How PDE5 Inhibitors Work

An erection is a neurovascular event — it requires proper nerve signaling, healthy blood vessels, and adequate blood flow working in sequence. When a man is sexually stimulated, the brain sends signals down the parasympathetic nervous system that trigger the release of nitric oxide (NO) in the smooth muscle cells lining the penile blood vessels.

Nitric oxide activates an enzyme called guanylate cyclase, which converts GTP into cyclic guanosine monophosphate (cGMP). cGMP is the key molecular messenger — it causes smooth muscle to relax, penile arteries to dilate, and blood to rush into the corpora cavernosa (the two cylinders of erectile tissue), filling and pressurizing them until the penis becomes erect.

PDE5 (phosphodiesterase type 5) is the enzyme the body uses to break down cGMP and end this process. PDE5 inhibitors — sildenafil, tadalafil, vardenafil, avanafil — work by blocking PDE5, preventing the breakdown of cGMP, and extending the window during which the physiological conditions for erection are maintained.

This is why men who take a PDE5 inhibitor and then wait passively for something to happen often conclude the medication isn't working. The medication's job is to maintain the cGMP signal once sexual stimulation has produced it — not to initiate the signal in the first place.