title: The molecular targets of approved treatments for pulmonary arterial hypertension.
abstract: Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)--prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy.
authors.affiliation: Service de Pneumologie, DHU Thorax Innovation, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Paris, France Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, Paris, France INSERM Unité 999, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: University of Giessen and Marburg Lung Center (UGMLC), member of the German Center of Lung Research (DZL), Giessen, Germany Department of Medicine, Imperial College London, London, UK.
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
mesh_terms: D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011453:Prostaglandins / Q000008:administration & dosage / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D010726:Phosphodiesterase Inhibitors; D011453:Prostaglandins; D011720:Pyrazoles; D011743:Pyrimidines; C542595:riociguat
keywords: Primary Pulmonary Hypertension