Pharmacodynamics and Pharmacokinetics of Injectable Pimobendan and Its Metabolite, O-Desmethyl-Pimobendan, in Healthy Dogs

Abstract

Objectives: This study was designed to thoroughly evaluate the effects of bolus pimobendan at a dose of 0.15 mg/kg on cardiac functions, hemodynamics, and electrocardiographic parameters together with the pharmacokinetic profile of pimobendan and its active metabolite, o-desmethyl-pimobendan (ODMP), in anesthetized dogs.Methods: Nine beagle dogs were anesthetized and instrumented to obtain left ventricular pressures, aortic pressures, cardiac outputs, right atrial pressures, pulmonary arterial pressures, pulmonary capillary wedge pressures, electrocardiograms. After baseline data were collected, dogs were given a single bolus of pimobendan, and the pharmacodynamic parameters were obtained at 10, 20, 30, 60, and 120 min. Meanwhile, the venous blood was collected at baseline and 2, 5, 10, 20, 30, 60, 120, 180, 360, and 1,440 min after administration for the determination of pharmacokinetic parameters.Results: Compared with baseline measurements, the left ventricular inotropic indices significantly increased in response to intravenous pimobendan, as inferred from the maximum rate of rise in the left ventricular pressure and the contractility index. Conversely, the left ventricular lusitropic parameters significantly decreased, as inferred from the maximum rate of fall in the left ventricular pressure and the left ventricular relaxation time constant. Significant increases were also noted in cardiac output and systolic blood pressure. Decreases were observed in the systemic vascular resistance, pulmonary vascular resistance, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure. The heart rate increased, but the PQ interval decreased. There was no arrhythmia during the observed period (2 h). The mean maximum plasma concentration (in μg/L) for ODMP was 30.0 ± 8.8. Pimobendan exerted large volume of distribution ~9 L/kg.Conclusions: Intravenous pimobendan at the recommended dose for dogs increased cardiac contraction and cardiac output, accelerated cardiac relaxation but decreased both vascular resistances. These mechanisms support the use of injectable pimobendan in acute heart failure.

Pimobendan prevents cardiac dysfunction, mitigates cardiac mitochondrial dysfunction, and preserves myocyte ultrastructure in a rat model of mitral regurgitation

“…In HF, the mitochondria are dysfunctional resulting in impaired myocardial energetics (e.g., decreased ATP content) subsequently less ATP available for muscular relaxation [ 15 ]. Several studies in dogs [ 16 – 18 ] have shown improvement of diastolic function by pimobendan which could be partly explained by our findings.…”

“…Pimobendan, a benzimidazole-pyridazinone derivative, so-called inodilator, acts by inhibiting PDE-III leading to increased concentrations of cAMP and sensitizing the cardiac contractile apparatus to intracellular calcium, producing vasodilation and positive inotropic effects that have been demonstrated in several species [ 18 , 22 – 25 ]. This study showed that pimobendan maintained cardiac contractility through the end of the experiment.…”

High‐output cardiac failure in a dog secondary to hepatic vascular malformation

“…This decision was made based on studies evaluating intravenous pimobendan in healthy dogs, in which pimobendan resulted in an increased stoke volume, increased cardiac output and decreased systemic vascular resistance. 17,18 Our patient already had evidence consistent with increased stroke volume and increased cardiac output on Echo coupled with the concern for decreased systemic vascular resistance with high-output cardiac failure, thus we ultimately elected not to start pimobendan in our patient. Additional factors taken into account during the clinical decisionmaking process included the absence of data that supports pimobendan administration in patient with high-output cardiac failure and mindfulness of the financial impact on the client.…”

“…Although pimobendan therapy is part of the standard of care for treating congestive heart failure in dogs with myxomatous mitral valve disease, 15,16 this drug was not prescribed in this patient due to concern for further reduction in systemic vascular resistance due to the vasodilatory effects from inhibition of phosphodiesterase III. This decision was made based on studies evaluating intravenous pimobendan in healthy dogs, in which pimobendan resulted in an increased stoke volume, increased cardiac output and decreased systemic vascular resistance 17,18 . Our patient already had evidence consistent with increased stroke volume and increased cardiac output on Echo coupled with the concern for decreased systemic vascular resistance with high‐output cardiac failure, thus we ultimately elected not to start pimobendan in our patient.…”

Haemodynamic Effects of Pimobendan during General Anaesthesia in Healthy Senior Dogs: A Prospective, Randomised, Triple-Blinded, Placebo-Controlled Clinical Study

“…Previous studies have shown that the increase in cardiac contractility from pimobendan is similar to that provided by dobutamine but with a longer duration of effect. This fact, combined with the absence of pro-arrhythmogenic effects, makes pimobendan a beneficial drug for improving CO and achieving hemodynamic stabilisation in a sustained manner over time [ 16 , 17 , 18 , 19 ].…”