Targeted Pharmacological Therapies in Pulmonary Arterial Hypertension: From Endothelin, Nitric Oxide and Prostacyclin to Bmp/Activin Signalling

Pulmonary arterial hypertension (PAH) is a rare, progressive pre-capillary pulmonary vascular disease in which obliterative remodelling of small pulmonary arteries increases pulmonary vascular resistance (PVR) and, if untreated, leads to right-ventricular failure and premature death. This narrative review summarises the pharmacology of targeted therapies for PAH (World Health Organization [WHO] Group 1 pulmonary hypertension) within the contemporary diagnostic and treatment framework of the 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines and the 2024 7th World Symposium on Pulmonary Hypertension (WSPH). Literature was identified through structured searches of PubMed/MEDLINE, Scopus, the Cochrane Library and ClinicalTrials.gov, with priority given to international guidelines, WSPH proceedings, phase 3 randomised controlled trials and meta-analyses. Four therapeutic signalling pathways are now recognised. Endothelin receptor antagonists (bosentan, ambrisentan, macitentan) block endothelin-1 signalling; phosphodiesterase type 5 inhibitors (sildenafil, tadalafil) and the soluble guanylate cyclase stimulator riociguat enhance nitric oxide–cyclic guanosine monophosphate signalling; and prostacyclin-pathway agents (epoprostenol, treprostinil, iloprost and the selective IP-receptor agonist selexipag) augment cyclic adenosine monophosphate signalling. Sotatercept, an activin-signalling inhibitor acting on the bone morphogenetic protein/activin pathway, is the first approved therapy primarily directed at vascular remodelling and has reduced clinical worsening in the STELLAR, ZENITH and HYPERION trials. For each class, the review discusses molecular target, route and dosing, pharmacokinetics, adverse effects, drug interactions, monitoring, pregnancy considerations and landmark trial evidence, distinguishing surrogate endpoints from morbidity and mortality outcomes. Acute vasoreactivity testing, high-dose calcium-channel blockers, multidimensional risk stratification, initial combination therapy, risk-guided sequential escalation, and supportive management are also addressed. Treatment of PAH has evolved from single-pathway vasodilator therapy to risk-adapted multidrug regimens and, more recently, remodelling-directed therapy. Important evidence gaps remain, including management of PAH with cardiopulmonary comorbidities, precision risk stratification, long-term treatment sequencing and the optimal positioning of sotatercept.