Key result
Intravenous carvedilol significantly increased heart rate and velocity of fiber shortening at zero load at doses ≥310 µg/kg and 10 µg/kg, respectively, without affecting systemic pressures.
Why the study?
Does intravenous carvedilol alter acute cardiovascular hemodynamics and what are its pharmacokinetics in healthy dogs?
Does intravenous carvedilol alter acute cardiovascular hemodynamics and what are its pharmacokinetics in healthy dogs?
Supports further evaluation in canine disease models; leaves open clinical translation from healthy subjects.
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. Catheters were placed in the aorta, left ventricle, and right atrium to record systemic and pulmonary pressures and determine vascular resistance and cardiac output. Electrocardiograms (leads I, aVF, and V3) were recorded to determine electrocardiographic changes. Variables were measured before and after IV injection of incremental doses of carvedilol (cumulative doses, 10, 30, 70, 150, 310, and 630 microg/kg of body weight; n = 6) or vehicle alone (6). Pharmacokinetic analysis was performed, using 2 conscious dogs given 160 microg of carvedilol/kg as a single IV injection. RESULTS: Heart rate and velocity of fiber shortening at zero load (Vmax) increased slightly but significantly from baseline values at doses of carvedilol > or = 310 microg/kg and 10 microg/kg, respectively. Carvedilol did not affect systemic and pulmonary pressures or vascular resistances. Intravenous administration of approximately 150 microg of carvedilol/kg resulted in a plasma carvedilol concentration of approximately 100 ng/ml. Mean 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, the reduction in afterload and positive inotropic effect that we observed would be beneficial for treating heart failure and minimizing the cardiotoxic effects of doxorubicin.
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Sawangkoon et al. (2000) studied Healthy (n=14). Carvedilol vs. Vehicle alone was evaluated on Cardiovascular effects (heart rate, velocity of fiber shortening at zero load, systemic and pulmonary pressures, vascular resistances). Intravenous carvedilol significantly increased heart rate and velocity of fiber shortening at zero load at doses ≥310 µg/kg and 10 µg/kg, respectively, without affecting systemic pressures.
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