|Drug class||Phosphodiesterase 3 inhibitor|
|Main uses||Heart failure|
|Side effects||Ventricular arrhythmia, low blood pressure, headache|
|Bioavailability||100% (as IV bolus, infusion)|
|Protein binding||70 to 80%|
|Elimination half-life||2.3 hours (mean, in CHF)|
|Excretion||Urine (85% as unchanged drug) within 24 hours|
|Chemical and physical data|
|Molar mass||211.224 g·mol−1|
|3D model (JSmol)|
|Melting point||315 °C (599 °F)|
Milrinone, sold under the brand name Primacor, is a medication used to treat heart failure. It may be used short term in those in who other medications are not sufficient. It is given by injection into a vein.
Common side effects include ventricular arrhythmia, low blood pressure, and headache. Other side effects may include low potassium and long term use may increase death. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decreases vascular resistance.
Milrinone was approved for medical use in the United States in 1987. It is available as a generic medication. In the United Kingdom 10 mg cost the NHS about £20 as of 2021. In the United States this amount costs about 5 USD.
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.
In critically ill with evidence of cardiac dysfunction there is limited good quality evidence to recommend its use.
It is given as an initial dose of 50 ucg/kg over 10 minutes followed by 0.375 to 0.75 ucg/kg/min.
Milrinone is administered IV only and eliminated unchanged in the urine. Dose adjustment is required for people with kidney impairment.
Mechanism of action
Overall, milrinone supports ventricular functioning of the heart by decreasing the degradation of cyclic adenosine monophosphate (cAMP) and thus increasing phosphorylation levels of many components in the heart that contribute to contractility and heart rate. Milrinone is used as a drug that causes positive ionotrophy 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 arrhythmias.
cAMP causes increased activation of protein kinase A (PKA). PKA is an enzyme that phosphorylates many elements of the contractile machinery within the heart cell. In the short term this leads to an increased force of contraction. Phosphodiesterases are enzymes 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.
Milrinone is a phosphodiesterase-3 inhibitor. This drug inhibits the action of phosphodiesterase-3 and thus prevents degradation of cAMP. 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 myofilaments. Phosphorylation of calcium channels permits an increase in calcium influx into the cell. This increase in calcium influx results in 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.
Contractility of the heart
People experiencing some forms of heart failure have a significant decrease in the contractile ability of muscle cells in the heart (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 can cause many systemic implications such as fatigue, syncope and other issues associated with decreased blood flow to peripheral tissues.
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