Milrinone

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 Y
ATC code	C01CE02
PubChem	CID 4197
DrugBank	DB00235
ChemSpider	4052 Y
UNII	JU9YAX04C7 Y
KEGG	D00417 Y
ChEBI	CHEBI:50693 Y
ChEMBL	CHEMBL189 Y
Chemical data
Formula	C12H9N3O
Mol. mass	211.219 g/mol
SMILES	eMolecules & PubChem
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) Y Key:PZRHRDRVRGEVNW-UHFFFAOYSA-N Y
Physical data
Density	1.344 g/cm³
Melt. point	315 °C (599 °F)
Boiling point	449 °C (840 °F)
Y (what is this?)  (verify)

Milrinone, commonly known and marketed as the drug Primicor, 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 of 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 increase 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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