Calcium channel blockers have been used in IPAH with limited success. The development of intravenous prostanoids significantly improved treatment options for patients with PAH but were generally limited to patients in NYHA classes III and IV.This was in part due to the extremely poor survival for patients in these classes, as well as the expense and difficulty of administering intravenous prostanoids. Over the last five years, two classes of oral medications have become available for the treatment of PH that has expanded the number of patients who are candidates for treatment. They have allowed practitioners outside of specialized centers to treat PH patients.

Pathophysiology
Vasoconstriction, vascular wall remodeling, and thrombosis in situ are key mechanisms in the development of PH. Histopathology of pulmonary arteries reveals characteristic plexiform changes, intimal fibrosis, increased medial wall thickness, and arteriolar occlusion.These findings suggest that endothelial injury and abnormal vascular repair are important pathophysiologically, though the exact cascade of molecular events leading to the development of IPAH remains unclear. The identification of mediators consistent with endothelial and vascular dysfunction have led to the development of novel treatment options that are discussed in more detail below.

Transforming growth factor (TGF)-β1, an important cytokine for normal and aberrant tissue repair, has been implicated in PH pathogenesis, and genetic alterations in TGF-β signaling predisposing to familial IPAH include mutations in the gene for the bone morphogenetic protein receptor (BMPR)2, polymorphisms of the activin-receptor-like kinase 1 (ALK-1) genex, and ‘micro-satellite instability’ (MSI) of the TGF-β receptor gene found in plexiform lesions. In patients with non-familial IPAH, elevation of angiopoietin-1 (Ang-1) levels in pulmonary artery smooth muscle cells leads to increased activation of Tie-2 receptors on vascular endothelial cells and the development of excessive muscularization of pulmonary arterioles. The constitutive expression of Ang-1 results in diminished BMPR1a levels, an endothelial coreceptor of BMPR2, and the progression to pulmonary hypertension by the TGF-β pathway. An imbalance between prostacyclin and thromboxane A2 favors vasoconstriction, smooth muscle cell proliferation, and enhanced coagulation, all of which predispose to development of PH. Other mechanisms that may be important in IPAH pathogenesis include elevated serotonin and adrenomedullin levels, decreases in serum and lung vaso-active intestinal peptide levels, and aberrant vascular response to vascular epithelial growth factor (VEGF).

Investigation into the role of nitric oxide (NO) demonstrates that its production is impaired in IPAH. Nitric oxide, previously known as endothelium-derived or -dependent relaxation factor, mediates vasodilatation by increasing cyclic GMP levels through the activation of guanylate cyclase. Cyclic GMP has a short half-life because it is rapidly degraded by phosphodiesterases (PDE). In the lung, phosphodiesterase type-five expression and activity are increased in chronic PH. Inhibition of cyclic GMP-specific PDE (PDE type-five inhibitors) has been shown in a number of animal models to augment pulmonary vascular response to NO and cause potent pulmonary vasodilatation.These studies provide the theoretical basis for using PDE type-five inhibitors in IPAH.