medigraphic.com
ISSN 0188-2198 (Impreso)

2015, Número S3

<< Anterior

Rev Mex Cardiol 2015; 26 (S3)


Levosimendán: farmacología, mecanismos de acción y usos actuales. Revisión

Salgado-Pastor SJ, Martínez-Ramírez L, Arce-Salinas CA

Idioma: Español
Referencias bibliográficas: 73
Paginas: 141-151
Archivo PDF: 375.61 Kb.


RESUMEN

Levosimendán es un fármaco de uso actual en pacientes con insuficiencia cardiaca descompensada; sus múltiples mecanismos de acción son independientes de los receptores β-adrenérgicos. Los mecanismos de acción mejor conocidos en la actualidad son sensibilización de la troponina C que le confiere efecto inotrópico positivo con modificación del acoplamiento ventricular, vasodilatador: a través de su mecanismo en los receptores cito-KATP con una disminución en la postcarga ventricular que influye en el acoplamiento ventrículo-arterial y mecanismo cardioprotector a través de los canales mito-K.
El uso en ciclos repetitivos para pacientes con insuficiencia cardiaca crónica con deterioro en su clase funcional plantea una probable solución temporal en pacientes en espera de tratamiento definitivo. Su uso en pacientes críticamente enfermos aún es controversial.


REFERENCIAS (EN ESTE ARTÍCULO)

  1. Edes I, Kiss E, Kitada Y, Powers FM, Papp JG, Kranias EG et al. Effects of levosimendan, a cardiotonic agent targeted to troponin c, on cardiac function and on phosphorylation and ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circulation Reseach. 1995; 77: 107-113.

  2. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol. 1997; 333: 249-259.

  3. Kopustinskiene DM, Pollesello P, Saris NE. Levosimendan is a mitochondrial K-ATP chanel opener. European J Pharmacol. 2001; 428: 311-314.

  4. Leprán I, Papp JG. Effect of long-term oral pretreatment with levosimendan on cardiac arrhythmias during coronary artery occlusion in conscious rats. Eur J Pharmacol. 2003; 464: 171-176.

  5. Kersten JR, Montgomery MW, Pagel PS, Warltier DC. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K (ATP) channels. Anesth Analg. 2000; 90: 5-11.

  6. Leprán I, Pollesello P, Vajda S, Varró A, Papp JG. Preconditioning effects of levosimendan in a rabbit cardiac ischemia–reperfusion model. J Cardiovasc Pharmacol. 2006; 48: 148-152.

  7. Rump AF, Acar D, Rösen R, Klaus W. Functional and antiischaemic effects of the phosphodiesterase inhibitor levosimendan in isolated rabbit hearts. Pharmacol Toxicol. 1994; 74: 244-248.

  8. Raasmaja A, Tal A, Nissinen E, Linden IB, Pohto P, Biochemical mechanisms of the novel cardiotonic agent OR-1259. J Mol Cell Cardiol. 1991; 23 (Suppl V), S129.

  9. Szilágyi S, Pollesello P, Levijoki J, Kaheinen P, Haikala H, Edes I et al. The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig. Eur J Pharmacol. 2004; 486: 67-74.

  10. Bokník P, Neumann J, Kaspareit G, Schmitz W, Scholz H, Vahlensieck U et al. Mechanisms of the contractile effects of levosimendan in the mammalian heart. J Pharmacol Exp Ther. 1997; 280: 277-283.

  11. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikainen PJ. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther. 2002; 40: 465-471.

  12. Puttonen J, Kantele S, Ruck A et al. Pharmacokinetics of intravenous levosimendan and its metabolites in subjects with hepatic impairment. J Clin Pharmacol. 2008; 48: 445-454.

  13. Kass DA, Solaro RJ. Mechanisms and use of calcium-sensitizing agents in the failing heart. Circulation. 2006; 113: 305-315.

  14. Despas F, Trouillet C, Franchitto N, Labrunee M, Galinier M, Senard JM et al. Levosimedan improves hemodynamics functions without sympathetic activation in severe heart failure patients: Direct evidence from sympathetic neural recording. Acute Cardiac Care. 2010; 12: 25-30.

  15. Antoniades C, Tousoulis D, Koumallos N, Marinou K, Stefanadis C. Levosimendan: beyond its simple inotropic effect in heart failure. Pharmacol Ther. 2007; 114: 184-197.

  16. Sorsa T, Heikkinen S, Abbott MB et al. Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem. 2001; 276: 9337-9343.

  17. Givertz MM, Andreou C, Conrad CH, Colucci WS. Direct myocardial effects of levosimendan in humans with left ventricular dysfunction: alteration of force-frequency and relaxation-frequency relationships. Circulation. 2007; 115: 1218-1224.

  18. Robertson IM, Sun YB, Li MX, Sykes BD. A structural and functional perspective into the mechanism of Ca2+ sensitizers that target the cardiac troponin complex. J Mol Cell Cardiol. 2010; 49: 1031-1041.

  19. Pagel PS, Hettrick DA, Warltier DC. Left ventricular mechanical consequences of dihydropyridine calcium channel modulation in conscious and anesthetized chronically instrumented dogs. Anesthesiology. 1994; 81: 190-208.

  20. Gruhn N, Nielsen-Kudsk JE, Theilgaard S, Bang L, Olesen SP, Aldershvile J. Coronary vasorelaxant effect of levosimendan, a new inodilator with calcium-sensitizing properties. J Cardiovasc Pharmacol. 1998; 31: 741-749.

  21. Erdei N, Papp Z, Pollesello P, Edes I, Bagi Z. The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br J Pharmacol. 2006; 148: 696-702.

  22. De Witt BJ, Ibrahim IN, Bayer E, Fields AM, Richards TA, Banister RE, Kaye AD An analysis of responses to levosimendan in the pulmonary vascular bed of the cat. Anesth Analg. 2002; 94: 1427-1433.

  23. Leather HA, Ver Eycken K, Segers P, Herijgers P, Vandermeersch E, Wouters PF. Effects of levosimendan on right ventricular function and ventriculovascular coupling inopen chest pigs. Crit Care Med. 2003; 31: 2339-2343.

  24. Grossini E, Molinari C, Caimmi PP, Uberti F, Vacca G. Levosimendan induces NO production through p38 MAPK, ERK and Akt in porcine coronary endothelial cells: role for mitochondrial K(ATP) channel. Br J Pharmacol. 2009; 156: 250-261.

  25. Eisen A, Fisman EZ, Rubenfire M et al. Ischemic preconditioning: nearly two decades of research. A comprehensive review. Atherosclerosis. 2004; 172: 201-210.

  26. Markou T, Makridou Z, Galatou E, Lazou A. Multiple signaling pathways underlie the protective effect of levosimendan in cardiac myocytes. European Journal of Pharmacology. 2011; 667: 298-305.

  27. Miura T Liu Y, Goto M et al. Mitochondrial ATP-sensitive K+ channels play a role in cardioprotection by Na+-H+ exchange inhibition against ischemia/reperfusion injury. J Am Coll Cardiol. 2001; 37: 957-963.

  28. Gross GJ, Peart JN. KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol. 2003; 285: H921-H930.

  29. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD. Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol. 2001; 280: H649-H657.

  30. Parissis JT, Andreadou I, Markantonis SL et al. Effects of Levosimendan on circulating markers of oxidative and nitrosative stress in patients with advanced heart failure. Atherosclerosis. 2007; 195: e210-e215.

  31. Krenz M, Oldenburg O, Wimpee H, Cohen MV, Garlid KD, Critz SD et al. Opening of ATP-sensitive potassium channels causes generation of free radicals in vascular smooth muscle cells. Basic Res Cardiol. 2002; 97: 365-373.

  32. Du Toit EF, Genis A, Opie LH, Pollesello P, Lochner A. A role for the RISK pathway and K(ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated guinea pig heart. Br J Pharmacol. 2008; 154: 41-50.

  33. Papp JG, Pollesello P, Varro AF, Vegh AS. Effect of levosimendan and milrinone on regional myocardial ischemia/reperfusion induced arrhythmias in dogs. J Cardiovasc Pharmacol Ther. 2006; 11: 129-135.

  34. Flevari P, Parissis JT, Leftheriotis D, Panou F, Kourea K, Kremastinos DT. Effect of levosimendan on ventricular arrhythmias and prognostic autonomic indexes in patients with decompensated advanced heart failure secondary to ischemic or dilated cardiomyopathy. Am J Cardiol. 2006; 98: 1641-1645.

  35. Tek M, Cavusoglu Y, Demirustu C et al. Levosimendan and dobutamine have a similar profile for potential risk for cardiac arrhythmias during 24-hour infusion in patients with acute decompensated heart failure. Turk Kardiyol Dern Ars. 2010; 38: 334-340.

  36. Cohen-Solal A, Logeart D, Huang B, Cai D, Nieminen MS, Mebazaa A. Lowered B-type natriuretic peptide in response to levosimendan or dobutamine treatment is associated with improved survival in patients with severe acutely decompensated heart failure. J Am Coll Cardiol. 2009; 53: 2343-2348.

  37. Moertl D, Berger R, Huelsmann M, Bojic A, Pacher R. Short term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B type natriuretic peptide levels in patients with decompensated chronic heart failure. Eur J Heart Fail. 2005; 7: 1156-1163.

  38. Aukrust P, Ueland T, Lien E et al. Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1999; 83: 376-382.

  39. Adamopoulos S, Parissis JT, Kremastinos DT. A glossary of circulating cytokines in chronic heart failure. Eur J Heart Fail. 2001; 3: 517-526.

  40. Adamopoulos S, Parissis JT, Iliodromitis EK et al. Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure. Am J Cardiol. 2006; 98: 102-106.

  41. Parissis JT, Karavidas A, Bistola V et al. Effects of levosimendan on flow-mediated vasodilation and soluble adhesion molecules in patients with advanced chronic heart failure. Atherosclerosis. 2008; 197: 278-282.

  42. Revermann M, Schloss M, Mieth A et al. Levosimendan attenuates pulmonary vascular remodeling. Intensive Care Med. 2011; 37: 1368-1377.

  43. Schwarte LA, Picker O, Bornstein SR, Fournell A, Scheeren TW Levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation in dogs. Crit Care Med. 2005; 33: 135-142.

  44. Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet. 2013; 381: 166-175.

  45. Jalanko M, Kivikko M, Harjola VP, Nieminen MS, Laine M. Oral levosimendan improves filling pressure and systolic function during long-term treatment. Scand Cardiovasc J. 2011; 45: 91-97.

  46. Antila S, Sundberg S, Lehtonen LA. Clinical pharmacology of levosimendan. Clin Pharmacokinet. 2007; 46: 535-552.

  47. Antila S, Pesonen U, Lehtonen L, Tapanainen P, Nikkanen H, Vaahtera K et al. Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators. Eur J Pharm Sci. 2004; 23: 213-222.

  48. Parissis JT, Farmakis D, Nieminen M. Classical inotropes and new cardiac enhancers. Heart Fail Rev. 2007; 12: 149-156.

  49. Hoffman TM. Newer inotropes in pediatric heart failure. J Cardiovasc Pharmacol. 2011; 58: 121-125.

  50. Follath F, Cleland JG, Just H et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low output heart failure (the LIDO study): a randomized double-blind trial. Lancet. 2002; 360: 196-202.

  51. Moiseyev VS, Poder P, Andrejevs N et al. 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: 1422-1432.

  52. Cleland JG, Freemantle N, Coletta AP, Clark AL. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail. 2006; 8: 105-110.

  53. Packer M, Colucci W, Fisher L, Massie BM, Teerlink JR, Young J et al. Effect of Levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JCHF. 2013; 1: 103-111.

  54. Mebazaa A, Nieminen MS, Packer M et al Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA. 2007; 297: 1883-1891.

  55. Landoni G, Mizzi A, Biondi-Zoccai G, Bignami E, Prati P, Ajello V et al. Levosimendan reduces mortality in controlled studies. Minerva Anestesiol. 2010; 76: 276-286.

  56. Thackray S, Easthaugh J, Freemantle N, Cleland JG. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure-a meta-regression analysis. Eur J Heart Fail. 2002; 4: 515-529.

  57. Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol. 2005; 96: 47G-58G.

  58. Maharaj R, Metaxa V. Levosimendan and mortality after coronary revascularization: a meta-analysis of randomised controlled trials. Crit Care. 2011; 15: R140.

  59. Zangrillo A, Biondi-Zoccai G, Mizzi A, Bruno G, Bignami E, Gerli C et al. Levosimendan reduces cardiac troponin release after cardiac surgery: a meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth. 2009; 23: 474-478.

  60. Landoni G, Mizzi A, Biondi-Zoccai G, Bruno G, Birnami E, Corno L et al. Reducing Mortality in Cardiac Surgery With Levosimendan: A Meta-analysis of randomized Controlled Trials. J Cardiothorac Vasc Anesth. 2009; 24: 51-57.

  61. De Hert SG, Lorsomradee S, Cromheecke S, Van der Linden PJ. The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg. 2007; 104 (4): 766-773.

  62. Flierl MA, Rittirsch D, Huber-Lang MS, Sarma JV, Ward PA. Molecular events in the cardiomyopathy of sepsis. Mol Med. 2008; 14: 327-336.

  63. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med. 2007; 35: 1599-1608.

  64. Levy RJ, Piel DA, Acton PD et al. Evidence of myocardial hibernation in the septic heart. Crit Care Med. 2005; 33: 2752-2756.

  65. Dellinger RP, Levy MM, Carlet JM et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008; 34: 17-60.

  66. Silverman HJ, Penaranda R, Orens JB, Lee NH. Impaired beta-adrenergic receptor stimulation of cyclic adenosine monophosphate in human septic shock: association with myocardial hyporesponsiveness to catecholamines. Crit Care Med. 1993; 21: 31-39.

  67. Inger M. Catecholamine treatment for shock- equally good or bad? Lancet. 2007; 370: 636-637.

  68. Morelli A, De CS, Teboul JL et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2005; 31: 638-644.

  69. Huang X, Lei S, Zhu MF, Jiang RL, Huang LQ, Xia GL et al. Levosimendan versus dobutamine in critically ill patients: a meta-analysis of randomized controlled trials. J Zhejiang Univ-Sci B. 2013; 14: 400-415.

  70. Nanas JN, Papazoglou PP, Terrovitis JV, Kanakakis J, Dalianis A, Tsolakis E et al. Hemodynamic effects of levosimendan added to dobutamine in patients with decompensated advanced heart failure refractory to dobutamine alone. Am J Cardiol. 2004; 94 (10): 1329-1332.

  71. Fuhrmann JT, Schmeisser A, Schulze MR, Wunderlich C, Schoen SP, Rauwolf T et al. Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit Care Med. 2008; 36 (8): 2257-2266.

  72. Comín-Colet J, Manito N, Segovia J et al. Multicenter, randomized, double-blind, parallel group, placebo-controlled trial to test the efficacy and safety of intravenous administration of intermittent doses of levosimendan in outpatients with advanced chronic heart failure. Heart Failure Congress; Seville, Spain. Presentation 545; 2015.

  73. Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail. 2008;29:2388-442.




2020     |     www.medigraphic.com