Pharmacology of Pulmonary Arterial Hypertension: An Overview of Current and Emerging Therapies

Abstract

Pulmonary arterial hypertension is a rare and devastating disease characterized by an abnormal chronic increase in pulmonary arterial pressure above 20 mmHg at rest, with a poor prognosis if not treated. Currently, there is not a single fully effective therapy, even though a dozen of drugs have been developed in the last decades. Pulmonary arterial hypertension is a multifactorial disease, meaning that several molecular mechanisms are implicated in its pathology. The main molecular pathways regulating the pulmonary vasomotor tone-endothelin, nitric oxide, and prostacyclin-are the most biologically and therapeutically explored to date. However, drugs targeting these pathways have already found their limitations. In the last years, translational research and clinical trials have made a strong effort in suggesting and testing novel therapeutic strategies for this disease. These approaches involve targeting the main molecular pathways with novel drugs, drug repurposing for novel targets, and also using combinatorial therapies. In this review, we summarize current strategies and drugs targeting the endothelin, nitric oxide, and prostacyclin pathways, as well as, the emerging new drugs proposed to cope with vascular remodelling, metabolic switch, perivascular inflammation, epigenetic modifications, estrogen deregulation, serotonin, and other neurohumoral mechanisms characteristic of this disease. Nowadays, pulmonary arterial hypertension remains an incurable disease; however, the incoming new knowledge makes us believe that new promising therapies are coming to the clinical arena soon.

Figure 1

Hallmarks of PAH. The initial endothelial dysfunction compromising vascular dilation and permeability is followed by perivascular inflammation, fibrosis, metabolic dysfunction, and vascular remodelling, all contributing to the rise in mPAP, RV hypertrophy, failure, and premature death: mPAP, mean pulmonary arterial pressure; RV, right ventricle; PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; CTEPH, chronic thromboembolic PH; PVR, pulmonary vascular resistance; PCWP, pulmonary capillary wedge pressure. Individual illustrations were kindly provided by Dr Carlos Galan-Arriola.

Figure 2

Current targets and therapies in PAH. ET, indicates endothelin; ET_A, endothelin receptor type A; ET_B, endothelin receptor type B; PGI2, prostaglandin I2; IP, PGI2 receptor; NO, nitric oxide; PDE5, phosphodiesterase type 5; sGC, soluble guanylate cyclase; GMP, guanosine triphosphate; cGMP, cyclic guanosine triphosphate; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; AC, adenyl cyclase; Ca-Ch, calcium channel. Individual illustrations were kindly provided by Dr. Carlos Galan-Arriola.