Mary Lee and Roohollah Sharifi
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the pathophysiologic mechanisms underlying the symptoms and signs of benign prostatic hyperplasia (BPH).
2. Recognize the symptoms and signs of BPH in individual patients.
3. List the desired treatment outcomes for a patient with BPH.
4. Identify factors that guide selection of a particular α-adrenergic antagonist for an individual patient.
5. Compare and contrast α-adrenergic antagonists versus 5α-reductase inhibitors in terms of mechanism of action, treatment outcomes, adverse effects, and interactions when used for management of BPH.
6. Describe the indications for combination drug treatment of BPH.
7. Describe the indications for surgical intervention of BPH.
8. Formulate a monitoring plan for a patient on a given drug treatment regimen based on patient specific information.
9. Formulate appropriate counseling information for patients receiving drug treatment for BPH.
KEY CONCEPTS
The lower urinary tract symptoms (LUTS) and signs of benign prostatic hyperplasia (BPH) are due to static, dynamic, or detrusor factors. The static factor refers to anatomic obstruction of the bladder neck caused by an enlarged prostate gland. The dynamic factor refers to excessive stimulation of α-adrenergic receptors in the smooth muscle of the prostate, urethra, and bladder neck. The detrusor factor refers to irritability of hypertrophied detrusor muscle as a result of longstanding bladder outlet obstruction.
Drug treatment goals for BPH include relieving obstructive and irritative voiding symptoms, preventing complications of disease, and reducing the need for surgical intervention.
Watchful waiting is indicated for patients with mild symptoms that are not bothersome.
Single-drug treatment with an α-adrenergic antagonist is preferred for patients with moderate or severe symptoms of BPH. Single-drug treatment with a 5α-reductase inhibitor should be reserved for patients with moderate or severe symptoms and significantly enlarged prostates of at least 30 g (1.05 oz).
Surgical intervention should be reserved for patients with severe LUTS due to BPH and those with complications of disease, such as recurrent urinary tract infections, recurrent severe gross hematuria, renal failure, and bladder calculi.
α-Adrenergic antagonists reduce the dynamic factor. They competitively antagonize α-adrenergic receptors, thereby causing relaxation of the bladder neck, prostatic urethra, and prostate smooth muscle. They do not shrink an enlarged prostate. The onset of action is days to weeks, depending on the need for up-titration of the daily dose to achieve a therapeutic response. Dose limiting adverse effects include hypotension and syncope. In addition, delayed or retrograde ejaculation has been reported. Combined use with antihypertensives, diuretics, or phosphodiesterase inhibitors can increase the risk of hypotensive episodes.
Among the α-adrenergic antagonists, modified-release alfuzosin is considered functionally uroselective because usual therapeutic doses produce relaxation of the bladder neck and prostatic smooth muscle with minimal peripheral vascular relaxation. Although alfuzosin appears to produce less hypotension than immediate-release formulations of terazosin and doxazosin, it is not clear if it has the same cardiovascular profile as tamsulosin. Although not uroselective, controlled-release doxazosin produces less hypotension than the immediate release formulation. Tamsulosin and silodosin are pharmacologically uroselective and exert greater antagonism of α1A- and α1D-receptors, which predominate in prostatic and bladder detrusor muscle, respectively, as compared to vascular α1B-receptors. Therefore, tamsulosin and silodosin can be initiated with a full therapeutic dose, which achieves peak effects sooner than with immediate-release formulations of terazosin and doxazosin, which must be up-titrated. Tamsulosin appears to have the lowest potential to cause hypotension. In various clinical trials, tamsulosin is well tolerated in the elderly and in patients taking diuretics and antihypertensives. It is also commercially available in a controlled-release dosage formulation. Therefore, with chronic use, tamsulosin can be taken once daily at the patient’s convenience.
5α-Reductase inhibitors shrink enlarged prostates, reducing symptoms caused by the static factor. They do so by inhibiting 5α-reductase that is responsible for intraprostatic conversion of testosterone to dihydrotestosterone, the active androgen that stimulates prostate tissue growth. The onset of action is slow with peak shrinkage of the prostate taking up to 6 months. Unlike treatment with α-adrenergic antagonists, 5α-reductase inhibitors have been shown to reduce the incidence of acute urinary retention and need for prostate surgery in patients with significantly enlarged prostate glands (more than 30 g), and those with prostate-specific antigen (PSA) serum levels of 1.5 ng/mL (1.5 mcg/L) or more. Because 5α-reductase inhibitors do not produce cardiovascular adverse effects, they are preferred for treatment of moderate to severe symptoms of BPH when the patient is at risk of hypotension, but wants to be treated medically. Adverse effects include gynecomastia, decreased libido, erectile dysfunction, and ejaculation disorders. Drug interactions are uncommon.
When monitoring efficacy of drug treatment for BPH, subjective end points include relief of obstructive and irritative voiding symptoms. Objective end points include improvements of urinary flow rates, decreased postvoid residual urinary volume, and decreased complications of disease.
INTRODUCTION
The prostate is a heart-shaped, chestnut-sized organ that encircles the portion of the proximal urethra that is located at the base of the urinary bladder. The prostate produces secretions, which are part of the ejaculate.
Benign prostatic hyperplasia (BPH) is the most common benign neoplasm in males who are at least 40 years of age. BPH can produce lower urinary tract voiding symptoms that are consistent with impaired emptying of urine from and storage of urine in the bladder. Medications are a common mode of treatment to reduce symptoms and/or delay complications of the disease. For this reason, clinicians should be knowledgeable about the medical management of this disease.
EPIDEMIOLOGY AND ETIOLOGY
BPH is present as microscopic disease in many elderly males.1 The prevalence increases with advancing patient age. However, only about 50% and 25% of patients with microscopic BPH disease develop an enlarged prostate on palpation and clinical voiding symptoms, respectively.2 It is estimated that 25% of males 40 years of age or more have voiding symptoms consistent with BPH, and 20% to 30% of all male patients who live to the age of 80 years will require a prostatectomy for severe voiding symptoms of BPH.2
Two etiologic factors for BPH include advanced patient age and the stimulatory effect of androgens.
• Prior to 40 years of age, the prostate in the adult male stays the same size, approximately 15 to 20 g. However, in males who have reached 40 years of age, the prostate undergoes a growth spurt, which continues as the male advances in age. Enlargement of the prostate can result in clinically symptomatic BPH.
• The testes and adrenal glands produce 90% and 10%, respectively, of circulating testosterone. Testosterone enters prostate cells, where predominantly type II 5α-reductase activates testosterone to dihydrotestosterone, which combines with a cytoplasmic receptor. The complex enters the nucleus and induces changes in protein synthesis which promote glandular tissue growth of the prostate. Thus, 5α-reductase inhibitors (e.g., finasteride and dutasteride) directly interfere with one of the major etiologic factors of BPH.
• The prostate is composed of two types of tissue: (a) glandular or epithelial tissue, which produces prostatic secretions, including prostate-specific antigen (PSA) and (b) muscle or stromal tissue, which can contract around the urethra when stimulated. Whereas androgens stimulate glandular tissue growth, androgens have no direct effect on stromal tissue. It has been postulated that stromal tissue growth may be stimulated by estrogen. Since testosterone is converted to estrogen in peripheral tissues in males, testosterone may be associated indirectly with stromal hyperplasia. Stromal tissue is innervated by α1A-receptors. When stimulated, prostatic stroma contracts around the urethra, narrowing the urethra and causing obstructive voiding symptoms.
PATHOPHYSIOLOGY
The symptoms and signs of BPH are due to static, dynamic, and/or detrusor factors. The static factor refers to anatomic obstruction of the bladder neck caused by an enlarged prostate gland. As the gland grows around the urethra, the prostate occludes the urethral lumen. The dynamic factor refers to excessive stimulation of α1A-adrenergic receptors in the smooth muscle of the prostate and urethra, which results in smooth muscle contraction. This reduces the caliber of the urethral lumen. The detrusor factor refers to bladder detrusor muscle instability, in which bladder muscle fibers have decompensated as a result of excessive, prolonged hypertrophy in response to prolonged bladder outlet obstruction. Patients with detrusor muscle instability will develop irritative voiding symptoms, such as urinary urgency and frequency.1 Detrusor muscle fibers are embedded with α1D-receptors. Therefore, it has been proposed that some α1D-adrenergic antagonists may be particularly useful for controlling these symptoms.3,4
In an enlarged gland, the epithelial/stromal tissue ratio is 1:5.1 Androgens stimulate epithelial, but not stromal tissue hyperplasia. Hence, androgen antagonism does not induce a complete reduction in prostate size to normal. This explains one of the limitations of the clinical effect of 5α-reductase inhibitors.
Stromal tissue is the primary locus of α1-adrenergic receptors in the prostate. An estimated 98% of the α-adrenergic receptors in the prostate are found in prostatic stromal tissue. Of the α1-receptors found in the prostate, 70% of them are of the α1A-subtype.4 This explains why α-adrenergic antagonists are effective for managing symptoms of BPH.
Symptoms of BPH are classified as obstructive or irritative. Obstructive symptoms result from failure of the urinary bladder to empty urine when the bladder is full. The patient will complain of reduced force of the urinary stream, urinary hesitation, dribbling, and straining to empty the bladder. Irritative symptoms result from the failure of the urinary bladder to store urine until the bladder is full. With longstanding bladder outlet obstruction, detrusor muscle fibers undergo hypertrophy so that the bladder can generate higher pressure to overcome the bladder outlet obstruction and empty urine from the bladder. Once maximal bladder muscle hypertrophy occurs, the muscle decompensates. The detrusor becomes irritable, contracting abnormally in response to small amounts of urine in the bladder. As a result, the patient complains of urinary frequency and urgency.
The natural history of untreated BPH is unclear in patients with mild symptoms. It is estimated that up to 38% of untreated men with mild symptoms will have symptom improvement over a 2.5- to 5-year period.5 It may be that such patients attribute their symptoms to aging, grow tolerant of their symptoms, or adopt behavioral changes in their lifestyle that minimize their voiding symptoms. On the other hand, a significant portion of patients with mild symptoms will likely experience disease progression. In one Veterans Affairs study, approximately one-third of men with mild BPH symptoms, who were initially randomized to watchful waiting, developed progressive symptoms and required surgical intervention within 5 years of initial diagnosis.6 Patients with moderate to severe symptoms can experience a decreased quality of life as daily activities are adjusted because of urinary incontinence. Also, such patients may develop complications of BPH, which include acute refractory urinary retention, renal failure, urinary tract infection, urinary incontinence, bladder stones, large bladder diverticuli, and recurrent gross hematuria. Predictors of disease progression include an enlarged prostate of at least 30 g (1.05 oz) or PSA of at least 1.5 ng/mL (1.5 mcg/L).7–9
Clinical Presentation and Diagnosis of BPH
General
Patients may or may not be in acute distress. In early stages of disease, the patient may complain of obstructive voiding symptoms. If untreated, in late stages of disease the patient may complain of irritative voiding symptoms, or acute urinary retention, which is painful due to maximal distention of the urinary bladder. Also, the patient may be symptomatic of disease complications, including urosepsis, pyelonephritis, cystitis, or overflow urinary incontinence.
Symptoms
Patients may complain of obstructive voiding symptoms (e.g., urinary hesitancy, decreased force of urinary stream, straining to void, incomplete bladder emptying, dribbling, and intermittency) and/or irritative voiding symptoms (e.g., urinary frequency, nocturia, dysuria, urgency, and urinary incontinence). Severity of symptoms should be assessed by the patient using a standardized instrument (e.g., the American Urological Association [AUA] Symptom Scoring Index; Table 52–1). However, it is important to recognize that a patient’s perception of the bothersomeness of his voiding symptoms may not match with the AUA Symptom Score. In this case, after thorough evaluation of the signs and complications of BPH disease, if present, the physician and patient should discuss the bothersomeness of the patient’s symptoms and decide together on the most appropriate course of treatment for the patient.1,10 Lower urinary tract symptoms (LUTS) is a term that refers to the collection of obstructive and irritative voiding symptoms characteristic of, but not specific for, BPH. That is, other urologic diseases (e.g., urinary tract infection, prostate cancer, prostatitis, or neurogenic bladder) can also cause LUTS.
Signs
• Enlarged prostate on digital rectal exam (DRE); check for prostate nodules or induration, which would suggest prostate cancer instead of BPH as the cause of the patient’s voiding symptoms
• Distended urinary bladder
• Rule out meatal stenosis or urethral masses, which could cause voiding symptoms similar to LUTS
• Check anal sphincter tone as an indirect assessment of peripheral innervation to the detrusor muscle of the bladder
Complications of Untreated BPH
Upper and lower urinary tract infection, urosepsis, urinary incontinence refractory urinary retention, chronic renal failure, bladder diverticuli, bladder stones, or recurrent gross hematuria.
Medical History
• Check the patient’s general health including previous surgery, presence of diabetes mellitus, or medications that may cause or worsen voiding symptoms.
• Have the patient provide a diary of his voiding pattern for the past week: date and time of each voiding, volume voided, and whether or not the patient had urinary leakage during the day.
Laboratory Tests
• Serum PSA: The combination of PSA and DRE of the prostate is used to screen for prostate cancer, which could also cause an enlarged prostate. Also PSA is a surrogate marker for an enlarged prostate due to BPH. Using a PSA greater than 1.5 ng/mL (1.5 mg/L) suggests that a patient has a prostate volume greater than 30 mm3 (30 g or 1.05 oz).11
• Urinalysis to rule out infection as a cause of the patient’s voiding symptoms; also check urinalysis for microscopic hematuria, which typically accompanies BPH.
• Plasma blood urea nitrogen (BUN) and serum creatinine may be increased as a result of long-standing bladder outlet obstruction. These tests are not routinely performed but rather are reserved for those patients in whom renal dysfunction is suspected.
Other Diagnostic Tests (Table 52–2)
• Decreased peak and mean urinary flow rate (less than 10–15 mL/s) on uroflowmetry; decreased urinary flow rate is not specific for BPH; it can also be due to other urologic disorders (e.g., urethral stricture, meatal stenosis, or bladder hypotonicity)
• Increased postvoid residual urine volume (PVR) (more than 50 mL)
• DRE to check for an enlarged prostate (more than 15–20 g) (0.5-0.7 oz)
• Transurethral cytoscopy reveals an enlarged prostate, which decreases urethral lumen caliber; information from this procedure helps the surgeon decide on the best surgical approach
• Transrectal ultrasound of the prostate; a transrectal probe is inserted to evaluate prostate size and best surgical approach
• Transrectal prostate needle biopsy to be done if the patient has areas of nodularity or induration on DRE; tissue biopsy can document the presence of prostate cancer, which can also cause enlargement of the prostate
• IV pyelogram (IVP) will show retention of radiocontrast in the bladder if the patient has bladder outlet obstruction due to an enlarged prostate; only indicated in patients with recurrent hematuria, recurrent urinary tract infection, renal insufficiency, and urolithiasis
• Filling cystometry provides information on bladder capacity, detrusor contractility, and the presence of uninhibited bladder contractions, which could also cause LUTS
Patient Encounter 1, Part 1
AA is a 65-year-old male patient with an AUA symptom score of 19, urinary hesitancy, a slow urinary stream, urinary frequency, and nocturia. He wakes up three times every night to void. A DRE reveals an enlarged prostate of approximately 40 g (1.4 oz). His PSA is 4 ng/mL (4 mcg/L).
What stage of BPH does this patient have?
TREATMENT
Desired Outcomes
• Reducing or eliminating obstructive and irritative voiding symptoms. An improvement in the AUA Symptom Score should be observed. Drug treatment with an α-adrenergic antagonist or 5α-reductase inhibitor is expected to reduce the AUA Symptom Score by 30% to 50%, improve peak and mean urinary flow rate by 1 to 3 mL/s, and decrease PVR to normal (less than 50 mL total) when compared to pretreatment baseline values. The AUA Symptom Score may not correlate with response to therapy.
• Slowing disease progression. When compared to baseline, symptoms and serum BUN and creatinine should improve, stabilize, or decrease to the normal range with treatment.
• Preventing disease complications and reducing the need for surgical intervention.
• Avoiding or minimizing adverse treatment effects.
• Providing economical therapy.
• Maintaining or improving quality of life.
Table 52–1 Questions to Determine the AUA Symptom Score
Directions for the patient: The patient should be asked to respond to each question based on the absence or presence of symptoms over the past month. For each question, the patient can respond using a 1–5 scale, where 0 = not at all or none; 1 = less than 1 time in 5; 2 = less than half of the time; 3 = about half of the time; 4 = more than half of the time; and 5 = almost always
Directions for the clinician: After the patient completes the questionnaire, the scores for individual items should be tallied for a final score. Scores of 0–7 = mild symptoms; scores of 8–19 = moderate symptoms; scores more than 20 = severe symptoms
Questions to Assess Obstructive Voiding Symptoms
1. How often have you had a sensation of not emptying your bladder completely after you finished urinating?
2. How often have you found you stopped and started again several times when you urinated?
3. How often have you had a weak urinary stream?
4. How often have you had to push or strain to begin urinating?
Questions to Assess Irritative Voiding Symptoms
5. How often have you found it difficult to postpone urination?
6. How often have you had to urinate again less than 2 hours after you finished urinating?
7. How many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?
From Ref. 10.
FIGURE 52–1. Algorithm for selection of treatment for BPH based on symptom severity and presence of disease complications.
General Approach to Treatment
Until recently, the principal approach to treatment focused on reducing BPH symptoms (Fig. 52–1, Tables 52–1, 52–2, and 52–3). However, treatment should also slow disease progression and decrease complications of BPH.
For patients with mild symptoms, which the patient does not consider to be bothersome, watchful waiting is a reasonable approach to treatment. The patient is instructed to schedule return visits to the clinician every 3 to 6 months. At each visit, the patient’s symptoms are reassessed using the AUA Symptom Scoring Index, and results are compared to baseline (Table 52–1). In addition, the patient is educated about avoiding factors that worsen obstructive and irritative voiding symptoms (Table 52–4). The DRE is repeated annually. If the patient’s symptoms are unchanged, then watchful waiting is continued. If the patient’s symptoms worsen, then specific treatment is initiated.10
Table 52–2 Objective Tests Used to Assess the Size of the Prostate and Complications of BPH
Table 52–3 Staging the Severity of BPH Based on AUA Symptom Score and Example Signs of Disease
Table 52–4 Drugs That Can Cause Irritative or Obstructive Voiding Symptoms
For patients with moderate to severe symptoms, the patient is usually offered drug treatment first. α-Adrenergic antagonists are preferred over 5α-reductase inhibitors because the former have a faster onset of action (days to a few weeks) and improve symptoms independent of prostate size. 5α-reductase inhibitors have a delayed onset of action (i.e., peak effect may be delayed for up to 6 months) and are seldom effective in patients with smaller size prostate glands (less than 30 g or 1.05 oz). Drug treatment must be continued as long as the patient responds (Table 52–5).10
Table 52–5 Comparison of α-Adrenergic Antagonists and 5α-Reductase Inhibitors for Treatment of BPH
For patients with complications of BPH disease (e.g., recurrent urinary tract infection, urosepsis, urinary incontinence, refractory urinary retention, chronic renal failure, large bladder diverticuli, recurrent severe gross hematuria, or bladder calculi secondary to prolonged urinary retention), surgery is indicated. Although it is potentially curative, surgery can result in significant morbidity, including erectile dysfunction, retrograde ejaculation, urinary incontinence, bleeding, or urinary tract infection.12 The gold standard is a prostatectomy, which can be performed transurethrally or as an open surgical procedure, which can be performed suprapubically or retropubically. To avoid complications of prostatectomy, minimally invasive surgical procedures, such as transurethral incision of the prostate, transurethral needle ablation, or transurethral microwave thermotherapy, are options.10,12,13 Drug treatment is used in patients with severe disease when the patient refuses surgery or when the patient is not a surgical candidate because of concomitant diseases.
In the Multiple Treatment of Prostate Symptoms Study, it was found that selected patients with moderate to severe symptoms will benefit from a combination of α-adrenergic antagonist plus 5α-reductase inhibitor drug therapy.14Specifically, the use of doxazosin plus finasteride is more effective than doxazosin alone or finasteride alone in relieving symptoms, reducing the need for prostatectomy, and decreasing the incidence of BPH complications in patients at highest risk of developing disease complications (i.e., those with prostate size of at least 40 g [1.4 oz]). Combination therapy is more expensive than monotherapy and also produces more adverse effects. Therefore, the clinician should discuss the advantages and disadvantages of combination therapy with a patient before deciding on a final treatment regimen.
Nonpharmacologic Therapy
To reduce nocturia, patients should be instructed to stop drinking fluids several hours before going to bed, and then voiding before going to sleep. During the day, patients should avoid excessive caffeine and alcohol intake, as these may cause urinary frequency. Patients should avoid taking nonprescription medications that can worsen obstructive voiding symptoms (e.g., antihistamines or decongestants) (Table 52–4). In addition, toilet mapping (knowing the location of toilets on the way to and from various destinations) may help reassure the patient that he can still continue with many of his routine daily activities. Patients are also advised to lose weight, if overweight. Because testosterone is converted to estrogen in fat tissue, an alteration in the testosterone:estrogen ratio occurs in overweight men, similar to that which occurs in elderly males, which may contribute to the development of BPH 15–17
Although a variety of herbal agents are used for symptomatic management, including pygeum (African plum), secale cereale (rye pollen), and hypoxis rooperi (South African star grass), objective evidence of efficacy is lacking.18,19 Also, in a randomized, double-blind, and placebo-controlled clinical trial, saw palmetto was no different than placebo in improving symptoms or increasing peak urinary flow rate.20
Pharmacologic Therapy
α-Adrenergic Antagonist Monotherapy21
α-Adrenergic antagonists reduce the dynamic factor causing BPH symptoms. These drugs competitively antagonize α-adrenergic receptors, thereby causing relaxation of the bladder neck, prostatic urethra, and prostate smooth muscle. A secondary mechanism of action may be that α-adrenergic antagonists induce prostatic apoptosis,22 which suggests that these agents may cause some shrinkage of an enlarged prostate. However, the clinical importance of this remains to be elucidated.
All α-adrenergic antagonists are considered equally effective in relieving symptoms.10 In various clinical trials, 30% to 80% of patients experience improvement in AUA Symptom Score by 30% to 45% and 20% to 40% of patients experience urinary flow rate increases of 2 to 3 mL/s.15 The onset of action is days to weeks, depending on the need for titration of the dose from a subtherapeutic starting dose to a therapeutic dose. An adequate clinical trial is considered to be at least 1 to 2 weeks of continuous treatment at a full maintenance dose with any of these agents.10 Durable responses have been demonstrated for up to 5 years of continuous use of terazosin,23 10 years with doxazosin,24 and 6 years with tamsulosin.25 However, some patients will develop disease progression despite treatment. α-Adrenergic antagonists are hepatically catabolized. Therefore, in patients with significant hepatic dysfunction, these drugs should be used in the lowest possible dose. With the exception of silodosin, these drugs do not require dosage modification in patients with renal dysfunction. These agents can be differentiated by their adverse effect profile. Dose limiting adverse effects include hypotension and syncope, which are more common with immediate-release terazosin and doxazosin, less frequent with extended-release doxazosin and alfuzosin, and least frequent with uroselective α-adrenergic antagonists.26,27 Delayed or retrograde ejaculation has been reported most often with tamsulosin 0.8 mg orally once a day. Combined use with antihypertensives, diuretics, or phosphodiesterase inhibitors can lead to additive blood pressure-lowering effects; however, this appears to be less of a problem with tamsulosin.26,27
α-Adrenergic antagonists are recommended as first-line treatment for moderate to severe BPH. The agents in this pharmacologic class can be classified by several characteristics (Table 52–6):
• Generation of α-adrenergic antagonist. First-generation agents (e.g., phenoxybenzamine) block presynaptic and postsynaptic α-adrenergic receptors. Whereas blockade of postsynaptic α-adrenergic receptors is desirable for BPH management, blockade of presynaptic α-adrenergic receptors is undesirable, as it results in release of catecholamines and tachycardia. Thus, first-generation α-adrenergic antagonists are not used for treatment of BPH.28 Second-generation α-adrenergic antagonists block postsynaptic α-adrenergic receptors in the bladder neck, prostate, and peripheral vasculature. Hypotensive adverse effects are dose-related and common. Examples include terazosin, doxazosin, and alfuzosin. Third-generation α-adrenergic antagonists (e.g., tamsulosin, silodosin) selectively block postsynaptic α1A-receptors, which concentrate in the prostate. As a result, hypotensive adverse effects are less common than with second-generation agents.
• Uroselectivity. Pharmacologic uroselectivity refers to preferential inhibition of α1A-and α1D-receptors, which predominate in the prostatic stroma and bladder detrusor muscle, respectively.21Pharmacologically uroselective α1A-adrenergic antagonists have the potential to produce less hypotension, as they have a lower propensity to antagonize α1B-adrenergic receptors in the peripheral vasculature. Tamsulosin and silodosin are the only commercially available α-adrenergic antagonists with pharmacologic uroselectivity. In contrast, despite the potential of inhibiting α-adrenergic receptors in both the prostate and peripheral vasculature, functionally uroselective α-adrenergic antagonists in usually-prescribed doses, produce effective relaxation of prostatic smooth muscle with minimal vascular vasodilation. Thus, blood pressure-lowering effects are mild or absent. The only functionally uroselective α-adrenergic antagonist is alfuzosin extended-release tablets. The mechanism of functional uroselectivity is unclear. It may be related to a drug formulation which produces a higher concentration in target tissues than in nontarget tissues.28 Both pharmacologically and functionally uroselective agents appear to be clinically uroselective, in that they improve BPH symptoms without causing cardiovascular adverse effects in humans.21
Pharmacologic and functional uroselectivity are dose-related phenomena. Large daily doses of tamsulosin or alfuzosin may cause loss of uroselectivity with resultant hypotension and dizziness in some patients.
• Need for up-titration of daily dose. Up-titration required for immediate-release terazosin and doxazosin. It is minimally required for extended-release doxazosin and tamsulosin. It is not required for extended-release alfuzosin or silodosin.
• Plasma half-life. α-Adrenergic receptors with short plasma half-lives (e.g., prazosin) require multiple doses during the day. This is challenging for most patients, and, thus, prazosin is not recommended for BPH.10
• Dosage formulation. Immediate-release formulations of terazosin and doxazosin are quickly absorbed and produce high peak plasma levels. Modified- or extended-release formulations of doxazosin, alfuzosin, and tamsulosin produce lower peak levels, but more sustained therapeutic plasma levels, than immediate-release formulations and have less potential for producing hypotensive episodes. This allows for initiation of treatment with a therapeutic dose and once daily dosing.29–31
• Adverse effects. Hypotensive adverse effects of α-adrenergic antagonists can range from asymptomatic blood pressure reductions to dizziness and syncope. This adverse effect is most commonly associated with immediate-release terazosin and doxazosin; is less commonly associated with extended-release alfuzosin and extended-release doxazosin, and silodosin; and least commonly associated with tamsulosin.26,27 To minimize first-dose syncope from terazosin and doxazosin immediate-release, a slow up-titration from a subtherapeutic dose of 1 mg/day to a therapeutic dose is essential. The first dose should be given at bedtime so that the patient can sleep through the peak serum concentration of the drug when the adverse effect is most likely to occur. A 3- to 7-day interval between each dosage increase should be allowed, and the patient should be maintained on the lowest effective dose of α-adrenergic antagonist. If the patient is noncompliant with his regimen of terazosin or doxazosin, and he skips or interrupts treatment, the α-adrenergic antagonist should be restarted using the usual starting dose and then retitrated up. He should not be instructed to simply double up on missed doses or resume treatment with his currently prescribed daily dose, as this can lead to significant hypotension.
Table 52–6 Comparison of Pharmacologic Properties of α-Adrenergic Antagonists
Ejaculation disorders, including delayed and retrograde ejaculation, occur with all adrenergic antagonists. Although largely thought to be due to pharmacologic blockade of peripheral α-adrenergic receptors at the bladder neck (i.e., the bladder neck is unable to close during ejaculation in the presence of α-adrenergic blockade), a CNS mechanism of action cannot be discounted.32 The incidence appears to be dose-related and highest with tamsulosin 0.8 mg daily, occurring in up to 26% of treated patients.33 Ejaculation disorders generally do not necessitate discontinuation of treatment. Although they may decrease the patient’s satisfaction with the quality of sexual intercourse, ejaculation disorders are not harmful to the patient.
Rhinitis and malaise occur with α-adrenergic antagonists and are an extension of the pharmacologic blockade of α-adrenergic receptors in the vasculature of the nasal mucosa and in the CNS, respectively. Tolerance often develops to these adverse effects and they rarely require discontinuation of treatment. Avoid use of topical or oral decongestants, as these may exacerbate obstructive voiding symptoms. Cautious use of antihistamines with anticholinergic adverse effects is also recommended in patients with BPH, as these drugs may cause acute urinary retention in patients with an obstructed bladder neck.
Floppy iris syndrome has been reported with α-adrenergic antagonists, most often with tamsulosin. In response to tamsulosin, the iris dilator muscle relaxes. As a result, in a tamsulosin-treated patient who is undergoing cataract surgery, the iris can become flaccid, billow out, or become floppy. This can interfere with the surgical procedure and increase the risk of intraoperative and postoperative complications. A patient who plans to undergo cataract surgery is advised to inform his ophthalmologist that he is taking an α-adrenergic antagonist. Although the drug will not need to be held or discontinued, the ophthalmologist can plan to use certain surgical techniques, for example, iris hooks or iris expansion rings, to deal with the drug’s effect on the iris dilator muscle.34,35
Alfuzosin has been linked to two cases of hepatitis.36,37 The cause-effect relationship remains to be elucidated.
• Potential for drug interactions. Hypotensive adverse effects of terazosin and doxazosin can be additive with those of diuretics, antihypertensives, and phosphodiesterase inhibitors (e.g., sildenafil). In patients at greatest risk for hypotension, or in those patients who tolerate hypotension poorly, including those with poorly controlled coronary artery disease or severe orthostatic hypotension, tamsulosin 0.4 mg appears to be the safest choice.38,39 In patients who cannot tolerate tamsulosin, a 5α-reductase inhibitor or prostatectomy should be considered. When initiating sildenafil, tadalafil, or vardenafil, patients who are taking α-adrenergic antagonists should be stabilized first on a fixed dose of the α-adrenergic antagonist, and patients should be instructed to allow a 4-hour interval between the α-adrenergic antagonist and the phosphodiesterase inhibitor to minimize the likelihood of hypotensive effects.
Among the α-adrenergic antagonists, tamsulosin and silodosin are unique in that they are third-generation α-adrenergic antagonists. They are pharmacologically uroselective and exert greater antagonism of α1A- and α1D-receptors, which predominate in prostatic and bladder detrusor muscle. Tamsulosin exerts comparatively low antagonism of vascular α1B-receptors. Therefore, tamsulosin can be started with a therapeutic dose, which achieves peak effects sooner than terazosin and doxazosin immediate-release, which must be up-titrated. Tamsulosin appears to have the lowest potential to cause hypotension.26,27 In various clinical trials, tamsulosin has minimal hypotensive adverse effects and is well tolerated in the elderly, as well as in patients taking diuretics, antihypertensives, or phosphodiesterase inhibitors. It is also commercially available in a modified-release dosage formulation, which is dosed at 0.4 mg orally once a day. With chronic use, tamsulosin can be taken at any time of the day and at the patient’s convenience. Although the package insert states that the dose can be increased to 0.8 mg daily, no consistent improvement in clinical efficacy has been observed in patients taking the higher dose.26 It is not clear at this time whether silodosin has the same clinical cardiovascular safety profile as tamsulosin.
Patient Encounter 2, Part I
BB has moderate BPH symptoms and is started on tamsulosin 0.4 mg orally once a day. After 2 to 3 weeks, BB states that his symptoms have not improved. He is not experiencing any drug-related adverse effects.
What should be the next step in management of this patient?
In patients with BPH and hypertension, it is not recommended to use an α-adrenergic antagonist alone to treat both disorders. In the ALLHAT study, where doxazosin was compared to other agents for treatment of essential hypertension, doxazosin was associated with a higher incidence of congestive heart failure. Therefore, in patients with hypertension and BPH, it is recommended that an appropriate antihypertensive be added to an α-adrenergic antagonist.26
5α-Reductase Inhibitor Monotherapy
5α-Reductase inhibitors reduce the static factor, which results in shrinkage of an enlarged prostate. They do so by inhibiting 5α-reductase, which is responsible for intraprostatic conversion of testosterone to dihydrotestosterone, the active androgen that stimulates prostate tissue growth. In the prostate, there are two subtypes of 5α-reductase; the majority is the type II isoenzyme type and the minority is the type I isoenzyme type. In addition, 5α-reductase inhibitors induce apoptosis of prostatic epithelial cells.40 The onset of action is slow with peak shrinkage of the prostate taking up to 6 months.10 Unlike α-adrenergic antagonists, 5α-reductase inhibitors are used to prevent BPH-related complications and disease progression. Finasteride has been shown to reduce the incidence of acute urinary retention and need for prostate surgery in patients with significantly enlarged prostate glands (greater than 40 g [1.4 oz]),14 and those with serum levels of PSA of at least 1.5 ng/mL (1.5 mcg/L).11 Because 5α-reductase inhibitors do not produce cardiovascular adverse effects, they are preferred for men with moderate to severe BPH who are at risk of developing complications of BPH (i.e., the patient has an enlarged prostate of at least 30 g [1.05 oz]), and has a PSA of greater than 1.5 ng/mL (1.5 mg/L).8,11,41
With regard to their use for the symptomatic treatment of BPH, 5α-reductase inhibitors relieve BPH symptoms in 30% to 70% of patients and increase urinary flow rate by 1 to 2 mL/s, which is less improvement than that seen with α-adrenergic antagonists.10,14 A minimum of 6 months is required to evaluate the effectiveness of treatment. This is a disadvantage in patients with moderate to severe symptoms, as it will take that long to determine if the drug is or is not effective. Durable responses have been demonstrated in responding patients treated up to 6 years with finasteride and 4 years with dutasteride.42,43 These agents are hepatically metabolized. No specific recommendations for dosage modification are currently available in patients with significant hepatic dysfunction; however, due to drug specificity for its enzyme target, it is unlikely that any dosage adjustment will be required. No dosage adjustment is needed in patients with renal impairment. Adverse effects include decreased libido, erectile dysfunction, and ejaculation disorders, which generally decrease in frequency with continued use, and gynecomastia and breast tenderness.33,40 Serum testosterone levels increase by 10% to 20% in treated patients; however, the clinical significance of this is not clear at this time.10 Drug interactions are uncommon. These drugs do produce a mean 50% decrease in serum levels of PSA. Therefore, to preserve the usefulness of this laboratory test as a diagnostic and monitoring tool, it is recommended that prescribers obtain a baseline PSA prior to the start of treatment and repeat it at least annually during treatment. A significantly elevated PSA in treated patients is an indicator for further diagnostic workup.44 Exposure to 5α-reductase inhibitors is contraindicated in pregnant females, as the drugs may cause feminization of a male fetus. Pregnant females should not handle these drugs unless they are wearing gloves.
5α- Reductase inhibitors include finasteride and dutasteride. Finasteride is a selective type II 5α-reductase inhibitor, whereas dutasteride is a nonselective type I and II 5α-reductase inhibitor. When compared to finasteride, dutasteride produces a faster and more complete inhibition of 5α-reductase in prostate cells. However, no difference in clinical efficacy or adverse effects has been demonstrated between these two agents. Thus, finasteride and dutasteride are considered therapeutically interchangeable (Table 52–7).45
By reducing serum levels of dihydrotestosterone, which is linked to the development of prostate cancer, it has been hypothesized that 5α-reductase inhibitors may prevent the development of prostate cancer. The Predict Trial reported that finasteride reduced the detection of prostate cancer with prostatic needle biopsy by 25%; however, higher-grade tumors were more common in treated patients.46 This finding is likely due to the fact that the drug-induced shrinkage of the prostate increased the probability that the prostate needle biopsy procedure was able to obtain cancerous tissue.46 The ongoing Reduce Trial, which will follow dutasteride-treated patients for 4 years, may provide more clarification on this issue.47
Combination Therapy
A combination of an α-adrenergic antagonist and 5α-reductase inhibitor may be considered in symptomatic patients at high risk of BPH complications, which are defined as those with an enlarged prostate of at least 30 g (1.05 oz) and a PSA of at least 1.5 ng/mL (1.5 mcg/L). In such patients, combination therapy will relieve voiding symptoms and also may reduce the risk of developing BPH-related complications and reduce the need for prostatectomy by 67%.12,14 Because combination therapy is more expensive and associated with the array of adverse effects associated with each drug in the combination, clinicians should discuss the advantages and disadvantages of each treatment regimen with the patient before a final decision is made.10
Patient Encounter 1, Part 2
AA is started on finasteride 5 mg orally once a day. Four weeks later the patient returns for a follow-up visit and complains that he is not experiencing any symptom improvement.
What should be the next step in management of this patient?
Table 52–7 Comparison of Pharmacologic Properties of 5α-Reductase Inhibitors
To streamline and reduce the cost of treatment regimens, it has been suggested that the α-adrenergic antagonist may be discontinued after the first 6 to 12 months of combination therapy. However, long-term treatment is required to determine if such a regimen is as effective as continuous combination therapy.48,49
Another enhancement to BPH symptom management is the addition of an anticholinergic agent to an α-adrenergic antagonist. The rationale for the anticholinergic agent is that irritative symptoms (e.g., urinary urgency and frequency) are thought to be due to hyper-reactive bladder detrusor muscle contraction, which can be ameliorated by blockade of acetylcholine receptors.49,50 Also, α1D-adrenergic receptors in the detrusor muscle, which cause muscle contraction when stimulated, can be blocked by α-adrenergic antagonists. As a result, use of an α-adrenergic antagonist may also decrease involuntary bladder muscle contraction and increase the bladder’s compliance. Thus, the combination may have an additive pharmacologic effect on relieving irritative voiding symptoms.51,52 A recent study documenting the addition of tolterodine to tamsulosin showed significant irritative symptom improvement, more than what was observed with tamsulosin alone. No cases of urinary retention were reported.51
OUTCOME EVALUATION
Once the peak effects of drug treatment are expected to occur, monitor the drug for effectiveness. Assess symptom improvement using the AUA Symptom Scoring Index. A reduction in symptom score is anticipated with symptom improvement. However, it should be noted that the AUA Symptom Score may not match the patient’s perception of the bothersomeness of his voiding symptoms. If the patient perceives his symptoms as bothersome, independent of the AUA Symptom Score, consideration should be given to modifying the patient’s treatment regimen. Similarly, a patient may regard his symptoms as not bothersome even though the AUA symptom score is high. In this case, the physician should objectively assess symptoms at baseline and during treatment by performing a repeat uroflowmetry, which can detect an improvement in peak and mean urinary flow rate. If the patient shows a response to treatment, instruct the patient to continue the drug regimen and have the patient return at 6-month intervals for monitoring. If the patient shows an inadequate response to treatment, the dose of α-adrenergic antagonist can be increased (except for extended-release alfuzosin) until the patient’s symptoms improve or until the patient experiences adverse drug effects.
For the α-adrenergic antagonists, the severity of hypotensive-related adverse effects, which may manifest as dizziness or syncope, may require a dosage reduction or a slower up-titration of immediate-release terazosin or doxazosin, or halting the up-titration of the α-adrenergic antagonist. If the patient develops adverse effects at this dose, the drug should be discontinued. Other adverse effects of α-adrenergic antagonists are nasal congestion, malaise, headache, and ejaculation disorders. None of these generally require discontinuation of treatment and these often improve as treatment continues. For the 5α-reductase inhibitors, the most bothersome adverse effects are decreased libido, erectile dysfunction, and ejaculation disorders. In sexually active males, erectile dysfunction may be improved with erectogenic drugs; however, this adverse effect may necessitate discontinuation of treatment.
Table 52–8 Summary of Adverse Effects of α-Adrenergic Antagonists and 5α-Reductase Inhibitors and Management Suggestions
During continuing treatment of BPH, the patient should undergo an annual repeat PSA and DRE. A rising PSA level suggests that the patient has worsening BPH, new-onset prostate cancer, or that the patient is noncompliant with his regimen of 5α-reductase inhibitor. An abnormal DRE suggestive of prostate cancer would reveal a nodule or area of induration on the prostate, or a gland that is fixed in place. In such a case, a prostate biopsy is required to rule out prostate cancer.
Drug treatment failures may result from a variety of factors. Initial failure to respond to α-adrenergic antagonists occurs in 20% to 70% of treated patients. It is likely in these patients that the static factor may predominate as the cause of symptoms in these patients. In these patients, adding a 5α-reductase inhibitor may be helpful. Initial failure to respond to 5α-reductase inhibitors occurs in 30% to 70% of treated patients. It is likely that the dynamic factor may predominate as the cause of symptoms in these patients. In these patients, switching to or adding an α-adrenergic antagonist may be helpful. In contrast, drug treatment failures after an initial good response to drug therapy will likely be an indication of progressive BPH disease. In such patients, surgical intervention may be indicated.
Patient Care and Monitoring
• Monitor the patient for the drug’s effectiveness in relieving symptoms by using the AUA Symptom Scoring Index. Monitor to ensure that the score improves and that the patient subjectively feels that symptoms have improved. If the patient has no improvement after several weeks of a therapeutic dose of α-adrenergic antagonist or after 6 months of a 5α-reductase inhibitor, consider surgical intervention. Alternatively, if the patient was on a 5α-reductase inhibitor alone, it may be reasonable to consider adding an α-adrenergic antagonist.
• If the patient is started on an α-adrenergic antagonist, monitor the patient for hypotension, dizziness, or syncope. If present, assess the severity of each symptom. Reduce the drug dose, switch to a uroselective α-adrenergic antagonist, or discontinue the drug, as necessary. If the patient has malaise or rhinitis, reassure the patient that these are usual, but bothersome, adverse effect, that often improve with continued therapy.
• If the patient is started on a 5α-reductase inhibitor, monitor the patient for drug-induced decreased libido, erectile dysfunction, or ejaculation disorders. If severe, discontinue the drug.
Table 52–8 summarizes the adverse effects of the agents used to treat BPH and includes management suggestions for these situations.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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