indication

For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease.

pharmacology

Levosimendan is a new Ca²⁺-sensitizing inotropic agent. Ca²⁺ sensitizers represent a new class of inotropic agents, which overcome the disadvantages associated with currently available inotropic agents in as they are not associated with an increased risk of arrhythmias, cell injury and death due to Ca²⁺ overload in myocardial cells; they do not increase the activation energy; and they have the potential to reverse contractile dysfunction under pathophysiologic conditions, such as acidosis or myocardial stunning. Levosimendan has not been approved for use in the U.S. or Canada.

mechanism of action

Levosimendan appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This stabilizes the calcium-induced conformational change of troponin C, thereby (1) changing actin-myosin cross-bridge kinetics apparently without increasing the cycling rate of the cross-bridges or myocardial ATP consumption, (2) increasing the effects of calcium on cardiac myofilaments during systole and (3) improving contraction at low energy cost (inotropic effect). Calcium concentration and, therefore, sensitization decline during diastole, allowing normal or improved diastolic relaxation. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic effect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca²⁺ sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent in experimental animals and humans.

biotransformation

Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects.

absorption

The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients.

half life

Eliminination half-life is approximately 1 hour.