| Indication |
For the treatment of erectile dysfunction and to relieve symptoms of pulmonary arterial hypertension (PAH). |
| Pharmacodynamics |
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. |
| Mechanism of action |
Sildenafil inhibits the cGMP-specific phosphodiesterase type 5
(PDE5) which is responsible for degradation of cGMP in the corpus
cavernosum located around the penis. Penile erection during sexual
stimulation is caused by increased penile blood flow resulting from the
relaxation of penile arteries and corpus cavernosal smooth muscle. This
response is mediated by the release of nitric oxide (NO) from nerve
terminals and endothelial cells, which stimulates the synthesis of cGMP
in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and
increased blood flow into the corpus cavernosum. The inhibition of
phosphodiesterase type 5 (PDE5) by sildenafil enhances erectile function
by increasing the amount of cGMP. |
| Absorption |
>90% absorbed with ~40% reaching systemic circulation unchanged following first-pass metabolism |
| Volume of distribution |
|
| Protein binding |
96% |
| Metabolism |
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. |
| Route of 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). |
| Half life |
4 hours |
| Clearance |
Not Available |
| Toxicity |
Not Available |
