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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 mechanisms—dynamic and static—that 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.

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