EFFICACY OF SELECTIVE ALPHA-1 RECEPTOR BLOCKERS (TAMSULOSIN) IN FACILITATING THE PASSAGE OF RENAL STONES AFTER EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY

BACKGROUND & OBJECTIVE: Urinary system stone disease is a common entity. Small renal stones are preferably treated using Extracarporeal Shock Wave Lithotripsy (ESWL) technique. Passage of stone fragments result in pain, hematuria and urinary tract obstruction. This can be avoided by the use selective α-1 receptor antagonists like Tamsulosin. However, their efficacy remains a matter of debate. In this study the role of selective α-1 blocker was evaluated in facilitating spontaneous expulsion of renal stone fragments after ESWL. The objective of our study was to find out the Efficacy of Tamsulosin (Selective α-1 blocker) in facilitating the transit of stone fragments (4-7mm) after ESWL. Follow up X-ray KUB was used to confirm the stone clearance. Efficacy was measured in terms of stone expulsion rate. METHODOLOGY: It was randomized controlled trial including 150 patients coming to outpatient department of Urology Lahore General Hospital, Lahore from January 25, 2010 to July 25, 2010. Total 150 patients with renal stones broken down into fragments (4-7mm) after ESWL were enrolled using non-probability purposive sampling technique. Patients were categorized into group A and B. Patients of group A received cap. Tamsulosin 0.4mg along with Tab. Diclofenac sodium 50mg. Whereas, patients belonging to group B received only diclofenac sodium 50 mg twice daily. Patients underwent ESWL every three weeks, in case of non-fragmentation, to the maximum of 4 sessions. All the patients were followed with X Ray KUB for stone clearance. The data of all patients was incorporated into pre designed Performa. Statistical evaluation of clinical variables done in terms of efficacy i.e. stone clearance. RESULTS: Stone clearance rate of patients in group A was 86.6% as compared to only 76% in group B. Usage of selective α-1 blockers in group A enhanced the stone clearance rate as compared to group B. However this difference was statistically insignificant (p-value-0.094). CONCLUSION: There was increased stone clearance in alpha one blocker group but not statistically significant. Further studies with larger sample size are required to evaluate the role of Selective α-1 blockers (Tamsulosin) after ESWL.

eases spontaneous expulsion of small ureteric [9] calculi . To ease spontaneous expulsion of d i s t a l u r e t e r i c c a l c u l i i n a d j u v a n t pharmacological medications like alpha b l o c k e r s , c a l c i u m c h a n n e l b l o c k e r, prostaglandins inhibitors and steroids are being [10] used . Another study has revealed that 71-98% of distal ureteric stones below the size of 5mm pass spontaneously whereas spontaneous expulsion rate is only 25-53% in stones [10] measuring 5-10mm . Furthermore, another study concluded that symptom duration more than 4 weeks increases the chances of complications from 7% to 20%. Stones smaller than 4mm are expelled in 1.6 weeks as compared to 2.8weeks which is the average time taken by the stones 4-6 mm. No stone [11] more than 6mm passed spontaneously . αblockers are of two types which are α-1 and α-2 blockers. α-1 blockers are further divided into three subtypes. α-1a receptors are located in bladder neck, prostate and posterior urethra whereas α-1b receptors are present in the smooth muscles of the vessels. Detrusor muscle [12] and lower ureter contain α-1d receptors . Ureteric α-1 receptors inhibit smooth muscle tone and also decreases the amplitude and frequency of peristalsis. This decreases the intra-ureteric pressure. Urine exerts pressure above the calculus at the same time when intraureteric falls below it. This causes a suction effect which helps in stone progression and [6] expulsion . Non steroidal anti-inflammatory drugs have long been used in patients with renal colic because of their action on ureteral blood [13] flow, smooth muscle, and edema . In the setting of ureteral obstruction, renal blood flow increases initially resulting in increased collecting system pressure, an effect thought to be mediated by prostaglandins E2 and nitric o x i d e . N S A I D s i n h i b i t t h e e n z y m e cyclooxygenase which is responsible for the synthesis of prostaglandins from fatty acids. Inhibition of prostaglandin production may reduce renal pelvic and ureteral pressure, promote relaxation of ureteral smooth muscle, and reduce ureteral edema. As such inhibition of prostaglandins synthesis may not only reduce the pain and obstruction associated with ureteral stone fragments but also increases stone expulsion rate. The provision of endoscopic instruments and experience of the treating physician affects the treatment choice out of available options which could be watchful waiting, extracorporeal shock wave lithotripsy, intracorporeal lithotripsy using ureteroscope [14] and ureterolithotomy . None of the treatment options guarantees a stone free state. Although stone clearance is mainly dependent on size and location, there are some unmodifiable factors like ureteric anatomy and stone composition. Modifiable risk factors include smooth muscle spasm and mucosal edema which occurs due to [15] stone impaction .

METHODOLOGY:
This randomized controlled trial was conducted at the department of Urology, Lahore General Hospital, Lahore for a period of 6 months i.e., from January 25, 2010 to June 24, 2010. Total 150 patients were selected using nonprobability purposive sampling. Two groups were made i.e., group-A and group-B. 75 cases in each group were enrolled. All patients of age between 15-50 years from either gender, who presented in our department with single renal stone 5-20mm in size diagnosed on X -ray KUB were included in the study. However, patients having history of previous unsuccessful ESWL, concomitant use of calcium channel blockers or corticosteroids (on previous available medical record), previous history of pyeloureteral surgery, vertebral malformation, serum Creatinine > 1.5 mg/dl on labs, coagulopathy (PT > 2 seconds, APTT> 2 seconds, INR > 1.5), solitary functioning kidney or patient wishes for immediate stone removal were excluded from the study. A total of 150 patients presenting in Urology OPD were enrolled for study as per inclusion and exclusion criteria. After full explanation of clinical trial and informed consent, patients were asked about their demographic profile. All patients divided into two groups using lottery method. Patients of group-A were given Cap. Tamsulosin 0.4mg just before sleep along with Tab. Diclofenac 50mg twice daily. The group-B only got Tab. Diclofenac 50mg Bid. All patients underwent ESWL every 3 weeks until procedure was efficaceous or for 3 months, whichever was earlier. At the most total of four sessions of ESWL performed for each patient. ESWL was performed using a lithotripter of electromagnetic variety i.e., Modulith -SLX-F-2, Storz Medical. ESWL was performed by a lithotripsy technician, under supervision of doctor from urology department. Treatment was continued until stone expulsion or until the need for auxiliary procedure. The primary end point was the stone clearance (as per operational definition), confirmed with the help of plain X-ray KUB performed after every three weeks before each session of ESWL. Data collected on pre-designed Performa by researchers. Quantitative variables like age were presented as mean±S.D. Whereas, qualitative variables like gender and efficacy were presented as frequency and percentage. The outcome variable i.e. stone expulsion was compared between the groups using Chi-square test. P= 0.05 will be considered significant. Data analysis was performed using SPSS v-11.

DISCUSSION:
Recently, urological field has shown significant advancement e.g., ESWL and ureterorenscopy which is commonly used in management of ureteric stones. However, these interventions [6] are not risk free . Kidney function significantly deteriorates if patient is kept on watchful waiting for longer duration. Different studies have shown that lower ureteric stones undergo spontaneous expulsion in 25-54% cases. However, it may require more than 10 days and [16] considerable amount of analgesia . Stones residing in the ureter cause colicky pain and non-visible hematuria. Invasive treatment is indicated when there is visible hematuria, superadded infection or intractable pain. Transit of stone via ureter is controlled by many factors which are especially related to ureter and stone. Medical therapy is mostly aimed at modifying the ureteric factors. Many drugs have been used for this purpose which includes steroids, calcium channel blockers and alpha blockers. As ureteral smooth muscles have alpha-1 receptors, suggestion were made that blockade of these receptors may reduce ureteric peristalsis and thus facilitate stone passage. The clearance was achieved in maximum number of patients within first three weeks of therapy in our study. In other words prolonged use of tamsulosin did not help clear the stone as much as it did in early days of therapy. This study evaluated the tamsulosin in isolation for its efficacy in stone clearance. Yilmaz et al compared three different alpha blockers as a medical expulsion therapy in lower ureteric [17] stones . They divided 114 patients divided into four groups who received placebo, tamsulosin, terazosin and doxazosin. All patients were observed for 1 month. Expulsion rate in control group was 53.57%, in doxazosin group 75.86%, terazosin group was 78.57%, tamsulosin group was 79.31%. They found that all the alpha blockers are equally effective in enhancing spontaneous expulsion of distal ureteral stones and corticosteroid therapy may

Figure-I: Distribution of patients by Stone
Clearance at follow up (n=150). [18] not be necessary . There are significant benefits of cost effectiveness of this therapy as compared to ESWL or ureteroscopy. Use of Tamsulosin as an adjunctive therapy has been studied by many researchers. In a randomized control trial, role of Tamsulosin was studied in 48 patients who underwent ESWL in distal ureteric stones measuring 6-15mm. Mean stone size in Tamsulosin group was 8.6 mm as compared to 8.2 mm in non-Tamsulosin group. After 15 days, the stone free rate was 70.8% and 33.3% in Tamsulosin and non-Tamsulosin group respectively (p=.019). So, the investigators concluded that use of Tamsulosin therapy not only enhances stone clearance rate [16] but also minimizes complication rate . In the present study, 150 were divided into group-A ( Ta m s u l o s i n ) a n d g r o u p -B ( w i t h o u t Tamsulosin). Each group had 75 patients. The patients in group-A, in which we used tamsulosin, demonstrated a higher stone passage rate as compared to group-B. In group-B stone passage rate at the end of study, was 76% as compared to 86.6% in group-A (Tamsulosin group). Stone clearance rate was statistically insignificant in Tamsulosin group. p-value was insignificant (0.094) but there was considerable difference in results in terms of efficacy. In group-A, 10.6% additional patients passed the stone fragmented when compared with group B. This difference in earlier stone clearance in both groups was also observed at th th 6 and 12 weeks. Stone clearance was observed to be highest among both groups in the first three weeks of therapy after ESWL, with 50.6 % efficacy in group A and 42.6% efficacy in group-B. The clearance gradually decreased in subsequent weeks, with more stone clearance rates in group-A, except for th clearance at 9 week as compared to group-B (Table-III

CONCLUSION:
Small renal stone fragments after ESWL should be managed conservatively to facilitate their passage through ureter. We have concluded that Tamsulosin therapy in distal ureteric stones did not make any statistical difference in terms of efficacy but still, there is considerable difference in stone clearance. It also decreases stone expulsion time. Based on comparison with international studies, we recommended alpha-1 antagonists to facilitate the passage of renal stone fragments after ESWL. Post-ESWL Tamsulosin therapy is a cheap option which improves patient satisfaction. But this drug needs to be further evaluated in our setup for its use in stone disease patients undergoing shockwave lithotripsy.