Review of the use of sildenafil in the treatment of erectile dysfunction in any associated pathology

Erectile dysfunction (ED) is a well-known pathology that is predicted to grow in the coming years. This is due to both an increase in the life expectancy of men and an increase in the prevalence of various diseases. ED is a complex pathology that negatively affects men’s self-esteem, the quality of sexual satisfaction, interpersonal relationships and the quality of life. Risk factors for ED include the use of alcohol, tobacco, and a number of medications.

Erectile function is a key indicator of men’s quality of life. The projections of the World Health Organization show that by 2025 the prevalence of ED in the world will reach 322 million people, in the USA it occurs in 31.1% of men, and deviations from the norm of erectile function are detected in 90%.

Erectile dysfunction is a problem that affects more than half of men between the ages of 40 and 70. This raises serious concerns due to the negative impact of ED on their self-esteem and quality of life. The incidence of ED increases with age, but it should be remembered that it is not an inevitable consequence of aging, and age does not exclude the presence of sexual interest in men. ED also has a negative effect on the partners of men with ED, causing them to have secondary sexual dysfunction.

Research in the neurophysiology of erection has led to significant progress in the treatment of patients with ED. They were crowned with the creation of a fundamentally new agent in the treatment of this disease – the phosphodiesterase-5 (PDE-5) inhibitor sildenafil, which meets all modern requirements for ED therapy. Sildenafil is recognized as the first line of treatment for ED, highly effective and reliable, easy to use, has few side effects and is currently the gold standard in the treatment of ED.

It is known that men with the maximum (4th) degree of hardness of erection and women whose partners have the same degree of hardness of erection experience higher satisfaction with sex and more often have it in comparison with men whose hardness of erection is not optimal. Meanwhile, it has been proven that sildenafil provides 20 times greater penetration ability than placebo, and such PDE-5 inhibitors as vardenafil – only 7.5 times, and tadalafil – only 1.4 times. Sildenafil begins to act after 20 minutes and continues to work up to 5 hours, although many patients in practice note the duration of the effect to improve erection for more than 24 hours. The safety of sildenafil was confirmed at doses 8 times higher than the maximum recommended. Among the most common side effects are headache and facial flushing, which do not last long and go away on their own.

The efficacy and safety of sildenafil has been confirmed in patients with ED of a wide variety of etiologies. By 2003 alone, more than 20 million people worldwide had received sildenafil treatment with excellent results. The incidence of side effects from the cardiovascular system in patients taking sildenafil did not differ from that in the general population. Sildenafil has been shown to be safe and effective in patients taking a variety of medications, including several antihypertensive drugs simultaneously, selective serotonin reuptake inhibitors, cardiovascular and antidiabetic agents. Thiazide diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers, warfarin, acetylsalicylic acid do not affect the pharmacokinetics of sildenafil. The main side effects – transient – occur, as a rule, when a dosage of 100 mg is used and are characterized by a slight or moderate severity (headache, redness of the face and neck, nasal congestion, dyspepsia). The most important contraindication to the use of sildenafil is nitrate therapy, due to the risk of hypotension.

S. Sunwoo et al. conducted a post-marketing study on the safety and efficacy of sildenafil. Out of 651 men with ED, a total of 71 adverse events were recorded that developed in 56 patients (8.6%), among which the most frequent were hot flushes (5.6%), headache (2.6%), palpitations (1.0%), anxiety (0.5%) and an increased level of alanine aminotransferase (0.5%). These results demonstrated that sildenafil was very well tolerated.

An analysis of the latest published data from a randomized, double-blind, placebo-controlled study in men with ED who received sildenafil again demonstrated the drug’s high efficacy. Study participants received sildenafil for 12 weeks. The estimation was carried out using a logistic regression model. Positive results were obtained on all parameters of the International Index of Erectile Function (ICEF) scale.

ED in patients with diabetes mellitus is associated with a high risk of cardiovascular events. Endothelial dysfunction, vascular changes and the development of fibrosis – these are the changes that are characteristic of patients with diabetes. In patients with diabetes mellitus, ED is most refractory to treatment with PDE-5 inhibitors, but long-term use of sildenafil improves endothelial function, preserves vascular smooth muscle, and reduces the degree of fibrosis in such patients. This ultimately has a double effect – it reduces the risk of cardiovascular disease and improves erectile function in diabetics.

ED is highly dependent on the release of nitric oxide (NO) in endothelial cells. Insulin resistance is the cause of endothelial dysfunction, which is characterized by decreased synthesis and release of NO. A prospective, randomized, placebo-controlled, double-blind study of 30 men with ED, insulin resistance and poor response to sildenafil showed that insulin resistance may be sufficient to offset this effect. The insulin resistance index HOMA was measured in the studied patients (its level ≥3 was considered to be significantly high). Patients were randomized into 2 groups: 1) receiving metformin (n = 17) and 2) receiving placebo (n = 13). After metformin treatment, patients showed a significant improvement in erectile function according to the IIEF-5 scale and a significant decrease in the HOMA index from the 2nd month of treatment (IIEF-5: 17.0 ± 6.0 versus 14.3 ± 3.9, p = 0.01; HOMA: 3.9 ± 1.6 versus 5.5 ± 2.4, p = 0.01) before the 4th month of treatment (IIEF-5: 19.8 ± 3.8 versus 14.3 ± 3.9, p = 0.005; HOMA: 4.5 ± 1.9 versus 5.5 ± 2.4, p = 0.04); there were no changes in these parameters in the placebo group. Thus, one should not forget about the biochemical mechanisms of endothelial dysfunction and the ways of complex effects on it.

Decreased vascular endothelial function is associated with ED in patients with type 2 diabetes. Double-blind, placebo-controlled prospective study L. Deyoung et al. (2012), which was attended by 24 men, was conducted in order to find out: can the daily use of sildenafil change endothelial function and increase the degree of erection rigidity in a group of patients with diabetic ED? The subjects were randomized into 2 groups: the 1st received daily sildenafil at a dose of 50 mg (n = 12), the 2nd – placebo (n = 12) for 10 weeks. Erectile function was assessed using the IIEF-5 scale, and endothelial function was determined by measuring the magnitude of the brachial artery dilatation. Both groups did not have significant differences in the age of patients, the duration of type 2 diabetes mellitus, the duration of ED and its baseline values. Associated factors, including smoking, alcohol use, hypertension, and hyperlipidemia, were also similar. At the end of the 10-week study, patients who received daily sildenafil significantly improved the degree of erection stiffness according to the IIEF-5 scale (p <0.001) and increased the value of the brachial artery dilatation (p <0.01).

Side effects that occur during treatment with sildenafil are short-lived – an average of 3.9 hours after administration, while after taking vardenafil and tadalafil, they last an average of 7.7 and 14.9 hours, respectively.

Alcohol intake in moderate doses has no effect on the pharmacokinetics and hemodynamics of sildenafil when taken together. Studies have shown that taking sildenafil simultaneously with alcohol does not lead to changes in cardiac output, heart rate, blood pressure and peripheral vascular resistance.

ED is often associated with depressive disorders. Sildenafil has been shown to be effective in men with depression and ED. S.H. Kennedy et al. (2011) demonstrated that ED is a predictor of depression. In 104 men treated with sildenafil, after 6 weeks. there were significant changes, indicating that the drug significantly reduced depression and at the same time improved erectile function.

Erectile dysfunction and the clinical manifestations of urinary dysfunction share many common risk factors and are common in older men. PDE-5 inhibitors can lead to relaxation of the smooth muscle of the urinary tract, which led to their study as a means of pathogenetic therapy in patients with benign prostatic hyperplasia (BPH) and symptoms of lower urinary tract dysfunction (LUT). A MEDLINE search of available studies evaluated six 12-week clinical studies of the combined use of alpha-blockers and sildenafil in patients with BPH. Three uncontrolled studies (168 participants total) examined the effect of sildenafil dosage on the severity of symptoms of impaired LUT function. Two large studies have shown that the lesser the degree of ED in a patient, the fewer the manifestations of LUT disorders. In one prospective, 369, placebo-controlled study, sildenafil 100 mg daily in men with ED and symptoms of impaired LUT function significantly improved urine flow rate, with the highest baseline outflow impairment being the best. In an open-label comparative study of 62 men who received sildenafil 25 mg alone or sildenafil 25 mg in combination with alfuzosin 10 mg, combination therapy resulted in greater improvement in both erectile function and LUT symptoms. Sildenafil, the authors of the study believe, can improve the state of LUT, and although its effect in this regard is not so significant, treatment is economical and safe and drugs of this group can take their rightful place in the combination therapy of benign BPH.

There are no published studies on the treatment of sildenafil in patients with sexual dysfunction who are taking antidepressants to improve their quality of life.

An interesting prospective randomized study involving 150 patients with ED and symptoms of impaired LUT function caused by BPH. The patients were divided into 3 equal groups, comparable on the IPSS and IIEF scales. Within 4 months. patients in group 1 received sildenafil at a dose of 50 mg as monotherapy, patients in group 2 received doxazosin 2 mg, and patients in group 3 received a combination of both drugs. After that, the symptoms of impaired LUT function were assessed on the IPSS scale, erectile function, uroflowmetry was performed, and the volume of residual urine was assessed. Sildenafil as monotherapy caused a moderate improvement in the symptoms of impaired LUT function, significantly increased the number of points on the IIEF scale and had little effect on the urine flow rate and its residual volume. The combination of sildenafil and doxazosin produced more significant improvement in all parameters than either drug alone. The authors believe that there is a close relationship between the symptoms of impaired LUT function and ED, and the combination therapy with these drugs is effective in patients with a combination of these symptoms.

H. Cui et al. (2014) conducted a study to evaluate the efficacy and safety of low doses of tadalafil, taken in combination with sildenafil (if necessary). The study involved 180 patients with severe ED, divided into 2 groups: patients in group 1 received tadalafil 5 mg once a day, patients in group 2 received tadalafil 5 mg and additionally sildenafil at a dose of 50 mg on demand. The results in the combined drug therapy group were significantly better than in the tadalafil monotherapy group. There were no differences between the two groups in the incidence of adverse events. Thus, sildenafil at a dose of 50 mg has proven itself as a drug that is effectively used even in the treatment of ED with other PDE-5 inhibitors.

M. Spitzer et al. (2013) demonstrated the effects of sildenafil on the hypothalamic-pituitary-gonadal axis in men with ED and low testosterone. The study involved 140 men aged 40–70 years. At the beginning of the study and after the administration of sildenafil, the levels of sex steroids and gonadotropins were determined. The level of free testosterone significantly increased by an average of 110 pmol / l. This was accompanied by a parallel increase in serum dihydrotestosterone (by 0.17 nmol / L) and estradiol (by 14 pmol / L) and a significant suppression of luteinizing hormone, which was due to the direct effect of sildenafil at the testicular level. Androstenedione and estrone levels increased by 1.3 nmol / L and 10.7 pmol / L, respectively, supporting the possible effect of sildenafil on adrenal steroidogenesis.

J. Buvat et al. (2008) presented the results of a multicenter, parallel group study conducted over two 4-week periods. At baseline, patients received 50 mg of sildenafil for 4 weeks. In period 2, patients were randomized in a double-blind, placebo-controlled study to receive sildenafil 50 mg and 100 mg for 4 weeks. All patients were over the age of 18 and suffered from ED (the sum of points on the ICEF scale was 25 or more). Of the 492 patients included in the study, 476 (97%) completed the 1st period and 473 (96%) – the 2nd period. Patients receiving sildenafil at a dose of 50 mg in the 1st period noted an increase in the average score for erectile function from 12.8 to 22.5 (p <0.001) and an improvement in the quality of erection and sexual function. In patients titrated to 100 mg (237 people), a more significant improvement was noted. At any dosage, the most common adverse events were headache, facial flushing due to hot flushes in the area. Neither the frequency nor the severity of adverse events increased with increasing dosage to 100 mg.

In order to investigate the effect of two different doses of sildenafil in patients with ED, H. Li et al. (2015) conducted a study involving 3674 patients, of whom 977 received sildenafil at a dose of 50 mg and 2697 at a dose of 100 mg. In both groups, the patients had an increase in the average monthly frequency of intercourse, improved erectile function, general condition and self-esteem, and increased sexual satisfaction. Despite the higher degree of comorbidity, patients receiving the 100 mg dose of sildenafil showed better results compared to those taking the drug at a lower dosage.

Sildenafil is the leading drug for the treatment of ED and is recommended as a first-line treatment by the European and American urological societies.