Sildenafil in the treatment of pulmonary hypertension

Abstract

The therapy of pulmonary hypertension has evolved rapidly in the last 10 years from the use of non-selective vasodilators to drugs that specifically target pulmonary vasodilation, endothelial function, and vascular remodeling. Sildenafil is a phosphodiesterase type 5 inhibitor that has an expanding role in the treatment of pulmonary hypertension. Case series and small studies, as well as the first large randomized controlled trial, have demonstrated the safety and efficacy of sildenafil in improving mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and exercise tolerance in pulmonary arterial hypertension. It may be useful in adults, children, and neonates after cardiac surgery, with left heart failure, in fibrotic pulmonary disease, high altitude exposure, and thromboembolic disease, and in combination with other therapies for pulmonary hypertension, such as inhaled iloprost. The oral formulation and favorable adverse effect profile make sildenafil an attractive alternative in the treatment of selected patients with pulmonary hypertension.

Figure 1

Mechanism of vasodilatory and antiproliferative effects of sildenafil. NO from vascular endothelial cells stimulates the activity of sGC which produces cGMP from GTP. Sildenafil inhibits the breakdown of cGMP to GMP by PDE 5, increasing cellular concentrations of cGMP which increases the formation of PKG. Competitive inhibition of PDE inhibits breakdown of cAMP which stimulates increased production of PKA. Vasodilation results primarily from modulation of ion channel activity by cGMP with a lesser contribution from increased levels of cAMP. Inhibition of smooth muscle cell proliferation occurs via increased levels of PKA and PKG. Abbreviations: AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; PDE 5, phosphodiesterase type 5, PKA, cAMP dependent protein kinase; PKG, cGMP dependent protein kinase; sGC, soluble guanylate cyclase.