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.

Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts

“…Nevertheless, we believe that our observations using METO are valuable from a mechanistic point of view in the specific context of the present study, where its effects are compared with those of IVA. Collectively, our results concur with in vivo studies where IVA, but not β-blockers used at clinically relevant doses, was found to be effective for HRR under basal conditions in healthy animals (1,10,19). However, it is noteworthy that both classes of drugs have been shown to be effective at reducing HR in vivo under conditions of increased HR.…”

“…However, it is noteworthy that both classes of drugs have been shown to be effective at reducing HR in vivo under conditions of increased HR. These include, for example, sympathetic stimulation and exercise as well as pathological conditions under which these drugs are normally prescribed in the clinic (1,14,19,24).With regard to the potential clinical relevance of this study, the lack of information in the literature about the impact of HRR per se on cardiac energy substrate metabolism created the impetus to characterize the acute effect of pure HRR by IVA in the isolated normoxic working healthy heart prior to its chronic effect being evaluated in a clinically relevant disease model for which potentially confounding factors such as cardiac gene remodeling will need to be considered (33,41). Despite the limitations of our study model, such as the basal conditions, absence of neuronal influence, and fixed compliance, we believe that this experimental model mimics to some extent the human transplanted heart, a condition for which IVA has been shown to be beneficial for the control of HR (16,27).…”

Evaluation of add on effect of carvedilol on standard protocol of digoxin, frusemide and benazepril in the management of dilated cardiomyopathy in dogs

“…The pharmacokinetic study of orally administred carvedilol showed that 1.5 mg/kg twice a day was well tolerated by healthy dogs with peak plasma concentration observed after 90 minutes (Arsenault et al, 2005). Similarly, the pharmacodynamic study of carvedilol in healthy dogs at dose rate of 1.5 mg/kg PO q12h) suggests successful attenuation of isoproterenol-induced changes in HR (55 -76%) and BP (80-100%) upto12 hours post medication (Gordon et al, 2006). In a clinical study on dogs with chronic Mitral valvular disease, chronic administration of carvidilol at dose rate of 0.3 mg/kg PO q12h for 3 month resulted improvement in score of quality of life and a reduction in systolic blood pressure however, did not improved the Echocardiographic parameters significantly (Marcondes-Santos et al, 2007).…”

Management of Chronic Congestive Heart Failure Caused by Myxomatous Mitral Valve Disease in Dogs: A Narrative Review from 1970 to 2020

“…During the 2000s, the experimental studies that tested in dogs the efficacy of drugs used for CHF in humans (DMH) were fewer than in the previous decades . In contrast, there was an increase in studies published in veterinary medicine journals that evaluated the treatment of CHF in dogs, both experimental [216][217][218][219][220][221][222][223][224][225][226][227][228][229][230][231] and carried out in patients with spontaneous MMVD. The scientific publications on drugs tested in dogs with CHF secondary to MMVD (DNAD) were more numerous than in previous years, and many studies were performed on ACE inhibitors [232][233][234][235], β-blockers [236][237][238], sildenafil [239,240], amiodarone [241], diuretics [242], isosorbide 5-mononitrate [243], and amlodipine [244].…”