg/kg), disopyramide (DSP) (5 mg/kg) and mexiletine (MXT) (5 mg/kg), which were administered intravenously 5 min before ligation of the coronary artery. Compared to control rats that underwent identical experimental procedures, all 3 drugs significantly lowered the mortality rate from 90% of the control group to 20, 20 and 0% for moricizine, DSP and MXT groups. The incidence of ventricular fibrillation (Vf) was also decreased significantly by these drugs. The duration of ventricular tachycardia (VT) and Vf of surviving rats in drug groups were 111.7 +/- 35.0 sec, 71.6 +/- 29.4 sec and 32.9 +/- 14.6 sec for moricizine, DSP and MXT, respectively. Many of the drug treated rats could be restored to the normal sinus rhythm and survived. All 3 drugs slowed the heart rate significantly, but as for the blood pressure only MXT showed significant suppressing effect. In conclusion, moricizine has the same significant preventive effect on reperfusion induced ventricular tachyarrhythmias as DSP and MXT.
Triggered activity due to delayed after depolarization has been postulated to be one of the generation mechanisms of some arrhythmias, especially that due to digitalis toxicity. The present experiment demonstrates an in vivo canine model of ventricular arrhythmias that were triggered by ventricular stimulation during administration of low doses of ouabain. Ventricular ectopic beats could be induced by stimulation before the occurrence of spontaneous ventricular arrhythmia, and the coupling interval of the first ectopic beat was shortened as the stimulation rate increased. Verapamil (0.2 mg/kg, i.v.) was ineffective in suppressing the occurrence of the triggered ventricular ectopic beats, but lidocaine (1 and 3 mg/kg, i.v.) and disopyramide (0.3 and 1 mg/kg, i.v.) were effective in suppressing these digitalis-induced triggered ventricular ectopic beats in a dose-dependent fashion.
Using the islet perifusion preparation and the isolated rat pancreas in situ perfusion preparation, the effects of disopyramide (Diso) on insulin secretion were studied. In an isolated pancreatic islet perifusion experiment, Diso (300 micrograms/ml) produced a significant increase in the immunoreactive insulin (IRI) level in the perfusate. The Diso-induced IRI rise was not affected by pretreatment with various autonomic blocking agents, such as propranolol, phentolamine or atropine. In an isolated rat pancreas in situ perfusion experiment, the IRI level in the perfusate increased significantly after the administration of Diso (300 micrograms/0.1 ml) under the perfusion of Krebs-Ringer bicarbonate buffer solution containing 0.3% glucose (0.3% glucose buffer), but not under the perfusion of Krebs-Ringer bicarbonate buffer solution containing 0.1% glucose (0.1% glucose buffer). The Diso-induced IRI rise was not affected by pretreatment with the autonomic blocking agents. Diso suppressed the IRI rise which was induced by additional glucose application (25%, 0.2 ml) under the perfusion of 0.1% glucose buffer, but not under the perfusion of 0.3% glucose buffer. Furthermore, Diso also suppressed the hypersecretion of insulin induced by increasing the glucose concentration from 0.1% to 0.3% in the perfusion fluid. The suppressing action of Diso on glucose-stimulated insulin secretion was partially recovered after pretreatment with propranolol or phentolamine. These findings show that Diso has both stimulatory and inhibitory effects on insulin secretion processes, and that the inhibitory action of Diso is suppressed by high glucose solution.
Atrial flutter occurring in patients with the Wolff-Parkinson-White syndrome is extremely uncommon. We describe a patient with this arrhythmia which converted to sinus rhythm and normal conduction following intravenous administration of disopyramide.
The effect of disopyramide phosphate (DP) infusion (1 mg/Kg and 2 mg/Kg BW) on ventricular fibrillation threshold (VFT) was studied in anesthetized dogs. In the 1 mg/Kg group, the VFT increased 47% above the control level immediately after infusion. In the 2 mg/Kg group, a delayed increase in VFT was observed after the initial period and VFT was not correlated with the plasma concentration of DP. This phenomenon was abolished by pretreatment with methacholine. These results suggested an anticholinergic action of DP on the VFT. In the ischemic dogs produced by acute coronary occlusion, DP prevented a decrease in VFT.
A single dosis of disopyramide (100 mg), given intravenously in 10 min to 30 patients admitted in the coronary or respiratory care unit, induces a reduction of cardiac output of 13.4%, which is highly statistically significant, without altering the systemic and pulmonary pressures. The heart rate is also slightly diminished.