Selection of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension: A Comprehensive Narrative Review

One of the major mechanisms in the pathogenesis of pulmonary arterial hypertension (PAH) is mediated by elevated levels of endothelin (ET)-1, which activates both ET_A and ET_B receptors in the pulmonary vasculature. Endothelin receptor antagonists (ERAs) are established treatments for PAH, and three agents-bosentan, ambrisentan, and macitentan-are approved for use in adults in the USA. All are orthosteric antagonists of ET-1 and bind with high affinity to the ET_A receptor, which is found largely on vascular smooth muscle cells (SMCs) and involved in vasoconstriction. Bosentan and macitentan also bind to the ET_B receptor, which is upregulated on SMCs and downregulated on endothelial cells in PAH, resulting in vasoconstriction, cell proliferation, and vascular remodeling. Studies show all three ERAs are efficacious in treating PAH as monotherapy or in combination with other PAH drugs and are generally well tolerated, but all can cause fetal harm and are contraindicated in pregnancy. However, there are no head-to-head clinical trials providing a comprehensive comparison of the overall efficacy and safety of ERAs in PAH. Consequently, we examined the literature on ERAs in PAH through a targeted search of the PubMed/MEDLINE database. This narrative review explores the role of ET-1 in PAH underlying the rationale for ET receptor antagonism. It also discusses the differing physicochemical and pharmacokinetic properties of each ERA and how these unique characteristics influence their receptor binding and kinetics, mechanisms of action, therapeutic effects, dosing frequency, and safety in PAH. In the absence of head-to-head clinical trials assessing their comparative efficacy and safety, it is important to understand both the similarities and the distinguishing characteristics of the three ERAs approved in PAH, to inform individualized treatment selection.