Relevance
Patients with residual pulmonary hypertension who have had successful heart valve surgery should not receive sildenafil.
This is evidenced by the results of the first randomized trial presented at the European Congress of Cardiology 2021. It is well known that the vasodilator sildenafil is widely used in the treatment of erectile dysfunction, but the drug is also effective in patients with pulmonary arterial hypertension.
What are the dangers of potency enhancing drugs containing sildenafil?
It's no secret that erection problems are quite widespread among the stronger sex. Naturally, among colleagues, relatives, friends and, especially, girlfriends, you want to preserve your image of a confident, successful and strong man. Strong in all respects, including intimately. Therefore, when faced with a similar situation, a man, as a rule, is in no hurry to see a doctor, hoping to solve the problem on his own. And thereby not only aggravates erectile dysfunction, but often adds serious health problems to them. We talked about this with Oleg Nikolaevich Malyshev, an andrologist of the highest category at the Multidisciplinary Medical Center, Moscow:
— Drug therapy plays the most important role in the treatment of erectile dysfunction. For many years, sildenafil has been most often used as the main medication in this treatment. This substance provides an erection subject to sexual stimulation. Sildenafil was initially tested in clinical trials as a drug to lower blood pressure in hypertension. However, during research work with it, an interesting side effect was discovered: the drug not only reduced blood pressure, but also significantly increased blood flow in the groin area in men, thus provoking the occurrence of an erection. Due to these properties of sildenafil, it was decided to create a drug based on it for the treatment of erectile dysfunction. However, when using sildenafil in a standard dose sufficient to lower blood pressure, an erection occurred rather slowly and did not last long. Of course, with the practical use of such a drug, its value would be small: no one would wait long enough for an erection to appear, which, moreover, would soon disappear.
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The way out of the situation was to increase the dosage of sildenafil in the drug, due to which an erection began to occur quite quickly and lasted throughout the entire sexual intercourse. However, there is also a certain danger in using sildenafil: as we remember, one of the effects of taking it is hypotensive. When the dosage of the active substance is increased, a sharp drop in blood pressure occurs; in the presence of chronic cardiovascular diseases, the likelihood of fatal complications increases significantly: vascular collapse, heart attack or stroke.
In order to avoid negative side effects, pharmacists are constantly working to create a drug with a gradual release of sildenafil, which would ensure the rapid occurrence and long-term maintenance of an erection without the danger of a sharp drop in blood pressure. And it is Russian pharmacists who have significantly succeeded in this. Thus, the drug, created by specialists of the domestic enterprise Ozon Pharma, contains hypromellose (microcrystalline cellulose) as a matrix. It, like a sponge, holds sildenafil, gradually dissolves in the stomach and, accordingly, gradually releases the active substance.
The unique structure of the tablet ensures a prolonged effect of the drug - it works almost twice as long as analogues at a minimal cost of administration compared to them. In this case, the active substance is released evenly throughout the entire duration of the drug’s action, its amount in the blood as a result remains almost constant, without peaks, which avoids sharp fluctuations in blood pressure.”
Do not be afraid of the need to take medications for erectile dysfunction. Proper use of modern, high-quality medicines prescribed by a doctor as part of complex therapy for potency disorders will help restore male strength and, along with it, self-confidence
Methods
In order to evaluate the effectiveness of sildenafil in patients with residual pulmonary hypertension after heart valve surgery, the SIOVAC study was performed. This was a multicenter, double-blind, placebo-controlled, parallel-group study.
Patients underwent cardiac catheterization to confirm pulmonary hypertension.
200 patients from 17 Spanish clinics were randomized 1:1 to sildenafil 40 mg three times daily (n=104) or placebo (n=96) for 6 months.
The patients underwent clinical, laboratory and instrumental examinations after 3 and 6 months of observation. The primary endpoint was a composite of death from all causes, hospitalization for heart failure, worsening exercise capacity, and self-reported worsening of well-being after initiation of therapy.
results
- At 6 months of follow-up, 33 patients (33%) in the sildenafil group, compared with 14 patients (15%) in the control group, showed worsening (odds ratio for improvement, 0.39; 95% CI, 0.22-0 .67; p<0.001).
- Noteworthy was the 2-fold increase in the risk of hospitalization for decompensated heart failure in patients receiving sildenafil.
- 3 patients in the sildenafil group died, while 2 deaths occurred in the control group (p=0.63).
- Serious clinical events—death and rehospitalization for heart failure—occurred earlier and more frequently during sildenafil therapy (hazard ratio, 2.0; 95% CI, 1.0-4.0; p=0.044).
Principal investigator Dr Javier Bermejo (Madrid, Spain) noted that long-term use of sildenafil in patients with residual pulmonary hypertension and valvular heart disease should be avoided. At the same time, it is necessary to conduct studies that will propose strategies for the prevention and treatment of this complication in patients with valvular pathology.
Source:
ESC congress news. 29 August 2021.
New aspects of the use of sildenafil in the treatment of erectile dysfunction
S.I. GAMIDOV
1, 2, Doctor of Medical Sciences, Professor,
R.I.
OVCHINNIKOV 1, Ph.D.,
A.Yu.
POPOVA 1, 2, Ph.D.
1 — Department of Andrology and Urology of the Federal State Budgetary Institution “Scientific Center of Obstetrics, Gynecology and Perinatology named after.
Academician V.I. Kulakov" Ministry of Health of Russia, Moscow 2 -
Department of Obstetrics, Gynecology, Perinatology and Reproductology of the First Moscow State Medical University named after.
THEM. Sechenov Ministry of Health of Russia Currently, there are a large number of effective methods of drug treatment for erectile dysfunction (ED).
The choice of treatment method is determined by its invasiveness. In case of insufficient effectiveness, they move from a less invasive technique to a more invasive one. Thus, most clinicians begin treatment with oral phosphodiesterase type 5 (PDE5) inhibitors, followed by other oral medications, intracavernosal injections, or vacuum devices if they are ineffective. Combination treatment is also possible. If such methods are ineffective, surgical interventions may be performed. Sildenafil citrate 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 agents [1]. The number of patients taking these drugs continues to increase in parallel with the increasing prevalence of ED.
In 1998, the drug sildenafil citrate was approved for clinical use and became widely known. This moment not only became the 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 spheres, as well as in public perception of sexual pathology.
Sildenafil became the first effective and safe oral drug for the treatment of ED. The story of the discovery of sildenafil is an example of how a chance observation can have a huge impact on the course of scientific progress. During clinical trials of a new antianginal drug, researchers noted that although taking the drug is not accompanied by a significant clinical improvement in angina, in many patients it leads to the development of a kind of “side effect”, which consists in improving erectile function. This observation led to the study of the possibility of using this substance in the treatment of ED.
However, one should not think that the discovery of sildenafil was pure luck. It was preceded by the accumulation of knowledge about the role of nitric oxide NO in ensuring the normal functional state of the cardiovascular system, which was initiated by Furchgott and Zawadski [2].
The discovery of sildenafil, a selective PDE5 inhibitor, led to numerous fundamental studies showing that this type of enzyme dominates in cavernous tissue, which ensures the selectivity of the drug. It should be noted that these studies also made it possible to clarify the mechanisms of action of other drugs that have been used in clinical practice for a long time, in particular papaverine and prostaglandin E1 [3], and significantly expand knowledge about the mechanism of erection and its disorders leading to ED.
The emergence of sildenafil also had a great impact on clinical research in the field of sexual medicine. In recent years, terminology has been clarified and new definitions for various forms of sexual dysfunction have been developed. Clinical trials of sildenafil have stimulated the creation of new diaries and questionnaires to assess the state of male sexual function. Analysis of demographic indicators of participants in large-scale clinical trials has revealed risk factors for ED, which, in turn, has contributed to the understanding of its pathogenesis.
The appearance of sildenafil had a huge public outcry. A large number of ED patients who had not previously consulted a doctor received hope for a cure, and to date, millions of men around the world have returned to normal sexual life thanks to taking this drug.
The dose of the drug is selected by titration, starting from 50 mg, followed by a dose change (either decreasing to 25 mg or increasing to 100 mg) depending on the effect and tolerability. Sildenafil is taken once a day, 1 hour before intended sexual intercourse. The effect of the drug begins 40-60 minutes after administration and lasts for 3-5 hours, and according to some data, up to 12 hours [3]. It is important to note that taking the drug by itself does not lead to an erection and sexual stimulation is necessary for its effect to begin.
Sildenafil is contraindicated in patients taking nitrates, patients with hypotension, severe hepatic impairment (the drug is metabolized by hepatic cytochrome P450 3A4) and patients with pigmentary retinopathy.
The clinical effectiveness of sildenafil has been assessed in numerous studies conducted around the world. Carson et al. pooled data from 11 double-blind, placebo-controlled studies that included a total of nearly 3,000 patients with ED. After 12 weeks after starting to take the drug, 76% of men receiving sildenafil and 22% receiving placebo noted an improvement in erection, while the percentage of successful attempts at sexual intercourse was 66 and 26% in the first and second groups, respectively. The effectiveness of different doses of sildenafil was 65% for 25 mg, 74% for 50 mg and 82% for 100 mg. The high effectiveness of sildenafil was noted in different age groups. Thus, among patients younger and older than 65 years, the effectiveness of sildenafil was 77.6% and 69.2%, respectively. A significantly higher effectiveness of sildenafil, compared to placebo, also occurred in patients with ED of varying severity and different etiologies [4].
Pharmacotherapy of ED in special categories of patients
As is known, arterial hypertension is one of the risk factors for ED. Although sildenafil has some antihypertensive effects, the drug is safe in patients with hypertension, both those receiving and not receiving antihypertensive drugs [5, 6]. The effectiveness of sildenafil in patients with ED suffering from arterial hypertension is high. Among patients with arterial hypertension of various origins, taking placebo and sildenafil was accompanied by an improvement in erection in 18 and 70% of patients, respectively. Among men taking two or more antihypertensive drugs, these figures were 17.6 and 71% [6].
Another well-known risk factor for ED is smoking. The effectiveness of sildenafil among smokers was not inferior to that among non-smokers (80 and 74%, respectively) [4].
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 aggravates depressive symptoms. Treatment with sildenafil was not only highly effective in patients with depression in improving erectile function, but was also accompanied by a decrease in the severity of depressive symptoms [7].
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 corresponds to data obtained in the general population of patients with ED [8].
Special groups of patients with ED that are difficult to treat are patients with diabetes mellitus (DM) and those who have undergone radical prostatectomy (RP).
In patients with diabetes, the effectiveness of sildenafil depends on the severity of diabetes and the presence of its complications. Thus, in a study by Carson et al., among patients with diabetes without complications, an improvement in erection was noted by 8% of patients receiving placebo and 69% of those receiving sildenafil. In the presence of one complication, these figures were 12 and 43%, and in the presence of two complications, 10 and 43%, respectively. In all groups, the effectiveness of sildenafil was significantly higher than placebo [4].
The effectiveness of ED treatment after RP is determined by a number of factors. According to 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 [9].
In addition, a feature of the course of ED in such patients is the possibility of progressive improvement of erection for up to 4 years after surgery, and therefore the ineffectiveness of a particular treatment method can be finally judged only several years after surgery. This is confirmed by data from a survey of 316 patients with ED after RP, which in 95% of cases was of 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. and 60% from 18 to 24 months. after surgery [10].
Analysis of the effectiveness and tolerability of sildenafil
Despite the high effectiveness of sildenafil, there remains a certain number of patients in whom taking this drug does not lead to an improvement in erection. In many cases, this is due to improper medication administration [11]. Patients, especially at the beginning of treatment, should be advised to take sildenafil on an empty stomach at least 30 minutes before the start of sexual activity. It is also important to explain to patients that the effect of the drug develops only against the background of adequate sexual arousal and largely depends on it. In many cases, treatment should be started with 100 mg, which will allow for maximum response early in treatment and give patients confidence in the success of treatment. In addition, studies have shown that in some patients the maximum effect of sildenafil is achieved by the 6th-8th dose, and therefore in many patients the final assessment of the effectiveness of the drug should be made after several attempts to use it.
Noteworthy is the work of Eisenhardt et al., who found that the clinical effectiveness of sildenafil depends on genetic factors. When analyzing the relationship between the GNB3 C825T gene polymorphism and ACE I/D, it was found that in the group of carriers of the GNB3 825C allele, sildenafil was effective in only 50% of men, while among those with the TT genotype this figure exceeded 90%. Similar results were obtained regarding 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% [12].
The long-term effectiveness of sildenafil was also studied by Montorsi et al., who surveyed 2,618 patients taking the drug for 3 years. Overall, 96% of these patients were satisfied with the treatment and only 1.6% discontinued it due to low effectiveness. Laboratory studies also did not confirm the existence of the effect of tachyphylaxis when taking sildenafil [13].
An important characteristic of any pharmacological drug is its side effects. The most common side effects when taking sildenafil include headache (7%), facial flushing (7%), dizziness (2%), dyspepsia (1.8%), nasal congestion (1.4%) and visual disturbances. , usually in the form of blue coloring of objects (1.2%). In most studies, the incidence of side effects and treatment failures as a result of their development was comparable in the groups of patients receiving sildenafil and placebo. It should also be noted that the frequency of side effects decreases as the drug is taken. Thus, in the Carson study, the frequency of all side effects, except for visual impairment and dyspeptic disorders, decreased while taking the drug. Headaches at the beginning of the study were noted by 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% [14]. It is also important that two thirds of patients increased their dose of sildenafil during this study. Thus, with long-term use, the frequency of most side effects of sildenafil does not exceed that of placebo.
There is increasing interest in the possibility of using sildenafil for various diseases in addition to ED. In a study by Sairam et al. The effect of sildenafil on the severity of urinary disorders in patients with ED was assessed. After 1 and 3 months. after the start of treatment, a significant decrease in the severity of lower urinary tract symptoms was noted, which was accompanied by an improvement in erectile function [15].
Taking sildenafil leads to an improvement in the condition of patients with primary and secondary pulmonary hypertension. Another possible direction for future research with sildenafil is the use of this drug in the treatment of endothelial dysfunction.
Safety of sexual activity in patients with cardiovascular diseases
Sexual intercourse in most cases is accompanied by physical activity. This makes some people, and primarily men suffering from cardiovascular diseases and their partners, worry about the possibility of developing various complications due to sexual activity, which can lead to limitation or complete abandonment of it. These fears are reinforced by stories of famous people whose deaths allegedly occurred during sexual intercourse. At the same time, research data show that the risk of cardiovascular complications in patients suffering from cardiac pathology during and immediately after sexual activity, although it exists, is relatively low. For example, the risk of developing a myocardial infarction in a healthy 50-year-old man over the course of a year is 1%. As a result of sexual activity, this risk increases to 1.01% in a healthy man and to 1.1% in a man with a confirmed diagnosis of coronary artery disease [16]. The absolute risk of developing cardiovascular complications for a healthy man is one in a million. This rate increases to two chances in a million within two hours of intercourse for a healthy man and to 20 chances in a million for a man with CHD.
During sexual intercourse, on average, a man’s maximum heart rate reaches 120–130 beats/min, while systolic blood pressure rises to 150–180 mmHg. Art. These indicators take place within only 3-5 minutes with an average duration of sexual intercourse from 5 to 15 minutes. The level of stress on the heart is usually expressed in metabolic equivalents (METs). One MET corresponds to an energy requirement expressed in resting oxygen consumption, which is 3.5 ml oxygen/kg 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 METs, depending on the intensity and position. This corresponds to walking 1.5 km in 20 minutes or climbing 20 steps in 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 everyday 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 [16]. In accordance with these recommendations, all patients are divided into 3 risk groups depending on the number of risk factors for coronary artery disease they have and/or the severity of cardiovascular pathology. Most patients are at low risk and do not require additional cardiac examination before resuming sexual activity, which does not pose a risk to them. Patients from the average risk group require additional cardiac examination, after which they are classified as low or high risk. Patients at high risk have severe cardiovascular pathology, accompanied by severe heart failure. These patients require specialized treatment, after which the issue of the danger of sexual activity for them is again considered [16].
After the introduction of the first PDE5 inhibitor, sildenafil, into the clinic, reports began to appear of the development of serious cardiovascular complications, including myocardial infarction and sudden coronary death in people taking this drug. However, subsequent numerous studies have shown that the use of sildenafil is not accompanied by clinically significant changes in hemodynamics and cardiac activity at rest and during exercise, both in healthy individuals and in patients with coronary artery disease, as well as in patients receiving antihypertensive drugs. It is important to note that the assessment of hemodynamics and cardiac activity was carried out under loads that occur during sexual intercourse. These data were confirmed by long-term clinical observation.
Changes in cavernous electrical activity and hemodynamics of the penis during treatment
To assess the effect of sildenafil on cavernous electrical activity and hemodynamics of the penis, we conducted our own study. 291 patients with ED of various etiologies aged 21-73 years (average 59.1 ± 14.7 years) after examination, which included the International Index of Erectile Function (IIEF) questionnaire, pharmacodopplerography (FDG) and electromyography (EMG) of the penis , were divided into groups comparable in age, severity, suspected etiology and pathogenesis of ED. The sildenafil group included 81 patients who took 25-100 mg of sildenafil 1 hour before sexual intercourse for 6 months. The control examination, carried out monthly, included a survey of IIEF, FDG and EMG of the penis.
The IIEF “erectile function” indicator during treatment with sildenafil increased by 61.7% (p < 0.05). In 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). End-diastolic velocity significantly decreased by 27.2% (p < 0.05). In penile EMG, 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) [17].
Thus, according to the results of FDG, sildenafil affects both arterial and venous blood flow in the penis, which makes it primarily indicated for vasculogenic ED. EMG showed an improvement in cavernous electrical activity with sildenafil treatment, apparently due to improved penile hemodynamics and cavernous tissue oxygenation. In addition, according to the results of the IIEF questionnaire, sildenafil provides a rapid and lasting rehabilitation effect.
Conclusion
The clinical effectiveness of sildenafil has been assessed 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, which makes it primarily indicated for vasculogenic ED. With treatment, an improvement in cavernous electrical activity is observed, which justifies its use in neurogenic ED. According to the results of the IIEF survey, sildenafil provides a rapid and lasting therapeutic effect, its effectiveness and safety are assessed as good. Both with short-term use and long-term use, sildenafil does not cause dependence or addiction. The appearance on the market of a new drug, sildenafil Olmax Strong, produced in accordance with European quality standards and at the same time affordable, makes the therapeutic arsenal of a urologist-andrologist more diverse and improves the quality of life of a larger number of patients with ED.
Literature
1. Wespes E, Amar E, Hatzichristou D et al. EAU Guidelines on Erectile Dysfunction: An Update. Eur Urol. 2006; 49: 806-815. 2. Furchgott RF, Zawadski JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288:373–376. 3. Krane RJ. Changes in ED therapy in the Viagra era. World J Urol 2001; 19:23-24. 4. Carson CC, Burnett AL, Levine LA, Nehra A. The efficacy of Sildenafil citrate (Viagra) in patients with erectile dysfunction. Urology 2002; 60: 12 27. 5. Vandi Y, Klein L, Nassar S et al. Effects of Sildenafil citrate on blood pressure in normotensive and hypertensive men. Urology 2002; 59: 747 752. 6. Kloner RA, Brown M, Prisant LM et al. Effects of Sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Sildenafil Study Group. Am 1 Hypertens 2001; 14: 70 73. 7. Numberg HG, Seidman SN, Gelenberg AJ et al. Depression, antidepressant therapies, and erectile dysfunction: clinical trials of Sildenafil citrate (Viagra) in treated and untreated patients with depression. Urology 2002; 60: 58 66. 8. Fowler CJ, Miller JR, Sharief MK et al. A double blind, randomized study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis. J Neurol Neurosurg Psychiatry 2005; 76: 700-705. 9. Raina R, Laken MM, Agarwal A et al. Long term effect of Sildenafil citrate on erectile dysfunction after radical prostatectomy: a 3 year follow up. Urology 2003; 62:110 115. 10. Begg CB, Riedel ER, Bach PB et al. Variations in morbidity after radical prostatectomy. N Engl J Med 2002; 346: 1138 1144. 11. McCullough AR, Barada JH, Fawzy A et al. Achieving treatment optimization with Sildenafil citrate in patients with erectile function. Urology 2002; 60: 28 37. 12. Eisenhardt A, Siffert W. Genetic risk factors for erectile dysfunction and genetic determinants of drug response - on the way to improve drug safety? Hertz 2003; 28: 304-313. 13. Steers WD. Tachyphylaxis and phosphodiesterase type 5 inhibitors. J Urol 2002; 168: 207-209. 14. Carson CC. Sildenafil citrate treatment for erectile dysfunction: rate of adverse events decreases with time. J Urol 2002; 167 (suppl): 179-183. 15. Sariam K, Kulinsbaya E, McNicholas TA et al. Sildenafil influences lower urinary tract symptoms. BIU Int 2002; 90: 836-839. 16. Nehra A, Jackson G, Miner M et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc. 2012; 87(8): 766-78. 17. Gamidov S.I., Ovchinnikov R.I., Popova A.Yu. Sildenafil citrate in the treatment of men with erectile dysfunction. Urology 2014; 6: 99-103. 18. Mulhall JP. Understanding erectile dysfunction medication preference studies. Curr Opin Urol 2004; 14: 367-373. 19. Tevlin K.B., Brook Y.F. Issues of choosing a PDE-5 inhibitor: effectiveness and safety. Experimental and clinical urology. 2013; 2:46–50.
Source:
Medical Council, No. 11, 2015
