Pimobendan Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:408556559
Width:200
Chirality:Racemic mixture
Tradename:Vetmedin, others
Dailymedid:Pimobendan
Routes Of Administration:By mouth
Atcvet:yes
Atc Prefix:C01
Atc Suffix:CE90
Legal Us:Rx-only
Legal Us Comment:[1] [2]
Legal Status:Rx-only
Bioavailability:60 to 65%
Elimination Half-Life:0.4 hours
Excretion:In feces
Cas Number:74150-27-9
Pubchem:4823
Unii:34AP3BBP9T
Kegg:D01133
Chembl:24646
Chemspiderid:4657
Iupac Name:(RS)-6-[2-(4-Methoxyphenyl)-1''H''-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one
C:19
H:18
N:4
O:2
Smiles:CC1CC(=O)NN=C1C2=CC3=C(C=C2)N=C(N3)C4=CC=C(C=C4)OC
Stdinchi:1S/C19H18N4O2/c1-11-9-17(24)22-23-18(11)13-5-8-15-16(10-13)21-19(20-15)12-3-6-14(25-2)7-4-12/h3-8,10-11H,9H2,1-2H3,(H,20,21)(H,22,24)
Stdinchikey:GLBJJMFZWDBELO-UHFFFAOYSA-N

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);[7] 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 (2019 ACVIM Consensus Statement).[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.

Combinations

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

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).

Further reading

Notes and References

  1. Web site: Vetmedin- pimobendan tablet, chewable . DailyMed . 19 October 2023 . 30 April 2024 . 15 April 2024 . https://web.archive.org/web/20240415220638/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5441e5b2-cdc0-477a-bd9a-ec5f8d912281 . live .
  2. Web site: Vetmedin-CA1- pimobendan tablet, chewable . DailyMed . 28 July 2022 . 30 April 2024.
  3. Gordon SG, Miller MW, Saunders AB . Pimobendan in heart failure therapy—a silver bullet? . Journal of the American Animal Hospital Association . 42 . 2 . 90–3 . 2006 . 16527909 . 10.5326/0420090 .
  4. Häggström J, Boswood A, O'Grady M, etal . 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. . 22. 5. 1124–35. July 2008 . 18638016 . 10.1111/j.1939-1676.2008.0150.x . 10.1.1.661.3009. free .
  5. Web site: Kusuri-no-Shiori Drug Information Sheet . April 2005 . RAD-AR Council, Japan . 6 August 2008 . 22 July 2011 . https://web.archive.org/web/20110722121958/http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=54 . live .
  6. Web site: FDA Approves First Generic Pimobendan for Management of Congestive Heart Failure in Dogs . U.S. Food and Drug Administration (FDA) . 25 April 2024 . 30 April 2024 . 29 April 2024 . https://web.archive.org/web/20240429214907/https://www.fda.gov/animal-veterinary/cvm-updates/fda-approves-first-generic-pimobendan-management-congestive-heart-failure-dogs . live .
  7. Web site: NADA 141-273 VETMEDIN Pimobendan Chewable Tablets Dogs .
  8. Web site: Application Number 141-556 Vetmedin®-CA1 (pimobendan) Chewable Tablets Dogs . https://web.archive.org/web/20221129220152/https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/12512 . 29 November 2022 .
  9. Web site: FDA Conditionally Approves First Drug to Delay Onset of Congestive Heart Failure in Dogs . U.S. Food and Drug Administration (FDA) . 16 June 2022 . 30 April 2024 . 1 December 2023 . https://web.archive.org/web/20231201201906/https://www.fda.gov/animal-veterinary/cvm-updates/fda-conditionally-approves-first-drug-delay-onset-congestive-heart-failure-dogs . live .
  10. Hata K, Goto Y, Futaki S, Ohgoshi Y, Yaku H, Kawaguchi O, Takasago T, Saeki A, Taylor TW, Nishioka T . Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine . Circulation . 86 . 4 . 1291–301 . October 1992 . 1394935 . 10.1161/01.cir.86.4.1291 .
  11. Goto Y, Hata K . Mechanoenergetic effect of pimobendan in failing dog hearts . Heart and Vessels . Suppl 12 . 103–5 . 1997 . 9476556 .
  12. Verdouw PD, Hartog JM, Duncker DJ, Roth W, Saxena PR . Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties . European Journal of Pharmacology . 126 . 1–2 . 21–30 . July 1986 . 2875884 . 10.1016/0014-2999(86)90733-8 .
  13. Kanno N, Kuse H, Kawasaki M, Hara A, Kano R, Sasaki Y . Effects of pimobendan for mitral valve regurgitation in dogs . The Journal of Veterinary Medical Science . 69 . 4 . 373–7 . April 2007 . 17485924 . 10.1292/jvms.69.373 . free .
  14. Web site: NADA 141-273, Approved by FDA Vetmedin (pimobendan) Chewable Tablets Cardiac drug for oral use in dogs only . 2007 . Boehringer Ingelheim Vetmedica, Inc. . 2 December 2014 . https://web.archive.org/web/20150206032743/http://vetmedin.com/Vetmedin%20Insert_6-07.pdf . 6 February 2015 . dead .
  15. McManamey AK, DeFrancesco TC, Meurs KM, Papich MG . Pharmacokinetics of pimobendan after oral administration to dogs with myxomatous mitral valve disease . Journal of Veterinary Internal Medicine . 37 . 6 . 2003–2010 . November 2023 . 37776546 . 10658550 . 10.1111/jvim.16891 .
  16. Hanzlicek AS, Gehring R, Kukanich B, Kukanich KS, Borgarelli M, Smee N, Olson EE, Margiocco M . Pharmacokinetics of oral pimobendan in healthy cats . Journal of Veterinary Cardiology. 14 . 4 . 489–96 . December 2012 . 23116650 . 10.1016/j.jvc.2012.06.002 .

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