Prostate hyperplasia: scalpel or pills?
Modern drug therapy of benign prostatic hyperplasia
L.M.Gorilovsky, MD, Professor, D.A.Lakhno, PhD, Research Institute of Urology, Moscow
Journal "Medical Council" No. 7-8 (2010)
Published on the website "Remedium"One of the most common urological diseases of elderly men is benign prostatic hyperplasia (BPH).
According to epidemiological data, the prevalence of BPH in most countries reaches 20% in 50-year–old men, 50% in 60-year–olds, 57% in 70-year–olds and 80% in 80-year-olds. The average referral rate for BPH in Russia, according to N.A.Lopatkin et al., in 2000 was 113-125 per 100,000 male population. According to some researchers, the probability of undergoing surgical treatment in a man over the age of 60 with prostate hyperplasia and lower urinary tract symptoms reaches 39% [1].
Thus, BPH is one of the most common diseases leading to surgical intervention. Increasing life expectancy leads to an increase in the number of men suffering from BPH, and improving their quality of life reduces tolerance to the disease, preventing them from continuing an active lifestyle.
Demographic studies of the World Health Organization, indicating a significant increase in the population over the age of 60, emphasize the socio-economic significance and relevance of this problem. The growth rate of this disease significantly outstrips the growth of the world's population as a whole. It should be noted that the elderly population has great vital, productive and intellectual potential, which should be fully used by society.
The progression of BPH consists in the deterioration of clinical indicators, including an increase in the volume of the prostate gland, the weighting of the SNMP and a decrease in the maximum volumetric rate of urination (Qmax), an increased risk of acute urinary retention (OSM) and the need for surgical treatment of BPH, as well as a decrease in the quality of life associated with BPH [2].
Due to the fact that frequent urination, sluggish urine stream, stranguria, nocturnal pollakiuria, which are the main symptoms of BPH, significantly worsen the quality of life, the main task of the urologist is to timely diagnose these diseases and carry out early therapeutic measures aimed at improving the quality of life (Gorilovsky L.M., 2004).
According to modern concepts, the diagnostic complex for the examination of a patient with BPH includes: collection of anamnesis, quantitative assessment of symptoms and "quality of life" using the International Scale for Assessing Symptoms of Prostate Diseases – IPSS (the table is given in the article "Prostate Adenoma: know your maneuver" – VM); examination of the level of prostate specific antigen (PSA), urea and serum creatinine; analysis of urine and prostate secretions; finger rectal examination; transabdominal ultrasound examination of the kidneys and bladder with determination of the amount of urine; transrectal ultrasonography, uroflowmetry. In some cases, it is necessary to perform urodynamic studies.
Until recently, a urologist and a patient diagnosed with BPH faced a choice: either to carry out surgical treatment, or to wait and observe. Surgical treatment was meant to be a trans-bubble or posadilon prostatectomy or transurethral resection of the prostate with its modifications. Recently, along with an increase in the incidence of BPH, the number of methods of treatment of these patients has increased significantly. First of all, there were medications with which you can achieve a good effect, especially in the initial stages of the disease.
Advances in the knowledge of the pathogenesis of prostatic hyperplasia and the creation of medications with a pathogenetically directed mechanism of action have led to the fact that drug therapy of certain categories of patients has become truly effective. Modern pharmacotherapy allows many patients to avoid unwanted surgical treatment and the associated menacing complications, such as irreversible urinary incontinence and loss of sexual function, followed by a violation of the quality of life [3].
And although drug treatment does not relieve the patient from prostatic hyperplasia, it makes it possible to significantly reduce complaints, improve impaired urination and normalize the quality of life. Drug therapy for lower urinary tract symptoms has been actively used for 15 years with BPH. In the early 1990s, long-acting selective α-blockers – terazosin and doxazosin - appeared, and a few years later, the first 5α-reductase inhibitors appeared on the pharmaceutical market. These two groups of drugs have become the main ones for the treatment of BPH, dramatically reducing the number of transurethral resections of the prostate. For example, in the USA, the number of transurethral and open adenomectomies decreased from 250,000 in 1987 to 88,000 in 2000 [4].
When choosing a treatment method, the doctor should evaluate the data of instrumental research methods and the problems the patient has, reflected in the IPSS questionnaire. As an element of a standard examination of such patients, it is recommended to evaluate the subjective perception of the severity of BPH symptoms and the effectiveness of its treatment. This is due to the fact that the most frequent symptoms are often not the most disturbing for patients [5].
Diagnostic criteria for prescribing conservative therapy for the diagnosis of BPH are: the total IPSS score is greater than 7 and less than 19; the maximum urine flow rate (Qmax) is more than 5 ml / s; the volume of residual urine is not more than 150 ml; the presence of contraindications to surgical treatment due to concomitant diseases; refusal of the patient from surgery. According to the 4th International Consultation on BPH (1997), absolute indications for surgical treatment are: urinary retention; recurrent macrohematuria due to benign enlargement of the prostate gland; large diverticula of the bladder; renal insufficiency, bladder stones or recurrent infections of the genitourinary tract due to infravesical obstruction [6].
The group of choice for the symptomatic treatment of obstructive symptoms of BPH are blockers of α-adrenergic receptors, the effects of which are directed at elements of the autonomic nervous system, which are components in the dynamic component of infravesical obstruction in BPH. Alpha-blockers reduce symptoms and improve urodynamic parameters, however, their similar effect has not been demonstrated to stop the progression of BPH and reduce the risk of the need for surgical treatment of BPH.
Tamsulosin (omnik (Astellas Pharma); tulosin (Egis)) is the most effective alpha–adrenoblocker used for the medical treatment of BPH. Its unique application features (efficacy without side effects, no need for dose titration, no effect on blood pressure) may be due to both a relatively low therapeutic dosage of 0.4 mg with the greatest α-blocking effect, and selectivity to the subtype (a1a-adrenergic receptors). Tamsulosin selectively and competitively blocks postsynaptic a1A-adrenoreceptors located in the smooth muscles of the prostate gland, the neck of the bladder and the prostatic part of the urethra. This leads to a decrease in the tone of the smooth muscles of the prostate gland, the neck of the bladder and the prostatic part of the urethra, improving the outflow of urine. At the same time, the symptoms of obstruction and irritation associated with benign prostatic hyperplasia decrease.
Tamsulosin's ability to affect a1A-adrenoreceptors is 20 times greater than its ability to interact with a1B-adrenoreceptors located in vascular smooth muscles. Due to its high selectivity, the drug does not cause any clinically significant decrease in systemic blood pressure in both patients with hypertension and patients with normal baseline blood pressure. The bioavailability of tamsulosin is about 90%, and a stable concentration in the blood with daily intake is achieved in an average of 5 days. The main place of tamsulosin metabolism is the liver, and enzymes from the cytochrome group play an important role in this process. The most common side effects of tamsulosin are nasal congestion, headaches and ejaculation disorders. The pharmacological characteristics of tamsulosin are of great clinical importance. The absence of a significant effect on the cardiovascular system avoids titration of the tamsulosin dose. Thus, the maximum clinical effect of its use is achieved fairly quickly. The clinical efficacy of tamsulosin at a standard dose (0.4 mg 1 time per day) has been thoroughly studied in several multicenter randomized, placebo–controlled, double-blind studies conducted in Europe and North America, in which more than 1300 patients participated. These studies have confirmed the long-term efficacy and safety of tamsulosin as a drug for pharmacotherapy of benign prostatic hyperplasia [7].
Omnik okas is a controlled release tablet based on a matrix using a nonionic type gel, which provides a long and slow release of tamsulosin and gives sufficient exposure with weak fluctuations for 24 hours. This ensures round-the-clock effective control over the symptoms of the lower urinary tract.
Data from several international studies on the effectiveness of the use of alpha-blockers indicate that many patients, along with a decrease in the severity of LUPUS, note an improvement in sexual function. It is assumed that the reason for this effect is the polyvalent mechanism of action of alpha-blockers, which contributes to improving blood circulation of the pelvic organs and overall improving the quality of life of the patient [8].
As noted above, for all their advantages, alpha-blockers are not able to influence the progression of the disease. In case of a high risk of disease progression (prostate gland volume exceeds 50-60 cm3), it is recommended to introduce 5α-reductase inhibitors into therapy. It is known that 5α-reductase inhibitors are able to inhibit the progression of the disease as a result of inhibition of the conversion of testosterone into dihydrotestosterone, an androgen, which is considered the main factor affecting the hyperplastic growth of prostate tissue. 5α-reductase inhibitors not only inhibit the further growth of BPH, but also reduce the size of the prostate if it is enlarged [9, 10]. Of the drugs used for the conservative treatment of men suffering from BPH, only 5α-reductase inhibitors are able to influence the pathophysiological mechanisms underlying the disease. There are two isoforms of 5α-reductase (type 1 and type 2). Today, two drugs from the group of 5α-reductase inhibitors that significantly reduce the volume of the prostate gland are available in Russia – finasteride and dutasteride. Finasteride, which blocks type 2 5α-reductase, has been known for a long time, and the effect of its administration becomes obvious, on average, after six months of treatment. Dutasteride is 45 times more potent type 5α-P inhibitor than finasteride, and 2.5 times more potent type 5α-P inhibitor. It provides a more pronounced suppression of DHT in serum (a93% vs. 70%). These characteristics cause an earlier onset of the effect: a decrease in prostate size and an increase in Qmax. In Western countries, dutasteride under the commercial name avodart was registered and approved for clinical use in 2002, in Russia – in 2005. The efficacy and safety of dutasteride was evaluated in a generalized analysis that included 3 placebo-controlled, two-year, double-blind studies.
Already 2 weeks after the start of treatment with dutasteride, serum dihydrotestosterone levels decreased by more than 90%, and this decrease persisted until the end of the study. For 2 years, the volume of the prostate decreased by 25.7%. In addition, against the background of treatment with dutasteride, there was a persistent decrease in the severity of symptoms of the disease, an increase in Qmax and a decrease in the risk of developing OZM by 57% and the need for surgical treatment by 48% [11]. For adult men, including elderly patients, the recommended oral dose is 500 mcg (1 capsule) 1 time per day.
The most significant side effects of dutasteride monotherapy are: impotence, change (decrease) in libido, ejaculation disorder, gynecomastia. Analysis of the data obtained during the placebo-controlled studies mentioned above showed that the adverse events that occurred were usually mild or moderate in severity and most often related to disorders of sexual function. At the same time, both in the avodart group and in the placebo group in the vast majority of patients (89 and 94%, respectively) there were no disorders of sexual function. It should be noted that statistically significant differences between the dutasteride and placebo groups, as a rule, were observed only during the first 6 months of therapy in terms of the frequency of reported adverse events associated with taking drugs. In the course of further treatment, the differences between the groups on the most frequent adverse events disappeared.
Various pharmacological characteristics and mechanism of action of α1-adrenoblockers and 5α-reductase inhibitors serve as the basis for the development and application of rational combination therapy. The combination of avodart (dutasteride) and tamsulosin was studied during a 4-year, multicenter, randomized trial using the "CombAT" blind method. The study involved parallel groups of 4,844 men (average age 50 years) with a clinical diagnosis of BPH. The indicator on the international scale of prostate disease manifestations was more than 12, prostate volume – more than 30 cm, PSA level – 1.5–10 mg/ ml, maximum urination rate (Qmax) – more than 5-15 ml / s, the minimum volume of urine excreted – 125 mg. They took tamsulosin 0.4 g daily orally; dutasteride 0.5 mg or a combination thereof. The primary endpoint of observation for 4 years was the occurrence of acute urinary retention or surgical intervention for benign prostatic hyperplasia. The secondary endpoints of the study were the analysis of clinical progression of BPH, symptoms, Qmax, prostate volume, safety and tolerability. The results of combination therapy were much superior to tamsulosin monotherapy, but not dutasteride monotherapy. Combination therapy has shown not only a reduction in the relative risk of acute urinary retention or surgery for BPH, but also significantly better results relative to both monotherapy in reducing the risk of clinical progression of BPH. The data obtained during the 4-year ComBat study support the use of combination therapy with tamsulosin and dutasteride in men with moderate or severe SNMP developed in connection with BPH [12].
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