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Aldosteron und Aldosteronrezeptorantagonisten in der Herzinsuffizienztherapie

Aldosterone and aldosterone receptor antagonists in the therapy of cardiac failure

  • Klinische Pharmakologie
  • Published:
Clinical Research in Cardiology Supplements Aims and scope

Zusammenfassung

Aldosteron und dem Aldosteronrezeptor können neben Effekten auf den Elektrolyt- und Wasserhaushalt weitere Rollen in der Pathophysiologie kardiovaskulärer Erkrankungen zugeschrieben werden. Diese Effekte betreffen z. B. Blutdruck (durch direkte Aldosteroneffekte auf Gefäße und ZNS), Hypertrophie und Remodeling. Mit Spironolacton und Eplerenon stehen 2 Aldosteronrezeptorantagonisten für den Dauergebrauch zur Verfügung, die ihre klinische Wirksamkeit in endpunktbasierten Studien gezeigt haben. Spironolacton hat zusätzlich zur antagonistischen Wirkung am Mineralokortikoidrezeptor Wirkungen am Testosteron- und Progesteronrezeptor, die zu endokrinen Nebenwirkungen führen können. Entsprechende UAW fehlen bei Eplerenon, das als selektiver Aldosteronrezeptorantagonist klassifiziert werden kann. Eplerenon hat eine kürzere Plasmahalbwertszeit als die aktiven Metabolite von Spironolacton. Eplerenon wird durch CYP3A4 metabolisiert, hier müssen pharmakokinetische Interaktionen bedacht werden. Wesentlich bei der Kombination von Aldosteronrezeptorantagonisten mit anderen prognoseverbessernden Substanzen in der Herzinsuffizienztherapie ist die Kontrolle der Kaliumspiegel und der Nierenfunktion. Die Dosierungsempfehlungen sollten unbedingt beachtet werden. Besonderer Aufmerksamkeit hinsichtlich der Entwicklung einer Hyperkaliämie bedürfen Patienten mit Einschränkung der Nierenfunktion. Aldosteronantagonisten sollten bei einer glomerulären Filtrationsrate unter 50 ml/min nicht eingesetzt werden.

Abstract

In addition to the classical effects exerted by aldosterone on water and electrolyte haemostasis, recent data suggest additional roles in the pathophysiology of cardiovascular diseases. Examples are the regulation of blood pressure (by direct aldosterone effects on vessels and the CNS), myocardial hypertrophy and remodelling. Two aldosterone receptor antagonists, spironolactone and eplerenone, are currently available for the long-term therapy of chronic heart failure. Both compounds have clearly demonstrated their efficacy in heart failure treatment in end-point based clinical trials. Spironolactone, in addition to its antagonistic effects on the mineralocorticoid receptor, has anti-androgenic and gestagenic actions which can lead to endocrine side effects. Eplerenone selectively blocks aldosterone receptors and thus lacks adverse effects caused by non-specific steroid receptor blockade. The elimination half-life of eplerenone is shorter than the half-life of the active metabolites of spironolactone. Eplerenone is metabolised by CYP3A4, and pharmacokinetic interactions with inhibitors and inducers of this enzyme have to be considered. Essential for the clinical use of aldosterone antagonists in heart failure is the careful monitoring of potassium levels and renal function. The recommended doses should be followed precisely. Higher doses increase the risk of developing life-threatening hyperkalemia. Particular attention has to be paid to patients with impaired renal function. Aldosterone receptor antagonists should not be used when the glomerular filtration rate is below 50 ml/min.

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Literatur

  1. Pitt B, Zannad F, Remme WJ et al. (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341: 709–717

    Article  PubMed  Google Scholar 

  2. Pitt B, Remme W, Zannad F et al. (2003) Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348: 1309–1321

    Article  PubMed  Google Scholar 

  3. Hoppe UC, Bohm M, Dietz R et al. (2005) Guidelines for therapy of chronic heart failure. Z Kardiol 94: 488–509

    Article  PubMed  Google Scholar 

  4. Tait SA, Tait JF, Coghlan JP (2004) The discovery, isolation and identification of aldosterone: reflections on emerging regulation and function. Mol Cell Endocrinol 217: 1–21

    Article  Google Scholar 

  5. Stockand JD (2002) New ideas about aldosterone signaling in epithelia. Am J Physiol Renal Physiol 282: F559–576

    PubMed  Google Scholar 

  6. Menard J (2004) The 45-year story of the development of an anti-aldosterone more specific than spironolactone. Mol Cell Endocrinol 217: 45–52

    Article  PubMed  Google Scholar 

  7. Losel R, Schultz A, Wehling M (2004) A quick glance at rapid aldosterone action. Mol Cell Endocrinol 217: 137–141

    Article  PubMed  Google Scholar 

  8. Losel R, Schultz A, Boldyreff B, Wehling M (2004) Rapid effects of aldosterone on vascular cells: clinical implications. Steroids 69: 575–578

    Article  PubMed  Google Scholar 

  9. Mihailidou AS, Funder JW (2005) Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system. Steroids 70: 347–351

    Article  PubMed  Google Scholar 

  10. Mihailidou AS, Mardini M, Funder JW (2004) Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C. Endocrinology 145: 773–780

    Article  PubMed  Google Scholar 

  11. Funder JW (2005) The nongenomic actions of aldosterone. Endocr Rev 26: 313–321

    Article  PubMed  Google Scholar 

  12. Jaffe IZ, Mendelsohn ME (2005) Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res

  13. Christ M, Wehling M, Kirsch E et al. (2005) Enhancement of beta-adrenergic cAMP-signaling by the mineralocorticoid receptor. Mol Cell Endocrinol 231: 23–31

    Article  PubMed  Google Scholar 

  14. Beggah A, Escoubet B, Puttini S et al. (2002) Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes. Proc Natl Acad Sci USA 99: 7160–7165

    Article  PubMed  Google Scholar 

  15. Berger S, Bleich M, Schmid W et al. (1998) Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc Natl Acad Sci USA 95: 9424–9429

    Article  PubMed  Google Scholar 

  16. Lecain E, Yang TH, Tran Ba Huy P (2003) Steroidogenic enzyme expression in the rat cochlea. Acta Otolaryngol 123: 187–191

    Article  PubMed  Google Scholar 

  17. Gomez-Sanchez EP, Ahmad N, Romero DG, Gomez-Sanchez CE (2005) Is aldosterone synthesized within the rat brain? Am J Physiol Endocrinol Metab 288: E342–346

    Article  PubMed  Google Scholar 

  18. Funder JW (2004) Cardiac synthesis of aldosterone: going, going, gone ...? Endocrinology 145: 4793–4795

    Article  PubMed  Google Scholar 

  19. Gomez-Sanchez EP, Ahmad N, Romero DG, Gomez-Sanchez CE (2004) Origin of aldosterone in the rat heart. Endocrinology 145: 4796–4802

    Article  PubMed  Google Scholar 

  20. Tsutamoto T, Wada A, Maeda K et al. (2003) Transcardiac gradient of aldosterone before and after spironolactone in patients with congestive heart failure. J Cardiovasc Pharmacol 41 [Suppl 1]: S19–22

    Google Scholar 

  21. Tsutamoto T, Wada A, Maeda K et al. (2000) Spironolactone inhibits the transcardiac extraction of aldosterone in patients with congestive heart failure. J Am Coll Cardiol 36: 838–844

    Article  PubMed  Google Scholar 

  22. Mizuno Y, Yoshimura M, Yasue H et al. (2001) Aldosterone production is activated in failing ventricle in humans. Circulation 103: 72–77

    PubMed  Google Scholar 

  23. Spat A, Hunyady L (2004) Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev 84: 489–539

    Article  PubMed  Google Scholar 

  24. Lisurek M, Bernhardt R (2004) Modulation of aldosterone and cortisol synthesis on the molecular level. Mol Cell Endocrinol 215: 149–159

    Article  PubMed  Google Scholar 

  25. Okubo S, Niimura F, Nishimura H et al. (1997) Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest 99: 855–860

    PubMed  Google Scholar 

  26. Jorde UP, Vittorio T, Katz SD et al. (2002) Elevated plasma aldosterone levels despite complete inhibition of the vascular angiotensin-converting enzyme in chronic heart failure. Circulation 106: 1055–1057

    Article  PubMed  Google Scholar 

  27. Pascual-Le Tallec L, Lombes M (2005) The mineralocorticoid receptor: a journey exploring its diversity and specificity of action. Mol Endocrinol 19(9): 2211–2221

    Article  PubMed  Google Scholar 

  28. Rogerson FM, Brennan FE, Fuller PJ (2004) Mineralocorticoid receptor binding, structure and function. Mol Cell Endocrinol 217: 203–212

    Article  PubMed  Google Scholar 

  29. Funder JW, Pearce PT, Smith R, Campbell J (1989) Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology 125: 2224–2226

    PubMed  Google Scholar 

  30. Seckl JR (2004) 11beta-hydroxysteroid dehydrogenases: changing glucocorticoid action. Curr Opin Pharmacol 4: 597–602

    Article  PubMed  Google Scholar 

  31. Lombes M, Kenouch S, Souque A et al. (1994) The mineralocorticoid receptor discriminates aldosterone from glucocorticoids independently of the 11 beta-hydroxysteroid dehydrogenase. Endocrinology 135: 834–840

    Article  PubMed  Google Scholar 

  32. Farman N, Rafestin-Oblin ME (2001) Multiple aspects of mineralocorticoid selectivity. Am J Physiol Renal Physiol 280: F181–192

    PubMed  Google Scholar 

  33. Hellal-Levy C, Couette B, Fagart J et al. (1999) Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors. FEBS Lett 464: 9–13

    Article  PubMed  Google Scholar 

  34. Brilla CG, Pick R, Tan LB et al. (1990) Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 67: 1355–1364

    PubMed  Google Scholar 

  35. Brilla CG, Matsubara LS, Weber KT (1993) Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension. Am J Cardiol 71: 12A–16A

    Article  PubMed  Google Scholar 

  36. Brown NJ (2003) Eplerenone: cardiovascular protection. Circulation 107: 2512–2518

    Article  PubMed  Google Scholar 

  37. Hostetter TH, Ibrahim HN (2003) Aldosterone in chronic kidney and cardiac disease. J Am Soc Nephrol 14: 2395–2401

    Article  PubMed  Google Scholar 

  38. Rocha R, Rudolph AE, Frierdich GE et al. (2002) Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 283: H1802–1810

    PubMed  Google Scholar 

  39. Rocha R, Funder JW (2002) The pathophysiology of aldosterone in the cardiovascular system. Ann N Y Acad Sci 970: 89–100

    PubMed  Google Scholar 

  40. Suzuki G, Morita H, Mishima T et al. (2002) Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure. Circulation 106: 2967–2972

    Article  PubMed  Google Scholar 

  41. Fraccarollo D, Galuppo P, Schmidt I et al. (2005) Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction. Cardiovasc Res 67: 97–105

    Article  PubMed  Google Scholar 

  42. Fraccarollo D, Galuppo P, Hildemann S et al. (2003) Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol 42: 1666–1173

    Article  PubMed  Google Scholar 

  43. Qin W, Rudolph AE, Bond BR et al. (2003) Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res 93: 69–76

    Article  PubMed  Google Scholar 

  44. Funder JW, Pearce PT, Myles K, Roy LP (1990) Apparent mineralocorticoid excess, pseudohypoaldosteronism, and urinary electrolyte excretion: toward a redefinition of mineralocorticoid action. Faseb J 4: 3234–3238

    PubMed  Google Scholar 

  45. Funder JW (2004) Is aldosterone bad for the heart? Trends Endocrinol Metab 15: 139–142

    Article  PubMed  Google Scholar 

  46. Rossi GP, Di Bello V, Ganzaroli C et al. (2002) Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension 40: 23–27

    Article  PubMed  Google Scholar 

  47. Young WF Jr (2003) Minireview: primary aldosteronism – changing concepts in diagnosis and treatment. Endocrinology 144: 2208–2213

    Article  PubMed  Google Scholar 

  48. Stowasser M, Gordon RD (2004) Primary aldosteronism – careful investigation is essential and rewarding. Mol Cell Endocrinol 217: 33–39

    Article  PubMed  Google Scholar 

  49. Sato A, Saruta T (2003) Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy. Am J Hypertens 16: 781–788

    Article  PubMed  Google Scholar 

  50. McKelvie RS, Yusuf S, Pericak D et al. (1999) Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 100: 1056–1064

    PubMed  Google Scholar 

  51. Farquharson CA, Struthers AD (2000) Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 101: 594–597

    PubMed  Google Scholar 

  52. Prisant LM, Krum H, Roniker B et al. (2003) Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy? J Clin Pharmacol 43: 1203–1210

    Article  PubMed  Google Scholar 

  53. Pitt B, Reichek N, Willenbrock R et al. (2003) Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 108: 1831–1838

    Article  PubMed  Google Scholar 

  54. Hayashi M, Tsutamoto T, Wada A et al. (2003) Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 107: 2559–2565

    Article  PubMed  Google Scholar 

  55. Modena MG, Aveta P, Menozzi A, Rossi R (2001) Aldosterone inhibition limits collagen synthesis and progressive left ventricular enlargement after anterior myocardial infarction. Am Heart J 141: 41–46

    Article  PubMed  Google Scholar 

  56. Pitt B, White H, Nicolau J et al. (2005) Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am College Cardiol 46: 425–431)

    Article  Google Scholar 

  57. Beygui F, Collet JP, Benoliel JJ et al. (2006) High plasma aldosterone levels on admission are associated with death in patients presenting with acute ST-elevation myocardial infarction. Circulation 114: 2604–2610

    Article  PubMed  Google Scholar 

  58. Zannad F, Alla F, Dousset B et al. (2000) Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 102: 2700–2706

    PubMed  Google Scholar 

  59. MacFadyen RJ, Barr CS, Struthers AD (1997) Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 35: 30–34

    Article  PubMed  Google Scholar 

  60. de Gasparo M, Joss U, Ramjoué HP et al. (1987) Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharm Exp Ther 240: 650–656

    Google Scholar 

  61. Garthwaite SM, McMahon EG (2004) The evolution of aldosterone antagonists. Mol Cell Endocrinol 217: 27–31

    Article  PubMed  Google Scholar 

  62. Overdiek HW, Merkus FW (1987) The metabolism and biopharmaceutics of spironolactone in man. Rev Drug Metab Drug Interact 5: 273–302

    PubMed  Google Scholar 

  63. Overdiek HW, Hermens WA, Merkus FW (1985) New insights into the pharmacokinetics of spironolactone. Clin Pharmacol Ther 38: 469–474

    PubMed  Google Scholar 

  64. Gardiner P, Schrode K, Quinlan D et al. (1989) Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites. J Clin Pharmacol 29: 342–347

    PubMed  Google Scholar 

  65. Krause W, Karras J, Seifert W (1983) Pharmacokinetics of canrenone after oral administration of spironolactone and intravenous injection of canrenoate-K in healthy man. Eur J Clin Pharmacol 25: 449–453

    Article  PubMed  Google Scholar 

  66. Los LE, Colby HD (1994) Binding of spironolactone metabolites in vivo to renal mineralocorticoid receptors in guinea pigs. Pharmacology 48: 86–92

    PubMed  Google Scholar 

  67. Corvol P, Michaud A, Menard J et al. (1975) Antiandrogenic effects of spironolactones: mechanism of action. Endocrinology 97: 52–58

    PubMed  Google Scholar 

  68. de Gasparo M, Whitebread SE, Preiswerk G et al. (1989) Antialdosterones: Incidence and prevention of sexual side effects. J Steroid Biochem 32: 223–227

    Article  PubMed  Google Scholar 

  69. Cook CS, Hauswald C, Oppermann JA, Schoenhard GL (1993) Involvement of cytochrome P-450IIIA in metabolism of potassium canrenoate to an epoxide: mechanism of inhibition of the epoxide formation by spironolactone and its sulfur-containing metabolite. J Pharmacol Exp Ther 266: 1–7

    PubMed  Google Scholar 

  70. Cook CS, Hauswald CL, Schoenhard GL et al. (1988) Difference in metabolic profile of potassium canrenoate and spironolactone in the rat: mutagenic metabolites unique to potassium canrenoate. Arch Toxicol 61: 201–212

    Article  PubMed  Google Scholar 

  71. Cook CS, Berry LM, Kim DH et al. (2002) Involvement of CYP3A in the metabolism of eplerenone in humans and dogs: differential metabolism by CYP3A4 and CYP3A5. Drug Metab Dispos 30: 1344–1351

    Article  PubMed  Google Scholar 

  72. Cook CS, Zhang L, Ames GB et al. (2003) Single- and repeated-dose pharmacokinetics of eplerenone, a selective aldosterone receptor blocker, in rats. Xenobiotica 33: 305–321

    Article  PubMed  Google Scholar 

  73. Cook CS, Berry LM, Bible RH et al. (2003) Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans. Drug Metab Dispos 31: 1448–1455

    Article  PubMed  Google Scholar 

  74. Cook CS, Berry LM, Burton E (2004) Prediction of in vivo drug interactions with eplerenone in man from in vitro metabolic inhibition data. Xenobiotica 34: 215–228

    Article  PubMed  Google Scholar 

  75. Juurlink DN, Mamdani MM, Lee DS et al. (2004) Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 351: 543–551

    Article  PubMed  Google Scholar 

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Interessenkonflikt

Prof. Eschenhagen und T. Rau erhielten Honorare von verschiedenen Pharma-Firmen, u. a. vom Hersteller von Eplerenon (INSPRA®), Fa. Pfizer. Trotz des möglichen Interessenkonflikts ist der Beitrag unabhängig und produktneutral.

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  1. Institut für Klinische und Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg Eppendorf, Martinistraße 52, 20246, Hamburg, Deutschland

    T. Rau & T. Eschenhagen

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Rau, T., Eschenhagen, T. Aldosteron und Aldosteronrezeptorantagonisten in der Herzinsuffizienztherapie. Clin Res Cardiol Suppl 2, 55–64 (2007). https://doi.org/10.1007/s11789-006-0025-x

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