2010/06/05

VIAGRA

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 ml / min) reduced clearance of sildenafil, the drug should be prescribed in initial dose of 25 mg.

Since patients with hepatic insufficiency reduced clearance of sildenafil, the appointment of the drug to start with a dose of 25 mg.

Viagra is not indicated for use in persons under the age of 18 years.

Dosage adjustment in elderly patients is not required.

CONTRAINDICATIONS: Hypersensitivity to any component of the drug; joint appointment with the donators of NO (amilnitrit or nitrates) because of the possibility of strengthening their hypotensive action. Drugs for treatment of erection disorders, including sildenafil, should not be considered in patients for whom sexual activity is undesirable (eg, patients with severe diseases of the cardiovascular system, such as unstable angina or heart failure, marked).

SIDE EFFECTS: were transient, mild or moderate. During the study the frequency and severity of side effects increased with increasing dose. The most frequent side effects were as follows: the nervous system - headache (10,8%), dizziness (2.9%) of the cardiovascular system - flushing of the skin (10,9%), feeling of palpitation (1% ) from the digestive tract - dyspepsia (3%) from the organ of vision - blurred vision, sensitivity to light (2,5%), hromatopsiya (1,1%) from the respiratory system - rhinitis (nasal congestion) (2,1%). Some patients 1 h after taking the drug at a dose of 100 mg at the 100-color test Farnsworth-Munsell revealed a slight and temporary violation of color vision (blue / green), and 2 hours after taking the medication any changes were observed. A possible mechanism of these changes in the recognition of colors due to inhibition of PDE 6, which is included in fotopreobrazuyuschy cascade of the retina. Sildenafil did not affect the sharpness and contrast of view, indicators electroretinogram, intraocular pressure and the results pupilometrii. In the after-period, there was unusual or rare reaction against the administration of the drug: from the immune system - hypersensitivity reactions (including skin rashes), and cardiovascular - tachycardia, hypotension, syncope, epistaxis; part of the digestive tract - vomiting, by the authority view - eye pain, redness of eyes; from the reproductive system - prolonged erections and / or priapism.

Cautions: some risk of adverse effects on the cardiovascular system caused by sexual activity, therefore, before prescribing the drug should conduct a survey patient. Viagra shows vasodilating effect, which resulted in a slight and temporary decrease in blood pressure, therefore, sildenafil enhances the hypotensive effect of organic nitrates.

Sensitivity to vasodilator indicated for patients with obstruction of the outflow path of the left ventricle (aortic stenosis, obstructive hypertrophic cardiomyopathy) and a syndrome of systemic atrophy, manifested a violation of autonomic control of blood pressure.

In placebo-controlled trial of sildenafil 100 mg was well tolerated by patients with early stage macular degeneration, and caused no significant changes in vision acuity, color vision, etc.

The use of Viagra has no effect on cardiac output and reduces blood flow in stenosed coronary arteries, and the degree of reduction of systolic and diastolic blood pressure an average of 6-9%. Acceptance of the drug had no effect on exercise tolerance in patients with erectile dysfunction and stable angina, about which they regularly took antianginal medications (except nitrates).

The drug should be used with caution in patients with anatomical deformities of the penis (such as triangulation, cavernous fibrosis or Peyronie's disease) or patients with diseases that can lead to priapism (sickle cell anemia, multiple myeloma, or leukemia).

Some patients with retinitis pigmentosa caused by a defect noted genetically PDE retina as sufficient experience in the use of Viagra they do not have to appoint a drug to such patients should be cautious.

Viagra is not designed for use in women.

Since during clinical trials of sildenafil were observed dizziness and blurred vision, should determine an individual patient reaction to the reception of Viagra before driving or working with potentially dangerous machinery.

INTERACTION: Sildenafil metabolism is mediated primarily by cytochrome P450 (CYP), in particular its isoforms ZA4 (main route) and 2C9 (minor route). Thus, inhibitors of these isoenzymes may reduce the elimination of sildenafil. With the exception of ritonavir, which is not recommended to assign simultaneously with sildenafil, patients receiving simultaneous other inhibitors of CYP3A4, the recommended initial dose of sildenafil is 25 mg.

Population pharmacokinetic analysis of the results of clinical studies have demonstrated reduction in clearance of sildenafil, while applying it with inhibitors of CYP 3A4 (such as ketoconazole, erythromycin, cimetidine). Cimetidine, a nonspecific inhibitor of CYP, while the appointment of healthy volunteers in a dose of 800 mg / day caused an increase in the concentration of sildenafil in the blood plasma by 56%. Although the frequency of side effects while taking a CYP 3A4 inhibitors in these patients was not increased, the initial dose of sildenafil should be 25 mg.

In the case of a single dose of sildenafil 100 mg simultaneously with erythromycin, a specific inhibitor of CYP3A4 (500 mg 2 times a day for 5 days), we observed an increase in sildenafil AUC by 182%.

The simultaneous appointment of saquinavir - HIV protease inhibitor, which is an inhibitor of CYP3A4 (1200 mg 3 times daily) and sildenafil (100 mg dose) led to an increase in the maximum concentration of sildenafil in the blood serum of 140% and increased AUC by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir. Strong inhibitors of CYP3A4, such as ketoconazole and itraconazole, have a more pronounced effect.

Simultaneous reception of ritonavir - HIV protease inhibitor, which is a high-P450 inhibitor, in the equilibrium state (500 mg 2 times a day) with sildenafil (100 mg single dose) increases by 4 times the highest concentration of sildenafil in the blood serum and increased 11-fold AUC. After 24 h the concentration of sildenafil in plasma was approximately 200 ng / ml, whereas in the case of receiving only sildenafil to a concentration of 5 ng / ml. This is due to the influence of ritonavir on the cytochrome P450 isoenzymes. Sildenafil has no effect on the pharmacokinetics of ritonavir. Given these results, co-administration of sildenafil and ritonavir is not recommended, but if such a combination still used, the dose of sildenafil should not exceed 25 mg for 2 days (1948 h).

Grapefruit juice, which is a weak inhibitor of CYP3A4, affects the metabolism of sildenafil in the wall of the intestine and can lead to a slight increase of its level in blood plasma.

Single dose antacid (magnesium hydroxide / aluminum hydroxide) did not affect the bioavailability of sildenafil.

According to a population pharmacokinetic analysis, inhibitors of CYP2C9 (such as tolbutamide, warfarin), inhibitors of CYP2D6 (such as selective serotonin reuptake inhibitors, tricyclic antidepressants) and thiazide diuretics, loop and Potassium-sparing diuretics, ACE inhibitors, calcium channel blockers, antagonists in -adrenoceptor stimulants and metabolic CYP450 (such as rifampicin, barbiturates) do not affect the pharmacokinetics of sildenafil.

In healthy volunteers found no effect of receiving azithromycin 500 mg / day for 3 days at AUC, maximum blood concentration and the time of her accomplishments, clearance and elimination half-life of sildenafil and its major metabolites.

Safety and efficacy of combination of sildenafil with other drugs that are intended for the treatment of erection disorders have not been studied, therefore, to appoint such combinations is not recommended.

Studies in vitro on human platelets indicate that sildenafil increases the antiplatelet properties of sodium nitroprusside.

In vitro cildenafil is a weak inhibitor of cytochrome P450 isoforms, namely isozymes 1A2, 2S9, 2S19, 2D6, 2E1 and ZA4. If you use it in the recommended doses is unlikely that his ability to change the pharmacokinetics of substrates of these isoenzymes.

No evidence of significant interaction in vivo sildenafil at a dose of 50 mg of tolbutamide at a dose of 250 mg or warfarin 40 mg, each of which is metabolised CYP2C9, was not revealed. Sildenafil in the application of a dose of 50 mg does not increase the duration of bleeding caused by acetylsalicylic acid (at a dose of 150 mg).

Sildenafil (50 mg) did not increased the severity of the hypotensive effect of alcohol in healthy volunteers, whose maximum average concentration of alcohol in the blood of 80 mg / dl.

During the special studies of the interaction while taking 100 mg of sildenafil with amlodipine in patients with hypertension were recorded additional reduction in systolic blood pressure of 8 mm Hg. Art. Supplementary reduction of diastolic BP by 7 mm Hg. Art.

Sildenafil when receiving a dose of 100 mg does not alter the equilibrium pharmacokinetics HIV protease inhibitors - saquinavir and ritonavir, which are inhibitors of CYP3A4.

Through the influence on the exchange of NO / cGMP sildenafil increases the severity of the hypotensive effect of nitrates. The use of sildenafil in combination with nitrates or other NO donators contraindicated.

The simultaneous use of α-adrenoreceptor blocker doxazosin 4 mg and sildenafil 25 mg in patients with benign prostatic hyperplasia was accompanied by an additional reduction in systolic and diastolic BP by 7 mm. Over 4 hours after taking the drugs were noted occasional cases of postural hypotension. Simultaneous reception of Viagra and α-adrenoceptor blockers can cause the development of symptomatic hypotension in some patients.

Safety analysis showed no differences in the profile of side effects in patients who only take sildenafil or sildenafil in combination with other antihypertensive drugs.

OVERDOSE: in studies involving healthy volunteers, with the single dose of the drug in doses of 800 mg side effects were similar to those observed when taking Viagra at lower doses, but the frequency of their development and the severity increased. In case of overdose typically spend standard supportive therapy. Dialysis does not accelerate the elimination of the drug, because sildenafil is closely associated with blood plasma proteins