Aldosterone Synthase Inhibitors and the Treatment of Essential Hypertension.

Abstract

Approximately 10% of hypertensive patients have treatment-resistant hypertension defined as uncontrolled hypertension despite taking effective doses of 3 classes of antihypertensive drugs including a calcium channel blocker, thiazide diuretic, and an angiotensin-converting enzyme inhibitor or angiotensin-2 receptor blocker. The Pathway-2 study of treatment-resistant hypertensives randomized to receive an additional low dose of spironolactone demonstrated that addition of the mineralocorticoid receptor (MR) antagonist lowered the blood pressure (BP) more effectively than placebo, bisoprolol, or doxazosin. The extent of BP lowering by spironolactone was predicted by the baseline aldosterone–renin ratio (1). Aldosterone excess is common in patients with treatment-resistant hypertension and about 20% of these patients meet current criteria for primary aldosteronism (PA) (2). The importance of aldosterone synthesis in primary hypertension was demonstrated several decades ago by lowering the BP of patients with low renin hypertension with aminoglutethimide, an inhibitor of the mitochondrial side chain cleavage enzyme (CYP11A1) (3). Only aldosterone levels significantly decreased; those of deoxycorticosterone, cortisol, and other steroids were unchanged or increased (3). Spironolactone, the most used MR antagonist, has significant adverse effects including hyperkalemia and off-target effects through the androgen and progesterone receptors. Newer more selective MR antagonists including eplerenone and finerenone are less effective antihypertensives. An alternative approach to treat hypertension due to inappropriate aldosterone levels is to target its synthesis.