Indications
Milrinone is approved for the short-term management of patients experiencing acute decompensated heart failure. Its usage is recommended for a duration not exceeding 48 hours. Administration should be performed in a clinical setting that allows for close monitoring using electrocardiographic equipment to promptly address potential cardiac events, including the risk of ventricular arrhythmias.
Pharmacodynamics
Pharmacologically, milrinone is a bipyridine derivative known for its positive inotropic and lusitropic properties, which result in peripheral vasodilation. It operates within a therapeutic concentration range of 100 to 300 ng/mL, exerting minimal effects on heart rate. This makes it valuable in addressing decompensated congestive heart failure. The drug demonstrates sigmoidal pharmacodynamics, whereby increases in plasma concentration beyond a certain point confer no additional hemodynamic advantage. While beneficial, milrinone's intravenous and oral use may be associated with a heightened incidence of ventricular arrhythmias, and long-term oral administration correlates with an elevated risk of sudden death. The data do not support the safety or efficacy of continued use beyond 48 hours, necessitating careful monitoring for cardiac dysfunction. Owing to its predominant renal excretion, dose adjustments are prudent in patients with compromised renal function.
Absorption
When administered intravenously at a bolus dose ranging from 10 to 100 μg/kg, milrinone produces noticeable hemodynamic effects within 60 seconds, with peak effects observed between 2 to 5 minutes. The area under the plasma concentration-time curve (AUC) is notably dependent on the dose administered.
Metabolism
Studies conducted on animals indicate that milrinone undergoes metabolism through two oxidative pathways, though these pathways process only a minor fraction of the administered dose. The principal metabolite formed is the O-glucuronide metabolite.
Mechanism of Action
Milrinone functions as a partial competitive inhibitor of phosphodiesterase III (PDE-III), with an IC50 ranging from 0.66 to 1.3 μM. By inhibiting PDE-III, milrinone elevates intracellular cAMP levels, which directly contributes to its pharmacological effects, such as enhanced cardiac contractility (positive inotropy), improved cardiac relaxation (positive lusitropy), and vasodilation. This mechanism of action is particularly beneficial in patients with heart failure, who often exhibit downregulated or desensitized β-adrenergic receptors due to prolonged sympathetic nervous system activation. Unlike agents that act through β-adrenergic receptors, milrinone's action on cAMP is independent of these receptors, allowing it to be effectively combined with β-agonists or antagonists. Consequently, milrinone provides a unique therapeutic option for improving cardiac function and perfusion in patients with compromised β-adrenergic signaling.
