Eplerenone

Eplerenone
Names
Pronunciation/ɛpˈlɛrənoʊn/
Trade namesInspra, Epnone, Dosterep, others
Other namesSC-66110; CGP-30083; 9-11α-Epoxymexrenone; 9,11α-Epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone
IUPAC name
  • methyl (4aS,4bR,5aR,6aS,7R,9aS,9bR,10R)-4a,6a-dimethyl-2,5'-dioxo-2,4,4',4a,5',5a,6,6a,8,9,9a,9b,10,11-tetradecahydro-3H,3'H-spiro[cyclopenta[7,8]phenanthro[4b,5-b]oxirene-7,2'-furan]-10-carboxylate
Clinical data
Drug classAldosterone antagonist, potassium-sparing diuretic[1]
Main usesHeart failure, high blood pressure[2]
Side effectsHigh blood potassium, diarrhea, breast enlargement, abdominal pain[2]
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
    Routes of
    use    		By mouth (tablets)
    Onset of actionWithin 2 weeks[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa603004
    Legal
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    Pharmacokinetics
    Bioavailability~70%[3]
    Protein binding~50% (33–60%) (primarily to α1-acid glycoprotein)[3][4]
    MetabolismLiver (CYP3A4)[3][4]
    Metabolites6β-OH-EPL, 6β,21-OH-EPL, 21-OH-EPL, 3α,6β-OH-EPL[3] (All inactive)[3]
    Elimination half-life4–6 hours[5]
    ExcretionUrine (67%), feces (32%)[6]
    Chemical and physical data
    FormulaC24H30O6
    Molar mass414.498 g·mol−1
    3D model (JSmol)
    SMILES
    • COC(=O)[C@@H]4C\C1=C\C(=O)CC[C@]1(C)[C@@]65O[C@@H]6C[C@@]3(C)[C@@H](CC[C@]23CCC(=O)O2)[C@H]45
    InChI
    • InChI=1S/C24H30O6/c1-21-7-4-14(25)10-13(21)11-15(20(27)28-3)19-16-5-8-23(9-6-18(26)30-23)22(16,2)12-17-24(19,21)29-17/h10,15-17,19H,4-9,11-12H2,1-3H3/t15-,16+,17-,19+,21+,22+,23-,24-/m1/s1 checkY
    • Key:JUKPWJGBANNWMW-VWBFHTRKSA-N checkY

    Eplerenone, sold under the brand name Inspra among others, is a medication used to treat heart failure and high blood pressure.[2] For high blood pressure it is a second line treatment.[2] It is taken by mouth.[2] Effects generally occur within 2 weeks.[2]

    Common side effects include high blood potassium, diarrhea, breast enlargement, and abdominal pain.[2] Other side effects may include arrhythmias, angioedema, and low blood pressure with standing.[1] It is a aldosterone antagonist and a potassium-sparing diuretic.[1]

    Eplerenone was approved for medical use in the United States in 2002.[2] It is available as a generic medication.[1] In the United Kingdom a month of medication costs the NHS about £25.[1] This amount in the United States costs about 19 USD as of 2021.[7]

    Medical uses

    Heart failure

    Eplerenone reduces risk of death in patients with heart failure,[8] particularly in patients with recent myocardial infarction (heart attack).[9]

    High blood pressure

    Eplerenone lowers blood pressure in people with primary hypertension.[10] Eplerenone also reduces arterial stiffness and vascular endothelial dysfunction.[11]

    For persons with resistant hypertension, eplerenone is safe and effective for reducing blood pressure,[12] particularly in persons with resistant hypertension due to hyperaldosteronism.[13][14]

    Dosage

    For heart failure it is generally started at 25 mg once per day and than increased to 50 mg once per day.[1]

    Side effects

    Common side effects include: hyperkalaemia, hypotension, dizziness, and reduced renal clearance.[15] Eplerenone may have a lower incidence than spironolactone of sexual side effects such as feminization, gynecomastia, impotence, low sex drive and reduction of size of male genitalia.[16] This is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes.[5] When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone.[5]

    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. [17]

    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,[18] potassium supplements and other potassium-sparing diuretics.

    Pharmacology

    Eplerenone is an antimineralocorticoid, or an antagonist of the mineralocorticoid receptor (MR).[19] 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."[20] The drug controls high blood pressure by blocking the binding of aldosterone to the mineralocorticoid receptor (MR) in epithelial tissues, such as the kidney.[5] Blocking the action of aldosterone decreases blood volume and lowers blood pressure.[21] It has 10- to 20-fold lower affinity for the MR relative to spironolactone,[19] and is less potent in vivo as an antimineralocorticoid.[5] However, in contrast to spironolactone, eplerenone has little affinity for the androgen, progesterone, and glucocorticoid receptors.[19][5] It also has more consistently observed non-genomic antimineralocorticoid effects relative to spironolactone (see membrane mineralocorticoid receptor).[5] Eplerenone differs from spironolactone in its extensive metabolism, with a short half-life and inactive metabolites.[5]

    Eplerenone seems to be about 50 to 75% as potent as spironolactone as an antimineralocorticoid.[22] Hence, 25 mg/day spironolactone may be equivalent to approximately 50 mg/day eplerenone.[23]

    History

    Eplerenone was patented in 1983 and approved for medical use in the United States in 2002.[24][21]

    Society and culture

    Eplerenone is currently approved for sale in Canada, the US, EU, Netherlands and Japan.[21] Eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension.[16]

    See also

    References

    1. 1 2 3 4 5 6 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 206. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    2. 1 2 3 4 5 6 7 8 9 "Eplerenone Monograph for Professionals". Drugs.com. Archived from the original on 19 August 2020. Retrieved 23 July 2021.
    3. 1 2 3 4 5 Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 743–. ISBN 978-1-60913-345-0. Archived from the original on 1 August 2020. Retrieved 6 July 2021.
    4. 1 2 Sica DA (January 2005). "Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis". Heart Failure Reviews. 10 (1): 23–9. doi:10.1007/s10741-005-2345-1. PMID 15947888. S2CID 21437788.
    5. 1 2 3 4 5 6 7 8 Struthers A, Krum H, Williams GH (April 2008). "A comparison of the aldosterone-blocking agents eplerenone and spironolactone". Clinical Cardiology. 31 (4): 153–8. doi:10.1002/clc.20324. PMC 6652937. PMID 18404673.
    6. ↑ Frishman WH, Cheng-Lai A, Nawarskas J (4 January 2005). Current Cardiovascular Drugs. Springer Science & Business Media. pp. 246–. ISBN 978-1-57340-221-7. Archived from the original on 1 August 2020. Retrieved 6 July 2021.
    7. ↑ "Eplerenone Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 17 January 2021. Retrieved 23 July 2021.
    8. ↑ Frankenstein L, Seide S, Täger T, Jensen K, Fröhlich H, Clark AL, Seiz M, Katus HA, Nee P, Uhlmann L, Naci H, Atar D (March 2020). "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". Heart Fail Rev. 25 (2): 161–171. doi:10.1007/s10741-019-09832-y. PMID 31364027.
    9. ↑ De Luca L (October 2020). "Established and Emerging Pharmacological Therapies for Post-Myocardial Infarction Patients with Heart Failure: a Review of the Evidence". Cardiovasc Drugs Ther. 34 (5): 723–735. doi:10.1007/s10557-020-07027-4. PMID 32564304.
    10. ↑ Tam TS, Wu MH, Masson SC, Tsang MP, Stabler SN, Kinkade A, et al. (February 2017). "Eplerenone for hypertension". The Cochrane Database of Systematic Reviews. 2: CD008996. doi:10.1002/14651858.CD008996.pub2. PMC 6464701. PMID 28245343.
    11. ↑ Sakima A, Arima H, Matayoshi T, Ishida A, Ohya Y (March 2021). "Effect of Mineralocorticoid Receptor Blockade on Arterial Stiffness and Endothelial Function: A Meta-Analysis of Randomized Trials". Hypertension. 77 (3): 929–937. doi:10.1161/HYPERTENSIONAHA.120.16397. PMID 33461316.
    12. ↑ Dahal K, Kunwar S, Rijal J, Alqatahni F, Panta R, Ishak N, Russell RP (November 2015). "The Effects of Aldosterone Antagonists in Patients With Resistant Hypertension: A Meta-Analysis of Randomized and Nonrandomized Studies". American Journal of Hypertension. 28 (11): 1376–85. doi:10.1093/ajh/hpv031. PMID 25801902.
    13. ↑ Morimoto S, Ichihara A (August 2020). "Management of primary aldosteronism and mineralocorticoid receptor-associated hypertension". Hypertens Res. 43 (8): 744–753. doi:10.1038/s41440-020-0468-3. PMID 32424201.
    14. ↑ Spence JD (May 2017). "Rational Medical Therapy Is the Key to Effective Cardiovascular Disease Prevention". The Canadian Journal of Cardiology. 33 (5): 626–634. doi:10.1016/j.cjca.2017.01.003. PMID 28449833.
    15. ↑ Rossi S (2006). Australian Medicines Handbook 2006. Australian Medicines Handbook. ISBN 978-0-9757919-2-9.
    16. 1 2 Craft J (April 2004). "Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure". Proceedings. 17 (2): 217–20. doi:10.1080/08998280.2004.11927973. PMC 1200656. PMID 16200104.
    17. ↑ Tam TS, Wu MH, Masson SC, Tsang MP, Stabler SN, Kinkade A, et al. (February 2017). "Eplerenone for hypertension". The Cochrane Database of Systematic Reviews. 2: CD008996. doi:10.1002/14651858.CD008996.pub2. PMC 6464701. PMID 28245343.
    18. ↑ LoSalt Advisory Statement Archived 2005-12-10 at the Wayback Machine (PDF)
    19. 1 2 3 Delyani JA (April 2000). "Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology". Kidney International. 57 (4): 1408–11. doi:10.1046/j.1523-1755.2000.00983.x. PMID 10760075.
    20. ↑ Brown NJ (May 2003). "Eplerenone: cardiovascular protection". Circulation. 107 (19): 2512–8. doi:10.1161/01.CIR.0000071081.35693.9A. PMID 12756192.
    21. 1 2 3 "Inspra (Eplerenone)". Drug Development Technology. Archived from the original on 2016-04-26. Retrieved 2016-04-19.
    22. ↑ Struthers A, Krum H, Williams GH (April 2008). "A comparison of the aldosterone-blocking agents eplerenone and spironolactone". Clin Cardiol. 31 (4): 153–8. doi:10.1002/clc.20324. PMC 6652937. PMID 18404673.
    23. ↑ Peter L. Thompson (28 January 2011). Coronary Care Manual. Elsevier Health Sciences. pp. 254–. ISBN 0-7295-7927-1. Archived from the original on 28 August 2021. Retrieved 6 July 2021.
    24. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 459. ISBN 9783527607495. Archived from the original on 2021-04-18. Retrieved 2021-07-06.
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