Pharmacology: Pharmacodynamics: The physiological mechanism of erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.
Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but enhances the effect of NO by inhibiting the phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.
When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.
Pharmacokinetics: Sildenafil pharmacokinetics are dose-proportional over the recommended dose range.
It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil.
Absorption: Sildenafil is rapidly absorbed after oral administration, with absolute bioavailability of about 40% (range 25%-63%). In man, the mean maximum free plasma concentration of sildenafil following a single oral dose of 100 mg is approximately 18 ng/mL or 38 nM. Maximum observed plasma concentrations are reached within 30-120 min (median 60 min) of oral dosing in fasted state. When sildenafil is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 min and a mean reduction in Cmax of 29%.
Distribution: The mean steady-state volume of distribution (VSS) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein-binding is independent of total drug concentrations.
Metabolism: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolized, with a terminal half-life of approximately 4 hrs.
Elimination: The total body clearance of sildenafil is 41 L/hr with a resultant terminal phase half-life of 3-5 hrs. After either oral or IV administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).