Eplerenone

Last updated on: 18.12.2020

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Definition
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Eplerenone is an orally administrable, competitive aldosterone antagonist, a synthetically produced aldosterone analogue that is primarily used to relieve the heart, in addition to the treatment of heart failure after a heart attack. This is to prevent the risk of further heart attacks and their consequences. It also reduces the risk of cardiac death due to acute heart failure.

Pharmacodynamics (Effect)
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Potassium-sparing diuretics of the triamter type act in the late distal tubule and in the proximal sections of the collecting ducts. There they inhibit the sodium channels. By decreasing sodium influx into the tubular epithelial cells, the rate of exchange of sodium for potassium is decreased. This effectively conserves potassium, and the effect on diuresis of sodium is small.

Aldosterone antagonists: Aldosterone exerts its effect via activation of mineralocorticoid reticulum. Thus, it increases the expression of the Na+-Cl symporter in the early distal tubule and the expression of epithelial Na+ channels in the late distal tubule and collecting duct. The aldosterone receptor antagonists spironolactone as well as eplerenone prevent the interaction between aldosterone and its receptor. This reduces Na+ reabsorption.

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Spectrum of action
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Eplerenone binds to mineralocorticoid receptors (aldosterone receptor). By blocking the receptor, the interaction between aldosterone and its receptor is prevented. That is, Na+ reabsorption and K+ and H+ excretion in the collecting tube of the nephron of the kidney are reduced. Thus, the excretion of salt and water is increased. The blood volume decreases and the heart is relieved. At the same time less potassium is lost. This is why Eplerenon is also counted among the group of potassium-sparing diuretics. Unlike all other diuretics, aldosterone antagonists do not act via the luminal side of the tubular epithelia. In addition, their onset of action is significantly delayed (1-2 days after application).

In addition, the concentration of free aldosterone in the body increases. This in turn causes the adrenal glands to stop producing aldosterone. At the same time, less renin is produced in the kidneys. This endopeptidase is at the beginning of the blood pressure regulating renin-angiotensin-aldosterone system (RAAS). Overall, eplerenone has an antihypertensive effect. However, therapeutically, the natriuretic effect is in the background and the cardioprotective effect in heart failure is in the foreground (Pelliccia F et al. 2015).

Eplerenone is excreted unchanged in about 32% via the intestine and about 67% in the urine. The elimination half-life of eplerenone is approximately 3 to 6 hours. The metabolism of eplerenone occurs mainly via cytochrome3A4.

Indication
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Patients with NYHA class II (chronic) heart failure

Pregnancy/nursing period
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Pregnancy: Eplerenone should be used with caution in pregnant women as there are no conclusive data on the use of eplerenone during pregnancy.

Lactation: It is not known whether eplerenone passes into breast milk after oral administration. Since the potential for side effects of eplerenone on the breastfed infant is not known, a decision should be made whether to breastfeed or to discontinue the drug, taking into account the benefit to the mother (SmPC).

Dosage and method of use
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Initial 25 mg/day, target dose within 4 weeks 50 mg/day.

Do not start treatment with eplerenone in patients with serum potassium > 5.0 mmol/l. Serum potassium levels must be determined before initiation of therapy with eplerenone, within the 1st week of treatment, 1 month after initiation of therapy, or after dose adjustment. Thereafter, potassium levels must be monitored periodically as needed.

Dose adjustment according to serum potassium level (refer to the respective SmPC for more detailed information).

Children and Adolescents: Safety and efficacy in children and adolescents have not been established.

Elderly patients: No adjustment of the initial dose is required. Due to an age-related decline in renal function and an increased drug load from mild to moderate hepatic insufficiency, the risk of hyperkalemia is increased in elderly patients. Regular serum potassium monitoring is recommended.

Renal impairment: Mild renal impairment: adjustment of initial dose is not required. Regular monitoring of serum potassium levels is recommended.

Moderate renal impairment (creatinine clearance 30 to 60 ml/min): 25 mg every 2nd day is recommended as the initial dose. The dose should be adjusted based on the potassium level.

Creatinine clearance < 50 ml/min: Use with caution as no experience is available. Doses greater than 25 mg daily have not been studied.

Severe renal insufficiency (creatinine clearance < 30 ml/min): Use is contraindicated. Eplerenone is not dialyzable.

Hepatic insufficiency: No adjustment of the initial dose is required. However, in patients with mild to moderate hepatic insufficiency, frequent and regular monitoring of serum potassium levels is recommended, particularly in elderly patients, as increased systemic drug exposure to eplerenone may occur.

Undesirable effects
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Hyperkalemia, most common and important ADR (Lainscak M et al. 2015).

Sodium deficiency

Hypotension

Headache

Gastrointestinal disorders, renal dysfunction and dyslipidemia.

Dermatological UAW: are described as rare. Occasionally urticarial exanthema occurs during therapy.

Interactions
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Pharmacodynamic interactions

  • Potassium-sparing diuretics and potassium preparations: risk of hyperkalaemia
  • ACE inhibitors and sartans: hyperkalemia
  • Lithium: increased lithium toxicity
  • Ciclosporin, Tacrolimus: renal dysfunction and hyperkalemia
  • Nonsteroidal anti-inflammatory drugs (NSAIDs): acute renal failure especially in elderly and/or dehydrated patients
  • Trimethoprim: hyperkalemia
  • Alpha blockers (e.g., prazosin, alfuzosin): orthostatic hypotension
  • Tricyclic antidepressants, neuroleptics, amifostine, baclofen: orthostatic hypotension
  • Glucocorticoids, tetracosactide: reduction of antihypertensive effect

Pharmacokinetic interactions

  • Digoxin: increase in systemic exposure (AUC) with digoxin by 16%.
  • Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin and telithromycin): ketoconazole (twice 200 mg daily) AUC increase of eplerenone by 441%. Concurrent use with strong CYP3A4 inhibitors is contraindicated.
  • Weak to moderate CYP3A4 inhibitors (erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole): 98-187% increase in eplerenone AUC. Daily eplerenone dose should not exceed 25 mg daily.
  • CYP3A4 inducers (St. John's wort): decrease eplerenone AUC by 30%. Concomitant administration of strong CYP3A4 inducers (St. John's wort, carbamazepine, phenytoin, phenobarbital, St. John's wort) is not recommended.

Contraindication
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Hypersensitivity to eplerenone

Patients with serum potassium levels > 5.0 mmol/l at initiation of treatment

Patients with severe renal impairment (eGFR = estimated glomerular filtration rate <30 ml/min/1.73 m2)

Patients with severe hepatic insufficiency (Child-Pugh class C)

Patients receiving potassium-sparing diuretics or potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, clarithromycin)

Literature
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  1. Hundt JE et al (2019) Mineralocorticoid Receptor Antagonists Stimulate Human Hair Growth ex vivo. Skin Pharmacol Physiol 32:344-348.
  2. Lainscak M et al (2015) Safety profile of mineralocorticoid receptor antagonists: spironolactone and eplerenone. Int J Cardiol 200:25-29.
  3. Maubec E et al. (2015) Topical mineralocorticoid receptor blockade limits glucocorticoid-induced epidermal atrophy in human skin. J Invest Dermatol 135:1781-1789.
  4. Karagiannis D et al (2019) the Effect of Eplerenone in Chronic Central Serous Chorioretinopathy Refractory to Photodynamic Therapy. Semin Ophthalmol 34:436-441.
  5. Pelliccia F et al (2015) Efficacy and safety of mineralocorticoid receptors in mild to moderate arterial hypertension. Int J Cardiol 200: 8-11.

Last updated on: 18.12.2020