Aldosterone Antagonists

Treatment of hypertension (may be used alone or in combination with other antihypertensive agents); treatment of CHF following acute MI

Mechanism of Action
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 and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.

Eplerenone 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.

Dosing (adults)
Oral:
Hypertension: Initial: 50 mg once daily; may increase to 50 mg twice daily if response is not adequate; may take up to 4 weeks for full therapeutic response. Doses >100 mg/day are associated with increased risk of hyperkalemia and no greater therapeutic effect.

Concurrent use with moderate CYP3A4 inhibitors: Initial: 25 mg once daily

Congestive heart failure (post-MI): Initial: 25 mg once daily; dosage goal: titrate to 50 mg once daily within 4 weeks, as tolerated

Dosage adjustment per serum potassium concentrations for CHF:
<5.0 mEq/L:
Increase dose from 25 mg every other day to 25 mg daily or
Increase dose from 25 mg daily to 50 mg daily

5.0-5.4 mEq/L: No adjustment needed

5.5-5.9 mEq/L:
Decrease dose from 50 mg daily to 25 mg daily or
Decrease dose from 25 mg daily to 25 mg every other day or
Decrease does from 25 mg every other day to withhold medication

>/= 6.0 mEq/L: Withhold medication until potassium <5.5 mEq/L, then restart at 25 mg every other day

Dosage adjustment in renal impairment:
Patients with hypertension with Clcr<50 mL/minute or serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females: Use is contraindicated; risk of hyperkalemia increases with declining renal function

Patients with CHF post-MI: Use with caution
Supplied
Tablet [film coated]: 25 mg, 50 mg

Mechanisms of Action
Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule.

Aldosterone antagonist activity
Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and the nephrotic syndrome. By competing with aldosterone for receptor sites, spironolactone provides effective therapy for the edema and ascites in those conditions. Spironolactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy.

Spironolactone is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension.

Through its action in antagonizing the effect of aldosterone, spironolactone inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss.

Spironolactone has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism.

Adults: Oral:
To reduce delay in onset of effect, a loading dose of 2 or 3 times the daily dose may be administered on the first day of therapy.
CHF, severe (with ACE inhibitor and a loop diuretic ± digoxin): 25 mg/day, increased or reduced depending on individual response and evidence of hyperkalemia

Edema, hypokalemia: 25-200 mg/day in 1-2 divided doses

Hypertension (JNC 7): 25-50 mg/day in 1-2 divided doses

Diagnosis of primary aldosteronism: 100 to 400 mg/day in 1-2 divided doses

Elderly: Initial: 25 to 50 mg/day in 1-2 divided doses, increasing by 25-50 mg every 5 days as needed.

Dosing interval in renal impairment:
Clcr 10-50 mL/minute: Administer every 12-24 hours.
Clcr<10 mL/minute: Avoid use.

Supplied
Tablet: 25 mg, 50 mg, 100 mg