Resistant hypertension is defined as blood pressure (BP) that remains above goal in spite of compliance with full doses of 3 or more antihypertensive medications of different classes. Ideally, a thiazide-like diuretic should be included in this 3 drug regimen. Classically, the recommendation has been to add a mineralocorticoid receptor antagonist such as spironolactone or eplerenone to the regimen of these resistant hypertensive patients to gain BP control. The study that deserves major credit for establishing this practice is the Prevention And Treatment of Hypertension With Algorithm based therapY (PATHWAY) study (Williams B, et al. Lancet. 386:2059–2068, 2015). PATHWAY compared the mineralocorticoid receptor antagonist spironolactone to doxazosin and bisoprolol in patients with resistant hypertension and demonstrated that spironolactone was overwhelmingly more successful in controlling the patient's BP and was also very well tolerated. The results of PATHWAY established aldosterone antagonists as the best add-on therapy for patients with resistant hypertension. However, spironolactone and other steroidal mineralocorticoid receptor antagonists such as eplerenone do have major adverse effects which can limit their use. These include sex hormone-related adverse effects such as gynecomastia and breast tenderness in women and erectile dysfunction and feminization in men. A solution to this problem, which is currently under active development, is use of non-steroidal mineralocorticoid receptor antagonists such as esaxerenone and finerenone (Figure 1). These non-steroidal mineralocorticoid receptor antagonists are bulky molecules which bind to the mineralocorticoid receptors and effectively prevent their activation. Specifically, esaxerenone has been shown to be as effective as eplerenone in lowering BP and to be well tolerated in Japanese patients with essential hypertension. Esaxerenone also has no sex hormone-dependent adverse effects. The question now is whether the non-steroidal mineralocorticoid receptor antagonists are to be the answer for resistant and refractory hypertension.
Figure 1. Molecular Structures of Steroids and MR Blockers
Adapted from: Tezuka Y, Ito S. The time to reconsider mineralocorticoid receptor blocking strategy: Arrival of nonsteroidal mineralocorticoid receptor blockers. Curr Hypertens Rep. 2022 Jul;24(7):215–224. doi: 10.1007/s11906-022-01177-6.