A New Drug for Resistant Hypertension: Aprocitentan

Resistant hypertension (RH) is defined as uncontrolled blood pressure (BP) despite the use of three or more antihypertensive agents of different pharmacological classes. The treat-ment of resistant hypertension remains a challenge, as it is associated with a heightened risk of cardiovascular events. Many preclinical studies have demonstrated the importance of the endo-thelin pathway in resistant hypertension; however, the therapeutic application of endothelin an-tagonists in clinical practice has been limited due to various factors. Recently, in March 2024, the FDA approved aprocitentan, an orally active endothelin-1 (ET-1) receptor antagonist that inhibits the binding of ET-1 to ETA and ETB receptors. This is the first medication with a novel mechanism for the treatment of resistant hypertension. This review aims to summarise the avail-able evidence on the discovery, chemical nature, pharmacokinetics, pharmacodynamics, effi-cacy, and safety of the novel drug aprocitentan in the pharmacotherapy of resistant hyperten-sion. The landmark PRECISION trial demonstrated a significant BP-lowering effect with the use of the dual endothelin receptor antagonist aprocitentan in the treatment of resistant hyper-tension. Aprocitentan was shown to be particularly effective in patients over 75 years of age, those with a higher cardiovascular-risk profile, patients with diabetes, and individuals with ad-vanced chronic kidney disease (CKD). As a dual receptor antagonist, aprocitentan demonstrated a lower risk of fluid retention and vascular leakage, adverse effects previously observed with other endothelin receptor antagonists. Its mechanism of action, improved efficacy, and excellent tolerability make aprocitentan a promising therapeutic option for resistant hypertension. It may be particularly effective in the treatment of patients with comorbidities, such as diabetes and CKD.