化合物信息

Drug Groups

approved; investigational

Description

Sildenfail is a vasoactive agent used to treat erectile dysfunction and reduce symptoms in patients with pulmonary arterial hypertension (PAH). Sildenafil elevates levels of the second messenger, cGMP, by inhibiting its breakdown via phosphodiesterase type 5 (PDE5). PDE5 is found in particularly high concentrations in the corpus cavernosum, erectile tissue of the penis. It is also found in the retina and vascular endothelium. Increased cGMP results in vasodilation which facilitates generation and maintenance of an erection. The vasodilatory effects of sildenafil also help reduce symptoms of PAH.

Indication

For the treatment of erectile dysfunction and to relieve symptoms of pulmonary arterial hypertension (PAH).

Pharmacology

Erections are controlled by the parasympathetic nervous system. Upon sexual stimulation, a decrease in vascular resistance is mediated by acetylcholine and nitric oxide resulting in vasodilation. The hemodynamic mechanism of an erection is comprised of five stages. During the latent stage, arterial and carvernous smooth muscle relaxation occurs. Vasodilation results in high levels of blood flow causing the penis to grow to its full size. This stage is called tumescence. During the full-erection stage, blood flow fills penis sinusoids and outflow is restricted. This is followed by the rigid-erection phase during which the cavernous muscles contract causing the penis to become rigid. Little blood flow occurs during this stage. During the final stage, detumescence, the cavernous muscles relax and blood flows out of the penis. Erectile dysfunction may occur when there is insufficient blood supply to the penis or when the penis is unable to prevent outflow of blood from the penis. Sildenafil is a specific inhibitor of PDE5, an enzyme responsible for the breakdown of cGMP to 5’-GMP. Increased levels of cGMP stimulate vasodilation and facilitate the generation and maintenance of erections. These vasodilatory effects also help decrease symptoms of PAH. Sildenfail also exhibits some activity against PDE6 (10 times less potentcy compared to PDE5), a PDE isoform found predmoninantly in the retina. This activity is responsible for the blue tinged vision experienced by users of sildenafil.

Affected Organisms

Biotransformation

Sildenafil appears to be completely metabolized in the liver to 16 metabolites. Its metabolism is mediated mainly by cytochrome P450 microsomal isozymes 3A4 (major route) and 2C9 (minor route). The major circulating metabolite, N-demethylated metabolite, has PDE selectivity similar to the parent drug and ~50% of its in vitro potency. The N-demethylated metabolite is further metabolized to an N-dealkylated N,N-de-ethylated metabolite. Sildenafil also undergoes N-dealkylation followed by N-demethylation of the piperazine ring.

Absorption

>90% absorbed with ~40% reaching systemic circulation unchanged following first-pass metabolism

Half Life

4 hours

Protein Binding

96%

Elimination

Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).

Distribution

* 105 L

References

External Links