Pimobendane

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Pimobendan
Clinical data
AHFS/Drugs.com	International Drug Names
Routes of; administration	Oral
ATCvet code	Template:Infobox drug/formatATCvet; Template:Infobox drug/formatATCvet;
Legal status
Legal status	In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	60 to 65%
Elimination half-life	0.4 hours
Excretion	In feces
Identifiers
	IUPAC name (RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one;
CAS Number	74150-27-9 ;
PubChem CID	4823;
ChemSpider	4657 ;
UNII	34AP3BBP9T;
KEGG	D01133 ;
ChEMBL	ChEMBL24646 ;
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C19H18N4O2
Molar mass	334.37 g/mol
3D model (JSmol)	Interactive image;
	SMILES CC1CC(=O)NN=C1C2=CC3=C(C=C2)N=C(N3)C4=CC=C(C=C4)OC;
	InChI InChI=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) ; Key:GLBJJMFZWDBELO-UHFFFAOYSA-N ;
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Pimobendan (or pimobendane)(INN) is a veterinary medication manufactured by Boehringer Ingelheim under the trade names Vetmedin and Acardi (Japan). It is both a calcium sensitizer and a selective inhibitor of phosphodiesterase III (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.^[1] Research has shown that 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 angiotensin-converting-enzyme (ACE) inhibitor.^[2] Under the trade name Acardi, it is available for human use in Japan.^[3]

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.^[4] ^[5] Pimobendan also causes peripheral vasodilation by inhibiting the function of phosphodiesterase III. 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.^[6]^[7]

Pharmacokinetics

Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60-65%.^[8] Bioavailability is markedly decreased when ingested with food. 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.^[9] The half-life of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 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 suffering from 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 (trade name Enacard) or benazepril (Fortekor). These drugs inhibit the action of angiotensin-converting enzyme, producing a balanced vasodilation, along with other potentially favorable effects.

Other drugs may also be used as required to manage certain arrhythmias that are often associated with heart disease.

Synthesis

Pimobendan can be synthesized beginning with anisoyl chloride.

References

↑ Gordon SG, Miller MW, Saunders AB (2006). "Pimobendan in heart failure therapy—a silver bullet?". J Am Anim Hosp Assoc. 42 (2): 90–3. PMID 16527909.
↑ Häggström J, Boswood A, O'Grady M; et al. (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. 22 (5): 1124–35. doi:10.1111/j.1939-1676.2008.0150.x. PMID 18638016.
↑ "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan. April 2005. Retrieved 2008-08-06.
↑ Hata K1, Goto Y, Futaki S, Ohgoshi Y, Yaku H, Kawaguchi O, Takasago T, Saeki A, Taylor TW, Nishioka T, et al. Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine. Circulation. 1992 Oct;86(4):1291-301.
↑ Goto Y1, Hata K. Mechanoenergetic effect of pimobendan in failing dog hearts. Heart Vessels. 1997;Suppl 12:103-5.
↑ Verdouw PD, Hartog JM, Duncker DJ, Roth W, Saxena PR. Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties. Eur J Pharmacol. 1986 Jul 15;126(1-2):21-30.
↑ Kanno N, Kuse H, Kawasaki M, Hara A, Kano R, Sasaki Y. Effects of pimobendan for mitral valve regurgitation in dogs. J Vet Med Sci. 2007 Apr;69(4):373-7.
↑ http://www.vetmedin.com/Vetmedin%20Insert_6-07.pdf
↑ Hanzlicek AS1, Gehring R, Kukanich B, Kukanich KS, Borgarelli M, Smee N, Olson EE, Margiocco M. Pharmacokinetics of oral pimobendan in healthy cats. J Vet Cardiol. 2012 Dec;14(4):489-96.

Template:Phosphodiesterase inhibitors

[1] Gordon SG, Miller MW, Saunders AB (2006). "Pimobendan in heart failure therapy—a silver bullet?". J Am Anim Hosp Assoc. 42 (2): 90–3. PMID 16527909.

[2] Häggström J, Boswood A, O'Grady M; et al. (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. 22 (5): 1124–35. doi:10.1111/j.1939-1676.2008.0150.x. PMID 18638016.

[3] "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan. April 2005. Retrieved 2008-08-06.

[4] Hata K1, Goto Y, Futaki S, Ohgoshi Y, Yaku H, Kawaguchi O, Takasago T, Saeki A, Taylor TW, Nishioka T, et al. Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine. Circulation. 1992 Oct;86(4):1291-301.

[5] Goto Y1, Hata K. Mechanoenergetic effect of pimobendan in failing dog hearts. Heart Vessels. 1997;Suppl 12:103-5.

[6] Verdouw PD, Hartog JM, Duncker DJ, Roth W, Saxena PR. Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties. Eur J Pharmacol. 1986 Jul 15;126(1-2):21-30.

[7] Kanno N, Kuse H, Kawasaki M, Hara A, Kano R, Sasaki Y. Effects of pimobendan for mitral valve regurgitation in dogs. J Vet Med Sci. 2007 Apr;69(4):373-7.

[8] ttp://www.vetmedin.com/Vetmedin%20Insert_6-07.pdf

[9] Hanzlicek AS1, Gehring R, Kukanich B, Kukanich KS, Borgarelli M, Smee N, Olson EE, Margiocco M. Pharmacokinetics of oral pimobendan in healthy cats. J Vet Cardiol. 2012 Dec;14(4):489-96.

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v t e Vasodilators used in cardiac diseases (C01D)
Nitrates	Glyceryl trinitrate • Isosorbide dinitrate • Isosorbide mononitrate • Molsidomine • Pentaerythritol tetranitrate
Quinolone vasodilators	Flosequinan
Others	Itramin tosilate • Prenylamine • Oxyfedrine • Benziodarone • Carbocromen • Hexobendine • Etafenone • Heptaminol • Imolamine • Dilazep • Trapidil • Molsidomine • Efloxate • Cinepazet • Cloridarol • Nicorandil • Linsidomine • Nesiritide • Gapicomine