Sildenafil is a potent selective inhibitor of cGMP -specific phosphodiesterase type 5 (PDE5 ).
The implementation 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 PDE5, which is responsible for the disintegration of cGMP.
Sildenafil selective in relation to PDE5 in vitro , its activity against PDE5 exceeds activity against other known phosphodiesterase isoenzymes: PDE6 – 10 times; PDE1 – more than 80 times; PDE2, PDE4, PDE7-PDE11 – more than 700 times. Sildenafil is 4,000 times more selective with respect to PDE5 compared with PDE3, which is of paramount importance, since PDE3 is one of the key enzymes in the regulation of myocardial contractility.
A prerequisite for the effectiveness of sildenafil is sexual stimulation.
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 receiving sildenafil in a dose of 100 mg was 8.3 mm Hg, and diastolic blood pressure – 5.3 mm Hg. 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 ischemic heart 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 the cardiac output and did not disturb the blood flow in the stenotic coronary arteries, and also led to an increase (by about 13%) of adenosine-induced coronary blood flow in both the stenotic 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 moment when the severity of symptoms of angina pectoris 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 100 mg compared with patients who received placebo.
In a randomized, double-blind, placebo-controlled study, the effect of varying doses of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and arterial hypertension taking more than two antihypertensive drugs was studied . Sildenafil improved erection in 71% of men compared with 18% in the placebo group. The frequency of adverse effects was comparable to that in other groups of patients, as well as in individuals taking more than three antihypertensive drugs.
Studies of visual impairment
Some patients after 1 h after taking sildenafil in a dose of 100 mg using the Farnsworth-Munsel 100 test revealed a slight and transient impairment of the ability to distinguish between shades of color (blue / green). 2 h after taking the drug, these changes were absent. It is believed that the violation of color vision is caused by inhibition of PDE6, which is involved in the process of transmitting light 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, as assessed by special visual tests (visual acuity, Amsler grid , color perception, color passage modeling, Humphrey perimeter, and photostress ).
The efficacy and safety of sildenafil was evaluated in 21 randomized, double-blind, placebo-controlled studies of up to 6 months in 3,000 patients aged 19 to 87 with erectile dysfunction of various etiologies (organic, psychogenic, or mixed). The efficacy of the drug was evaluated globally using an erection diary, an international index of erectile function ( validated questionnaire on the state of sexual function) and a partner survey.
The effectiveness of sildenafil , defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all the studies conducted and has been confirmed in long-term studies lasting for 1 year. In studies using a fixed dose, the ratio of patients who reported that therapy improved their erection was: 62% (dose of sildenafil 25 mg), 74% (dose of sildenafil 50 mg) and 82% (dose of sildenafil 100 mg), compared with 25 % in the placebo group. Analysis of the international index of erectile function showed that, in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, allowed to achieve satisfaction from sexual intercourse and general satisfaction.
According to generalized data, among patients who reported improved erections with sildenafil treatment were 59% of patients with diabetes, 43% of patients undergoing radical prostatectomy, and 83% of patients with spinal cord injuries (compared to 16%, 15% and 12% in the placebo group respectively).
Pharmacokinetics in special clinical situations
In healthy elderly people (over 65 years), the clearance of sildenafil is reduced, and the concentration of free active substance in plasma is about 40% higher than its concentration in young (18-45 years) patients.
In case of mild (CK 50-80 ml / min) and moderate (CK 30-49 ml / min) renal failure, the pharmacokinetic parameters of sildenafil after oral administration at a dose of 50 mg do not change.
With severe renal failure (CK ≤ 30 ml / min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared with those in normal renal function in patients of the same age group.
In patients with cirrhosis of the liver (class A and B on the Child- Drink scale ), the clearance of sildenafil decreases, leading to an increase in AUC (84%) and Cmax (47%) compared with those in normal liver function in patients of the same age group . Pharmacokinetics Sildenafil in patients with severely impaired liver function (class C on the Child- Drink scale ) has not been studied.
The drug is taken orally.
For most patients, the recommended dose is 50 mg approximately 1 hour before sexual activity. Given the efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg.
The maximum recommended dose is 100 mg. The maximum recommended frequency of use is 1 time / day .
Elderly patients dose adjustment is not required.
In case of renal failure of mild and moderate severity (CK 30-80 ml / min) dose adjustment is not required, in case of severe renal failure ( CK < 30 ml / min) the dose is reduced to 25 mg.
Since the elimination of sildenafil is impaired in patients with liver damage (for example, cirrhosis), the dose of the drug can be reduced to 25 mg.
Combined use with other drugs
When combined with ritonavir, the maximum single dose of sildenafil should be 25 mg, the frequency of application – 1 time in 48 hours.
When combined with inhibitors of CYP3A4 isoenzyme (erythromycin, ketoconazole, itraconazole), the initial dose sildenafil should be 25 mg.
To minimize the risk of postural hypotension in patients taking alpha blockers , you should start taking sildenafil only after stabilization of hemodynamics is achieved in these patients. The feasibility of reducing the initial dose of sildenafil should be considered .
With a single dose of up to 800 mg, the adverse events were comparable to those of sildenafil at lower doses, but were more common.
Treatment: if necessary, conduct symptomatic therapy. Hemodialysis does not accelerate the clearance of sildenafil, since the latter is actively associated with plasma proteins and is not excreted in the urine.
The effect of other drugs on the metabolism of sildenafil
Sildenafil metabolism occurs mainly in the liver under the action of CYP3A4 isoenzymes (main route) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil .
With simultaneous use of CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine ), a decrease in the clearance of sildenafil was noted.
Cimetidine (at a dose of 800 mg), which is a nonspecific inhibitor of CYP3A4, when administered concurrently with sildenafil (at a dose of 50 mg) causes an increase in plasma concentration of sildenafil by 56%.
A single dose of sildenafil in a dose of 100 mg simultaneously with erythromycin – a specific CYP3A4 inhibitor (when taking erythromycin 500 mg 2 times / day for 5 days) – against the background of reaching a constant level of erythromycin in the blood leads to an increase in AUC of sildenafil by 182%.
With simultaneous use of sildenafil (once at a dose of 100 mg) and saquinavir (at a dose of 1200 mg 3 times / day ), which is both an HIV protease inhibitor and a CYP3A4 inhibitor, against the background of reaching a constant level of saquinavir in the blood, Cmax Sildenafil in the blood increased by 140%, and AUC increased by 210%. Sildenafil had no effect on the pharmacokinetic parameters of saquinavir.
More potent inhibitors of CYP3A4 isoenzyme, such as ketoconazole or itraconazole, may cause more pronounced changes in pharmacokinetics sildenafil.
The simultaneous use of sildenafil (once in a dose of 100 mg) and ritonavir (500 mg 2 times / day), which is an HIV protease inhibitor and a strong inhibitor of cytochrome P450 isoenzymes, against the background of achieving a constant level of ritonavir in the blood leads to an increase in Cmax Sildenafil by 300% (4 times), and AUC by 1000% (11 times). After 24 h, the concentration of sildenafil in the blood plasma was approximately 200 ng / ml (with a single use of sildenafil alone – 5 ng / ml).
If sildenafil is taken in recommended doses by patients receiving simultaneously strong inhibitors of CYP3A4, then Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.
A single antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability sildenafil.
CYP2C9 isoenzyme inhibitors (such as tolbutamide , warfarin ), CYP2D6 isoenzyme (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide – like diuretics, ACE inhibitors and calcium antagonists do not affect pharmacokinetics sildenafil.
Simultaneous administration of azithromycin (500 mg / day for 3 days) does not affect the AUC, Cmax, Tmax, elimination rate constant, and T1 / 2 of sildenafil or its main circulating metabolite.