Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-76fb5796d-vvkck Total loading time: 0 Render date: 2024-04-29T14:54:46.681Z Has data issue: false hasContentIssue false

8 - Levosimendan

Published online by Cambridge University Press:  15 December 2009

By
Scott Mercer  and
Andrew Rhodes
Edited by
Jeremy Cashman  and
Michael Grounds
Scott Mercer
Affiliation:
Pharmacy St Thomas' Hospital Lambeth Palace Road London SEI 7EH UK
Andrew Rhodes
Affiliation:
St George's Hospital Blackshaw Road London SW17 0QT UK
Jeremy Cashman
Affiliation:
St George's Hospital, London
Michael Grounds
Affiliation:
St George's Hospital, London
Get access

Summary

Calcium sensitisers are a new class of positive inotropic drugs that are potentially useful in the treatment of acute decompensated heart failure. They have a unique mechanism of action that differs from other available intravenous agents such as dobutamine, a β-agonist, and milrinone, a phosphodiesterase inhibitor. Unlike dobutamine and milrinone, calcium sensitisers increase myocardial contractility without increasing cytosolic calcium release, reducing myocardial energy demand and the incidence of serious arrhythmias. Clinical trials have focused on demonstrating improved survival with levosimendan when compared to placebo and dobutamine. Levosimendan is the first intravenous calcium sensitiser to be approved in Europe for the treatment of acute decompensated heart failure.

Pharmacology

Chemical structure

Levosimendan is a pyridazinone-dinitrile derivative with the chemical name ((R) − (4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl)hydrazono)propanedinitrile. Levosimendan is the levo-isomer of the racemic compound simendan. It is moderately lipophilic with a small molecular weight (280.29) and is a weak acid (pKa 6.26).

Pharmacological action

β-adrenergic agonists and phosphodiesterase inhibitors produce positive inotropic effects by increasing intracellular concentrations of free calcium. This energy-dependent process involves increasing the intracellular concentration of cyclic adenosine monophosphate (cAMP). Levosimendan has a dual mechanism of action, acting as a positive inotrope and a vasodilator. The positive inotropic effect of levosimendan is achieved by calcium sensitisation rather than increasing intracellular free calcium concentration, therefore avoiding the energy-dependent process. Levosimendan binds to cardiac troponin C and stabilises the conformational changes of troponin C, facilitating actin-myosin cross-bridge formation. This binding occurs in a calcium concentration-dependent manner.

Type
Chapter
Information
Recent Advances in Anaesthesia and Intensive Care , pp. 131 - 142
Publisher: Cambridge University Press
Print publication year: 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ng, TMH. Levosimendan, a new calcium-sensitizing inotrope for heart failure. Pharmacotherapy 2004; 24: 1366–84.CrossRefGoogle ScholarPubMed
Sorsa, T, Heikkinen, S, Abbott, MB, et al. Binding of levosimendan, a calcium sensitiser, to cardiac troponinC. J Biol Chem 2001; 276: 9337–43.CrossRefGoogle Scholar
McBride, BF, White, CM. Levosimendan: implications for clinicians. J Clin Pharmacol 2003; 43: 1071–81.CrossRefGoogle ScholarPubMed
Brixius, K, Reicke, S, Schwinger, RHG. Beneficial effects of the Ca2 + sensitizer levosimendan in human myocardium. Am J Physiol Heart Circ Physiol 2002; 282: H131–7.CrossRefGoogle Scholar
Hasenfuss, G, Pieske, B, Castell, M, et al. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 1998; 98: 2141–7.CrossRefGoogle ScholarPubMed
Haikala, H, Kaheinen, P, Levijoki, J, Linden, IB. The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovasc Res 1997; 34: 536–46.CrossRefGoogle ScholarPubMed
Ajiro, Y, Hagiwara, N, Katsube, Y, Sperelakis, N, Kasanuki, H. Levosimendan increases L-type Ca2 + current via phosphodiesterase-3 inhibition in human cardiac monocytes. Eur J Pharmacol 1997; 333: 249–59.Google Scholar
Janssen, PM, Datz, N, Zeitz, O, Hasenfuss, G. Levosimendan improves diastolic and systolic function in failing human myocardium. Eur J Pharmacol 2000; 404: 191–9.CrossRefGoogle ScholarPubMed
Yokoshiki, H, Katsube, Y, Sunagawa, M, Sperelakis, N. Levosimendan, a novel Ca2 + sensitizer, activates the glibenclamide-sensitive K+ channels in rat arterial monocytes. Eur J Pharmacol 1997; 333: 249–59.CrossRefGoogle Scholar
Michaels, AD, McKeown, B, Kostal, M, et al. Effects of intravenous levosimendan on human coronary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake. Circulation 2005; 111: 1504–9.CrossRefGoogle ScholarPubMed
Jonsson, EN, Antila, S, McFadyen, L, Lehtonen, L, Karlsson, MO. Population pharmacokinetics of levosimendan in patients with congestive heart failure. Br J Clin Pharmacol 2004; 57: 412–15.Google Scholar
Kivikko, M, Antila, S, Eha, J, Lehtonen, L, Pentikainen, PJ. Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol 2002; 42: 43–51.CrossRefGoogle ScholarPubMed
Figgitt, DP, Gillies, PS, Goa, KL. Levosimendan. Drugs 2001; 61: 613–27.CrossRefGoogle ScholarPubMed
Jonsson, EN, Antila, S, McFayden, L, Lehtonen, L, Karlsson, MO. Population pharmacokinetics of levosimendan in patients with congestive heart failure. Br J Clin Pharmacol 2003; 55: 544–51.CrossRefGoogle ScholarPubMed
Antila, S, Kivikko, M, Lehtonen, L, et al. Pharmacokinetics of levosimendan and its circulating metabolites in patients with heart failure after an extended continuous infusion of levosimendan. Br J Clin Pharmacol 2004; 57: 412–15.CrossRefGoogle ScholarPubMed
Follath, F, Cleland, JG, Just, H, et al. Steering Committee and Investigators of the Levosimendan Infusion versus Dobutamine (LIDO) Study. Efficacy and safety of intravenous levosimendan compared to dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002; 360: 196–202.CrossRefGoogle Scholar
Moiseyev, VS, Poder, P, Andrejevs, N, et al. RUSSLAN Study Investigators. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 2002; 23: 1422–32.CrossRefGoogle Scholar
Johansson S, Apajaslo M, Sarapohja T, Garratt C. Effect of levosimendan treatment on length of hospital and intensive care stay in the REVIVE I study (abstract). Presented at: 24th International Symposium on Intensive Care and Emergency Medicine, Mar 20–Apr 2, 2004, Brussels, Belgium. http://ccforum.com/content/8/S1/P88.
Zairis, MN, Apostolatos, C, Anastasiadis, P, et al. The effect of the calcium sensitizer or an inotrope or none in chronic low-output decompensated heart failure: results from the Calcium Sensitizer or Inotrope or None in Low Output Heart Failure study (CASINO) (abstract). J Am Coll Cardiol 2004; 43 (Suppl 1): A206–7.CrossRefGoogle Scholar
Mebazaa, A, Cohen-Solal, A, Kleber, F, et al. Study design of a mortality trial with intravenous levosimendan (the SURVIVE study) in patients with acutely decompensated heart failure. Crit Care 2004; 8 (Suppl 1): P87.CrossRefGoogle Scholar
Packer M. REVIVE II: Multicentre placebo-controlled trial of levosimendan on clinical status in acutely decompensated heart failure. Program and abstracts from the American Heart Association Scientific Sessions 2005; November 13–16, 2005 Dallas, Texas. Late Breaking Clinical Trials II.
Lehtonen, L, Sundberg, S. The contractility enhancing effect of the calcium sensitizer levosimendan is not attenuated by carvidelol in healthy subjects. Eur J Clin Pharmacol 2002; 58: 449–52.CrossRefGoogle Scholar
Antila, S, Eha, J, Heinpalu, M, et al. Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril. Eur J Clin Pharmacol 1996; 49: 451–8.CrossRefGoogle ScholarPubMed
Sundberg, S, Lehtonen, L. Haemodynamic interactions between the novel calcium sensitizer levosimendan and isosorbide-5-mononitrate in healthy subjects. Br J Clin Pharmacol 2000; 55: 793–9.Google Scholar
Antila, S, Järvinen, A, Honkanen, T, et al. Pharmacokinetic and pharmacodynamic interactions between the novel calcium sensitizer levosimendan and warfarin. Eur J Clin Pharmacol 2000; 56: 705–10.CrossRefGoogle Scholar
Antila, S, Järvinen, A, Honkanen, T, et al. A new calcium sensitizing agent levosimendan has no pharmacokinetic or pharmacodynamics interaction with warfarin (abstract no. 382). Eur J Clin Pharmacol 1997; 52: Suppl A128.Google Scholar
Antila, S, Honkanen, T, Lehtonen, L, Neuvonen, PJ. The CYP3A4 inhibitor intraconazole does not affect the pharmacokinetics of a new calcium-sensitizing drug levosimendan. Int J Clin Pharmacol Ther 1998; 36: 446–9.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

  • Levosimendan
    • By Scott Mercer, Pharmacy St Thomas' Hospital Lambeth Palace Road London SEI 7EH UK, Andrew Rhodes, St George's Hospital Blackshaw Road London SW17 0QT UK
  • Edited by Jeremy Cashman, Michael Grounds
  • Book: Recent Advances in Anaesthesia and Intensive Care
  • Online publication: 15 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544521.009
Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

  • Levosimendan
    • By Scott Mercer, Pharmacy St Thomas' Hospital Lambeth Palace Road London SEI 7EH UK, Andrew Rhodes, St George's Hospital Blackshaw Road London SW17 0QT UK
  • Edited by Jeremy Cashman, Michael Grounds
  • Book: Recent Advances in Anaesthesia and Intensive Care
  • Online publication: 15 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544521.009
Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

  • Levosimendan
    • By Scott Mercer, Pharmacy St Thomas' Hospital Lambeth Palace Road London SEI 7EH UK, Andrew Rhodes, St George's Hospital Blackshaw Road London SW17 0QT UK
  • Edited by Jeremy Cashman, Michael Grounds
  • Book: Recent Advances in Anaesthesia and Intensive Care
  • Online publication: 15 December 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544521.009
Available formats
×