indication

For improvement of survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction.

pharmacology

Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.

mechanism of action

Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.

toxicity

The most likely symptoms of human overdosage would be anticipated to be hypotension or hyperkalemia. However, no cases of human overdosage with eplerenone have been reported.

biotransformation

Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma.

absorption

The absolute bioavailability of eplerenone is unknown.

half life

4-6 hours

drug interactions

Amiloride: Increased risk of hyperkalemia. Monitor serum potassium levels during concomitant threapy.

Bicalutamide: CYP3A4 Inhibitors like bicalutamide may increase the serum concentration of eplerenone. A lower starting dose of eplerenone (25 mg once daily) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4.

Clarithromycin: The macrolide, clarithromycin, may increase the effect and toxicity of eplerenone.

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. The combination of eplerenone with any strong CYP3A4 inhibitor is contraindicated.

Erythromycin: This CYP3A4 inhibitor increases the effect and toxicity of eplerenone

Fluconazole: This CYP3A4 inhibitor increases the effect and toxicity of eplerenone

Itraconazole: Itraconazole may increase the effect and toxicity of eplerenone.

Ketoconazole: Ketoconazole, a CYP3A4 inhibitor, may increase the effect and toxicity of eplerenone.

Lithium: Eplerenone increases serum levels of lithium

Nefazodone: Nefazodone increases the effect and toxicity of eplerenone

Nelfinavir: The protease inhibitor, nelfinavir, may increase the effect and toxicity of eplerenone.

Polystyrene sulfonate: Risk of alkalosis in renal impairment

Potassium: This association presents an increased risk of hyperkalemia

Ritonavir: This protease inhibitor, ritonavir, may increase the effect and toxicity of eplerenone.

Saquinavir: This CYP3A4 inhibitor increases the effect and toxicity of eplerenone

Spironolactone: This association presents an increased risk of hyperkalemia

Telithromycin: Telithromycin may reduce clearance of Eplerenone. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Eplerenone if Telithromycin is initiated, discontinued or dose changed.

Trandolapril: Increased risk of hyperkalemia. Monitor serum potassium levels.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Triamterene: This association presents an increased risk of hyperkalemia

Troleandomycin: The macrolide, troleandomycin, may increase the effect and toxicity of eplerenone.

Verapamil: This CYP3A4 inhibitor increases the effect and toxicity of eplerenone

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of eplerenone by decreasing its metabolism. Concomitant therapy is contraindicated.