Correlation Between Pharmacokinetics and Inotropic and Electrophysiologic Responses to Digitoxin in the Intact Dog

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We attempted to correlate inotropic and electrophysiologic digitoxin effects with serum digitoxin concentrations during 8 hr after a single dose. Eight pentobarbital-anesthetized Labrador dogs were given 2.0 mg digitoxin intravenously. Left heart catheterization and His bundle registration were performed. Pacing and programed electrical stimulation were used to determine heart rate-independant changes in dP/dt. intra-atrial, atrioventricular (AV). His-Purkinje. and intraventricular conduction velocity. The effective (A-ERP) and functional (A-FRP) refractory periods of the atrium and the functional nodal refractory period (AV-FRP) were measured. Serum digitoxin concentrations were determined by radioimmunoassay. Median serum digitoxin half-time was 5.7 hr. The dPIdt increased after digitoxin, with maximum values after 2 hr. Digitoxin concentration correlated with the inotropic response after 4 hr. Heart rate fell significantly within 2 min and remained below control values for the 8 hr observation period concomitant with an increase in AV-nodal conduction time and AV-FRP. A-ERP increased significantly in the late elimination phase, while A-FRP increased slightly initially and remained high. No consistent correlation was found between the electrophysiologic variables and serum concentrations. We conclude that the two main effects of digitoxin, the inotropic and electrophysiologic, are dissociated in the elimination phase after a single dose.

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