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| Clinical data | |
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| AHFS/Drugs.com | Monograph |
| MedlinePlus | a601020 |
| Routes of administration | IV only |
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| Pharmacokinetic data | |
| Bioavailability | 100% (as IV bolus, infusion) |
| Protein binding | 70 to 80% |
| Metabolism | Liver (12%) |
| Eliminationhalf-life | 2.3 hours (mean, in CHF) |
| Excretion | Urine (85% as unchanged drug) within 24 hours |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.071.709 |
| Chemical and physical data | |
| Formula | C12H9N3O |
| Molar mass | 211.224 g·mol−1 |
| 3D model (JSmol) | |
| Density | 1.344 g/cm3 |
| Melting point | 315 °C (599 °F) |
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Milrinone, sold under the brand namePrimacor, is a pulmonary vasodilator[2] used in patients who haveheart failure. It is aphosphodiesterase 3 inhibitor that works to increase theheart's contractility and decrease pulmonary vascular resistance. Milrinone also works tovasodilate 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, studies suggest that milrinone may exhibit some negativeside effects that have caused some debate about its use clinically.[3][4]
Overall, milrinone supportsventricular functioning of the heart by decreasing the degradation ofcyclic adenosine monophosphate (cAMP) and thus increasing phosphorylation levels of many components in the heart that contribute to contractility andheart rate. 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 atrialarrhythmias.[5] 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.[6] In critically ill patients with evidence of cardiac dysfunction there is limited good quality evidence to recommend its use.[7]
Milrinone is administered IV only and eliminated unchanged in the urine. Dose adjustment is required for patients with renal impairment.[8]
People experiencing some forms of heart failure have a significant decrease in the contractile ability of muscle cells in the heart (cardiomyocytes).[9] 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 ofcalcium.[10] Calcium permitsmyosin andactin 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.[11] When contractility is decreased the amount of blood being pumped out of the heart intocirculation is decreased as well. This reduction incardiac output can cause many systemic implications such asfatigue,syncope and other issues associated with decreased blood flow to peripheral tissues.[12]
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 ofprotein kinase A (PKA). PKA is an enzyme thatphosphorylates many elements of the contractile machinery within the heart cell. In the short term this leads to an increased force of contraction.Phosphodiesterases areenzymes 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.[13]
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 themyofilaments. Phosphorylation ofcalcium channels permits an increase in calcium influx into the cell. This increase in calcium influx results in increased contractility. PKA also phosphorylatespotassium channels promoting their action. Potassium channels are responsible forrepolarization of the cardiomyocytes therefore increasing the rate at which cells candepolarize 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.[13]
Milrinone is a commonly used therapy for severepulmonary arterial hypertension (PAH),[14] often in combination with other medications such assildenafil.[15]Targeting PDE3 with optimal doses and timing, milrinone preventsallergic inflammation in HDM-driven models of allergic airway inflammation.[16]
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.[17]
Common adverse effects includeventricular arrhythmias (includingventricular ectopy andnonsustained ventricular tachycardia),supraventricular arrhythmias,hypotension, andheadache.[18]
The reaction between4-methylpyridine andmethyl acetate gives 4-pyridyl acetone (4-acetonylpyridine) [6304-16-1] (1). TheKnoevenagel condensation type reaction between this and DMF-dimethylacetal [4637-24-5] (2) affordsCID:3018775 (3). Then base catalyzed reaction of this withcyanoacetamide (4) completes the synthesis of milrinone (5).
