The efficacy and safety of using sildenafil citrate in the treatment of erectile dysfunction

Currently, there are a fairly large number of effective methods of drug treatment of erectile dysfunction (ED). The choice of treatment method is determined by its invasiveness. In the case of insufficient effectiveness, a less invasive technique is transferred to a more invasive one. Thus, most clinicians begin treatment with an oral phosphodiesterase type 5 (PDE5) inhibitor, which is ineffective with intracavernous injections or vacuum devices. Combined treatment is also possible. With the ineffectiveness of such techniques, it is possible to carry out surgery (falloprosthetics).

Sildenafil is the first PDE5 inhibitor

PDE5 inhibitors are highly effective and safe oral drugs for the treatment of ED and are recommended as first line therapy. The number of patients taking these drugs continues to increase in parallel with the increasing prevalence of ED.

In 1998, the drug sildenafil was approved for clinical use. This moment became not just a starting point for the existence of another drug on the pharmacological market. It turned out to be the beginning of a new era in the field of sexual medicine, marked by a real breakthrough in the fundamental and clinical areas, as well as in the public perception of sexual pathology.

Sildenafil was the first effective and safe oral treatment for ED. The history of the discovery of sildenafil was preceded by the accumulation of knowledge about the role of nitric oxide in maintaining the normal functional state of the cardiovascular system, which was initiated by R.R. Furchgott and J.V. Zawadski. However, the current use of the drug as a therapy for ED is an example of how accidental observation can have a huge impact on the course of scientific progress. In the course of clinical trials of the antianginal properties of sildenafil, researchers noted that although taking the drug is not accompanied by a significant clinical improvement in the course of angina pectoris, in many patients it leads to the development of a kind of “side effect”, which consisted in improving erectile function. This observation prompted further research into the potential use of this substance in the treatment of ED.

The discovery of sildenafil, a selective PDE-5 inhibitor, has led to numerous fundamental studies showing that it is this type of enzyme that dominates in the cavernous tissue, which ensures the selectivity of the drug. It should be noted that these studies also made it possible to elucidate the mechanisms of action of other drugs that have been used in clinical practice for a long time, in particular papaverine and prostaglandin E1, and significantly expand knowledge about the mechanism of erection and its disorders leading to ED.

The emergence of sildenafil has also greatly influenced clinical research in the field of sexual medicine. In recent years, the terminology has been clarified, new definitions of various forms of sexual dysfunctions have been developed. Sildenafil clinical trials have stimulated the creation of new diaries and questionnaires to assess the status of male sexual function. Analysis of the demographic indicators of participants in large-scale clinical trials revealed risk factors for ED, which, in turn, contributed to the understanding of its pathogenesis.

The emergence of sildenafil had a huge public response. A large number of patients with ED, who had not previously seen a doctor, received hope for the restoration of sexual function, and to date, millions of men around the world have returned to normal sex life thanks to the use of this drug.

The dose of the drug is selected by titration, starting from 50 mg, followed by a change in the dose (either a decrease to 25 mg or an increase to 100 mg), depending on the effect and tolerability. Sildenafil is taken 1 r. / Day, 1 hour before the expected sexual intercourse. The action of the drug begins 40-60 minutes after ingestion and lasts for 3-5 hours. It is important to note that taking the drug by itself does not lead to an erection and sexual stimulation is necessary to start its action.

Sildenafil is contraindicated in patients taking nitrates, patients with hypotension, severe hepatic impairment (the drug is metabolized by hepatic cytochrome P450 3A4) and retinopathy pigmentosa.

The clinical efficacy of sildenafil has been evaluated in numerous studies conducted around the world. S.S. Carson et al. pooled data from 11 double-blind, placebo-controlled trials involving a total of nearly 3,000 patients with ED. After 12 weeks. after the start of taking the drug, 76% of men who received sildenafil and 22% who received placebo noted an improvement in erection, while the percentage of successful attempts at sexual intercourse was 66 and 26% in the 1st and 2nd groups, respectively. The efficacy of various doses of sildenafil was 65% for 25 mg, 74% for 50 mg, 82% for 100 mg. The high efficacy of sildenafil was noted in different age groups. Thus, among patients under the age of 65 and under the age of 65, the effectiveness of sildenafil was 77.6 and 69.2%, respectively. Significantly higher efficacy of sildenafil compared to that of placebo was also observed in patients with ED of varying severity and etiology.

Use of sildenafil in special categories of patients with ED

As you know, arterial hypertension (AH) is one of the risk factors for ED. Although sildenafil has some antihypertensive effects, this drug is safe in hypertensive patients, both receiving and not receiving antihypertensive drugs. The efficacy of sildenafil in patients with ED and hypertension is high. Among patients with hypertension of various origins, taking placebo and sildenafil was accompanied by an improvement in erection in 18 and 70% of patients, respectively. Among men who took 2 or more antihypertensive drugs, these figures were 17.6 and 71%.

Smoking is another well-known risk factor for ED. The effectiveness of sildenafil among smokers was not inferior to that among nonsmokers (80 and 74%, respectively).

Many epidemiological studies have shown that depression is the second most common cause of ED after cardiovascular risk factors. In addition, the presence of ED exacerbates depressive symptoms. Treatment with sildenafil was not only highly effective in patients with depression in terms of improving erectile function, but was also accompanied by a decrease in the severity of depressive manifestations.

Various neurological diseases, as mentioned above, can also cause the development of ED. According to studies, the effectiveness of sildenafil among patients with parkinsonism, multiple sclerosis and spinal cord injuries exceeds 80%, which is consistent with the data obtained in the general population of patients with ED.

Patients with diabetes mellitus (DM) and patients undergoing radical prostatectomy (RP) are special groups of patients with ED difficult to treat.

In patients with diabetes, the effectiveness of sildenafil depends on the severity of the underlying disease and the presence of its complications. So, in the study of S.S. Carson et al. among patients with diabetes without complications, improved erection was noted by 8% of patients receiving placebo, and 69% of patients receiving sildenafil. In the presence of 1 complication, these indicators were 12 and 43%, and 2 – 10 and 43%, respectively. In all groups, the efficacy of sildenafil was significantly higher than that of placebo.

The effectiveness of ED treatment after RP is determined by a number of factors. According to R. Raina et al., Treatment with sildenafil was effective in 71.7% of patients after bilateral nerve-sparing RP, in 50% after unilateral nerve-sparing RP, and only in 15% of patients with ED after non-nerve-sparing surgery.

In addition, a feature of the course of ED in such patients is the possibility of a progressive improvement in erection for up to 4 years after the operation, and therefore finally the ineffectiveness of one or another method of treatment can be judged only several years after the operation. This is confirmed by the data of examination of 316 patients with ED after RP, which in 95% of cases had a bilateral nerve-sparing nature. The effectiveness of sildenafil was 26% during the first 6 months, 36% – in the period from 6 to 12 months, 50% – from 12 to 18 months, 60% – from 18 to 24 months. after operation.

Analysis of the efficacy and tolerability of sildenafil

Despite the high effectiveness of sildenafil, a certain number of patients remain in whom taking this drug does not lead to an improvement in erection. In many cases, this is due to inappropriate medication. Patients, especially at the beginning of treatment, should be advised to take sildenafil on an empty stomach at least 30 minutes before the onset of sexual activity. It is also important to explain to patients that the action of the drug develops only against the background of adequate sexual arousal and largely depends on it. In many cases, treatment should be started at 100 mg, which will maximize response early in treatment and instill confidence in patients that it will be successful. In addition, studies have shown that in some patients, the maximum effect of sildenafil is achieved by 6-8 doses, and therefore in many patients the final assessment of the drug’s effectiveness should be carried out after several attempts to use it.

Noteworthy is the work of A. Eisenhardt et al., Who found that the clinical efficacy of sildenafil depends on genetic factors. When analyzing the relationship between the polymorphism of the genes GNB3 C825T and ACE I / D, it was found that in the group of carriers of the allele GNB3 825C, sildenafil was effective only in 50% of men, while among owners of the TT genotype this figure exceeded 90%. Similar results were obtained with respect to the ACE I / D polymorphism – among carriers of the ACE D allele, the effectiveness of sildenafil did not exceed 50%, while in men with genotype II it was 75%.

The long-term efficacy of sildenafil was also investigated by Montorsi et al., Who surveyed 2,618 patients who took the drug for 3 years. Overall, 96% of these patients were satisfied with the treatment, and only 1.6% discontinued it due to low efficiency. The remaining 2.4% of patients stopped taking the drug for other reasons. Laboratory studies have not confirmed the existence of a tachyphylaxis effect with sildenafil.

An important characteristic of any pharmacological drug is its side effects. The most common side effects when taking sildenafil are headache (7%), facial flushing (7%), dizziness (2%), dyspeptic disorders (1.8%), nasal congestion (1.4%) and visual impairment , usually in the form of blue coloration of objects (1.2%).

It should also be noted that the incidence of side effects decreases as the drug is taken. So, in the study of S.S. Carson, the incidence of all side effects, except for visual impairment and dyspeptic disorders, decreased during the period of taking the drug. Headaches at the beginning of the study were noted in 7% of patients with ED, and after 16 weeks. – less than 1%, the frequency of dizziness also decreased from 7% to less than 1%, and nasal congestion – from 1.4% to less than 0.5%. An important circumstance is also the fact that 2/3 of patients in the course of this study increased the dose of sildenafil. Thus, with long-term use, the incidence of most side effects of sildenafil does not exceed that of placebo.

There is growing interest in the possibility of using sildenafil for various diseases in addition to ED. In a study by K. Sairam et al. the effect of sildenafil on the severity of urinary disorders in patients with ED was evaluated. After 1 and 3 months. after the start of treatment, there was a significant decrease in the severity of symptoms of lower urinary tract dysfunction, which was accompanied by an improvement in erectile function.

Taking sildenafil leads to an improvement in the condition of patients with primary and secondary pulmonary hypertension. Another possible direction for future research on sildenafil is the use of this drug in the treatment of endothelial dysfunction.

Safety of sexual activity in patients with cardiovascular diseases

In most cases, sexual intercourse is accompanied by physical activity. This makes some people, primarily men, suffering from cardiovascular diseases, and their partners, to worry about the possibility of developing various complications due to sexual activity, which can lead to restriction or complete rejection of it. These fears are reinforced by stories of famous people who allegedly died during intercourse. At the same time, research data show that the risk of cardiovascular complications in patients with cardiac pathology during and immediately after sexual activity, although there is, is relatively low. For example, the risk of developing myocardial infarction in a healthy 50-year-old man within 1 year is 1%. As a result of sexual activity, this risk increases to 1.01% in a healthy man and up to 1.1% in a man with a confirmed diagnosis of ischemic heart disease (IHD). According to these data, the absolute risk of developing cardiovascular complications for a healthy man is 1 chance in 1 million.This indicator rises to 2 chances in 1 million within 2 hours after intercourse for a healthy man and up to 20 chances out of 1 million for a man. suffering from ischemic heart disease.

During intercourse, on average, the maximum heart rate of a man reaches 120-130 beats / min, while systolic blood pressure rises to 150-180 mm Hg. Art. These indicators take place within only 3-5 minutes with an average duration of intercourse from 5 to 15 minutes. The level of stress on the heart is usually expressed in metabolic equivalents (MET). One MET corresponds to the energy requirement expressed in oxygen consumption at rest, which is 3.5 ml of oxygen / 1 kg of body weight per minute. In most cases, during sexual activity with a usual partner, the load is 2-3 METs (with a maximum value of 5-6 METERS), depending on the intensity and posture. This corresponds to walking 1.5 km for 20 minutes or climbing 20 steps for 10 seconds. All of the above indicates that sexual activity in familiar conditions and with a familiar partner does not pose a greater danger for both a healthy man and a patient with coronary artery disease than various forms of daily physical activity.

In order to standardize the assessment of cardiac risk in men with coronary artery disease who resume sexual activity, several recommendations have been created, the most widely known of which are the Princeton Recommendations. In accordance with these recommendations, all patients are divided into 3 risk groups, depending on the number of risk factors for coronary heart disease and / or the severity of cardiovascular pathology. Most of the patients belong to the low-risk group and do not need additional cardiac examination before resuming sexual activity, which is not dangerous for them. Patients from the middle-risk group require additional cardiac examination, after which they are classified as low or high-risk. High-risk patients have severe cardiovascular disease with severe heart failure. These patients need specialized treatment, after which the question of the degree of danger for them of sexual activity is again considered.

Changes in cavernous electrical activity and hemodynamics of the penis during treatment with sildenafil

To assess the effect of sildenafil on cavernous electrical activity and penile hemodynamics, we conducted our own study. 291 patients with ED of various etiology aged 21-73 years (average 59.1 ± 14.7 years) after a survey that included a questionnaire for assessing male sexual health (International Index of Erectile Function (IIEF)), pharmacodopplerography (FDG) and electromyography (EMG) of the penis were divided into groups comparable in age, severity, presumptive etiology and pathogenesis of ED. The sildenafil group included 81 patients who took 25-100 mg of sildenafil 1 hour before intercourse for 6 months. Control examination, carried out monthly, included questionnaires by ICEF, FDG and EMG of the penis.

The indicator “erectile function” of IIEF during treatment with sildenafil increased by 61.7% (p <0.05). with fdg after treatment with sildenafil, the peak systolic velocity in the cavernous arteries and the resistance index increased by 16.1 and 34.6%, respectively (p <0.05). the end diastolic velocity significantly decreased by 27.2% (p <0.05). with emg of the penis during treatment with sildenafil, the proportion of normoreflex emg curves increased by 43.2%, and the number of areflex emg curves significantly decreased by 73.2% (p <0.05).

Thus, according to the results of FDG, sildenafil affects the parameters of both arterial and venous blood flow in the penis, which makes it indicated in the first place for vasculogenic ED. With EMG, there was an improvement in the cavernous electrical activity during treatment with sildenafil, apparently due to the improvement of the hemodynamics of the penis and oxygenation of the cavernous tissue. In addition, according to the results of the ICEF questionnaire, sildenafil gives a fast and stable rehabilitation effect.

New drugs based on sildenafil

The pharmaceutical market is represented not only by the original drug sildenafil, but also by the so-called generics, one of which is the drug Dynamico.

The preferences of patients when choosing drugs are influenced by many factors, including the effectiveness, quality of erections, persistence of improvement, the speed of onset and duration of drug action, as well as the spectrum of side effects. Efficacy and safety are the most important factors in determining patient preference. Research results show that the clinical effectiveness of Dynamo is comparable to that of the original drug. In addition, the incidence of side effects (headache, skin flushing) was even lower than that of other sildenafil drugs. This is very important for those patients who have experienced adverse events during the therapy. The drug Dynamic provides high-quality erection with a minimum of side effects and does not cause addiction or dependence.

The appearance on the market of new effective and safe drugs that can improve the quality of life of patients with ED, makes the therapeutic arsenal of the urologist-andrologist more diversified and allows an increase in the number of patients satisfied with such treatment.

Conclusion

The clinical efficacy of sildenafil has been evaluated in a large number of studies conducted in many countries around the world. Taking the drug leads to an improvement in erectile function in patients of different ages, regardless of the etiology, severity and duration of ED. The effectiveness of the drug is long-term. Sildenafil affects both arterial and venous blood flow in the penis, therefore, the drug is indicated, including for vasculogenic ED. With sildenafil treatment, there is an improvement in cavernous electrical activity, which justifies its use in neurogenic ED. According to the results of the ICEF questionnaire, sildenafil has a fast and lasting therapeutic effect. The efficacy and safety of sildenafil are rated as good. With both short-term and long-term use, sildenafil is non-addictive.