Pharmacology of levosimendan: inotropic, vasodilatory and cardioprotective effects

Abstract

SUMMARYWhat is known and objective: Positive inotropic agents are frequently used in acute decompensated heart failure (ADHF) due to left ventricular systolic dysfunction. These agents are known to improve cardiac performance and peripheral perfusion in the short-term treatment. However, several preclinical and clinical studies emphasized detrimental effects of these drugs on myocardial oxygen demand and on sympathetic tone entailing arrhythmogenesis. Levosimendan is an inotropic agent with an original mechanism of action. This review focuses on major data available for levosimendan. Methods: A literature search was conducted in the PubMed database by including studies published in English using combinations of the following key words, levosimendan, inotropic drugs and acute heart failure. Furthermore, bibliographies of selected references were also evaluated for relevant articles. The collection for this review was limited to the most recently available human and animal data. Results and discussion: Levosimendan's vasodilatory and cardioprotective effects are mediated by calcium sensitization of contractile proteins and opening of adenosine triphosphate (ATP)-dependent K+ channels in vascular smooth muscle cells and on mitochondrial ATP-sensitive potassium [mito.K(ATP)] channels. This inotropic agent has mild PDE inhibitory action. Unlike other inotropic agents, levosimendan improves cardiac performance without activating the sympathetic nervous system. Moreover, there are evidences that levosimendan has additional anti-inflammatory and anti-apoptotic properties that prevent cardiac toxicity and contributes to positive hemodynamic response of the drug. Four randomized trials evaluated the effects of levosimendan on mortality in patients with acute decompensated chronic heart failure; nevertheless, a clear benefit has not been demonstrated so far. Although levosimendan is indicated for the treatment of ADHF (class of recommendation IIa, level of evidence B), it is has not been approved in all countries.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

“…Stosowanie lewosimendanu jest preferowane w stosunku do dobutaminy w celu odwrócenia efektu zablokowania receptorów β-adrenergicznych, jeżeli uprzednie podawanie LBA uważa się za główną przyczynę hipoperfuzji [572]. Jednocześnie lewosimendan jest lekiem rozszerzającym naczynia, czyli nie jest odpowiedni w terapii pacjentów z hipotonią (SBP < 85 mm Hg) lub wstrząsem kardiogennym, chyba że w połączeniu z innymi lekami inotropowymi lub obkurczającymi naczynia [559,573,574]. Leki inotropowe, zwłaszcza te działające w mechanizmie adrenergicznym, mogą powodować tachykardię zatokową oraz wywoływać niedokrwienie mięśnia sercowego i zaburzenia rytmu serca, dlatego wymagane jest monitorowanie EKG w trakcie ich podawania.…”

Inotropes and vasopressors

“…Vasodilation is caused by decreasing the myofilaments sensitivity in smooth muscles to calcium and by activating ATP-dependent potassium channels which results in hyperpolarization, decreased Ca2+entry and vasodilation (16). These effects occur without an increase in intracellular cAMP or calcium (29,30). Therefore, it does not impair diastolic relaxation and cardiac rhythm (1,30).…”

“…Further studies are necessary and large clinical trials are currently being conducted in order to investigate the role of levosimendan in the treatment of severely ill patients other than those with heart failure and those undergoing cardiac surgery where the role of this drug is already well determined. Levosimendan has a short elimination half-life, but its metabolite OR-1896, which has similar calcium-sensitizing effect as levosimendan, hasa much longer elimination half-life of around 96 hours (18,29). It is administered as a continuous infusion, mostly without a loading dose, over 24-hours.…”

“…Effects of levosimendan are dose-dependent. It is administered at infusion rates of 0.05-0.6 μg/ kg/min (14,29). At rates higher than 0.2 μg/kg/min, there is a greater incidence of side effects such as headache, nausea and hypotension (30).…”

Use of levosimendan in cardiogenic shock

“…Due to the failure of classic inotrope agents, a sensitizer agent, levosimendan, has been used as rescue therapy in such situations. This drug has both positive inotropic and myocardial relaxing properties, which increase the affinity of myofilaments within the myocardial cell to calcium without raising intracellular concentrations of calcium or AMPc [5][6][7][8] . Levosimendan can improve the hemodynamic status of patients with CS without increasing the consumption of myocardial oxygen and without increasing the risk of arrhythmia 9,10 ; however, few studies have been conducted on the use of levosimendan to treat CS.…”