Viagra Sildenafil Interesting Facts

Viagra - a reliable drug for treating erectile dysfunction. He does not act by itself,
and assists in the presence of natural desire and inclination to commit the sexual act.
The drug is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5).
The physiological mechanism of erection involves release of nitric oxide (NO) in the cavernous body during sexual stimulation. Nitric oxide activates the enzyme guanylate cyclase, which leads to increased
cyclic guanosine monophosphate (cGMP), relaxation of smooth muscle and corpus cavernosum
increased blood flow to the penis.
Viagra has no direct relaxing effect on isolated human corpus cavernosum,
but also actively enhances the relaxing effect of NO on this tissue by inhibiting PDE5,
which is responsible for the breakdown of cGMP in the cavernous body.
When sexually aroused, the local release of NO under the influence of sildenafil results
to PDE5 inhibition and increase cGMP in the cavernous body, resulting in
relaxation of smooth muscles and increasing blood flow in the cavernous body.
The use of Viagra at recommended doses, is ineffective in the absence of sexual stimulation.
Studies in vitro showed a high selective effect of sildenafil on PDE5.
The activity of sildenafil against PDE5 than its activity against other known
isoforms of phosphodiesterase (10 times - FDE6, more than 80 times - FDE1, more than 700 times - FDE2,
FDE3 and FDE4, FDE7 - FDE11). Thus possible to avoid negative side effects.
Regarding PDE5 Viagra is approximately 4000 times more active than in respect
FDE3 - cAMP-specific phosphodiesterase involved in the regulation of contractions of the heart,
makes the risks of negative impacts of the drug on heart action almost nil.
On the other hand due to the low selectivity against FDE6 some patients
1 h after taking Viagra in doses of 100 mg showed slight and reversible disruption of distinction
color (blue / green) with the test Farnsworth-Munsell 100;
2 hours after taking the drug, these changes disappeared.
Violations of established mechanisms of color vision is oppression FDE6,
which is involved in the transmission of light in the retina.
Studies in vitro have shown that the effect of sildenafil on FDE6 just 10 times inferior to its activity
against PDE5.
Viagra has no effect on visual acuity, sensitivity to contrast, elektroretinogrammy,
intraocular pressure or pupil diameter.
Sildenafil at a dose of 100 mg had no effect on locomotor activity or morphology of sperm in their single dose in healthy volunteers.
These clinical
Acute administration of Viagra in doses up to 100 mg did not cause clinically significant changes in ECG
in healthy volunteers.
The maximum decrease in systolic blood pressure in the prone position in the application of the drug inside
a dose of 100 mg was on average 8.4 mmHg The corresponding decrease in diastolic blood pressure
in the prone position was 5.5 mm Hg
More marked, but similarly transient effect on blood pressure was observed in patients
simultaneously treated with nitrates.
In studies the impact of single dose of sildenafil 100 mg on hemodynamics
in 14 patients with severe coronary artery disease
(stenosis> 70% at least one coronary artery) averages
reduction in systolic and diastolic blood pressure were respectively 7% and 6% on
normal level. Systolic pressure in the pulmonary artery was reduced by an average of 9%.
Viagra did not influence cardiac output and will not compromise the blood flow through stenosed
coronary artery, which resulted from the improvement (13% approximately) reserve
adenosine-induced coronary blood flow (as in the stenosed and
in intact arteries).
Efficacy and safety of sildenafil was studied in 21 randomized, double-blind,
placebo-controlled study lasting up to six months. Viagra used
more than 3000 patients with erectile disorders of various etiologies (organic,
psychogenic, mixed) aged 19 to 87 years.
Effectiveness was determined on the basis of overall assessment, diaries, recording an erection,
evaluation of the international index of erectile function (IIEF, a questionnaire designed to assess sexual function), and survey partners.
The effectiveness of sildenafil, which was estimated by the ability to provide advance preparation and conservation of an erection sufficient for sexual intercourse, was demonstrated in all 21 studies and was maintained during long-term treatment (1 year). If you are using Viagra in a fixed-dose proportion of patients reported improvement in erectile function, was 62% (25 mg), 74% (50 mg) and 82% (100 mg), while placebo - 25%. In addition to improving erectile function, IIEF analysis showed that treatment with Viagra improves as orgasm, satisfaction with sexual intercourse and overall satisfaction.
In all studies, the proportion of patients with diabetes, indicating improvement in the treatment of
Viagra, accounted for 59% of patients after radical prostatectomy - 43% of patients
with spinal cord injury - 83% (versus 16%, 15% and 12% of patients receiving placebo,
respectively).

Pharmacokinetics

The pharmacokinetics of sildenafil is dose-dependent when administered in the recommended dose range.
The elimination of the drug occurs mainly through hepatic metabolism (mainly the isoenzymes of cytochrome P450 3A4) with the formation of the active metabolite, on properties similar to sildenafil.
Suction
After receiving the drug inside sildenafil is rapidly absorbed. Absolute bioavailability averages 41% (25-63%). After receiving the drug inside the fasting Cmax is reached within 30-120 min (average 60 minutes).
When you receive Viagra in combination with fatty food reduces the rate of absorption, Tmax is increased by 60 min, and Cmax decreased by an average of 29%.
Distribution
Vd sildenafil at steady state an average of 105 liters, indicating that its distribution in the tissue.
Sildenafil and its major circulating N-desmetilovy metabolite approximately 96% bound to plasma proteins.
Protein binding is not dependent on the total concentration of sildenafil.
In healthy volunteers who received Viagra (single dose of 100 mg), less than 0.0002% (average 188 ng) dose was found in semen after 90 min after administration.
Metabolism
Sildenafil is metabolized, primarily by CYP 3A4 (major route) and CYP 2C9 (non-substantive way) microsomal isoenzymes of the liver. Sildenafil is a weak inhibitor of isoenzymes of cytochrome P450 - 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IK50 <150 mmol). In applying Sildenafil at recommended doses, it is unlikely that sildenafil is able to influence the clearance of substrates of these isoenzymes.
The main circulating metabolite, which is formed by the N-desmetilirovaniya Sildenafil undergoes further metabolism.
On the selectivity of action on PDE metabolite comparable with sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil.
Concentration of metabolite in plasma is approximately 40% from those of sildenafil.
N-desmetilmetabolit undergoes further metabolism, and its terminal T1 / 2 is about 4 hours
Withdrawal
Total clearance of Viagra from the body is equal to 41 l / h, T1 / 2 in the terminal phase - 3-5 hours after ingestion or in / to the introduction of sildenafil is excreted as metabolites primarily in the faeces (approximately 80% of the dose introduced into) and to a lesser extent in the urine (about 13% of the administered oral dose).
Pharmacokinetics in special clinical cases
The increase in the level of sildenafil in plasma (AUC) influence the following factors: age over 65 years (an increase of AUC by 40%), inadequate liver function (eg, liver cirrhosis, 84%), severe renal insufficiency (CC <30 ml / min , 100%), concomitant administration of drugs - inhibitors of cytochrome P450 3A4 (eg, erythromycin, 182%, saquinavir, 210%).
In healthy elderly (65 years and older) volunteers sildenafil clearance was reduced, and the concentration of free active substance in the plasma by approximately 40% higher than its concentration in healthy young (18-45 years) volunteers.
In volunteers with mild (CC 50-80 ml / min) and moderate (CC 30-49 ml / min) renal insufficiency pharmacokinetic parameters of sildenafil after oral single dose (50 mg) did not change.
In volunteers with severe renal insufficiency (QA <= 30 ml / min) decreased clearance of sildenafil, which resulted in approximately a twofold increase in AUC (100%) and Cmax (88%) compared with those of volunteers, matched for age, who had no renal impairment.
In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance is decreased, which led to an increase in AUC (84%) and Cmax (47%) compared with those of volunteers with normal liver function, matched by age.

Indications

- Erectile dysfunction, characterized by the inability to achieve or maintain penile erection sufficient for sexual intercourse.
The drug Viagra is effective only when there is sexual stimulation.

Dosage regimen

The drug is taken orally.
For most patients the recommended dose is 50 mg; take medication if necessary for about 1 hour before sexual activity. Given the efficacy and tolerability the dose may be increased to 100 mg or decreased to 25 mg.
The maximum recommended frequency of application - 1 times / day.
In applying the drug in patients aged over 65 years, patients with impaired hepatic function, patients with severe renal insufficiency and in patients receiving both drugs - inhibitors of cytochrome P450 3A4 (eg, erythromycin, saquinavir), there is an increase in plasma levels of Sildenafil that may contribute to increase the effectiveness of the drug, and the possible appearance of side effects. Can expect that even more powerful inhibitors of cytochrome P450 3A4 such as ketoconazole or itraconazole may lead to increased levels of sildenafil in plasma. Should discuss whether the use of the drug in a dose of 25 mg / day for similar groups of patients.
The product is not intended for use in patients under the age of 18 years.

Side effects

Side effects are more common than 5% of patients taking sildenafil as needed, are given in the table.



Side effects in reported incidents of adverse effects (%)
Viagra (n = 734) Placebo (n = 725)
Headache * 16% 4%
Tides * 10% 1%
Dyspepsia * 7% 2%


* - A side effect reported in clinical studies.
In clinical studies, II / III phase with the selection of doses for patients treated with sildenafil as needed, there were between 1% and 5% following a clinically significant side effects, as well as those phenomena whose relationship with the drug intake was possible:
On the part of the organism as a whole: asthenia, pain, abdominal pain, back pain, infection, flu-like syndrome.
From the cardiovascular system: vasodilation (side effect reported in clinical studies).
From the digestive system: diarrhea, nausea.
The part of the musculoskeletal system: joint pain, muscle pain.
From the central nervous system and peripheral nervous system: dizziness (side effect reported in clinical studies), increased muscle tone, insomnia.
On the part of the respiratory system: nasal congestion, pharyngitis, rhinitis (side effect reported in clinical studies), sinusitis, respiratory infections, respiratory dysfunction.
Dermatological reactions: rash.
From the senses: vision changes (mild and transient, mostly change the color of objects, as well as increased perception of light and blurred vision - a side effect reported in clinical studies), conjunctivitis.
The part of the urinary system: urinary tract infections.
On the part of the reproductive system: dysfunction of the prostate.
Using Viagra in doses greater than recommended, the side effects were similar to the above, but usually more often.
The following adverse events were recorded during postmarketing use.
Since the cardiovascular system: hypotension, syncope, tachycardia, palpitations.
From the digestive system: vomiting (side effect reported in clinical studies).
On the part of the reproductive system: prolonged erection and / or priapism.
From the sense organs: eye pain, redness of eyes.
Other: allergic reactions.
Side effects were usually transient and light to moderate.
In studies with fixed dose rate of side effects increased with increasing dose.
The nature of side effects in studies where doses were selected, since such studies better reflect the recommended scheme of application, was comparable to that in studies with fixed doses.
Contraindications

- Hypersensitivity to the ingredients.
Viagra contraindicated in patients treated continuously or intermittently donator of nitric oxide, organic nitrates or nitrates in any form, as sildenafil enhances the hypotensive effect of nitrates, taken continuously or in an emergency.

Pregnancy and lactation

The product is not intended for use in women.
There are no adequate and strictly controlled trials in pregnancy and lactation in women took place.
Results of experimental studies
Reproduction studies in rats and rabbits, oral use of sildenafil did not exert teratogenic effects, had no effect on reproductive function and did not cause any violation of the peri / postnatal development.

Cautions

For the diagnosis of erectile dysfunction, determine their possible causes and select appropriate treatment is necessary to collect a complete medical history and thorough physical examination.
Sexual activity is a risk for heart disease, in this regard before any therapy at the violations of erection doctor may deem it necessary to study the cardiovascular system.
In clinical trials Viagra has systemic vasodilating effect, which leads to a transient reduction of blood pressure. This effect has little value or no leads to any consequences in most patients. However, until the appointment of sildenafil physician must carefully weigh the risk of undesirable manifestations vasodilating action in patients with certain concomitant diseases, especially against the background of sexual activity. Increased sensitivity to the vasodilator observed in patients with obstruction of left ventricular output tract (eg aortic stenosis, hypertrophic cardiomyopathy), as well as the rare atrophy in multiple different systems, manifested severe violation of autonomic control of blood pressure.
Preparations intended for the treatment of erectile dysfunction, should be used with caution in patients with anatomical deformation of the penis (eg, angulation, cavernous fibrosis or Peyronie's disease) and patients with diseases that predispose to the development of priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
Preparations intended for the treatment of erectile dysfunction, should not be given to men for whom sexual activity is undesirable.
Safety and effectiveness of Viagra when used in combination with other tools designed for the treatment of erectile dysfunction, were not studied, so the use of such combinations is not recommended.
Studies of human platelets in vitro suggest that Viagra increases antiagregantny effect of sodium nitroprusside (nitric oxide donator).
No information about the safety of Sildenafil in patients with diseases which are accompanied by bleeding, or exacerbation of peptic ulcer, no, so in these patients the drug should be used with caution.
A small number of patients with hereditary retinitis pigmentosa are inherited disorders of phosphodiesterases in the retina. No information about the safety of sildenafil in patients with retinitis pigmentosa is not, in this regard such patients sildenafil should be used with caution.
Use in Pediatrics
Sildenafil is not intended for use in children and adolescents under the age of 18 years.
Results of experimental studies
There was no evidence of carcinogenicity of the drug as a 24-month study in rats at doses 42 times the maximum recommended dose for humans (MRD), calculated per kilogram of body weight (and approximately 5 times the MRD, as calculated in mg/m2 of body surface ) and at 18-21-month study in mice at doses 5 times the MRD, calculated in mg / kg body weight (and approximately 2 times the MRD in mg/m2 of body surface).
Bacterial and in vivo tests to study the mutagenicity were negative.