Axcel Sildenafil Mechanism of Action

Pharmacology: Sildenafil, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5).
Mechanism of Action: The physiologic mechanism of erection of the penis involves 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 nitric oxide (NO) by inhibiting 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. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1>700-fold for PDE2, PDE3 and PDE4, PDE7-PDE11). The approximately 4000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in the control of cardiac contractility.
Pharmacokinetics: Sildenafil pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent sildenafil.
Absorption: Sildenafil is rapidly absorbed after oral administration, with mean absolute bioavailability of 41% (range 25-63%). Sildenafil inhibits the human PDE5 enzyme in vitro by 50% at a concentration of 3.5nM. In man, the mean maximum free plasma concentration of sildenafil following a single oral dose of 100mg is approximately 18ng/ml, or 38nM. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the 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 minutes and a mean reduction in Cmax of 29%, however, the extent of absorption was not significantly affected (AUC decreased by 11%).
Distribution: The mean steady state volume of distribution (Vss) for sildenafil is 105L, 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 and an in vitro potency for PDE5 approximately 50% of the parent drug. The terminal half-lives of sildenafil and the N-desmethyl metabolite are about 4 hours.
Elimination: The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 hours. After either oral or intravenous 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 administered oral dose). Clearance may be reduced in the elderly and in patients with hepatic or severe renal impairment.