Pimobendan

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); and for use with concurrent therapy for congestive heart failure (e.g.,furosemide, etc.) as appropriate on a case-by-case basis. It is also indicated for the delay of onset of congestive heart failure in dogs with Stage B2 preclinical myxomatous mitral valve disease.

Mechanism of action

Pimobendan is a positive inotrope, and its main function is to increase 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 healthy hearts, it elevates oxygen and energy consumption to a level comparable to that achieved with dobutamine; however, in pathological hearts, this effect may not occur. Pimobendan also causes peripheral vasodilation by inhibiting the function of phosphodiesterase 3 (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.

Pharmacokinetics

Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60–65%. Food decreases the bioavailability of the aqueous solution although the effect on the tablet form is unknown. 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. 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.

Combinations

Pimobendan is often used in combination with three other drugs to palliate dogs with heart failure (pulmonary edema, pleural effusion, ascites). These are:

• Furosemide, a diuretic, to reduce edema and effusion.
• 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.
• An ACE inhibitor, often enalapril (brand name Enacard) or benazepril (Fortekor). These drugs inhibit the action of angiotensin-converting enzyme, producing a balanced vasodilation, along with other potentially favorable effects.

Synthesis

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).

References

References

1. (19 October 2023). "Vetmedin- pimobendan tablet, chewable".
2. (28 July 2022). "Vetmedin-CA1- pimobendan tablet, chewable".
3. (2006). "Pimobendan in heart failure therapy—a silver bullet?". Journal of the American Animal Hospital Association.
4. (July 2008). "Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study". J. Vet. Intern. Med..
5. (April 2005). "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan.
6. (25 April 2024). "FDA Approves First Generic Pimobendan for Management of Congestive Heart Failure in Dogs".
7. "NADA 141-273 VETMEDIN Pimobendan Chewable Tablets Dogs".
8. "Application Number 141-556 Vetmedin®-CA1 (pimobendan) Chewable Tablets Dogs".
9. (16 June 2022). "FDA Conditionally Approves First Drug to Delay Onset of Congestive Heart Failure in Dogs".
10. (May 2019). "ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs". Journal of Veterinary Internal Medicine.
11. (October 1992). "Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine". Circulation.
12. (1997). "Mechanoenergetic effect of pimobendan in failing dog hearts". Heart and Vessels.
13. (July 1986). "Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties". European Journal of Pharmacology.
14. (April 2007). "Effects of pimobendan for mitral valve regurgitation in dogs". The Journal of Veterinary Medical Science.
15. (2007). "NADA 141-273, Approved by FDA Vetmedin (pimobendan) Chewable Tablets Cardiac drug for oral use in dogs only". Boehringer Ingelheim Vetmedica, Inc..
16. (November 2023). "Pharmacokinetics of pimobendan after oral administration to dogs with myxomatous mitral valve disease". Journal of Veterinary Internal Medicine.
17. (December 2012). "Pharmacokinetics of oral pimobendan in healthy cats". Journal of Veterinary Cardiology.
18. "5-Alkyl:pyridazinyl substd. benzimidazole derivs. - useful as cardiovascular agents, antivirals, interferon inducers and ulcer inhibitors".
19. "Pyridazinone-substituted benzimidazoles and salts".