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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/13 23:02:45」(JST)

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Milrinone, commonly known and marketed as the drug Primacor, is a medication used in patients suffering from heart failure. Milrinone is a phosphodiesterase-3 inhibitor that works to increase contractility in a failing heart. Milrinone also works to vasodilate vessels which helps alleviate increased pressures (afterload) on the heart thus improving the hearts pumping action. Milrinone has been used in those suffering from heart failure for many years. However, in recent studies the drug has been shown to exhibit some negative side effects that have caused some debate about its use clinically.

Background Information on Heart Failure and Contractility

Those suffering from heart failure have a significant decrease in the contractile ability of heart cells (cardiomyocytes). This impaired contractility occurs through a number of mechanisms. One 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 of Milrinone

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.

Conclusion

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 suffering from heart failure and an effective therapy to maintain heart function following cardiac surgeries.

Synthesis

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

References

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

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UpToDate Contents

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1. 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
2. 昇圧剤および強心剤の使用 use of vasopressors and inotropes
3. 急性非代償性心不全の治療：治療の要素 treatment of acute decompensated heart failure components of therapy
4. 心腎症候群：予後および治療 cardiorenal syndrome prognosis and treatment
5. 肺性心 cor pulmonale

English Journal

A clinical assay for the measurement of milrinone in plasma by HPLC mass spectrometry.

Chihoho B, Sage AB, Smolenski RT, Vazir A, Rose ML, Banner NR, Leaver NV.SourceRoyal Brompton and Harefield NHS Foundation Trust, Harefield, Middlesex, UK.
Biomedical chromatography : BMC.Biomed Chromatogr.2012 May;26(5):566-70. doi: 10.1002/bmc.1675. Epub 2011 Sep 8.
Milrinone is a bipyridine phosphodiesterase inhibitor with positive inotropic and vasodilatory effects. As interest in longer term use of intravenous therapy increases, it becomes essential to monitor its plasma concentration owing to a narrow therapeutic range, an increased half-life in renal failu
PMID 21905056

The natriuretic peptides BNP and CNP increase heart rate and electrical conduction by stimulating ionic currents in the sinoatrial node and atrial myocardium following activation of guanylyl cyclase-linked natriuretic peptide receptors.

Springer J, Azer J, Hua R, Robbins C, Adamczyk A, McBoyle S, Bissell MB, Rose RA.AbstractNatriuretic peptides (NPs) are best known for their ability to regulate blood vessel tone and kidney function whereas their electrophysiological effects on the heart are less clear. Here, we measured the effects of BNP and CNP on sinoatrial node (SAN) and atrial electrophysiology in isolated hearts as well as isolated SAN and right atrial myocytes from mice. BNP and CNP dose-dependently increased heart rate and conduction through the heart as indicated by reductions in R-R interval, P wave duration and P-R interval on ECGs. In conjunction with these ECG changes BNP and CNP (100nM) increased spontaneous action potential frequency in isolated SAN myocytes by increasing L-type Ca(2+) current (I(Ca,L)) and the hyperpolarization-activated current (I(f)). BNP had no effect on right atrial myocyte APs in basal conditions; however, in the presence of isoproterenol (10nM), BNP increased atrial AP duration and I(Ca,L). Quantitative gene expression and immunocytochemistry data show that all three NP receptors (NPR-A, NPR-B and NPR-C) are expressed in the SAN and atrium. The effects of BNP and CNP on SAN and right atrial myocytes were maintained in mutant mice lacking functional NPR-C receptors and blocked by the NPR-A antagonist A71915 indicating that BNP and CNP function through their guanylyl cyclase-linked receptors. Our data also show that the effects of BNP and CNP are completely absent in the presence of the phosphodiesterase 3 inhibitor milrinone. Based on these data we conclude that NPs can increase heart rate and electrical conduction by activating the guanylyl cyclase-linked NPR-A and NPR-B receptors and inhibiting PDE3 activity.
Journal of molecular and cellular cardiology.J Mol Cell Cardiol.2012 May;52(5):1122-34. Epub 2012 Feb 1.
Natriuretic peptides (NPs) are best known for their ability to regulate blood vessel tone and kidney function whereas their electrophysiological effects on the heart are less clear. Here, we measured the effects of BNP and CNP on sinoatrial node (SAN) and atrial electrophysiology in isolated hearts
PMID 22326431

Japanese Journal

併用療法(ドブタミンとミルリノン) (冠動脈疾患(下)診断と治療の進歩) -- (虚血性心筋症の臨床)

加藤真帆人,平山篤志
日本臨床 69 (1010増刊9), 428-433, 2011-11
NAID 40019062523

ミルリノンとカルペリチドの低用量併用療法を実施した重症心不全の犬5例 (日本獣医師会学会学術誌) -- (小動物臨床関連部門)

有田申二,有田昇,日笠喜朗
日本獣医師会雑誌 64(9), 728-732, 2011-09
NAID 40018977118

Related Pictures

★リンクテーブル★

リンク元	「100Cases 76」「ミルリノン」
拡張検索	「milrinone lactate」

「100Cases 76」

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 cat.	C (US)
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
Mol. 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
Melt. point	315 °C (599 °F)
Boiling point	449 °C (840 °F)
(what is this?) (verify);

　　[★]

☆case76　頭痛

■glossary

傾眠 drowsiness 正常、病的の区別なく眠り込む場合に用いられる

意識不鮮明　 confusion 周囲に対する認識や理解は低下し、思考の清明さや、記憶の正確さが失われる

錯乱　 confusion　夢幻様状態より見当識障害と思考の滅裂が見られる状態(PSY.40)

MA = Master of Arts 文学修士

　The Master of Arts (BrE: MA, UsE: M.A.) is awarded in Arts, Humanities, Theology and Social Sciences (Wikipedia)

graduate student 大学院生

rousable adj. 覚醒できる、目を覚ますことができる

rouse vt. ～の目を覚まさせる、呼び起こす。喚起する、鼓舞する、奮起させる。(感情を)起こさせる、かき立てる

lateralize vt. (生理)(大脳が)(左右半球に心的機能差がある、左右差がある。(器官・機能・活動などが)大脳の(左右いずれかの)片側優位下にある。(医学)(障害などが)大脳の片半球にあると診断される

乳頭浮腫 papilledema 原因を問わず視神経乳頭が腫脹している状態

うっ血乳頭 choked disc 脳圧亢進による乳頭浮腫

■症例

24歳、男性　精神学の修士過程を専攻している大学院生

主訴：激しい頭痛

現病歴：頭部全体に痛みがある。2回嘔吐。傾眠と錯乱が認められるようになった。明るい光を嫌う()he finds bright lights uncomfortable。

既往歴：病気の既往はない。アレルギーはない。タバコ1日10本。アルコール24 unit/week(缶ビール(350ml)13.7本/週)。薬は服用してない。

家族歴：彼女と同居。3歳と4歳の子供がいる。

・診察 examination

　見た感じ紅潮しており、調子が悪そう。体温：39.2℃。項部硬直あり(he has stiffness on passice flexion of his neck)。皮疹なし。副鼻腔に圧痛なし。鼓膜所見は正常。脈拍：120/分。血圧：98/74 mmHg。心血管系、胸部、腹部に異常所見なし(normal)。意識レベル低下。命令に応じて覚醒する(JCS10？)。局所神経症状認めない。眼底所見正常

・検査 investigation

　血液検査

　　白血球：上昇。血清 Na：低下。血清尿素：上昇。血清クレアチニン：上昇。血液培養：検査中

　画像検査

　　胸部X線：異常所見なし。頭部 CT：正常

　心電図：洞性頻脈

　腰椎穿刺

　　髄液所見：混濁。白血球：増多。蛋白：増多。糖：低下(普通の人の血糖100mg/dLと考える。→　1g/L　→　1/180　mol/L　→　5.56 mmol/L。グラム染色：結果待ち

■Q

　診断、鑑別診断、管理

■A

　細菌性髄膜炎、髄膜炎・クモ膜下出血、経験的抗菌薬投与・