The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide

Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects, the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (), these are the only parameters which can be reported without qualification as to the concentration. The mean ± SD total body clearance of unbound drug in the eight subjects was 5.40± 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of , while the renal clearance of total disopyramide is dependent upon .     

Hypertrophic cardiomyopathy in childhood and adolescence – strategies to prevent sudden death

Clinically overt hypertrophic cardiomyopathy is the most common cause of sudden unexpected death in childhood and has significantly higher sudden death mortality in the 8‐ to 16‐year age range than in the 17‐ to 30‐year age range. A combination of electrocardiographic risk factors (a limb‐lead ECG voltage sum >10 mV) and/or a septal wall thickness >190% of upper limit of normal for age (z‐score > 3.72) defines a paediatric high‐risk patient with great sensitivity. Syncope, blunted blood pressure response to exercise, non‐sustained ventricular tachycardia and a malignant family history are additional risk factors. Of the medical treatments used, only beta‐blocker therapy with lipophilic beta‐blockers (i.e. propranolol, metoprolol or bisoprolol) have been shown to significantly reduce risk of sudden death, with doses ≥6 mg/kg BW in propranolol equivalents giving around a tenfold reduction in risk. Disopyramide therapy is a very useful adjunct to beta‐blockers to improve prognosis in those patients that have dynamic outflow obstruction in spite of large doses of beta‐blocker, and its use in patients with hypertrophic cardiomyopathy is not associated with significant pro‐arrhythmia mortality. Calcium‐channel blockers increase the risk of heart failure‐associated death in hypertrophic cardiomyopathy (HCM) patients with severe generalized hypertrophy and should be avoided in such patients. Amiodarone does not protect against sudden death, and long‐term use in children usually has to be terminated because of side effects. Therapy with internal cardioverter defibrillator implantation has high paediatric morbidity, 27% incidence of inappropriate shocks, and does not absolutely protect against mortality but is indicated as secondary prevention or in very high‐risk patients.     

Potentially fatal interaction between azithromycin and disopyramide

A patient on disopyramide developed disopyramide toxicity when treated concurrently with azithromycin. Evidence of toxicity included an elevated serum disopyramide level and ventricular tachycardia requiring cardioversion. The azalide antibiotic presumably inhibited dealkylation of disopyramide to its major metabolite, mono-N-dealkyldisopyramide. Physicians should avoid using azithromycin in patients on disopyramide. If this drug combination is unavoidable, disopyramide levels must be closely monitored.     

Efficacy of disopyramide in conversion and prophylaxis of post-thyrotoxic atrial fibrillation

Summary Rhythm conversion in patients with post-thyrotoxic atrial fibrillation (AF) has been performed with disopyramide in order to evaluate the conversion rate and to test its effect on the maintenance of sinus rhythm after cardioversion.The duration of AF ranged from 9 to 122 months (mean 31.8 months). Of 81 patients, 12 (15%) with relatively short duration AF were converted to sinus rhythm with disopyramide. The remaining 69 patients required DC cardioversion, which restored sinus rhythm in 58 patients. The 58 DC-converted patients were divided into two groups: a disopyramide group (D group) and a non-disopyramide group (non-D group). The D group received disopyramide 300 mg per day for 3 months after DC cardioversion and the non-D group did not receive anti-arrhythmic drugs. During the early observation period, only one patient relapsed in the D group into AF, but 5 successive patients in the non-D group reverted to AF, forcing discontinuation of the non-D protocol. A second DC cardioversion performed on 3 of those 5 patients was followed by maintenance therapy with disopyramide 300 mg per day, and they remained in sinus rhythm. With the inclusion of those three subjects, sinus rhythm was still present in 44 of the total of 58 patients converted by DC (76%) at the time of follow-up (64 months).Thus, disopyramide was effective in rhythm conversion and it was essential for the maintenance of sinus rhythm after cardioversion in patients with post-thyrotoxic AF.     

Dispersion of Filtered P Wave Duration by P Wave Signal-Averaged ECG Mapping System:

INTRODUCTION: Although it is desirable to know drug efficacy before initiating antiarrhythmic therapy, there have been no methods for this evaluation. P wave signal-averaged ECG (P-SAECG) is useful to detect subtle changes in disturbance of atrial conduction. The purpose of this present study was to test whether P-SAECG mapping system would give any information on the efficacy of disopyramide on the prevention of paroxysmal atrial fibrillation (PAF). METHODS AND RESULTS: P-SAECG was performed before disopyramide treatment, at 3 hours after a single dose of oral disopyramide (200 mg), and after 4 weeks of disopyramide treatment (300 mg/day). After measuring the filtered P wave duration by the vector magnitude and mapping methods, we calculated filtered P wave duration dispersion, difference between the maximal and minimal filtered P wave duration within 16 chest leads at these three time points. Filtered P wave duration and filtered P wave duration dispersion before treatment were longer in 32 patients with symptomatic PAF than in 31 healthy volunteers. Disopyramide was effective for suppression of PAF in 17 patients and ineffective in 15 patients after 4 weeks of treatment. Filtered P wave duration was similarly prolonged at 3 hours in the two groups, whereas filtered P wave duration dispersion at 3 hours after the disopyramide administration behaved differently; it decreased in all of the effective group and increased in all of the ineffective group. The effective patients were prospectively followed with the same treatment for 6 months. In 16 (94%) of these 17 effective patients, no PAF was documented and they remained to be asymptomatic. CONCLUSIONS: Thus, measuring filtered P wave duration dispersion with the P-SAECG mapping method after a single administration may predict the long-term efficacy of disopyramide in patients with PAF.     

Effect of mexiletine,amiodarone and disopyramide on the excitability and refractoriness of canine cardiac fibers: Possible relation to antiarrhythmic drug action and classification

Summary We tested the hypothesis of Campbell [1] that the effect of the sodium channel-blocking antiarrhythmic drugs on postrepolarization refractoriness i.e., relation between action potential duration (APD) and effective refractory period (ERP) is determined by the drug's effect on the recovery from V_max block. We studied the effects of two antiarrhythmic drugs with fast (mexiletine, amiodarone), and one with slow (disopyramide) kinetics of recovery from V_max block, at two different basic cycle lengths (BCL), on ERP/APD ratio in cardiac dog Purkinje and ventricular muscle fibers. ERP was measured using stimuli of 2 ms duration and 1.0 to 5.0 times diastolic threshold strength. The three drugs altered the kinetics of recovery from V_max block in the manner previously reported by us and other investigators. In both fiber types, mexiletine increased and the other two drugs did not change the ERP/APD ratio. We concluded that the magnitude of postrepolarization refractoriness could not be predicted from the kinetics of the V_max block. Also, the effect of the drug on the ERP/APD ratio could be altered by changes in the stimulus strength and the BCL.This study was supported in part by the Herman C. Krannert Fund; by Grants HL-06308 and HL-07182 from the National Heart, Lung, and Blood Institute of the National Institutes of Health; by the American Heart Association, Indiana Affiliate, and by the Veterans Administration.     

Electrophysiological Effects of Intravenous Disopyramide Phosphate on the Wolff-Parkinson-White Syndrome

The effects of a single intravenous infusion of 2mg/kg body weight disopyramide phosphate (DP) on the mode of initiation of reentrant supraventricular tachycardia were assessed in seven patients with Wolff-Parkinson-White (WPW) syndrome using bundle of His electrograms and the ventricular extrastimulus method. The delta wave disappeared in three patients after DP. However, retrograde conduction via the accessory pathway persisted even after DP administration in all patients. These effects contributed to the induction of reciprocating tachycardia after DP. The retrograde functional refractory period of the His-Purkinje system (HPS) and the effective refractory period of the accessory pathway were increased in all cases and contributed to the development of reentry HPS. After DP, the zone of reentry HPS widened in four cases (including a newly developed case) and remained unchanged in three cases. Reentrant supraventricular tachycardia zones widened in three cases; these widened reentrant supraventricular tachycardia zones were induced by the widened reentry HPS, that is, reentry HPS was followed by the reentrant supraventricular tachycardia. This study demonstrates that persistence of retrograde accessory pathway conduction and widened reentry HPS which might be dose-related after DP could be the retrograde determinants affecting the reentrant supraventricular tachycardia zone.     

Oral disopyramide for the acute treatment of severe outflow obstruction in hypertrophic cardiomyopathy in the ICU setting

When severe COPD and obstructive hypertrophic cardiomyopathy (HCM) coexist, management is challenging and complex. Drug contraindications limit pharmacologic options. Patients may not be candidates for surgical septal myectomy due to severe pulmonary disease. We describe a case of an elderly woman with severe reactive COPD who presented with an infectious exacerbation and dyspnea that progressed to near intubation due to heart failure from coexistent obstructive HCM. Transthoracic echocardiography revealed massive asymmetric septal hypertrophy and a diffusely hyperkinetic left ventricle with a left ventricular outflow tract (LVOT) gradient of 92 mm Hg. Two and a half hours after oral administration of disopyramide, LVOT gradient had decreased to 25 mm Hg with a corresponding immediate improvement in symptoms.     

Supernormal conduction and atrial echo beats in the dog

The occurrence of the supernormal conduction phenomenon duringthe vulnerable period, overriding phase 3 of the action potentialand the relative refractory period, suggests that it could playa significant role in the asynchrony of conduction and inducereetrant arrhythmias. To support this hypothesis, the evolutionof the supernormal conduction phenomenon, the echo beats inducedby atrial stimulation, the monophasic action potential (MAP_a),the effective (ERP) and functional refractory periods (FRP)and the ratio ERP/MAP_a have been studied under the influenceof disopyramide which reduces the supernormal conduction phenomenon.Three groups of dog were evaluated: control, sympathectomizedand atropinized dogs. MAP_a duration was not modified in eithergroup and the FRP lengthened in all groups irrespective of whetheratrial echo beats persisted or not. The ERP and the ERP/MAP_aare more specific. The supernormal conduction phenomenon isthe factor that follows the evolution of the echo beats withthe most accuracy: it diminished or disappeared in all casesin which the echo beats disappeared. It was not modified in80% of the cases where the echo beats persisted; there was a‘grey-zone’ in which one-third of the cases witha reduction of less than 75% of the supernormal conduction phenomenonshowed the persistence of echo beats: there is probably a criticalpoint in that zone where there is enough regression of thisphenomenon to prevent echo beats.