Indications
Levosimendan is used primarily for the short-term treatment of acutely decompensated severe chronic heart failure (CHF). It is also under investigation for potential applications in the treatment of various heart diseases.
Pharmacodynamics
Levosimendan is classified as a calcium (Ca2+)-sensitizing inotropic agent, representing a novel category of cardiovascular drugs. Unlike many traditional inotropic agents, levosimendan enhances myocardial contractility without increasing the risk of arrhythmias or cellular damage frequently caused by calcium overload in cardiac cells. It does not raise activation energy and may help reverse contractile dysfunction in certain pathophysiological conditions, such as acidosis or myocardial stunning. It is important to note that levosimendan has not yet received approval for use in the United States or Canada.
Absorption
The absorption of levosimendan demonstrates high bioavailability. In healthy individuals, the oral bioavailability is approximately 85 ± 6%, while in patients, it is relatively consistent at 84 ± 4%.
Metabolism
Levosimendan undergoes complete metabolism in the body. Its metabolism results in the formation of active metabolites, specifically OR-1855 and OR-1896, which may contribute to the prolongation of the drug's hemodynamic effects.
Mechanism of Action
Levosimendan functions by enhancing myofilament calcium sensitivity through its binding to cardiac troponin C in a calcium-dependent manner. This interaction stabilizes the calcium-induced conformational change in troponin C, which in turn affects actin-myosin cross-bridge kinetics without significantly altering the cycling rate of the cross-bridges or increasing myocardial ATP consumption. As a result, there is an increased impact of calcium on cardiac myofilaments during systole, facilitating enhanced contraction at a low energy cost, characterized by its inotropic effect. During diastole, the calcium concentration decreases, which reduces sensitization and allows for normal or improved diastolic relaxation. Furthermore, levosimendan induces vasodilation by activating ATP-sensitive potassium channels. Through its combined inotropic and vasodilatory properties, levosimendan effectively boosts cardiac output without elevating myocardial oxygen demand. Additionally, levosimendan exhibits selective inhibition of phosphodiesterase (PDE)-III, contributing to its inotropic effects under specific experimental conditions. Studies indicate that levosimendan may act primarily as a calcium sensitizer at lower concentrations, while its role as a PDE-III inhibitor becomes more pronounced at higher concentrations in both experimental animal models and human studies.
