Viagra Sildenafil facts

Viagra (sildenafil)

Sildenafil is a compound for the oral treatment of erectile dysfunction.


Summary
Sildenafil acts by inhibiting the enzyme phosphodiesterase type 5 in the corpus cavernosum, which in conjunction with sexual stimulation leads to increased blood flow to the penis and improve erections. The recommended dose is 50 mg to be taken approximately one hour before sexual activity. This dose resulted in improved erections in about 75% of men. The most common side effects were headache, flushing, dyspepsia, dizziness and visual disturbances. Sildenafil should not be given in combination with nitrates, as this may cause excessive hypotension. Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (eg patients with severe cardiovascular disorders such as unstable angina or severe heart failure). Sildenafil is also contraindicated in severe hepatic impairment, hypotension, recent stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa, where the safety of these subgroups have not yet been studied.


 
MPA score

Sildenafil is a valuable addition to the therapeutic armamentarium in erectile dysfunction. The drug can not be used in certain risk groups. By sildenafil is administered orally, it has advantages over the currently available agents administered via injection into the corpus cavernosum or intraurethrally.

 
Active ingredient and dosage form

Viagra (Sildenafil)

Sildenafil is an achiral substance having a pH-dependent solubility. In Viagra tablets used in the form of a salt with citric acid, which has its greatest solubility (24 mg / ml) at pH 2.0. The pharmaceutical form is conventional tablets from which the drug is rapidly released and absorbed. Sildenafil citrate is a stable compound itself and in the current formulation.
Indication

Treatment of erectile dysfunction, which is the inability to achieve or maintain an erection sufficient for satisfactory sexual activity.

 

Viagra Sildenafil

 


Background Viagra

The physiological mechanism associated with erection involves the release of nitric oxide in the corpus cavernosum during sexual stimulation. Nitric oxide activates the enzyme guanylate cyclase, resulting in increased levels of cyclic guanosinmonofosat (cGMP). This, in turn, relaxation of smooth muscle of the corpus cavernosum and increased blood flow that leads to an erection. Sildenafil inhibits the enzyme phosphodiesterase type 5 in the corpus cavernosum. This enzyme breaks down cGMP. Inhibition of the enzyme leads to increased levels of cGMP and through the mechanisms described above, an improved erection.


Clinical Efficacy
Of a total of 21 clinical studies, 14 studies have been conducted to evaluate the effect of sildenafil. Of these, four placebo-controlled, randomized, double-blind, multicenter studies are classified as main studies (1, 2). In most studies defined erectile dysfunction as the inability to achieve and / or maintain an erection sufficient for satisfactory sexual activity. The four main studies recruited patients with erectile dysfunction of organic or psychogenic etiology or mixed forms; however, was not included patients with spinal cord injury (these were studied separately). Efficacy was evaluated with a questionnaire, the International Index of Erectile Function (IIEF), which consists of 15 questions, with answers to each question are rated on a 5 - or 6-point scale. The primary endpoint of the main studies were two of the questions in IIEF, which answers to the questions provide information about how often during the past four weeks as the man got an erection sufficient to initiate intercourse, and how many times the man was able to maintain his erection during an initiated intercourse. Responses were rated from 1 (almost never / never) to 5 (almost always / always). Among secondary endpoints were response to the remaining questions in the IIEF, a questionnaire to the partner, a question regarding an overall assessment of whether the treatment had improved erections, as well as an assessment of quality of life.

Two of the main studies, which had a duration of three months and six months, using fixed doses of 25, 50 or 100 mg was taken about an hour before sexual activity. In all these trials approximately 1,000 patients. In both studies, sildenafil after three months, a statistically significant positive effect on the primary endpoint, and the effect persisted even after six months in the longer of the studies. A dose-response relationship could be demonstrated. In fixed dose studies, the proportions of patients reported improved erections 62% for 25 mg, 74% for 50 mg and 82% for 100 mg of sildenafil compared with 25% for the placebo group.

The other two main studies used flexible doses of sildenafil. More than 600 patients were included in these studies had a duration of three months and six months. In one study, the starting dose of 50 mg of sildenafil with the possibility of dose escalation to 100 mg or a dose reduction to 25 mg. The second study used a starting dose of 25 mg with the option to increase the dose to 50 or 100 mg. In both trials after three months, a statistically significant effect on the primary endpoint. Although for most secondary efficacy variables were significant effects. Partner's perception of the patient's ability to get and maintain an erection was significantly superior to sildenafil than with placebo in both studies. In the two studies with flexible doses held 74.3% and 82.4% of patients that treatment had improved their erections, while the corresponding figures for the placebo groups were 16.3% and 24% respectively.

In a separate study of over 150 patients with erectile dysfunction as a result of traumatic spinal cord injury sildenafil, a statistically significant positive effect for this diagnostic group. For patients with erectile dysfunction due to diabetes mellitus, the effect of sildenafil is generally slightly worse than for patients in the main study (who had erectile dysfunction of mixed etiology).


Pharmacodynamics


Pharmacotherapeutic group: Drugs used in erectile dysfunction.
ATC code G04BE03 (proposed).

Sildenafil is an oral treatment for erectile dysfunction. In natural conditions, ie, sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.

The physiological mechanism responsible for erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), which causes relaxation of smooth muscle in the corpus cavernosum and allowing inflow of blood.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, which is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO / cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased levels of cGMP in the corpus cavernosum. Because sexual stimulation is required for sildenafil to produce its intended beneficial pharmacological effects.

In vitro studies have shown that sildenafil has between 80 and 10,000-fold selectivity for PDE5 than other isoforms of the phosphodiesterase (PDE 1, 2, 3 and 4). In particular, sildenafil 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. Selectivity is 10 times higher than for PDE6 which is involved in phototransduction in the retina.

Two clinical studies were specifically designed to assess the time window after dosing during which sildenafil could produce an erection in response to sexual stimulation. In a study of penile plethysmography (RigiScan) in fasted patients, the median time to erection with 60% rigidity (sufficient for sexual intercourse) was 25 minutes (range 12-37 minutes) for patients receiving sildenafil. In a separate RigiScan study, sildenafil was still able to produce an erection during sexual stimulation 4-5 hours after dosing.

Sildenafil causes mild and transient decreases in blood pressure, which in most cases does not provide any clinical effect. The mean reduction in supine systolic blood pressure after an oral dose of 100 mg of sildenafil was 8.4 mmHg. The corresponding change in supine diastolic blood pressure was 5.5 mm Hg. These decreases in blood pressure are consistent with the vasodilatory effects of sildenafil, probably due to increased cGMP levels in vascular smooth muscle. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.

When tested using the Farnsworth-Munsell 100 hue test were mild and transient differences in color discrimination (blue / green) in some individuals one hour after ingestion of a 100 mg dose. No effects were shown two hours after dosing. The mechanism for this change in color discrimination is likely an inhibition of PDE6, which is involved in phototransduction in the retina. Sildenafil has no effect on visual acuity or contrast sensitivity.

There was no effect on motility and morphology of sperm after a single oral dose of 100 mg of sildenafil in healthy volunteers.


Further information on clinical trials
In clinical trials sildenafil was administered to more than 3000 patients aged 19-87. The following patient groups were represented: elderly (21%), patients with hypertension (24%), diabetes mellitus (16%), ischemic heart disease and other cardiovascular diseases (14%), hyperlipidemia (14%), spinal cord injury (6%), depression (5%), transurethral resection of the prostate (5%), radical prostatectomy (4%). The following groups were excluded or were represented to a lesser extent in clinical trials: patients with pelvic surgery or radiotherapy, patients with severe renal or hepatic impairment and patients with certain cardiovascular conditions.

In fixed dose studies, the proportions of patients reported improved erections 62% (25 mg), 74% (50 mg) and 82% (100 mg) compared with 25% on placebo. In controlled clinical trials, the proportion of patients who discontinued the studies was low and similar to placebo.

Across all trials, the proportion of patients reporting improvement on sildenafil were as follows: psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), older (67%), diabetes mellitus (59%) , ischemic heart disease (69%), hypertension (68%), TURP - transurethral prostate (61%), radical prostatectomy (43%), spinal cord injury (83%), depression (75%). In long-term studies were maintained and no additional safety concerns were detected.


Pharmacokinetics


Absorption
Sildenafil is rapidly absorbed. Peak plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute bioavailability is 41% (range 25-63%). Following oral dosing of sildenafil AUC and Cmax increase proportionately with dose over the recommended dose range (25-100 mg).

When sildenafil is taken with food, absorption is reduced with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%.


Distribution
The mean volume of distribution at steady state (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both bound to plasma proteins is approximately 96%. Protein binding is independent of total drug concentrations.

In healthy volunteers receiving sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) of the administered dose was present in ejaculate 90 minutes after dosing.


Metabolism
Sildenafil is cleared predominantly by the hepatic microsomal isoenzymes CYP3A4 (major route) and CYP2C9 (minor route). The major circulating metabolite results from N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 hours.


Elimination
Clearance of sildenafil is 41 l / h with a resultant terminal half-life of 3-5 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).
Pharmacokinetics in special patient groups:

Mature
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to the concentrations in healthy younger volunteers (18-45 years). Corresponding increase in free sildenafil plasma concentration was approximately 40% due to age-differences in plasma protein binding.

Renal Insufficiency
In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml / min), the pharmacokinetics of a single oral 50 mg dose is not altered. The mean AUC and Cmax of the N-desmethyl metabolite increased 126% and 73% respectively, compared to age-matched volunteers with no renal impairment. Because of the large inter-subject variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL / min), sildenafil clearance was reduced, resulting in increases in AUC (100%) and Cmax (88%) compared to age-matched volunteers with no renal impairment. Moreover, the AUC (79%) and Cmax (200%) was significantly N-desmethyl metabolite.

Hepatic Insufficiency
In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil has not been studied in patients with severe hepatic impairment.
Security Valuation

Safety assessment is based on a total of approximately 3,000 patients enrolled in phase II / III program (2, 3). In the placebo-controlled phase II / III studies treated 2,340 patients with sildenafil. More than 550 patients have been treated with sildenafil for over a year.

Sildenafil has vasodilator properties, resulting in a transient drop in blood pressure. Co-administration of sildenafil and nitrates (such as nitroglycerin) may be an enhancement of the hypotensive effect of nitrates, which can cause excessive hypotension. It is therefore important to emphasize that co-administration of sildenafil and nitric oxide donors or nitrates in any form is contraindicated.

Certain subgroups of patients were excluded from the clinical trials. The safety of these subgroups have not been studied and the use of sildenafil is contraindicated until further information is available. This applies to the following diagnostic groups: severe hepatic impairment, hypotension, recent stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa. Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (eg patients with severe cardiovascular disorders such as unstable angina or severe heart failure).

In the flexible dosstudierna, where the dosage is most like that of the SPC recommended dosage, the most common treatment-related side effects headache 12.8%, redness 10.4%, dyspepsia 4.6%, visual disturbances 1.9%, dizziness 1.2 % and 1.1% nasal congestion. Muscle pain was reported when sildenafil was administered more frequently than the recommended dosage. Results from trials with fixed doses shows a dose-response relationship for the most common treatment-related adverse events. Vision disturbances, considered to result from that sildenafil inhibit the enzyme phosphodiesterase type 6, as found in the retina. Sildenafil inhibits, as previously mentioned, particularly phosphodiesterase type 5 in corpus cavernosum, but then also the type 6 of the retina (about ten times higher selectivity for the former). the eye disturbance, who were of a transient nature, has been described as a change in color vision, increased sensitivity to light or blurred vision. In studies with fixed doses of sildenafil increased frequency of visual disturbances ranging from 1.6% for 50 mg to 10.7% for 100 mg and 41.9% for 200 mg. Because of the effects on vision, and because these diagnostic groups were excluded from the clinical trials, sildenafil is contraindicated in known hereditary degenerative disease of the retina such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal fosfodiestesteraser).


Sildeanfil

Literature
1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998; 338:1397-1404.
2nd The manufacturers filed, unpublished documentation.
3rd Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH. Clinical safety of oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impotence Res 1998; 10:69-74