Milrinone

Milrinone
Names
IUPAC name
  • 2-Methyl-6-oxo-1,6-dihydro-3,4'-bipyridine-5-carbonitrile
Clinical data
Drug classPhosphodiesterase 3 inhibitor[1]
Main usesHeart failure[2]
Side effectsVentricular arrhythmia, low blood pressure, headache[2]
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		IV only
    External links
    AHFS/Drugs.comMonograph
    US NLMMilrinone
    MedlinePlusa601020
    Legal
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability100% (as IV bolus, infusion)
    Protein binding70 to 80%
    MetabolismLiver (12%)
    Elimination half-life2.3 hours (mean, in CHF)
    ExcretionUrine (85% as unchanged drug) within 24 hours
    Chemical and physical data
    FormulaC12H9N3O
    Molar mass211.224 g·mol−1
    3D model (JSmol)
    Density1.344 g/cm3
    Melting point315 °C (599 °F)
    SMILES
    • c1cnccc1-c2c(C)[nH]c(=O)c(C#N)c2
    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) checkY
    • Key:PZRHRDRVRGEVNW-UHFFFAOYSA-N checkY

    Milrinone, sold under the brand name Primacor, is a medication used to treat heart failure.[2] It may be used short term in those in who other medications are not sufficient.[2] It is given by injection into a vein.[2]

    Common side effects include ventricular arrhythmia, low blood pressure, and headache.[2] Other side effects may include low potassium and long term use may increase death.[2] It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decreases vascular resistance.[1]

    Milrinone was approved for medical use in the United States in 1987.[2] It is available as a generic medication.[1] In the United Kingdom 10 mg cost the NHS about £20 as of 2021.[1] In the United States this amount costs about 5 USD.[3]

    Medical use

    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.[4]

    In critically ill with evidence of cardiac dysfunction there is limited good quality evidence to recommend its use.[5]

    Milrinone is a commonly used therapy for severe pulmonary arterial hypertension (PAH),[6] often in combination with other medications such as sildenafil.[7]

    Dosage

    It is given as an initial dose of 50 ucg/kg over 10 minutes followed by 0.375 to 0.75 ucg/kg/min.[1]

    Milrinone is administered IV only and eliminated unchanged in the urine. Dose adjustment is required for people with kidney impairment.

    Side effects

    Common adverse effects include ventricular arrhythmias (including ventricular ectopy and nonsustained ventricular tachycardia), supraventricular arrhythmias, hypotension, and headache.[8]

    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.[9]

    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.

    References

    1. 1 2 3 4 5 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 210. ISBN 978-0857114105.
    2. 1 2 3 4 5 6 7 8 "Milrinone Monograph for Professionals". Drugs.com. Archived from the original on 21 January 2021. Retrieved 18 November 2021.
    3. ↑ "Milrinone Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 20 April 2021. Retrieved 18 November 2021.
    4. ↑ British National Formulary. 66 ed. London: BMJ Group and Pharmaceutical Press; Sept 2013
    5. ↑ Koster G, Bekema HJ, Wetterslev J, Gluud C, Keus F, van der Horst IC (September 2016). "Milrinone for cardiac dysfunction in critically ill adult patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis". Intensive Care Medicine. 42 (9): 1322–35. doi:10.1007/s00134-016-4449-6. PMC 4992029. PMID 27448246.
    6. ↑ McNamara PJ, Shivananda SP, Sahni M, Freeman D, Taddio A (January 2013). "Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide". Pediatric Critical Care Medicine. 14 (1): 74–84. doi:10.1097/PCC.0b013e31824ea2cd. PMID 23132395. S2CID 7696208.
    7. ↑ Hui-li G (June 2011). "The management of acute pulmonary arterial hypertension". Cardiovascular Therapeutics. 29 (3): 153–75. doi:10.1111/j.1755-5922.2009.00095.x. PMID 20560976.
    8. ↑ "Milrinone Lactate Monograph". drugs.com. Archived from the original on 2019-04-19. Retrieved 2021-10-21.
    9. ↑ Fleming GA, Murray KT, Yu C, Byrne JG, Greelish JP, Petracek MR, et al. (October 2008). "Milrinone use is associated with postoperative atrial fibrillation after cardiac surgery". Circulation. 118 (16): 1619–25. doi:10.1161/CIRCULATIONAHA.108.790162. PMC 2770257. PMID 18824641.
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