Adverse Effects of Mineralocorticoid Receptor Antagonist Administration

Abstract

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.

The Time to Reconsider Mineralocorticoid Receptor Blocking Strategy: Arrival of Nonsteroidal Mineralocorticoid Receptor Blockers

“…Evaluation of the transcriptional activity of those steroidal receptors demonstrated that spironolactone blocks ligand binding to human glucocorticoid receptors (GR), androgen receptors (AR), and progesterone receptors (PR) with IC 50 values of 2600, 640, and 180 nM, respectively (Table 1 ) [ 16 ]. Furthermore, spironolactone also acts as a moderate agonist for ARs and PRs, contributing to off-target side effects such as gynecomastia and irregular menstruation [ 15 ]. To compensate for those unfavorable nature of spironolactone, eplerenone was synthesized as a more selective MRB.…”

“…Since the discovery in 1957 of a unique class of synthetic steroids, “spirolactones” which abolish aldosterone effects [ 9 ], several mineralocorticoid receptor blockers (MRBs) have been developed and proven to contribute to organ protection, particularly in heart failure (HF), diabetic kidney disease (DKD), and chronic kidney disease (CKD), beyond its antihypertensive effects [ 8 , 10 – 12 ]. In the current situation, spironolactone (SC-9420) and eplerenone (SC-66110, CGP-30083) are two major steroidal MRBs supported by abundant clinical evidence from many momentous trials, while those studies also elucidate limitations of those steroidal MRBs in hypertension treatment, including both renal-related and off-target side effects [ 13 – 15 ].…”

Effects of sodium‐glucose cotransporter‐2 inhibitors and aldosterone antagonists, in addition to renin‐angiotensin system antagonists, on major adverse kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A systematic review and network meta‐analysis

“…6 However, due to their low selectivity, these classic MRAs may lead to serum potassium elevation, the development of gynaecomastia, female menstrual disorders, and other undesirable effects, which limits their clinical use, especially in combination with RAAS blockade. 7 In recent years, evidence has shown that the novel nonsteroidal MRA finerenone has excellent selectivity for the mineralocorticoid receptor and may have a smaller effect on serum potassium levels than classic MRAs. 8,9 However, there are no kidney outcome trials that have directly compared the efficacy of these classes.…”

“…In addition, a growing amount of evidence indicates that the use of mineralocorticoid receptor antagonist (MRA) medications also contributes to slowing the progression of CKD 6 . However, due to their low selectivity, these classic MRAs may lead to serum potassium elevation, the development of gynaecomastia, female menstrual disorders, and other undesirable effects, which limits their clinical use, especially in combination with RAAS blockade 7 . In recent years, evidence has shown that the novel nonsteroidal MRA finerenone has excellent selectivity for the mineralocorticoid receptor and may have a smaller effect on serum potassium levels than classic MRAs 8,9 .…”

Phase 1 Studies to Define the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone in Healthy Volunteers

“…Disadvantages associated with therapeutic applications of existing steroidal MRAs include the poor specificity of spironolactone for MRs, which may therefore be associated with adverse events (AEs) related to sex hormone activity, such as breast tenderness, gynecomastia, and menstrual irregularity 17 . In addition, eplerenone has weaker affinity than spironolactone for androgen and progesterone receptors but is contraindicated in diabetic patients with proteinuria and moderate or severe renal dysfunction because of an increased risk of hyperkalemia 2,18 …”