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PubMed1980

Cardiac depression by intravenous disopyramide in patients with left ventricular dysfunction.

The hemodynamic effects of disopyramide phosphate were studied in nine patients with left ventricular dysfunction. After control measurements, administration of a 2 mg/kg bolus of disopyramide phosphate over 5 or 15 minutes was followed by a 20 minute 0.4 mg/kg/hour infusion and a 15 minute recovery period. Response to the 5 and 15 minute bolus injection was similar. Maximum hemodynamic effects occurred immediately after the bolus was given; there were decrements in systolic pressure (142 to 124 mm Hg)(p less than 0.005), cardiac index (2.5 to 1.8 liters/min/m2)(p less than 0.001) and stroke index (29.4 to 20.6 ml/beat/m2)(p less than 0.001), and increases in right atrial pressure (9 to 12 mm Hg)(p less than 0.005) and total peripheral resistance (21.2 to 25.7 U)(p less than 0.005). Two studies had to be terminated after the bolus was given due to profound hemodynamic deterioration. In the remainder, the systolic pressure returned to control by the end of the infusion, whereas the mean arterial pressure increasd significantly (92 to 96 mm Hg)(p less than 0.01). Little further change in mean arterial pressure, cardiac and stroke index, and total peripheral resistance occurred during the recovery period. These data indicated that intravenous disopyramide phosphate is a potent cardiac depressant when given over 5 to 15 minutes to patients with left ventricular dysfunction. It is concluded that disopyramide should not be administered to such patients unless conventional therapy fails. In such circumstances it should be used with extreme caution and careful monitoring.

Aged↗
PubMed1995

The activation gate of cardiac Na+ channel modulates voltage- and pH-dependent unbinding of disopyramide.

To assess the drug unbinding process from receptor sites in cardiac Na+ channels, we examined the recovery kinetics of disopyramide-blocked Na+ current (INa) in isolated guinea-pig ventricular myocytes using the whole-cell variation of the patch-clamp technique. In the presence of disopyramide (20 microM), the time course of INa recovery from use-dependent block (unbinding) was described by a double exponential function. Although the time constant for the fast phase (tau f) of recovery was unchanged at different membrane voltages, the slow phase (tau s) increased with hyperpolarizing membrane potential: 4.4 +/- 0.2 s at a holding potential of -90 mV and 6.4 +/- 0.3 s at -140 mV (n = 10, P < 0.01). The slow time constant of INa recovery was also increased by acidification. These findings suggest that disopyramide molecules can escape from the receptor site through the hydrophobic pathway after deprotonation, because slowing of recovery from use-dependent block by acidification is caused by a decreased deprotonation rate of receptor-bound drug molecules. In addition to the hydrophobic escape, the roles of the fast inactivation gate and activation gate (m-gate) were evaluated during the recovery process. After inhibition of the fast inactivation process of INa by pretreatment with chloramine-T (2 mM), the fast phase of recovery from use-dependent block by disopyramide was abolished.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1989

Disopyramide induces insulin secretion and plasma glucose diminution: studies using the in situ canine pancreas.

The mechanism of disopyramide-induced hypoglycemia, a life-threatening complication in the antiarrhythmic drug treatment, is still controversial. To elucidate this, we have evaluated plasma insulin (IRI) and glucagon (IRG) responses in the pancreatic vein (PV) of the in situ pancreas as well as responses of plasma IRI, IRG, and glucose in the femoral artery (FA) to disopyramide phosphate administration in anesthetized dogs. First, infusion of disopyramide at a dose of 50 mg for ten minutes directly into the pancreatic artery, but not the vehicle, increased significantly plasma IRI concentration in the PV (P less than .05 or less), where the IRI response started within three minutes and reached a peak of 2.8-fold preinfusion value at 30 minutes after starting the infusion (n = 7). Plasma IRI concentration in the FA also increased slightly but significantly (P less than .05). Plasma IRG concentration in the PV initially decreased significantly (P less than .05 or less) and in the FA at one point (P less than .05) during the infusion, and then increased significantly after cessation of the infusion, showing a peak of 1.9-fold preinfusion value at 60 minutes in the PV and the FA (P less than .05). Plasma glucose concentration in the FA decreased slowly and significantly after the infusion (P less than .05 or less) and fell by 16% of the baseline value at 60 minutes (P less than .05). Second, serum disopyramide concentration of 13.7 +/- 2.8 micrograms/mL at ten minutes, which corresponds to a twofold to threefold concentration of the human therapeutic level (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Determination of unbound fraction of disopyramide in plasma: a comparison of equilibrium dialysis, ultrafiltration through dialysis membranes and ultrafree anticonvulsant drug filters.

A simple, rapid ultrafiltration technique for determination of free drug concentration in plasma is described and compared with equilibrium dialysis and ultrafiltration through dialysis membranes. When used for disopyramide protein binding studies, this method requires only 1 ml of plasma and up to 20 samples may be filtered simultaneously in 20-40 min. Commercially available Ultrafree anticonvulsant drug filters are used, these are attached to 2 ml leur tip syringes, which provide the pressure gradient for filtration. Compared to equilibrium dialysis this technique is far quicker and permits protein binding to be measured at the drug concentration in the original plasma. Ultrafiltration through dialysis membranes was found to be more tedious and time-consuming than it was through Ultrafree filters. Adsorption of disopyramide from the plasma sample and protein leakage were also problems with this method. Leakage of protein did not occur with either Ultrafree filters or equilibrium dialysis. With the Ultrafree method, recovery of 14C-labeled disopyramide in buffer at 1.1 micrograms/ml and 8.4 micrograms/ml was 87% and 89% respectively. In carefully controlled experiments, a comparison of the Ultrafree method with equilibrium dialysis and ultrafiltration gave comparable values for the free fraction of the drug for total concentrations from 0.3-8 microgram/ml disopyramide.

Blood Proteins↗
PubMed1986

Measurement of plasma disopyramide as a guide to paediatric use.

We have studied the relationship between age, daily dose, plasma concentration and clinical efficacy of disopyramide in a group of paediatric patients. Twelve children with ventricular and 3 with supraventricular arrhythmias were treated with oral disopyramide. The initial dose was 3-6 mg/kg per day. This was adjusted until a pre-dose plasma concentration greater than 2 mg/I was achieved. Seven patients were judged to have responded to the treatment on clinical criteria. No symptoms or signs of toxicity were observed. In some of the children the dose of disopyramide required to achieve a plasma concentration greater than 2 mg/l was greatly in excess of the normal adult dose. Generally the youngest children required the highest dose, but the variation was wide. The dose could not be predicted from the age, the body weight or the surface area of the patient. In children high doses of disopyramide may be needed to achieve effective plasma concentrations of the drug; such doses are not associated with adverse effects. Measurement of the plasma concentration is necessary to guard against premature termination of therapy.

Administration, Oral↗
PubMed1987

Effects of disopyramide on the isolated rabbit aorta and pulmonary artery.

1. Disopyramide (8 X 10(-5)-4 X 10(-4) M) contracted the rabbit aortic strips and this could be prevented by verapamil or by omitting Ca2+ from Krebs solution. 2. Disopyramide (1.5-6 X 10(-5) M) significantly potentiated the contractile response of the rabbit aortic strips to noradrenaline, clonidine and methoxamine but not that of potassium chloride. 3. Disopyramide (2-6 X 10(-5) M) attenuated the contractile response of the rabbit pulmonary artery to transmural electrical stimulation but potentiated response to noradrenaline. Similar results were observed with the portal vein. 4. The relaxant effect of acetylcholine, on the rabbit aortic ring precontracted with noradrenaline, was blocked by disopyramide while the relaxant effect of adenosine-5'-triphosphate (ATP) was not blocked.

Animals↗
PubMed1989

Acute effect of disopyramide on atrial fibrillation in the Wolff-Parkinson-White syndrome.

Disopyramide was administered intravenously to 54 patients during atrial fibrillation and predominantly pre-excited QRS configuration at the time of electrophysiologic study. All patients had Wolff-Parkinson-White syndrome and no patient had coexistent heart disease. The drug was given during sustained atrial fibrillation (n = 45) or during sinus rhythm before induction of atrial fibrillation for patients whose atrial fibrillation was self-terminating in the control state (n = 9). Atrial fibrillation converted to sinus rhythm within 15 min after disopyramide in 37 (82%) of the 45 patients. The shortest RR intervals between two pre-excited cycles increased from 208 +/- 42 to 293 +/- 117 ms (p less than 0.0001). The average RR interval of all cycles prolonged from 332 +/- 60 to 396 +/- 117 ms(n = 45, p less than 0.0001). The 9 patients in whom pre-excitation was abolished after the drug had a significantly longer initial shortest RR interval than that of the 36 patients in whom pre-excitation persisted (246 +/- 47 versus 199 +/- 36 ms, p = 0.0022). No patients developed significant hemodynamic or other adverse effects after disopyramide. These data support the intravenous use of disopyramide in patients with normal ventricular function who have atrial fibrillation and a predominant ventricular response over an accessory atrioventricular pathway.

Adolescent↗
PubMed1999

Effects of oral repetitive loading of disopyramide on acute-onset atrial fibrillation with concurrent monitoring of serum drug concentration.

We investigated the efficacy and safety of oral repetitive loading of disopyramide, for the termination of acute-onset (i.e., therapy started within 2 days after the onset of palpitations) atrial fibrillation (AF) in 96 consecutive patients, with concurrent monitoring of the serum concentration of this agent in fifteen of the patients. Outpatients with AF verified by standard electrocardiogram (ECG) were hospitalized and received disopyramide (200 mg) every 4-6 h, with a maximal dose of 800 mg daily, until the termination of AF under ECG monitoring was obtained. Conversion to sinus rhythm occurred within the first day of treatment in 88 patients (92%), on the second day of treatment in six patients (6%), and on the third and fifth days of treatment in the remaining two patients. No major adverse effects, such as hypotension, congestive heart failure, proarrythmic events or systemic embolism were noted. The serum levels of disopyramide evaluated in fifteen of the enrolled patients were found to be maintained within the therapeutic range throughout the treatment period. In spite of the absence of any placebo-controlled group in this study, these findings suggest that repetitive oral loading of disopyramide (200 mg) with an interval of 4-6 h is effective and safe for the termination of acute-onset AF under a stable therapeutic serum drug concentration, hence offering the possibility of self-medication for patients with episodic AF.

Acute Disease↗
PubMed1984

Simultaneous quantitation of disopyramide and its mono-dealkylated metabolite in human plasma by fused-silica capillary gas chromatography using nitrogen-phosphorus specific detection.

A nitrogen-specific detector gas-liquid chromatographic assay method is reported which provides improved selectivity and sensitivity for disopyramide and its mono-N-dealkylated metabolite using a crosslinked fused-silica capillary column. The quantitation of disopyramide and mono-N-dealkylated disopyramide was accomplished by injecting trifluoroacetic anhydride-treated samples containing derivatized internal standard p- chlorodisopyramide , into a gas chromatograph equipped with a nitrogen--phosphorus detector and an automatic liquid sampler. A 25 m X 0.31 mm crosslinked, 5% phenylmethyl silicone-coated fused-silica column was utilized and samples were injected using the splitless injection mode. Linearity was observed in the range 0.05-5.00 micrograms/ml for disopyramide and 0.02-3.00 micrograms/ml for the mono-N-dealkylated metabolite. The coefficient of variation was found to be within 10% for both compounds in the concentration range studied.

Chromatography, Gas↗
PubMed1980

Resolution, absolute configuration, and antiarrhythmic properties of the enantiomers of disopyramide, 4-(diisopropylamino)-2-(2-pyridyl)-2-phenylbutyramide.

Disopyramide was resolved by fractional crystallization of its diastereomeric bitartrate salts from methanol-acetone. Diastereomeric sulfonamides prepared from (+)-camphor-10-sulfonyl chloride and the primary amines obtained by LiAlH4 reduction of the resolved bases were separable by high-performance LC and were used to show that within experimental error resolution of disopyramide was complete. The absolute configuration was determined by X-ray crystallography. (+)-[(2R)-(-)-4-(Diisopropylamino)-2-(2-pyridyl)-2-phenylbutyramide (+)-(2R,3R)-bitartrate] crystallizes in space group P212121: a = 14.789 (4), b = 18.151 (4), c = 9.878 (2) A; Z = 4: Dx = 1.225, Dm (flotation C6H6/CCl4) = 1.226 g cm-3. The structure was solved by direct methods. The enantiomeric bitartrates were tested for antiarrhythmic properties. The enantiomeric bitartrate salts were equally effective in prolonging the effective refractory period (ERP) of rabbit ventricle. At 3 x 10(-6) M, the (-)-bitartrate [from (2S)-(+)-disopyramide] increased the ERP 21.8 +/- 6.3 ms and the (+)-bitartrate [from (2R)-(-)-disopyramide] increased the ERP 25.8 +/- 3.6 ms. At 1.5 x 10(-5) M no significant difference was noted, as the increases in the ERP were 41.2 +/- 8.9 and 50.5 +/- 6.3 ms for the (-)- and %+)-bitartrate, respectively.

Animals↗
PubMed1999

Effects of disopyramide and verapamil on renal disposition and nephrotoxicity of cisplatin in rats.

PURPOSE: The purpose of this study was to determine the effects of disopyramide and verapamil on the renal handling of cisplatin (CDDP) and nephrotoxicity in rats. The stereoselective effect of verapamil was also studied. METHODS: CDDP was administered to rats by i.v. bolus injection or by infusion at a constant rate with or without concomitant administration of racemic disopyramide, racemic verapamil, or each verapamil enantiomer. The concentrations of CDDP in plasma and in the kidney and liver were determined by HPLC. In separate experiments, CDDP was administered as described above, and blood urea nitrogen (BUN) was monitored for 7 days. RESULTS: The BUN level after administration of CDDP was significantly reduced by coadministration of either disopyramide or verapamil. Renal accumulation of CDDP was significantly reduced by these drugs, whereas accumulation into the liver was not significantly changed. The relationship between the BUN levels and the area under the curve of CDDP concentration in the kidney versus time (AUCk) was analyzed using a sigmoid Emax model; this showed that the reduced BUN levels were explained by the AUCk. Furthermore, verapamil showed stereoselective inhibition of the renal accumulation of CDDP. CONCLUSIONS: The renal accumulation of CDDP was inhibited by disopyramide and verapamil, and this inhibition resulted in the amelioration of nephrotoxicity.

Animals↗
PubMed1981

Disopyramide hemodialysis and kinetics in patients requiring long-term hemodialysis.

Disopyramide hemodialysis and kinetics after 200 mg orally in six patients receiving long-term hemodialysis were examined. Mean volume of distribution (area) was 66.5 +/- 13 l. Mean times of the peak serum concentration and mean peak serum concentration were 2.3 +/- 0.9 hr and 3.1 +/- 0.9 microgram/ml. Mean absorption half-life (t 1/2) was 21.6 +/- 12.5 min. Mean disopyramide elimination t 1/2 during dialysis was 16.8 +/- 11.9 hr, not significantly different from mean elimination t 1/2 without dialysis of 16.1 +/- 5.2 hr. End-dialysis bath concentrations of disopyramide showed that not more than 2.4% of the dose was dialyzed during a 2-hr dialysis period. Our data indicate that at therapeutic concentrations disopyramide was not appreciably dialyzed.

Adult↗
PubMed1984

Intravenous disopyramide: safety and efficacy of a new dosage regimen.

The efficacy and safety of a new dosage regimen of intravenous disopyramide in ventricular arrhythmias were evaluated in 10 patients. Each had at least four premature ventricular contractions (PVCs)/min during a 30-min period before dosing. By the classification of Lown et al., grade III arrhythmia was present in four patients, grade IVA in three patients, and grade IVB in three patients. Disopyramide was injected intravenously as a bolus of 0.5 mg/kg over 5 min. Each patient received two to three additional boluses of same strength with 5-min intervals between each dosing during the first hour. Continuous intravenous infusion was started with the first bolus and continued at a rate of 1 mg/kg/hr for 3 hr and at 0.4 mg/kg/hr for 15 hr. All patients had continuous Holter monitoring throughout the 18-hr treatment period and for 30 to 60 min before treatment. In eight patients the grade of arrhythmia after drug decreased and the frequency of PVCs fell by 70% to 100% (greater than 85% in six patients and less than 85% in two patients), and the response persisted during the continuous infusion. In two patients PVC frequency increased. For the group as a whole, PVC frequency decreased on the average by 68.4%. Therapeutic serum levels (greater than 2 micrograms/ml) were reached after the first or second bolus and were maintained during the continuous infusion period. There were no side effects necessitating termination of disopyramide infusion. The dosage regimen of intravenous disopyramide evaluated was effective in 60% of patients with ventricular arrhythmia, induced no severe toxic effects, and rapidly achieved therapeutic serum levels that were maintained during continuous infusion.

Adult↗
PubMed1981

Disopyramide and neuromuscular transmission.

The effect of disopyramide on neuromuscular transmission has been studied using the rat isolated phrenic nerve-diaphragm preparation. The response of the muscle to indirect nerve stimulation was decreased in the presence of disopyramide 5.6 x 10(-6) mol litre-1 (P less than 0.05), total blockade occurring at 5.6 x 10(-4) mol litre-1. Marked augmentation of the response to direct muscle stimulation was recorded in the presence of disopyramide 1.8 x 10(-4)-5.6 x 10(-4) mol litre-1. Disopyramide 5.6 x 10(-6) mol litre-1 caused a leftward shift of the log concentration response for tubocurarine and decreased the antagonist effect of neostigmine.

Animals↗
PubMed1995

An overdose fatality in a child involving disopyramide and sulindac.

The results of an accidental overdose fatality in a child involving disopyramide and sulindac are reported in this paper. Quantitation of disopyramide was performed by gas chromatography using codeine as the internal standard. Sulindac was assayed by high- performance liquid chromatography using ketoprofen as the internal standard. The postmortem blood concentrations of disopyramide and sulindac were 41.3 and 12.2 mg/L, respectively. The concentrations of disopyramide and sulindac were also quantitated in the liver, in bile, and in urine.

Anti-Arrhythmia Agents↗
PubMedDate not supplied

Effects of disopyramide on reperfusion arrhythmias in dogs.

We tested the effect of disopyramide on reperfusion arrhythmias in mongrel dogs. The control group consisted of 27 dogs. Twenty-nine dogs received two intravenous doses of disopyramide (total: 5.3 mg/kg) before and during the occlusion of the left anterior descending coronary artery. The blood levels of disopyramide averaged 3.95 +/- 0.95 micrograms/ml and 5.9 +/- 1.1 micrograms/ml, 2.5 and 9.5 min after the ligation. The incidence of reperfusion arrhythmias was significantly (p less than 0.05) lower in the treated group (7.5%) than in the control group (33.3%). Disopyramide also lowered the incidence of arrhythmias during the occlusion period (14% vs. 52%, p less than 0.01). Both groups showed a correlation between the incidence of arrhythmias during the occlusion period and on reperfusion.

Animals↗
PubMedDate not supplied

Comparative electrophysiological effects of disopyramide and bepridil on rabbit atrial, papillary, and Purkinje tissue: modification by reduced extracellular potassium.

The electrophysiological actions of bepridil were compared with those of disopyramide in rabbit atrial, Purkinje, and papillary muscles in both normokalaemic (5.6 mM K+) and low K+ medium. In normokalaemic medium, the major electrophysiological effects of bepridil (10-40 microM) were a reduction in the maximum rate of rise of phase 0 of the action potential (MRD) of atrial and Purkinje fibres and prolongation of the atrial action potential duration (APD). Higher concentrations (40-100 microM) reduced MRD of papillary muscle without markedly affecting APD. Disopyramide (40-100 microM) reduced MRD and prolonged APD in similar concentrations in all three tissues. Reducing extracellular (EC) K+ to 2.8 mM decreased the effects of bepridil on MRD in all tissues but only significantly reduced the response to disopyramide in papillary muscle. Enhancement of APD prolongation by disopyramide in all tissues resulted when EC K+ was reduced, whereas only papillary muscle APD showed a marked prolongation in response to bepridil. These results demonstrate that the class I effect of bepridil is highly K+ dependent. It may be expected that QTc prolongation produced by both these drugs will be more marked in patients with low serum potassium levels.

Action Potentials↗
PubMedDate not supplied

Comparative effects of disopyramide and its mono-N-dealkylated metabolite in conscious dogs with chronic atrioventricular block: plasma concentration-response relationships.

In animals and humans, the antiarrhythmic agent disopyramide is primarily metabolized by mono-N-dealkylation. The effects of disopyramide and its N-dealkylated metabolite (MND) were investigated in 13 conscious dogs with chronic atrioventricular (A-V) block and implanted atrial pacing electrodes. Our data clearly show that both compounds used within the therapeutic plasma level range induced lengthening of the atrial effective refractory period (AERP) as reflected by the diminution of the maximal atrial frequency determined by pacing. However, at equivalent drug plasma concentrations, disopyramide induced a more marked decrease (1.2-1.7 times) in the maximal atrial frequency than did its metabolite. Both compounds increased mean arterial pressure (MAP) and atrial rate and decreased ventricular rate, but the effects on MAP and atrial rate were more marked with disopyramide than with MND. Thus, with regard to these cardiovascular parameters, the parent drug and MND possess distinct pharmacodynamic profiles, which may in part be related to their respective vagolytic power.

Animals↗