PDE5

PDE5, or phosphodiesterase type 5, is an enzyme that hydrolyzes cyclic guanosine monophosphate (cGMP) to 5'-GMP, thereby limiting cGMP-mediated signaling. It belongs to the phosphodiesterase family and is encoded by the PDE5A gene on the X chromosome. The enzyme is expressed in smooth muscle, including vascular and cavernosal tissues, and helps regulate smooth muscle tone in several organs.

In the nitric oxide–cGMP pathway, nitric oxide stimulates soluble guanylate cyclase to increase cGMP, which activates protein kinase G and promotes smooth muscle relaxation. PDE5 accelerates the breakdown of cGMP, terminating this signal. PDE5 inhibitors bind to the catalytic site of PDE5, increasing cGMP levels and prolonging vasodilation, especially in penile and pulmonary vasculature.

Clinically, PDE5 inhibitors such as sildenafil, tadalafil, vardenafil, and avanafil are used to treat erectile dysfunction, with efficacy dependent on sexual stimulation. They are also approved for pulmonary arterial hypertension and, in some cases, for benign prostatic hyperplasia. Nitrates and nitric oxide donors must not be used with PDE5 inhibitors due to the risk of severe hypotension. Common adverse effects include headaches, flushing, dyspepsia, nasal congestion, and color-vision changes.

Pharmacokinetics and development: Sildenafil was approved in 1998, followed by other inhibitors. Pharmacokinetic profiles differ: sildenafil has an approximate 4-hour half-life and can be affected by fatty meals, whereas tadalafil has a longer half-life (about 17.5 hours) and can be used daily for some indications.