Eplerenone, marketed under brand name Inspa or Espler, is an aldosterone antagonist used primarily in the treatment of heart failure with reduced ejection fraction (HFrEF), particularly following myocardial infarction. It may also be considered as an add-on therapy in resistant hypertension; however, the majority of evidence in this setting supports the use of spironolactone (another drug in a same class), with fewer studies directly evaluating eplerenone. It is also a

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

al antimineralocorticoid of the

spirolactone Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirol ...

group and a selective aldosterone receptor antagonist (SARA).

Medical uses

Heart failure

Eplerenone and other Mineralocorticoid receptor antagonists have been demonstrated to reduce the risk of death and hospitalisation in patients with heart failure with reduced ejection fraction (HFrEF) who have a left ventricular ejection fraction (LVEF) of 40% or less. It has also been demonstrated to increase LVEF by an average of 4.95%. These benefits are seen when used with other cornerstone heart failure therapies such as an ACE inhibitor or ARB, beta-blocker and a diuretic .

Hypertension

Eplerenone lowers blood pressure in patients with primary hypertension. Eplerenone also reduces arterial stiffness and vascular endothelial dysfunction. For persons with resistant hypertension, eplerenone is safe and effective for reducing blood pressure, particularly in persons with resistant hypertension due to hyperaldosteronism.

Central serous chorioretinopathy

Eplerenone is often prescribed for people with central serous chorioretinopathy (CSC). However, the most recent and largest

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

showed that eplerenone has no significant effect on chronic CSC that has been untreated for four months. There was one relatively large prospective, interventional case-control study that was tested in acute CSC that showed improved resolution of subretinal fluid in treatment group vs observational group (which is standard of care) with 45% resolution at end of 1st month, 55% at end of 2nd month, and 62% at end of 3rd month (vs 10%, 21%, and 31% in standard of care group). Study also showed faster resolution of visual acuity at the end of each month with 92% and 100% in the first two months vs 74% and 86% with resolution reaching 100% after the third month in standard of care group.

Adverse effects

Common

adverse drug reaction An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or may result from the combination of two or more drugs. The meaning of this ...

s (ADRs) associated with the use of eplerenone include: hyperkalaemia,

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

, dizziness, and reduced renal clearance. Eplerenone is associated with a lower incidence of sexual side effects, such as gynecomastia, impotence, and low sex drive, compared to spironolactone, likely due to its more selective action on the aldosterone receptor. This is because other antimineralocorticoids have structural elements of the

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

molecule, causing progestogenic and antiandrogenic outcomes. When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone. Currently, there is not enough evidence available from the randomized controlled trials on side effects of eplerenone to do a benefit versus risk assessment in people with primary hypertension.

Interactions

Eplerenone is primarily metabolized by the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

. Thus the potential exists for adverse drug interactions with other drugs that induce or inhibit CYP3A4. Specifically, the concomitant use of the CYP3A4 potent inhibitors

ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...

and

itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...

is contraindicated. Other CYP3A4 inhibitors including

erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...

saquinavir Saquinavir, sold under the brand name Invirase among others, is an antiretroviral medication used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. I ...

, and

verapamil Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be use ...

should be used with caution. Other drugs that increase

potassium Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...

concentrations may increase the risk of hyperkalemia associated with eplerenone therapy, including salt substitutes, potassium supplements and other

potassium-sparing diuretic Potassium-sparing diuretics or antikaliuretics refer to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The ster ...

Pharmacology

Eplerenone is an antimineralocorticoid, or an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...

(MR). Eplerenone is also known chemically as 9,11α-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone and "was derived from spironolactone by the introduction of a 9α,11α-epoxy bridge and by substitution of the 17α-thoacetyl group of spironolactone with a carbomethoxy group." The drug controls high blood pressure by blocking the binding of

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...

to the mineralocorticoid receptor (MR) in

epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

tissues, such as the kidney. Blocking the action of

decreases blood volume and lowers blood pressure. It has 10- to 20-fold lower

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the MR relative to

spironolactone Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication. It can be used to treat edema, fluid build-up due to hepatic cirrhosis, liver disease or kidney disease. It is also used to reduce risk o ...

, and is less potent ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' as an antimineralocorticoid. However, in contrast to spironolactone, eplerenone has little affinity for the

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

, and

glucocorticoid receptor The glucocorticoid receptor (GR or GCR) also known by its gene name ''NR3C1'' ( nuclear receptor subfamily 3, group C, member 1) is the steroid receptor for glucocorticoids such as cortisol. The GR is expressed in almost every cell in the bod ...

s. It also has more consistently observed non-genomic antimineralocorticoid effects relative to spironolactone (see membrane mineralocorticoid receptor). Eplerenone differs from spironolactone in its extensive metabolism, with a short half-life and inactive metabolites. Eplerenone seems to be about 50 to 75% as potent as spironolactone as an antimineralocorticoid. Hence, 25 mg/day spironolactone may be equivalent to approximately 50 mg/day eplerenone.

Society and culture

Eplerenone was patented in 1983 and approved for medical use in the United States in 2002. Eplerenone is approved for sale in Canada, the US, the EU, Netherlands, and Japan.

Economics

Eplerenone costs an estimated $2.93 per day when treating

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...

and $5.86 per day when treating

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

Brand names

In the US, Inspra is marketed by Viatris after Upjohn was spun off from Pfizer.

References

{{Mineralocorticoid receptor modulators Antimineralocorticoids Epoxides Lactones Methyl esters Drugs developed by Pfizer Pregnanes Spirolactones Spiro compounds