Sildenafil and Erectile dysfunction (ED). ED is an urgent problem of urology. This is due not only to its high prevalence in the population, but also to a revision of views on the causes of this problem, 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 operations).
Sildenafil and the causes of erectile dysfunction
Traditionally, the causes of erectile dysfunction are divided into organic and psychogenic. However, psychogenic factors, as a rule, are of a secondary nature, reflecting the response of the patient’s higher nervous activity to the primary violation of sexual function. Thus, in the vast majority of cases, ED is caused by organic disorders of blood circulation and innervation of the penis, which is confirmed by numerous fundamental studies of the mechanisms of erection and clinical experience in the treatment of patients with ED.
Among the organic causes of erectile dysfunction, there are hormonal disorders associated with a primary or secondary decrease in testosterone levels due, for example, to a trauma, inflammation of the testicles or an increased content of prolactin in the body, which suppresses the production of testosterone. ED can also be caused by systemic vascular damage in the framework of atherosclerosis, diabetic macroangiopathy and neuropathy, auto-intoxication in the framework of renal and hepatic insufficiency, demyelinating diseases of the central nervous system (multiple sclerosis, Alzheimer’s disease), exposure to medications (antidepressants). In addition, ED can be caused by a traumatic violation 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 is ED, which occurs as a result of the loss of the veno-occlusive mechanism in the veins of the penis, which leads to a rapid loss of erection.
Based on the above facts, the appearance of erection disorders in socially active men should be a reason to consult a doctor. Unfounded advertising of herbal medicines and dietary supplements in the media has led to the fact that patients are self-medicating for a long time. Often, they turn to specialists who already have pronounced vascular and neurogenic disorders, accompanied by severe fibrosis of the cavernous bodies, which leads to an increase in the frequency of penile endoprosthetics.
Mechanisms of the occurrence and maintenance of an erection
We will briefly describe the main mechanisms of the emergence and maintenance of an erection. Somatic innervation of the penis is carried out from the sacral center of erection, which is located at the S2–S4 level. In the latter, the impulses come from the cerebral cortex as a result of audiovisual and tactile stimulation. At the ends of the efferent fibers, nitric oxide is released, which is the main mediator of relaxation of the vascular bed of the cavernous bodies 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 appearance of an erection. Nitric oxide is synthesized from the amino acid L-arginine after exposure to the enzyme NO-synthetase. Penetrating through the cell membrane and activating the cyclic guanosine monophosphate (cGMP) production system, nitric oxide leads to relaxation of 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, it is necessary to include mechanisms that prevent the outflow of venous blood from the penis. This effect is achieved by compressing the venous plexus between the protein membrane and the cavernous sinuses. Additional compression is performed by arbitrary contraction of the sciatic-cavernous muscles. The enzyme cGMP-phosphodiesterase type 5 blocks the system of intracellular cGMP production, thus causing detumescence.
The sympathetic innervation of the penis is also responsible for the termination of erection, the sympathetic center is located at the level of Th4–L2, and the effect occurs through the release of norepinephrine and interaction with alpha-adrenergic receptors of cavernous smooth muscle cells. In the future, there is a reduction of smooth muscle cells, which leads to the loss of an erection.
Medical treatment of erectile dysfunction
Phosphodiesterase inhibitors of type 5 affect the relaxation of smooth muscle cells due to competitive interaction with phosphodiesterase of type 5 and contribute to the accumulation of cGMP inside smooth muscle cavernous cells, as well as in the cells of the smooth muscle layer of the arteries of the penis. To date, there are five drugs of the phosphodiesterase 5 inhibitor class on the market: sildenafil (viagra), vardenafil, tadalafil, udenafil and afanafil. All of them are characterized by a similar mechanism of action and approximately the same security profile. Currently, according to the recommendations of the European and American Associations of Urologists, a particular drug is prescribed depending on the patient’s preferences or personal experience, as well as in accordance with the recommendations of a urologist. Accordingly, in order to instruct the patient and determine the optimal dosage regimen of the drug in the presence of concomitant diseases in the patient, the doctor 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 conducting 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 a new antianginal drug, scientists noted a side effect that consisted in improving erectile function. Moreover, unlike other drugs available on the market at that time for the treatment of ED, there were no cases of priapism against the background of its reception.
The appearance of sildenafil was the impetus for 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 for assessing the state of men’s sexual function. The analysis of demographic indicators of participants in large-scale clinical trials revealed risk factors for ED, which in turn contributed to the understanding of the mechanisms of its development. Evidence began to accumulate that most cases of ED are based on a somatic nature, and psychological problems are often secondary to the primary lesion of blood vessels or nerves. Patients with erectile dysfunction who had not previously consulted doctors received hope for improving sexual function, and by now millions of men around the world have returned to sexual life thanks to taking this drug.
The clinical efficacy of sildenafil citrate has been studied in numerous studies. One of the largest meta-analyses combined data obtained in 11 double-blind placebo-controlled studies, which included a total of more than 2500 patients with erectile dysfunction. In the main group, an improvement in erection was noted in 76% of patients compared to 22% in the placebo group, which led to a significant discrepancy in the frequency of successful attempts of sexual intercourse – 66 and 26%, respectively. The effectiveness of different dosages of the drug was 65% for 25 mg, 74% for 50 mg and 82% for 100 mg. The high efficacy of sildenafil was noted in different age groups. In the category of patients younger than 65 years, the effectiveness of the drug was 77.6% compared to 69.2% in the older age group. According to studies, 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 inhibitors of type 5, there is a certain cohort of patients in whom taking this drug does not lead to an improvement in erection. Among the possible reasons, incorrect medication intake is noted. 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 be started with a maximum therapeutic dosage of 100mg, which will allow you to get the maximum result 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 or eighth intake, and therefore in many patients the final assessment of the effectiveness of the drug should be made after several attempts to use it.
Safety of sildenafil
The safety profile is an important characteristic of any pharmacological drug. The most frequent adverse events when taking sildenafil include headache (7%), redness of the face (7%), dizziness (2%), dyspeptic disorders (1.8%), nasal congestion (1.4%) and impaired color perception (1.2%). In most studies, the frequency of adverse events and treatment refusals caused by them was comparable in the groups of patients receiving sildenafil and placebo. The frequency of adverse events decreases as the duration of taking the drug increases. In another study, the frequency of all side effects, except visual disturbances and dyspeptic disorders, decreased during the duration of taking the drug. At the beginning of the study, headaches were noted by 7% of patients, 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%, while two-thirds of patients increased the dose of sildenafil during this study. With prolonged use, the frequency of adverse events of sildenafil does not exceed that for placebo.
Sildenafil was the first effective oral drug for the treatment of ED. With its appearance, a new era began in the development of andrology, which in recent years has become an independent section of modern urology. The clinical efficacy of sildenafil has been evaluated in a large number of studies conducted in many countries of the world. Taking the drug leads to an improvement in erectile function in patients of different ages, regardless of the etiology, severity and timing of ED.