The primary focus of current medical management of ES is on reducing the PVR and, by extension, the right-to-left shunting and cyanosis. Medications and treatments that have detrimental effects must be avoided. For example, calcium channel–blocking agents must be avoided; even though these medications produce reductions in the PVR, they also produce unacceptably greater reductions in the SVR, effectively exacerbating the right-to-left shunting.

Sildenafil and l-arginine are effective in decreasing or reducing the degree of pulmonary hypertension. l-Arginine is converted to nitric oxide (NO) in vivo, which activates guanylate cyclase. Guanylate cyclase increases the level of cyclic guanosine monophosphate (cGMP), which is instrumental in relaxing the smooth muscles of the pulmonary blood vessels. Sildenafil inhibits the degradation of cGMP, thus fostering greater cGMP availability. Sildenafil works synergistically with inhaled NO to enhance the effects of both in the NO-cGMP pathway. Combining sildenafil with l-arginine enhances the NO-cGMP pathway in an effort to effectively reduce the PVR.

Two other medications are used to treat ES patients: epoprostenol and bosentan. Epoprostenol is a prostacyclin analogue that has two primary pharmacologic actions: direct vasodilation of pulmonary and systemic vascular beds and inhibition of platelet aggregation. It also contributes to bronchodilation. This medication must be administered via a permanent central venous access.