ALPHA BLOCKERS


















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
Prazosin vs Others for Hypertension in Male Veterans, NEJM (1993) [PubMed abstract]
  • 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
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • Side effects (prazosin vs placebo): fatigue 13% vs 8%; sleepiness 12% vs 6%; dizziness 12% vs 5% (all statistically significant)

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.
Blood pressure lowering efficacy of alpha blockers for primary hypertension, Cochrane meta-analysis (2004) [PubMed abstract]
  • 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
  • In general, alpha-blockers are no longer recommended among preferred agents to treat hypertension
  • See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations



Overview
  • One large trial evaluated the effects of doxazosin on cardiovascular disease outcomes
ALLHAT study - Doxazosin vs Chlorthalidone for CVD, JAMA (2000) [PubMed abstract]
  • 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
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



Alpha blockers in BPH
  • As men age, the prostate gland tends to enlarge. If the prostate becomes too big, it may obstruct urine flow.
  • Alpha blockers relax smooth muscle in the prostate and bladder neck. Through this action, they can help facilitate urine flow. All alpha blockers except prazosin are approved to treat BPH.
  • There are no good trials that have compared different alpha blockers head-to-head. The AUA states that all alpha blockers appear to be equally effective [10].
  • The European Association of Urology (EAU) summarized 13 randomized, controlled trials that evaluated the effects of alpha blockers in BPH and came to the following conclusions:
    • Alpha blockers improve symptom scores in BPH 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
  • 5-alpha reductase inhibitors (5ARIs) are medications that inhibit testosterone and cause the prostate to shrink
  • 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 alone and in combination with alpha blockers. Those trials are detailed below.
MTOPS trial - Doxazosin vs Finasteride vs Combination Therapy, NEJM (2003) [PubMed abstract]
  • 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
  • AUA symptom scores at one year had improved significantly when compared to placebo in Groups 2 and 4, but not in Group 3
  • Group 4 had significantly greater improvement in the AUA symptom score than all other groups over the course of the study

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.
COMBAT study - Tamsulosin vs Dutasteride vs Combination Therapy, European Urology (2010) [PubMed abstract]
  • 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
  • Starting at 8 months, Group 1 had a higher incidence of the primary outcome compared to Groups 2 and 3

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
Professional recommendations
EAU recommendations
  • Alpha blockers should be offered to men with moderate-to-severe BPH symptoms
  • Combination therapy (alpha blocker + 5ARI) should be offered to men with moderate-to-severe symptoms, enlarged prostates, and reduced Qmax
  • Combination therapy is not recommended for therapy expected to last < 1 year
  • Discontinuation of alpha blocker after 6 months of combination therapy might be considered in men with moderate BPH [9]
AUA recommendations
  • Alpha blockers should be offered to men with moderate-to-severe BPH symptoms
  • Combination therapy (alpha blocker + 5ARI) is appropriate for patients with BPH symptoms and prostate enlargement based on imaging (ex. ultrasound), elevated PSA, and/or enlargement felt on digital rectal exam [10]
Summary
  • Alpha blockers are effective at relieving the symptoms of BPH both acutely and long-term
  • Alpha blockers work immediately to relieve symptoms where 5ARIs can take months to greater than a year to effectively relieve symptoms
  • Alpha blockers do not appear to decrease the risk of urinary retention or prostate surgery where 5ARIs do
  • Combination therapy is superior to alpha blockers alone in treating men with significant symptoms who have an enlarged prostate on exam
  • Patients on combination therapy may consider stopping the alpha blocker after 6 months to a year when the 5ARI has shrunk the size of the prostate. While this may work for some, the COMBAT and MTOPS trial both showed that combination therapy was superior to 5ARI therapy alone for at least 4 years.



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.
Tamsulosin vs Placebo for Ureteral Stone Passage, JAMA Internal Medicine (2018) [PubMed abstract]
  • 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
  • 7.4% of patients in Group 2 crossed over to tamsulosin
  • In subgroup analysis, there was no significant difference in passage rates for stones > 5 mm in diameter (p=0.45)
  • In subgroup analysis, there was no significant difference in passage rates for stone location, although upper ureter stones showed a trend towards significance (Group 1 - 41.8%, Group 2 - 29.4%, p=0.17)

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.
Tamsulosin vs Placebo for Distal Ureteral Stones, Annals of EM (2016) [PubMed abstract]
  • 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
  • About 19% of patients in each group had no follow-up CT or had urologic intervention

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.
Tamsulosin vs Nifedipine vs Placebo for Kidney Stones, Lancet (2015) [PubMed abstract]
  • 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
  • Subgroup analyses that considered stone size and stone location found no significant effect of either intervention when compared to placebo. These analyses were underpowered.

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



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 [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)
  • 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

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 0.8mg 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
  • The incidence of fatigue with tamsulosin is 7-9% in trials (versus 5.5% for patients taking placebo) [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

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






Kidney disease
Alfuzosin (Uroxatral®)
  • No dosage adjustment necessary in mild-to-moderate kidney disease
  • Alfuzosin should be used with caution in patients with severe kidney disease (CrCl < 30ml/min)
Doxazosin (Cardura®, Cardura XL®)
  • The manufacturer's PI states that studies have not shown significant pharmacokinetic alterations of doxazosin in patients with "renal impairment"
  • Manufacturer makes no specific dosage recommendation
Prazosin (Minipress®)
  • Manufacturer makes no specific dosage recommendation
Silodosin (Rapaflo®)
  • For patients with moderate kidney disease (CrCl 30 - 50ml/min), silodosin dose should be 4 mg a day
  • Silodosin should not be used in patients with severe kidney disease (CrCl < 30 ml/min)
Tamsulosin (Flomax®)
  • No dosage adjustment necessary in patients with kidney disease
  • Patients with CrCl < 10ml/min have not been studied
Terazosin (Hytrin®)
  • No dosage adjustment necessary in patients with kidney disease

Liver disease
Alfuzosin (Uroxatral®)
  • Alfuzosin should not be taken by patients with moderate-to-severe liver disease
  • Alfuzosin has not been studied in patients with mild liver disease
Doxazosin (Cardura®, Cardura XL®)
  • Doxazosin should not be taken by patients with severe liver disease
  • Doxazosin should be used with caution in patients with mild-moderate liver disease
  • Manufacturer makes no specific dosage recommendation
Prazosin (Minipress®)
  • Manufacturer makes no specific dosage recommendation
Silodosin (Rapaflo®)
  • For patients with mild-to-moderate liver disease, no dose adjustment is necessary
  • Silodosin should not be used in patients with severe liver disease
Tamsulosin (Flomax®)
  • Patients with moderate liver disease do not need dosage adjustment
  • Tamsulosin has not been studied in patients with severe liver disease
Terazosin (Hytrin®)
  • Manufacturer makes no specific dosage recommendation

Cataract surgery

Gastrointestinal disorders (Cardura XL® only)

Heart failure

Prolonged QT interval



Drug interactions

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


  • NOTE: Information on metabolic pathways presented here is from the manufacurer's PI, FDA website, and a handful of published reviews. Other metabolic pathways may exist; therefore, the information is not meant to be all-inclusive.
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