Benign prostatic hyperplasia: Evaluation and medical management in primary care

MEDICAL MANAGEMENT

Drugs for BPH include alpha-adrenergic blockers, 5-alpha reductase inhibitors, anticholinergics, beta-3 agonists, and phosphodiesterase-5 inhibitors. Costs of selected agents in these classes are listed in Table 2.

Alpha-adrenergic receptor blockers

Alpha-adrenergic receptors are found throughout the body and modulate smooth muscle tone.²⁴ The alpha-1a receptor is the predominant subtype found in the bladder neck and prostate²⁵ (Figure 2) and is a target of therapy. By antagonizing the alpha-1a receptor, alpha-blockers relax the smooth muscle in the prostate and bladder neck, reduce bladder outlet resistance, and improve urinary flow.²⁶

In clinical trials in BPH, alpha-blockers improved the symptom score by 30% to 45% and increased the peak urinary flow rate by 15% to 30% from baseline values.²⁷ These agents have a rapid onset (within a few days) and result in significant symptom improvement. They are all about the same in efficacy (Table 3),^28–36 with no strong evidence that any one of them is superior to another; thus, decisions about which agent to use must consider differences in receptor subtype specificity, adverse-effect profile, and tolerability.

In the Medical Therapy of Prostatic Symptoms (MTOPS) trial,³⁷ men randomized to the alpha-blocker doxazosin had a 39% lower risk of BPH progression than with placebo, largely due to symptom score reduction. However, doxazosin failed to reduce the risk of progressing to acute urinary retention or surgical intervention. Though rapidly effective in reducing symptoms, alpha-blocker monotherapy may not be the best option in men at higher risk of BPH progression, as discussed below.

Before starting this therapy, patients must be counseled about common side effects such as dizziness, fatigue, peripheral edema, orthostatic hypotension, and ejaculatory dysfunction. The incidence of adverse effects varies among  agents (Table 4).^{28–30,34,35,38,39}

To maximize efficacy of alpha-blocker therapy, it is imperative to understand dosing variations among agents.

Alpha-blockers are classified as uroselective or non-uroselective based on alpha-1a receptor subtype specificity. The non-uroselective alpha-blockers doxazosin and terazosin need to be titrated because the higher the dose the greater the efficacy, but also the greater the blood pressure-lowering effect and other side effects.²⁵ Though non-uroselective, alfuzosin does not affect blood pressure and does not require dose titration. Similarly, the uroselective alpha-blockers tamsulosin and silodosin can be initiated at a therapeutic dose.

Terazosin, a non-uroselective agent, can lower blood pressure and often causes dizziness. It should be started at 2 mg and titrated to side effects, efficacy, or maximum therapeutic dose (10 mg daily).²⁸

Doxazosin has a high, dose-related incidence of dizziness (up to 20%) and must be titrated, starting at 1 mg to a maximum 8 mg.³⁰

Alfuzosin, tamsulosin, and silodosin do not require titration and can be initiated at the therapeutic doses listed in Table 3. Of note, obese patients often require 0.8 mg tamsulosin for maximum efficacy due to a higher volume of distribution.

Before initiating an alpha-blocker, a physician must determine whether a patient plans to undergo cataract surgery, as the use of alpha-blockers is associated with intraoperative floppy iris syndrome. This condition is marked by poor intraoperative pupil dilation, increasing the risk of surgical complications.⁴⁰ It is unclear whether discontinuing alpha-blockers before cataract surgery reduces the risk of intraoperative floppy iris syndrome. As such, alpha-blocker therapy should be delayed in patients planning to undergo cataract surgery.

5-Alpha reductase inhibitors

Prostate growth is androgen-dependent and mediated predominantly by dihydrotestosterone, which is generated from testosterone by the action of 5-alpha reductase. There are two 5-alpha reductase isoenzymes: type 1, expressed in the liver and skin, and type 2, expressed primarily in the prostate.

There are also two 5-alpha reductase inhibitors: dutasteride and finasteride. Dutasteride inhibits both isoenzymes, while finasteride is selective for type 2. By inhibiting both isoenzymes, dutasteride reduces the serum dihydrotestosterone concentration more than finasteride does (by 95% vs 70%), and also reduces the intraprostatic dihydrotestosterone concentration more (by 94% vs 80%).^41–43 Both agents induce apoptosis of prostatic stroma, with a resultant 20% to 25% mean reduction in prostate volume.^41,42

Finasteride and dutasteride are believed to mitigate the static obstructive component of BPH, with similar improvements in urinary flow rate (1.6–2.2 mL/sec) and symptom score (–2.7 to – 4.5 points) in men with an enlarged prostate.^41,42 Indeed, data from the MTOPS trial showed that men with a prostate volume of 30 grams or greater or a PSA level of 1.5 ng/mL or greater are most likely to benefit from 5-alpha reductase inhibitors.³⁷ Maximum symptomatic improvement is seen after 3 to 6 months of 5-alpha reductase inhibitor therapy.

In addition to improving urinary flow and lower urinary tract symptoms, finasteride has been shown to reduce the risk of disease progression in men with prostates greater than 30 grams.⁴⁴ Compared with placebo, these drugs significantly reduce the risk of developing acute urinary retention or requiring BPH-related surgery, a benefit not seen with alpha-blockers.³⁷ To estimate prostate volume, most practitioners rely on digital rectal examination. Though less precise than transrectal ultrasonography, digital rectal examination can identify men with significant prostatic enlargement likely to benefit from this therapy.

Before starting 5-alpha reductase inhibitor therapy, patients should be counseled about common adverse effects such as erectile dysfunction (occurring in 5%–8%), decreased libido (5%), ejaculatory dysfunction (1%–5%), and gynecomastia (1%).

Combination therapy

The MTOPS trial³⁷ randomized patients to receive doxazosin, finasteride, both, or placebo. The combination of doxazosin (an alpha-blocker) and finasteride (a 5-alpha reductase inhibitor) reduced the risk of disease progression to a greater extent than doxazosin or finasteride alone. It also reduced the IPSS more and increased the peak urinary flow rate more. Similar results have been seen with the combination of dutasteride and tamsulosin.⁴⁵

Given its superior efficacy and benefits in preventing disease progression, combination therapy should be considered for men with an enlarged prostate and moderate to severe lower urinary tract symptoms.

Anticholinergic agents

Anticholinergic agents block muscarinic receptors within the detrusor muscle, resulting in relaxation. They are used in the treatment of overactive bladder for symptoms of urinary urgency, frequency, and urge incontinence.

Anticholinergics were historically contraindicated in men with BPH because of concern about urinary retention. However, in men with a postvoid residual volume less than 200 mL, anticholinergics do not increase the risk of urinary retention.⁴⁶ Further, greater symptom improvement has been demonstrated with the addition of anticholinergics to alpha-blocker therapy for men with BPH, irritative lower urinary tract symptoms, and a low postvoid residual volume.⁴⁷

Beta-3 agonists

Anticholinergic side effects often limit the use of anticholinergic agents. An alternative in such instances is the beta-3 agonist mirabegron. By activating beta-3 adrenergic receptors in the bladder wall, mirabegron promotes detrusor relaxation and inhibits detrusor overactivity.⁴⁸ Mirabegron does not have anticholinergic side effects and is generally well tolerated, though poorly controlled hypertension is a contraindication to its use.

Phosphodiesterase-5 inhibitors

Phosphodiesterase-5 (PDE5) inhibitors are a mainstay in the treatment of erectile dysfunction. These agents act within penile corporal smooth muscle cells and antagonize PDE5, resulting in cyclic guanosine monophosphate accumulation and smooth muscle relaxation. PDE5 is also found within the prostate and its inhibition is believed to reduce prostatic smooth muscle tone. Randomized studies have demonstrated significant improvement in lower urinary tract symptoms with PDE5 inhibitors, with an average 2-point IPSS improvement on a PDE5 inhibitor compared with placebo.⁴⁹

Tadalafil is the only drug of this class approved by the FDA for the treatment of lower urinary tract symptoms, though other agents have demonstrated similar efficacy.

Dual therapy with a PDE5 inhibitor and an alpha-blocker has greater efficacy than either monotherapy alone; however, caution must be exercised as these agents are titrated to avoid symptomatic hypotension. Lower urinary tract symptoms and sexual dysfunction often coexist; PDE5 inhibitors are appropriate in the management of such cases.

SURGERY FOR BPH

Even with effective medical therapy, the disease will progress in some men. In the MTOPS trial,³⁷ the 4-year incidence of disease progression was 10% for men on alpha-blocker or 5-alpha reductase inhibitor monotherapy and 5% for men on combination therapy; from 1% to 3% of those in the various treatment groups needed surgery. With this in mind, patients whose symptoms do not improve with medical therapy, whose symptoms progress, or who simply are interested in surgery should be referred for urologic evaluation.

A number of effective surgical therapies are available for men with BPH (Table 5), providing excellent 1-year outcomes including a mean 70% reduction in IPSS and a mean 12 mL/sec improvement in peak urinary flow.⁵⁰ Given the efficacy of surgical therapy, men who do not improve with medical therapy who demonstrate any of the findings outlined in Table 1 warrant urologic evaluation.

Acknowledgments: We would like to thank Mary Ellen Amos, PharmD, and Kara Sink, BS, RPh, for their assistance in obtaining the suggested wholesale pricing information included in Table 2.