Pharmacotherapy for Idiopathic Pulmonary Arterial Hypertension During the Past 25 Years

Anna M. Hackman, Pharm.D.; Thomas E. Lackner, Pharm.D., FASCP


Pharmacotherapy. 2006;26(1):68-94. 

In This Article

Cellular Pathology

Idiopathic pulmonary arterial hypertension is the consequence of three characteristic pathologic elements: in situ thrombosis, vasoconstriction, and vascular wall remodeling. In situ thrombosis, evident in most patients, may be associated with a hypercoaguable state, fibrinolytic defects, platelet abnormalities, and injury to the endothelium.[12,13] Vasoconstriction is thought to be the result of endothelial dysfunction, causing an imbalance in endothelium-derived, vasoactive mediators such as nitric oxide, prostacyclin, thromboxane, and endothelin-1. Studies have shown that patients with IPAH exhibit decreased production of the vasodilator nitric oxide in the pulmonary vasculature, as well as impaired production of prostacyclin, a potent endogenous vasodilator and inhibitor of platelet aggregation.[14,15] In contrast, production of thromboxane, an ecosanoid that acts to constrict pulmonary blood vessels and enhance platelet aggregation, is increased in IPAH, as is production of endothelin-1, a vasoconstrictive and pro-proliferative peptide in the pulmonary endothelium.[15,16]

Finally, pulmonary vascular wall remodeling occurs secondary to chronic pulmonary vasoconstriction, resulting in a smaller cross-sectional area and decreased distensibility in pulmonary vessels. In the early stages of IPAH, this remodeling involves smooth muscle hypertrophy, which may be reversed with oral vasodilator therapy such as calcium channel blockers.[17] Later stages of the disease, however, exhibit cellular proliferation and hyperplasia of the intimal, medial, and adventitial layers of small pulmonary arteries and arterioles (Figure 1).[18] Until the introduction of recently approved drug therapies, this late-stage remodeling had been considered to be irreversible by the time a patient presented and IPAH was diagnosed.[18]

Pathogenesis of pulmonary arterial hypertension. In susceptible patients, pulmonary arterial hypertension occurs from an insult to the pulmonary vascular bed. This insult results in an injury that progresses to produce the characteristic pathologic features. HIV = human immunodeficiency virus; BMPR2 = bone morphogenetic protein receptor II gene, which is believed to be the gene responsible for the inherited form of the disease. (From reference 18 with permission.)

Another mechanism of vasoconstriction may be dysfunctional smooth muscle cells in the pulmonary vasculature. Inhibition of voltage-gated potassium channels on these cells increases the influx of calcium and therefore the degree of muscle contraction. In healthy individuals, low levels of oxygen activate these hypoxia-sensitive channels, resulting in vasodilation. In IPAH, however, these potassium channels are turned off. The result is increased intracellular calcium concentrations, leading to vasoconstriction and smooth muscle hypertrophy.[18,19]