Sildenafil (Viagra, Revatio)

Detailed overview

Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor and the first agent to make erectile dysfunction a tablet-treatable condition. Pfizer originally developed it for angina pectoris; in trials the cardiac effect remained modest, but improved erections observed as a side effect opened a new indication. It was approved as Viagra in 1998. The mechanism is worth understanding precisely, because it explains the drug's single most important practical property. On sexual stimulation, nerve endings in the corpus cavernosum release nitric oxide, which generates cyclic GMP, which relaxes smooth muscle. The PDE5 enzyme degrades cGMP. Sildenafil inhibits that degradation, so it does not initiate an erection but amplifies and sustains an EXISTING signal. Without stimulation nothing happens, and that is not a fault but a consequence of the mechanism. The same signalling pathway operates in the pulmonary arteries, which is why it gained a second approval in 2005 as Revatio, at a lower three-times-daily dose, for pulmonary arterial hypertension (summarised in the Bhogal 2019 review). Cardiovascular safety is the most frequent question and the answer has two layers. Analyses by Jackson 2006 and Carson 2005 found that PDE5 inhibitors did not increase cardiac events versus placebo in clinical trials. Kloner 2000, however, identifies the real danger precisely: co-administration with nitrates. Both agents attack the same vasodilatory pathway at two points, and the result can be an unpredictable, severe drop in blood pressure. This is not a theoretical risk and it cannot be solved by timing or dose reduction.