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Revision as of 12:38, 24 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 460463385 of page Milrinone for the Chem/Drugbox validation project (updated: 'DrugBank').		Latest revision as of 04:22, 18 September 2024 edit Citation bot (talk | contribs)Bots5,429,162 edits Removed parameters. | Use this bot. Report bugs. | Suggested by Neko-chan | Category:CS1 maint: DOI inactive as of February 2024‎ | #UCB_Category 278/293
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			{{short description|Chemical compound}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
	{{Drugbox		{{Drugbox
	| Verifiedfields = changed		| Watchedfields = changed
	| verifiedrevid = 414088890		| verifiedrevid = 462252550
	| IUPAC_name = 2-methyl-6-oxo-1,6-dihydro-3,4'-bipyridine-5-carbonitrile		| IUPAC_name = 2-Methyl-6-oxo-1,6-dihydro-3,4'-bipyridine-5-carbonitrile
	| image = Milrinone.svg		| image = Milrinone.svg
	<!--Clinical data-->		<!--Clinical data-->
	| tradename =		| tradename =
	| Drugs.com = {{drugs.com|monograph|milrinone-lactate}}		| Drugs.com = {{drugs.com|monograph|milrinone-lactate}}
	| MedlinePlus = a601020		| MedlinePlus = a601020
	| pregnancy_US = C		| legal_EU = Rx-only
			| legal_EU_comment = <ref>{{cite web | title = Active substance: milrinone | work = List of nationally authorised medicinal products | publisher = European Medicines Agency | date = 10 June 2022 | url = https://www.ema.europa.eu/documents/psusa/milrinone-list-nationally-authorised-medicinal-products-psusa/00002064/202110_en.pdf }}</ref>
	| legal_status = Rx-only		| legal_status = Rx-only
	| routes_of_administration = IV only		| routes_of_administration = IV only
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	| bioavailability = 100% (as IV bolus, infusion)		| bioavailability = 100% (as IV bolus, infusion)
	| protein_bound = 70 to 80%		| protein_bound = 70 to 80%
	| metabolism = Hepatic (12%)		| metabolism = Liver (12%)
	| elimination_half-life = 2.3 hours (mean, in CHF)		| elimination_half-life = 2.3 hours (mean, in CHF)
	| excretion = Urine (85% as unchanged drug) within 24 hours		| excretion = Urine (85% as unchanged drug) within 24 hours
	<!--Identifiers-->		<!--Identifiers-->
			| IUPHAR_ligand = 5225
	| CASNo_Ref = {{cascite|correct|CAS}}
	| CAS_number_Ref = {{cascite|correct|??}}		| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 78415-72-2		| CAS_number = 78415-72-2
	| ATC_prefix = C01		| ATC_prefix = C01
	| ATC_suffix = CE02		| ATC_suffix = CE02
	| ATC_supplemental =		| ATC_supplemental =
	| PubChem = 4197		| PubChem = 4197
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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	| KEGG_Ref = {{keggcite|correct|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = D00417		| KEGG = D00417
	| ChEBI_Ref = {{ebicite|changed|EBI}}		| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 50693		| ChEBI = 50693
	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 189		| ChEMBL = 189
	<!--Chemical data-->		<!--Chemical data-->
	| C=12 | H=9 | N=3 | O=1		| C=12 | H=9 | N=3 | O=1
			| SMILES = c1cnccc1-c2c(C)c(=O)c(C#N)c2
	| molecular_weight = 211.219 g/mol
	| smiles = Cc1c(cc(c(=O)1)C#N)c2ccncc2
	| InChI = 1/C12H9N3O/c1-8-11(9-2-4-14-5-3-9)6-10(7-13)12(16)15-8/h2-6H,1H3,(H,15,16)
	| InChIKey = PZRHRDRVRGEVNW-UHFFFAOYAY
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C12H9N3O/c1-8-11(9-2-4-14-5-3-9)6-10(7-13)12(16)15-8/h2-6H,1H3,(H,15,16)		| StdInChI = 1S/C12H9N3O/c1-8-11(9-2-4-14-5-3-9)6-10(7-13)12(16)15-8/h2-6H,1H3,(H,15,16)
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	| density = 1.344		| density = 1.344
	| melting_point = 315		| melting_point = 315
	| boiling_point = 449		| boiling_point =
	}}		}}
			'''Milrinone''', sold under the brand name '''Primacor''', is a pulmonary vasodilator<ref>{{cite journal | vauthors = Baxter FJ, Whippey A | title = Amniotic Fluid Embolism Treated With Inhaled Milrinone: A Case Report | journal = A&A Practice | volume = 14 | issue = 13 | pages = e01342 | date = November 2020 | pmid = 33185413 | doi = 10.1213/XAA.0000000000001342 | s2cid = 226851766 }}</ref> used in patients who have ]. It is a ] that works to increase the ] and decrease pulmonary vascular resistance. Milrinone also works to ] which helps alleviate increased pressures (]) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, studies suggest that milrinone may exhibit some negative ] that have caused some debate about its use clinically.<ref>{{cite journal | vauthors = Packer M | title = Calcium channel blockers in chronic heart failure. The risks of "physiologically rational" therapy | journal = Circulation | volume = 82 | issue = 6 | pages = 2254–2257 | date = December 1990 | pmid = 2242549 | doi = 10.1161/01.cir.82.6.2254 | s2cid = 11255642 | doi-access = }}</ref><ref>{{cite journal | vauthors = Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML | display-authors = 6 | title = Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group | journal = The New England Journal of Medicine | volume = 325 | issue = 21 | pages = 1468–1475 | date = November 1991 | pmid = 1944425 | doi = 10.1056/NEJM199111213252103 | doi-access = free }}</ref>
			Overall, milrinone supports ]ing of the heart by decreasing the degradation of ] (cAMP) and thus increasing phosphorylation levels of many components in the heart that contribute to contractility and ]. Milrinone is used as a drug that causes positive inotropy and it will lead to an increased force of contraction. Milrinone use following cardiac surgery has been under some debate because of the potential increase risk of postoperative atrial ]s.<ref>{{cite journal | vauthors = Fleming GA, Murray KT, Yu C, Byrne JG, Greelish JP, Petracek MR, Hoff SJ, Ball SK, Brown NJ, Pretorius M | display-authors = 6 | title = Milrinone use is associated with postoperative atrial fibrillation after cardiac surgery | journal = Circulation | volume = 118 | issue = 16 | pages = 1619–1625 | date = October 2008 | pmid = 18824641 | pmc = 2770257 | doi = 10.1161/CIRCULATIONAHA.108.790162 }}</ref> However, in the short term milrinone has been deemed beneficial to those experiencing heart failure and an effective therapy to maintain heart function following cardiac surgeries. There is no evidence of any long term beneficial effects on survival.<ref>{{cite book | title = British National Formulary | edition = 66th | location = London | publisher = BMJ Group and Pharmaceutical Press | date = September 2013 }}</ref> In critically ill patients with evidence of cardiac dysfunction there is limited good quality evidence to recommend its use.<ref>{{cite journal | vauthors = Koster G, Bekema HJ, Wetterslev J, Gluud C, Keus F, van der Horst IC | title = Milrinone for cardiac dysfunction in critically ill adult patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis | journal = Intensive Care Medicine | volume = 42 | issue = 9 | pages = 1322–1335 | date = September 2016 | pmid = 27448246 | pmc = 4992029 | doi = 10.1007/s00134-016-4449-6 }}</ref>
			Milrinone is administered IV only and eliminated unchanged in the urine. Dose adjustment is required for patients with renal impairment.<ref>{{Cite web |title=Milrinone Dosage Guide + Max Dose, Adjustments |url=https://www.drugs.com/dosage/milrinone.html |access-date=2023-01-03 |website=] |language=en}}</ref>
			==Contractility in the heart==
			{{Main|Myocardial contractility}}
			People experiencing some forms of heart failure have a significant decrease in the contractile ability of muscle cells in the heart (]s).<ref>{{cite journal | vauthors = de Tombe PP | title = Altered contractile function in heart failure | journal = Cardiovascular Research | volume = 37 | issue = 2 | pages = 367–380 | date = February 1998 | pmid = 9614494 | doi = 10.1016/s0008-6363(97)00275-7 | doi-access = free }}</ref> This impaired contractility occurs through a number of mechanisms. Some of the main problems associated with decreased contractility in those with heart failure are issues arising from imbalances in the concentration of ].<ref>{{cite journal | vauthors = Ward ML, Crossman DJ | title = Mechanisms underlying the impaired contractility of diabetic cardiomyopathy | journal = World Journal of Cardiology | volume = 6 | issue = 7 | pages = 577–584 | date = July 2014 | pmid = 25068018 | pmc = 4110606 | doi = 10.4330/wjc.v6.i7.577 | doi-access = free }}</ref> Calcium permits ] and ] to interact which allows initiation of contraction within the cardiomyocytes. In those with heart failure there may be a decreased amount of calcium within the cardiomyocytes reducing the available calcium to initiate contraction.<ref>{{cite journal | vauthors = Szent-Györgyi AG | title = Calcium regulation of muscle contraction | journal = Biophysical Journal | volume = 15 | issue = 7 | pages = 707–723 | date = July 1975 | pmid = 806311 | pmc = 1334730 | doi = 10.1016/S0006-3495(75)85849-8 | bibcode = 1975BpJ....15..707S }}</ref> When contractility is decreased the amount of blood being pumped out of the heart into ] is decreased as well. This reduction in ] can cause many systemic implications such as ], ] and other issues associated with decreased blood flow to peripheral tissues.<ref>{{cite book | vauthors = King J, Lowery DR | chapter = Physiology, Cardiac Output |date=2022 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK470455/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29262215 }}</ref>
			==Mechanism of action==
			Milrinone is a phosphodiesterase-3 inhibitor. This drug inhibits the action of phosphodiesterase-3 and thus prevents degradation of cAMP. Normally, cAMP causes increased activation of ] (PKA). PKA is an enzyme that ] many elements of the contractile machinery within the heart cell. In the short term this leads to an increased force of contraction. ]s are ] responsible for the breakdown of cAMP. Therefore, when phosphodiesterases lower the level of cAMP in the cell they also lower the active fraction of PKA within the cell and reduce the force of contraction.<ref name=":0">{{cite book | vauthors = Zimmerman J, Cahalan M | chapter = Chapter 22 - Vasopressors and Inotropes |date= January 2013 | chapter-url= https://www.sciencedirect.com/science/article/pii/B9781437716795000223 | veditors = Hemmings HC, Egan TD | title = Pharmacology and Physiology for Anesthesia |pages=390–404 |access-date=2023-03-14 |place=Philadelphia |publisher=W.B. Saunders | doi = 10.1016/B978-1-4377-1679-5.00022-3 |language=en |isbn=978-1-4377-1679-5| s2cid = 79282649 }}</ref>
			With increased cAMP levels there is an increase in the activation of PKA. This PKA will phosphorylate many components of the cardiomyocyte such as calcium channels and components of the ]s. Phosphorylation of ]s permits an increase in calcium influx into the cell. This increase in calcium influx results in increased contractility. PKA also phosphorylates ] channels promoting their action. Potassium channels are responsible for ] of the cardiomyocytes therefore increasing the rate at which cells can ] and generate contraction. PKA also phosphorylates components on myofilaments allowing actin and myosin to interact more easily and thus increasing contractility and the inotropic state of the heart. Milrinone allows stimulation of cardiac function independently of β-adrenergic receptors which appear to be down-regulated in those with heart failure.<ref name=":0" />
			== Clinical use ==
			Milrinone is a commonly used therapy for severe ] (PAH),<ref>{{cite journal | vauthors = McNamara PJ, Shivananda SP, Sahni M, Freeman D, Taddio A | title = Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide | journal = Pediatric Critical Care Medicine | volume = 14 | issue = 1 | pages = 74–84 | date = January 2013 | pmid = 23132395 | doi = 10.1097/PCC.0b013e31824ea2cd | s2cid = 7696208 }}</ref> often in combination with other medications such as ].<ref>{{cite journal | vauthors = Hui-li G | title = The management of acute pulmonary arterial hypertension | journal = Cardiovascular Therapeutics | volume = 29 | issue = 3 | pages = 153–175 | date = June 2011 | pmid = 20560976 | doi = 10.1111/j.1755-5922.2009.00095.x | doi-access = free }}</ref>
			Targeting PDE3 with optimal doses and timing, milrinone prevents ] in HDM-driven models of allergic airway inflammation.<ref>{{cite journal | vauthors = Beute J, Lukkes M, Koekoek EP, Nastiti H, Ganesh K, de Bruijn MJ, Hockman S, van Nimwegen M, Braunstahl GJ, Boon L, Lambrecht BN, Manganiello VC, Hendriks RW, KleinJan A | display-authors = 6 | title = A pathophysiological role of PDE3 in allergic airway inflammation | journal = JCI Insight | volume = 3 | issue = 2 | date = January 2018 | pmid = 29367458 | pmc = 5821178 | doi = 10.1172/jci.insight.94888 | doi-access = free }}</ref>
			It can be used in cardiopulmonary bypass cases, as it increases the flow in saphenous grafts and has a beneficiary effect in left ventricle function.<ref name="Arbeus Axelsson Friberg Magnuson 2009 pp. 48–53">{{cite journal | vauthors = Arbeus M, Axelsson B, Friberg O, Magnuson A, Bodin L, Hultman J | title = Milrinone increases flow in coronary artery bypass grafts after cardiopulmonary bypass: a prospective, randomized, double-blind, placebo-controlled study | journal = Journal of Cardiothoracic and Vascular Anesthesia | volume = 23 | issue = 1 | pages = 48–53 | date = February 2009 | pmid = 18834820 | doi = 10.1053/j.jvca.2008.07.005 | publisher = Elsevier BV }}</ref>
			==Adverse effects==
			Common adverse effects include ]s (including ] and ]), ]s, ], and ].<ref>{{cite web | url = https://www.drugs.com/monograph/milrinone-lactate.html | title = Milrinone Lactate Monograph | publisher = ] }}</ref>
			==Synthesis==
			Patents:<ref>BE886336 idem G. Y. Lesher, R. E. Philion, {{US patent|4313951}} (1982 both to Sterling).</ref><ref>{{cite patent | inventor = Lesher GY, Gruett MD | country = US | number = 4264603 | gdate = 1981 | assign1 = Sterling Drug Inc. }}</ref><ref>{{cite patent | inventor = Singh B | country = US | number = 4413127 | gdate = 1983 | assign1 = Sterling }}</ref> Journal syntheses:<ref>{{cite journal | vauthors = Singh B | date = 1985 | title = A Novel Synthesis of 1,6-Dihydro-2-methyl-6-oxo-5-carbonitrile (Milrinone) | journal = Heterocycles | volume = 23 | issue = 6 | pages = 1479 | doi = 10.3987/R-1985-06-1479 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Shiao MJ, Shyu LM, Chen CF | date = 1990 | title = Synthesis of Milrinone, a Cardiotonic Agent | journal = Heterocycles | volume = 31 | issue = 3 | pages = 523 | doi = 10.3987/COM-89-5276 | doi-access = free }}</ref> Sino ultramodern:<ref>{{Cite patent| country = CN | number = 104326975 | inventor = Yan H, Deng A | title = Preparation method of high-purity milrinone | gdate = 2015 | assign1 = ZHENGZHOU SIHUAN MEDICINE ARTICLE Co Ltd }}</ref><ref>{{Cite patent | country = CN | number = 104387320 | inventor = Ao L, Zhang B, Pan J, Chen Y | title = Preparation Method for High-Purity Milrinone | gdate = 2018 | assign1 = Huzhou Zhanwang Pharmaceutical Co., Ltd.}}</ref> Prec:<ref>{{Cite patent | country = CN | number = 103848779 | gdate = 2014 | assign1 = University of Jinan | title = Preparation method of 1-(4-pyridyl) acetone | inventor = Tan X, Jing Y, Wang F, Liu H, Yu U }}</ref>]]
			The reaction between ] and ] gives 4-pyridyl acetone (4-acetonylpyridine) ('''1'''). The ] type reaction between this and DMF-dimethylacetal ('''2''') affords ('''3'''). Then base catalyzed reaction of this with ] ('''4''') completes the synthesis of milrinone ('''5''').
			== References ==
			{{reflist}}
			== External links ==
			*
			{{Phosphodiesterase inhibitors}}
			{{Cardiac stimulants excluding cardiac glycosides}}
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