Pharmacological properties: oral chemotherapy in treating patients with erectile dysfunction, a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE 5).

Sildenafil has no direct relaxing effect on isolated cavernous body, but significantly increases the relaxing effect of nitrous oxide (NO) by inhibition of the PDE 5, is responsible for the splitting of cGMP in the cavernous bodies. When you activate the pathway NO / cGMP, which occurs with sexual stimulation, inhibition of PDE 5 sildenafil increases the concentration of cGMP in the cavernous bodies. Therefore, for the manifestation of pharmacotherapeutic effect of sildenafil should be sexual stimulation.

In vitro found that sildenafil has a selectivity for PDE 5. His influence on the PDE 5 more pronounced than on other known phosphodiesterases (10 times stronger than for PDE 6, 80 times - compared to the PDE 1, 700 times - with PDE 2, 4, 7-11, 400 times - with PDE W, which is involved in the processes of regulation of heart rate).

In healthy volunteers in single dose of sildenafil 100 mg have been no reported clinically significant ECG changes. The use of sildenafil resulted in a slight or moderate blood pressure decrease, which usually does not affect the therapeutic effect. The mean maximum decrease in systolic blood pressure in the supine position after ingestion of 100 mg was 8.4 mmHg. Art. The corresponding change in diastolic blood pressure in the supine position was 5.5 mm Hg. Art. BP decrease is due to vasodilating action of sildenafil, which may be due to increased concentration of cGMP in smooth muscles of blood vessels. More pronounced decrease in blood pressure was noted in patients who are simultaneously taking nitrates.

Sildenafil is rapidly absorbed from the digestive tract. The maximum plasma concentration achieved after 30-120 min (mean 60 min) after oral administration on an empty stomach. Absolute oral bioavailability of 40% (within 25-63%). If the drug is taken with fatty foods, the rate of absorption is reduced and the time to reach maximum plasma concentrations increased by an average of 60 minutes, and the maximum plasma concentration is reduced by an average of 29%. Sildenafil inhibits PDE 5 in vitro by 50% at concentration of 3 5 nM. The average concentration in blood plasma after administration of sildenafil 100 mg is about 18 ng / ml or 38 nM.

The average volume of distribution of sildenafil in the equilibrium state is equal to 105 liters, indicating that its distribution in tissues. How to sildenafil and its main circulating in the blood of N-dismetilovy metabolite, by approximately 96% bound to plasma proteins of blood. Protein binding does not depend on the concentration of the drug.

In healthy volunteers who received sildenafil (single dose 100 mg), 90 min after drug administration in the ejaculate was determined less than 0.0002% sildenafil (mean 188 ng) on the accepted dose.

Sildenafil is metabolized primarily liver isoenzymes localized in microsomes, CYP3A4 (major route) and CYP2C9 (minor route). The main circulating in the blood metabolite formed by N-dimetilirovaniya sildenafil. This metabolite is characterized by selective action on the PDE 5, but the degree of selectivity on the PDE 5 is approximately 50% of the selectivity of sildenafil. The concentration of this metabolite in blood plasma is approximately 40% of the concentration of sildenafil. N-dismetilovy metabolite is metabolized, and subsequently during its half-life of approximately 4 hours

The total clearance of sildenafil is 41 l / h, half-life - 3-5 pm Sildenafil is excreted as metabolites, mainly in the faeces (approximately 80% of the applied dose) and to a lesser extent - in the urine (approximately 13% of the applied dose).

In healthy elderly volunteers (65 years and older) are marked decline in the clearance of sildenafil, and the concentration of sildenafil and its metabolite N-dismetilovogo approximately 40% higher than in healthy young volunteers (18-45 years).

In volunteers with mild and moderate (creatinine clearance - 30-80 ml / min) renal insufficiency Pharmacokinetics of sildenafil after oral administration of a single dose of 50 mg did not change. Volunteers with severe (creatinine clearance ≤ 30 mL / min) renal insufficiency decreased clearance of sildenafil, which led to an increase in AUC (100%) and increased the maximum concentration in blood (88%) compared with volunteers of similar age without disabilities function kidneys.

In volunteers with mild to moderate liver cirrhosis expressed (functional class A and B on the classification of Child-Pugh) decreased clearance of sildenafil, which led to an increase in AUC (84%) and increased the maximum plasma concentrations (47%) compared to c those of the volunteers of similar age without hepatic failure. Pharmacokinetics of sildenafil in patients with severely impaired liver function were studied.

INDICATIONS: Treatment of patients with impaired erection, which is defined as the inability to attain and maintain an erection of the penis, necessary to the sexual act.

APPLICATION: to develop the effect of the drug must be sexual stimulation. The recommended dose for persons older than 18 years is 50 mg, taken orally approximately 1 hour before sexual intercourse. Given the efficacy and tolerability, the dose is increased to 100 mg or decrease to 25 mg. The maximum recommended dose is 100 mg, the maximum frequency of intake - 1 times per day. The effect of Viagra while eating develops later than when receiving an empty stomach.

Patients with mild renal insufficiency and moderate (creatinine clearance of 30-80 ml / min), dosage regimen adjustment is not required. Because patients with severe renal insufficiency (creatinine clearance <30>