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This activity is supported by an educational grant from Watson Laboratories, Inc.

Flow of Progress: Optimizing Current Treatment Strategies and the Pharmacist's Role in Benign Prostatic Hyperplasia

Shilpa Amara, PharmD
Drug Information Specialist
Barnabas Health
West Orange, New Jersey

 
Disclosures
The following contributors have no relevant financial relationships with commercial interests to disclose.
 
Faculty
Shilpa Amara, PharmD
 
Pharmacy Times Office of Continuing Professional Education
Planning Staff—Judy V. Lum, MPA, and Steve Lin, PharmD
 
Pharmacy Times
Editorial Staff
Kirk McKay and David Allikas
 
PTOCPE uses an anonymous peer reviewer as part of content validation and conflict resolution. The peer reviewer has no relevant financial relationships with commercial interests to disclose.
 
LEARNING Objectives:
Upon completion of this educational activity, participants should be able to:
  1. Discuss the epidemiology and pathophysiology of benign prostatic hyperplasia(BPH).
  2. Recognize the impact of BPH on patients and their quality of life.
  3. Examine current treatment strategies for the management of BPH, including special considerations in managing comorbidities.
  4. Discuss the pharmacist’s role in managing BPH, including addressing treatment expectations, medication safety, and patient compliance.
Target audience: Pharmacists
Type of activity: Knowledge
Release date: November 12, 2013
Expiration date: November 12, 2015
Estimated time to complete activity: 2 hours
 
Description: Description: harmacy Times/Ascend Media Office of Continuing Professional EducationPharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 2.0 contact hours (0.2 CEUs) under the ACPE universal activity number 0290-0000-13-159-H01-P. The activity is available for CE credit through November 12, 2015.


When I get older, losing my hair, many years from now ... will you still need me, will you still [treat] me, when I’m sixtyfour? —The Beatles The answer seems to be a resounding yes, judging from statistics that bear the good news of an overall increase in US life expectancy: the latest statistics suggest a spike from 75.2 to 78.2 years of age between 1990 and 2010.1 Just like the timeless Beatles tune, the world’s population is reveling in an era of longevity— thanks to unprecedented advances in the medical treatment of many lifecurtailing diseases. But while Americans are living longer, they are also more prevalently afflicted with age-related chronic diseases1 that result in numerous comorbidities and the critical need for pharmacists to be intricately involved in the management of polypharmacy that is inevitably grounded in the medical care of older Americans. Benign prostatic hyperplasia (BPH) is undoubtedly one of the most common age-related chronic conditions in men, the majority of whom are likely to be affected by other comorbidities (eg, hypertension, cardiovascular disease, erectile dysfunction).
 
Epidemiology and Pathophysiology of BPH
Considered among the top 10 most commonly diagnosed diseases in men older than 50 years, BPH is characterized by the proliferation of stromal and epithelial cells beginning in the area around the prostatic urethra.2,3 The prevalence of histopathologic BPH is age-dependent, with initial development occurring after 40 years of age.4 After 60 years of age, the prevalence of BPH rises sharply, reaching 82% by 80 years of age. Within the context of an aging US population, the prevalence and incidence of BPH has increased steadily, with age-adjusted prevalence of BPH among hospitalized patients nearly doubling between 1998 and 2007. By 2030, 20% of the US population will be 65 years or older, which will include more than 20 million men. Significantly, the fastest growing segment of the older adult population is the oldest age group: those older than 85 years. Current estimates indicate that the number of Americans 80 years or older will rise from 9.3 million in 2000 to 19.5 million in 2030. These trends point to substantial increases in the number of BPH cases within the next several decades.5

BPH manifests as irritative and obstructive lower urinary tract symptoms (LUTS), including difficulty urinating, frequent urination, urgency with leaking and dribbling, nocturia, a weak and intermittent stream, and sensation of incomplete bladder emptying.2,3 More than half of men in their 60s and up to 90% of men in their 70s and 80s experience at least some of these symptoms, and nearly half of all men 80 years and older experience severe LUTS.3 Beyond increasing age, identified risk factors for BPH have historically been few, including race, family history, and androgen stimulation. Recent insights, however, have revealed several new risk factors, including serum dihydrotestosterone (DHT), obesity, glucose homeostasis, metabolic syndrome, diet, exercise, and inflammation.5

In 1 recent prospective study of community- dwelling men, those with the highest midlife levels of DHT had nearly 3 times the risk of subsequent BPH compared with those with the lowest levels. The 5-alpha-reductase inhibitors (finasteride and dutasteride) decrease serum concentrations of DHT; however, these agents have not been shown to prevent incident BPH. Numerous studies have consistently observed increased adiposity, body weight, and waist circumference in association with increased prostate volume. Moreover, obesity has been shown to increase the risks of BPH surgery, urinary symptom progression, initiation of BPH medical therapy, and LUTS.5 Men diagnosed with at least 3 components of the metabolic syndrome (obesity, glucose intolerance, dyslipidemia, hypertension) exhibit an 80% increased prevalence of LUTS compared with those with no components. Diabetes, in particular, has been associated with increased risks of prostate enlargement, LUTS, and BPH-related surgery. Systemic inflammation, potentially related to the metabolic syndrome, has been implicated in malignant and nonmalignant prostate growth, with some studies indicating that nonsteroidal anti-inflammatory drug use may reduce BPH-related symptoms. Increased physical activity and a diet rich in fruits, vegetables, polyunsaturated fatty acids, linoleic acid, and vitamin D may decrease risks of BPH.5

The pathophysiology of BPH is not well elucidated but is likely multifactorial, with several theories in existence. One explanation involves hormonal dynamics, whereby the higher estrogento- androgen ratio within prostate tissue that occurs with age potentially stimulates growth and proliferation of prostate cells.6,7 Another theory focuses on accumulation of the testosterone metabolite DHT, which may contribute to prostate growth and reactivation of dormant prostate cells later in life. The prostate depends on androgens for embryologic development and for maintenance of size and function in the mature male. Testosterone, the major circulating androgen, is metabolized by 5-alphareductase to DHT. In order for testosterone to be active in the prostate, it must be converted to DHT; therefore, DHT is the androgen responsible for normal and hyperplastic prostate growth.7 Within the prostate, DHT initiates RNA synthesis, protein synthesis, and cell replication. As men age, they continue to produce DHT, despite producing less testosterone. The accumulation of a high level of DHT may contribute to prostate cell growth.

BPH is known to have static (also referred to as “fixed”) and dynamic components. The static component involves mechanical obstruction of the bladder, which is caused by the enlarged prostate intruding into the bladder floor and leading to constriction of the bladder neck and urethra, which subsequently increases bladder outlet resistance. The dynamic component involves increased adrenergic tone, leading to smooth muscle contraction around the prostatic urethra, particularly in the bladder neck.8 Both of these components contribute to obstructive (or voiding) symptoms of BPH, which include hesitancy or straining, weak stream, incomplete bladder emptying, and intermittent stream. Increasing bladder outlet resistance causes thickening and irritation of the bladder, leading to irritative (or storage) symptoms, including frequent urination, urgency with leaking or dribbling, and nocturia. In some cases, obstruction may become severe, causing acute urinary retention and need for catheterization. Untreated moderate to severe BPH may cause numerous complications, such as recurrent urinary tract infections, renal insufficiency, and bladder stones. In addition, men with severe BPH are at risk for nonuroligic effects, including falls (>50% increase in risk), impairment in activities of daily living, and depression.5

Management of BPH
Generally, patients with mild degrees of BPH and associated LUTS may be managed with “watchful waiting” and lifestyle modifications. These measures may include timed voiding or decreased fluid intake. Avoiding triggers (eg, smoking, spicy foods, caffeine-containing fluids), treating constipation, reducing doses of drugs (eg, antihistamines) that affect the bladder adversely, and “bladder training” (eg, drinking a measured amount of fluid and allowing bladder to empty at timed intervals) may all improve LUTS. If significant symptoms persist despite conservative measures, initiation of medical management is indicated and may proceed algorithmically.2,9 Pharmacologic treatment of BPH can be broadly divided into antiadrenergic and antiandrogenic approaches, with alpha1-adrenergic receptor antagonists (alpha blockers) and 5-alpha-reductase inhibitors (5-ARIs) being well-established representatives of the 2 therapeutic avenues (Table).2

Antiadrenergic Treatment
Increased understanding of the role of alpha1-adrenergic stress hormone receptors in prostate physiology has led to the use of alpha1-adrenergic receptor antagonists (alpha blockers) as first-line agents in the symptomatic treatment of BPH.2,9,10 Targeting the dynamic component of BPH, these agents (alfuzosin, doxazosin, terazosin, tamsulosin, silodosin) bind to alpha1-adrenergic receptors in the bladder neck and prostate, preventing sympathetic activation of these receptors by the neurotransmitter norepinephrine. This action relaxes the bladder and prostate smooth muscle tissue, decreasing urethral resistance, improving urine flow, and reducing BPH symptoms.2,3

Three distinct alpha1-adrenergic receptor subtypes have been identified (ie, alpha1A, alpha1B, alpha1D), with alpha1A receptors being the dominant subtype in the prostate, bladder base and neck, urethra, vas deferens, and seminal vesicles.1 The alpha1A subtype comprises 85% of alpha1-adrenergic receptors in BPH tissue and is known to regulate contraction of prostate smooth muscle (part of the contributing pathogenic processes in BPH). Other receptor subtypes, alpha1B in particular, are expressed in the vasculature and regulate contraction of blood vessels, especially in response to postural redistribution of blood volume. Therefore, blockade of alpha1B receptors may lead to vasodilation, which may be a desirable effect in the presence of both BPH and hypertension, but may lead to orthostatic hypotension with associated symptoms (eg, dizziness, syncope). In contrast, selective blockade of alpha1Areceptor subtypes potentially results in a more therapeutically focused effect on reduction of prostatic smooth muscle tone, with less likelihood of vasodilation.

Three of the alpha blockers used in BPH (ie, terazosin, doxazosin, alfuzosin) are characterized as nonsubtype selective because they show equal affinity for all alpha1 receptors. Tamsulosin has equal affinity for alpha1A and alpha1D receptors and lower affinity for alpha1B receptors. Silodosin exhibits greater affinity for alpha1A receptors versus alpha1B and alpha1D.11,12 Essentially, all of the alpha blockers are believed to be similarly efficacious, with patients’ symptoms usually resolving fairly quickly. Improvements in storage and voiding symptoms may occur within 24 hours and will usually not take longer than 7 days. Alpha blocker monotherapy does not prevent the progression of BPH, but patients can expect a durable response for up to 4 years. The main distinction between these agents is in their side effect profile, which is related to the aforementioned differences in their affinities for the various alpha receptor subtypes. Typical side effects include postural hypotension, dizziness, rhinitis, asthenia, sexual dysfunction, and abnormal ejaculation.10 The greatest safety concern associated with the use of these agents is the occurrence of vasodilatory symptoms (eg, dizziness, orthostatic hypotension) resulting from inhibition of alpha1 receptors in the systemic vasculature, which has been known to particularly affect patients with cardiovascular comorbidities and those concomitantly using antihypertensive and/or phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil).9,10 Elderly patients, patients in certain settings (eg, hot bath/ climate), or dehydrated patients are also at risk for drug-induced orthostasis.

Within the context of cardiovascular morbidity, arterial hypertension and congestive heart failure are associated with chronic activation of the sympathetic nervous system. This activation translates into a greater availability of noradrenaline at vascular alpha1 receptors and, hence, a potentially greater effect of blocking them using antagonists. This provides the rationale for a possibly increased likelihood of cardiovascular side effects of alpha1-receptor blockers in such patients. Therefore, in these individuals, vasodilatory symptoms may be minimized by the use of agents (silodosin, tamsulosin) that more selectively antagonize the alpha1A subtype.10 As both LUTS/BPH and hypertension/heart failure are more prevalent with increasing age, a considerable comorbidity is to be expected. The importance of such comorbidities might be even greater than age alone, as recent data suggest that BPH and hypertension are associated with each other, even after adjusting for age. In previous years, clinicians have recommended alpha1 blocker monotherapy for patients with both hypertension and BPH, as many of these agents were originally developed as antihypertensives. However, evidence from outcome trials suggests that alpha1 blockers should not be used as firstline antihypertensive therapy, and the most recent American Urologic Association and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines recommend independent treatment with the most appropriate pharmacologic agents for each condition.13 Considering the side effect differences between the alpha blocking agents, it is particularly important to distinguish between these agents at the prescribing stage and caution against therapeutic substitution of selective alpha1A agents for nonselective alpha1 agents at the dispensing stage.

Table: Available Treatments for BPH
 
Receptor Selectivity
Dosing Range
Alfuzosin
10 mg daily
Doxazosin
1-8 mg daily
Silodosin
+
8 mg daily
Tamsulosin
+
0.4-0.8 mg daily
Dutasteride
+
0.5 mg daily
Finasteride
+
5 mg daily
BPH = benign prostatic hyperplasia.
Adapted from reference 2.
   

Antiandrogenic Treatment
5-ARIs (finasteride, dutasteride) act by blocking the conversion of testosterone to DHT, which, as previously discussed, leads to cellular and glandular growth of the prostate. After 3 to 6 months of treatment, when DHT absorption into the prostate has been reduced, the prostate shrinks and symptoms of BPH improve, specifically the static disease component and the mechanical obstruction of the bladder.14 The 2 known 5-alpha reductase isoenzymes (type 1 and type 2) exist in varying concentrations in benign and malignant prostate cells. Finasteride is known to inhibit only the type 2 receptors, whereas dutasteride inhibits both the type 1 and type 2 receptors.9 The additional inhibition results in a greater reduction of DHT by dutasteride compared with finasteride; however, there are no data from direct comparator trials to suggest that the clinical efficacy of the 2 5-ARIs is different.2 Both finasteride and dutasteride have been shown to reduce the risk of acute urinary retention and the need for prostate surgery. These agents (1) are not appropriate for men who do not have evidence of prostate enlargement and (2) are associated with gynecomastia and sexual-related adverse effects (eg, impotence, ejaculatory disorders, decreased libido).9 In addition, 5-ARIs come with precautions for women, particularly dispensing pharmacists, who should not handle crushed or broken tablets when they are pregnant or may become pregnant due to the possibility of absorption and subsequent potential risk to a male fetus.

Because 5-ARIs are known to decrease androgen receptor activity, these agents were at one point investigated for potential prevention of prostate cancer, and in 2 large earlier trials, they were indeed found to reduce the risk of prostate cancer by approximately 25%.15 On the other hand, these agents were also associated with an increased risk of highgrade prostate cancer (Gleason scores of 8-10) in both trials. Based on these findings, the FDA issued an associated safety announcement in 2011, and product labeling was subsequently revised to include a warning regarding the risk of high-grade prostate cancer. To further complicate the issue, a more recent study that assessed 5-ARI use among 27,000 men diagnosed with prostate cancer and 134,000 controls found that the use of these drugs was associated with a decreased risk of cancer (Gleason scores of 2-7) and no evidence of an increased risk of cancer (Gleason scores of 8-10) after 4 years of treatment.15 Due to the conflicting nature of the accumulating evidence, definitive conclusions regarding 5-ARIs and prostate cancer risk are lacking.

Combination Therapy
Combination therapy with alpha blockers and 5-ARIs addresses both the static and dynamic components of BPH. While alpha blockers relax smooth muscle of the prostate and urethra, 5-ARIs reduce the size of the prostate. Patients with severe symptoms, large prostates, and high prostate-specific antigen values who are at highest risk of disease progression are thought to benefit most from combination therapy.2 One large earlier study that examined whether therapy with doxazosin, finasteride, or a combination of both could prevent BPH disease progression found an approximately 60% risk reduction in progression of disease and development of acute urinary retention in the combination versus placebo arm. The monotherapy arms of doxazosin and finasteride both showed reduced risk of clinical progression, but the effect was not as robust as that seen in the combination arm.16 A later trial that examined the combination of dutasteride and tamsulosin in men with a higher risk of BPH progression demonstrated similar results (an approximately 60% reduced risk of acute urinary retention and decreased symptoms and need for surgery after 4 years of treatment).17

Other Treatments
In patients who have persistent bladderrelated symptoms after treatment with alpha blockers and 5-ARIs, addition of an anticholinergic agent (eg, extendedrelease tolterodine) may relieve symptoms such as micturition frequency, nocturia, and urinary incontinence.9 Patients taking PDE5 inhibitors for the treatment of erectile dysfunction reported experiencing an improvement in irritative voiding symptoms (eg, frequency, urgency); based on those anecdotal reports, formal related studies were initiated and resulted in recent approval of tadalafil for the treatment of LUTS secondary to BPH with or without simultaneous erectile dysfunction.9 Cardiovascular precautions are in place, urging against use of tadalafil in patients taking nitrates and in combination with alpha blockers, all of which may increase the risk of hypotension.

The Pharmacist’s Role
Considering that most patients with BPH have associated comorbidities and are thus managed with polypharmacy, there is a definitive need for pharmacists to be actively involved in educating patients and interacting with prescribers on optimal management of BPH. Pharmacists can counsel patients with BPH on behavioral techniques, such as fluid restriction and caffeine avoidance after evening meals, as well as administering diuretics solely in the morning rather than close to bedtime. These simple changes often lead to considerable symptom improvement. Pharmacists can also screen patient profiles for medications (eg, sympathomimetics, antidepressants, antihistamines, bronchodilators, diuretics) that may exacerbate LUTS.18 In addition, pharmacists should focus on promoting medication safety (eg, ensuring dose titration and monitoring for hypotension in patients receiving alpha blockers), setting treatment expectations (eg, onset of symptom relief with therapy), and optimizing medication adherence (eg, recommending once-daily medications).

One important aspect of communicating with patents about any disease state is having the ability to identify and address common misconceptions, which have become highly prevalent in our current information-enriched, Internet-laced society. For example, many patents fear that BPH is linked with prostate cancer; they should be told about the benign nature of BPH, yet urged to obtain regular screenings for prostate cancer. Many patients assume that dietary supplements are safer than prescription medication for any chronic condition, including BPH. They prefer to take highly advertised yet unproven dietary supplements over seeking medical attention for BPH-related symptoms. As frontline health care providers, pharmacists should emphasize that many of these products have not been shown in controlled studies to have efficacy in BPH, may interact with prescription medications, and may cause significant adverse effects.

Pharmacists can also interact with physicians regarding selection of therapy in the presence of various concomitant conditions (eg, cardiovascular disease) and preexisting treatments (eg, antihypertensive agents). They can also advise physicians on the current pharmacologic treatment approach for BPH. In general, first-line therapy for men with significant LUTS (regardless of prostate size) continues to be alpha blocker monotherapy. Men at high risk for disease progression may be treated with alpha blocker/5- ARI combination therapy for at least 9 months. If after taking combination therapy for 3 months, symptoms of frequency and urgency persist, an anticholinergic agent may be added. After 9 months, the 5-ARI should be exerting its maximal effect; therefore, an attempt to discontinue the alpha blocker can be made. If the patient notices deterioration in voiding symptoms immediately after stopping the alpha blocker, then it can be resumed. If the patient has a durable improvement in LUTS, he could be maintained on 5-ARI monotherapy. If the patient still has frequency, urgency, or other voiding symptoms, as well as erectile dysfunction, then addition of a daily PDE5 inhibitor may be considered.9

Conclusion
Undoubtedly, BPH is one of the more prevalent chronic conditions associated with the growing elderly population and is progressive in nature. If left untreated, BPH can result in worsening of symptoms, leading to significantly impaired quality of life and to complications such as acute urinary retention and renal failure. Several decades ago, the only management option available for BPH was surgery; only in the 1990s did medical therapy emerge as the predominant treatment for BPH. Today, multiple pharmacologic classes exist, with both monotherapy and combination therapy employed at various stages of the condition. In individualizing these treatments, important considerations include patients’ symptoms and risk of disease progression, as well as their concomitant conditions and medications. Pharmacists can play a vital role in ensuring that patients are well educated about this disease and receive optimal treatment regimens.


References
  1. US Burden of Disease Collaborators. The state of US health, 1990-2010. Burden of diseases, injuries, and risk factors [online]. JAMA. 2013.
  2. American Urological Association. AUA guideline on management of benign prostatic hyperplasia (BPH). Revised 2011.
  3. Wei JT, Calhoun E, Jacobsen SJ. Urologic Diseases in America Project: benign prostatic hyperplasia. J Urol. 2008;179(5 suppl.):S75-S80.
  4. Berry SJ, Coffey DS, Walsh PC, et al. The development of human benign prostatic hyperplasia with age. J Urol. 1984;132:474.
  5. JK Parsons. Benign prostatic hyperplasia and male lower urinary tract symptoms: epidemiology and risk factors. Curr Bladder Dysfunct Rep. 2010;5:212-218.
  6. Issacs JT, Coffey DS. Etiology and disease process of benign prostatic hyperplasia. Prostate Suppl. 1989;2:33.
  7. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5a-reductase inhibition in human benign hyperplasia. Eur Urol. 2000;37:367-380.
  8. Issa MM, Regan T. Medical therapy for benign prostatic hyperplasia: present and future impact. Am J Managed Care. 2007;13:S4-S9.
  9. Elterman DS, Barkin J, Kaplan SA. Optimizing the management of benign prostatic hyperplasia. Ther Adv Urol. 2012;4(2):77-83.
  10. Shrivastava A, Gupta VB. Various treatment options for benign prostatic hyperplasia: a current update. J Midlife Health. 2012;3(1):10-19
  11. Schwinn DA, Roehrborn CG. a1-Adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol. 2008;15:193-199.
  12. Michel MC, The forefront for novel therapeutic agents based on the pathophysiology of the lower urinary tract dysfunction: alpha-blockers in the treatment of male voiding dysfunction: how do they work and why do they differ in tolerability? J Pharmacol Sci. 2010;112:151- 157.
  13. White WB, Moon T. Treatment of benign prostatic hyperplasia in hypertensive men. J Clin Hypertens (Greenwich). 2005;7(4):212-217.
  14. Nickel JC. Comparison of clinical trials with finasteride and dutasteride. Rev Urol. 2004;6(suppl 9):S31-S39.
  15. Robinson D, Garmo H, Bill-Axelson A, et al. Use of 5a-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population based case-control study. BMJ. 2013;346:f3406.
  16. 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.
  17. Barkin J. Review of dutasteride/tamsulosin fixed-dose combination for the treatment of benign prostatic hyperplasia: efficacy, safety, and patient acceptability. Patient Prefer Adherence. 2011;5:483-490.
  18. Wuerstle MC, Van Den Eeden SK, Poon KT, et al. Contribution of common medications to lower urinary tract symptoms in men. Arch Intern Med. 2011;171(18):1680-1682.
Flow of Progress: Optimizing Current Treatment Strategies and the Pharmacist's Role in Benign Prostatic Hyperplasia
Expires
11-12-2015
Credits
2.00
UAN
0290-0000-13-159-H01-P
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