- ACRONYMS AND DEFINITIONS
- AUA - American Urological Association
- AUA symptom score - a standardized questionnaire used to assess and quantify BPH symptoms
- BPH - Benign prostatic hypertrophy/hyperplasia
- CrCl - Creatinine clearance
- CVD - Cardiovascular disease
- EAU - European Association of Urology
- ED - Erectile dysfunction
- IFIS - Intraoperative floppy iris syndrome
- IPSS - International prostatism symptom score
- JNC 8 - Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure
- LUTS - Lower urinary tract symptoms
- MI - Myocardial infarction
- Qmax - Qmax is defined as the peak flow rate of urine in milliliters/second
- RCT - Randomized controlled trial
- Tam - Tamsulosin
- 5ARI - 5 alpha reductase inhibitors
- DRUGS IN CLASS
- Alpha blockers
- Alfuzosin (Uroxatral®)
- Doxazosin (Cardura®, Cardura XL®)
- Prazosin (Minipress®)
- Silodosin (Rapaflo®)
- Tamsulosin (Flomax®)
- Terazosin (Hytrin®)
- Combination products
- Jalyn® (tamsulosin + dutasteride)
- MECHANISM OF ACTION
- Alpha-1 receptors
- There are 3 types of alpha-1 receptors: Alpha 1A, Alpha 1B, and Alpha 1D
- Alpha-1 receptors are found throughout the body in various tissues, and their actions when stimulated are tissue-specific
- For the purposes of reviewing alpha blockers, the following is generally true:
- Alpha-1A and 1D receptors
- Found in the bladder, ureters, and prostate
- Stimulating alpha-1A and 1D receptors inhibits urine flow
- Alpha-1B receptors
- Found in arteries and veins
- Stimulating alpha-1B receptors causes vasoconstriction and raises blood pressure
- Alpha blockers
- Alpha blockers differ by which types of alpha-1 receptors they block
- Nonselective (block all alpha receptors)
- Doxazosin
- Prazosin
- Terazosin
- Selective for Alpha-1A and Alpha-1D
- Alfuzosin
- Silodosin
- Tamsulosin
- Blood pressure-lowering (doxazosin, prazosin, terazosin only)
- Three alpha blockers are approved for the treatment of hypertension - doxazosin, prazosin, terazosin
- Alpha-1B receptors are present in the smooth muscle of blood vessels, and they are stimulated by adrenaline
- Stimulating alpha-1B receptors causes vessels to constrict and blood pressure rises
- Alpha blockers block stimulation of alpha-1B receptors and inhibit blood vessels from constricting [26]
- Prostate relaxation (all alpha blockers except prazosin)
- Alpha-1A and 1D receptors are abundant in the prostate and bladder neck
- Stimulating alpha-1A and 1D receptors in the prostate and bladder causes smooth muscle to contract and obstructs urine flow
- Alpha blockers prevent stimulation of alpha-1A and 1D receptors causing smooth muscle to relax and thus facilitating urine flow [1, 2, 3, 19, 23, 24, 26]
- Ureteral relaxation
- The ureter is a tube-like organ that carries urine from the kidney to the bladder
- When kidney stones are present, they may pass through the ureters
- Blocking alpha-1A receptors in the ureters causes the ureters to relax and kidney stones may pass easier [26]
- FDA-APPROVED INDICATIONS
- Alfuzosin (Uroxatral®)
- Benign prostatic hyperplasia (BPH)
- Doxazosin (Cardura®)
- Benign prostatic hyperplasia (BPH)
- Hypertension
- Doxazosin (Cardura XL®)
- Benign prostatic hyperplasia (BPH)
- Prazosin (Minipress®)
- Hypertension
- Silodosin (Rapaflo®)
- Benign prostatic hyperplasia (BPH)
- Tamsulosin (Flomax®)
- Benign prostatic hyperplasia (BPH)
- Terazosin (Hytrin®)
- Benign prostatic hyperplasia (BPH)
- Hypertension
- HYPERTENSION (doxazosin, terazosin, prazosin)
- Overview
- Only three alpha blockers (doxazosin, prazosin, terazosin) are approved to treat hypertension. Cardura XL® (doxazosin extended-release) is not FDA-approved to treat hypertension, but it appears to have a similar effect on blood pressure as standard doxazosin. [22]
- A randomized controlled trial and a Cochrane meta-analysis that looked at the effects of different alpha blockers on hypertension are detailed below
- The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
- Male veteran
- DBP 95 - 109 mmHg off medications
Baseline characteristics
- Average age 59 years
- Average BP 152/99 mmHg
- Black race - 48%
- Current smoker - 32%
Randomized treatment groups
- Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
- Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
- Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
- Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
- Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
- Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
- Group 2 (186 patients) - Placebo
- There was a washout period of 4 - 8 weeks before randomization
- Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results
Average BP reduction at the end of the titration phase (SBP/DBP mmHg) | ||||||
---|---|---|---|---|---|---|
HCTZ | Atenolol | Captopril | Clonidine | Diltiazem | Prazosin | Placebo |
14 / 10 | 11 / 12 | 9 / 10 | 16 / 12 | 13 / 14 | 12 / 11 | 3 / 5 |
|
Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.
- STUDY
- A Cochrane meta-analysis looked at the effects of alpha blockers on blood pressure
- The analysis only found 9 relevant studies that compared alpha blockers to placebo in the treatment of hypertension
- A summary of the effects of the individual drugs is presented here
- NOTE: Blood pressure reductions are reported as drug effect minus placebo effect. Blood pressures were taken at the end of the dosing interval (trough levels).
- Doxazosin (3 trials)
- Doxazosin reduced systolic blood pressure an average of 6.42 mmHg
- Doxazosin reduced diastolic blood pressure an average of 3.53 mmHg
- Prazosin (2 trials)
- Prazosin reduced systolic blood pressure an average of 10.38 mmHg
- Prazosin reduced diastolic blood pressure an average of 6.90 mmHg
- Terazosin (4 trials)
- Terazosin reduced systolic blood pressure an average of 6.59 mmHg
- Terazosin reduced diastolic blood pressure an average of 4.40 mmHg [4]
- Professional recommendations
- See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
- CARDIOVASCULAR DISEASE
- Overview
- The ALLHAT trial detailed below evaluated the effects of doxazosin on cardiovascular disease outcomes
- The doxazosin and chlorthalidone arms of the ALLHAT study enrolled 24,335 patients with hypertension and at least one risk factor for heart disease
Main inclusion criteria
- Age > 55 years
- SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
- One of the following: previous MI or stroke, left ventricular hypertrophy, type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
- History of hospitalized or treated symptomatic heart failure and/or EF < 35%
Baseline characteristics
- Average age 67 years
- Race: White - 47% | Black - 32% | Hispanic - 16%
- Women - 47%
- Average BP - 145/83
- Receiving treatment for hypertension - 90%
- Qualifying risk factor: CVD - 45% | Diabetes - 35% | Smoker - 22% | LVH - 20% | Low HDL - 12%
Randomized treatment groups
- Group 1 (15,268 patients) - Chlorthalidone 12.5 - 25 mg a day
- Group 2 (9067 patients) - Doxazosin 2 - 8 mg a day
- Treatment was titrated to a BP goal of < 140/90
- If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25 -100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
- There were 2 other treatment arms in the full study (amlodipine and lisinopril) that are not presented here
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results
Duration: After a median follow-up of 3.3 years, the doxazosin arm was stopped early because of an increased risk of major CVD events | |||
Outcome | Chlorthalidone | Doxazosin | Comparisons |
---|---|---|---|
Primary outcome (4-year rate) | 6.3% | 6.26% | RR 1.03, 95%CI [0.90 - 1.17], p=0.71 |
Overall mortality (4-year rate) | 9.08% | 9.62% | RR 1.03, 95%CI [0.90 - 1.15], p=0.56 |
Stroke (4-year rate) | 3.61% | 4.23% | RR 1.19, 95%CI [1.01 - 1.40], p=0.04 |
Congestive heart failure (4-year rate) | 4.45% | 8.13% | RR 2.04, 95%CI [1.79 - 2.32], p<0.001 |
Taking additional BP meds at 3 years | 37% | 44% | N/A |
Findings: Our data indicate that compared with doxazosin, chlorthalidone yields essentially equal risk of CHD death/nonfatal MI but significantly reduces the risk
of combined CVD events, particularly CHF, in high-risk hypertensive patients
- Professional recommendations
- See hypertension guidelines for a review of recommended therapies in CVD
- Summary
- Alpha blockers have a modest effect in lowering blood pressure
- After doxazosin's disappointing results in the ALLHAT trial, their use in treating hypertension has fallen out of favor
- Other classes of blood pressure medications have better outcome data and should be used first
- In patients with hypertension and benign prostatic hypertrophy (BPH), doxazosin or hytrin may be considered since the two conditions can be treated with one medication
- BENIGN PROSTATIC HYPERPLASIA (BPH)
- Alpha blockers in BPH
- As men age, the prostate gland tends to enlarge, a condition called benign prostatic hyperplasia. BPH starts around the age of 40, and the condition becomes near-ubiquitous with age, with 60% of 60-year-olds being affected and 80% of eighty-year-olds. If the prostate becomes too big, it may obstruct urine flow.
- Alpha blockers relax smooth muscle in the prostate and bladder neck, and this can help facilitate urine flow. All alpha blockers except prazosin are approved to treat BPH. There are no good head-to-head trials that have compared different alpha blockers to each other. The AUA states that all alpha blockers appear to be equally effective. [10]
- The EAU looked at 13 RCTs that evaluated the effects of alpha blockers in BPH and came to the following conclusions:
- Alpha blockers improve BPH symptom scores by 30 - 45% when compared to baseline
- Alpha blockers improve measures of urine flow (peak flow rate of urine in ml/second) by 20 - 25% when compared to baseline
- Improvement in symptoms can be seen within hours to days, while full effects can take weeks
- In one large trial, the effects of doxazosin were still significant after an average follow-up of 4.5 years (see MTOPS trial below)
- Of note, the placebo group often has marked improvement in symptom score and urine flow in BPH trials when compared to baseline [9,12,13]
- 5-alpha reductase inhibitors (5ARIs) in BPH
- Prostate enlargement is dependent on a potent androgen called 5-alpha-dihydrotestosterone (DHT). An enzyme called type II 5-alpha-reductase converts testosterone to DHT in the prostate gland. 5-alpha reductase inhibitors (5ARIs) block this enzyme and prevent the formation of DHT.
- The effects of 5ARIs are not immediate, and it can take > 1 year for the prostate to shrink enough to improve symptoms of BPH. Alpha blockers are often prescribed with 5ARIs to improve symptoms of BPH in the short term.
- Two large randomized trials have compared alpha blockers to 5ARIs and their combination in men with BPH. Those trials are detailed below.
- The MTOPS trial enrolled 3047 men with BPH symptoms
Main inclusion criteria
- Age ≥ 50 years
- AUA BPH symptom score of 8 - 30 (scale is 0 [no symptoms] - 35 [severe symptoms])
- Maximum urinary flow rate between 4 - 15 ml/second with a voided volume of at least 125 ml
Main exclusion criteria
- Prior medical or surgical intervention for BPH
- BP < 90/70
- PSA > 10 ng/ml
Baseline characteristics
- Average age 63 years
- Average AUA score - 16.9
- Average prostate volume - 36.3 ml
- Maximum urine flow rate - 10.5 ml/sec
- Average post-void residual - 68 ml
- Average PSA - 2.4
Randomized treatment groups
- Group 1 (737 patients) - Placebo
- Group 2 (756 patients) - Doxazosin 4 - 8 mg per day
- Group 3 (768 patients) - Finasteride 5 mg once daily
- Group 4 (786 patients) - Finasteride 5 mg once daily + Doxazosin 4 - 8 mg per day (combination therapy)
Primary outcome: Composite of an increase from baseline of ≥ 4 points in the AUA symptom
score, acute urinary retention, renal insufficiency, recurrent urinary tract infection, or urinary incontinence
Results
Duration: Average of 4.5 years | |||||
Outcome | Placebo | Doxazosin | Finasteride | Combo | Comparisons |
---|---|---|---|---|---|
Primary outcome (events/100 person-year) | 4.5 | 2.7 | 2.9 | 1.5 | 2 vs 1 p<0.001 | 3 vs 1 p=0.002 | 4 vs 1 p<0.001 | 4 vs 2 p<0.001 | 4 vs 3 p<0.001 |
Acute urinary retention (events/100 person-year) | 0.6 | 0.4 | 0.2 | 0.1 | 2 vs 1 p=0.23 | 3 vs 1 p=0.009 | 4 vs 1 p<0.001 |
Invasive therapy due to BPH (events/100 person-year) | 1.3 | 1.3 | 0.5 | 0.4 | 3 vs 1 p<0.001 | 4 vs 1 p<0.001 |
Serum PSA (median % change from baseline at 1 year) | +15% | +13% | -50% | -50% | N/A |
Dizziness (events/100 person-year) | 2.29 | 4.41 | 2.33 | 5.35 | 2 vs 1 p<0.05 | 4 vs 1 p<0.05 |
Asthenia (events/100 person-year) | 2.06 | 4.08 | 1.56 | 4.20 | 2 vs 1 p<0.05 | 4 vs 1 p<0.05 |
Erectile dysfunction (events/100 person-year) | 3.32 | 3.56 | 4.53 | 5.11 | 3 vs 1 p<0.05 | 4 vs 1 p<0.05 |
Decreased libido (events/100 person-year) | 1.40 | 1.56 | 2.36 | 2.51 | 3 vs 1 p<0.05 | 4 vs 1 p<0.05 |
Abnormal ejaculation (events/100 person-year) | 0.83 | 1.10 | 1.78 | 3.05 | 3 vs 1 p<0.05 | 4 vs 1 p<0.05 |
|
Findings: Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia
significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy.
- The COMBAT study enrolled 4844 men with BPH
Main inclusion criteria
- Age ≥ 50 years
- BPH diagnosis
- IPSS ≥ 12
- Prostate volume ≥ 30 ml by transrectal US
- PSA ≥ 1.5 mg/ml
- Qmax > 5 ml/sec and ≤ 15 ml/sec w ith minimum voided volume ≥ 125 ml
Main exclusion criteria
- PSA > 10 ng/ml
- History of prostate cancer
- Previous prostatic surgery
- History of urinary retention within 3 months
- 5ARI use within 6 months or d utasteride use within 12 months
Baseline characteristics
- Average age 66 years
- Average IPSS score 16
- Average prostate volume - 54 ml
- Average PSA - 4
- Average Qmax - 10.7 ml/sec
- A verage postvoid residual - 68 ml
- Previous alpha blocker use - 50%
- Previous 5ARI use - 11%
Randomized treatment groups
- Group 1 (1611 patients) - Tamsulosin 0.4 mg once daily
- Group 2 (1623 patients) - Dutasteride 0.5 mg once daily
- Group 3 (1610 patients) - Tamsulosin 0.4 mg once daily + Dutasteride 0.5 mg once daily (combination therapy)
Primary outcome: Composite of acute urinary retention or BPH-related prostatic surgery at 4 years
Results
Duration: 4 years | ||||
Outcome | Tamsulosin | Dutasteride | Combo | Comparisons |
---|---|---|---|---|
Primary outcome | 11.9% | 5.2% | 4.2% | 3 vs 1 p<0.001 | 3 vs 2, p=0.18 |
BPH-related acute urinary retention | 5.1% | 2.3% | 1.6% | 3 vs 1, p<0.001 | 3 vs 2, p=0.17 |
BPH-related surgery | 7.8% | 3.5% | 2.4% | 3 vs 1, p<0.001 | 3 vs 2, p=0.074 |
Symptom worsening (IPSS increase ≥ 4 points) | 14.2% | 13.1% | 8.6% | 3 vs 1, p<0.001 | 3 vs 2, p<0.001 |
PSA (median % change from baseline) | +18.4% | -56% | -57.1% | N/A |
Drug discontinuation | 39% | 33% | 31% | N/A |
Erectile dysfunction | 5% | 7% | 9% | N/A |
Retrograde ejaculation | 1% | < 1% | 4% | N/A |
Decreased libido | 2% | 3% | 4% | N/A |
|
Findings: The 4-year COMBAT data provide support for the long-term use of dutasteride and tamsulosin combination therapy in men with moderate-to-severe
UTS due to BPH and prostatic enlargement
AUA 2021 BPH recommendations |
---|
Initial evaluation
|
Initial treatment
|
Follow-up
|
- Lifestyle modification therapy for BPH symptoms
- Reduction of fluid intake at specific times aimed at reducing urinary frequency when most inconvenient (e.g. at night or when going out in public)
- Avoidance/moderation of intake of caffeine or alcohol, which may have a diuretic and irritant effect, thereby increasing fluid output and enhancing frequency, urgency, and nocturia
- Double voiding technique - urinating as much as possible, relaxing for a few moments, and then urinating again
- Urethral milking to prevent post-micturition dribble
- Distraction techniques such as penile squeeze, breathing exercises, perineal pressure, and mental tricks to take the mind off the bladder and toilet to help control overactive bladder symptoms
- Bladder retraining that encourages men to hold on when they have urgency to increase their bladder capacity and the time between voids
- Reviewing medications and optimizing the time of administration or substituting drugs for others that have fewer urinary effects (e.g discontinuing diuretics if possible)
- Treating and preventing constipation - a full bowel can put pressure on the bladder and urethra, making it more difficult to urinate [38]
- KIDNEY STONES
- Overview
- Kidney stones occur when minerals crystallize and form masses in the renal collecting system
- Renal stones are typically asymptomatic. If a renal stone passes into the ureter, it usually becomes symptomatic.
- The size of the stone dictates whether it will be able to pass through the ureters into the bladder. See natural course of ureteral stones for more.
- The ureters have alpha-1A receptors on their surface. Blocking these receptors with alpha blockers causes the ureters to relax and dilate. Alpha blocker-induced dilation could theoretically facilitate the passage of kidney stones. [26]
- Three randomized controlled trials that looked at the effects of alpha blockers on kidney stone passage are detailed below.
- The study enrolled 512 patients presenting to the ER with newly-diagnosed, symptomatic ureteral stones < 9 mm in diameter
Main inclusion criteria
- Symptomatic ureteral stone < 9 mm in diameter confirmed on CT scan
Main exclusion criteria
- Concurrent UTI
- Prior ureter/kidney surgery
Baseline characteristics
- Average age 40 years
- Average stone size - 3.8 mm
- Stone size ≤ 4 mm - 74% of patients
- Stone location: Ureterovesical junction - 44% | Distal ureter - 24% | Proximal ureter 17%
Randomized treatment groups
- Group 1 (267 patients) - Tamsulosin 0.4 mg once daily for 30 days
- Group 2 (245 patients) - Placebo once daily for 30 days
Primary outcome: The primary outcome was passage of a ureteral stone within 28 days after randomization, as
determined by the participant’s visualization or physical capture of the stone
Results
Duration: 28 days | |||
Outcome | Tamsulosin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 49.6% | 47.3% | p=0.60 |
Stone passed on follow-up CT (N=238) | 83.6% | 77.6% | p=0.24 |
Surgery for stone | 6.5% | 6.9% | p=0.89 |
|
Findings: Tamsulosin did not significantly increase the stone passage rate compared with placebo. Our findings do not support the use of tamsulosin for
symptomatic urinary stones smaller than 9 mm. Guidelines for medical expulsive therapy for urinary stones may need to be revised.
- A study in the Annals of Emergency Medicine enrolled 403 patients with distal ureteral stones who presented to the ER with ureteral colic
Main inclusion criteria
- Distal ureteral stone ≤ 10 mm on CT scan (distal ureter defined as distal to the sacroiliac joint)
Main exclusion criteria
- GFR < 60 ml/min
- Temp > 100.4°F
Baseline characteristics
- Median stone size - 3.8 mm
- Stones 5-10 mm in size - 26%
- Vesicoureteric junction stone - 64%
Randomized treatment groups
- Group 1 (198 patients) - Tamsulosin 0.4 mg once daily for 28 days
- Group 2 (195 patients) - Placebo once daily for 28 days
- A prespecified subgroup analysis comparing stone < 5 mm to stones 5-10 mm was performed. Randomization was stratified by stone size (< 5 mm and 5-10 mm)
Primary outcome: The coprimary outcomes were stone expulsion and time to stone expulsion. Stone expulsion was defined as absence
of stone on repeated, noncontrast, limited pelvic CT at 28 days. Time to stone expulsion in days was defined as self-reported definitive passage of the calculus or first
day of a pain-free 48-hour period, with calculus absent on repeated CT.
Results
Duration: 28 days | |||
Outcome | Tamsulosin | Placebo | Comparisons |
---|---|---|---|
Stone expulsion (overall) | 87% | 82% | diff 5%, 95%CI [-3 to 13] |
Stone expulsion for stones < 5 mm (N=239) | 88% | 89.5% | diff -1.5%, 95%CI [-9.5 to 6.5] |
Stone expulsion for stones 5 - 10 mm (N=77) | 83% | 61% | diff 22%, 95%CI [3.1 to 41.6] |
Median time to stone passage (overall) | 7 days | 11 days | p=0.10 |
|
Findings: We found no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.
- A study in the Lancet enrolled 1167 patients with newly diagnosed kidney stones presenting to hospitals with ureteral colic
Main inclusion criteria
- 18 - 65 years of age
- One kidney stone ≤ 10 mm in diameter in either ureter identified on CT scan
Main exclusion criteria
- Sepsis
- GFR < 30 ml/min
- Need for immediate intervention
Baseline characteristics
- Average age 42 years
- Average stone size 4.5 mm
- Stone size: ≤ 5 mm - 75% | > 5 mm - 25%
- Location: Upper ureter 24% | Middle ureter 11% | Lower ureter 65%
Randomized treatment groups
- Group 1 (391 patients) - Tamsulosin 0.4 mg once daily for 28 days
- Group 2 (387 patients) - Nifedipine 30 mg once daily for 28 days
- Group 3 (389 patients) - Placebo once daily for 28 days
Primary outcome: Spontaneous stone passage in 4 weeks (defined as the absence of need for additional interventions to assist
stone passage at 4 weeks after randomisation)
Results
Duration: 4 weeks | ||||
Outcome | Tamsulosin | Nifedipine | Placebo | Comparisons |
---|---|---|---|---|
Primary outcome | 81% | 80% | 80% | p>0.05 |
Average number of days to stone passage | 16.5 | 16.2 | 15.9 | p>0.05 |
|
Findings: Tamsulosin 400 μg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic
- Professional recommendations
- Summary
- The three randomized controlled trials detailed above found no overall benefit of tamsulosin in facilitating ureteral stone passage. In a subgroup analysis of the Annals of EM trial, tamsulosin significantly improved passage of stones that were 5 - 10 mm in size. There was also a trend towards improved passage rates with tamsulosin and stones > 5 mm (p=0.13) in the Lancet trial.
- In conclusion, tamsulosin has no proven benefit in facilitating kidney stone passage, although a small benefit cannot be ruled out for stones ≥ 5 mm in size and proximal stones
- SIDE EFFECTS
- Alfuzosin (Uroxatral®)
- Hypotension and lightheadedness
- Alfuzosin is selective for alpha-1A and 1D receptors in the bladder and prostate
- Despite this, it still has the potential to cause postural hypotension (low blood pressure when standing)
- Postural hypotension may be more common in patients taking blood pressure medications
- In one trial, symptoms of low blood pressure occurred in 6.3% of patients taking alfuzosin compared to 2.8% of patients taking placebo [19]
- Summary
- All alpha blockers may cause symptoms of low blood pressure in some patients
- The risk may be higher in patients taking other blood pressure medications
- Patients should be aware of the possibility and avoid activities where dizziness, lightheadedness, or passing out could be dangerous
- The effects are typically experienced when starting the drug, when increasing the dosage, or when restarting the drug after not taking for a few days
- The effects tend to subside with time (typically over a week)
- Once the effects, if any, have resolved, patients can resume normal activities after alpha blocker dosing
- Prolonged QT interval
- Alfuzosin has been shown to prolong the QT interval of the cardiac cycle (see prolonged QT interval for more)
- Patients with congenital or acquired prolonged QT interval should not take alfuzosin
- Patients taking other medications that may prolong the QT interval should avoid alfuzosin [19]
- Sexual dysfunction
- Alfuzosin does not appear to have a significant effect on sexual function or ejaculation [17,19]
- Intraoperative floppy iris syndrome (IFIS)
- IFIS is a syndrome where the iris (colored part of the eye) is floppy and flaccid
- IFIS can complicate eye surgery, particularly cataract surgery
- In 2005, it was discovered that alpha blockers are associated with an increased risk of IFIS
- Tamsulosin has the highest risk of IFIS (43-90% in studies)
- The risk with alfuzosin is much less than tamsulosin
- In one small study, 2 out of 13 patients (15.4%) who had taken alfuzosin had IFIS during cataract surgery compared to 19 out of 22 patients (86.4%) who had taken tamsulosin [18]
- Summary
- All alpha blockers can cause IFIS
- The risk appears to be much greater with tamsulosin than with the other alpha blockers
- It is unclear if stopping alpha blockers prior to eye surgery has an effect on the severity or incidence of IFIS
- Patients who anticipate having eye surgery should not start alpha blockers prior to surgery
- Patients on alpha blockers who are planning eye surgery should make sure their surgeon is aware they are taking one
- Priapism
- Priapism is an erection that lasts for hours and will not subside with ejaculation
- Priapism can lead to permanent impotence if untreated
- In very rare cases, alpha blockers have been associated with priapism
- Doxazosin (Cardura® and Cardura XL®)
- Hypotension and lightheadedness
- Doxazosin is a nonselective A1 receptor blocker that can lower blood pressure
- Postural hypotension (low blood pressure when standing) may occur with any alpha blocker
- The effect may be more common in patients taking other blood pressure medications
- Cardura XL is absorbed more slowly that Cardura so it may carry a lower risk of hypotension
- In trials, symptoms of low blood pressure have occurred in up to 20% of patients taking doxazosin (placebo incidence around 9%) [1,12]]
- Summary
- All alpha blockers may cause symptoms of low blood pressure in some patients
- The risk may be higher in patients taking other blood pressure medications
- Patients should be aware of the possibility and avoid activities where dizziness, lightheadedness, or passing out could be dangerous
- The effects are typically experienced when starting the drug, when increasing the dosage, or when restarting the drug after not taking for a few days
- The effects tend to subside with time (typically over a week)
- Once the effects, if any, have resolved, patients can resume normal activities after alpha blocker dosing
- Sexual dysfunction
- Doxazosin does not appear to have a significant effect on sexual function or ejaculation [19,35]
- Intraoperative floppy iris syndrome (IFIS)
- IFIS is a syndrome where the iris (colored part of the eye) is floppy and flaccid
- IFIS can complicate eye surgery, particularly cataract surgery
- In 2005, it was discovered that alpha blockers are associated with an increased risk of IFIS
- Tamsulosin has the highest risk of IFIS (43-90% in studies) [10]
- The risk with doxazosin appears to be much less than tamsulosin
- In one small study, 1 out of 18 eyes (6%) in patients taking doxazosin had IFIS [20]
- Summary
- All alpha blockers can cause IFIS
- The risk appears to be much greater with tamsulosin than with the other alpha blockers
- It is unclear if stopping alpha blockers prior to eye surgery has an effect on the severity or incidence of IFIS
- Patients who anticipate having eye surgery should not start alpha blockers prior to surgery
- Patients on alpha blockers who are planning eye surgery should make sure their surgeon is aware they are taking one
- Fatigue
- Doxazosin may cause significant fatigue
- In studies, about 8 - 12% of patients on doxazosin complain of fatigue (placebo incidence 2-6%) [1, 5]
- Swelling of the feet and legs (edema)
- In some studies, doxazosin has been associated with a small increase in the risk for swelling of the feet and legs (2.7% of patients on doxazosin vs 0.7% of patients on placebo) [1]
- Priapism
- Priapism is an erection that lasts for hours and will not subside with ejaculation
- Priapism can lead to permanent impotence if untreated
- In very rare cases, alpha blockers have been associated with priapism
- Prazosin (Minipress®)
- Hypotension and lightheadedness
- Prazosin is a nonselective A1 receptor blocker, and it can lower blood pressure
- Postural hypotension (low blood pressure when standing) may occur with any alpha blocker
- The effect may be more common in patients taking other blood pressure medications
- Symptoms of low blood pressure have occurred in up to 10% of patients taking prazosin in trials [23]
- Summary
- All alpha blockers may cause symptoms of low blood pressure in some patients
- The risk may be higher in patients taking other blood pressure medications
- Patients should be aware of the possibility and avoid activities where dizziness, lightheadedness, or passing out could be dangerous
- The effects are typically experienced when starting the drug, when increasing the dosage, or when restarting the drug after not taking for a few days
- The effects tend to subside with time (typically over a week)
- Once the effects, if any, have resolved, patients can resume normal activities after alpha blocker dosing
- Sexual dysfunction
- Prazosin does not appear to have a significant effect on sexual function or ejaculation [19,35]
- Intraoperative floppy iris syndrome (IFIS)
- IFIS is a syndrome where the iris (colored part of the eye) is floppy and flaccid
- IFIS can complicate eye surgery, particularly cataract surgery
- In 2005, it was discovered that alpha blockers are associated with an increased risk of IFIS
- Tamsulosin has the highest risk of IFIS (43-90% in studies) [10]
- The risk of IFIS with prazosin is not well-defined
- Summary
- All alpha blockers can cause IFIS
- The risk appears to be much greater with tamsulosin than with the other alpha blockers
- It is unclear if stopping alpha blockers prior to eye surgery has an effect on the severity or incidence of IFIS
- Patients who anticipate having eye surgery should not start alpha blockers prior to surgery
- Patients on alpha blockers who are planning eye surgery should make sure their surgeon is aware they are taking one
- Fatigue
- The incidence of fatigue with prazosin is 6-8% in trials [23]
- Priapism
- Priapism is an erection that lasts for hours and will not subside with ejaculation
- Priapism can lead to permanent impotence if untreated
- In very rare cases, alpha blockers have been associated with priapism
- Silodosin (Rapaflo®)
- Hypotension and lightheadedness
- Silodosin is selective for alpha-1A and 1D receptors in the prostate and bladder
- Despite this, it still has the potential to cause postural hypotension (low blood pressure when standing)
- In trials, symptoms of low blood pressure occurred in 3.2% of patients taking silodosin versus 1% of patients on placebo [24]
- Summary
- All alpha blockers may cause symptoms of low blood pressure in some patients
- The risk may be higher in patients taking other blood pressure medications
- Patients should be aware of the possibility and avoid activities where dizziness, lightheadedness, or passing out could be dangerous
- The effects are typically experienced when starting the drug, when increasing the dosage, or when restarting the drug after not taking for a few days
- The effects tend to subside with time (typically over a week)
- Once the effects, if any, have resolved, patients can resume normal activities after alpha blocker dosing
- Sexual dysfunction
- Silodosin can cause changes in ejaculation
- In the past, it was thought that silodosin may cause "retrograde ejaculation," a condition where sperm is ejaculated back into the bladder. The mechanism for this was believed to occur from silodosin-induced relaxation of the bladder neck.
- Several recent studies have shown that alpha blockers actually cause a decrease in semen/ejaculatory volume, not retrograde ejaculation. The mechanism appears to occur through blockade of alpha-1A receptors on seminal vesicles (organ where sperm is stored) [31,32]
- Clinical studies
- In a small trial, 15 healthy men were given silodosin 4 mg twice a day for 3 days
- The following effects on ejaculation were seen:
- All men developed complete loss of ejaculatory volume/semen
- Three days after stopping the medication, ejaculatory volume returned to normal [32]
- Silodosin PI
- The silodosin PI states that in two trials, abnormal ejaculation was reported in 28% of patients taking silodosin 8 mg a day versus 1% of patients on placebo [24]
- Summary
- Silodosin may cause a decrease in sperm/ejaculatory volume in a significant number of men
- Based on recent studies, this appears to be caused by inhibition of the seminal vesicles and not "retrograde ejaculation" as once believed
- The effect appears to resolve quickly after the drug is stopped
- Intraoperative floppy iris syndrome (IFIS)
- IFIS is a syndrome where the iris (colored part of the eye) is floppy and flaccid
- IFIS can complicate eye surgery, particularly cataract surgery
- In 2005, it was discovered that alpha blockers are associated with an increased risk of IFIS
- Tamsulosin has the highest risk of IFIS (43-90% in studies) [10]
- The incidence of IFIS with silodosin is not well-defined
- Summary
- All alpha blockers can cause IFIS
- The risk appears to be much greater with tamsulosin than with the other alpha blockers
- It is unclear if stopping alpha blockers prior to eye surgery has an effect on the severity or incidence of IFIS
- Patients who anticipate having eye surgery should not start alpha blockers prior to surgery
- Patients on alpha blockers who are planning eye surgery should make sure their surgeon is aware they are taking one
- Priapism
- Priapism is an erection that lasts for hours and will not subside with ejaculation
- Priapism can lead to permanent impotence if untreated
- In very rare cases, alpha blockers have been associated with priapism
- Tamsulosin (Flomax®)
- Hypotension and lightheadedness
- Tamsulosin is selective for alpha-1A and 1D receptors in the prostate and bladder
- Despite this, it still has the potential to cause postural hypotension (low blood pressure when standing)
- In trials, symptoms of low blood pressure occurred in 15% of patients taking 0.4mg of tamsulosin, 17% of patients taking 0.8mg of tamsulosin, and 10% of patients on placebo [2]
- Summary
- All alpha blockers may cause symptoms of low blood pressure in some patients
- The risk may be higher in patients taking other blood pressure medications
- Patients should be aware of the possibility and avoid activities where dizziness, lightheadedness, or passing out could be dangerous
- The effects are typically experienced when starting the drug, when increasing the dosage, or when restarting the drug after not taking for a few days
- The effects tend to subside with time (typically over a week)
- Once the effects, if any, have resolved, patients can resume normal activities after alpha blocker dosing
- Sexual dysfunction
- Tamsulosin can cause changes in ejaculation
- In the past, it was thought that tamsulosin may cause "retrograde ejaculation," a condition where sperm is ejaculated back into the bladder. The mechanism for this was believed to occur from tamsulosin-induced relaxation of the bladder neck.
- Several recent studies have shown that alpha blockers actually cause a decrease in semen/ejaculatory volume, not retrograde ejaculation. The mechanism appears to occur through blockade of alpha-1A receptors on seminal vesicles (organ where sperm is stored) [31,32]
- Clinical studies
- In a small trial, 53 healthy men were given tamsulosin 0.8 mg a day for 5 days
- The following effects on ejaculation were seen:
- Tamsulosin 0.8 mg a day caused a decrease in ejaculatory volume (defined as greater than 20% decrease from baseline) in 90% of patients
- No ejaculation or complete loss of ejaculatory volume occurred in 35% of subjects
- No difference in sperm count was found in post-ejaculate urine [35]
- Tamsulosin PI
- The tamsulosin PI states that abnormal ejaculation was reported in 8.4% of patients taking 0.4mg of tamsulosin, 18% of patients taking 0.8mg of tamsulosin, and 0.2% of patients on placebo [2]
- Summary
- Tamsulosin may cause a decrease in sperm/ejaculatory volume in a significant number of men
- Based on recent studies, this appears to be caused by inhibition of the seminal vesicles and not "retrograde ejaculation" as once believed
- The effect appears to resolve quickly after the drug is stopped [31,32]
- Intraoperative floppy iris syndrome (IFIS)
- IFIS is a syndrome where the iris (colored part of the eye) is floppy and flaccid
- IFIS can complicate eye surgery, particularly cataract surgery
- In 2005, it was discovered that alpha blockers are associated with an increased risk of IFIS
- Tamsulosin has the highest risk of IFIS (43 - 90% in studies) [10]
- In one small study, 19 out of 22 patients (86%) exposed to tamsulosin had IFIS [18]
- Summary
- All alpha blockers can cause IFIS
- The risk appears to be much greater with tamsulosin than with the other alpha blockers
- It is unclear if stopping alpha blockers prior to eye surgery has an effect on the severity or incidence of IFIS
- Patients who anticipate having eye surgery should not start alpha blockers prior to surgery
- Patients on alpha blockers who are planning eye surgery should make sure their surgeon is aware they are taking one
- Fatigue
- In trials, the incidence of fatigue was 7 - 9% in tamsulosin-treated patients compared to 5.5% in placebo-treated patients [2]
- Priapism
- Priapism is an erection that lasts for hours and will not subside with ejaculation
- Priapism can lead to permanent impotence if untreated
- In very rare cases, alpha blockers have been associated with priapism
- Terazosin (Hytrin®)
- Hypotension and lightheadedness
- Terazosin is a nonselective alpha-1 receptor blocker, and it can cause symptoms of low blood pressure
- Postural hypotension (low blood pressure when standing) may occur with any alpha blocker
- The effect may be more common in patients taking other blood pressure medications
- In trials, symptoms of low blood pressure have occurred in up to 28% of patients [3]
- Summary
- All alpha blockers may cause symptoms of low blood pressure in some patients
- The risk may be higher in patients taking other blood pressure medications
- Patients should be aware of the possibility and avoid activities where dizziness, lightheadedness, or passing out could be dangerous
- The effects are typically experienced when starting the drug, when increasing the dosage, or when restarting the drug after not taking for a few days
- The effects tend to subside with time (typically over a week)
- Once the effects, if any, have resolved, patients can resume normal activities after alpha blocker dosing
- Sexual dysfunction
- Terazosin does not appear to have a significant effect on sexual function or ejaculation [3]
- Intraoperative floppy iris syndrome (IFIS)
- IFIS is a syndrome where the iris (colored part of the eye) is floppy and flaccid
- IFIS can complicate eye surgery, particularly cataract surgery
- In 2005, it was discovered that alpha blockers are associated with an increased risk of IFIS
- Tamsulosin has the highest risk of IFIS (43-90% in studies) [10]
- The risk of IFIS with terazosin is not well-defined
- Summary
- All alpha blockers can cause IFIS
- The risk appears to be much greater with tamsulosin than with the other alpha blockers
- It is unclear if stopping alpha blockers prior to eye surgery has an effect on the severity or incidence of IFIS
- Patients who anticipate having eye surgery should not start alpha blockers prior to surgery
- Patients on alpha blockers who are planning eye surgery should make sure their surgeon is aware they are taking one
- Fatigue
- The incidence of fatigue with terazosin is up to 12% in some trials (versus 4.3% for patients taking placebo) [3]
- Priapism
- Priapism is an erection that lasts for hours and will not subside with ejaculation
- Priapism can lead to permanent impotence if untreated
- In very rare cases, alpha blockers have been associated with priapism
- CONTRAINDICATIONS
- All alpha blockers
- Known hypersensitivity
- Alfuzosin (Uroxatral®)
- Severe liver disease (Child-Pugh B and C)
- Concurrent Strong CYP3A4 inhibitors
- Silodosin (Rapaflo®)
- Severe liver disease (Child-Pugh score ≥ 10)
- Concurrent Strong CYP3A4 inhibitors
- PRECAUTIONS
- Kidney disease
- Alfuzosin (Uroxatral®)
- CrCl ≥ 30 ml/min: no dosage adjustment necessary
- CrCl < 30 ml/min: use caution
- Doxazosin (Cardura®)
- Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function.
- Doxazosin (Cardura XL®)
- Manufacturer makes no recommendation
- Prazosin (Minipress®)
- Manufacturer makes no recommendation
- Silodosin (Rapaflo®)
- CrCl ≥ 50 ml/min: no dose adjustment necessary
- CrCl 30 - 49 ml/min: dose is 4 mg once daily
- CrCl < 30 ml/min: DO NOT USE
- Tamsulosin (Flomax®)
- No dosage adjustment necessary in patients with kidney disease. However, it has not been studied in patients with CrCl < 10ml/min.
- Terazosin (Hytrin®)
- Impaired renal function had no significant effect on the elimination of terazosin, and dosage adjustment of terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary.
- Liver disease
- Alfuzosin (Uroxatral®)
- Child-Pugh A: has not been studied. Use caution.
- Child-Pugh B and C: DO NOT USE
- Doxazosin (Cardura®)
- Child-Pugh A and B: monitor for hypotension. Use caution.
- Child-Pugh C: DO NOT USE
- Doxazosin (Cardura XL®)
- Child-Pugh A and B: monitor for hypotension. Use caution.
- Child-Pugh C: has not been studied. Not recommended.
- Prazosin (Minipress®)
- Manufacturer makes no recommendation
- Silodosin (Rapaflo®)
- Child-Pugh A and B: no dose adjustment necessary
- Child-Pugh C: has not been studied. Not recommended.
- Tamsulosin (Flomax®)
- Child-Pugh A and B: no dose adjustment necessary
- Child-Pugh C: has not been studied
- Terazosin (Hytrin®)
- Manufacturer makes no recommendation
- Cataract surgery
- Alpha blockers are associated with a syndrome called Intraoperative Floppy Iris Syndrome (IFIS)
- IFIS is discussed under side effects above
- Gastrointestinal disorders (Cardura XL® only)
- Cardura XL® may be affected by gastrointestinal disorders
- Patients at risk for obstruction should use caution because the Cardura XL® tablet is nonabsorbable
- Patients with constipating conditions may absorb higher amounts of Cardura XL®
- Heart failure
- In the ALLHAT study, doxazosin was associated with a greater risk for heart failure when compared to chlorthalidone (see high blood pressure above)
- Nonselective alpha blockers (doxazosin, terazosin, prazosin) should probably be avoided in patients with heart failure [7]
- Prolonged QT interval
- Alfuzosin has been shown to prolong the QT interval of the cardiac cycle (see prolonged QT interval for more)
- Patients with congenital or acquired prolonged QT interval should not take alfuzosin
- Patients taking other medications that may prolong the QT interval should avoid alfuzosin [19]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All Alpha Blockers
- Antipsychotics (Zyprexa®, Risperdal®, Abilify®, etc.) - Antipsychotics can block alpha receptors. When antipsychotics are taken with alpha blockers, risk of orthostatic hypotension may increase
- Mirtazapine (Remeron®) - Mirtazapine blocks alpha receptors. It may potentiate the effects of alpha blockers.
- Phosphodiesterase-5 inhibitors (Viagra®, Cialis®, Levitra®, etc.) - Erectile dysfunction (ED) medications (also called phosphodiesterase-5 inhibitors) and alpha blockers can interact causing a drop in blood pressure. When taking these medications together, patients should be aware of the possibility and take appropriate precautions.
- Precautions that may help attenuate the interaction include:
- Patients should have stable blood pressure on their alpha blocker before starting ED medication
- ED medication should be added to alpha blocker at lowest dose possible
- If patient is already taking ED medication, alpha blocker should be started at lowest dose possible [25]
- Alfuzosin (Uroxatral®)
- Atenolol - Alfuzosin appears to increase blood levels of atenolol and vice versa
- CYP3A strong inhibitors - Strong inhibitors of CYP3A4 can increase alfuzosin blood levels significantly. Alfuzosin should not be taken with strong CYP3A inhibitors. Caution should be used with other CYP3A inhibitors.
- Drugs that prolong the QT interval - Alfuzosin may prolong the QT interval. Do not combine with other QT-prolonging drugs
- Doxazosin (Cardura XL®)
- Constipating medications - Medications that slow the gastrointestinal tract (e.g. anticholinergic medications) can increase the absorption of Cardura XL® and increase its effect.
- Silodosin (Rapaflo®)
- CYP3A strong inhibitors - Strong inhibitors of CYP3A4 can increase silodosin blood levels significantly. Silodosin should not be taken with strong CYP3A inhibitors. Caution should be used with other CYP3A inhibitors.
- P-glycoprotein inhibitors - P-glycoprotein inhibitors can increase silodosin blood levels significantly. Silodosin should not be taken with P-glycoprotein inhibitors.
- Valproic acid (Depakote®) - Silodosin blood levels may be increased by valproic acid
- Tamsulosin (Flomax®)
- CYP3A strong inhibitors - Strong inhibitors of CYP3A4 can increase tamsulosin blood levels significantly. Tamsulosin should not be taken with strong CYP3A inhibitors. Caution should be used with other CYP3A inhibitors.
- CYP2D6 strong inhibitors - Strong inhibitors of CYP2D6 can increase tamsulosin blood levels significantly. Caution should be used when tamsulosin is taken with CYP2D6 inhibitors.
- Terozosin (Hytrin®)
- Verapamil - Terazosin blood levels may be increased by verapamil
Metabolism and clearance | ||||
---|---|---|---|---|
Drug | CYP2C19 | CYP2D6 | CYP3A4 | P-glycoprotein |
Alfuzosin | - | - | Substrate | - |
Doxazosin | Substrate | Substrate | Substrate | Inhibitor |
Prazosin | - | - | - | Substrate and inducer |
Silodosin | - | - | Substrate | Substrate |
Tamsulosin | - | Substrate | Substrate | - |
Terazosin | Not well-defined |
- LONG-TERM SAFETY
- Alpha blockers have been prescribed for greater than 20 years
- They can have significant side effects and drug interactions
- When prescribed appropriately, they are generally considered safe
- DOSING
- BIBLIOGRAPHY
- 1 - Doxazosin PI
- 2 - Tamsulosin PI
- 3 - Terazosin PI
- 4 - PMID 19821331
- 5 - PMID 8446138
- 6 - PMID 19588327
- 7 - PMID 10789664
- 8 - PMID 18822025
- 9 - EAU guidelines on Treatment of Non-neurogenic Male LUTS 2011
- 10 - AUA guidelines on the management of BPH 2010
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- 14 - PMID 19560860
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- 16 - EAU guidelines on Urolithiasis 2011
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- 18 - PMID 17586379
- 19 - Alfuzosin PI
- 20 - PMID 19668424
- 21 - PMID 16162024
- 22 - PMID 18559700
- 23 - Prazosin PI
- 24 - Silodosin PI
- 25 - PMID 16387566
- 26 - PMID 21195469
- 27 - PMID 20821851
- 28 - PMID 19825505
- 29 - Guidelines on Urolithiasis 2011 European Assoc of Urology
- 30 - PMID 17993340
- 31 - PMID 17010010
- 32 - PMID 18399947
- 33 - PMID 16952675
- 34 - PMID 25998582
- 35 - EAU 2015 Guidelines on Urolithiasis
- 36 - PMID 26194935 - Tamsulosin for stones
- 37 - PMID 34384237 - Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA GUIDELINE PART I-Initial Work-up and Medical Management, J Urol (2021)
- 38 - EAU Guideline on Management of Non-Neurogenic Male Lower Urinary Tract Symptoms (2020)