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
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