Drug Therapy of Primary Pulmonary Hypertension

Primary pulmonary hypertension (PPH) is a rare but life-threatening disease. Median survival, from the time of diagnosis, is considered to be 2.8 years. However, therapeutic medical advances over the past 2 decades have resulted in significant improvements in quality of life and survival in patients with PPH. Because pulmonary vasoconstriction, endothelial cell proliferation, smooth muscle cell proliferation, and in situ thrombosis contribute to the development of this disease, treatment with vasodilators, anti-proliferative agents, and anticoagulants is recommended. Currently, oral administration of calcium channel antagonists and intravenous infusion of epoprostenol (prostacyclin) are established as treatment of PPH. Epoprostenol has vasoprotective effects including vasodilation, anti-platelet aggregation, and inhibition of smooth muscle cell proliferation. Interestingly, prostacyclin synthase deficiency in the lungs, and impaired prostacyclin production, have been linked to the development of pulmonary hypertension in this disease. As a result, continuous intravenous infusion of epoprostenol has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with PPH. The dramatic success of long-term intravenous prostacyclin is now leading to the development of epoprostenol analogs using newer drug delivery systems (oral beraprost, aerosolized iloprost, and subcutaneous treprostinil). In addition, promising drugs including endothelin antagonists and type V phosphodiesterase inhibitors have recently been developed. Furthermore, gene therapy with endothelial nitric oxide synthase gene or prostacyclin synthase gene may hold great promise in the treatment of PPH. Finally, accurate evaluation of disease severity and the efficacy of vasodilator therapy are important in the management of patients with PPH. In addition to invasive assessment by cardiac catheterization, we recommend repeated measurements of plasma brain natriuretic peptide, serum uric acid, and the distance walked in 6 minutes. These noninvasive parameters may be helpful as part of the evaluation of treatment in patients with PPH and, in particular, as a guide to the selection and timing for alternative therapies.