Pharmacological properties pharmacodynamics. Mechanism of action. Sildenafil is an oral medication that is intended for the treatment of erectile dysfunction. During sexual arousal, the drug renews reduced erectile function by increasing blood flow to the penis. The physiological mechanism of penile erection consists in the release of nitric oxide (NO) in the cavernous body during sexual stimulation.
The released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in the level of cGMP, which, in turn, causes relaxation of the smooth muscles of the cavernous body, contributing to increased blood flow. Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase-5 (PDE-5) in the cavernous body, where PDE-5 is responsible for the breakdown of cGMP. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not have a direct relaxing effect on the isolated human cavernous body, but it powerfully enhances the relaxing effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated, which occurs during sexual stimulation, sildenafil inhibition of PDE-5 leads to an increase in cGMP levels in the cavernous body. Thus, in order for sildenafil to cause the necessary pharmacological effect, sexual arousal is necessary. Influence on pharmacodynamics. In vitro studies have demonstrated the selectivity of the effect of sildenafil on PDE-5, which takes an active part in the erection process. The effect of sildenafil on PDE-5 is more powerful than on other known PDEs.
This effect is 10 times more powerful than the effect on PDE-6, which takes part in the processes of phototransformation in the retina. When using the maximum recommended doses, the selectivity of sildenafil to PDE-5 is 80 times higher than its selectivity to PDE-1, 700 times higher than to PDE-2, PDE-3, PDE-4, PDE-7, PDE-8, PDE-9, PDE-10 and PDE-11. In particular, the selectivity of sildenafil to PDE-5 is 4000 times higher than its selectivity to PDE-3 — cGMP-specific isoform of PDE, which participates in the regulation of heart contractions. Pharmacokinetics Absorption. Sildenafil is rapidly absorbed.
Cmax of the drug in blood plasma is reached for 30-120 minutes (with a median of 60 minutes) after its oral administration on an empty stomach. The average absolute bioavailability after oral administration is 41% (with a range of values of 25-63%). In the recommended dose range (25-100 mg), the AUC and Cmax values of sildenafil after oral administration increase proportionally to the dose. When using sildenafil during meals, the degree of absorption decreases with an average lengthening of Tmax to 60 minutes and an average decrease in Cmax by 29%. Distribution. The average equilibrium volume of distribution (Vd) is 105 liters, which indicates the distribution of the drug in the tissues of the body. After a single oral administration of sildenafil at a dose of 100 mg, the average Cmax of sildenafil is about 440 ng / ml (the coefficient of variation is 40%). Since the binding of sildenafil and its main N-desmethyl metabolite to plasma proteins reaches 96%, the average Cmax of free sildenafil reaches 18 ng/ml (38 nmol). The degree of binding to plasma proteins does not depend on the total concentrations of sildenafil. In healthy volunteers who used sildenafil once at a dose of 100 mg, after 90 minutes, < 0.0002% (on average — 188 ng) of the applied dose was determined in the ejaculate. Biotransformation.
Sildenafil metabolism is carried out mainly with the participation of microsomal liver isoenzymes CYP 3A4 (main pathway) and CYP 2C9 (secondary pathway). The main circulating metabolite is formed by N-demethylation of sildenafil. The selectivity of the metabolite with respect to PDE-5 is comparable to the selectivity of sildenafil, and the activity of the metabolite with respect to PDE-5 is approximately 50% of the activity of the starting substance. The concentrations of this metabolite in blood plasma are approximately 40% of the concentrations of sildenafil in blood plasma. The N-demethylated metabolite undergoes further metabolism, and the T-half is approximately 4 hours. Elimination.
The total clearance of sildenafil is 41 l/h, predestining a Half-life of 3-5 hours. Both after oral and after intravenous administration, the excretion of sildenafil in the form of metabolites is carried out mainly with feces (about 80% of the administered oral dose) and to a lesser extent with urine (about 13% of the administered oral dose). Pharmacokinetics in special groups of patients Elderly patients. In healthy elderly volunteers (aged ≥65 years) there was a decrease in the clearance of sildenafil, which predetermined an increase in plasma concentrations of sildenafil and its active N-demethylated metabolite by approximately 90% compared with the corresponding concentrations in healthy young volunteers (18-45 years). Due to age differences in binding to plasma proteins, the corresponding increase in the plasma concentration of free sildenafil was about 40%.
Kidney failure. In volunteers with mild to moderate renal impairment (creatinine clearance — 30-80 ml / min), the pharmacokinetics of sildenafil remained unchanged after its single oral administration at a dose of 50 mg. The average AUC and Cmax of the N-demethylated metabolite increased by 126 and 73%, respectively, compared with such indicators in volunteers of the same age without impaired renal function. However, due to the high interindividual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 ml/min), sildenafil clearance decreased, which led to average increases in AUC and Cmax by 100 and 88%, respectively, compared with volunteers of the same age without renal impairment. In addition, the AUC and Cmax values of the N-demethylated metabolite were significantly increased by 200 and 79%, respectively. Liver failure. In volunteers with mild and moderate cirrhosis of the liver (classes A and B according to the Child-Pugh classification), the clearance of sildenafil decreased, which led to an increase in AUC (84%) and Cmax (47%) compared with volunteers of the same age without liver dysfunction.
The pharmacokinetics of sildenafil in patients with severe hepatic impairment has not been studied. Indications Viagra The drug Viagra is recommended for men with erectile dysfunction, which is defined as the inability to achieve or maintain an erection of the penis necessary for successful sexual intercourse. Sexual arousal is necessary for the effective action of the drug Viagra. The use of Viagra Viagra. The drug is intended for oral administration. Viagra ODT. The drug is administered orally. The drug should be used immediately after the tablet has been removed from the blister. The tablet should be put on the tongue, wait for its disintegration, and then swallow. The drug can be taken with or without water. If it is necessary to apply a dose of 100 mg, the second tablet should be taken only after the complete disintegration of the first tablet. It is recommended to use the drug on an empty stomach, since when using the drug simultaneously with fatty foods, there is a significant delay in absorption compared to using tablets on an empty stomach. Viagra and Viagra ODT. Adults. The recommended dose for adults is 50 mg, which is taken as needed approximately 1 hour before sexual intercourse.
Considering the efficacy and tolerability, the dose can be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The frequency of use of the maximum recommended dose of the drug is 1 time per day. When using the drug Viagra during a meal, the effect of the drug may occur later than when it is used on an empty stomach. If it is necessary to apply a dose of 25 mg, it is recommended to use sildenafil, film-coated tablets of 25 mg. Elderly patients. The need for dose adjustment in elderly patients (≥65 years) absent. Patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 30-80 ml/min), the recommended dose is the same as indicated above in the "Adults" section. Since sildenafil clearance is reduced in patients with severe renal insufficiency (creatinine clearance <30 ml / min), the use of the drug should begin with a dose of 25 mg. Depending on the efficacy and tolerability of the drug, the dose can be increased to 50 and 100 mg.
Patients with hepatic insufficiency. Since sildenafil clearance is reduced in patients with hepatic insufficiency, for example, with cirrhosis, the use of the drug should begin with a dose of 25 mg. Depending on the efficacy and tolerability of the drug, the dose can be increased to 50 and 100 mg. Patients using other types of treatment. If patients simultaneously use CYP 3A4 inhibitors (see INTERACTIONS), the possibility of using an initial dose of 25 mg should be considered . In order to minimize the risk of orthostatic hypotension, the condition of patients using alpha-adrenergic blockers should be stabilized before the use of sildenafil. The possibility of using an initial dose of sildenafil 25 mg should also be considered .
Contraindications hypersensitivity to the active substance or any other component of the drug. Simultaneous use with NO donors (such as amyl nitrite) or nitrates in any form is contraindicated, since it is known that sildenafil affects the pathways of NO/cGMP metabolism and potentiates the hypotensive effect of nitrates. Simultaneous use of PDE-5 inhibitors (including sildenafil) it is contraindicated with guanylate cyclase stimulants, such as riociguate, since it can cause symptomatic hypotension (see INTERACTIONS).