Editors' note: This article is an updated excerpt from "Pimobendan: Understanding its cardiac effects in dogs with myocardial disease," which appeared in Veterinary Medicine's October 2006 issue.
To understand the pharmacology and therapeutic potential of pimobendan, clinicians should be familiar with the mechanisms of cardiac muscle contraction in healthy and diseased hearts.
Myocardial contraction (i.e. excitation-contraction coupling) begins when a depolarization wave reaches a myocyte.2 In excitation-contraction coupling, action potentials depolarize cardiac muscle cell membranes, with phase 2 of the action potential triggering calcium release from the sarcoplasmic reticulum.5 Normal cardiac muscle is distinct from skeletal and smooth muscle in that it relies on both extracellular (L-type calcium channels) and intracellular (sarcoplasmic reticulum) calcium sources for muscle contraction.
Myocardial failure, best typified by dilated cardiomyopathy, is characterized by alterations of myocyte integrity and severely disturbed intracellular calcium handling.6 Cytosolic calcium ion concentrations are adequate, but the sensitivity of troponin-C to calcium ions is impaired.6,7
PHARMACOLOGY OF PIMOBENDAN
Pimobendan's principal inotropic mechanism is troponin-C calcium sensitization, and this positive inotropic effect is accomplished with only a small increase in myocardial energy consumption. Pimobendan also causes peripheral arteriolar dilation, coronary artery dilation, pulmonary artery dilation, and peripheral venodilation by inhibiting phosphodiesterases III and V in vascular smooth muscle.1-4,8
USE IN DOGS
Pimobendan treatment is initiated in symptomatic dogs with congestive heart failure that may benefit from positive inotropic action. The total dose is 0.5 mg/kg daily, which is divided into two doses (not necessarily equal) given 12 hours apart.9 The Vetmedin chewable tablet sizes are 1.25, 2.5, and 5 mg. The tablets are scored, and the calculated dose should be given to the nearest half-tablet increment.
Advanced dilated cardiomyopathy
Pimobendan's strongest indication is to treat patients with advanced dilated cardiomyopathy because they have poor left ventricular systolic function and reduced ejection fraction. They are subject to increased afterload as a result of dilation of the left ventricle with inadequate wall hypertrophy and arteriolar constriction (caused by activation of the renin-angiotensin-aldosterone system and increased plasma norepinephrine concentrations). This increased afterload negatively affects stroke volume and ejection fraction. Through phosphodiesterase III and V inhibition, pimobendan promotes both arteriolar and venous dilation, reducing afterload and preload, respectively.
We administer pimobendan in dogs with cardiomyopathy in the face of overt or impending congestive heart failure. Clinical findings consistent with impending congestive heart failure include a gallop heart sound, atrial fibrillation, and nocturnal dyspnea. Pulmonary or hepatic vein distention on radiographic and ultrasonographic examination is also consistent with impending congestive heart failure.
Degenerative mitral valve disease
Patients with degenerative mitral valve disease have good contractility as assessed by echocardiography, even when the left heart is severely dilated. Thus, the inotropic action of pimobendan would seem to be of little value. However, the vasodilator action may contribute to preload and afterload reduction.
For dogs with degenerative mitral valve disease, we add pimobendan when overt or impending congestive heart failure occurs in the face of ACE inhibitor, spironolactone, and amlodipine treatment. According to owners, most dogs with overt signs of advanced heart disease feel better and have improved activity tolerance within a few days of adding pimobendan to existing treatment. The clinical improvement may not correlate with hemodynamic improvement. In these cases, pimobendan may have a central nervous system effect that promotes a feeling of physical and mental well-being in dogs as demonstrated by other phosphodiesterase inhibitors (i.e. propentofylline).
Pimobendan can be administered safely with diuretics, ACE inhibitors, and digoxin.3 The modest vasodilator action of pimobendan is additive to that produced by ACE inhibitors. However, we have not encountered arterial hypotension or a drop in measured systolic blood pressure in any dog in which pimobendan was added to ACE inhibitor monotherapy. Additive vasodilator action should be expected with nitrates (isosorbide dinitrate or nitroglycerin), amlodipine (Norvasc—Pfizer), or carvedilol (Coreg—GlaxoSmithKline). We have encountered mild clinically evident systemic hypotension in only one dog with advanced degenerative mitral valve disease when pimobendan was added to a combination therapy of an ACE inhibitor and amlodipine. We have not observed overt adverse effects with the combination of pimobendan, an ACE inhibitor (enalapril or benazepril), and spironolactone or furosemide treatment in dogs with congestive heart failure. In fact, improved heart function resulting from pimobendan treatment may permit a small reduction of the furosemide dosage.
Theoretically, pimobendan may increase the rate of intestinal digoxin absorption.10 In our clinical experience, the coadministration of pimobendan with digoxin has neither increased paired serum digoxin concentrations nor resulted in concentrations within the upper 40th percentile of our reference range. We seldom add digoxin to pimobendan therapy except in the face of atrial fibrillation in dogs with advanced dilated cardiomyopathy.
Serial Holter recordings in our patients with atrial fibrillation have shown that pimobendan does not seem to markedly attenuate the effects of digoxin on reducing atrioventricular conduction. In boxers and Doberman pinschers with advanced dilated cardiomyopathy that we have treated with pimobendan, digoxin, an ACE inhibitor, and furosemide, the ventricular response rates have usually been below 140 beats/min for more than 85% of the approximate 24-hour Holter recording time. In addition, the combination of pimobendan with amiodarone or mexiletine or both has been well-tolerated in boxers and Doberman pinschers with advanced dilated cardiomyopathy and severe ventricular arrhythmias.
Pimobendan has not been evaluated in dogs used for breeding, in pregnant or lactating dogs, in dogs younger than 6 months old, or in dogs with congenital heart defects, diabetes mellitus, or other serious metabolic diseases. Clinical findings or adverse effects reported during a field study included polyuria, polydipsia, vomiting, azotemia, inappetence, lethargy, diarrhea, dyspnea, pleural effusion, cough, ascites, heart murmur, weakness and ataxia, and syncope.9 Sudden death may also occur.9 A dose-related sinus tachycardia can result,4 and as with any strong inotropic agent, ventricular tachyarrhythmias may develop or worsen while pimobendan is administered.11 Ventricular tachyarrhythmias are of particular concern in Doberman pinschers and boxers but could occur in any dog with advanced dilated cardiomyopathy. Pimobendan's effect on myocytes—conserved energy demand with small increases in intracellular calcium concentration—may reduce the likelihood of a proarrhythmic effect,12 but additional studies are warranted.
In our experience in treating patients with advanced dilated cardiomyopathy, pimobendan's durability as a positive inotropic agent in dogs may not be as good as that reported in human studies. Thus, prematurely administering pimobendan to patients with only mild to moderate myocardial failure caused by dilated cardiomyopathy could result in decreased effectiveness later in the course of the disease. For this reason, we recommend initiating pimobendan for patients with advanced cardiomyopathy.
Pimobendan's efficacy in cats has not been reported. Hypertrophic cardiomyopathy is the most common cardiomyopathy in cats, and pimobendan is contraindicated.
Pimobendan is an inodilator used to treat overt or impending congestive heart failure in dogs. Studies have either demonstrated or suggested a favorable influence when pimobendan is used as adjunctive therapy (e.g. with an ACE inhibitor, furosemide, digoxin) in patients with advanced dilated cardiomyopathy or degenerative mitral valve disease.9,13,14 In our experience with more than 100 dogs, pimobendan is well-tolerated and has few adverse effects. Pimobendan should not be used as a replacement for, but rather as cotherapy with, other cardiac drugs to enhance the quality of life in dogs with overt or impending congestive heart failure.
Justin D. Thomason, DVM, DACVIM (small animal internal medicine)
Department of Clinical Sciences
Center for Veterinary Health Sciences
Oklahoma State University
Stillwater, OK 74078
Tiffany K. Fallaw, BS, RVT
Clay Calvert, DVM, DACVIM (small animal internal medicine)
Department of Small Animal Medicine and Surgery
College of Veterinary Medicine
University of Georgia
Athens, GA 30605
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