WordNet

a salt or ester of lactic acid

PrepTutorEJDIC

乳を出す

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/02/12 12:23:59」(JST)

wiki en

[Wiki en表示]

Milrinone, commonly known and marketed under the brand name Primacor, is a medication used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, recent studies suggest that milrinone may exhibit some negative side effects that have caused some debate about its use clinically.^{[citation needed]}

Overall, milrinone supports ventricular functioning 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 heart rate. Milrinone use following cardiac surgery has been under some debate because of the potential increase risk of postoperative atrial arrhythmias. 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.^[1]

Contractility in the heart

People experiencing heart failure have a significant decrease in the contractile ability of heart cells (cardiomyocytes). 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 calcium. Calcium permits myosin and actin 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. When contractility is decreased the amount of blood being pumped out of the heart into circulation is decreased as well. This reduction in cardiac output causes many systemic implications such as fatigue, syncope and other issues associated with decreased blood flow to peripheral tissues.

Mechanism of action

There are receptors on cardiomyocytes called β-adrenergic receptors. These receptors are stimulated by molecules such as norepinephrine and epinephrine. Stimulation of these receptors causes a cascade of events ultimately leading to increase cyclic adenosine monophosphate (cAMP) within the cell. Cyclic adenosine monophosphate causes increase activation of protein kinase A (PKA). PKA is a protein that phosphorylates many components within the cardiomyocytes and either activates or inhibits their action. Phosphodiesterases are enzymes responsible for the breakdown of cAMP. Therefore, when phosphodiesterases break down cAMP the amount of PKA within the cell decreases as well.

Milrinone is a phosphodiesterase-3 inhibitor. This drug inhibits the action of phosphodiesterase-3 and thus prevents degradation of cAMP. With increase cAMP levels there is an increase activation of PKA. This PKA will phosphorylate many components of the cardiomyocyte such as calcium channels and components of the myofilaments. Phosphorylation of calcium channels permits an increase in calcium influx into the cell. This increase in calcium influx permits increased contractility. PKA also phosphorylates potassium channels promoting their action. Potassium channels are responsible for repolarization of the cardiomyocytes therefore increasing the rate at which cells can depolarize 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.

Adverse effects

In recent years many studies have been performed showing that milrinone use may present potential adverse side effects in heart failure patients. Following cardiac surgery milrinone has been used as a therapy to maintain ventricular function of the heart. A study conducted by Fleming and colleagues has shown that milrinone use may be associated with increase atrial fibrillation following cardiac surgery. In another study by Smith and colleagues, milirinone appeared to generate a 3-fold increase in tachyarrythmias following surgery for congenital heart disease. However, other studies suggest that milrinone is extremely beneficial in maintaining heart function in the short term following surgical procedures.^{[citation needed]}

Synthesis

Singh, B.; 1983, U.S. Patent 4,413,127.

References

^ British National Formulary. 66 ed. London: BMJ Group and Pharmaceutical Press; Sept 2013

Anonymous. Milrinone for Acute Exacerbations of CHF: Routine Use Not Recommended. Formulary Journal. May 2000;37(5): 227.
Fleming G, Murray K, Yu C, Byrne J, Greelish J, Petracek M et al. Milrinone Use Is Associated With Postoperative Atrial Fibrillation After Cardiac Surgery. The Journal of the American Heart Association. 29 Sept 2008;118:1619-1625.
Packer M, Carver J, Rodeheffer R, Ivanhoe R, DiBianco R, Zeldis S et al. Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure. The New England Journal of Medicine. 21 Nov 1991;325(21):1468-1475.
Sablotzki A, Starzmann W, Schebel R, Grond S and Czeslik E. Selective Pulmonary Vasodilation with Inhaled Aerosolized Milrinone in Heart Transplant Candidates. Canadian Journal of Anesthesia. 18 Apr 2005;52(10):1076-1083.
Smith A, Owen J, Borgman K, Fish F, and Kannankeril P. Relation of MIlrinone After Surgery for Congenital Heart Disease to Significant Postoperative Tachyarrhythmias. American Journal of Cardiology. 1 Dec 2011;108(11):1620-1624.
Yan C, Miller C and Abe, J. Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart. Circulation Research. 2007;100:589-501.
Yano M, Kohno M, Oskusa T, Mochizuki M, Yamada J, Kohno M et all. Effect of Milrinone On Left Ventricular Relaxation and Calcium Uptake Function of Cardiac Sarcoplasmic Reticulum. American Journal of Physiology. 9 May 2000;279(4):1898-1905.

External links

Mechanism of action

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. Peripartum cardiomyopathy: Treatment and prognosis
2. 乳児および小児における心不全のマネージメント management of heart failure in infants and children
3. 収縮能障害による心不全における強心剤 inotropic agents in heart failure due to systolic dysfunction
4. 敗血症性ショック：小児における蘇生後の継続的マネージメント septic shock ongoing management after resuscitation in children
5. 成人における重症敗血症および敗血症性ショックの評価およびマネージメント evaluation and management of severe sepsis and septic shock in adults

English Journal

Anaesthetic and ICU management of aneurysmal subarachnoid haemorrhage: A survey of European practice.

Velly LJ1, Bilotta F, Fàbregas N, Soehle M, Bruder NJ, Nathanson MH; European Neuroanaesthesia and Critical Care Interest Group (ENIG).
European journal of anaesthesiology.Eur J Anaesthesiol.2015 Mar;32(3):168-76. doi: 10.1097/EJA.0000000000000163.
BACKGROUND: Many aspects of the perioperative management of aneurysmal subarachnoid haemorrhage (SAH) remain controversial. It would be useful to assess differences in the treatment of SAH in Europe to identify areas for improvement.OBJECTIVE: To determine the clinical practice of physicians treatin
PMID 25303971

Preliminary experience with combined inhaled milrinone and prostacyclin in cardiac surgical patients with pulmonary hypertension.

Laflamme M1, Perrault LP1, Carrier M1, Elmi-Sarabi M2, Fortier A3, Denault AY4.
Journal of cardiothoracic and vascular anesthesia.J Cardiothorac Vasc Anesth.2015 Feb;29(1):38-45. doi: 10.1053/j.jvca.2014.06.012. Epub 2014 Oct 17.
OBJECTIVE: To retrospectively evaluate the effects of combined inhaled prostacyclin and milrinone to reduce the severity of pulmonary hypertension when administered prior to cardiopulmonary bypass.DESIGN: Retrospective case control analysis of high-risk patients undergoing cardiac surgery.SETTING: S
PMID 25440627

Milrinone for the Treatment of Acute Heart Failure After Acute Myocardial Infarction: A Systematic Review and Meta-analysis.

Tang X1, Liu P, Li R, Jing Q, Lv J, Liu L, Liu Y.
Basic & clinical pharmacology & toxicology.Basic Clin Pharmacol Toxicol.2015 Jan 27. doi: 10.1111/bcpt.12385. [Epub ahead of print]
Despite advancements in modern medicine, the treatment of acute heart failure (AHF) after acute myocardial infarction (AMI) remains challenging. Milrinone is effective in the treatment of chronic congestive heart failure, but its safety and efficacy in patients with AHF after AMI have not been syste
PMID 25625413

Japanese Journal

Hemodynamic effects of IV milrinone lactate in pediatric patients with septic shock

BARTON P
Chest 109, 1302-1312, 1996
NAID 30034120535

「ミルリノン」

Milrinone
Systematic (IUPAC) name
	2-methyl-6-oxo-1,6-dihydro-3,4'-bipyridine-5-carbonitrile
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a601020
Pregnancy; category	US: C;
Legal status	℞ Prescription only;
Routes	IV only
Pharmacokinetic data
Bioavailability	100% (as IV bolus, infusion)
Protein binding	70 to 80%
Metabolism	Hepatic (12%)
Half-life	2.3 hours (mean, in CHF)
Excretion	Urine (85% as unchanged drug) within 24 hours
Identifiers
CAS number	78415-72-2
ATC code	C01CE02
PubChem	CID 4197
DrugBank	DB00235
ChemSpider	4052
UNII	JU9YAX04C7
KEGG	D00417
ChEBI	CHEBI:50693
ChEMBL	CHEMBL189
Chemical data
Formula	C12H9N3O
Molecular mass	211.219 g/mol
	SMILES Cc1c(cc(c(=O)[nH]1)C#N)c2ccncc2;
	InChI InChI=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) ; Key:PZRHRDRVRGEVNW-UHFFFAOYSA-N ;
Physical data
Density	1.344 g/cm3
Melting point	315 °C (599 °F)
Boiling point	449 °C (840 °F)
(what is this?) (verify)