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ATC code: G04B E03.
Pharmacology: Pharmacodynamics: Sildenafil is a selective inhibitor of phosphodiesterases (PDEs), with the greatest selectivity for PDE type 5. At least 10 isoenzyme families of PDE have been identified, several of which (e.g. PDE types 5 and 6) selectively hydrolyze cyclic guanosine monophosphate (cGMP) relative to cyclic adenosine monophosphate (cAMP).
Sildenafil selectively inhibits cGMP-specific PDE type 5, the principal isoenzyme involved in the metabolism of cGMP to GMP in the corpora cavernosa of the penis and clitoris, PDE types 2 and 3 also are present in these corpora cavernosa, and sildenafil also inhibits these isoenzymes albeit substantially less potently (i.e., requires doses exceeding usual therapeutic levels). PDE type 5 also has been isolated from lung, platelets, kidney, spleen and various vascular (e.g., penile and clitoral corpora cavernosa) and visceral smooth muscle (e.g., gastric fundus, esophageal sphincter, colon) and skeletal muscle but not from cardiac muscle. By inhibiting PDE type 5, sildenafil causes accumulation of cGMP in various tissues, including the penile and clitoral corpora cavernosa. The role of cGMP as a modulator of cAMP signal transduction pathways remains to be more fully elucidated, but ex vivo studies indicate that sildenafil does not appear to appreciably affect cAMP tissue concentrations.
Sildenafil also exhibits some activity against other PDE isoenzymes. In vitro, sildenafil is about 10 times more active against PDE type 5 than against PDE type 6, greater than 70-80 times more active against PDE type 5 than against PDE type 1, greater than 1000 times more active against PDE type 5 than against PDE types 2 and 4, and 4000 times more active against PDE type 5 than against PDE type 3. PDE type 3 is involved in cardiac contractility, vascular smooth muscle relaxation (vasodilation), and platelet aggregation, and PDE type 6 (photoreceptor PDE) is found in the retina and involved in phototransduction.
Pharmacokinetics: Absorption: Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). After oral dosing of sildenafil AUC and Cmax increase in proportion with dose over the recommended dose range (25-100 mg).
When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in tmax of 60 minutes and a mean reduction in Cmax of 29%.
Distribution: The mean steady state volume of distribution (Vd) for sildenafil is 105 l, indicating distribution into the tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/ml (CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the mean maximum free plasma concentration for sildenafil of 18 ng/ml (38 nM). 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. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 h.
Elimination: The total body clearance of sildenafil is 41 l/h with a resultant terminal phase half-life of 3-5 h. 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).
