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. NO 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 readily absorbed with peak plasma concentrations achieved approximately 60 minutes after oral administration in the fasted state. Sildenafil undergoes extensive metabolism in the GI mucosa during absorption and on first pass through the liver. Hence, sildenafil's mean absolute oral bioavailability is only about 41%. Taking sildenafil with food, particularly with a high fat meal, delays absorption and decreases maximum plasma sildenafil concentration possibly due to delayed gastric emptying.
Sildenafil is about 96% bound to plasma protein and its mean apparent steady state volume of distribution is approximately 105 L.
Sildenafil is primarily metabolized in the liver through the hepatic cytochrome P450 (CYP450) enzymes 3A4 and 2C9 and excreted mainly as metabolites mainly in the feces and to a lesser extent in the urine. The active N-desmethyl metabolite is reported to account for about 20% of sildenafil's pharmacologic activity and reach plasma concentrations that are about 40% of those seen with sildenafil.
Sildenafil's apparent terminal half-life ranges from 3 to 5 hours over the dose range of 25 mg and 200 mg. This allows an appropriate duration of therapeutic effect while preventing accumulation of the drug with chronic once-daily dosing.
Old age (65 years and older) increases sildenafil and N-desmethyl metabolite (active metabolite) plasma levels by about 90% compared to those seen in younger volunteers (18- 45 years old) due to reduced clearance of sildenafil. The corresponding increase in free sildenafil plasma concentration was approximately 40% due to the age-differences in plasma protein binding.
Compared with patients with no hepatic impairments, sildenafil clearance was reduced in patients with hepatic impairment (Child-Pugh A and B). Sildenafil has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Increased sildenafil levels were observed in patients with severe renal impairment (CLcr ≤30 mL/min). However, sildenafil pharmacokinetics was not altered in patients with mild (CLcr 50-80 mL/min) to moderate (CLcr 30-49 mL/min) renal impairment.