INSPRA 50

Indications

• Hypertension
• Heart failure with reduced ejection fraction
• Heart failure with preserved ejection fraction
• Adjunct therapy post-myocardial infarction in patients with heart failure

Dosage

Adults: Initially 25 mg daily, then increased to 50 mg daily within 4 weeks of initial treatment. For patients with concomitant use of moderate CYP3A4 inhibitors, the maximum recommended dose is 25 mg daily.

Mechanism of action

Eplerenone binds to the mineralocorticoid receptor, blocking the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone system (RAAS). This inhibition prevents aldosterone-induced sodium reabsorption in the kidneys and other tissues, leading to decreased blood pressure. Eplerenone is relatively selective for mineralocorticoid receptors compared to glucocorticoid, progesterone, and androgen receptors.

Pharmacodynamics

Eplerenone, as an aldosterone receptor antagonist, leads to sustained increases in plasma renin and serum aldosterone due to the inhibition of the negative feedback mechanism of aldosterone on renin secretion. While plasma renin activity and aldosterone levels may increase, these do not counteract eplerenone's effects on blood pressure, allowing it to effectively manage hypertension and heart failure symptoms.

Pharmacokinetics

Eplerenone is well absorbed following oral administration and undergoes extensive hepatic metabolism, primarily via CYP3A4. It has a bioavailability of approximately 35% due to first-pass metabolism. The drug has a half-life of about 5 hours. Eplerenone is excreted mainly in urine as metabolites, with less than 5% of the dose excreted unchanged. Renal function can affect its pharmacokinetics, necessitating dosage adjustments in patients with renal impairment.

Contra-indications

• Hyperkalaemia

Adverse effects

• Hyperkalaemia
• Hypotension
• Dizziness
• Fatigue
• Renal impairment
• Gastrointestinal disturbances

Interactions

• Cobicistat - Severe (increases exposure)
• Idelalisib - Severe (increases exposure)
• St John's Wort - Severe (decreases exposure)
• Rifampicin - Severe (decreases exposure)
• Cenobamate - Moderate (decreases exposure)
• Amiodarone - Unknown (increases exposure)
• Dronedarone - Unknown (increases exposure)
• Antifungals (azoles) - Unknown (increases exposure)
• Crizotinib - Unknown (increases exposure)
• Imatinib - Unknown (increases exposure)

Precautions

• Use with caution in elderly patients
• Monitor renal function and serum electrolytes, especially potassium
• Consider lower doses in patients with chronic kidney disease
• Avoid concurrent use with potassium-conserving drugs

Pregnancy

Eplerenone is not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Eplerenone is excreted in breast milk; caution is advised when used during breastfeeding.

Storage

Store at room temperature, in a dry place, away from direct sunlight.

Formulations

• Tablets: 25 mg, 50 mg

Mechanism of action

Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors 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. Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors. Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with the inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulation levels do not overcome the effect of eplerenone on blood pressure. Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, brain) tissues and increases blood pressure through induction of sodium resorption and possibly other mechanisms.

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.