Description
Eplerenone is used alone or in combination with other medications to treat high blood pressure. Eplerenone is in a class of medications called mineralocorticoid receptor antagonists. It works by blocking the action of aldosterone, a natural substance in the body that raises blood pressure.
Pharmacodynamics
Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.
Biological activity
Eplerenone belongs to a class of drugs called aldosterone antagonists. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions.
Eplerenone works by interfering with the activity of a steroid in your body called aldosterone. Aldosterone acts to increase the amount of sodium and water you retain. This increased sodium and water can cause high blood pressure, which can in turn cause heart failure.
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, potassium supplements and other potassium-sparing diuretics.
Overview
Eplerenone is in a class of medications called mineralocorticoid receptor antagonists. It can be used individually or in combination with other medications to treat hypertension by blocking the action of aldosterone, a natural substance in the body that raises blood pressure.
Chemical properties
Eplerenone is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH-independent. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0.
Mechanism of action
Aldosterone,with many physiological and pathological effects, can cause central blood pressure and endothelial injury (catecholamines enhance its role), reduce heart rate variability, induce ventricular arrhythmias, and promote retention of sodium, potassium and magnesium loss, promote myocardial fibrosis, necrosis and inflammation, damage the fibrinolytic system.
Angiotensin converting enzyme inhibitors (also called angiotensin converting enzyme inhibitors, referred to as ACEI) and angiotensin Ⅱ receptor antagonist ARB aldosterone can inhibit the secretion of adrenaline, but after a period of treatment.The release of aldosterone was restored,which may even exceed the baseline plasma concentration levels. Despite adequate treatment of ACEI and ARB, aldosterone-induced damage can still happen, so it is necessary to use aldosterone receptor antagonists in the treatment of hypertension. Clinical studies have shown that patients who are not satisfied with the efficacy of ACEI or ARB therapy can add eplerenone along with the treatment.
Non-selective aldosterone receptor antagonist spironolactone can reduce mortality in patients with congestive heart failure, However, the side effects of male hyperplasia and other diseases associated with sex hormones have limited its application in the treatment of hypertension.
Adverse effects
Common adverse drug reactions (ADRs) associated with the use of eplerenone include: hyperkalaemia, hypotension, dizziness, altered renal function, and increased creatinine concentration.
References
https://en.wikipedia.org/wiki/Eplerenone
https://medlineplus.gov/druginfo/meds/a603004.html
http://www.rxlist.com/inspra-drug.htm
Description
Eplerenone derives its antihypertensive effect by blocking the binding of aldosterone
at the mineralocorticoid receptor (MR). The drug, which was previously approved
only for the oral treatment of hypertension, is now indicated to improve survival of
stable patients with left ventricular systolic dysfunction (ejection fraction ＜40%) and
clinical evidence congestive heart failure (CHF) after an acute myocardial infarction.
Aldosterone is a key hormone in the renin-angiotensin-aldosterone system (RAAS),
which is of critical importance in the development and progression of hypertension,
cardiac remodeling and other cardiovascular diseases. The purpose of RAAS is to
control sodium, potassium, and fluid volume balance. Aldosterone binds to MRs in
both epithelial (e.g. kidney) and nonepithelial (e.g. heart, blood vessels, and brain)
tissues and increases blood pressure through induction of sodium reabsorption and
possibly other mechanisms. The actions of aldosterone can be blocked by
spironolactone (Aldactone
), a relatively nonselective MR antagonist that has been
used in clinical practice for many years. Eplerenone, a structural analog of
spironolactone, is a highly selective MR antagonist, with significantly lower affinity
for other nuclear receptors. It can be prepared by several related ways, with the key
step being the introduction of 11-a-hydroxy group on the steroid scaffold via
microbiological conversion. The presence of the 11-a-hydroxy group permits the
derivation of the epoxy functionality found in eplerenone. Following oral
administration, eplerenone is well absorbed and reaches peak plasma concentrations
in～2 h. The bioavailability of eplerenone is 98% and it is cleared predominantly by
CYP3A4 metabolism, with an elimination half-life of 4–6 h. Steady state is reached
within two days. Eplerenone therapy is typically initiated with 25 mg once daily oral
dosing and, if tolerated by the patient, titrated to 50 mg once daily. In a clinical
study, eplerenone significantly reduced deaths in congestive heart failure patients
after a heart attack, above and beyond standard therapy, including ACE inhibitors
and β-blockers. The trial in more than 6600 hospitalized patients demonstrated a
15% reduction in the risk of death for eplerenone compared with placebo, in addition
to standard treatment. The most commonly reported adverse events associated with
eplerenone are hyperkalemia and increased creatine.
Description
Eplerenone is a mineralocorticoid receptor antagonist. It is selective for the mineralocorticoid receptor over glucocorticoid, androgen, progesterone, and estrogen receptors in radioligand binding assays (IC
50s = 138, 6,920, 523, >10,000, and 5,702 nM, respectively). Eplerenone inhibits aldosterone-induced mineralocorticoid activity in a luciferase assay (IC
50 = 122 nM).
In vivo, eplerenone (100 mg/kg per day) reduces urinary albumin secretion and glomerulosclerosis in the Dahl salt-sensitive rat model of hypertension and nephropathy. It reduces myocardial IL-1β levels and collagen deposition, as well as improves left ventricular systolic dysfunction in a mouse model of acute myocardial infarction. Formulations containing eplerenone have been used in the treatment of hypertension and heart failure after myocardial infarction.
Chemical Properties
White Solid
Originator
Ciba-Geigy (Novartis) (US)
Uses
Eplerenone is an aldosterone antagonist with an IC50 of 0.36 μM. It is used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone, though it may be more specific for the mineralocorticoid receptor and is sp
Uses
Selective aldosterone receptor antagonist (SARA), structurally similar to Spiranolactone. Eplerenone is used alone or in combination with other medications to treat high blood pressure. Eplerenone is in a class of medications called mineralocorticoid receptor antagonists. It works by blocking the action of aldosterone, a natural substance in the body that raises blood pressure.
Definition
ChEBI: Eplerenone is a steroid acid ester, a methyl ester, an oxaspiro compound, a gamma-lactone, an organic heteropentacyclic compound, a 3-oxo-Delta(4) steroid and an epoxy steroid. It has a role as an aldosterone antagonist and an antihypertensive agent. It derives from a hydride of a pregnane.
brand name
Inspra (Searle).
General Description
Eplerenone, 9,11α-epoxy-17α-hydroxy-3-oxopregn-4-ene-7α,21-dicarboxylic acid, γ-lactone,methyl ester (Inspra), is a newer aldosterone antagonist that isused for the treatment of hypertension.
Biological Activity
Selective mineralocorticoid (aldosterone) receptor antagonist (IC 50 = 360 nM). Displays > 27-fold selectivity over androgen, progesterone and estrogen receptors (IC 50 > 10 μ M). Orally active antihypertensive in vivo .
Biochem/physiol Actions
Eplerenone is an aldosterone antagonist more specific for the mineralocorticoid receptor than spironolactone (S3378), having lower affinity for progesterone, androgen, and glucocorticoid receptors.
Clinical Use
A newer drug, eplerenone, has a structure similar to that of spironolactone and a similar mechanism of action. It was initially approved for use in the treatment of
hypertension but it can now be used in the treatment of patients with left ventricular systolic dysfunction and congestive heart failure after myocardial infarction.
Synthesis
250 mL of dichloromethane was added to each of the four reaction flasks, and 20 g of methyl (7α,17α)-17-hydroxy-3-oxo-pregna-4,9(11)-dien-7,21-dicarboxylate-gamma-lactone (Compound 2), 48 g of trichloroacetamide, and 18 g of potassium acetate were added sequentially under stirring until complete dissolution. The reaction mixture was cooled to 10 °C and 160 mL of 30% hydrogen peroxide solution was slowly added dropwise for a controlled time of 45 minutes. After the dropwise addition, the reaction temperature was raised to 15 °C, the reaction was continued to be stirred, and the progress of the reaction was monitored by TLC until the disappearance of the raw material point. Upon completion of the reaction, layering was performed and the aqueous layer was extracted with dichloromethane (50 mL × 2). The organic layer was combined and washed sequentially with 3% sodium bisulfite solution (25 mL × 2), cold 1N NaOH solution, 3% dilute hydrochloric acid, water and saturated saline. The organic layer was dried by adding anhydrous Na2SO4 for 1 h. The desiccant was removed by filtration and the filtrate was concentrated to obtain a white solid. The resulting white solid was dissolved in 160 mL of butanone and stirred until completely dissolved. The solution was concentrated to 45% of the original volume under atmospheric pressure and the concentration was stopped. The solution was cooled naturally to 20°C, then cooled to 0°C with ice brine, kept for 1 hour and filtered, and the filter cake was washed with butanone. The filter cake was dried at 90 °C for 4 h to give 19.0 g (2'R,4aS,4bR,5aR,6aS,9aS,9bR,10R)-methyl 4a,6a-dimethyl-2,4'-dioxo-3,4,4a,4',5a,5',6,6a,8,9,9a,9b,10,11-tetradecanedihydro-2H,3'H-spiro[cyclopentadieno [1,2]phenanthro[4,4a-b]oxirane-7,2'-furan]-10-carboxylic acid ester (eplerenone), yield 91.3%, content 99.7%.
Drug interactions
Potentially hazardous interactions with other drugsACE inhibitors or AT-II antagonists: enhanced
hypotensive effect; risk of severe hyperkalaemia.Anti-arrhythmics: concentration increased by
amiodarone - reduce eplerenone dose.amiodarone - reduce eplerenone dose.
Antibacterials: concentration increased by
clarithromycin and telithromycin - avoid;
concentration increased by erythromycin - reduce
eplerenone dose; concentration reduced by rifampicin
- avoid; avoid with lymecycline; increased risk of
hyperkalaemia with trimethoprim.Antidepressants: concentration reduced by St John’s
wort - avoid; increased risk of postural hypotension
with tricyclics; enhanced hypotensive effect with
MAOIs.Antiepileptics: concentration reduced by
carbamazepine, fosphenytoin, phenytoin,
phenobarbital and primidone - avoid.Antifungals: concentration increased by itraconazole
and ketoconazole - avoid; concentration increased by
fluconazole - reduce eplerenone dose.Antihypertensives: enhanced hypotensive effect,
increased risk of first dose hypotensive effect with
post-synaptic alpha-blockers.Antivirals: concentration increased by ritonavir -
avoid; concentration increased by saquinavir - reduce
eplerenone doseCiclosporin: increased risk of hyperkalaemia and
nephrotoxicityCytotoxics: increased risk of nephrotoxicity and
ototoxicity with platinum compounds.NSAIDs: increased risk of hyperkalaemia (especially
with indometacin); increased risk of nephrotoxicity;
antagonism of diuretic effect.Potassium salts: increased risk of hyperkalaemia.Lithium: reduced lithium excretion - avoidTacrolimus: increased risk of hyperkalaemia and
nephrotoxicity.CYP3A4 inhibitors: Do not exceed a dose of 25 mg
daily for eplerenone.CYP3A4 inducers: reduced eplerenone
concentration - avoid.
Metabolism
Eplerenone metabolism is primarily mediated via
CYP3A4. No active metabolites of eplerenone have
been identified in human plasma. Less than 5% of
an eplerenone dose is recovered as unchanged drug
in the urine and faeces. Following a single oral dose
of radiolabelled drug, approximately 32% of the dose
was excreted in the faeces and approximately 67% was
excreted in the urine
References
[1] Patent: CN104725461, 2016, B. Location in patent: Paragraph 0056; 0057; 0058; 0059
[2] Patent: WO2005/92913, 2005, A1. Location in patent: Page/Page column 32-39
[3] Helvetica Chimica Acta, 1997, vol. 80, # 2, p. 566 - 585
[4] Patent: EP1223174, 2002, A2. Location in patent: Example 47A
[5] Patent: EP1223174, 2002, A2. Location in patent: Example 42
