The Pharmacokinetics of Sildenafil

Penile erection occurs as a result of the influx of blood into the corpora cavernosa. This influx of blood is the result of the relaxation of smooth muscle of the corpora cavernosa, produced by the increase in cyclic guanosine monophosphate (cGMP) in turn induced by the release of nitric oxide (NO), activating the enzyme guanylate cyclase, during sexual stimulation. Sildenafil is a potent and specific inhibitor of phosphodiesterase type 5 (FD5), the enzyme responsible for degradation of cGMP in the corpus cavernosum. Thus sildenafil enhances the effects of nitric oxide and enhances the erection and maintenance over time. Sildenafil does not act in the absence of sexual stimulation. Sildenafil is characterized by its high specificity for the FD5, presenting weak effects (80-4000 times lower) over other known FD (FD1, FD2, FD3, FD4), the only exception being the FD6.

Sildenafil lowers blood pressure. This effect is dose related and is greater in patients taking nitrates..

Pharmacokinetics
Sildenafil is rapidly absorbed after oral administration in fasting, peak plasma concentrations are reached about one hour after administration (30-120 minutes). Fatty foods delay absorption. The absolute bioavailability is about 40%. The volume of distribution is 105 l. Both sildenafil and its major metabolite N-desmethyl circulate almost completely (96%) bound to plasma proteins. Sildenafil is eliminated primarily by hepatic metabolism (especially 3A4 isoenzyme cytochrome P-450 and secondarily by the 2C9 isoenzyme) and is converted to an active metabolite which is considered responsible for about 20% of the pharmacological effects. The terminal half-life of sildenafil and its major metabolite is about 4 hours. Excretion is mainly in the feces (80% of the administered dose) in the form of metabolites and to a lesser extent (13%) in urine. In patients 65 years or older decreased clearance of sildenafil higher than in younger individuals plasma concentrations was observed. In individuals with mild to moderate alteration not sildenafil pharmacokinetics observed after administration of a single oral dose of 50 mg. In patients with severe renal impairment (creatinine clearance <30 ml / min) decreased clearance of sildenafil and doubling the AUC and peak plasma concentration (Cmax.) Is reported. Decreased clearance of sildenafil, increased AUC (84%) and Cmax was also reported. (47%) in individuals with liver cirrhosis.

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