Instructions for use of Viagra
Active substance: Sildenafil (Sildenafil)Concentration of active substance (mg): 100
Sildenafil is a potent selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5).The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the cavernous body during sexual stimulation. This, in turn, leads to an increase in the level of cGMP, subsequent relaxation of the smooth muscle tissue of the cavernous body and an increase in blood flow. Sildenafil does not have a direct relaxing effect on the isolated cavernous body in humans, but enhances the effect of NO by inhibiting tadalafil 5mg, which is responsible for the breakdown of cGMP. Sildenafil is selective against PDE5 in vitro, its activity against PDE5 exceeds the activity against other known phosphodiesterase isoenzymes: PDE6 - 10 times; PDE1 - more than 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. Sildenafil is 4000 times more selective against PDE5 compared to PDE3, which is of crucial importance, since PDE3 is one of the key enzymes regulating myocardial contractility. A prerequisite for the effectiveness of sildenafil is sexual stimulation. Clinical data from cardiological studies, the use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic blood pressure in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg, and diastolic blood pressure was 5.3 mmHg.
A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates. In a study of the hemodynamic effect of sildenafil in a single dose of 100 mg in 14 patients with severe coronary artery disease (more than 70% of patients had stenosis of at least one coronary artery), systolic and diastolic blood pressure at rest decreased by 7% and 6%, respectively, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output and did not disrupt blood flow in stenosed coronary arteries, and also led to an increase (by about 13%) in adenosine-induced coronary blood flow in both stenosed and intact coronary arteries. In a double-blind placebo-controlled study, 144 patients with erectile dysfunction and stable angina, taking antianginal drugs (except nitrates), performed physical exercises until the severity of angina symptoms decreased. The duration of the exercise was significantly longer (19.9 sec; 0.9-38.9 sec) in patients taking sildenafil in a single dose of sildenafil citrate 100 mg compared with patients receiving placebo. In a randomized, double-blind, placebo-controlled study, the effect of changing the dose of sildenafil (up to 100 mg) was studied in men (n=568) with erectile dysfunction and hypertension taking more than two antihypertensive drugs. Sildenafil improved erection in 71% of men compared to 18% in the placebo group. The frequency of adverse effects was comparable to that in other groups of patients, as well as in those taking more than three antihypertensive drugs.
Studies of visual disturbances in some patients 1 hour after taking sildenafil at a dose of 100 mg using the Farnsworth-Munsel 100 test revealed a slight and transient impairment of the ability to distinguish shades of color (blue / green). 2 hours after taking the drug, these changes were absent. It is believed that color vision impairment is caused by inhibition of PDE6, which is involved in the process of light transmission in the retina of the eye. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure or pupil diameter. In a placebo-controlled cross-sectional study of patients with proven early-age macular degeneration (n=9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by special visual tests (visual acuity, Amsler lattice, color perception, color passage modeling, Humphrey perimeter and photostress).The efficacy and safety of sildenafil were evaluated in 21 randomized, double-blind, placebo-controlled trials lasting up to 6 months in 3,000 patients aged 19 to 87 with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was evaluated globally using an erection diary, an international index of erectile function (a validated questionnaire on the state of sexual function) and a partner survey. The efficacy of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and has been confirmed in long-term studies lasting 1 year. In fixed-dose studies, the ratio of patients who reported that therapy improved their erection was: 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose) and 82% (sildenafil 100 mg dose), compared with 25% in the placebo group.
Analysis of the international index of erectile function showed that in addition to improving the erection, treatment with sildenafil also increased the quality of orgasm, allowed to achieve satisfaction from sexual intercourse and general satisfaction.According to generalized data, 59% of diabetic patients, 43% of patients who underwent radical prostatectomy and 83% of patients with spinal cord injuries were among the patients who reported an improvement in erection during treatment with sildenafil (compared with 16%, 15% and 12% in the placebo group, respectively).
The pharmacokinetics of sildenafil in the recommended dose range is linear. Absorption After ingestion, sildenafil is rapidly absorbed. Absolute bioavailability averages 40% (25-63%). In vitro, sildenafil at a concentration of approximately 1.7 ng/ml (3.5 nM) suppresses human PDE5 by 50%. After a single oral administration of 100 mg of the drug, the average Cmax of free sildenafil is 18 ng / ml (38 nM) and is achieved when taken on an empty stomach for an average of 60 minutes (30-120 minutes).When taken in combination with fatty foods, the absorption rate decreases; Tmax increases by 60 minutes, and Cmax decreases by an average of 29%. However, the degree of absorption does not significantly change (AUC decreases by 11%).The distribution of sildenafil in the equilibrium state is on average 105 liters. The binding of sildenafil and its main circulating N-desmethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of sildenafil. Less than 0.0002% of the dose (on average 188 ng) was detected in semen 90 minutes after taking the drug. Metabolism Sildenafil is metabolized mainly in the liver under the action of isoenzymes CYP3A4 (main pathway) and CYP2C9 (minor pathway).
The main circulating active metabolite, which is formed as a result of N-demethylation of sildenafil, undergoes further metabolism. According to the selectivity of action on PDE , the metabolite is comparable to sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma is approximately 40% of that of sildenafil. The N-demethyl metabolite undergoes further metabolism; its T1/2 is about 4 hours. The total clearance of sildenafil from the body is 41 l / h, and the final T1 /2 is 3-5 hours. After oral administration, sildenafil is excreted as metabolites, mainly with feces (approximately 80% of the dose) and to a lesser extent with urine (approximately 13% of the dose).Pharmacokinetics in special clinical cases in healthy elderly people (over 65 years old), the clearance of sildenafil is reduced, and the concentration of free active substance in plasma is approximately 40% higher than its concentration in young (18-45 years old) patients. Age does not have a clinically significant effect on the incidence of side effects. With mild renal insufficiency (CC 50-80 ml / min) and moderate (CC 30-49 ml / min) severity, the pharmacokinetic parameters of sildenafil after a single oral dose of 50 mg do not change. With severe renal insufficiency (CC < 30 ml /min), the clearance of sildenafil decreases, this leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared to those with normal renal function in patients of the same age group. In patients with cirrhosis of the liver (class A and B on the Child-Pugh scale), the clearance of sildenafil decreases, which leads to an increase in AUC (84%) and Cmax (47%) compared to those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (class C on the Child-Pugh scale) has not been studied.
Treatment of erectile dysfunction characterized by the inability to achieve or maintain an erection of the penis sufficient for satisfactory sexual intercourse. Sildenafil is effective only with sexual stimulation.