Acute cardiovascular effects and pharmacokinetics of carvedilol in healthydogs

Objective-To determine acute cardiovascular effects and pharmacokinetics of carvedilol in healthy dogs. Animals-14 mature healthy Beagles. Procedure-12 dogs were anesthetized with morphine and alpha-chloralose. Cat heters were placed in the aorta, left ventricle, and right atrium to record systemic and pulmonary pressures and determine vascular resistance and car diac output. Electrocardiograms (leads I, aVF, and V-3) were recorded to de termine electrocardiographic changes. Variables were measured before and af ter IV injection of incremental doses of carvedilol (cumulative doses, 10, 30, 70, 150, 310, and 630 mu g/kg of body weight; n = 6) or vehicle alone ( 6). Pharmacokinetic analysis was performed, using 2 conscious dogs given 16 0 mu g of carvedilol/kg as a single IV injection. Results-Heart rate and velocity of fiber shortening at zero load (V-max) in creased slightly but significantly from baseline values at doses of carvedi lol greater than or equal to 310 mu g/kg and 10 mu g/kg, respectively. Carv edilol did not affect systemic and pulmonary pressures or vascular resistan ces. Intravenous administration of approximately 150 mu g of carvedilol/kg resulted in a plasma carvedilol concentration of approximately 100 ng/ml. M ean elimination half life was 54 minutes, half-life of distribution was 3.5 minutes, and volume of distribution was 2,038 ml/kg. Conclusions and Clinical Relevance-The therapeutic plasma concentration of carvedilol in humans is 100 ng/ml. At that plasma concentration in dogs, th e reduction in afterload and positive inotropic effect that we observed wou ld be beneficial for treating heart failure and minimizing the cardiotoxic effects of doxorubicin.