Milrinone

Last updated
Milrinone
Milrinone.svg
Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a601020
Routes of
administration 		IV only
ATC code
Legal status
Legal status
  • EU:Rx-only [1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (as IV bolus, infusion)
Protein binding 70 to 80%
Metabolism Liver (12%)
Elimination half-life 2.3 hours (mean, in CHF)
Excretion Urine (85% as unchanged drug) within 24 hours
Identifiers
  • 2-Methyl-6-oxo-1,6-dihydro-3,4'-bipyridine-5-carbonitrile
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.071.709 OOjs UI icon edit-ltr-progressive.svg
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)
  • c1cnccc1-c2c(C)[nH]c(=O)c(C#N)c2
  • 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) Yes check.svgY
  • Key:PZRHRDRVRGEVNW-UHFFFAOYSA-N Yes check.svgY
   (verify)

Milrinone, sold under the brand name Primacor, is a pulmonary vasodilator [2] used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate 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 negative side effects that have caused some debate about its use clinically. [3] [4]

Contents

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 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 atrial arrhythmias. [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]

Contractility in the heart

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 of calcium. [10] 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. [11] 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. [12]

Mechanism of action

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 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. [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 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. [13]

Clinical use

Milrinone is a commonly used therapy for severe pulmonary arterial hypertension (PAH), [14] often in combination with other medications such as sildenafil. [15] Targeting PDE3 with optimal doses and timing, milrinone prevents allergic 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]

Adverse effects

Common adverse effects include ventricular arrhythmias (including ventricular ectopy and nonsustained ventricular tachycardia), supraventricular arrhythmias, hypotension, and headache. [18]

Synthesis

Thieme Patents: Journal syntheses: Sino ultramodern: Prec: Milrinone synthesis.svg
Thieme Patents: Journal syntheses: Sino ultramodern: Prec:

The reaction between 4-methylpyridine and methyl acetate gives 4-pyridyl acetone (4-acetonylpyridine) [6304-16-1] (1). The Knoevenagel condensation type reaction between this and DMF-dimethylacetal [4637-24-5] (2) affords CID:3018775 (3). Then base catalyzed reaction of this with cyanoacetamide (4) completes the synthesis of milrinone (5).

Related Research Articles

<span class="mw-page-title-main">Cardiac glycoside</span> Class of organic compounds

Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by inhibiting the cellular sodium-potassium ATPase pump. Their beneficial medical uses are as treatments for congestive heart failure and cardiac arrhythmias; however, their relative toxicity prevents them from being widely used. Most commonly found as secondary metabolites in several plants such as foxglove plants, these compounds nevertheless have a diverse range of biochemical effects regarding cardiac cell function and have also been suggested for use in cancer treatment.

<span class="mw-page-title-main">Premature ventricular contraction</span> Skipped beat with ventricular origin

A premature ventricular contraction (PVC) is a common event where the heartbeat is initiated by Purkinje fibers in the ventricles rather than by the sinoatrial node. PVCs may cause no symptoms or may be perceived as a "skipped beat" or felt as palpitations in the chest. PVCs do not usually pose any danger.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

<span class="mw-page-title-main">Sarcoplasmic reticulum</span> Menbrane-bound structure in muscle cells for storing calcium

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

<span class="mw-page-title-main">Cardiac muscle</span> Muscular tissue of heart in vertebrates

Cardiac muscle is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of the heart. The cardiac muscle (myocardium) forms a thick middle layer between the outer layer of the heart wall and the inner layer, with blood supplied via the coronary circulation. It is composed of individual cardiac muscle cells joined by intercalated discs, and encased by collagen fibers and other substances that form the extracellular matrix.

An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in Homo sapiens

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

<span class="mw-page-title-main">Phospholamban</span> Mammalian protein found in Homo sapiens

Phospholamban, also known as PLN or PLB, is a micropeptide protein that in humans is encoded by the PLN gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the calcium (Ca2+) pump in cardiac muscle cells.

<span class="mw-page-title-main">T-tubule</span> Extensions in cell membrane of muscle fibres

T-tubules are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. With membranes that contain large concentrations of ion channels, transporters, and pumps, T-tubules permit rapid transmission of the action potential into the cell, and also play an important role in regulating cellular calcium concentration.

Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of tissue, that is, between filaments of myosin (thick) and actin (thin) tissue. The degree of binding depends upon the concentration of calcium ions in the cell. Within an in vivo intact heart, the action/response of the sympathetic nervous system is driven by precisely timed releases of a catecholamine, which is a process that determines the concentration of calcium ions in the cytosol of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction.

<span class="mw-page-title-main">Levosimendan</span> Pharmaceutical drug

Levosimendan (INN) is a calcium sensitizer used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax. Overall the drug has a two fold mechanism of action. It leads to greater inotrophy by increasing the calcium sensitivity as it binds to troponin and this results in a greater positive inotrophic force. Secondly, the drug is able to open ATP sensitive potassium channels in vascular smooth muscle cells, and the vascular dilatory effects of the drug lead to a decreased preload and afterload, putting less work on the heart. This drug is in the process of review by the FDA but has not been approved for use in the United States yet.

Urocortin 2 (Ucn2) is an endogenous peptide in the corticotrophin-releasing factor (CRF) family.

<span class="mw-page-title-main">Amrinone</span> Chemical compound

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high-gain CICR, which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.

<span class="mw-page-title-main">Catecholaminergic polymorphic ventricular tachycardia</span> Medical condition

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.

<span class="mw-page-title-main">PDE3 inhibitor</span>

A PDE3 inhibitor is a drug which inhibits the action of the phosphodiesterase enzyme PDE3. They are used for the therapy of acute heart failure and cardiogenic shock.

<span class="mw-page-title-main">S100-A1</span> Protein-coding gene in the species Homo sapiens

Protein S100-A1, also known as S100 calcium-binding protein A1 is a protein which in humans is encoded by the S100A1 gene. S100A1 is highly expressed in cardiac and skeletal muscle, and localizes to Z-discs and sarcoplasmic reticulum. S100A1 has shown promise as an effective candidate for gene therapy to treat post-myocardially infarcted cardiac tissue.

Cardiac physiology or heart function is the study of healthy, unimpaired function of the heart: involving blood flow; myocardium structure; the electrical conduction system of the heart; the cardiac cycle and cardiac output and how these interact and depend on one another.

<span class="mw-page-title-main">Heart failure with preserved ejection fraction</span> Medical condition

Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the left ventricle is maximally filled – is normal, defined as greater than 50%; this may be measured by echocardiography or cardiac catheterization. Approximately half of people with heart failure have preserved ejection fraction, while the other half have a reduction in ejection fraction, called heart failure with reduced ejection fraction (HFrEF).

Calcium buffering describes the processes which help stabilise the concentration of free calcium ions within cells, in a similar manner to how pH buffers maintain a stable concentration of hydrogen ions. The majority of calcium ions within the cell are bound to intracellular proteins, leaving a minority freely dissociated. When calcium is added to or removed from the cytoplasm by transport across the cell membrane or sarcoplasmic reticulum, calcium buffers minimise the effect on changes in cytoplasmic free calcium concentration by binding calcium to or releasing calcium from intracellular proteins. As a result, 99% of the calcium added to the cytosol of a cardiomyocyte during each cardiac cycle becomes bound to calcium buffers, creating a relatively small change in free calcium.

References

  1. ↑ "Active substance: milrinone" (PDF). List of nationally authorised medicinal products. European Medicines Agency. 10 June 2022.
  2. ↑ Baxter FJ, Whippey A (November 2020). "Amniotic Fluid Embolism Treated With Inhaled Milrinone: A Case Report". A&A Practice. 14 (13): e01342. doi:10.1213/XAA.0000000000001342. PMID   33185413. S2CID   226851766.
  3. ↑ Packer M (December 1990). "Calcium channel blockers in chronic heart failure. The risks of "physiologically rational" therapy". Circulation. 82 (6): 2254–2257. doi:10.1161/01.cir.82.6.2254. PMID   2242549. S2CID   11255642.
  4. ↑ Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, et al. (November 1991). "Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group". The New England Journal of Medicine. 325 (21): 1468–1475. doi: 10.1056/NEJM199111213252103 . PMID   1944425.
  5. ↑ 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): 1619–1625. doi:10.1161/CIRCULATIONAHA.108.790162. PMC   2770257 . PMID   18824641.
  6. ↑ British National Formulary (66th ed.). London: BMJ Group and Pharmaceutical Press. September 2013.
  7. ↑ 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): 1322–1335. doi:10.1007/s00134-016-4449-6. PMC   4992029 . PMID   27448246.
  8. ↑ "Milrinone Dosage Guide + Max Dose, Adjustments". Drugs.com . Retrieved 2023-01-03.
  9. ↑ de Tombe PP (February 1998). "Altered contractile function in heart failure". Cardiovascular Research. 37 (2): 367–380. doi: 10.1016/s0008-6363(97)00275-7 . PMID   9614494.
  10. ↑ Ward ML, Crossman DJ (July 2014). "Mechanisms underlying the impaired contractility of diabetic cardiomyopathy". World Journal of Cardiology. 6 (7): 577–584. doi: 10.4330/wjc.v6.i7.577 . PMC   4110606 . PMID   25068018.
  11. ↑ Szent-Györgyi AG (July 1975). "Calcium regulation of muscle contraction". Biophysical Journal. 15 (7): 707–723. Bibcode:1975BpJ....15..707S. doi:10.1016/S0006-3495(75)85849-8. PMC   1334730 . PMID   806311.
  12. ↑ King J, Lowery DR (2022). "Physiology, Cardiac Output". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   29262215.
  13. 1 2 Zimmerman J, Cahalan M (January 2013). "Chapter 22 - Vasopressors and Inotropes". In Hemmings HC, Egan TD (eds.). Pharmacology and Physiology for Anesthesia. Philadelphia: W.B. Saunders. pp. 390–404. doi:10.1016/B978-1-4377-1679-5.00022-3. ISBN   978-1-4377-1679-5. S2CID   79282649 . Retrieved 2023-03-14.
  14. ↑ 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.
  15. ↑ Hui-li G (June 2011). "The management of acute pulmonary arterial hypertension". Cardiovascular Therapeutics. 29 (3): 153–175. doi: 10.1111/j.1755-5922.2009.00095.x . PMID   20560976.
  16. ↑ Beute J, Lukkes M, Koekoek EP, Nastiti H, Ganesh K, de Bruijn MJ, et al. (January 2018). "A pathophysiological role of PDE3 in allergic airway inflammation". JCI Insight. 3 (2). doi: 10.1172/jci.insight.94888 . PMC   5821178 . PMID   29367458.
  17. ↑ Arbeus M, Axelsson B, Friberg O, Magnuson A, Bodin L, Hultman J (February 2009). "Milrinone increases flow in coronary artery bypass grafts after cardiopulmonary bypass: a prospective, randomized, double-blind, placebo-controlled study". Journal of Cardiothoracic and Vascular Anesthesia. Elsevier BV. 23 (1): 48–53. doi:10.1053/j.jvca.2008.07.005. PMID   18834820.
  18. ↑ "Milrinone Lactate Monograph". drugs.com.
  19. ↑ BE886336 idem G. Y. Lesher, R. E. Philion, U.S. patent 4,313,951 (1982 both to Sterling).
  20. ↑ US 4264603,Lesher GY, Gruett MD,issued 1981, assigned to Sterling Drug Inc.
  21. ↑ US 4413127,Singh B,issued 1983, assigned to Sterling
  22. ↑ Singh B (1985). "A Novel Synthesis of 1,6-Dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile (Milrinone)". Heterocycles. 23 (6): 1479. doi:10.3987/R-1985-06-1479 (inactive 2024-02-17).{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link)
  23. ↑ Shiao MJ, Shyu LM, Chen CF (1990). "Synthesis of Milrinone, a Cardiotonic Agent". Heterocycles. 31 (3): 523. doi:10.3987/COM-89-5276 (inactive 2024-02-17).{{cite journal}}: CS1 maint: DOI inactive as of February 2024 (link)
  24. ↑ CN 104326975,Yan H, Deng A,"Preparation method of high-purity milrinone",issued 2015, assigned to ZHENGZHOU SIHUAN MEDICINE ARTICLE Co Ltd
  25. ↑ CN 104387320,Ao L, Zhang B, Pan J, Chen Y,"Preparation Method for High-Purity Milrinone",issued 2018, assigned to Huzhou Zhanwang Pharmaceutical Co., Ltd.
  26. ↑ CN 103848779,Tan X, Jing Y, Wang F, Liu H, Yu U,"Preparation method of 1-(4-pyridyl) acetone",issued 2014, assigned to University of Jinan
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.