An update on efficacy and safety of alpha-blockers in the treatment of distal ureteric stones: narrative review

Abstract

Background

Alpha-blockers prescribed as medical expulsion therapy (MET) have replaced minimally invasive procedures as the primary line of treatment for minor ureteric stones. This study aims to investigate the efficacy of MET with alpha-blockers in terms of stone expulsion rate and time and evaluate the safety of several alpha-blockers.

Methodology

Google Scholar, PubMed, and Web of Science databases were searched for relevant publications using keywords published between December 2013 and August 2021. Additional relevant research was found by looking through the references in the articles.

Results

To determine the efficacy and safety of alpha-blockers as a medical expulsive therapy for the management of distal ureteral stones, 15 studies were included, 12 randomized control trials, 2 retrospective observational studies, and 1 prospective study. The most commonly studied primary endpoint was stone expulsion rate and time. According to findings, silodosin appears to be more effective than other alpha-blockers. The data revealed no life-threatening adverse effects were associated with alpha-blockers.

Conclusion

Alpha-blockers are recommended as the first-line therapy for distal ureteral stones. Silodosin was the most efficacious medicine, according to the data. The side effects of alpha-blockers, on the other hand, were minor, consisting primarily of orthostatic hypotension. The alpha-blocker choice differs from urologist to urologist in the management of MET, depending on their experience and the patient's condition.

1 Background

Ureteral stones frequently appear with acute upper urinary system blockage and discomfort, necessitating fast stone clearance [1]. The occurrence varies by geographical region, with greater rates in the Middle East, Western India, and the Southern USA, likely due to the high water and soil content in those places and the hot weather and dehydration [2]. Urinary stones result from various metabolic, environmental, and nutritional factors. They are typically calcium oxalate with the precipitation of additional calcium salts, uric acid, or other compounds [3]. Ureteral stones account for about 20% of all urolithiasis cases. Roughly 70% of ureteral stones are found in the bottom portion of the ureter and are referred to as distal ureteral stones [4]. Women excrete more citrate and less calcium than males, which may explain why men have a higher rate of stone illness [5]. Colicky pain is the most common symptom of ureteral stones, with nearly half of patients presenting within 5 years of the onset of calculi [2].

The size, location, composition of the stone, degree of obstruction, symptoms, and anatomy of the urinary system all play a role in determining the best therapeutic option, and doctors are regularly asked to recommend appropriate therapy [6, 7]. The distal ureteric stone treatment is classified into three categories: observation and medical therapy, shock wave lithotripsy ureteroscopy, and open surgery laparoscopic stone removal [8]. Alpha-blockers, calcium channel antagonists, phosphodiesterase inhibitors, and corticosteroids are some of the medications used for medical expulsive therapy (MET), and they have all been demonstrated to help ureteric stone pass [9]. The goal of MET is to increase fluid intake in order to raise urine volume and hydrostatic pressure, as well as ureteric peristaltic activity [10]. The passage of the stone is aided by relaxation of the ureteric smooth muscle, a decrease in ureteral mucosal oedema, and an increase in the hydrostatic pressure proximal to the stone in MET [11]. In the first line of treatment for small ureteric stones, alpha-blockers administered as MET have replaced minimally invasive methods. Alpha-blockers are recommended by the American Urological Association (AUA) and the European Association of Urology (EAU) to treat ureteric stones [12]. The smooth muscle of the ureter is treated with a variety of medications that work in different ways [13]. The three subtypes of a1-adrenergic receptors are 1A, a1B, and 1D, with a1D > a1A > a1B as the distribution of these receptors in the distal ureter [14]. The ureter’s wall is made up of smooth muscle. Internally, it is lined with the alpha-1-adrenergic receptor, especially in the lower one-third of the ureter, also known as the distal ureter [15]. Blocking alpha-1-adrenergic receptors, particularly propulsive antegrade peristalsis, aid stone ejection [13]. The most widely prescribed alpha-blockers for medical expulsive therapy are tamsulosin, alfuzosin, silodosin, and naftopidil [16].

This study aims to see how effective MET was with alpha-blockers regarding stone expulsion rate and distal ureteric stone expulsion time. The secondary goal was to assess various alpha-blockers' safety and find the safest alpha-blocker.

2 Methodology

The relevant articles published from December 2013 to August 2021 were searched in Google Scholar, PubMed, and Web of Science databases. The articles were limited to the English language. The search keywords were “safety, efficacy alpha-blocker”, and “alpha-blocker treatment ureteric calculus”. Article references were also checked to find additional relevant studies. The results of the articles were analysed based on the inclusion criteria. All the selected articles were published in peer-reviewed and indexed journals. The included studies were research results that focused on distal urinary stones with a study population of adults that were managed by alpha-blockers. Studies with pre- or post-lithotripsy were not eligible for review. All the scientific articles meeting the inclusion criteria were critically reviewed by at least two authors and the information is summarized in this narrative review.

3 Results

Fifteen studies, including 12 randomized control trials (RCTs), 2 retrospective observational studies, and 1 prospective study, were included in determining the efficacy and safety of alpha-blockers as MET for managing distal ureteric stones. Agents studied include tamsulosin, silodosin, alfuzosin, and naftopidil.

Studies had similar inclusion criteria including patients above 18 years, and a calculus demonstrated in the distal ureter with the stone size less than 10 mm. Exclusion criteria included patients with fever, urinary tract infection (UTI), hydronephrosis, bilateral ureteric stone, solitary kidney, an extra stone in the upper urinary system, previous surgical history on the ipsilateral ureter, pregnant women, patients with diabetes, renal insufficiency, cardiovascular disease, and hypotension. Study duration varied between seven days to one month.

The most commonly studied primary endpoint was expulsion rate and time, which was successful passing of the stone and the secondary goal was to assess the safety of alpha-blockers.

Four RCTs that compared tamsulosin with placebo or any other drug except alpha-blockers showed that tamsulosin had a better expulsion rate and time. [3, 17,18,19]. But studies conducted by Puvvada S et al. and Kc HB et al. showed that tadalafil was better when compared to tamsulosin in terms of expulsion rate and time taken for stone expulsion [20, 21].

When monotherapy of tamsulosin was compared with combination therapy of tamsulosin + trospium chloride, tamsulosin + tadalafil combination therapy proved to be more effective [2, 8].

An RCT conducted by Kohjimoto Y et al. concluded that naftopidil was better than flopropione in terms of expulsion rate and time [22]. Among 2 RCTs, which compared tamsulosin with silodosin, it was found that silodosin was better in expulsion rate and time. [6, 23] but expulsion time contrasted by the studies regulated by Elgalaly H et al. and Imperatore V et al. [12, 24]. The study conducted by Shabana W et al. showed that combination therapy of tamsulosin and methylprednisolone is better than monotherapy with tamsulosin. It was the same as in the case of alfuzosin combination therapy [10].

A retrospective observational study comparing tamsulosin, alfuzosin, and silodosin proved that silodosin was the most effective drug regarding stone expulsion rate and time taken for stone expulsion [5].

No serious adverse effects were associated with the use of alpha-blockers. Most commonly reported adverse effects included orthostatic hypotension, palpitation, headache, dizziness, backache, abnormal ejaculation, retrograde ejaculation, gastritis, fatigue, nasal congestion, constipation, nausea, diarrhoea, asthenia, increased erection, dry mouth, flushing, muscle cramps, dyspepsia, sexual dysfunction, collapse, vomiting, and hearing problem [2, 3, 5, 6, 8, 10, 12, 17,18,19,20,21,22,23,24]. The detailed results are described in Table 1.

Table 1 Efficacy and safety of alpha-blockers

4 Conclusion

An ideal treatment for distal ureteral stone should help improve stone clearance rate and expulsion time with minimal pain and without significant detrimental adverse effects. The results from the research studies with alpha-blockers look very promising. In the light of the findings, we recommend using alpha-blockers to treat distal ureteral stones as the first-line treatment. The results suggest that silodosin was the most efficacious drug. However, adverse effects associated with alpha-blockers were limited, mainly orthostatic hypotension. The choice of the alpha-blocker varies from urologist to urologist based on their expertise in the field and patient condition. As more alpha-blockers are marketed, more combinations permutations will come into the market. However, to the best of our knowledge, information on the combination therapy of alpha-blockers with other drug classes is minimal.