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.

• Amides
• Cardiovascular Agents
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (moderate)
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP2E1 Inhibitors
• Cytochrome P-450 CYP2E1 Substrates
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (moderate)
• Cytochrome P-450 CYP3A4 Substrates
• Enzyme Inhibitors
• Genito Urinary System and Sex Hormones
• Gynecological Antiinfectives and Antiseptics
• Phosphodiesterase 5 Inhibitors
• Phosphodiesterase Inhibitors
• Piperazines
• Purines
• Sulfonamides
• Sulfones
• Sulfur Compounds
• Urological Agents
• Vasodilator Agents

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

• Erectile Dysfunction (ED)
• NYHA Functional Class II-III Pulmonary arterial hypertension

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.

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

• 105 L

96%

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).

4 hours

• Humans and other mammals