Sildera Mechanism of Action

Pharmacology: Pharmacodyanmics: Erectile dysfunction: Does not directly cause penile erections, but affects the response to sexual stimulation. The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which result in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE-5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum; at recommended doses, it has no effect in the absence of sexual stimulation.
Pharmacokinetics: Sildenafil is rapidly absorbed after an oral dose, with a bioavailability of about 40% (25% to 63%). Onset of action is about 60 minutes and duration of action is about 2-4 hours. Peak plasma concentrations are attained within 30 to 120 minutes but delayed by 60 minutes with a high fat meal; the rate of absorption is reduced when sildenafil is given with food and slower with a high fat meal. Sildenafil is widely distributed into tissues and is about 96% bound to plasma proteins. It is metabolised in the liver mainly by cytochrome P450 isoenzymes CYP3A4 (the major route) and CYP2C9 (minor route). The major metabolite, N-desmethylsildenafil (UK-103320) also has some activity. Volume of distribution at steady state (V_dss) is 105 litres. The terminal half-life of sildenafil and the N-desmethyl metabolite are about 4 hours. Sildenafil is excreted as metabolites, mainly in the faeces (80%), and to a lesser extent the urine (13%). Clearance may be reduced in the elderly and in patients with hepatic or severe renal impairment.