2. UroToday Home
  3. Recent Abstracts
  4. Men's Health
  5. BPH - Benign Prostatic Enlargement

Medical Management

BPH - Treatment Assessment - Medical Treatments

  • The goals of treatment for BPH include relieving LUTS, decreasing BOO, improving bladder emptying, ameliorating detrusor instability, reversing renal insufficiency, and preventing disease progression, which may include a deterioration of symptoms, future episodes of gross hematuria, UTI, acute urinary retention, or the need for surgical intervention.
  • A significant proportion of men with LUTS will not choose medical or surgical intervention because the symptoms are not bothersome, the complications of treatment are perceived to be greater than the inconvenience of the symptoms, and there is a reluctance to take a daily pill owing to side effects and/or the cost of treatment.
  • Medical therapies extensively investigated for BPH include α-adrenergic blockers, 5α-reductase inhibitors, and recently phosphodiesterase inhibitors (PDEIs) and several combinations of these agents.
  • Approximately 30% of American men older than 50 years have moderate to severe symptoms.
  • 6.5 to 8.7 million men are eligible to discuss BPH treatment options.
  • The primary objective of medical therapy is to improve urinary symptoms.
  • For mild-to-moderate symptoms, a period of watchful waiting is sometimes recommended in which no pharmacotherapy is prescribed.
  • As symptoms progress, alpha-antagonists are typically the first-line agents due to their efficacy and rapid response seen upon initiation.
  • Alpha-antagonists are a useful option in the management of moderate-to-severe LUTS secondary to BPH.
  • Alpha-antagonists are the most effective agents used to treat the moderate-to-severe and bothersome symptoms associated with bladder outlet obstruction (BOO) secondary to BPH.
  • Symptoms related to urinary storage including frequency, nocturia, urgency, and incontinence are generally reported as the most bothersome with the largest impact on QOL.
  • These symptoms are lessened by the use of alpha-antagonists.
  • The alpha-antagonists reduce BOO by decreasing the alpha-adrenergic tone of the smooth muscle within the prostate.

Alpha-antagonists

  • Alpha-antagonists act by relaxing the smooth muscle of the prostate and bladder neck to improve urine flow and to reduce bladder outlet obstruction.
  • The approved drugs in this class include:
  1. terazosin Hytrin®
  2. doxazosin Cardura®
  3. tamsulosin Flomax®
  4. alfuzosin Uroxatral®
  5. silodosin Rapaflo®
  • There are three subtypes of alpha-receptors identified within the prostate (a1A, a1B, and a1D), with about 70% of the subtypes being a1A.
  • The a1B subtype is located primarily in the peripheral vasculature and is vital to blood pressure regulation, with very little effect on BPH.
  • All available alpha-antagonists have activity at all receptors, with only two being semiselective for the a1A subtype, tamsulosin and silodosin.
  • Tamsulosin is more selective for all subtypes, but the ratio of selectivity for the a1A subtype to a1B or a1D is greater for silodosin than tamsulosin.
  • Despite this higher receptor affinity, all alpha-antagonists with the exception of silodosin seem to have equal clinical efficacy, though clinical studies comparing all agents are currently lacking.
  • The main difference between the various alpha-antagonists appears to be their side-effect profiles.
  • The second-generation alpha-antagonists (alfuzosin, doxazosin, terazosin) are all likely to have hypotensive and other syncopal events associated with their use, with alfuzosin causing less hypotension than the other two second-generation medications.
  • These adverse effects are dose related, so the lowest effective dose should be used.
  • Alfuzosin may also cause abnormal ejaculations; however, the newer generation agents, tamsulosin and silodosin, are more likely to cause abnormal ejaculations, with silodosin causing more retrograde ejaculation than tamsulosin.
  • Dizziness has been associated with all agents.
  • Although rare, another adverse effect of the alpha-antagonists is intraoperative floppy iris syndrome (a complication of cataract surgery).
  • When offered alpha-antagonist treatment, men should be asked if cataract surgery is planned, and therapy should be delayed until after the procedure is completed.
  • Tamsulosin has the most reported cases of floppy iris syndrome.
  • All agents should be started at the lowest dose if the patient is concurrently taking a phosphodiesterase type 5 (PDE-5) inhibitor and vice versa because of the possibility of a systemic hypotensive reaction with concurrent use.
  • Alfuzosin and silodosin are contraindicated in use with concurrent potent CYP3A4 inhibitors, and silodosin is not recommended for use with potent P-glycoprotein inhibitors.
  • If symptoms persist despite optimization of alpha-antagonists, or a patient is unable to tolerate side effects related to their use, 5-alpha-reductase inhibitors may be added to the regimen.

5-Alpha-reductase Inhibitors:

  • The 5-alpha-reductase inhibitor class has been shown to improve LUTS in the presence of BPH.
  • Finasteride (Proscar), and dutasteride (Avodart), inhibit production of the hormone DHT, which is involved with prostate enlargement.
  • The use of either of these drugs can either prevent progression of growth of the prostate or actually shrink the prostate in some men.
  • These drugs can lower prostate-specific antigen (PSA) test levels.
  • These medications differ in the extent that they are able to block the 5-alpha-reducatase conversion of testosterone to dihydrotestosterone (DHT) within the body.
  • By inhibiting the formation of DHT, 5-alpha-reducatase inhibitors are able to mitigate the effects that androgens have on the prostate.
  • Androgenic effects include proliferation of prostate cells, decrease in prostate cell apoptosis, and elevation of rate of angiogenesis within the prostate.
  • Finasteride works solely on the 5-alpha-reductase type II enzyme by inhibiting about 70% of the conversion of testosterone to DHT within the body.
  • Dutasteride has been shown to inhibit both 5-alpha-reductase type I and type II, preventing 95% conversion of testosterone to DHT.
  • As a result of the high prevalence of 5-alpha-reductase type II enzymes present within the prostate and genital tissue, any clinical benefits seen from dutasteride’s inhibition of both 5-alpha-reductase enzymes have not been evident. However, no comparative trials have been reported.
  • Meta-analyses have demonstrated an improved IPSS and peak urinary flow rate in patients who have prostate volumes >30 mL upon initiating therapy.
  • Individuals with lower prostate volumes have not shown statistically significant improvement in their symptom scores or peak urinary flow rates and will most likely not benefit from a 5-alpha-reductase inhibitor.
  • When using an agent in this class, if prostate specific antigen (PSA) levels are monitored for the detection of prostate cancer, one must understand that 5-alpha-reductase inhibitors typically decrease a patient’s PSA by about 50%.
  • Because of delayed prostatic response to this class of medications, after 3 to 6 months of therapy practitioners should double the PSA level drawn if a patient is on a 5-alpha-reductase inhibitor in order to appropriately assess the patient’s true level.
  • If PSA levels increase or do not follow this trend, further urologic workup is warranted.
  • In addition, dutasteride dosage reductions may be warranted in patients concurrently taking CYP3A4 and CYP3A5 inhibitors.
  • It should also be noted that 5-alpha-reductase inhibitors differ in their reported length of activity, with finasteride’s half-life estimated to be around 6 to 8 hours while dutasteride’s is estimated to be 5 weeks.
  • Appropriate treatment duration of at least 6 months should be allowed before a response is evaluated.
  • Clinically important adverse effects in this class are decreased libido, decreased semen quantity during ejaculation, and impotence.
  • Furthermore, gynecomastia is reported as a potential, though infrequent, adverse event.
  • It should be noted that all adverse effects have been shown to diminish after the first year of treatment.

Combination Therapy

  • The AUA guidelines for BPH state that with an enlarged prostate, the use of a combination alpha-antagonist and 5-alpha-reductase inhibitor is effective and appropriate.
  • n short-term studies, the alpha-antagonists were equally efficacious and safe compared with combination therapy but were better than 5-alpha-reductase inhibitor therapy alone.23,24 However, in long-term studies in men with enlarged prostates, combination therapy with both alpha-antagonist and 5-alpha-reductase inhibitor has demonstrated clear benefit when compared to either agent alone in preventing disease progression and improving symptoms.25 In addition, combination therapy significantly reduces the risk of acute urinary retention as well as the need for invasive procedures to correct the disorder.
  • Recently, clinical evidence has emerged for using tolterodine, an antimuscarinic, in the treatment of overactive bladder and BPH if symptoms are not controlled with monotherapy with an alpha-antagonist.
  • Current literature evaluates combination therapy only with an alpha-antagonist.
  • Tolterodine works by blocking the effects of acetylcholine on the central and peripheral nervous system, thus blunting the bladder contraction effects known to occur when acted upon by the cholinergic nervous system.
  • Clinical trials have demonstrated improvements in patients who did not have an overactive bladder but suffered from LUTS that were irritative in nature (i.e., frequency, urgency, and nocturia).
  • Tolterodine is the only antimuscarinic to date that has been studied in combination treatment of BPH.
  • It is important to note that tolterodine should only be used in combination with alpha-antagonists in patients with BPH who have a postvoid residual volume (PVR) of less than 250 to 300 mL because of the risk of urinary retention with antimuscarinic medications.
  • The most common adverse effect that has been reported with tolterodine for this indication is dry mouth, with a reported incidence of up to 24%.
  • Other adverse events described were similar to placebo.

Phosphodiesterase type 5 Inhibitors:

  • The only PDE5 inhibitor approved for the treatment of BPH is tadalafil (Cialis®)
  • The mechanism of action is that tadalafil relaxes muscles near the prostate. 

References

  • Andersson KE, Gratzke C. Pharmacology of alpha1-adrenoceptor antagonists in the lower urinary tract and central nervous system. Nat Clin Pract Urol. 2007;4:368-378.
  • Barry MJ, Fowler FJ, Jr., O'Leary MP, and the Measurement Committee of the AUA: The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 148:1549-1557, 1992.
  • Burnett AL, Wein AJ. Benign prostatic hyperplasia in primary care: what you need to know. J Urol. 2006;175:S19-S24.
  • Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol. 1975;47:193-202.
  • Chapple CR. Pharmacological therapy of benign prostatic hyperplasia/lower urinary tract symptoms: an overview for the practicing clinician. BJU Int. 2004;94:738-744.
  • Chapter 1: AUA guideline on the management of benign prostatic hyperplasia: diagnosis and treatment recommendations. American Urological Association.http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines/archived-guidelines/chapt_1_appendix.pdf. Accessed April 20, 2012.
  • Chatziralli IP, Sergentanis TN. Risk factors for intraoperative floppy iris syndrome: a meta-analysis. Ophthalmology. 2011;118:730-735.
  • Cialis (tadalafil) package insert. Indianapolis, IN: Eli Lilly; October 2011.
  • Dolder CR. Dutasteride: a dual 5-alpha reductase inhibitor for the treatment of symptomatic benign prostatic hyperplasia. Ann Pharmacother. 2006;40:658-665.
  • Gallegos PJ, Frazee LA. Anticholinergic therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia. Pharmacotherapy. 2008;28:356-365.
  • Kawabe K, Yoshida M, Homma Y, for the Silodosin Clinical Study Group. Silodosin, a new alpha 1A-adrenoreceptor selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 2006;98:1019-1024.
  • Kirby RS, Roehrborn C, Boyle P, et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology. 2003;61:119-126.
  • Kumar VL, Wahane VD. Current status of 5-alpha reductase inhibitors in the treatment of benign hyperplasia of prostate. Indian J Med Sci. 2008;62:167-175.
  • Lee M. Alfuzosin hydrochloride for the treatment of benign prostatic hyperplasia. Am J Health Syst Pharm. 2003;60:1426-1439.
  • Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med. 1996;33:533-539.
  • McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387-2398.
  • McVary KT. BPH: epidemiology and comorbidities. Am J Manag Care. 2006;12(suppl 5):S122-S128.
  • Nickel JC. BPH: costs and treatment outcomes. Am J Manag Care. 2006;12(suppl 5):S141-S148.
  • Price DT, Schwinn DA, Lomasney JW, et al. Identification, quantitation, and localization of mRNA for three distinct alpha 1 adrenergic receptor subtypes in human prostate. J Urol. 1993;150:546-551.
  • Rapaflo (silodosin) package insert. Morristown, NJ: Watson Pharma; May 2011.
  • Scher HI. Chapter 91. Benign and malignant diseases of the prostate. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. www.accessmedicine.com.cuhsl. creighton.edu/content.aspx? aID=2893170. Accessed February 24, 2011.
  • Trueman P, Hood SC, Nayak US, Mrazek MF. Prevalence of lower urinary tract symptoms and self-reported diagnosed “benign prostatic hyperplasia,” and their effect on quality of life in a community-based survey of men in the UK. BJU Int. 1999;83:410-415.
  • Uroxatral (alfuzosin) package insert. New York, NY: Sanofi-aventis Inc; May 2011.
  • Van Dijk MM, de la Rosette JJ, Michel MC. Effects of alpha1-adrenoceptor antagonists on male sexual function. Drugs. 2006;66:287-301.