Pimobendan: Understanding its cardiac effects in dogs with myocardial disease

Preview

• Pimobendan has positive inotropic and vasodilator effects in dogs.

• Beneficial in dogs with advanced dilated cardiomyopathy or mitral valve disease, pimobendan is administered along with other cardiac drugs, such as ACE inhibitors, furosemide, or digoxin. It should not be used as sole therapy.

• It is given orally at a dosage of 0.2 to 0.6 mg/kg daily divided into two doses given 12 hours apart.

• Few adverse effects have been observed in dogs receiving the drug.

• It has been used in some countries in Europe for several years and is undergoing studies in dogs in the United States.

Pimobendan (Vetmedin—Boehringer Ingelheim), a benzimidazole-pyridazinone drug, is classified as an inodilator because of its nonsympathomimetic, nonglycoside positive inotropic (through myocardial calcium sensitization) and vasodilator properties.1-4 As such, pimobendan increases ventricular contractility and reduces preload and afterload in patients with advanced cardiac insufficiency. Pimobendan is approved for use in dogs to treat congestive heart failure originating from valvular insufficiency or dilated cardiomyopathy in some countries in Europe and in Canada, Mexico, and Australia and is currently undergoing Food and Drug Administration (FDA) review in the United States.

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.

NORMAL MYOCARDIAL CONTRACTION

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 Cardiac muscle is distinct from skeletal and smooth muscle in that it relies on both extracellular and intracellular calcium sources for muscle contraction. Increases in cyclic adenosine monophosphate (camp), either from beta-adrenergic stimulation or phosphodiesterase iii inhibition, promote the opening of l-type calcium channels in cardiac myocytes and result in an influx of a small concentration of extracellular calcium ions at t tubule foot plates close to the sarcoplasmic reticulum. The small influx of extracellular calcium ions causes the release of a large concentration of calcium ions from the ryanodine receptors of the sarcoplasmic reticulum into the cytosol.5 The cytosolic calcium ions are immediately bound by the protein calmodulin.5 Calmodulin activates muscle contraction by delivering calcium ions to troponin c, a protein of the thin myofilaments of cardiac muscle.

Excitation-contraction coupling is an energy-consuming process requiring hydrolysis of adenosine triphosphate (ATP).2 Muscle contraction results from the interrelationship of four proteins: actin, myosin, troponin, and tropomyosin. The polymerization of actin and myosin results in sarcomere shortening and is inhibited by tropomyosin, troponin I, and ATP at rest.5 When calcium ions bind to troponin C, a steric conformational change occurs in the troponin-tropomyosin complex, troponin I inhibition of myosin adenosinetriphosphatase (ATPase) is removed, and ATP is hydrolyzed,5 which initiates contraction through the ratcheting action of actin over myosin.2

MYOCARDIAL FAILURE

Myocardial failure, best typified by dilated cardiomyopathy, is characterized by alterations of myocyte integrity. It is difficult to establish whether an observed biochemical abnormality is the principal cause of myocardial dysfunction, a general consequence of cellular damage, or an adaptive change to the heart failure state.6 Regardless of the cause, biochemical alterations are prominent, and intracellular calcium handling is severely disturbed in the failing myocardium.7 Cytosolic calcium ion concentrations are adequate, but the calcium ions' effect on troponin c is impaired.6,7 This suggests that myocardial failure is, in part, the result of loss of sensitivity of troponin c to intracellular calcium ions and is in agreement with pimobendan's calcium sensitization effect in improving contractility. In addition, in the face of myocardial failure, beta1-adrenergic receptor down-regulation results in decreased camp production, attenuating cardiac myocyte phosphodiesterase iii inhibition.7

PHARMACOLOGY OF PIMOBENDAN

As stated above, pimobendan is a benzimidazole-pyridazinone derivative with positive inotropic and vasodilator properties.3 Pimobendan has phosphodiesterase iii inhibitor activity, similar to that of amrinone and milrinone, that reduces the breakdown of camp.1 The increase in camp concentration results in exaggerated phosphorylation of protein kinase a, which activates the l-type calcium channel8 and stimulates the sarcoplasmic reticulum to release a large concentration of calcium ions into the cytosol. The resultant increased calcium binding to troponin c allows actin-myosin interaction and results in a positive inotropic effect. Although this mechanism may explain the inotropic effects of pimobendan, the increase of cytosolic calcium concentration is modest relative to the marked increase in contractility, which suggests another mechanism for increased contractility.2

Pimobendan's principal inotropic mechanism is myocardial calcium sensitization, which is apparently related to an increased affinity of troponin C for calcium ions.2 Increased calcium binding to troponin C modulates the polymerization of actin and myosin and enhances myocardial contraction. This positive inotropic effect is accomplished with only a small increase in myocardial energy consumption. In other words, pimobendan doesn't alter the ratio of ATP metabolism rate per unit of contraction force.7 This energy conservation coupled with only small increases in intracellular calcium concentration may reduce the likelihood of arrhythmias.9

Pimobendan also causes vasodilation by inhibiting phosphodiesterases III and V in vascular smooth muscle.1,10 Unlike the increase in calcium concentration in cardiac muscle cells, when cAMP concentrations are increased in smooth muscle cells, protein kinase C is inactivated and intracellular calcium concentrations are decreased. In this manner, pimobendan causes peripheral arteriolar dilation, coronary artery dilation, pulmonary artery dilation, and peripheral venodilation.1-4,10

After oral administration of pimobendan, the absolute bioavailability of the active drug is 60% to 63%.2 In people, the plasma elimination half-life is about 30 minutes, and the principal active metabolite elimination half-life is about two hours.4 Most of the drug is eliminated in the feces.2

STUDIES IN DOGS

Although there are few published reports, pimobendan has been studied in dogs since the late 1980s. Pimobendan is safe and effective in dogs with mitral valve disease and dilated cardiomyopathy at a dosage of 0.3 mg/kg given orally every 12 hours.3,11 A clinical trial demonstrated that Doberman pinschers with dilated cardiomyopathy treated with pimobendan, digoxin, enalapril, and furosemide survived significantly longer (median survival time 329 days) than those treated with digoxin, enalapril, and furosemide alone (median survival time 50 days).12

The initial studies in dogs with mitral-valve-disease–associated congestive heart failure suggest a benefit of pimobendan therapy. A six-month trial demonstrated that dogs receiving pimobendan and furosemide had fewer adverse outcomes (euthanasia, death, or drug withdrawal due to worsening of congestive heart failure) than dogs treated with an ACE inhibitor (ramipril) and furosemide.13 In addition, another study in dogs with mitral-valve-disease–associated congestive heart failure demonstrated improved quality of life and survival times in patients receiving pimobendan with or without furosemide compared with patients receiving an ACE inhibitor (benazepril) with or without furosemide.14

USE IN DOGS

As stated above, in some countries outside the United States, pimobendan is indicated in dogs to treat congestive heart failure caused by dilated cardiomyopathy or valvular insufficiency. Treatment is initiated in symptomatic patients that may benefit from positive inotropic action. The dosage range is 0.2 to 0.6 mg/kg daily divided into two doses given 12 hours apart.3 Each capsule should be given about one hour before meals, and the capsules should be given whole (not opened) to enhance intestinal absorption.3 The Vetmedin capsule sizes (1.25, 2.5, and 5 mg) were developed based on human dosage requirements. As is typical for many drugs, the dosage requirements for pimobendan in dogs are higher than those required in people. As such, the relatively small capsule sizes are inconvenient to administer to large dogs and contribute to the treatment cost.

Advanced dilated cardiomyopathy

Pimobendan's strongest indication is to treat advanced dilated cardiomyopathy. Patients with advanced dilated cardiomyopathy 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. However, pimobendan's myocardial phosphodiesterase inhibition is probably attenuated in the face of chronic, advanced dilated cardiomyopathy due to beta-receptor downregulation.2

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 vein distention on radiographic and echocardiographic examination is also consistent with impending congestive heart failure. Additional echocardiographic changes include increased pulmonary vein flow velocity and increased transmitral diastolic blood flow velocity during the early, rapid-filling phase of diastole. In our experience, pimobendan's positive inotropic effect in dogs with dilated cardiomyopathy is usually demonstrable by echocardiography within one week of initiating treatment.

Mitral valve disease

Patients with myxomatous mitral valve degeneration 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 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 the 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).

DRUG INTERACTIONS

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, at the University of Georgia Veterinary Teaching Hospital 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 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, ace inhibitor (enalapril or benazepril), spironolactone, and furosemide treatment in dogs with congestive heart failure. In fact, improved heart function resulting from pimobendan treatment may permit a small reduction of furosemide dosage. Concurrent use of pimobendan with a beta-blocker or calcium channel blocker may attenuate the positive inotropic action of pimobendan.

Theoretically, pimobendan may increase the rate of intestinal digoxin absorption.15 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. Based on serial Holter recordings in our patients with atrial fibrillation, pimobendan does not seem to markedly attenuate the effects of digoxin on reducing atrioventricular conduction. In boxers and Doberman pinschers with advanced dilated cardiomyopathy treated at the University of Georgia Veterinary Teaching Hospital 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, in our clinical experience, been well-tolerated in boxers and Doberman pinschers with advanced dilated cardiomyopathy and severe ventricular arrhythmias.

PRECAUTIONS

Pimobendan has not been evaluated in pregnant and lactating dogs. Administer pimobendan to pregnant or lactating dogs only if the potential benefits outweigh the potential risks. Although adverse effects are uncommon, polyuria, polydipsia, vomiting, diarrhea, and inappetence are possible. 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.16 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,9 but additional studies are warranted.

In our experience with advanced dilated cardiomyopathy, pimobendan's durability as a positive inotropic agent in dogs may not be as good as reported in human studies. Thus, premature administration of 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. It is for this reason that we recommend initiating pimobendan for patients with advanced cardiomyopathy.

At the University of Georgia Veterinary Teaching Hospital, we have prescribed pimobendan for more than 100 dogs and have followed each patient's progression. We have found pimobendan to be virtually free of overt adverse effects in dogs with either dilated cardiomyopathy or mitral valve degeneration. Mild diarrhea may have been attributable to pimobendan in one dog. We have not evaluated the potential effects of pimobendan on insulin metabolism, increased mitral regurgitation volume, or myocardial hypertrophy.

USE IN CATS

The efficacy of pimobendan in cats has not been reported. Hypertrophic cardiomyopathy is the most common cardiomyopathy in cats, and pimobendan is contraindicated. Although the manufacturer has not conducted any trials to determine the safety of pimobendan in cats, we have administered pimobendan in 10 cats with idiopathic dilated cardiomyopathy or advanced restrictive cardiomyopathy. We use a dosage of 0.6 mg/kg given orally every 12 hours. We have not encountered clinically relevant adverse effects. In our experience, when added to ace inhibitor and furosemide therapy in cats with restricted cardiomyopathy, pimobendan appeared to have no efficacy.

THE FUTURE OF PIMOBENDAN

Pimobendan has never been licensed in the United States to treat congestive heart failure in either dogs or people. However, pimobendan has been approved for veterinary use and has been used extensively in some countries of Europe by veterinarians for more than six years. Pimobendan studies in dogs are being conducted in the United States. We have been using pimobendan at the University of Georgia Veterinary Teaching Hospital for about four years, and clients have been pleased with the results. Currently, approval to obtain pimobendan for individual dogs can be requested from the fda Center for Veterinary Medicine.

SUMMARY

Pimobendan is an inodilator used to treat overt or impending congestive heart failure in dogs. Preliminary studies, although limited, 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 mitral valve disease.12,13 Pimobendan is well-tolerated in dogs and has a favorable adverse effects profile. 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)

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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