Levosimendan: A New Inodilatory Drug for the Treatment of Decompensated Heart Failure

Abstract

Levosimendan is a new calcium sensitizer developed for the treatment of congestive heart failure. Experimental studies indicate that levosimendan increases myocardial contractility and dilates both the peripheral and coronary vessels. Its positive inotropic effect is based on calcium-dependent binding of the drug to cardiac troponin C. It also acts as an opener of ATP-dependent potassium channels in vascular smooth muscle, thus inducing vasodilation. Although levosimendan acts preferentially as a calcium sensitizer it has also demonstrated selective phosphodiesterase III inhibitory effects in vitro. However, this selective inhibition does not seem to contribute to the positive action at pharmacologically relevant concentrations. Levosimendan has an active metabolite, OR-1896. Similarly to levosimendan, the metabolite exerts its positive inotropic and vasodilatory effects on myocardium and vasculature. The elimination half-life of levosimendan is about 1 hour. Thus, with intravenous administration, the parent drug rapidly disappears from the circulation after the infusion is stopped. The active metabolite, however, has a half-life of approximately 80 hours, and can be detected in circulation up to 2 weeks after stopping a 24-hour infusion of levosimendan. The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure. Both patients with ischemic and non-ischemic etiology have participated in the studies. Levosimendan produces significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance. With a loading dose, the effects on PCWP and cardiac ouput are seen within few minutes. There is no sign of development of tolerance even with a prolonged infusion up to 48 hours. Cardiac performance is improved with no significant increases in oxygen consumption or potentially malignant rhythm disorders. Due to the formation of an active metabolite, the hemodynamic effects are maintained up to several days after stopping levosimendan infusion. Compared to dobutamine, levosimendan produces similar increase in cardiac output but profoundly greater decrease in pulmonary capillary wedge pressure. On the contrary to dobutamine, the hemodynamic effects are not attenuated with concomitant beta-blocker use. Levosimendan has been shown to have favourable effects on symptoms of heart failure superior to placebo and at least comparable to dobutamine. Mortality and morbidity in levosimendan treated patients has been shown to be significantly lower when compared to dobutamine or placebo treated patients. The most common adverse events associated with levosimendan treatment are headache and hypotension, as a likely consequence of the vasodilating properties of the compound. In conclusion, levosimendan offers a new effective option for the treatment of acutely decompensated heart failure. Unlike traditio...

Perioperative Levosimendan Therapy Is Associated With a Lower Incidence of Acute Kidney Injury After Cardiac Surgery

“…Some of these studies have shown that the drug can increase cardiac output and renal blood flow (RBF) and reduce AKI incidence. [8][9][10][11] Levosimendan is a new inotrope, a pyridazinone-dinitrile derivative belonging to a group of calcium sensitizers. It binds to troponin C and facilitates a Ca 2+ -induced activation of the contractile apparatus in cardiac muscle.…”

Evoked Changes in Cardiovascular Function in Rats by Infusion of Levosimendan, OR-1896 [(R)-N-(4-(4-Methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide], OR-1855 [(R)-6-(4-Aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one], Dobutamine, and Milrinone: Comparative Effects on Peripheral Resistance, Cardiac Output, dP/dt, Pulse Rate, and Blood Pressure

“…Indeed, the i.v. formulation of levosimendan has been investigated in several clinical trials in subjects with decompensated heart failure (Kivikko and Lehtonen, 2005), whereby both efficacy and tolerability have been demonstrated in patients with heart failure resulting from either an ischemic or nonischemic etiology (Follath et al, 2002;Moiseyev et al, 2002). Efficacious plasma concentrations of levosimendan were assessed in an open-label, nonrandomized, Phase II study in patients diagnosed with heart failure (New York Health Association III-IV); a 24-h continuous infusion of levosimendan produced peak plasma concentrations of 62.6 ng/ml, and peak concentrations of OR-1896 and OR-1855, the two primary circulating metabolites of levosimendan, reached 5.5 and 6.8 ng/ml, respectively (Kivikko et al, 2002).…”

Classical inotropes and new cardiac enhancers

“…Levosimendan seems to augment cardiac contractile performance by increasing myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This mechanistic effect leads to the stabilization of calcium-induced conformational changes of troponin C and modification of actin-myocin cross-bridge kinetics, without causing an increase in cycling rate of the cross-bridges or myocardial ATP consumption [22,23]. Moreover, levosimendan is a powerful opener of ATP-sensitive potassium channels causing peripheral arterial and venous dilatation.…”

“…This biologic action is responsible for the drug-induced reduction of peripheral vascular resistance and cardiac after load. Thus, levosimendan can lead to significant increase of cardiac output through its combined positive inotropic and peripheral vasodilatory properties [22,23]. Levosimendan seems to substantially increase the diastolic coronary flow velocity and reserve via the activation of ATP-sensitive potassium channels on coronary vasculature.…”

“…A loading dose of drug should be avoided in patients with systolic blood pressure less than 90 mmHg. Due to the accumulation of OR-1896, a drug infusion for time interval longer than 24 h is not recommended [20][21][22][23].…”