Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Adverse Effects of Mineralocorticoid Receptor Antagonist Administration

Author(s): Manolis S. Kallistratos*, Andreas Pittaras, Iakovos Theodoulidis, Charris Grassos, Leonidas E. Poulimenos and Athanasios J. Manolis

Volume 24 , Issue 46 , 2018

Page: [5537 - 5541] Pages: 5

DOI: 10.2174/1381612825666190222144359

Price: $65


Background: Mineralocorticoid receptor antagonists consist of a class of drugs with pleiotropic beneficial effects in several cardiovascular diseases. However, physicians frequently overlook their use due to the adverse effects of such agents.

Objectives: To determine the adverse effects of mineralocorticoid receptor antagonists and to suggest clinically meaningful options. We present data on the two most administered agents of this class: spironolactone and eplerenone.

Method: We conducted an in-depth review of the existing international literature to draft a mini review about the mineralocorticoid receptor antagonists-related side effects.

Result: Mineralocorticoid receptor antagonists are associated with increased risk of hyperkalemia and acute deterioration of renal function. Of note, these adverse effects are dose-dependent, more common during the initial period of treatment, and are usually reversed after the withdrawal of therapy. Sex-related adverse events are noted mainly in spironolactone while switching to eplerenone could attenuate those.

Conclusion: Mineralocorticoid receptor antagonists therapy is significantly limited due to their side effects. The development of novel non-steroidal mineralocorticoid receptor antagonists could substantially widen the use of such agents.

Keywords: Mineralocorticoid receptor antagonist, spironolactone, eplerenone, hyperkalemia, acute kidney injury, adverse event.

Simpson SA, Tait JF, Wettstein A, et al. [Constitution of aldosterone, a new mineralocorticoid]Experientia 1954; 10(3): 132-3.
Garthwaite SM, McMahon EG. The evolution of aldosterone antagonists. Mol Cell Endocrinol 2004; 217(1-2): 27-31.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341(10): 709-17.
Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348(14): 1309-21.
Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev 1999; 79(1): 215-62.
Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol 2006; 48(10): 1977-85.
Faselis C, Boutari C, Doumas M, Imprialos K, Stavropoulos K, Kokkinos P. Novel drugs for hypertension and heart failure: struggling for a place under the sun. Curr Pharm Des 2017; 23(10): 1540-50.
Trevisan M, de Deco P, Xu H, et al. Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists. Eur J Heart Fail 2018; 20(8): 1217-26.
Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA 2009; 302(15): 1658-65.
Rassi AN, Cavender MA, Fonarow GC, et al. Temporal trends and predictors in the use of aldosterone antagonists post-acute myocardial infarction. J Am Coll Cardiol 2013; 61(1): 35-40.
Krogager ML, Torp-Pedersen C, Mortensen RN, et al. Short-term mortality risk of serum potassium levels in hypertension: A retrospective analysis of nationwide registry data. Eur Heart J 2017; 38(2): 104-12.
Vukadinović D, Lavall D, Vukadinović AN, Pitt B, Wagenpfeil S, Böhm M. True rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials: A meta-analysis. Am Heart J 2017; 188: 99-108.
Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1): 11-21.
Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348(14): 1309-21.
Vardeny O, Claggett B, Anand I, et al. Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail 2014; 7(4): 573-9.
Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014; 370(15): 1383-92.
Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348(14): 1309-21.
Struthers A, Krum H, Williams GH. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol 2008; 31(4): 153-8.
Alper AB, Campbell RC, Anker SD, et al. A propensity-matched study of low serum potassium and mortality in older adults with chronic heart failure. Int J Cardiol 2009; 137(1): 1-8.
Bowling CB, Pitt B, Ahmed MI, et al. Hypokalemia and outcomes in patients with chronic heart failure and chronic kidney disease: findings from propensity-matched studies. Circ Heart Fail 2010; 3(2): 253-60.
Goyal A, Spertus JA, Gosch K, et al. Serum potassium levels and mortality in acute myocardial infarction. JAMA 2012; 307(2): 157-64.
Ezekowitz JA, McAlister FA. Aldosterone blockade and left ventricular dysfunction: A systematic review of randomized clinical trials. Eur Heart J 2009; 30(4): 469-77.
Rossignol P, Cleland JG, Bhandari S, et al. Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study. Circulation 2012; 125(2): 271-9.
Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006; 1(5): 940-51.
Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: A systematic review and meta-analysis. Clin J Am Soc Nephrol 2009; 4(3): 542-51.
Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: A consensus approach. Am J Kidney Dis 2000; 36(3): 646-61.
Horisberger JD, Giebisch G. Potassium-sparing diuretics. Ren Physiol 1987; 10(3-4): 198-220.
Rifka SM, Pita JC, Vigersky RA, Wilson YA, Loriaux DL. Interaction of digitalis and spironolactone with human sex steroid receptors. J Clin Endocrinol Metab 1978; 46(2): 338-44.
Epstein M, Calhoun DA. Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. J Clin Hypertens (Greenwich) 2011; 13(9): 644-8.
Dickey RP, Stone SC. Drugs that affect the breast and lactation. Clin Obstet Gynecol 1975; 18(2): 95-111.
Braunstein GD. Gynecomastia. N Engl J Med 1993; 328(7): 490-5.
Jeunemaitre X, Chatellier G, Kreft-Jais C, et al. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol 1987; 60(10): 820-5.
Haynes BA, Mookadam F, Mookadam F. Male gynecomastia. Mayo Clin Proc 2009; 84(8): 672.
Deepinder F, Braunstein GD. Drug-induced gynecomastia: An evidence-based review. Expert Opin Drug Saf 2012; 11(5): 779-95.
Huffman DH, Kampmann JP, Hignite CE, Azarnoff DL. Gynecomastia induced in normal males by spironolactone. Clin Pharmacol Ther 1978; 24(4): 465-73.
Caminos-Torres R, Ma L, Snyder PJ. Gynecomastia and semen abnormalities induced by spironolactone in normal men. J Clin Endocrinol Metab 1977; 45(2): 255-60.
de Gasparo M, Joss U, Ramjoué HP, et al. Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther 1987; 240(2): 650-6.
de Gasparo M, Whitebread SE, Preiswerk G, Jeunemaître X, Corvol P, Ménard J. Antialdosterones: incidence and prevention of sexual side effects. J Steroid Biochem 1989; 32(1B): 223-7.
Karagiannis A, Tziomalos K, Papageorgiou A, et al. Spironolactone versus eplerenone for the treatment of idiopathic hyperaldosteronism. Expert Opin Pharmacother 2008; 9(4): 509-15.
Imprialos KP, Stavropoulos K, Doumas M, Tziomalos K, Karagiannis A, Athyros VG. Sexual dysfunction, cardiovascular risk and effects of pharmacotherapy. Curr Vasc Pharmacol 2018; 16(2): 130-42.
Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH. Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med 1977; 87(4): 398-403.
Riester A, Reincke M. Progress in primary aldosteronism: mineralocorticoid receptor antagonists and management of primary aldosteronism in pregnancy. Eur J Endocrinol 2015; 172(1): R23-30.
Stavropoulos K, Sotiriadis A, Patoulias D, et al. Pseudohyperaldosteronism due to mumijo consumption during pregnancy: A licorice-like syndrome. Gynecol Endocrinol 2018; 34(12): 1019-21.
Morton A, Panitz B, Bush A. Eplerenone for gitelman syndrome in pregnancy. Nephrology (Carlton) 2011; 16(3): 349.
Kamoun M, Mnif MF, Charfi N, et al. Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies. Am J Med Sci 2014; 347(1): 64-73.
Nohira T, Nakada T, Akutagawa O, et al. Pregnancy complicated with Bartter’s syndrome: A case report. J Obstet Gynaecol Res 2001; 27(5): 267-74.
de Arriba G, Sánchez-Heras M, Basterrechea MA. Gitelman syndrome during pregnancy: A therapeutic challenge. Arch Gynecol Obstet 2009; 280(5): 807-9.
Rigó J Jr, Gláz E, Papp Z. Low or high doses of spironolactone for treatment of maternal Bartter’s syndrome. Am J Obstet Gynecol 1996; 174(1 Pt 1): 297.
Groves TD, Corenblum B. Spironolactone therapy during human pregnancy. Am J Obstet Gynecol 1995; 172(5): 1655-6.
Craft J. Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure. Proc Bayl Univ Med Cent 2004; 17(2): 217-20.
Hutter DA, Berkowitz R, Davis SE III, Ashtyani H. Application of continuous positive airway pressure in hypoxemic acute respiratory failure associated with diastolic dysfunction in pregnancy. Congest Heart Fail 2006; 12(3): 174-5.
Cabassi A, Rocco R, Berretta R, Regolisti G, Bacchi-Modena A. Eplerenone use in primary aldosteronism during pregnancy. Hypertension 2012; 59(2): e18-9.
Ruilope LM, Tamargo J. Renin-angiotensin system blockade: Finerenone. Nephrol Ther 2017; 13(Suppl. 1): S47-53.
Arai K, Homma T, Morikawa Y, et al. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist. Eur J Pharmacol 2015; 761: 226-34.
Kolkhof P, Nowack C, Eitner F. Nonsteroidal antagonists of the mineralocorticoid receptor. Curr Opin Nephrol Hypertens 2015; 24(5): 417-24.
Mulder P. Finerenone improves diastolic function in a preclinical model of type 2 diabetes mellitus. Eur Heart J 2016; 37: 829.
Lentini S, Heinig R, Kimmeskamp-Kirschbaum N, Wensing G. Pharmacokinetics, safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone - results from first-in-man and relative bioavailability studies. Fundam Clin Pharmacol 2016; 30(2): 172-84.
Heinig R, Kimmeskamp-Kirschbaum N, Halabi A, Lentini S. Pharmacokinetics of the novel Non-steroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) in individuals with renal impairment. Clin Pharmacol Drug Dev 2016; 5(6): 488-501.
Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: A randomized, double-blind trial. Eur Heart J 2013; 34(31): 2453-63.
Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 2016; 37(27): 2105-14.
Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: A randomized clinical trial. JAMA 2015; 314(9): 884-94.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy