Kohagra Mechanism of Action

Phosphodiesterase-5 (PDE5) inhibitor.
Pharmacology: Pharmacodynamics: Sildenafil is a selective inhibitor of phosphodiesterases (PDEs). It has greatest selectivity for PDE type 5 (PDE5), an isoenzyme that inactivates cyclic guanosine monophosphate (cGMP). PDE5 is the predominant type in the corpus cavernosum of the penis and is involved in the breakdown (hydrolysis) of cGMP to GMP. Nitric oxide (NO) released in the corpus cavernosum during sexual stimulation is most likely the major neurotransmitter mediating physiologic penile erection. Nitric Oxide mediates relaxation of the vascular smooth muscle of the corpus cavernosum by activating soluble guanylate cyclase thereby increasing cGMP production. cGMP is a second messenger for G-protein-coupled receptor protein kinases involved in regulating the vascular tone of the arterioles of the corpus cavernosum. Sildenafil enhances penile erection by augmenting NO-mediated, cGMP-dependent vascular smooth muscle relaxation pathways. Upon NO release during sexual stimulation (resulting in increased cGMP production), Sildenafil (by inhibiting cGMP breakdown thus increasing cGMP levels in the corpus cavernosum) produces smooth muscle relaxation of the corpus cavernosum. Vascular smooth muscle relaxation in the corpus cavernosum leads to increased penile blood flow. Sildenafil has no effect on penile erection in the absence of sexual arousal.
Pharmacokinetics: Sildenafil is rapidly absorbed after an oral dose, with a bioavailability of about 40% Peak plasma concentrations occur within 30 to 120 minutes; the rate of absorption is reduced when sildenafil is given with food. Sildenafil is widely distributed into tissues and is about 96% bound to plasma proteins. It is metabolized in the liver mainly by cytochrome P-450 isoenzyme CYP3A4 (the major route) and CYP2C9. The major metabolite, N-desmethyl sildenafil (UK-103320) also has some activity. The terminal half-lives of sildenafil and the N-desmethyl metabolite are about 4 hours. Sildenafil is excreted as metabolites, mainly in the faeces, and to a lesser extent the urine clearance may be reduces in elderly and in patients with hepatic or severe renal impairment.