New antihypertensive has unique mechanism of action

October 21, 2002

Patients whose hypertension remains inadequately controlled despite the availability of several classes of antihypertensive drugs will soon have a therapeutic option with a unique mechanism of action. Eplerenone is the first agent that selectively binds to the mineralocorticoid receptor and blocks the binding of aldosterone.

 

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New antihypertensive has unique mechanism of action

Patients whose hypertension remains inadequately controlled will soon have a therapeutic option with a unique mechanism of action. On Sept. 30, the Food & Drug Administration granted marketing approval for eplerenone (Inspra, Pharmacia) for the treatment of mild to moderate hypertension alone or in combination with other antihypertensives.

Eplerenone is the first agent that selectively binds to the mineralocorticoid receptor and blocks the binding of aldosterone, said Cynthia Sanoski, Pharm.D., assistant professor of clinical pharmacy, Philadelphia College of Pharmacy. Spironolactone, which also blocks aldosterone, binds to androgen and progesterone receptors in addition to mineralocorticoid receptors, she said.

Sanoski and Mark Munger, Pharm.D., professor of clinical pharmacology, University of Utah, Salt Lake City, explained that this selectivity for the mineralocorticoid receptor gives eplerenone an improved side-effect profile compared with spironolactone in terms of endocrine-related adverse effects, such as gynecomastia, in males and abnormal vaginal bleeding in females.

Sanoski also pointed out that angiotensin converting enzyme (ACE) inhibitors do not always completely block the renin-angiotensin- aldosterone system (RAAS). With the long-term use of ACE inhibitors, aldosterone escape occurs, Sanoski explained, because non-RAAS pathways for aldosterone production exist. Eplerenone, however, will block aldosterone from binding right at the receptor, so it does not matter how the aldosterone is produced.

Munger and Sanoski agreed that the principal risk of treatment with eplerenone is hyperkalemia. Eplerenone therapy is contraindicated in patients with a serum potassium level > 5.5 mEq/L. Use of eplerenone is also contraindicated in patients with Type 2 diabetes and micro- albuminuria, both said.

According to Sanoski and Munger, eplerenone use is contraindicated in male patients with a serum creatinine level > 2.0 mg/dl and in female patients with a serum creatinine level > 1.8 mg/dl. Persons with creatinine clearance < 50.0 ml/min should not take eplerenone, they added.

Eplerenone use is contraindicated in patients treated concomitantly with potassium supplements or potassium-sparing diuretics, said Sanoski and Munger. They explained that use is also contraindicated in patients treated with strong inhibitors of the cytochrome P450 3A4 isoenzyme (CYP3A4), such as ketoconazole and itraconazole (Sporanox, Janssen-Ortho), because metabolism of eplerenone is predominantly mediated by the CYP3A4 isoenzyme.

Eplerenone is classified as a pregnancy category B, Sanoski said. Since no adequate and well-controlled studies have been done in pregnant women, eplerenone should be used with caution during pregnancy and lactation.

The safety and efficacy of eplerenone have not been established in pediatric patients, cautioned Sanoski, and it should not be used in children. Eplerenone can be safely used in older persons without any dosage adjustment, she continued.

In addition to the risk of hyperkalemia, Sanoski and Munger cited dizziness, fatigue, flu-like symptoms, coughing, and diarrhea as the adverse effects most commonly associated with eplerenone therapy.

The recommended starting dose for eplerenone therapy is 50 mg per day, Sanoski and Munger said. If the desired efficacy is not achieved within four weeks, the dosage can be increased to 50 mg b.i.d. The dosage should not exceed 50 mg b.i.d., they warned, because a greater effect on blood pressure is not seen above 100 mg and because higher dosages increase the risk of hyperkalemia.

Laboratory monitoring of patients taking eplerenone should include a metabolic panel, including serum potassium level, done at baseline and then repeated two to four weeks after initiating therapy, said Munger. Laboratory monitoring should also include liver function tests and, if the patient is being treated for hypercholesterolemia, a lipid panel, he added. Both Sanoski and Munger believe eplerenone will be available sometime in 2003.

Charlotte LoBuono

TIPS TO REMEMBER: Inspra

  • If patients start on potassium supplements or potassium-sparing diuretics, potassium levels should be measured at baseline and soon after starting treatment with these agents.

  • In patients taking weak CYP3A4 inhibitors, such as erythromycin, saquinavir (Invirase, Hoffmann-La Roche), verapamil, and fluconazole (Diflucan, Pfizer), the recommended starting dosage of Inspra is 25 mg per day.

  • The Food & Drug Administration is investigating Inspra for the treatment of heart failure.

 

Charlotte LoBuono. New antihypertensive has unique mechanism of action. Drug Topics 2002;20:12.