Eplerenone

Eplerenone is a selective aldosterone blocker (SAB) approved for the treatment of essential hypertension. Oral eplerenone reduced BP effectively in patients with essential hypertension, both as monotherapy and in combination with other agents. The drug is generally well tolerated; the risk of hyperkalemia can be managed through careful selection and monitoring of patients. Preliminary data suggest that treatment of hypertension with eplerenone may provide protective effects against end-organ disease; further work is needed to elucidate the clinical significance of these findings, and to evaluate the outcome of treatment of hypertension in terms of cardiovascular morbidity and mortality and quality of life. In the meantime, as the first SAB to become available, eplerenone is an interesting addition to the drugs currently available for the treatment of hypertension.

Eplerenone is an SAB with up to 1000-fold higher binding affinity for the mineralocorticoid receptor than for other steroid receptors, such as those for progesterone and androgens. Eplerenone competitively inhibits aldosterone binding to mineralocorticoid receptors and blocks its effects in both epithelial and nonepithelial tissues, including the kidney, heart, and vasculature. In animal models, in addition to causing natriuresis, eplerenone reduced vascular and myocardial fibrosis, attenuated the effects of vasoactive mediators on the vascular endothelium, and reduced cardiac hypertrophy.

After oral administration, eplerenone is rapidly absorbed with a mean peak plasma concentration (C_max) of 1.72 μg/mL achieved approximately 1.2 hours after administration of a single 100mg dose; the mean area under the plasma concentration-time curve (AUC) was 9.54 μg · h/mL. Steady-state concentrations are reached within 2 days. Eplerenone is approximately 33–66% protein bound, and the apparent volume of distribution at steady state was 43–90L. Eplerenone is extensively metabolized, predominantly by cytochrome P450 (CYP) 3A4; no active metabolites have been identified. The apparent plasma clearance of eplerenone was approximately 10 L/h and the elimination half-life was 3–6 hours. Following a single oral dose of eplerenone, 67% was eliminated in the urine and 32% in the feces.

Although C_max and AUC increased in patients with severe renal impairment, patients with moderate hepatic impairment, and elderly volunteers, the extent of the increased exposure does not necessitate dose adjustments in these patients. Nonetheless, eplerenone is not recommmended for use in patients with severe renal impairment (see Tolerability Summary). C_max and AUC were lower in Black patients than White patients. Coadministered inhibitors of CYP3A4 increased blood levels of eplerenone; strong inhibitors (e.g. ketoconazole) increased systemic exposure to eplerenone 5-fold and concomitant administration is contraindicated.

Eplerenone 25–400mg daily reduced BP significantly compared with placebo in patients with hypertension, with a clear dose response up to 100mg daily, and no effect on heart rate. At a dosage of 100mg daily, DBP was reduced by approximately 4–8mm Hg and SBP by 8–12mm Hg. Based on preliminary data, eplerenone 50–200mg once daily demonstrated similar antihypertensive activity to enalapril 10–40mg once daily in patients with mild-to-moderate hypertension and amlodipine 2.5–10mg once daily in patients with systolic hypertension. Eplerenone 50–200mg once daily showed at least as good efficacy as losartan 50–100mg once daily in patients with low-renin hypertension and greater efficacy in Black patients.

Eplerenone add-on therapy improved control of SBP and DBP with angiotensin II receptor antagonists (and, based on preliminary data, β-adrenoceptor antagonists), and control of SBP with ACE inhibitors (and calcium channel antagonists, based on preliminary data), with tolerability similar to monotherapy. In placebo-controlled trials, BP control was maintained for 24 hours with once daily dosages, although in one study 50mg twice daily reduced mean trough BP more than 100mg once daily.

Preliminary data also indicate that eplerenone decreased surrogate markers of end-organ protection in patients with hypertension, including microalbuminuria (at dosages of 50–200mg once daily) and left ventricular hypertrophy (200mg once daily). The combination of eplerenone with enalapril was more effective than eplerenone alone.

Based on the available data, eplerenone was generally well tolerated in patients with hypertension, with an overall incidence of adverse events similar to placebo; the most common adverse events in the hypertension studies were dizziness, fatigue, influenza-like symptoms, cough, and diarrhea, all with a low incidence (≤3%). The incidence of antiandrogenic and progestogenic adverse effects with eplerenone was similar to that for placebo. The incidence of hyperkalemia increased at a dosage of 400mg daily compared with lower dosages; the risk of hyperkalemia also increased in patients with renal insufficiency.