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Medicines that suppress adrenergic receptors have been used in clinical practice for quite a long time - since 1918. The first adrenergic blockers were ergot alkaloids, which were used for fairly wide indications - from migraines to long-term treatment of arterial hypertension. The clinical effects of total blockade of α-adrenergic receptors are very clear - this is the dilation of peripheral vessels, a drop in blood pressure, and tachycardia, which is of a reflex nature. Against this background, the effects associated with the influence on the urinary tract seem insignificant and insignificant. Therefore, α-blockers were previously classified as antihypertensive drugs.

The main factor limiting the widespread use of α-blockers in general therapeutic practice is the large number of side effects - tachycardia and tachyarrhythmia, hypersalivation, nasal congestion, diarrhea, visual impairment. These negative effects are more unpleasant than dangerous, but nevertheless they greatly reduce the patient’s quality of life and often lead to refusal of further treatment. Side effects of α-adrenergic blockers are a consequence of a direct pharmacological effect - blockade of α-adrenergic receptors. Therefore, correction of side effects during long-term use is difficult. On the other hand, α-blockers are practically devoid of their own toxicity.

High clinical efficacy, low toxicity and a large number of side effects caused by direct pharmacological effects led to the further development of the studied group of drugs to increase selectivity. The discovery of various subtypes of α-adrenergic receptors and clarification of their role made it possible to create selective α1-adrenergic blockers, which, compared to non-selective α-adrenergic blockers, have a much lesser effect on the cardiovascular system. Against this background, the results of blockade of α1-adrenergic receptors of the lower urinary tract acquired clinical significance, which made it possible to use these drugs for the treatment of urological patients. The main goal that was set during the development of these drugs was also achieved - the tolerability of treatment has increased significantly.

Despite their proven effectiveness in the treatment of benign prostatic hyperplasia, selective α1-blockers were initially positioned exclusively as antihypertensive agents. Only with the entry into the market of more effective and safe antihypertensive drugs from other pharmacological groups did it become obvious that vasoactive α1-blockers are uncompetitive in this area. In modern cardiological practice, α1-blockers are reserve drugs and are prescribed only to isolated patients, and the α-blocker prazosin, which has the greatest hypotensive effect in its pharmacological group, has been withdrawn from registration in the Russian Federation.

However, when treating patients suffering from benign prostatic hyperplasia, the same drugs showed quite acceptable results. Particularly attractive was the rapid achievement of a therapeutic effect within 2 - 4 weeks, and sometimes earlier. The ability of the drug to lower blood pressure in this clinical situation turned out to be completely unnecessary, even undesirable. A number of authors recommended the use of selective vasoactive α1-blockers for the treatment of patients suffering from combined urological and cardiac pathologies, but actual clinical practice has not confirmed the correctness of this proposal. Indeed, a large proportion of elderly men receiving long-term conservative treatment for benign prostatic hyperplasia simultaneously require constant use of antihypertensive drugs. However, urologists cannot carry out a full correction of antihypertensive therapy, and cardiologists and therapists cannot adequately assess the function of the lower urinary tract and reasonably prescribe treatment for benign prostatic hyperplasia.

Further studies showed that α1-adrenergic receptors are heterogeneous. Of the three identified subtypes, α1A and a1D receptors are predominantly present in the prostate and bladder neck, while the α1B subtype is characteristic of the cardiovascular system. Thus, it became possible to create highly selective drugs with a minimum number of side effects. The first vasoneactive α1-blocker was tamsulosin, which acts mainly on α1A and α1D receptors and, at therapeutic concentrations, has no effect on systemic hemodynamics.

The latest development is the creation of silodosin, an even more selective adrenergic blocker that predominantly suppresses α1A receptors, which allows minimizing the effect on the cardiovascular system and improving treatment tolerability. According to in vitro studies, the affinity of silodosin for α1A receptors is more than 160 times greater than the affinity of this drug for α1B receptors and more than 50 times for α1D receptors [1, 2]. The selectivity of silodosin for α1A receptors is approximately 17 times higher than that of tamsulosin [2].

RESEARCH RESULTS OF SILODOSIN

Table 1 shows the pharmacokinetic characteristics of silodosin. The bioavailability of the drug is 32%, the half-life is quite long - 11 hours, which determines its long-term effect (24 hours or more) and the possibility of use once a day. The drug is metabolized in the liver by the cytochrome P-450 system, after which the biotransformation products are excreted in the urine and feces. The effect of silodosin on cardiac activity and systemic blood pressure is minimal [3, 4].

Table 1. Pharmacokinetics of α-blockers

A drug	Prazosin	Doxazosin	Tamsulosin	Silodosin
Bioavailability (%)	50	65	100	32
Duration of action (hours)	7-10	24	24	24
Half-life (hours)	2-3	19-22	13	11
Liver/kidney excretion (%)	90/10	63/37	0/100	55/45
Hypotensive effect	++	+	0/+	0
Selectivity for postsynaptic α-adrenergic receptors of the prostate and bladder neck	0	+	++	++++

However, it is worth noting that selectivity towards any receptor subpopulation is a relative and strictly dose-dependent phenomenon. Selectivity is fully manifested only when low and medium therapeutic doses of the drug are used. With increasing concentration of the drug in the blood, this property progressively weakens. Therefore, the use of high dosages is inappropriate in most cases. These statements in pharmacology are an axiom. For α-blockers, this was further confirmed by a systematic review by TJ Wilt et al. (2003). Increasing the tamsulosin dosage to more than 0.4 mg/day. did not lead to an increase in the effectiveness of treatment, but was accompanied by a significant increase in the frequency of side effects [5]. This is directly related to the weakening of the selectivity of the drug, since directly toxic reactions (another reason for the increase in the frequency of undesirable effects) are not typical for α-adrenergic blockers.

EFFECTIVENESS OF SILODOSIN IN THE TREATMENT OF BENIGN PROSTATE HYPERPLASIA

The effectiveness of silodosin for the treatment of benign prostatic hyperplasia has been confirmed by three double-blind randomized studies. Two of them were carried out in the USA, one in Europe. American studies compared silodosin with placebo [3, 6]. A European study compared silodosin with placebo and tamsulosin [7, 8]. The course of therapy was 12 weeks. Treatment results were assessed by both subjective (IPSS scale) and objective methods (uroflowmetry).

In all studies, silodosin was significantly more effective in reducing the clinical manifestations of benign prostatic hyperplasia compared to placebo (p < 0.001). Moreover, patients in the main groups noted subjective improvement already on days 3–4 from the start of treatment (-4.2 vs -2.3 on the IPSS scale, p < 0.0001). An increase in Qmax was observed within 3–6 hours after taking the first dose of silodosin. By the end of the study, the maximum urinary flow rate in the groups of patients receiving silodosin was significantly higher compared to the control groups (p < 0.002). The average increase in this indicator was 2.9 - 3.8 ml/s [6, 7].

Across all studies, the proportion of patients who reported simultaneous subjective improvement in the feeling of incomplete emptying of the bladder, pollakiuria and nocturia among those receiving silodosin was higher than among those receiving placebo, and this pattern was noted as for the general sample (30.5 vs. 20.2%; p < 0.0001), and in relation to the group of patients who initially had nocturnal pollakiuria (two or more urinations per night) (34.9 vs 23.2%; p < 0.0001).

A number of patients, upon completion of the twelve-week course of therapy prescribed by the protocol, continued treatment with silodosin for another 40 weeks. The main purpose of these studies was to assess the safety of the drug. Against the background of long-term use of silodosin, the decrease in IPSS scores continued. However, the changes turned out to be relatively small: 0.82 - 1 point (p < 0.01 compared to the initial level) [6].

When patients receiving placebo were switched to silodosin, an average reduction in overall IPSS score of 2.7 to 3.0 points was achieved over 40 weeks (p < 0.001 compared to baseline) [7, 9].

Of particular interest is a non-comparative prospective study performed by Y. Matsukawa et al (2009). A four-week course of silodosin led to a significant decrease in bladder outlet obstruction, which was confirmed by uroflowmetry results (p < 0.0001). The same study noted a significant increase in bladder volume at the time of the first urge from 113 ml initially to 140 ml after a course of treatment with silodosin[10].

COMPARISON OF SILODOSIN WITH TAMSULOSIN

According to the results of a double-blind randomized study, silodosin is not inferior in effectiveness to tamsulosin. By the end of the twelve-week course of treatment, a slightly more pronounced decrease in subjective manifestations of benign prostatic hyperplasia was noted, but the differences did not reach a statistically significant level (-7.0 - 6.7 on the IPSS scale, p > 0.05). However, the proportion of patients who reported concurrent subjective improvement in voiding, pollakiuria, and nocturia was higher among those receiving silodosin compared with the same proportion of patients receiving tamsulosin or placebo (p > 0.05). This was noted both in the general sample and in the group of patients who initially reported two or more urinations per night [11].

SAFETY OF SILODOSIN THERAPY

Along with effectiveness, a very important parameter is the frequency of side effects, that is, the tolerability of therapy. According to a comprehensive analysis of the results of the three above-mentioned double-blind randomized studies, side effects (regardless of their severity) were noted by 34% of patients, and in 23.6% of patients the drug caused ejaculation disorders. The overwhelming majority of these patients, knowing about the high therapeutic effect of silodosin on BPH symptoms, chose to continue treatment. Only a few patients (3.9%) refused further use of silodosin due to the occurrence of ejaculation disorders [11].

In a detailed analysis, it was noted that in the group of patients who developed ejaculation disorders while taking silodosin, the effectiveness of treatment was higher. “Improvement in total IPSS by three points or more, as well as in maximum urinary flow rate by 3 ml/s or more at the end of the course of therapy, was 1.75 times higher in patients with ejaculation disorders that occurred while taking silodosin than in patients those who did not notice this side effect (p = 0.0127)” [12].

The incidence of side effects from the cardiovascular system while taking silodosin is 1.2%, which did not differ significantly from the control groups receiving placebo (1%) (p > 0.05) [11].

When taking antihypertensive drugs and silodosin simultaneously, the probability of developing orthostatic hypotension is 1.4%, but the differences also turned out to be insignificant both with the groups receiving silodosin monotherapy and with the control groups. It is quite obvious that patients who initially suffered from orthostatic hypotension or had at least one such episode in history, as well as those taking vasoactive α1-blockers for hypotensive purposes, were excluded from the analysis.

Comprehensive cardiac monitoring performed on patients during the aforementioned double-blind randomized studies also did not reveal a clinically significant effect of silodosin on the myocardium.

To confirm the low toxicity of silodosin in relation to the effect on the heart muscle, a separate study was conducted on the effect of a five-day course of silodosin at dosages of 8 mg and 24 mg. It was performed on healthy male volunteers and did not reveal clinically or statistically significant changes in heart rate and the state of the cardiac conduction system according to electrocardiography results [13].

DISCUSSION

According to the results of the studies, silodosin showed high efficacy in the treatment of benign prostatic hyperplasia and a completely acceptable safety profile. However, the question remains about the place of this drug in clinical practice.

Silodosin was generally comparable in effectiveness to tamsulosin. There are clinical situations where silodosin has demonstrated significantly greater efficacy compared to tamsulosin. In general, the conclusion made by MP Curran (2011) based on the results of the studies “silodosin is not inferior to tamsulosin in effectiveness” is formulated absolutely correctly from a pharmacological point of view. The fact is that generations of α-blockers differ not in effectiveness, but in tolerability. This setting has been repeatedly confirmed in studies, including double-blind, randomized ones. For example, let us note the work of JM Buzelin et al. (1993), which showed equal clinical efficacy of alfuzosin and prazosin for the treatment of benign prostatic hyperplasia. Significant differences were noted only in the frequency of side effects [15].

To paraphrase the above thesis, it can be noted that the selectivity that determines the generation of an α-blocker is reflected only in the frequency of side effects, without significantly affecting the clinical effectiveness. In general, α-adrenergic blockers, even the earliest ones, were never claimed to be insufficiently effective.

The frequency of side effects of silodosin and tamsulosin according to the pooled data from double-blind randomized studies was almost identical. In our opinion, a situation has arisen here, not uncommon in modern clinical pharmacology, when one has to choose between two drugs - good and very good. Both good and very good drugs are equally effective in a typical situation. But a very good drug requires special conditions to realize its potential. Large studies usually include average patients, thus excluding severe and complicated patients. Therefore, with this approach, it is not possible to identify overwhelming advantages.

Increased requirements may be placed on α-blockers in terms of selectivity in conditions that are clinically similar to the side effects of α-blockers. For example, a pre-existing tendency to hypotension, especially against the background of coronary heart disease (α-blockers increase myocardial oxygen demand and can provoke an attack of angina or arrhythmia), used to be a reason for refusing treatment of benign prostatic hyperplasia with α-blockers. Now it is quite reasonable to use silodosin. Tachycardia and tachyarrhythmia are currently well corrected with medication, but if there is a need to prescribe an α-blocker to such a patient, then higher selectivity is needed. Thus, we will reduce the risk of recurrence of rhythm disturbances. Due to its highest uroselectivity, silodosin is preferable if the patient is taking antihypertensive drugs, as well as PDE-5 inhibitors (tadalafil, sildenafil). Considering the predominantly elderly age of patients with BPH, the safety factor regarding the cardiovascular system when taking α-blockers simultaneously with antihypertensive drugs / PDE-5 inhibitors becomes especially relevant.

α-blockers can increase gastric secretion and gastrointestinal motility. Gastroenterological contraindications do not appear in the annotations of all drugs in this group. However, if the patient suffers from ulcers or erosions of the stomach, esophagus, duodenum, recurrent hyperacid gastritis and at the same time has indications for taking α-blockers, then the drug of choice will be the most selective of them - silodosin.

SUMMARY

The new α-blocker silodosin is a highly effective and safe drug for the treatment of benign prostatic hyperplasia. Silodosin is characterized by a rapid development of effect; it can be used in all patients suffering from BPH and having indications for taking α-blockers.

Due to its selectivity, which is superior to all analogs available on the market, silodosin has safety advantages in the treatment of BPH in patients suffering from hypotension, tachycardia, tachyarrhythmia, especially against the background of coronary heart disease, gastric and duodenal ulcers, and hyperacid gastritis. Silodosin does not increase the risk of hypotension in patients taking antihypertensive therapy (drugs acting on the reninangiotensin system, beta-blockers, calcium channel blockers and diuretics), as well as in patients taking PDE 5 inhibitors.

Silodosin is compatible with all groups of antihypertensive drugs, except vasoactive α-blockers. When silodosin is co-administered and antihypertensive therapy, no dosage adjustment is required.

Key words: benign prostatic hyperplasia, α-blockers, silodosin, uroselectivity.

Keywords: benign prostatic hyperplasia, α-adrenoblockers, silodosin, uroselectivity.

LITERATURE

Morishima S., Suzuki F., Nishimune A. Visualization and tissue distribution of a1-adrenoceptor in human prostate by the fluorescently labeled ligand Alexa-488-silodosin. // J. Urol., 2009. Dec 22; 183:812-9.
Tatemichi S., Kobayashi K., Maezawa A. A1-adrenoceptor subtype selectivity and organ specifi city of silodosin (KMD-3213) // Yakugaku Zasshi., 2006. Mar; 126: 209-16.
Watson Laboratories Inc. US prescribing information: Rapaflo (silodosin) [online]. Available from URL: https://www.watson. com [Accessed, 2011 Mar 2].
European Medicines Agency. Summary of product characteristics: Urorec (silodosin) [online]. Available from URL: https://www.ema.europa.eu [Accessed, 2011 Feb 20].
Wilt T., MacDonald R., Rutks I. Tamsulosin for benign prostatic hyperplasia. // Cochrane Databse of Systematic Reviews, 2003. No. 1. Accession Number PUBMED 12535426.
Marks LS, Gittelman MC, Hill LA Rapid efficacy of the highly selective A1-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. // J. Urol., 2009 Jun; 181(6):2634-40.
European Medicines Agency. CHMP assessment report for Urorec: procedure no EMEA/H/C/001092 [online]. Available from URL: https://www.ema.europa.eu [Accessed, 2011 Mar 2].
Chapple CR, Montorsi F., Tammela TL Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. // Eur Urol, 2011; 59: 342-52.
Hill LA Silodosin in the treatment of the signs and symptoms of benign prostatic hyperplasia: a 9-month, open-label extension study. // Urology, 2009. Dec; 74(6):1318-22
Matsukawa Y., Gotoh M., Komatsu T. Efficacy of for relieving benign prostatic obstruction: prospective pressure flow study. // J Urol, 2009 Dec; 182(6):2831-5.
Montorsi F. Profile of silodosin. Euro Urol 2010; 4 Suppl. 9:491-5.
Roehrborn CG, Kaplan SA, Lepor H. Symptomatic and urodynamic responses in patients with reduced or no seminal emission during silodosin treatment for LUTS and BPH. // Prostate Cancer Prostatic Dis. Epub, 2010 Dec 7.
Morganroth J., Lepor H., Hill LA Effects of the selective A1-adrenoceptor antagonist silodosin on ECGs of healthy men in a randomized, double-blind, placebocontrolled study. // Clin Pharmacol Ther, 2010 May; 87 (5):609-13
Curran MP Silodosin. Treatment of the symptoms of benign prostatic hyperplasia. // Drugs, 2011; 71 (7): 897-907.
Buzelin JM, Hebert M., Blondin P. Alpha-blocking treatment with alfusosin in symptomatic benign prostatic hyperplasia: comparative stydy with prazosin. // Br.J.Urol., 1993. Vol 72. N6.P.922-927. Accession number PUBMED 0732187.

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