Chemistry:Eplerenone

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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.[1][2] It may also be considered as an add-on therapy in resistant hypertension;[3] 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.[4]

It is also a steroidal antimineralocorticoid of the spirolactone group and a selective aldosterone receptor antagonist (SARA).[5]

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.[6][7] It has also been demonstrated to increase LVEF by an average of 4.95%.[7] These benefits are seen when used with other cornerstone heart failure therapies such as an ACE inhibitor or Angiotensin II receptor blocker, beta blocker, and a diuretic .[7]

Hypertension

Eplerenone lowers blood pressure in patients with primary hypertension.[8] Eplerenone also reduces arterial stiffness and vascular endothelial dysfunction.[9]

For persons with resistant hypertension, eplerenone is safe and effective for reducing blood pressure,[10] particularly in persons with resistant hypertension due to hyperaldosteronism.[11][12]

Central serous chorioretinopathy

Eplerenone is often prescribed for people with central serous chorioretinopathy (CSC). However, the most recent and largest randomized controlled trial showed that eplerenone has no significant effect on chronic CSC that has been untreated for four months.[13][14] 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.[15]

Adverse effects

Common adverse drug reactions (ADRs) associated with the use of eplerenone include: hyperkalaemia, hypotension, dizziness, and reduced renal clearance.[16] 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.[17][18] This is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes.[19] When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone.[19]

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.[8]

Interactions

Eplerenone is primarily metabolized by the cytochrome P450 enzyme CYP3A4. 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 and itraconazole is contraindicated. Other CYP3A4 inhibitors including erythromycin, saquinavir, and verapamil should be used with caution. Other drugs that increase potassium concentrations may increase the risk of hyperkalemia associated with eplerenone therapy, including salt substitutes,[20] potassium supplements and other potassium-sparing diuretics.

Pharmacology

Eplerenone is an antimineralocorticoid, or an antagonist of the mineralocorticoid receptor (MR).[21] 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."[22] The drug controls high blood pressure by blocking the binding of aldosterone to the mineralocorticoid receptor (MR) in epithelial tissues, such as the kidney.[19] Blocking the action of aldosterone decreases blood volume and lowers blood pressure.[23] It has 10- to 20-fold lower affinity for the MR relative to spironolactone,[21] and is less potent in vivo as an antimineralocorticoid.[19] However, in contrast to spironolactone, eplerenone has little affinity for the androgen, progesterone, and glucocorticoid receptors.[21][19] It also has more consistently observed non-genomic antimineralocorticoid effects relative to spironolactone (see membrane mineralocorticoid receptor).[19] Eplerenone differs from spironolactone in its extensive metabolism, with a short half-life and inactive metabolites.[19]

Eplerenone seems to be about 50 to 75% as potent as spironolactone as an antimineralocorticoid.[19] Hence, 25 mg/day spironolactone may be equivalent to approximately 50 mg/day eplerenone.[24]

Society and culture

Eplerenone was patented in 1983 and approved for medical use in the United States in 2002.[25][23] Eplerenone is approved for sale in Canada, the US, the EU, Netherlands, and Japan.[23]

Economics

Eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension.[26]

Brand names

In the US, Inspra is marketed by Viatris after Upjohn was spun off from Pfizer.[27][28][29]

References

  1. ↑ "Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction" (in en). New England Journal of Medicine 348 (14): 1309–1321. 2003-04-03. doi:10.1056/NEJMoa030207. ISSN 0028-4793. PMID 12668699. http://www.nejm.org/doi/abs/10.1056/NEJMoa030207. 
  2. ↑ "Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms" (in en). New England Journal of Medicine 364 (1): 11–21. 2011-01-06. doi:10.1056/NEJMoa1009492. ISSN 0028-4793. PMID 21073363. http://www.nejm.org/doi/abs/10.1056/NEJMoa1009492. 
  3. ↑ "Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association". Hypertension 72 (5): e53–e90. November 2018. doi:10.1161/HYP.0000000000000084. PMID 30354828. 
  4. ↑ "The Effects of Aldosterone Antagonists in Patients With Resistant Hypertension: A Meta-Analysis of Randomized and Nonrandomized Studies" (in en). American Journal of Hypertension 28 (11): 1376–1385. November 2015. doi:10.1093/ajh/hpv031. ISSN 0895-7061. PMID 25801902. https://academic.oup.com/ajh/article-lookup/doi/10.1093/ajh/hpv031. 
  5. ↑ "Eplerenone: a selective aldosterone receptor antagonist (SARA)". Cardiovascular Drug Reviews 19 (3): 185–200. 2001. doi:10.1111/j.1527-3466.2001.tb00064.x. PMID 11607037. 
  6. ↑ "Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials" (in en). Heart Failure Reviews 25 (2): 161–171. March 2020. doi:10.1007/s10741-019-09832-y. ISSN 1382-4147. PMID 31364027. http://link.springer.com/10.1007/s10741-019-09832-y. 
  7. ↑ 7.0 7.1 7.2 "Mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: a systematic review and network meta-analysis of 32 randomized trials". Current Problems in Cardiology 49 (7). 2024-07-01. doi:10.1016/j.cpcardiol.2024.102615. ISSN 0146-2806. PMID 38692445. https://linkinghub.elsevier.com/retrieve/pii/S0146280624002548. 
  8. ↑ 8.0 8.1 "Eplerenone for hypertension". The Cochrane Database of Systematic Reviews 2017 (2). February 2017. doi:10.1002/14651858.CD008996.pub2. PMID 28245343. 
  9. ↑ "Effect of Mineralocorticoid Receptor Blockade on Arterial Stiffness and Endothelial Function: A Meta-Analysis of Randomized Trials". Hypertension (Dallas, Tex.) 77 (3): 929–937. March 2021. doi:10.1161/HYPERTENSIONAHA.120.16397. PMID 33461316. 
  10. ↑ "The Effects of Aldosterone Antagonists in Patients With Resistant Hypertension: A Meta-Analysis of Randomized and Nonrandomized Studies". American Journal of Hypertension 28 (11): 1376–1385. November 2015. doi:10.1093/ajh/hpv031. PMID 25801902. 
  11. ↑ "Management of primary aldosteronism and mineralocorticoid receptor-associated hypertension". Hypertension Research 43 (8): 744–753. August 2020. doi:10.1038/s41440-020-0468-3. PMID 32424201. 
  12. ↑ "Rational Medical Therapy Is the Key to Effective Cardiovascular Disease Prevention". The Canadian Journal of Cardiology 33 (5): 626–634. May 2017. doi:10.1016/j.cjca.2017.01.003. PMID 28449833. 
  13. ↑ "Eplerenone does not improve vision in people with central serous chorioretinopathy" (in en). NIHR Evidence (National Institute for Health and Care Research). 25 March 2020. doi:10.3310/signal-000893. https://evidence.nihr.ac.uk/alert/eplerenone-does-not-improve-vision-in-people-with-central-serous-chorioretinopathy/. 
  14. ↑ "Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial". Lancet (London, England) 395 (10220): 294–303. January 2020. doi:10.1016/S0140-6736(19)32981-2. PMID 31982075. 
  15. ↑ "Oral Eplerenone Versus Observation in the Management of Acute Central Serous Chorioretinopathy: A Prospective, Randomized Comparative Study". Pharmaceuticals (Basel, Switzerland) 13 (8): 170. July 2020. doi:10.3390/ph13080170. PMID 32751370. 
  16. ↑ Australian Medicines Handbook 2006. Australian Medicines Handbook. 2006. ISBN 978-0-9757919-2-9. 
  17. ↑ "Eplerenone Versus Spironolactone in Resistant Hypertension: an Efficacy and/or Cost or Just a Men's Issue?" (in en). Current Hypertension Reports 21 (3): 22. 2019-03-02. doi:10.1007/s11906-019-0924-0. ISSN 1534-3111. PMID 30826898. https://link.springer.com/article/10.1007/s11906-019-0924-0. 
  18. ↑ "A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism" (in en-US). Journal of Hypertension 29 (5): 980–990. May 2011. doi:10.1097/HJH.0b013e3283455ca5. ISSN 0263-6352. PMID 21451421. https://journals.lww.com/jhypertension/abstract/2011/05000/a_double_blind,_randomized_study_comparing_the.24.aspx. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 "A comparison of the aldosterone-blocking agents eplerenone and spironolactone". Clinical Cardiology 31 (4): 153–158. April 2008. doi:10.1002/clc.20324. PMID 18404673. 
  20. ↑ "LoSalt Advisory Statement". http://www.losalt.com/docs/lo_salt_web_advice.pdf. 
  21. ↑ 21.0 21.1 21.2 "Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology". Kidney International 57 (4): 1408–1411. April 2000. doi:10.1046/j.1523-1755.2000.00983.x. PMID 10760075. 
  22. ↑ "Eplerenone: cardiovascular protection". Circulation 107 (19): 2512–2518. May 2003. doi:10.1161/01.CIR.0000071081.35693.9A. PMID 12756192. 
  23. ↑ 23.0 23.1 23.2 "Inspra (Eplerenone)". http://www.drugdevelopment-technology.com/projects/inspraeplerenonefort/. 
  24. ↑ Coronary Care Manual. Elsevier Health Sciences. 28 January 2011. pp. 254–. ISBN 978-0-7295-7927-8. https://books.google.com/books?id=QEltbLcmIN8C&pg=PA254. 
  25. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 459. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA459. 
  26. ↑ "Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure". Proceedings (Baylor University. Medical Center) 17 (2): 217–220. April 2004. doi:10.1080/08998280.2004.11927973. PMID 16200104. 
  27. ↑ "Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan". Pfizer. 16 November 2020. https://www.businesswire.com/news/home/20201116005378/en/. 
  28. ↑ "Inspra". https://www.pfizer.com/products/product-detail/inspra. 
  29. ↑ "Brands". 16 November 2020. https://www.viatris.com/en/products/brands. 



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