Hemodynamic and electrophysiologic effects of disopyramide enantiomers in a canine blood superfusion model.
The use of disopyramide is often limited because of adverse hemodynamic or electrophysiologic side effects. We compared the S(+) and R(-) enantiomers of disopyramide to the clinically used racemic mixture in a canine blood superfusion model. Eighteen support animals (group I) provided extracorporeal blood superfusion of isolated canine cardiac Purkinje fibers. Following administration of 2 mg/kg disopyramide intravenously (i.v.) [S(+), R(-), or racemic] hemodynamic and electrocardiographic parameters were temporally assessed in the support animals while simultaneous cellular electrophysiologic effects were recorded from the blood-superfused Purkinje fibers. An additional 13 animals (group II) underwent extended hemodynamic and pharmacokinetic analysis without the external atrioventricular (AV) shunt required for blood superfusion. Mean peak serum concentrations of racemic disopyramide and its enantiomers were similar (2.7 to 3.1 mg/L), but clearance was stereo-specific [half-life (t1/2) of 1.99 h for S(+) vs. 2.79 h for R(-) disopyramide]. Left ventricular (LV) function was impaired following drug administration, irrespective of optical rotation (cardiac output decreased by 20.8%, LV dP/dtmax decreased by 22.4%). Depression of phase 0 Vmax of the Purkinje fiber action potential was also nonstereo-dependent. S(+) disopyramide prolonged the QTC interval by 11.5% and increased terminal action potential duration (APD75) and effective refractory period (ERP) by 21.2 and 19.0%, respectively. R(-) disopyramide slightly increased the QTC interval (+2.3%) but decreased APD75 and ERP by 8.9 and 6.8%, respectively. The effect of racemic disopyramide on repolarization indexes was intermediate to that of its enantiomers. These data support nonstereodependent depression of both myocardial contractility and sodium channel conductance by disopyramide. Changes in APD and refractoriness were dependent on stereochemical configuration.
Kidwell
G A
GA
Department of Medicine, Ohio State University, Columbus.
Lima
J J
JJ
Schaal
S F
SF
Muir
W W
WW
D000818:Animals; D004206:Disopyramide / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004594:Electrophysiology; D006329:Heart Conduction System / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D010477:Perfusion; D011690:Purkinje Fibers / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013237:Stereoisomerism; D013997:Time Factors
D004206:Disopyramide