Eplerenone

A validated SPE-LC-MS/MS assay for Epierenone and its hydrolyzed metabolite in human urine, J.Pharm.BiomedAncd., 2003, 31, 103-115. 

Burton, E.G. Hribar, J.D. Zhang, L. Involvement of CYP3A in the metabolism of epierenone in humans and dogs Differentisil metabohsm by CYP3A4 tmd CYP3A5, Drug Metab.Dispos., 2002, 30, 1344-1351. [radioactivity detection ( C) LC-MS] 

Atypical dose-route-dependent food effects of epierenone in the dog Presence of food effects following intravenous dosing and lack of food effects of following ortil dosing, J.Pharm.ScL, 2002, 91, 607-614. 

Hribar, J.D. Hajdu, E. Liu, N.W. Pharmacokinetics and metabolism of [ C]eplerenone after oral administration to humans. Drug Metab.Dispos., 2003, 31, 1448-1455. [radioactivity detection LC-MS] 

Fischer, J. Zhang, J. Levin, S. Single-and repeated-dose pharmacokinetics of epierenone, a selective aldosterone receptor blocker, in rats, Xenobiotica, 2003, 33, 305-321. [LC-MS SPE] 

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ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

Antihypertensive drug name and dose is associated with compelling indications which are based on benefits from outcome studies or clinical guidelines. For example, the drug class aldosterone antagonists have eplerenone dosed at 25-50 mg per day which is indicated for heart failure patients after an Ml and supported by the EPHESUS trial. 

Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Trial... 

Eplerenone 25 mg once 50 mg once baseline and within 1 week of initiation and dose titration Adverse effects gynecomastia or breast tenderness, menstrual changes, hirsutism... 

In patients without contraindications, spironolactone is initiated at a dose of 12.5 to 25 mg daily, or occasionally on alternate days for patients with baseline renal insufficiency. Eplerenone is used at a dose of 25 mg daily, with the option to titrate up to 50 mg daily. Doses should be halved or switched to alternate-day dosing if creatinine clearance falls below 50 mL/minute. Potassium supplementation is often decreased or stopped after aldosterone antagonists are initiated, and patients should be counseled to avoid high-potassium foods. At anytime after initiation of therapy, if potassium concentrations exceed... 

Because the costs for chronic preventative pharmacotherapy are the same for primary and secondary prevention, while the risk of events is higher with secondary prevention, secondary prevention is more cost effective than primary prevention of CHD. Pharmacotherapy demonstrating cost effectiveness to prevent death in the ACS and post-MI patient includes fibrinolytics ( 2,000 to 33,000 cost per year of life saved), aspirin, glycoprotein Ilb/IIIa receptor blockers ( 13,700 to 16,500 per year of life added), (3-blockers (less than 5,000 to 15,000 cost per year of life saved), ACE inhibitors ( 3,000 to 5,000 cost per year of life saved), eplerenone ( 15,300 to 32,400 per year of life gained), statins ( 4,500 to 9,500 per year of life saved) and gemfibrozil ( 17,000 per year of life saved).49-58 Because cost-effectiveness ratios of less than 50,000 per added life-year are considered economically attractive from a societal perspective,49 pharmacotherapy described above for ACS and secondary prevention are standards of care because of their efficacy and cost attractiveness to payors. 

To reduce mortality, administration of an aldosterone antagonist, either eplerenone or spironolactone, should be considered within the first 2 weeks following MI in all patients who are already receiving an ACE inhibitor (or ARB) and have an EF of equal to or less than 40% and either heart failure symptoms or diagnosis of diabetes mellitus.3 Aldosterone plays an important role in heart failure and in MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, hypertension, left ventricular hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. Aldosterone antagonists have been shown in experimental and human studies to attenuate these adverse effects.70 Spironolactone decreases all-cause mortality in patients with stable, severe heart failure.71... 

Either eplerenone or spironolactone should be considered within the first 2 weeks after MI to reduce mortality in all patients already receiving an ACE inhibitor who have LVEF <40% and either heart failure symptoms or a diagnosis of diabetes mellitus. The drugs are continued indefinitely. Example oral doses include the following ... 

Eplerenone 25 mg initially target dose 50 mg once daily. 

Spironolactone and eplerenone block the mineralocorticoid receptor, the target site for aldosterone. In the kidney, aldosterone antagonists inhibit sodium reabsorption and potassium excretion. However, diuretic effects are minimal, suggesting that their therapeutic benefits result from other... 

Initial doses should be low (spironolactone 12.5 mg/day eplerenone 25 mg/day), especially in the elderly and those with diabetes or creatinine clearance <50 mL/min. A spironolactone dose of 25 mg/day was used in one major clinical trial. The eplerenone dose should be titrated to the target dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient. 

Aldosterone antagonists (spironolactone, eplerenone) are also potassium-sparing diuretics but are more potent antihypertensives with a slow onset of action (up to 6 weeks with spironolactone). 

Potassium-sparing diuretics may cause hyperkalemia, especially in patients with chronic kidney disease or diabetes, and in patients receiving concurrent treatment with an ACE inhibitor, ARB, NSAID, or potassium supplement. Eplerenone has an increased risk for hyperkalemia and is contraindicated in patients with impaired renal function or type 2 diabetes with proteinuria. Spironolactone may cause gynecomastia in up to 10% of patients, but this effect occurs rarely with eplerenone. 

The aldosterone antagonist eplerenone reduces CV morbidity and mortality in patients soon after an acute MI (within 3 to 14 days) in patients with... 

Spironolactone is poorly absorbed after oral administration and has a delayed onset of action it may take several days until a peak effect is produced. It has a somewhat slower onset of action than triamterene and amiloride (discussed later), but its natriuretic effect is modestly more pronounced, especially during long-term therapy. Spironolactone is rapidly and extensively metabolized, largely to the active metabohte canrenone. Canrenone and potassium canrenoate, its K+ salt, are available for clinical use in some countries outside the United States. Canrenone has a half-life of approximately 10 to 35 hours. The metabolites of spironolactone are excreted in both the urine and feces. New selective aldosterone receptor antagonists (SARA), such as eplerenone, have been developed but have not yet been introduced into clinical practice. Eplerenone and canrenone exhibit fewer steroidlike side effects (gynecomastia, hirsutism). 

Primary advantage of eplerenone over spironolactone is a potentially decreased incidence of endocrine-related adverse effects, such as gynecomastia or sexual dysfunction... 

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