Treating options are broadening for benign prostatic hyperplasia and R.Ph.s can help patients decide which drugs or herbs to use
With treatments for benign prostatic hyperplasia expanding, R.Ph.s can help patients decide which ones to use
Death, taxes, and benign prostatic hyperplasia (BPH)while not quite as inevitable as the first two, the third represents a sizable risk as men age. More than 50% of men in their 60s have some symptoms stemming from prostate enlargement, and as many as 90% of men in their 70s and 80s suffer from these symptoms.
While the disease is not life threatening, it can have a major impact on quality of life. Urinary urgency, frequency, weak stream, and hesitancy may cause discomfort, inconvenience, and embarrassment, as men need constant access to a restroom or find their sleep disturbed by multiple trips to the bathroom.
In the past, the only solution to those problems was surgery, with its associated risk of complications. But the last decade has seen the advent of pharmacotherapeutic agents that can help alleviate BPH symptoms without the need for invasive techniques.
The two classes of drugs currently available for BPH, the alpha-1
adrenergic blocking agents and 5-alpha- (or 5
) reductase inhibitors, are designed to target the dual mechanismsdynamic and staticthat contribute to the symptoms of BPH, explained Steven Levy, Pharm.D., geriatric pharmacy practice resident, Kingsbrook Jewish Medical Center/David Minkin Rehabilitation Center, and clinical instructor of pharmacy practice, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University. In the dynamic component, he said, "we see a constriction of the urethra through the prostate gland caused by [increased] smooth muscle tone." The muscle tone in this area is mediated by the alpha-1 receptors. The static component of BPH is associated with an increase in prostate size, which causes urinary flow obstruction.
Blockade of alpha-1 receptors results in "relaxation of the smooth muscle in the bladder neck and the prostate gland, thereby reducing the bladder outlet obstruction and promoting urinary flow through the urethra," Levy explained. The enzyme 5a-reductase mediates the conversion of testosterone to 5a- dihydrotestosterone (DHT), the androgen responsible for increasing the cellular proliferation of the prostate gland. Thus, he said, "the inhibition of the DHT can, in fact, decrease the enlargement of the prostate and alleviate the symptoms of BPH."
The quinazoline derivative alpha-blockers, Cardura (doxazosin, Pfizer) and Hytrin (terazosin, Abbott Laboratories), nonspecifically inhibit the alpha-1a, 1b, and 1c receptor subtypes. These drugs relax smooth muscle not only in the bladder neck and prostate but also in the vasculature, resulting in hypotensive effects. Both doxazosin and terazosin are indicated for hypertension as well as BPH; a third alpha-blocker, Minipress (prazosin, Pfizer), is approved only as an antihypertensive.
Because these drugs are associated with a first-dose syncope-like effect, Levy recommends that patients take the first dose either at bedtime or under the supervision of a healthcare professional. Even after the first dose, the risk of orthostatic hypotension persists. Patients can experience "a marked decrease in blood pressure and increase in heart rate, which can bring about lack of perfusion to the brain and cause them to pass out," he noted. This is especially of concern in the geriatric population, he said, "when we worry about the risk of falls and fractures." Patients must be cautioned about rising slowly from a prone position, he said, and they should be told that if they feel dizzy or faint, they should sit back down and call someone for help.
The once-daily doses of the quinazoline alpha-blockers should be taken at bedtime to minimize the risk of orthostatic hypotension. Patients are started at a low drug dose, which is gradually titrated upward to an effective dose. If patients miss two or three consecutive doses, they must restart the titration process.
Flomax (tamsulosin, Boehringer Ingelheim), the most recent entry in the alpha-blocker class, is specifically targeted toward the alpha-1a receptor subtype, which is found mainly in the bladder and urethral smooth muscle. Tamsulosin is presumed to have less of an effect on blood pressure than the other alpha-blockers, but its labeling still carries a warning about the risk of dizziness and fainting. Tamsulosin has an advantage in that the dose does not have to be titrated, said Michael P. O'Leary, M.D., M.P.H., associate professor of surgery, Harvard Medical School, and senior urologist, Brigham and Women's Hospital, Boston.
Tamsulosin may cause ejaculation abnormalities, and all the alpha- blockers carry warnings about a slight, but potentially serious, risk of priapism. Although tamsulosin is a sulfonamide, it differs structurally from the sulfonamide antibiotics and is not contraindicated in patients with sulfa allergy. According to the maker, patients with sulfa allergy were not excluded from the clinical trials of tamsulosin, and no sulfa-allergic patients who participated in trials had hypersensitivity reaction. What's more, the manufacturer said, there have been no reports of cross-allergenicity to date.
O'Leary was involved in a study that evaluated 600 men with BPH over up to six years of tamsulosin treatment. Statistically significant reductions in symptoms and improvements in quality of life were sustained throughout the duration of the study. He believes these long-term data are important. In the past, he said, "people would ask, 'If I go on this medication now, how likely is it to continue to help me, if it does help me?' And the answer is," he continued, "we know that at six years it still seems to be helping people."
While the alpha-blockers all provide similar symptom relief at a therapeutic dose, according to O'Leary, there may be differences in the speed of efficacy. An eight-week, open-label study that compared tamsulosin 0.4 mg q.d. and terazosin 5 mg q.d. (with standard titration schedule) in close to 2,000 men with BPH found that tamsulosin had a significantly more rapid onset of action. O'Leary pointed out that the therapeutic dose of terazosin is 10 mg, not 5 mg. However, he noted, clinicians often stop titrating at 5 mg, perhaps because of side effects.
While the alpha-blockers do not appear to affect prostate size, 5a-reductase inhibitor Proscar (finasteride, Merck) "can actually decrease the size of the prostate by about 24%," said Kelly A. Kelsey, Pharm.D., clinical pharmacist, Greenwood Health Center, University of Utah Hospitals and Clinics. The drug is indicated to reduce the risk of need for surgery, including transurethral resection of the prostate (TURP) and prostatectomy. Because of its different mechanism of action, finasteride usually takes longer to relieve patients' symptoms than the alpha-blockers.
Due to its effects on testosterone, finasteride's possible adverse effects include changes in sexual function such as decreased volume of ejaculate, impotence, and decreased libido. Inhibiting the conversion of testosterone to DHT may cause abnormalities in the genitalia of a male fetus of a pregnant woman who receives finasteride. The drug has no indication in women and should not be taken in this patient population. Additionally, women who are, or could become, pregnant should not handle crushed or broken finasteride tablets, because of the possibility of absorption of the drug. According to the manufacturer, there does not appear to be a risk to the fetus of a pregnant woman whose sexual partner is taking finasteride, because the drug achieves low concentrations in semen.
Kelsey advised cautious use of finasteride in patients with liver disease, because the drug is extensively metabolized by the liver. Finasteride lowers PSA levels by about half, even in the presence of prostate cancer. So in patients who've been taking the drug for six months or longer, PSA values should be doubled for an accurate assessment of prostate cancer risk.
Next year, the range of treatment options will broaden as a new drug becomes available in each of the drug classes used for BPH. GlaxoSmithKline's Duagen (dutasteride) gained approval last October, but has not yet been put on the market. Dutasteride is a 5a-reductase inhibitor that will provide another option to finasteride.
Sanofi-Synthelabo's Xatral (alfuzosin) received an approvable letter from the Food & Drug Administration late last year. The uroselective alpha-1 blocker, a quinazoline derivative, has been marketed in Europe for several years in formulations that required b.i.d. or t.i.d. dosing, but the manufacturer has now developed a once-daily, controlled-release dosage form. Clinical trials have shown the prolonged-release alfuzosin 10 mg q.d. is as effective as immediate-release alfuzosin 2.5 mg t.i.d.; the controlled-release form caused fewer vasodilatory-related events such as dizziness, headache, and orthostatic hypotension.
Alfuzosin is a functionally uroselective alpha-blocker; although it does not specifically target any alpha-1 receptor subtype, animal and human studies have shown that it distributes preferentially to the prostate. In studies, alfuzosin was shown to be more selective for prostatic tissue than tamsulosin, doxazosin, or terazosin. The prolonged-release drug did not cause clinically relevant changes to blood pressure or heart rate, and the most common adverse events in trials were dizziness, asthenia, and fatigue. No initial dose titration is needed. Kelsey believes that comparative studies with the other alpha-blockers are needed to establish whether alfuzosin actually has a better side-effect profile.
Patients who present with mildly symptomatic BPH are often assigned to the "watchful waiting" approach initially, Levy said. "It's important to understand that 30% to 50% of patients will spontaneously improve symptomatically," he noted.
When intervention is warranted, most patients with BPH and lower urinary tract symptoms "should at least be offered medical therapy first, before surgical therapy," said O'Leary. "If they fail medical therapy or are unhappy with it, surgical therapy is probably another option." Several minimally invasive techniques are available before resorting to the big guns of TURP or prostatectomy.
In choosing which drug to use, clinicians evaluate whether a patient's BPH is primarily dynamic or static. The alpha-blockers are effective very quickly, Kelsey said, but "men who have a greater obstruction due to the size or the way that the prostate has grown ... may benefit from finasteride more than other men with normal prostate size." Although there are no set BPH treatment guidelines, she said, physicians may sometimes start a patient on both an alpha-blocker for quick symptom relief and finasteride for reducing prostate size.
Such physicians "may withdraw the alpha-blocker after several months to see whether the symptoms have gone away because of the shrinkage of the size of the prostate by that time," Kelsey reported. Others, however, "may be reluctant to change anything" because of the patient's improvement in quality of life.
Until recently, there were no data to support the combination of an alpha-blocker and finasteride. But the results of the Medical Treatment of Prostatic Symptoms (MTOPS) trial, presented in May at the American Urological Association annual meeting, "may be changing the paradigm of treatment of BPH," Kelsey said. The double-blind, multicenter trial, which evaluated 3,000 men for nearly five years, compared doxazosin, finasteride, doxazosin plus finasteride, and placebo. Compared with either drug alone, combination therapy significantly reduced the incidence and delayed the clinical progression of BPH.
In the trial, progression was defined as acute urinary retention episodes, renal insufficiency, unacceptable incontinence, and recurrent urinary tract infectionsall potentially serious complications of BPHor a > 4-point rise in the score evaluating urinary symptoms. A momentous finding, according to Kelsey, was that 83% of patients in the placebo group had no progression.
"I think a lot of clinicians thought the prostate size would continue to increase, the symptoms would get worse, and there would be possibly risks of renal insufficiency," Kelsey explained. Yet the trial found that no cases of renal insufficiency developed secondary to BPH. Compared with placebo, reduction of risk for progression was 39% for doxazosin, 34% for finasteride, and 67% for combination therapy. While MTOPS answers some questions, Kelsey said, it also generates new questions about which patients are at risk for progression and who would benefit most from combination therapy. Further research is needed to answer these questions.
When choosing among the alpha-blockers, tamsulosin's slightly different side-effect profile can distinguish it from the other drugs in the class. While the quinazoline derivatives might be a good choice for poorly controlled hypertensive patients, Kelsey noted, tamsulosin may be "a better option for someone who does not need the blood pressure lowering or who has a cardiac condition that would be worsened by a sudden drop in blood pressure." For example, in patients with a history of heart attack or other circulatory problems, she said, "that sudden drop in blood pressure could be problematic."
An additional possible cardiovascular safety issue involving the quinazoline derivatives was raised by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The trial was designed to compare the cardioprotective properties of three antihypertensives from different classes (lisinopril, amlodipine, and doxazosin) with thiazide diuretic chlorthalidone. The doxazosin arm of the study was discontinued early after an interim analysis found that the alpha-blocker doubled the risk of congestive heart failure compared with chlorthalidone.
Following the announcement of these results, the use of doxazosin as first-line therapy for hypertension was discouraged. But experts disagree on whether ALLHAT has implications on the use of doxazosin for BPH. Because ALLHAT evaluated doxazosin for a different indication, O'Leary believes the trial is not germane to the use of the drug for BPH.
But while the patients in ALLHAT were not being treated for BPH, Levy said, "we're still using this agent in patients who do fit the criteria of those who were in the trial," namely patients over the age of 55 with hypertension and another risk for coronary heart disease. He believes it may be prudent to avoid the use of doxazosin "in those patients who have the comorbid conditions that predispose to congestive heart failure," and perhaps use tamsulosin instead.
However, if "a man didn't have high blood pressure to begin with, and he were started on an alpha-blocker for BPH symptoms, there's no information that I'm aware of that would say he's more at risk for developing congestive heart failure," Kelsey said.
Cost and formulary issues can often be important in drug selection. Because the quinazoline derivatives are available generically, they are often cheaper than the brand-name tamsulosin, which can be an issue for patients on Medicare with no prescription drug coverage. Although the onset of improvement with tamsulosin is faster, Kelsey said, a patient with mild symptoms for whom cost is a significant factor may be willing to wait a few weeks for relief, in which case one of the generic alpha-blockers might be a better choice.
As herbal remedies have gained popularity in recent years, treatments for BPH have been no exception. Herbs commonly used for BPH include saw palmetto (Serenoa repens), beta sitosterols, cernilton, and Pygeum africanum. Saw palmetto is proposed to work by decreasing DHT concentrations via a mechanism of action similar to finasteride's, Levy reported. Meta-analyses of short-term (four- to 48-week) randomized trials of saw palmetto found that the herb produced improvement in urinary symptoms and flow similar to finasteride with fewer adverse effects.
Beta sitosterols, derived from South African stargrass, are commonly found in combination herbal products, Kelsey said. Beta sitosterols also have been found to improve urinary symptoms and flow measures; in the short term, their use appears safe and effective.
Trials of cernilton, another herb touted for BPH, were limited by a short duration, small number of subjects, and poor reporting of outcomes, Kelsey said, "so there really wasn't enough information to establish efficacy." The extract of the African prune tree, Pygeum africanum, appears to be a useful treatment option, but further studies are needed to compare the herb with standard pharmacologic interventions, using standardized validated measures of efficacy.
Patients sometimes prefer an herbal product to a prescription drug because they don't have to see their doctor, so they avoid payment for an office visit, Kelsey said. They also may perceive that the herbs will be less expensive than the prescription medication, she added, and they may believe that herbs are safer. Yet these may be misconceptions. Because herbal products are not regulated, she cautioned, "there can be variation from one tablet to the next, and there can be variation from one bottle to the next in the amount of the active ingredients." In addition, she noted, these products can be contaminated. And some herbal products may be expensive.
If patients do choose to try herbal products, Kelsey recommends using products manufactured by companies that make other over-the-counter or Rx medications, in the hope that the good manufacturing process requirements they must meet on the regulated drug side also carry over to the herbal division.
BPH patients' drug profiles should be scrutinized for drugs that may interact with their BPH therapy or that may exacerbate their urinary symptoms. Patients on quinazoline alpha-blockers who are taking other antihypertensive medications should be warned of the potential for hypotension or orthostatic hypotension, Levy noted.
In particular, Kelsey pointed out, in patients taking an alpha-blocker, a beta-blocker may prevent the heart rate from increasing to compensate for low blood pressure; while this combination is not contraindicated, it should be closely monitored. Because diuretics can exacerbate frequency and urgency, she said, they are usually not recommended for the treatment of hypertension in patients with BPH. Patients should not take finasteride in combination with saw palmetto, she said, because of their similar mechanisms of action.
Tricyclic antidepressants and antipsychotics have innate anticholinergic properties and may increase the risk for urinary retention, Levy said. Similarly, on the OTC side of the counter, antihistamines and sympathomimetics such as pseudoephedrine have been implicated in increasing urinary retention. Some of the newer prescription antihistamines may be preferable, Kelsey stated.
|Drug||Cardura (doxazosin, Pfizer)||Proscar (finasteride, Merck)||Flomax (tamsulosin, Boehringer Ingelheim)||Hytrin (terazosin Abbott)|
|Dose||1 mg q.d. initially,titrate at 1- to 2-week intervals up to 8 mg q.d.||5 mg q.d. with or without food||0.4 mg q.d. half an hour following the same meal (may be increased to 0.8 mg)||1 mg initially, titrate up to 10 mg hs h|
|Availability||1-, 2-, 4-, 8-mg tablets||5-mg tablets||0.4-mg capsules||1-, 2-, 5-, 10-mg capsules|
The American Foundation for Urologic Disease (A.F.U.D., www.afud.org ) has designated this September as the fourth annual Prostate Health Month, an initiative with the goal of educating men about the importance of good prostate health. Sept. 8-14 will be BPH Awareness Week, during which time men with urinary tract symptoms will be encouraged to see their doctors to determine whether they have benign prostatic hyperplasia. A.F.U.D. has established a Web site, www.prostatehealth.com , and a toll-free number, 1-(800) 242-2383, to provide more information on prostate conditions.
A brochure on BPH is also available through the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), www.niddk.nih.gov/health/urolog/urolog.htm .
Tzipora Lieder. FOR MEN ONLY. Drug Topics 2002;17:26.