Aldosterone Antagonists in the Treatment of Heart Failure

Todd R. Marcy; Toni L. Ripley


Am J Health Syst Pharm. 2006;63(1):49-58. 

In This Article

Available Aldosterone Antagonists

Spironolactone is a nonselective competitive antagonist of the aldosterone receptor. Administration also results in antagonism of the androgen, glucocorticoid, and progesterone receptors.[44] Spironolactone is extensively and rapidly metabolized to active metabolites, which contribute to a major portion of the aldosterone inhibition.[45,46] The most significant metabolites are 7-α-thiomethylspirolactone (TMS), canrenone, and 6-β-hydroxy-7-α-thiomethylspirolactone (HTMS).[45] Although the half-life of spironolactone is 1.4 hours, the half-lives of the metabolites range from 14 to 22 hours.[45,46] The relative antimineralcorticoid activity for TMS, canrenone, and HTMS is 1.28, 1.10, and 0.32, respectively, compared with spironolactone.[45]

Food increases the bioavailability of spironolactone by 100%, the clinical effect of which is unknown.[45] Both spironolactone and canrenone are more than 90% protein bound, principally to albumin.[45,47] Spironolactone is completely metabolized in the liver by deacetylation, dethiolation, and thiomethylation.[47] The metabolites are excreted in the urine and bile.[45] The dosage of spironolactone should be reduced in elderly patients, as increased serum concentrations of the drug have been found in this population.[48]

Eplerenone is a selective aldosterone antagonist. It is chemically derived from spironolactone by the addition of a 9α,11α-epoxy bridge and by substitution of the 17α-thioacetyl group of spironolactone with a carbomethoxy group.[47,49] Eplerenone is well absorbed following oral administration, with a bioavailability of approximately 67% and reaching a peak plasma concentration in about 1.5 hours.[50,51] Food does not affect its absorption.[47] Eplerenone is metabolized by the cytochrome P-450 (CYP) isoenzyme 3A4 to inactive metabolites.[51,52] Eplerenone concentrations increase with the concomitant administration of the CYP 3A4 inhibitor ketoconazole, suggesting that dosage adjustments may be appropriate for patients receiving a potent CYP 3A4 inhibitor while taking eplerenone.[52] However, eplerenone does not inhibit CYP isoenzyme systems.[51] The metabolism of eplerenone may be altered in patients with advanced age, renal impairment, hepatic impairment, or heart failure. Because these conditions may result in elevated eplerenone concentrations, these patients require more frequent monitoring for the effects of eplerenone accumulation, including hyperkalemia.

Eplerenone is eliminated in the urine (67%) and feces (32%). Only 6.8% of the eliminated drug is unchanged as the parent compound.[50] The elimination half-life is approximately four to six hours.[51] Eplerenone is approximately 50% protein bound. Eplerenone exhibits minimal activity against androgen, glucocorticoid, or progesterone receptors.[44]

The relative antialdosterone effect of spironolactone and eplerenone is unclear. Using mineralocorticoid receptors removed from rats, eplerenone had a binding affinity for the mineralocorticoid receptor that was 20-fold less than that of spironolactone and half that of canrenone.[44] The same study found that a lower dose of eplerenone was needed to inhibit aldosterone binding in rats by 50% compared with spironolactone (0.8 mg/kg versus 1.7 mg/kg, respectively). The explanation for this is likely related to the drugs' relative availability at the receptor level, as eplerenone is significantly less protein bound than spironolactone or canrenone. In humans, however, eplerenone may be 50–75% as potent as spironolactone (milligram per milligram).[53] Table 1 compares the pharmacology and pharmacokinetics of spironolactone and eplerenone.