ミルリノン

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

0.4

0.42

<1 mg/mL

2.09e-01 g/L

>300 °C

> 300 °C

157.1 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: APCI+; Dataset: TOXCAST; Source Identifier: DTXSID5023324]

150.4 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Danger

H301+H311+H331 (38.4%): Toxic if swallowed, in contact with skin or if inhaled [Danger Acute toxicity, oral; acute toxicity, dermal; acute toxicity, inhalation]

P261, P262, P264, P270, P271, P280, P301+P316, P302+P352, P304+P340, P316, P321, P330, P361+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 73 reports by companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The most feared adverse effect of milrinone is its potential to induce hemodynamic changes and arrhythmias. Milrinone may cause ventricular tachyarrhythmia, leading to cardiac ischemia or sudden cardiac death. These changes are not shown to follow a dose-dependent relationship. Milrinone can cause an increase in venous vessel capacitance, leading to decreased preload and manifesting as headaches, syncope, and severe hypotension. Unlike tachyarrhythmias, hypotension occurs in a dose-dependent relationship.

Cardiovascular toxicity is primarily seen in chronically milrinone patients and manifests as tachyarrhythmias and sudden cardiac death. At high dosing, patients may also experience hypotension and syncope. Milrinone had a previous use as an oral formulation for outpatient use in patients with NYHA class III and IV chronic heart failure (CHF) to improve symptoms and decrease the frequency of hospital admissions. However, this practice was discontinued following the PROMISE trial in 1991 due to safety concerns. This double-blinded clinical trial assessed patients with CHF class III/IV placed on milrinone or placebo and ended early due to increased mortality in the milrinone group secondary to ventricular tachyarrhythmias and sudden cardiac death.

C01CE02

C - Cardiovascular system

QC - Cardiovascular system

Milrinone is a bipyridine derivative with positive inotropic and lusitropic effects that also results in peripheral vasodilation with minimal chronotropic effects over a therapeutic range of 100 to 300 ng/mL. As such, milrinone is used in decompensated congestive heart failure. Studies have demonstrated that milrinone exhibits sigmoidal effects, such that increasing milrinone plasma concentrations beyond a certain level results in no further hemodynamic changes. Despite milrinone's benefits, both intravenous and oral use has been associated with increased frequency of ventricular arrhythmias, and long-term oral use has been associated with an increased risk of sudden death; in general, there are no data to support the safety or efficacy of milrinone use beyond 48 hours and patients should be monitored closely for cardiac dysfunction. Also, as milrinone is primarily excreted renally, dose adjustments may be required in patients with impaired renal function.

Heart failure is a condition characterized by the heart's inability to provide adequate perfusion to the peripheral tissues, resulting in systemic symptoms including pulmonary, gastrointestinal, renal, and cerebral dysfunction. Although the biochemical and physiological processes underlying heart failure complex and variable, one such physiological response regulated by the sympathetic nervous system involves the eventual downregulation of cardiac β-receptors, decreased catecholamine sensitivity, and a corresponding decrease in adenylyl-cyclase-mediated signalling pathways. Increased intracellular cAMP, mainly acting through protein kinase A, increases sarcolemmal calcium release through L-type calcium channels as well as calcium re-uptake mediated by phospholamban and troponin I; these actions correspond to positive inotropic and lusitropic effects, respectively. Milrinone is a partial competitive inhibitor of phosphodiesterase III (PDE-III), with a measured IC₅₀ value of between 0.66 and 1.3 μM. As a PDE-III inhibitor, milrinone results in an increase in intracellular cAMP, responsible for its pharmacological effects, including positive inotropy, positive lusitropy, and vasodilation. As milrinone affects cAMP levels through PDE-III and not through β-adrenergic receptors, it is effective in patients who have downregulated or otherwise desensitized β-adrenergic receptors and can be administered together with β-agonists/antagonists.