Eplerenone

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Eplerenone
Eplerenone.svg
Systematic (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
Pronunciation /ɛpˈlɛrənn/
Trade names Inspra
AHFS/Drugs.com Monograph
MedlinePlus a603004
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
administration
Oral (tablets)
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~70%[1]
Protein binding ~50% (33–60%) (primarily to α1-acid glycoprotein)[1][2]
Metabolism Liver (CYP3A4)[1][2]
Metabolites 6β-OH-EPL, 6β,21-OH-EPL, 21-OH-EPL, 3α,6β-OH-EPL[1] (All inactive)[1]
Biological half-life 4–6 hours[3]
Excretion Urine (67%), feces (32%)[4]
Identifiers
CAS Number 107724-20-9 YesY
ATC code C03DA04 (WHO)
PubChem CID 5282131
IUPHAR/BPS 2876
DrugBank DB00700 YesY
ChemSpider 10203511 YesY
UNII 6995V82D0B YesY
KEGG D01115 YesY
ChEBI CHEBI:31547 YesY
ChEMBL CHEMBL1095097 YesY
Synonyms SC-66110; CGP-30083; 9-11α-Epoxymexrenone; 9,11α-Epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone
Chemical data
Formula C24H30O6
Molar mass 414.49
  (verify)

Eplerenone (INN) is a steroidal antimineralocorticoid of the spirolactone group that is used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone, though it is much more selective for the mineralocorticoid receptor in comparison (i.e., does not possess any antiandrogen, progestogen, glucocorticoid, or estrogenic effects), and is specifically marketed for reducing cardiovascular risk in patients following myocardial infarction. Eplerenone is a potassium-sparing diuretic, meaning that it helps the body get rid of water but still keep potassium.

Eplerenone was developed by Pharmacia Corporation, which was acquired by Pfizer in 2002.[5] It was marketed by Pfizer under the trade name Inspra. The US Food and Drug Administration (FDA) approved the drug for sale in the United States in 2002.[5] Eplerenone is currently approved for sale in the US, EU, Netherlands and Japan.[5] Relative to dosage, eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension.[6]

Medical uses[edit]

Heart Failure[edit]

Eplerenone is specifically indicated for the reduction of risk of cardiovascular death in people with heart failure and left ventricular dysfunction within 3–14 days of an acute myocardial infarction, in combination with standard therapies and as treatment against hypertension. A variant of the spirolactone group, Eplerenone was developed to contradict the depletion of essential potassium and magnesium levels that are common amongst other mineralocorticoid receptor antagonists.[7] It is a more expensive alternative to spironolactone.[8]

RALES = Randomized Aldactone Evaluation Study, EPHESUS = Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study[9] *Table derived from a study conducted by The Division of Medicine and Therapeutics at Ninewells Hospital and Medical School
Parameter RALES EPHESUS
Drug: Spironolactone Eplerenone
Patients enrolled (n) 1663 6632
Population/Inclusion Criteria NYHA Class III at the time of Enrollment NYHA Class I-IV
Target Dose 50 mg/d 50 mg/d
Mean Dose Achieved 26 mg/d 43.5 mg/d
Mean duration of follow-up 24 mo 16 mo
Diuretic 100% 60%

Hypertension[edit]

Eplerenone can be used individually or in combination with other medications to treat hypertension.[9] In an 8-week trial with 417 patients with mild to moderate hypertension, eplerenone decreased systolic and diastolic blood pressure in a dose-dependent manner.[10] Eplerenone effectively reduces blood pressure compared to agents such as spironolactone, enalapril, losartan and amlodipine, but its effect on mortality is still generally unknown.[10]

Adverse effects[edit]

Adverse effects of aldosterone occur in the heart and brain, due to changes in water retention and excretion of sodium and potassium.[9] Common adverse drug reactions (ADRs) associated with the use of eplerenone include: hyperkalaemia, hypotension, dizziness, altered renal function, and increased creatinine concentration.[11] 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.[12] This is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes.[9] When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone.[9]

Contraindications[edit]

Eplerenone is contraindicated in patients with hyperkalaemia, severe renal impairment (creatinine Cl less than 30 ml/min), or severe hepatic impairment (Child-Pugh score C). The manufacturer of eplerenone also contraindicates ( relative C.I. ) concomitant treatment with ketoconazole, itraconazole or other potassium-sparing diuretics (though the manufacturer still considers taking these drugs to be absolute C.I.) Potential benefits should be weighted against possible risks.

Drug interactions[edit]

Eplerenone is primarily metabolised 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 hyperkalaemia associated with eplerenone therapy, including salt substitutes,[13] potassium supplements and other potassium-sparing diuretics.

Pharmacology[edit]

Eplerenone is an antimineralocorticoid, or an antagonist of the mineralocorticoid receptor (MR).[14] 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".[10] The drug controls high blood pressure by binding the aldosterone hormone to the mineralocorticoid receptor (MR) in epithelial tissues, such as the kidney.[15] This helps to increase blood volume and regulate blood pressure.[5] It has 10- to 20-fold lower affinity for the MR relative to spironolactone,[14] and is less potent in vivo as an antimineralocorticoid.[16] However, in contrast to spironolactone, eplerenone has little affinity for the androgen, progesterone, and glucocorticoid receptors.[14][16] It also has more consistently observed non-genomic antimineralocorticoid effects relative to spironolactone (see membrane mineralocorticoid receptor).[16] Eplerenone differs from spironolactone in its extensive metabolism, with a short half-life and inactive metabolites.[9]

See also[edit]

References[edit]

  1. ^ a b c d e Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 743–. ISBN 978-1-60913-345-0. 
  2. ^ a b Sica, Domenic A. (2005). "Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis". Heart Failure Reviews. 10 (1): 23–29. doi:10.1007/s10741-005-2345-1. ISSN 1382-4147. 
  3. ^ Struthers, Allan; Krum, Henry; Williams, Gordon H. (2008). "A Comparison of the Aldosterone-blocking Agents Eplerenone and Spironolactone". Clinical Cardiology. 31 (4): 153–158. doi:10.1002/clc.20324. ISSN 0160-9289. 
  4. ^ William H. Frishman; Angela Cheng-Lai; James Nawarskas (4 January 2005). Current Cardiovascular Drugs. Springer Science & Business Media. pp. 246–. ISBN 978-1-57340-221-7. 
  5. ^ a b c d "Inspra (Eplerenone)". Drug Development Technology. Retrieved 2016-04-19. 
  6. ^ Craft, Jennifer (2004). "Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure". Proceedings (Baylor University. Medical Center). 17 (2): 217–220. 
  7. ^ Montalescot, Gilles; Pitt, Bertram; Sa, Esteban Lopez de; Hamm, Christian W.; Flather, Marcus; Verheugt, Freek; Shi, Harry; Turgonyi, Eva; Orri, Miguel (2014-09-07). "Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: The Randomized Double-Blind Reminder Study". European Heart Journal. 35 (34): 2295–2302. doi:10.1093/eurheartj/ehu164. ISSN 0195-668X. PMID 24780614. 
  8. ^ Chatterjee, S; Moeller, C; Shah, N; Bolorunduro, O; Lichstein, E; Moskovits, N; Mukherjee, D (August 2012). "Eplerenone is not superior to older and less expensive aldosterone antagonists.". The American Journal of Medicine. 125 (8): 817–25. doi:10.1016/j.amjmed.2011.12.018. PMID 22840667. 
  9. ^ a b c d e f Struthers, Allan; Krum, Henry; Williams, Gordon H. (2008-04-01). "A Comparison of the Aldosterone-blocking Agents Eplerenone and Spironolactone". Clinical Cardiology. 31 (4): 153–158. doi:10.1002/clc.20324. ISSN 1932-8737. 
  10. ^ a b c Brown, N. J. (20 May 2003). "Eplerenone: Cardiovascular Protection". Circulation. 107 (19): 2512–2518. doi:10.1161/01.CIR.0000071081.35693.9A. 
  11. ^ Rossi S, editor.Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006
  12. ^ Craft, Jennifer (April 2004). "Eplerenone". Proc (Bayl Univ Med Cent); Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure. Pub MedCentral. 17 (2): 217–20. PMC 1200656free to read. PMID 16200104. 
  13. ^ LoSalt Advisory Statement (PDF)
  14. ^ a b c Delyani, John A (2000). "Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology". Kidney International. 57 (4): 1408–1411. doi:10.1046/j.1523-1755.2000.00983.x. ISSN 0085-2538. 
  15. ^ Struthers, Allan; Krum, Henry; Williams, Gordon H. (April 2008). "A Comparison of the Aldosterone-blocking Agents Eplerenone and Spironolactone". Clinical Cardiology. 31 (4): 153–158. doi:10.1002/clc.20324. 
  16. ^ a b c Struthers A, Krum H, Williams GH (2008). "A comparison of the aldosterone-blocking agents eplerenone and spironolactone". Clin Cardiol. 31 (4): 153–8. doi:10.1002/clc.20324. PMID 18404673.