Eplerenone

Structural formula
General
Non-proprietary name	Eplerenone
other names	Epoxymexrenone 9.11 α- Epoxy-7 α - (methoxycarbonyl) -3-oxo-17 α -pregn-4-ene-21,17-carbolactone
Molecular formula	C 24 H 30 O 6
Brief description	white solid
External identifiers / databases
CAS number 107724-20-9 EC number 600-850-8 ECHA InfoCard 100.106.615 PubChem 443872 DrugBank DB00700 Wikidata Q423804
Drug information
ATC code	C03 DA04
Drug class	Aldosterone antagonist
Mechanism of action	Competitive inhibition of aldosterone Enhancement of Na + , Cl - and water excretion and K + retention Lowering blood pressure, lowering the preload and increasing the contraction force of the heart
properties
Molar mass	414.49 g mol −1
Physical state	firmly
solubility	almost insoluble in water hardly soluble in water and ethanol 96% bad in DMSO (20 g l −1 ) easily soluble in dichloromethane
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Eplerenone is a drug from the group of aldosterone antagonists that is used in the treatment of heart failure after a heart attack .

Clinical information

application

Eplerenone is approved as a supplement to standard therapy in the treatment of left ventricular dysfunction and existing heart failure after a recent myocardial infarction (heart attack) and is used in further therapy after this acute event.

3 to 14 days after an acute myocardial infarction, therapy is started with half the maintenance dose per day. The dose is increased to a fixed maintenance dose within 4 weeks while the serum potassium level is monitored . The narrow therapeutic limits of potassium levels require regular monitoring of the serum potassium level. If pretreatment or concomitant medication with weak to moderate CYP3A4 inhibitors, such as B. amiodarone , diltiazem and verapamil , the initial dose is also the maintenance dose.

Contraindications

Eplerenone should not be taken by patients

• with serum potassium values ​​above 5.0 mmol / l at the start of treatment
• with moderate to severe renal impairment
• with severe Child-Pugh Class C hepatic insufficiency
• who have been previously treated with potassium-sparing diuretics , potassium supplements, or strong CYP3A4 inhibitors (such as itraconazole , ketoconazole , ritonavir , nelfinavir , clarithromycin , telithromycin and nefazodone ).

Interactions with other means

Due to the metabolism via the isoenzyme CYP 3A4 of the cytochrome P450 , there are interactions with other drugs, which are also broken down in this way. If it is necessary to administer weak to moderate CYP3A4 inhibitors at the same time as eplerenone, the active ingredient accumulates and thus an increased effect, so that the maximum dosage is reduced to half the usual maintenance dose. The same circumstance also means that the simultaneous administration of strong CYP3A4 inhibitors is contraindicated. Known CYP3A4 inhibitors are e.g. B. grapefruit juice , valerian , turmeric or ginseng .

In the case of parallel administration of CYP3A4 inducers such as rifampicin , carbamazepine , phenytoin , phenobarbital or St. John's wort , a weakening of the effect up to loss of effect is to be expected. If digoxin is used at the same time, an increase in the digoxin level is to be expected.

Co-medication with ciclosporin or tacrolimus should be avoided because of the expected renal dysfunction and the increased risk of hyperkalemia ; the situation is similar with the administration of trimethoprim , AT ₁ antagonists and ACE inhibitors . A pain treatment with NSAIDs requires a balanced fluid balance to preserve renal function. When eplerenone is combined with alpha blockers , tricyclic antidepressants , neuroleptics , amifostine or baclofen, there is a possibility that the antihypertensive effect or orthostatic hypotension may be increased. Due to sodium and water retention, glucocorticoids can lead to a blood pressure-increasing effect, which eplerenone counteracts. An interaction with lithium has not yet been investigated.

Special patient groups

Even if animal studies have shown no effects on unborn life, eplerenone should only be used with caution after strict indications have been established, as sufficient data have not yet been collected on pregnant women. It cannot be ruled out that the drug could pass into breast milk, which would require weaning to protect the child from possible side effects.

In the case of existing metabolic defects or functional impairments, the use of eplerenone must be carefully considered. Severe forms of liver or kidney dysfunction are considered a contraindication (see also there). Patients with type II diabetes and microalbuminuria should be treated carefully and under close supervision.

unwanted effects

Common side effects are hyperkalemia, drowsiness, hypotension, diarrhea, nausea, kidney dysfunction, weakness or malaise. Occasionally, dehydration, hypercholesterolemia, hypertriglyceridemia, hyponatremia, insomnia, headache, orthostatic hypotension, leg artery thrombosis, pharyngitis, flatulence, vomiting, itching, back pain, leg cramps, elevated blood urea levels, or elevated creatinine levels may also occur.

Studies

The effect of eplerenone on morbidity and mortality in patients with acute myocardial infarction, which was complicated by left ventricular dysfunction and heart failure, was investigated in a double-blind, placebo-controlled study, as was the effectiveness of eplerenone in patients with chronic systolic heart failure with mild symptoms.

Pharmacological properties

Mechanism of action

Eplerenone binds with high selectivity to mineralocorticoid receptors , where the binding of aldosterone is competitively inhibited. Since aldosterone plays the role of a key hormone in the renin-angiotensin-aldosterone system (RAAS), which is significantly involved in blood pressure regulation and the pathophysiology of cardiovascular diseases, this leads to a sustained increase in plasma renin and aldosterone in serum, what directly inhibits the negative regulatory feedback of aldosterone on renin secretion. This then leads to an increased excretion of Na ⁺ , Cl ^- and water, which lowers the blood pressure and the preload, and increases K ⁺ retention, whereby the increased K ⁺ supply increases the contraction force ( inotropy ) of the heart muscle is strengthened.

Absorption and distribution in the body

After ingestion, the maximum plasma concentration is reached after approximately two hours and a steady state within 2 days, with plasma protein binding being approximately 50% and the apparent volume of distribution at steady state being 50 L. The absorption takes place independently of the food intake. The metabolism of eplerenone is mainly mediated via CYP3A4. With the help of radioactively labeled active substance, it was determined that approx. 32% is excreted with the faeces and approx. 67% with the urine , the plasma half-life is approx. 3 to 5 hours and the apparent plasma clearance is approx. 10 L / h.

The drug cannot be hemodialysed, which is problematic if it has accumulated.

Chemical-physical properties

Eplerenone has a structure similar to the basic steroid structure, which is also reflected in the way it works. Eplerenone is a white or almost white to pale yellow, crystalline powder. The substance shows polymorphism.

Trade names

Inspra (manufacturer Pfizer ), as well as generics

Individual evidence

1. ↑ ^{a b c d e} Data Eplerenone at Sigma-Aldrich , accessed on 15 June 2011 ( PDF ).
2. ↑ ^{a b c} European Pharmacopoeia, 8th edition, 4th supplement, monograph Eplerenon.
3. ↑ ^{a b c d e f g h i j} DAZ-Neue Arzneimittel / DAZ-Online (as of January 1, 2009).
4. ↑ ^{a b c d e} ABDA database (as of January 1, 2009) of DIMDI.
5. ↑ Grapefruit - New mechanism of interaction discovered . In: Pharmaceutical newspaper online . No. 35 , 2008 ( pharmische-zeitung.de [accessed on January 10, 2011]).
6. ↑ B. Pitt, W. Remme, F. Zannad, J. Neaton, F. Martinez, B. Roniker, R. Bittman, S. Hurley, J. Kleiman, M. Gatlin: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. In: N Engl J Med. 348 (14), 2003 Apr 3, pp. 1309-1321. PMID 12668699 .
7. ↑ F. Zannad, JJ McMurray, H. Krum, DJ van Veldhuisen, K. Swedberg, H. Shi, J. Vincent, SJ Pocock, B. Pitt: EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. In: N Engl J Med. 364 (1), 2011 Jan 6, pp. 11-21. PMID 21073363 .
8. ↑ ^{a b} Andreas Russ, Harald Bruckbauer: Arzneimittelpocket Plus 2008. 4th edition. 2007, ISBN 978-3-89862-287-5 .

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