Pimobendan: Difference between revisions

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{{Short description|Chemical compound}}
{{Short description|Chemical compound}}
{{Use dmy dates|date=April 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
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| verifiedrevid = 408556559
| verifiedrevid = 408556559
⚫
| IUPAC_name = (''RS'')-6-[2-(4-Methoxyphenyl)-1''H''-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2''H'')-one
| image = Pimobendan skeletal.svg
| image = Pimobendan skeletal.svg
| width = 200px
| width = 200
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| chirality = [[Racemic mixture]]
| chirality = [[Racemic mixture]]

| drug_name =
<!--Clinical data-->
<!--Clinical data-->
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| tradename = Vetmedin, others
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| Drugs.com = {{drugs.com|international|pimobendan}}
| DailyMedID = Pimobendan
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| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| pregnancy_category =
⚫
| routes_of_administration = [[By mouth]]
⚫
| ATCvet = yes
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| ATC_prefix = C01
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| ATC_suffix = CE90
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| ATC_supplemental =

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
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| legal_US_comment = <ref name="Vetmedin FDA label">{{cite web | title=Vetmedin- pimobendan tablet, chewable | website=DailyMed | date=19 October 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5441e5b2-cdc0-477a-bd9a-ec5f8d912281 | access-date=30 April 2024}}</ref><ref name="Vetmedin CA1 FDA label">{{cite web | title=Vetmedin-CA1- pimobendan tablet, chewable | website=DailyMed | date=28 July 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b461035d-9c3c-42e2-ae1a-3ad611fd5e8d | access-date=30 April 2024}}</ref>
| legal_status = Rx-only
| legal_status = Rx-only
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| routes_of_administration = Oral


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
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| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 74150-27-9
| CAS_number = 74150-27-9
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| ATCvet = yes
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| ATC_prefix = C01
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| ATC_suffix = CE90
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| ATC_supplemental =
| PubChem = 4823
| PubChem = 4823
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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<!--Chemical data-->
<!--Chemical data-->
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| IUPAC_name = (''RS'')-6-[2-(4-Methoxyphenyl)-1''H''-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2''H'')-one
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| C=19 | H=18 | N=4 | O=2
| C=19 | H=18 | N=4 | O=2
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| smiles = CC1CC(=O)NN=C1C2=CC3=C(C=C2)N=C(N3)C4=CC=C(C=C4)OC
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = GLBJJMFZWDBELO-UHFFFAOYSA-N
| StdInChIKey = GLBJJMFZWDBELO-UHFFFAOYSA-N

}}
}}


'''Pimobendan''' ([[International Nonproprietary Name|INN]], or '''pimobendane'''; trade names '''Vetmedin,''' '''Acardi''') is a veterinary medication. It is a calcium sensitizer and a selective inhibitor of [[phosphodiesterase 3]] (PDE3) with positive [[inotropic]] and [[vasodilator]] effects.
'''Pimobendan''' ([[International Nonproprietary Name|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]].<ref>{{cite journal |vauthors=Gordon SG, Miller MW, Saunders AB |title=Pimobendan in heart failure therapy—a silver bullet? |journal=Journal of the American Animal Hospital Association |volume=42 |issue=2 |pages=90–3 |year=2006 |pmid=16527909 |doi= 10.5326/0420090 }}</ref> 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]].<ref>{{cite journal |vauthors=Häggström J, Boswood A, O'Grady M, etal |title=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 |journal=J. Vet. Intern. Med. |volume= 22|issue= 5|pages= 1124–35|date=July 2008 |pmid=18638016 |doi=10.1111/j.1939-1676.2008.0150.x |citeseerx=10.1.1.661.3009|doi-access=free }}</ref> Under the brand name '''Acardi''', it is available for human use in Japan.<ref>{{cite web |url=http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=54 |title=Kusuri-no-Shiori Drug Information Sheet |date=April 2005 |publisher=RAD-AR Council, Japan |access-date=2008-08-06}}</ref> It is available as a [[generic medication]].<ref>{{cite web | title=FDA Approves First Generic Pimobendan for Management of Congestive Heart Failure in Dogs | website=U.S. [[Food and Drug Administration]] (FDA) | date=25 April 2024 | url=https://www.fda.gov/animal-veterinary/cvm-updates/fda-approves-first-generic-pimobendan-management-congestive-heart-failure-dogs | access-date=30 April 2024}}</ref>


== Medical uses ==
⚫
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]].<ref>{{cite journal |vauthors=Gordon SG, Miller MW, Saunders AB |title=Pimobendan in heart failure therapy—a silver bullet? |journal=J Am Anim Hosp Assoc |volume=42 |issue=2 |pages=90–3 |year=2006 |pmid=16527909 |doi= 10.5326/0420090|url=http://www.jaaha.org/cgi/pmidlookup?view=long&pmid=16527909}}</ref> 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]].<ref>{{cite journal |vauthors=Häggström J, Boswood A, O'Grady M, etal |title=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 |journal=J. Vet. Intern. Med. |volume= 22|issue= 5|pages= 1124–35|date=July 2008 |pmid=18638016 |doi=10.1111/j.1939-1676.2008.0150.x |citeseerx=10.1.1.661.3009|doi-access=free }}</ref> However, in clinical practice, it is often used in conjunction with an ACE inhibitor like [[enalapril]] or benazepril. Under the trade name Acardi, it is available for human use in Japan.<ref>{{cite web |url=http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=54 |title=Kusuri-no-Shiori Drug Information Sheet |date=April 2005 |publisher=RAD-AR Council, Japan |access-date=2008-08-06}}</ref>
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);<ref name="Vetmedin FDA label" /><ref>https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/832 {{PD-notice}}</ref> and for use with concurrent therapy for congestive heart failure (e.g.,furosemide, etc.) as appropriate on a case-by-case basis.<ref name="Vetmedin FDA label" /> 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).<ref name="Vetmedin CA1 FDA label" /><ref>https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/12512 {{PD-notice}}</ref><ref>{{cite web | title=FDA Conditionally Approves First Drug to Delay Onset of Congestive Heart Failure in Dogs | website=U.S. [[Food and Drug Administration]] (FDA) | date=16 June 2022 | url=https://www.fda.gov/animal-veterinary/cvm-updates/fda-conditionally-approves-first-drug-delay-onset-congestive-heart-failure-dogs | access-date=30 April 2024}} {{PD-notice}}</ref>


==Mechanism of action==
==Mechanism of action==
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==Combinations==
==Combinations==
{{Unreferenced section}}
Pimobendan is often used in combination with three other drugs to palliate dogs with heart failure (pulmonary edema, pleural effusion, ascites). These are:
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.
* [[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.
* [[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.
* 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.

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


==Synthesis==
==Synthesis==
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The reaction between p-anisoyl chloride [100-07-2] ('''1''') and [https://pubchem.ncbi.nlm.nih.gov/compound/20516917 CID:20516917] ('''2''') gives 4-[4-[(4-Methoxybenzoyl)amino]-3-nitrophenyl]-3-methyl-4-oxobutanoic acid, [https://pubchem.ncbi.nlm.nih.gov/compound/20516902 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''').
The reaction between p-anisoyl chloride [100-07-2] ('''1''') and [https://pubchem.ncbi.nlm.nih.gov/compound/20516917 CID:20516917] ('''2''') gives 4-[4-[(4-Methoxybenzoyl)amino]-3-nitrophenyl]-3-methyl-4-oxobutanoic acid, [https://pubchem.ncbi.nlm.nih.gov/compound/20516902 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''').

==See also==
*[[Levosimendan]]


==References==
==References==
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==Further reading==
==Further reading==
*{{cite journal |vauthors=Lee JA, Allen DG |title=Calcium sensitisers |journal=BMJ |volume=300 |issue=6724 |pages=551–2 |date=March 1990 |pmid=2108746 |pmc=1662365 |doi=10.1136/bmj.300.6724.551}}
* {{cite journal |vauthors=Lee JA, Allen DG |title=Calcium sensitisers |journal=BMJ |volume=300 |issue=6724 |pages=551–2 |date=March 1990 |pmid=2108746 |pmc=1662365 |doi=10.1136/bmj.300.6724.551}}

==External links==
*[http://www.vetmedin.com/ Official Vetmedin Product Website]
*[http://cavalierhealth.net/mitral_valve_disease.htm#A_Few_Words A Few Words About Pimobendan]


{{Phosphodiesterase inhibitors}}
{{Phosphodiesterase inhibitors}}
{{Vasodilators used in cardiac diseases}}
{{Vasodilators used in cardiac diseases}}
{{Portal bar | Medicine}}
{{Authority control}}


[[Category:Benzimidazoles]]
[[Category:Benzimidazoles]]

Revision as of 06:53, 30 April 2024

Pimobendan
Clinical data
Trade namesVetmedin, others
AHFS/Drugs.comInternational Drug Names
License data
Routes of
administration		By mouth
ATCvet code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60 to 65%
Elimination half-life0.4 hours
ExcretionIn feces
Identifiers
  • (RS)-6-[2-(4-Methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.168.193 Edit this at Wikidata
Chemical and physical data
FormulaC19H18N4O2
Molar mass334.379 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • CC1CC(=O)NN=C1C2=CC3=C(C=C2)N=C(N3)C4=CC=C(C=C4)OC
  • 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) ☒N
  • Key:GLBJJMFZWDBELO-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

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] 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.[15] 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

Thieme Patents:[16][17] Crystalline form:[18] ~93% (Page 22-23):[19] Key intermediate:[20]

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

  1. ^ a b c "Vetmedin- pimobendan tablet, chewable". DailyMed. 19 October 2023. Retrieved 30 April 2024.
  2. ^ a b "Vetmedin-CA1- pimobendan tablet, chewable". DailyMed. 28 July 2022. Retrieved 30 April 2024.
  3. ^ 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. PMID 16527909.
  4. ^ 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. CiteSeerX 10.1.1.661.3009. doi:10.1111/j.1939-1676.2008.0150.x. PMID 18638016.
  5. ^ "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan. April 2005. Retrieved 6 August 2008.
  6. ^ "FDA Approves First Generic Pimobendan for Management of Congestive Heart Failure in Dogs". U.S. Food and Drug Administration (FDA). 25 April 2024. Retrieved 30 April 2024.
  7. ^ https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/832 Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/12512 Public Domain This article incorporates text from this source, which is in the public domain.
  9. ^ "FDA Conditionally Approves First Drug to Delay Onset of Congestive Heart Failure in Dogs". U.S. Food and Drug Administration (FDA). 16 June 2022. Retrieved 30 April 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  10. ^ 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.
  11. ^ Goto Y1, Hata K. Mechanoenergetic effect of pimobendan in failing dog hearts. Heart Vessels. 1997;Suppl 12:103-5.
  12. ^ 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.
  13. ^ 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.
  14. ^ "Archived copy" (PDF). Archived from the original (PDF) on 6 February 2015. Retrieved 2 December 2014.{{cite web}}: CS1 maint: archived copy as title (link)
  15. ^ 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.
  16. ^ Volkhard Dipl Chem Dr Austel, 4 More », DE 2837161  (1981 to Thomae Gmbh Dr K).
  17. ^ Volkhard Austel, Joachim Heider, Wolfgang Eberlein, Willi Diederen, Walter Haarmann, U.S. patent 4,361,563 (1982 to Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung).
  18. ^ Marinus Maria Martinus BOEREN, 4 More », US 20110152283  (2011 to Eurovet Animal Health B.V.).
  19. ^ Christian Schickaneder, 4 More », WO 2011124638  (2011 to Novartis Ag).
  20. ^ Cao Lei, et al. CN 105968054  (2016 to Wisdom Pharmaceutical Co Ltd).

Further reading

Retrieved from "https://en.wikipedia.org/w/index.php?title=Pimobendan&oldid=1221487779"