Overview of Clinical Evidence of Sildenafil Use in the Treatment of Erectile Dysfunction
Erectile dysfunction (ED), or impotence, is a common condition in men of all ages. The traditional risk factors that provoke the development of erectile dysfunction include high blood pressure, diseases of the cardiovascular system, overweight, as well as operations on the pelvic organs, including prostatectomy. Almost all of these factors are components of metabolic syndrome, a multiple risk factor for cardiovascular disease (CVD). This is because, according to many researchers, endothelial dysfunction is at the root of both erectile dysfunction and cardiovascular disease. Numerous different studies, including double-blind, placebo-controlled studies, have examined the cardiovascular effects of sildenafilb, its effectiveness and safety. It should be noted that sildenafil has been used successfully for the treatment of erectile dysfunction in patients with underlying medical conditions, including diabetes mellitus. Sildenafil attracts patients with its rapid onset of action – on average 20 minutes after taking the tablet – and its duration is up to 12 hours. In addition to erectile dysfunction, sildenafil is also used for a number of other chronic conditions such as idiopathic pulmonary arterial hypertension, premature ejaculation, and the treatment of lower urinary tract symptoms.
Keywords: erectile dysfunction, sildenafil, PDE-5, treatment, safety.
Erectile dysfunction (ED) is one of the most common diseases of the male genital area. The disease occurs in men of all ages, but older age is a risk factor. According to the Massachusetts Male Aging Study, about 70% of men in their 70s suffer from symptoms of erectile dysfunction . It is very roughly estimated that about 300 million men have erectile dysfunction worldwide. Very often, ED is the first sign of cardiovascular disease in men, their harbinger. The increased availability of PDE5 inhibitors for the treatment of ED over the years has increased the level of their prescription by non-specialists and general practitioners as the first line of treatment for erectile dysfunction. Evidence from many studies suggests that sildenafil is suitable for the treatment of idiopathic pulmonary hypertension and also improves endothelial function [2, 3].
Some researchers note the effectiveness of sildenafil in premature ejaculation. However, so far clinical studies have not yielded unequivocal results in this area, and it is unclear whether sildenafil directly affects the ejaculation process, or whether its effect is based on an overall improvement in potency levels . The aim of this paper is to review the clinical evidence regarding the use of sildenafil in the treatment of erectile dysfunction.
Pharmacological Profile of Sildenafil
Sildenafil, a selective PDE-5 inhibitor, relaxes the smooth muscles of the vessels in the cavernous bodies of the penis. The maximum concentration in blood plasma is observed approximately one hour after taking sildenafil in tablet form. At the same time, the average half-life of the drug from the body is 5 hours.
According to the recommendations of the European Association of Urology, sildenafil therapy should be started with a dosage of 50 mg approximately one hour before intercourse. If necessary, under the supervision of a urologist, the dose is adjusted to 25 or 100 mg. The maximum daily dosage of sildenafil is 100 mg. A prerequisite for the onset of action of sildenafil is the presence of sexual stimulation or pronounced sexual desire. The average duration of action of the drug is 4-6 hours, but in about 13% of patients with hypersensitivity to sildenafil, the effect can be felt for up to 12 hours .
The pharmacokinetics of sildenafil is influenced by the amount and properties of food consumed: abundant and fatty foods slow down the absorption of sildenafil into the blood and weaken its effect.
Efficacy of Sildenafil in the Treatment of ED in Broad Populations of Men
The efficacy of sildenafil against erectile dysfunction was first scientifically confirmed in 1998. Sildenafil increased the ability of men with symptoms of erectile dysfunction to have normal intercourse by more than 50%. Sildenafil helps to achieve an erection and maintain it at a level sufficient for normal sexual activity. Placebo-controlled clinical studies in men with ED, divided into groups by age, race, etiology of ED, the presence and absence of bad habits and comorbidities, showed a high (from 40% to 60%) ability of sildenafil to improve erection .
The long-term efficacy of sildenafil for ED treatment has also shown good results. After 12-18 months of regular use of sildenafil in dosages of 25-100 mg after the cessation of therapy, more than 90% of men were satisfied with the quality of their erection. The overwhelming majority of research subjects did not refuse to participate in them and did not terminate them early. The averaged data from numerous studies allow us to derive the average parameter of the effectiveness of sildenafil at 86%. Despite the fact that in the early 200s in the scientific community there were assumptions about the risk of developing tachyphylaxis, that is, a condition when the therapeutic effect with prolonged use, especially repeated use, sharply decreases, later these fears were not confirmed. Sildenafil and all other PDE5 inhibitors do not cause tachyphylaxis or addiction .
Efficacy of Sildenafil in the Treatment of ED in Subpopulations of Men
Sildenafil was highly effective in virtually all subgroups of men with erectile dysfunction who participated in clinical trials. At the same time, in elderly men, the effectiveness of sildenafil is not reduced. Also, belonging to one or another ethnic group did not have any effect on the effectiveness of the drug . Sildenafil demonstrates high efficacy in patients with diabetes mellitus, despite the fact that traditionally men with diabetes mellitus are at increased risk of developing potency disorders. Sildenafil is also an effective treatment for erectile dysfunction resulting from radical prostatectomy, but only if the nerve bundles are preserved (up to three quarters of men who have undergone radical prostatectomy were able to return to sexual activity with sildenafil) .
In patients with ischemic heart disease in the compensation stage, sildenafil has shown high efficacy profiles and relative safety, but patients with IHD of any degree are advised to take sildenafil only after consulting a cardiologist. A similar situation is observed in men with mild and moderate arterial hypertension. Sildenafil is not recommended for patients with uncontrolled hypertension.
A contraindication for taking sildenafil is not renal failure, including conditions requiring dialysis, but in most cases, a dosage adjustment downward is required. Sildenafil has shown high efficacy profiles for spinal cord injuries as well as ED associated with psychological causes, including clinical depression. Some researchers even report the ability of sildenafil to have a positive effect on the course of Alzheimer’s disease. However, to date, these data only apply to animals and have not been conducted in humans. 
Quality of Life and Level of Treatment Satisfaction
Both clinicians and patients report significant increases in sex satisfaction after taking sildenafil compared to placebo. It is important that similar information is reported by the partners of men receiving ED sildenafil therapy. In cases of mild erectile dysfunction, satisfaction with treatment reaches 99%, moderate severity – 82%, severe – 56%.
According to clinical studies, the use of sildenafil for combating erectile dysfunction improves the quality of life of the vast majority of patients, even if not every intercourse they perform is successful. Regular intake of sildenafil as part of ED therapy helps to increase a man's self-esteem, his satisfaction with sexual relations, and improves the psychological climate in a couple. It is important that at the end of treatment, to one degree or another, the effect of sildenafil persists for quite a long time.
Safety of Sildenafil
Sildenafil, like other PDE5 inhibitors, has a number of side effects. The most common of these are headache, dizziness, facial flushing, dyspepsia, nasal congestion, color problems, and palpitations. Less common unwanted side effects include muscle pain, especially in the back muscles, chills, diarrhea, cardiac arrhythmias, allergic reactions, and hypersensitivity reactions. 
In most cases, each patient experiences no more than two side effects at the same time. All these sensations are dose-dependent, as a rule, they quickly disappear and do not require specific treatment. Almost none of the patients who took part in the clinical trials of sildenafil dropped out due to unexpectedly severe unpleasant side effects.
With more or less constant and prolonged use of sildenafil, side effects tend to subside and even disappear completely. Which side effects are most pronounced is influenced by the presence of concomitant diseases. For example, patients suffering from coronary heart disease and hypertension are more likely to develop cardiovascular side effects due to taking sildenafil than patients without these pathologies. 
In patients at risk of developing myocardial infarction, the use of sildenafil is not recommended, as well as in patients with unstable angina pectoris. At the same time, with stable angina pectoris, sildenafil does not cause deterioration in patients' condition. 
Of all the PDE-5 inhibitors, sildenafil is the only one approved for use in pulmonary arterial hypertension (PAH) due to its ability to improve arterial oxygenation. For PAH, sildenafil is taken on an ongoing basis every 8 hours. 
If a man has any problems with the cardiovascular system, it is recommended to conduct a thorough assessment of the patient's cardiovascular status, since in some diseases it is not even sildenafil itself that is unsafe, but the sexual activity that follows its intake. Particular attention should be paid to patients with moderate angina pectoris, myocardial infarction, suffered earlier than a year ago, congestive heart failure, unstable arrhythmias and high risk factors for coronary heart disease. If necessary, before starting treatment for erectile dysfunction and resuming sexual activity, the state of the cardiovascular system is normalized.
Combination of Sildenafil with Other Drugs
Due to the risk of severe hypotension, it is forbidden to use sildenafil in combination with any nitrate-based medications. Taking sildenafil together with alpha-blockers can also contribute to the development of hypotension, therefore, if it is impossible to cancel alpha-blockers, sildenafil is prescribed in the minimum dosage (25 mg). 
Effect of Sildenafil on Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)
Non-arterial anterior ischemic optic neuropathy (NAION), which is expressed in acute ischemia of the anterior optic nerve in the absence of provable arteritis, in some cases can be triggered by taking sildenafil. However, clinical data are insufficient for a more accurate analysis of the situation due to the relative rarity of this disease. 
Management of Treatment Failures
Traditionally, failure of treatment is considered to be the lack of effect of the drug with more than four attempts to use it at the maximum allowable safe dosage. However, in the case of erectile dysfunction, the situation is complicated by the fact that many patients do not provide adequate feedback. In case of a confirmed failure of treatment with sildenafil, it is recommended to turn to other PDE-5 inhibitors (vardenafil, tadalafil). In case of repeated failure, it is advised to resort to intracavernous therapy.
Sildenafil in Aging Men
Age-related deterioration in potency can be associated both with the accumulation of risk factors for the development of ED (concomitant diseases), and with a decrease in testosterone levels and age-related molecular changes. In older men, there is an increased level of sildenafil in the blood plasma, due to which the initial dose may be 25 mg.
Sildenafil in Premature Ejaculation
Sildenafilb has been shown to be effective in the treatment of premature ejaculation, with the combination of sildenafil and paroxetine having a particularly pronounced clinical effect. The mechanism of action of sildenafil on the inhibition of ejaculation is not yet clear, it presumably consists in the peripheral inhibition of the contractile reaction of the vas deferens, seminal vesicles, prostate and urethra. 
Sildenafil is a treatment for ED that has been shown to be highly effective in a variety of subpopulations, including those difficult to treat, such as those with diabetes mellitus or ED associated with radical prostatectomy. Sildenafil also has the potential to treat several other chronic conditions.