The review examines the epidemiology, etiology and pathogenesis of erectile dysfunction. The clinical effects of the most long-used drug for the treatment of erectile dysfunction, sildenafil, which is also a reference drug in comparative clinical studies of the effectiveness of phosphodiesterase type 5 inhibitors, are characterized. It is noted that taking sildenafil leads to an improvement in the condition of patients of different ages, regardless of the etiology, severity and timing of erectile dysfunction. Data on the safety of the drug sildenafil are provided. The prospects for long-term continuous use of the drug are discussed.
Introduction
Erectile dysfunction (ED) is a pressing problem in urology. This is due not only to the high prevalence of ED in the population, but also to a revision of views on the causes of ED, changes in therapeutic approaches, the study of the relationship between ED and symptoms of the lower urinary tract, the need to correct erectile dysfunction after various urological operations (radical prostatectomy, urethroplasty, transurethral endoscopic surgery) [1–3].
ED is defined as the permanent or temporary inability to achieve and maintain an erection sufficient for successful sexual intercourse. Despite the fact that ED is not life-threatening, the appearance of sexual disorders leads to rapid personal and social maladaptation of the patient. In addition, in some cases, ED may be the first symptom of serious diseases (diabetes mellitus, demyelinating diseases of the spinal cord).
According to classical population studies conducted in the 20th century, the prevalence of ED increases with age. In men over 21 years of age, the incidence of ED is 10%, and among men over 60 years of age this figure triples. In the most socially active category of men (40–70 years old), 50% suffer from ED. Moreover, the frequency of ED is approximately the same among representatives of all races and continents [4].
Description and main characteristics
Sildenafil is a drug used by men to increase potency. Contains the active ingredient of the same name and is available in the form of granules with different dosages of the main component - from 35 to 140.5 mg per 1 piece. The most well-known brand of the drug, which also contains sildenafil, is Viagra.
The product is dispensed from pharmacies only with a prescription. The shelf life is 3 years from the date of production. It must be stored under standard conditions - a dark place, temperature up to 25 degrees.
Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction
Sildenafil - the first PDE-5 inhibitor
PDE5 inhibitors are highly effective and safe oral medications for the treatment of ED and are recommended as first-line therapy [1].
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 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 history of the discovery of sildenafil was preceded by the accumulation of knowledge about the role of nitric oxide in ensuring the normal functional state of the cardiovascular system, which was initiated by RR Furchgott and JV Zawadski [2]. However, today's use of the drug as an ED therapy is an example of how a chance observation can have a huge impact on the course of scientific progress. During clinical trials of the antianginal properties of sildenafil, 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 further study of the possibility of using this substance in the treatment of ED.
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 of various forms of sexual disorders 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 patients with ED, who had not previously consulted a doctor, received hope for the restoration of sexual function, 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 1 time per day, 1 hour before intended sexual intercourse. The effect of the drug begins 40-60 minutes after administration and lasts for 3-5 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 pigmentary retinopathy [20].
The clinical effectiveness of sildenafil has been assessed in numerous studies conducted around the world. S.S. Carson et al. combined data obtained from 11 double-blind, placebo-controlled studies, including a total of almost 3 thousand patients with ED. After 12 weeks after starting to take the drug, an improvement in erection was noted by 76% of men receiving sildenafil and 22% of those receiving placebo, while the percentage of successful attempts at sexual intercourse was 66 and 26% in groups 1 and 2, respectively. The effectiveness of various doses of sildenafil was 65% for 25 mg, 74% for 50 mg, 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 that of placebo also occurred in patients with ED of varying severity and different etiologies [4].
The use of sildenafil in special categories of patients with ED
As is known, arterial hypertension (AH) 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 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 taking 2 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 terms of 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 is difficult to treat are patients with diabetes mellitus (DM) and patients who have undergone radical prostatectomy (RP).
In patients with diabetes, the effectiveness of sildenafil depends on the severity of the underlying disease and the presence of its complications. Thus, in the study by S.S. Carson et al. among patients with diabetes without complications, 8% of patients receiving placebo and 69% of those receiving sildenafil noted improved erection. In the presence of 1 complication, these figures were 12 and 43%, and in the presence of 2 complications, 10 and 43%, respectively. In all groups, the effectiveness of sildenafil was significantly higher than that of placebo [4].
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 [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, 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 [21]. 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 its success [21-23]. 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 effectiveness of the drug should be carried out after several attempts at its use [24, 37, 38].
Noteworthy is the work of A. 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 2618 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 [25]. The remaining 2.4% of patients stopped taking the drug for other reasons. Laboratory studies have not confirmed the existence of a tachyphylaxis effect 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%) [26].
It should also be noted that the frequency of side effects decreases as the drug is taken. Thus, in the study by S.S. Carson, the frequency 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 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]. An important circumstance is also that 2/3 of patients during this study increased the dose of sildenafil. Thus, with long-term use, the frequency 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 assessed. 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 [15].
Taking sildenafil leads to an improvement in the condition of patients with primary and secondary pulmonary hypertension [27, 28]. Another possible direction for future research with sildenafil is the use of this drug in the treatment of endothelial dysfunction [29-31].
Safety of sexual activity in patients with cardiovascular diseases
Sexual intercourse in most cases is accompanied by physical activity. This makes some people, 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 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 to 1.1% in a man with a confirmed diagnosis of coronary heart disease (CHD) [16]. According to these data, the absolute risk of developing cardiovascular complications for a healthy man is 1 chance in 1 million. This figure increases to 2 chances in 1 million within 2 hours after intercourse for a healthy man and to 20 chances in 1 million for a man. suffering from coronary artery disease [33].
During sexual intercourse, on average, a man’s maximum heart rate reaches 120-130 beats/min, while systolic blood pressure rises to 150-180 mm Hg. Art. [34]. 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/1 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 question of the degree of danger of sexual activity for them is again considered [16].
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 hemodynamics of the penis, we conducted our own study [17, 35, 36]. 291 patients with ED of various etiologies aged 21-73 years (average 59.1±14.7 years) after examination, which included a questionnaire to assess 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, suspected etiology and pathogenesis of ED [17]. 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
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 during treatment with sildenafil, apparently due to improved hemodynamics of the penis and oxygenation of cavernous tissue. In addition, according to the results of the IIEF survey, sildenafil provides a rapid, lasting rehabilitation effect.
New sildenafil drugs
The pharmaceutical market is represented not only by the original drug sildenafil, but also by so-called generics, one of which is the drug Dynamico.
Patient preferences when choosing drugs are influenced by many factors, including effectiveness, quality of erections, durability of improvement, speed of onset and duration of action of the drug, as well as the range of side effects [18]. Efficacy and safety are the most important factors determining patient preferences. The research results show that the clinical effectiveness of Dynamico 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 [17]. This is very important for those patients who experienced adverse events during therapy. The drug Dynamico provides high-quality erection with a minimum of side effects and does not cause addiction or dependence [17, 19].
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 a urologist-andrologist more diverse and allows an increase in the number of patients satisfied with such treatment.
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, so the drug is also indicated for vasculogenic ED. When treated with sildenafil, 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. The effectiveness and safety of sildenafil are assessed as good. With both short-term and long-term use, sildenafil does not cause dependence or addiction.
Contraindications
The use of Silenafil has a fairly wide range of contraindications:
- hypersensitivity to the active substance or auxiliary components of the drug;
- severe disturbances in liver function;
- low blood pressure (less than 90/50);
- recently suffered pathologies associated with cerebral circulatory disorders;
- recent myocardial infarction;
- phenylkenothuria;
- loss of vision in one eye;
- hereditary retinal dystrophy;
- simultaneous use with Amylnitrite, nitrates and other nitric oxide NO donors;
- simultaneous use with the drug "Ritonavir";
- children under 18 years of age.
There are other contraindications. For example, the drug is not recommended for use by men who should not be sexually active due to severe heart failure.
Hypertensive patients with blood pressure above 170/100 should take this medication with caution, as well as in the presence of:
- severe arrhythmia that threatens life;
- left ventricular obstruction;
- conditions that predispose to prialism;
- ischemic optic neuropathy;
- anatomical deviations of the penis (deformation, Peyronie's disease and others).
Causes of erectile dysfunction
Traditionally, the causes of erectile dysfunction are divided into organic and psychogenic. However, psychogenic factors, as a rule, are secondary in nature, reflecting the response of the patient’s higher nervous activity to a primary violation of sexual function. Thus, in the vast majority of cases, ED is caused by organic disorders of the blood circulation and innervation of the penis, which is confirmed by numerous fundamental studies of the mechanisms of erection and clinical experience in treating patients with ED.
Among the organic causes of erectile dysfunction are hormonal disorders associated with a primary or secondary decrease in testosterone levels due, for example, to trauma, inflammation of the testicles, or increased levels of prolactin in the body, which suppresses testosterone production. ED can also be caused by systemic damage to the vascular bed as part of atherosclerosis, diabetic macroangiopathy and neuropathy, autointoxication as part of renal and liver failure, demyelinating diseases of the central nervous system (multiple sclerosis, Alzheimer's disease), and exposure to medications (antidepressants). In addition, ED can be caused by traumatic disruption of the innervation and blood circulation of the penis as a result of operations on the pelvic organs, radiation and various injuries. A separate group of causes includes ED, which occurs as a result of the loss of the veno-occlusive mechanism in the veins of the penis, which leads to rapid loss of erection.
Based on the above facts, the appearance of erectile dysfunction in socially active men should be a reason to consult a doctor. Unsubstantiated advertising of herbal medicines and dietary supplements in the media has led to patients self-medicating for a long time. They often turn to specialists already having severe vascular and neurogenic disorders, accompanied by severe fibrosis of the corpora cavernosa, which leads to an increase in the frequency of penile arthroplasty.
Side effects
In some cases (often due to an overdose), minor side effects are possible:
- dyspepsia;
- dizziness;
- headache;
- feeling of nasal congestion;
- flushes of blood;
- temporary vision problems;
- noise in ears;
- hypersensitivity reactions.
In rare cases, the following were observed:
- temporary deafness;
- cardiopalmus;
- nosebleeds;
- skin rash;
- nausea;
- myalgia;
- chest pain;
- fast fatiguability;
- an erection that lasts too long.
"Sildenafil": instructions for use
The drug is taken orally and washed down with a small volume of water. The standard single dosage is 50 mg one hour before sexual intercourse. If the effect is insufficient, increase the dosage by 2 times (subject to normal tolerance and absence of contraindications). The maximum amount per day is 100 mg, frequency of use is 1 time per day.
For older people, the same dosages are established. In this case, the daily intake rate can be adjusted in the presence of certain diseases:
- Renal dysfunction – 25 mg.
- Liver dysfunction – 25 mg.
- Simultaneous use with other drugs such as Ketoconazole, Cimetidine (except Ritonavir), Erithoromycin - up to 25 mg.
These restrictions are not “hard” ones. If the effect is insufficient, the daily dosage can be gradually increased to 50 mg, then to 100 mg.
Description of the drug SILDENAFILUM
After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages 40% (25-63%). After a single oral dose of 100 mg, Cmax is 18 ng/ml and is achieved when taken on an empty stomach for 30-120 minutes. When taking sildenafil in combination with fatty foods, the rate of absorption is reduced; Tmax increases by 60 minutes, and Cmax decreases by an average of 29%. The Vd of sildenafil at steady state is on average 105 liters. Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of the total concentration of sildenafil. Less than 0.0002% of the dose (mean 188 ng) was detected in semen 90 minutes after sildenafil administration.
Sildenafil is metabolized mainly by the liver microsomal isoenzymes CYP3A4 (the main route) and CYP2C9.
The main circulating metabolite, which is formed as a result of N-desmethylation of sildenafil, undergoes further metabolism. In terms of selectivity of action on PDE, the metabolite is comparable to sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil itself. The concentration of the metabolite in plasma is approximately 40% of that of sildenafil. The N-desmethyl metabolite undergoes further metabolism; its terminal T1/2 is about 4 hours.
The total clearance of sildenafil from the body is 41 l/h, and T1/2 in the terminal phase is 3-5 hours. After oral administration, sildenafil is excreted in the form of metabolites mainly in feces (approximately 80% of the dose) and to a lesser extent in urine ( approximately 13% of the dose).
In elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of the free active substance in plasma is approximately 40% higher than its concentration in young (18-45 years) patients.
In case of mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal failure, the pharmacokinetic parameters of sildenafil after a single oral dose (50 mg) do not change. In severe renal failure (creatinine clearance ≤30 ml/min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared to those with normal renal function in patients of the same age group.
In patients with liver cirrhosis (Child-Pugh class A and B), the clearance of sildenafil is reduced, resulting in an increase in AUC (84%) and Cmax (47%) compared with those with normal liver function in patients of the same age group .
special instructions
One-time use is allowed without consulting a doctor, except in cases associated with severe pathologies of the cardiovascular system, kidneys or liver. For long-term use, preliminary consultation with a specialist is recommended.
In extremely rare cases, cardiac instability may occur. In case of overdose, myocardial infarction, including death, cannot be ruled out. Complications can develop during, after, or even without sexual intercourse.
Sildenafil leads to dilation of blood vessels, which leads to a slight, reversible decrease in blood pressure. Therefore, on the eve of the appointment, the doctor should assess the possible risks associated with a decrease in blood pressure.
Mechanisms of occurrence and maintenance of erection
Let us briefly describe the basic mechanisms of the occurrence and maintenance of an erection. Somatic innervation of the penis is carried out from the sacral erection center, which is located at the level of S2–S4. In the latter, impulses come from the cerebral cortex as a result of audiovisual and tactile stimulation. At the endings of the efferent fibers, nitric oxide is released, which is the main mediator of relaxation of the vascular bed of the corpora cavernosa of the penis. The production of nitric oxide in the endothelium of the vessels of the cavernous bodies leads to the expansion of the latter and the occurrence of an erection. Nitric oxide is synthesized from the amino acid L-arginine after exposure to the enzyme NO synthetase. By penetrating the cell membrane and activating the system for the production of cyclic guanosine monophosphate (cGMP), nitric oxide leads to relaxation of the smooth muscle cells of the vessels of the cavernous bodies of the penis both during systole and diastole. To maintain an erection during the time required for sexual intercourse, the inclusion of mechanisms that prevent the outflow of venous blood from the penis is required. This effect is achieved by compression of the venous plexus between the tunica albuginea and the cavernous sinuses. Additional compression is carried out using voluntary contraction of the ischiocavernosus muscles. The enzyme cGMP phosphodiesterase type 5 blocks the intracellular cGMP production system, thus causing detumescence. The sympathetic innervation of the penis is also responsible for the cessation of erection; the sympathetic center is located at the Th4–L2 level, and the effect occurs through the release of norepinephrine and interaction with alpha-adrenergic receptors of cavernous smooth muscle cells. Subsequently, smooth muscle cells contract, which leads to loss of erection.
Drug treatment of erectile dysfunction
Phosphodiesterase type 5 inhibitors affect the relaxation of smooth muscle cells through competitive interaction with phosphodiesterase type 5 and promote the accumulation of cGMP inside cavernous smooth muscle cells, as well as in the cells of the smooth muscle layer of the penile arteries. Today, there are five drugs in the class of phosphodiesterase type 5 inhibitors on the market: sildenafil, vardenafil, tadalafil, udenafil and afanafil. All of them are characterized by a similar mechanism of action and approximately the same safety profile. Currently, according to the recommendations of the European and American Urological Associations, a particular drug is prescribed depending on the patient’s preferences or personal experience, as well as in accordance with the recommendations of the urologist. Accordingly, in order to instruct the patient and determine the optimal dosage regimen for the drug if the patient has concomitant diseases, the physician must know the pharmacokinetic and pharmacodynamic characteristics of the drugs.
Clinical efficacy of sildenafil
Sildenafil is the most studied drug from the entire group of phosphodiesterase type 5 inhibitors. In addition, it is a reference drug for comparative clinical studies of the effectiveness of other phosphodiesterase type 5 inhibitors.
Sildenafil began to be used in the late 1990s, so the experience of its use exceeds 15 years. The history of the discovery of sildenafil is widely known: during clinical trials of the new antianginal drug, scientists noted a side effect, which was the improvement of erectile function. Moreover, unlike other drugs for the treatment of ED on the market at that time, no cases of priapism were observed while taking it.
The emergence of sildenafil prompted a number of clinical studies in this area. The term “impotence” has been replaced by the concept of “erectile dysfunction”, which implies the potential possibility of correcting existing disorders in the sexual sphere. Clinical studies of sildenafil have led to the development of new diaries and questionnaires to assess the state of male sexual function. Analysis of demographic indicators of participants in large-scale clinical trials made it possible to identify risk factors for ED, which in turn contributed to understanding the mechanisms of its development. Evidence has begun to accumulate that most cases of ED have an underlying somatic nature, and psychological problems are often secondary to primary vascular or nerve damage. Patients with erectile dysfunction who had not previously consulted a doctor received hope for improved sexual function, and to date, millions of men around the world have returned to their sexual lives thanks to taking this drug.
The clinical effectiveness of sildenafil citrate has been studied in numerous studies. One of the largest meta-analyses combined data obtained from 11 double-blind, placebo-controlled studies, which included a total of more than 2,500 patients with erectile dysfunction [4]. In the main group, an improvement in erection was noted in 76% of patients versus 22% in the placebo group, which led to a significant difference in the frequency of successful attempts at sexual intercourse - 66 and 26%, respectively. The effectiveness of various dosages of the drug 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. In the category of patients under 65 years of age, the effectiveness of the drug was 77.6% versus 69.2% in the older age group. According to research, the drug is effective compared to placebo in patients with erectile dysfunction, regardless of the cause of its development and severity.
Despite the high effectiveness of therapy with phosphodiesterase type 5 inhibitors, there remains a certain cohort of patients in whom taking this drug does not lead to an improvement in erection. Possible causes include improper medication administration [5]. Patients, especially at the beginning of treatment, should be advised to take sildenafil on an empty stomach at least 30 minutes before the planned start of sexual intercourse. Patients should be informed 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 begin with a maximum therapeutic dosage of 100 mg, which will allow for maximum results at the beginning of treatment and instill confidence in the success of therapy. In addition, studies have shown that in some patients the maximum effect of sildenafil is achieved by the sixth to eighth dose, and therefore in many patients the final assessment of the effectiveness of the drug should be made after several attempts to use it.
Sildenafil in the treatment of erectile dysfunction after prostatectomy
Effective selection of therapy for ED after prostatectomy is currently one of the urgent problems of urology, which is due to the increase in the number of operations, the development of nerve-saving surgical techniques, and the introduction of robotics. Numerous studies have examined risk factors for the onset of ED after surgery: type of surgery (non-nerve-sparing, mono- or bilateral nerve-sparing techniques), patient age, preservation of erection before surgery, socio-economic conditions (level of education, patient income), tumor stage, prostate size , urologist experience.
R. Raina et al. showed that sildenafil therapy is effective in 71.7% of patients after bilateral nerve-sparing surgery, in 50% after unilateral nerve-sparing prostatectomy and in 15% of patients after non-nerve-sparing surgery. It has been shown that one of the features of ED after radical prostatectomy is the possibility of progressive improvement of erection several years after surgery, therefore, long-term follow-up is necessary to make a final judgment about the effectiveness of therapy [6].
EK Hong et al. observed 316 patients with ED after radical prostatectomy, which in 95% of cases was bilateral nerve-sparing. The effectiveness of sildenafil was 26% during the first 6 months, 36% from 6 to 12 months, 50% from 12 to 18 months and 60% from 18 to 24 months after surgery [7].
Currently, most authors believe that to prevent the development of ED after radical prostatectomy, long-term use of phosphodiesterase type 5 inhibitors, and in particular sildenafil, in low therapeutic doses is necessary. This therapy is justified by data on the improvement of blood flow in the corpora cavernosa against the background of long-term continuous use of drugs, which serves as prevention of the development of a local scar-sclerotic process. H. Padma-Nathan et al. studied the effectiveness of sildenafil in the prevention of ED after radical prostatectomy [8]. As a result of the study, patients who underwent bilateral nerve-sparing surgery and did not suffer from ED before surgery, starting from the second month of the postoperative period, received sildenafil in doses of 100 and 50 mg or placebo at bedtime for 36 weeks. Eight weeks after stopping treatment, 27% of men receiving sildenafil reported the ability to lead a normal sexual life, compared with only 4% of those receiving placebo [8].
Sildenafil therapy can be an effective method of preventing ED in patients after radical prostatectomy as a result of improving the blood supply to the cavernous tissue, preventing the development of fibrotic changes in it. Long-term use of the drug in small doses for the rehabilitation of patients after transurethral and oncoproctological operations is based on the same principles [8].
