Pharmacodynamics of Carvedilol in Conscious, Healthy Dogs

Abstract

The purpose of the study reported here was to determine the magnitude and duration of beta-blocking efficacy, determine an effective dose and dosing interval, and document safety and tolerability of carvedilol given orally in clinically normal dogs. Pharmacodynamic data were evaluated in conscious, unrestrained, healthy hound dogs at baseline and after long-term oral administration of carvedilol (1.5 mg/kg of body weight PO q12h for .5 days). At baseline, heart rate (HR) and blood pressure (BP) data were collected continuously for 24 hours, and complete echocardiography was performed. This protocol was repeated after long-term oral carvedilol administration. Additionally, isoproterenol was administered to evaluate the magnitude and duration of the nonselective beta-blocking efficacy of carvedilol. An isoproterenol challenge was performed 0.75, 1.5, 2.25, 4, 6, 12, and 24 hours after carvedilol administration, with echocardiography being performed once at 2 hours. Plasma samples were obtained prior to each challenge time point for determination of plasma carvedilol concentration. Time series regression analysis indicated no difference between baseline and carvedilol-induced HR or BP trend lines in 6 of 8 dogs. In 2 of 8 dogs, HR, after long-term carvedilol administration, was reduced. Carvedilol attenuated isoproterenol-induced changes in HR by 54-76% through 12 hours and by 30% at 24 hours. The BP changes were attenuated by 80-100% through 12 hours. These data suggest that carvedilol (1.5 mg/kg PO q12h) in healthy, conscious dogs confers nonselective beta blockade for 12 hours, with minimal effects on resting HR, BP, and echocardiographic variables. Additionally, the magnitude of beta blockade correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful.

Retrospective review of carvedilol administration in 38 dogs with preclinical chronic valvular heart disease

“…16e19 While pharmacokinetic data demonstrated a low and variable oral bioavailability suggesting the requirement for a 6-h dosing interval, the pharmacodynamic data suggested a 12e24-h dosing interval is adequate to ensure betablockade. 16,17,19,20 Uechi et al reported the cardiovascular and renal effects of oral carvedilol (0.2e0.8 mg/kg q 24 h) in dogs with experimental MR and control dogs suggesting that a dose of 0.4 mg/kg PO q 24 h may be a reasonable target dose in dogs with heart disease. 20 Carvedilol is currently used by some veterinarians in preclinical CVD and other cardiac diseases, however dosing is variable.…”

“…Plasma carvedilol concentrations were not measured which is a significant limitation, given the reported high variability in carvedilol oral bioavailability in the dog. 17 Finally, due to the small sample size and limited ability to accurately classify cause of death in many of the dogs, the survival analysis was based on an endpoint of allcause mortality as opposed to cardiac mortality.…”