Eplerenone
• Background: Eplerenone (11α-Epoxymexrenone) is an orally administered aldosterone antagonist which is widely prescribed as an adjunct medication to treat hypertension and cardiac failure [1]. Eplerenone reduces blood pressure and improves survival in patients who have suffered from myocardial infarction [2]. The drug being highly specific to the aldosterone receptor, patients using eplerenone do not exhibit side-effects which are common for alternative blood-pressure reduction medications such as spironolactone [3]. Although eplerenone was chemically derived from the parent drug spironolactone, eplerenone is more efficient and safer as an anti-hypertensive drug. Eplerenone was first developed by Pharmacia Corporation (later acquired by Pfizer), and was approved by the FDA for sale in the US under the trade name Inspra® [4]. The drug is currently approved in EU, US, Canada, Japan and Netherlands for the treatment of hypertension [5]. In the US, eplerenone is also approved for improving heart function in patients with left ventricular systolic dysfunction following an acute myocardial infarction [6].
• Mode of Action: Aldosterone is the primary mineralocorticoid hormone in the human body and is produced by the adrenal gland [7]. It plays an essential role in sodium and potassium ion exchange in vital organs such as the kidneys, sweat glands and salivary glands [8]. In stressful conditions such as water loss or a deprivation of dietary sodium, the aldosterone system is life-saving as it maintains blood-pressure and homeostasis. Aldosterone exerts its effect by binding to mineralocorticoid receptor (MR) present on epithelial cells of organs such as the kidney, leading to an enhanced excretion of potassium ions and retention of sodium ions [9]. Since the balance between the levels of sodium and potassium ions, govern blood pressure, increase in blood aldosterone levels increases the chances of coronary artery disease, stroke, myocardial infarction and sudden death in heart patients [10, 11]. The level of plasma aldosterone is a critical factor which determines survival in patients with heart diseases [12]. Eplerenone, a MR antagonist, thus competes with aldosterone for binding at the MR [13]. The drug is highly selective for mineralocorticoid receptor and has little affinity for other steroid hormone receptors, making it the drug of choice to treat hypertension without any side-effects.
• Dosage, Administration and Pharmacokinetics: Eplerenone is primarily available as 25 or 50 mg tablets and is administered orally. The recommended dose of the drug for treating hypertension is usually 50-100 mg daily depending on the severity of the disease. Typical treatment regime starts with a 4-week administration of the drug. Blood-pressure and blood electrolyte (Sodium/Potassium ions) of the patient are monitored each week and periodically thereafter [6]. For treating heart failure, the recommended dose is 25 mg daily which may be continued for up to 4 weeks. The maximum effective dose is limited to 100 mg per day, beyond which there may be associated side-effects such as hyperkalemia [1]. Administration of a 100 mg oral tablet results in an absolute bioavailability of 69% [14]. Pharmacokinetic studies on healthy volunteers have demonstrated that a 100 mg dose of the drug results in a mean maximum plasma concentration (Cmax) of 1.72 μg/mL, which is reached 1.3 hours after drug administration [15]. Eplerenone is easily metabolised in the body. Metabolism of eplerenone is mediated by isozyme CYP3A4 of cytochrome P450 (CYP). Approximately 50% of administered eplerenone binds to plasma proteins, primarily apha l-acid glycoproteins. There are no active metabolites in the plasma after the drug has been completely metabolized. The drug has an elimination half-life of ≈4–6 hours [15]. Following administration of a single oral dose of the drug, approximately 32% of the drug is excreted in the feces and ~67% through urine. The elimination half-life of the drug is about 3 to 6 hours [6].
• Safety and Efficacy of Eplerenone in Clinical Trials: To assess the efficacy of eplerenone in treating hypertension and cardiac failure, several comprehensive and carefully controlled clinical trials have been performed in Japanese patients over the years. These studies have all pointed towards the general efficacy of the drug in clinical setting. The earliest of such reports was published in 2004, when the safety and efficacy of eplerenone was tested on 193 Japanese patients with essential hypertension. This randomized, placebo-controlled, multi-centered and double-blinded trial showed that patients receiving eplerenone treatment demonstrated a marked reduction in systolic (a reduction of 6.8-10.6 mm Hg.) as well as diastolic (a reduction of 6.9 to 7.5 mm of Hg.) blood-pressure. The control group receiving placebo showed a reduction of ~2.1 mm and ~3.0 mm. Hg of systolic and diastolic blood-pressures respectively. Eplerenone emerged victorious with significant efficacy in the treatment of essential hypertension compared to alternative medications. The added advantage of eplerenone is that it showed no side-effects in the patients [16]. In another study the efficacy of eplerenone as an adjunct therapy to alternative medications such as angiotensin-converting enzyme (ACE) inhibitor or a long acting calcium channel blocker (CCB) was assessed in a group of 68 Japanese patients suffering from essential hypertension. The study showed that the group which received eplerenone as an adjunct therapy demonstrated a reduction in blood-pressure after 4 weeks of treatment. This group demonstrated a further reduction in blood-pressure as the treatment continued up to 24 weeks. There were no significant differences in plasma sodium/potassium levels between the control group which received only alternate medication vs. the test group which received eplerenone as an adjunct therapy. The study demonstrated the beneficial anti-hypertensive effect of eplerenone when administered as an adjunct therapy in Japanese patients. This beneficial effect of the drug was shown to be independent of the patient’s renin profile and pre-treatment serum aldosterone levels [17]. In 2016, Pfizer Japan sponsored a large clinical trial to assess the safety and efficacy of eplerenone in a larger group of Japanese patients. A total of 3,166 patients were selected who never had a prior exposure to eplerenone. After only 12 weeks of treatment, a mean reduction of ~18 mm Hg of systolic and ~8 mm Hg of diastolic blood-pressure was observed in test patients compared to the control group. The only significant side-effect of the drug, hyperkalemia, was observed in only as few as 0.6% of the patients. The study reinforced the fact that eplerenone was not only efficient in blood-pressure management but also had minimum side-effects [18]. EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) was another placebo controlled and double-blinded clinical trial to assess the efficacy of eplerenone in Japanese patients with chronic heart failure due to a reduction in ejection fraction. Results indicated that 29.7% of the test group which received eplerenone treatment were later hospitalized for serious heart failure or death, whereas the comparative fraction in the placebo group was 32.7%. Eplerenone emerged to be moderately beneficial for congestive heart failure [19]. Similar clinical trials for the drug were conducted in the United States on a larger scale prior to its FDA approval in 2004. The EPHESUS (Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) project is one such clinical trial which was conducted to test the efficacy of eplerenone in the reduction of mortality in American patients with left ventricular dysfunction due to acute myocardial infarction. The eplerenone test group contained 3313 patients whereas the placebo group contained 3319 patients. Based on an 8 week treatments and a 16 month follow up period, there were 478 deaths in the eplerenone group while number of deaths for the placebo group was 554. The study concluded that administration of eplerenone markedly reduces morbidity and mortality in patients who have been suffering from left ventricular dysfunction following a fatal heart attack [2]. Eplerenone was approved for clinical use in Japan in 2007 for treating hypertension but, in contrast to Europe and USA, the drug has not yet been approved for the treatment of patients with chronic heart failure post-myocardial infarction [20].
• Precautions during Eplerenone Treatment: Patients suffering from elevated blood potassium levels, kidney disease or diabetes should consult with a doctor whether eplerenone is right for them. Eplerenone may increase blood potassium levels and this increase is more frequent in elder patients. Doctor should be consulted before using any salt/potassium supplement while undergoing eplerenone treatment. Patients with type 2 diabetes or elevated levels or blood creatinine should consult a doctor before eplerenone treatment [6]. Symptoms of eplerenone overdose might include severe dizziness, muscle weakness and/or irregular heartbeat. There are certain drugs (acebutolol, aldesleukin etc) which either interacts with eplerenone or its metabolites in vivo and should not be combined with eplerenone treatment.