Pimobendan (INN, or pimobendane), sold under the brand name Vetmedin among others, is a veterinary medication. It is a calcium sensitizer and a selective inhibitor of phosphodiesterase 3 (PDE3) with positive inotropic and vasodilator effects.
Pimobendan is used in the management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease (also previously known as endocardiosis), or dilated cardiomyopathy.[3] Research has shown that as a monotherapy, pimobendan increases survival time and improves quality of life in canine patients with congestive heart failure secondary to mitral valve disease when compared with benazepril, an ACE inhibitor.[4] Under the brand name Acardi, it is available for human use in Japan.[5] It is available as a generic medication.[6]
Medical uses
Pimobendan is indicated for the management of the signs of mild, moderate, or severe congestive heart failure in dogs due to clinical myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM);[1][7] and for use with concurrent therapy for congestive heart failure (e.g.,furosemide, etc.) as appropriate on a case-by-case basis.[1] It is also indicated for the delay of onset of congestive heart failure in dogs with Stage B2 preclinical myxomatous mitral valve disease (2019 ACVIM Consensus Statement).[2][8][9]
Mechanism of action
Pimobendan is a positive inotrope (increases myocardial contractility). It sensitizes and increases the binding efficiency of cardiac troponin in the myofibril to the calcium ions that are already present in systole. In normal hearts it increases the consumption of oxygen and energy to the same degree as dobutamine but in diseased hearts it may not.[10][11] Pimobendan also causes peripheral vasodilation by inhibiting the function of PDE3. This results in decreased resistance to blood flow through systemic arterioles, which decreases afterload (decreases the failing heart's workload) and reduces the amount of mitral regurgitation.[12][13]
Pharmacokinetics
Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60–65%.[14] Food decreases the bioavailability of the aqueous solution although the effect on the tablet form is unknown.[15] It is metabolized into an active metabolite (desmethylpimobendan) by the liver. The parent compound, pimobendan, is a potent calcium sensitizer while desmethylpimobendan is a more potent phosphodiesterase III inhibitor.[16] The half-life of pimobendan in the blood is 0.4 hours, and the half-life of its metabolite is two hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% bound to plasma proteins in circulation. This may have implications in patients with low blood protein levels (hypoproteinemia/hypoalbuminemia) and in patients that are on concurrent therapies that are also highly protein bound.
Pimobendan is often used in combination with three other drugs to palliate dogs with heart failure (pulmonary edema, pleural effusion, ascites). These are:
Spironolactone, an aldosterone antagonist. This has two actions, firstly, as a potassium-sparing diuretic, although its diuretic properties are small compared with those of furosemide. Secondly, it reduces aldosterone-mediated myocardial fibrosis, possibly slowing the progression of heart disease.
The reaction between p-anisoyl chloride [100-07-2] (1) and CID:20516917 (2) gives 4-[4-[(4-Methoxybenzoyl)amino]-3-nitrophenyl]-3-methyl-4-oxobutanoic acid, CID:20516902 (3). The reaction of this with hydrazine gives 5-methyl-6-[3-nitro-4-(4-methoxy-benzoylamino)-phenyl]-3-oxo-4,5-dihydro-2H-pyridazine [74149-73-8]. Catalytic hydrogenation reduces the nitro group giving [74149-74-9] (4). cyclization of the resulting ortho amino amide by means of a strong acid leads to the formation of the corresponding benzimidazole. There is thus obtained pimobendan (5).
^Gordon SG, Miller MW, Saunders AB (2006). "Pimobendan in heart failure therapy—a silver bullet?". Journal of the American Animal Hospital Association. 42 (2): 90–3. doi:10.5326/0420090. PMID16527909.
^Hata K, Goto Y, Futaki S, Ohgoshi Y, Yaku H, Kawaguchi O, et al. (October 1992). "Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine". Circulation. 86 (4): 1291–301. doi:10.1161/01.cir.86.4.1291. PMID1394935.
^Goto Y, Hata K (1997). "Mechanoenergetic effect of pimobendan in failing dog hearts". Heart and Vessels. Suppl 12: 103–5. PMID9476556.
^Verdouw PD, Hartog JM, Duncker DJ, Roth W, Saxena PR (July 1986). "Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties". European Journal of Pharmacology. 126 (1–2): 21–30. doi:10.1016/0014-2999(86)90733-8. PMID2875884.
^Hanzlicek AS, Gehring R, Kukanich B, Kukanich KS, Borgarelli M, Smee N, et al. (December 2012). "Pharmacokinetics of oral pimobendan in healthy cats". Journal of Veterinary Cardiology. 14 (4): 489–96. doi:10.1016/j.jvc.2012.06.002. PMID23116650.
^DE 2837161, Austel V, Diederen W, Eberlein W, Haarmann W, Heider J, "5-Alkyl:pyridazinyl substd. benzimidazole derivs. - useful as cardiovascular agents, antivirals, interferon inducers and ulcer inhibitors", published 6 March 1980, assigned to Boehringer Ingelheim Pharma GmbH and Co KG
^US 4361563, Austel V, Heider J, Eberlein W, Diederen W, Haarmann W, "Pyridazinone-substituted benzimidazoles and salts", issued 30 November 1982, assigned to Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung
