*3.3.4.1.1 Sildenafil*

It is a selective inhibitor of type 5 phosphodiesterase (5-PDEi), which specifically degrades cyclic guanosine monophosphate and its level is increased in pulmonary arteries. Normally, NO stimulates intracellular soluble guanylate cyclase resulting in increased levels of cGMP, which then acts to mediate smooth muscle relaxation; in PAH, there is a decrease in NO production from the endothelium. Therefore, sildenafil inhibits 5-PDEi, preventing degradation of cGMP and prolonging its effects. The SUPER-1 trial, a double-blind, and placebo-controlled trial demonstrated a significant increase in the walked distance of the 6MWT, in the WHO functional class and the hemodynamic parameters in the sildenafil group [38]. Thence, the SUPER-2 trial assessed long-term safety and tolerability of sildenafil treatment: it proved that the drug is generally well tolerated, and, after 3 years, the majority of patients (60%) who entered the SUPER-1 trial improved or maintained their functional status, and 46% maintained or improved 6MWT [39]. Common adverse effects of this therapy are diarrhea, dyspepsia, and flushing.

## *3.3.4.1.2 Tadalafil*

It is an alternative molecule and has a better pharmacokinetic profile than sildenafil. In the PHIRST-1 trial, tadalafil demonstrated a significant improvement in 6MWT and hemodynamic parameters, such as mPAP and PVR [40]. Common adverse effects of this therapy are myalgia, flushing, and headache.
