The study of erectile dysfunction has gone through several phases in its historical development. This evolution is typical for almost all diseases, but in the case of erectile dysfunction, this process proceeded relatively slowly and very unevenly. This was primarily due to the traditionally reserved attitude of the medical community towards sexual disorders. For a long time it was accepted to consider them as something not too significant, inferior in importance to “serious” diseases.
The situation began to change as a result of the accumulation of data on the urgency of the problem under discussion, as well as the mechanisms of its development and connection with other diseases. Currently, there is no doubt that erectile dysfunction is an extremely common disease, the frequency of which is characterized by a pronounced upward trend. Even if we consider that this violation only reduces the quality of life of patients, in modern conditions it is impossible to ignore such a large-scale problem.
Erectile dysfunction in most cases is a manifestation of systemic vascular lesions, and often an early sign. Understanding this fact automatically translates this problem into the category of “serious” – because cardiovascular diseases are the leading cause of death in most developed countries of the world.
Papaverine was one of the first drugs for the treatment of erectile dysfunction.
For the first time, data on the possibility of using this long and well-known drug for a new indication, namely, as an intracavernous therapy for erectile dysfunction, was published by the French vascular surgeon Ronald Virag in 1982.
The prerequisite for the discovery was the accidental observation of an erection in a patient who was mistakenly injected intra-arterially with papaverine during the formation of an epigastric-cavernous vascular anastomosis. The concept of intracavernous therapy was further developed by the English physiologist Giles Brindley, who discovered the pro-erectile effect of D-adrenergic blockers when administered intracavernously. Interestingly, this discovery was also to a certain extent accidental: Brindley revealed the pro-erectile effect of phentolamine empirically, performing intracavernous injections of various substances. These data have become a serious stimulus for studying the mechanisms of the development of erection and its disorders. The “breakthrough” was associated with the emergence of the first highly effective oral drug for the treatment of erectile dysfunction from the group of phosphodiesterase type 5 inhibitors, sildenafil. It is interesting that the discovery of this substance, or rather its effects on erection, as well as in the case of papaverine, was not a direct result of fundamental research, but was due to a favorable coincidence of circumstances. In the course of clinical trials of another antianginal drug, researchers at Pfizer Inc. noted that, although taking the medication 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 later became the reason for studying the possibility of using this substance in the treatment of erectile dysfunction.
To date, the problem of erectile dysfunction is attracting the attention of a wide variety of specialists, including cardiologists, endocrinologists and therapists. Works on this topic are published in scientific medical journals of various directions, which becomes obvious already by the number of publications related to the problem of erectile dysfunction (this figure has long since passed the milestone of 1000 per year, or almost 3 publications daily). Currently, the arsenal of methods for treating erectile dysfunction is very diverse. The choice of the most appropriate method in each specific case is determined by a number of factors, including the form of erectile dysfunction, clinical features, individual preferences and financial capabilities of the patient, as well as the invasiveness of one method or another. The latter factor is often of fundamental importance.
In the case of insufficient effectiveness, a less invasive technique is transferred to a more invasive one. As a rule, the treatment of erectile dysfunction begins with the appointment of oral phosphodiesterase type 5 inhibitors, with insufficient effectiveness of which other oral drugs, intracavernous injections or vacuum devices are used. It should be noted that this approach, in my opinion, does not quite correspond to the current understanding of the nature of most cases
erectile dysfunction, namely, their conditioning by systemic vascular disorders. In this regard, the identification and correction of metabolic disorders should play a significant role in the treatment of patients with erectile dysfunction. Such a practice can both improve the general health of patients up to the prevention of potentially life-threatening complications in some cases, and have a beneficial effect on the state of erectile function. The most important component of the treatment of patients with organic erectile dysfunction with vascular risk factors is lifestyle changes. If such an approach does not give a sufficient effect, or if the severity of the patient’s disorders seems to be quite pronounced to the clinician, it is necessary to supplement the correction of the lifestyle with medication. Weight loss may be a key step in the management of obese erectile dysfunction patients.
The primary goal of such treatment is to reduce body weight by 10%, while reaching a body mass index of less than 25 kg / m is considered optimal. There are three main methods of dealing with obesity: limiting the calorie intake of food consumed, increasing the amount of physical activity, and prescribing medications that are approved for such indications. In addition, along with the calorie content of food, its composition is also essential. In particular, the diet of a patient with metabolic syndrome, often with concomitant erectile dysfunction, should not contain more than 7% saturated fat and more than 200 mg cholesterol per day. In order to influence blood pressure, it is also necessary to limit salt intake. It should be noted that an increase in physical activity not only leads to a decrease in the volume of adipose tissue, but also has a beneficial effect on the existing metabolic disorders.
Patients with erectile dysfunction should devote at least 30 minutes a day to moderate physical activity. In the event that the measures described above are insufficient to correct the existing vascular and metabolic disorders, appropriate methods of drug therapy should be used. It should be noted, however, that phosphodiesterase inhibitors remain the drugs of choice even in patients with severe concomitant disorders, including diabetes mellitus and metabolic syndrome.
The pharmacological group of phosphodiesterase type 5 inhibitors is part of a fairly large class of drugs that inhibit the activity of various phosphodiesterases. These enzymes are present in all cells of the human body, regulating the content of cyclic nucleoside monophosphates, guanosine monophosphate and adenosine monophosphate. These molecules are one of the most important intracellular secondary messengers, and therefore the processes, the activity of which depends on the action of phosphodiesterases, are very diverse.
The main goal of the effect of type 5 phosphodiesterase inhibitors is vascular smooth muscle cells. The mechanism of action of cyclic guanosine monophosphate, common for all cells, is the activation of protein kinases.
In the tissue of the corpora cavernosa, nitric oxide NO released from nerve endings and / or endothelial cells triggers this biochemical cascade: NO diffuses into vascular smooth muscle cells and combines with the enzyme guanylate cyclase, as a result of which the activity of this enzyme significantly increases. The end result of subsequent processes is a decrease in the intracellular concentration of Ca 2+ ions, which in the tissue of the corpora cavernosa is manifested by the relaxation of smooth muscle cells. This causes an increase in arterial inflow with the subsequent activation of the venocytic mechanism and the development of an erection. It should be emphasized, however, that type 5 phosphodiesterase inhibitors by themselves do not induce erection and only facilitate its development in a “natural” way. Currently, there are 3 drugs available from the group of phosphodiesterase type 5 inhibitors: sildenafil, vardenafil and tadalafil. In general, sildenafil and vardenafil are similar in their pharmacokinetic parameters, although there is evidence that in some cases vardenafil is absorbed faster and, accordingly, begins its action earlier. As for tadalafil, its differences from the other two representatives of the group are more pronounced. From a pharmacodynamic point of view, tadalafil, like other representatives of this group, is a highly selective phosphodiesterase type 5 inhibitor.
However, the pharmacokinetics of this drug has a number of differences from analogues. Due to a different chemical structure (the piperazine ring of sildenafil and vardenafil is replaced by the hydrantoin ring), tadalafil is characterized by more stable absorption from the gastrointestinal tract and, most importantly, a significantly longer duration of action. While the half-life of vardenafil and sildenafil is about 4 hours, this figure for tadalafil is on average 17.5 hours, and in older men it can reach 21.6 hours. Such a long-term effect can radically change the approach to the treatment of erectile dysfunction in the use of tadalafil. It should be recalled that tadalafil, like other type 5 phosphodiesterase inhibitors, cannot be combined with nitrates due to the risk of severe hypotension. Taking nitrates becomes relatively safe only 48 hours after the last dose of tadalafil.
Thus, over the past three decades, interest in the problem of erectile dysfunction has grown significantly. This is due to the emergence of new effective methods of treating this disease, as
and with a better understanding of its nature and relationship with other disorders, primarily from the cardiovascular system. Currently, the arsenal of treatments for erectile dysfunction is quite wide.
In all patients, along with drug therapy, an effort should also be made to identify and eliminate vascular risk factors. First line the treatment of erectile dysfunction today are phosphodiesterase type 5 inhibitors. Among these drugs, tadalafil stands out, which has a significantly longer duration of action. This characteristic determines its clinical superiority over other representatives of this group, shown in a number of studies. In addition, the long duration of action makes tadalafil the most suitable phosphodiesterase type 5 inhibitor for regular use.