Health and Prostate

Recent developments in drug therapy have reduced the number of surgical procedures needed, although in men with severe symptoms, medications may delay but not prevent the need for surgery. Pharmacotherapy has been shown to result in clinically significant subjective improvement in symptoms with fewer side effects and is a viable initial option for all men. Alpha-blockers and 5-alpha-reductase inhibitors comprise the two classes of drugs used to treat benign prostatic hyperplasia (BPH). Table 2 summarizes the pharmacokinetics, dosing, and availability of the alpha-blockers and 5-alpha-reductase inhibitors for the management of BPH.

Table 2. Pharmacokinetics, Dosing and Availability of Agents Used in BPH Therapy
	Nonselective Alpha-Blockers			Selective Alpha1A-Blockers		5-alpha-Reductase Inhibitors
	Doxazosin (Cardura) Pfizer	Terazosin (Hytrin) Abbott	Prazosin (Minipress) Pfizer	Tamsulosin (Flomax) Boehringer Ingelheim	Alfuzosin (Xatral) Sanofi- Synthelabo	Finasteride (Proscar) Merck	Dutasteride (Avodart) GSK
Pharma-cokinetics
tmax	1-2 hrs	<1 hr	3 hrs	4-7 hrs	9 hrs	2-6 hours	2-3 hours
t/2	22 hrs	9.2-12 hrs	2-3 hrs	9-15 hrs	9.1 hrs	3-16 hrs	5-6 weeks
Elimination	Hepatic	Hepatic	Hepatic	Hepatic (CYP-450 undetermined)	Hepatic	Hepatic (CYP-3A3/4)	Hepatic (CYP-3A3/4)
Clinical onset of action	Within days to weeks	Within days to weeks	Within days to weeks	Within days to weeks	Within days to weeks	3-6 months	3-12 months
Dosing
Starting dose	0.5-2 mg QD	1 mg HS	1 mg BID	0.4 mg QD	10 mg QD	5 mg QD	0.5 mg QD
Target dose for BPH	8 mg QD	10 mg QD	2 mg BID	0.4-0.8 mg QD	10 mg QD	5 mg QD	0.5 mg QD
Availability
Approved by the FDA	Yes	Yes	Yes	Yes	No	Yes	Yes
Generic available	Yes	Yes	Yes	No	No	No	No
Available dosage forms	1 mg, 2 mg, 4 mg, 8 mg tabs	1, 2, 5, 10 mg caps/tabs	1 mg, 2 mg, 5 mg caps	0.4 mg caps	10 mg prolonged-release tabs	5 mg tabs	0.5 mg caps

Alpha-Blockers

Alpha-blockers act to relax smooth muscles, particularly those in the urinary tract and prostate. Studies indicate they are most beneficial in men whose prostates are not significantly enlarged. These agents tend to have an immediate beneficial effect and have minimal effect on sexual drive. By relaxing the muscles in and around the prostate, alpha-blockers increase urinary flow and improve symptoms. Because these agents are short acting, symptoms tend to return once patients stop taking the medication. Alpha-blockers are not known to affect prostate specific antigen (PSA) levels.

The alpha_1A-receptor subtype is found primarily in the bladder and urethral smooth muscle whereas other alpha-receptor subtypes, such as alpha_1B and alpha_1D are found in peripheral tissue. Therefore, alpha-blockers can be categorized as either nonselective, for the alpha_1A-, alpha_1B-, and alpha_1D-receptor subtypes, or selective for the alpha_1A-receptor subtype. Besides relaxing smooth muscles in the prostate, nonselective alpha-blockers also cause relaxation of blood vessels, which can lead to orthostatic hypotension. Nonselective alpha-blockers indicated for the treatment of symptomatic benign prostatic hyperplasia include quinazoline derivatives, such as terazosin and doxazosin. Prazosin is also a nonselective alpha-blocker; however, it is approved for hypertension and not BPH. Selective alpha-blockers, on the other hand, affect only the tissue around the prostate and have minimal effect on lowering blood pressure. Thus, it is important for clinicians to complete a full medical history and cardiovascular workup prior to determining the most appropriate alpha-blocker for their patients.

Doxazosin, terazosin, and prazosin undergo non-cytochrome (CY) P-450 hepatic metabolism; therefore CYP-450 drug interactions are not expected. Side effects associated with nonselective alpha-blockers include dizziness, headache, rapid heartbeat, and fatigue. The manufacturer of terazosin recommends that patients take the first dose at bedtime to minimize the risk of a severe first dose syncope effect. Subsequent doses may be administered once daily in the morning or nighttime. Although the manufacturer of doxazosin does not specifically recommend initiating the first dose at bedtime, advising patients to take the first dose at nighttime may help to minimize significant side effects.

There is some concern that because nonselective alpha-blockers are not first-line treatments for hypertension they may interfere with other medications being taken in men who are treated for high blood pressure. One large study using terazosin reported no danger from adding this drug to an antihypertensive regimen. Its greatest additive impact was with diuretics, but, in general, there was little difference in blood-pressure related side effects between men who took terazosin with other antihypertensive drugs and those who took the alpha-blocker alone.

Investigators of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) recently published the results of an interim analysis that showed cardiovascular risks involving doxazosin. Subjects who took doxazosin and chlorthalidone versus chlorthalidone alone had significantly greater risks for stroke (Relative Risk [RR] = 1.19; p=0.04), cardiovascular disease (RR = 1.25; p<0.001), and congestive heart failure by two-fold (RR = 2.04; p<0.001). Participants in this trial were hypertensive patients over the age of 55 years with at least one additional risk factor for coronary heart disease. Although some experts disagree that the ALLHAT results do not have implications in benign prostatic hyperplasia, clinicians must be aware of the patient characteristics of this trial that parallel those treated for BPH.

Selective alpha-blockers include tamsulosin, which was approved by the FDA in 1997, and alfuzosin, which is not currently approved for use in the U.S. These agents target only the smooth muscle of the prostate connective tissue. In general, studies have indicated that blood pressure reductions were similar in patients taking selective alpha-blockers compared to those taking placebo. Tamsulosin is administered 0.4 mg once a day. It should be taken 30 minutes following the same meal each day. If patients fail to respond to the 0.4 mg dose after two to four weeks of therapy, the dose may be increased to 0.8 mg once a day. Tamsulosin is a sulfonamide compound. We would consider a history of severe sulfonamide reaction as an absolute contraindication, although the manufacturer’s prescribing information does not list sulfonamides as a contraindication. Tamsulosin undergoes CYP-450 hepatic metabolism, however the specific isoenzyme system has not been well elucidated. Therefore, close monitoring of patients using polypharmacy is recommended. Side effects associated with selective alpha-blockers include fatigue, dizziness, sleepiness, runny nose, headache, sore throat, and weakness. Less common are nasal congestion and sexual dysfunction, which occurs in about 2% of cases. (It is important to be aware of look-alike/sound-alike similarities between terazosin and tamsulosin.)

5-Alpha-Reductase Inhibitors

These agents inhibit production of dihydrotestosterone. Finasteride has been on the market in the U.S. since 1992 for the treatment of symptomatic benign prostatic hyperplasia. Dutasteride, another agent in this class, was approved by the FDA in 2001 and is expected to be marketed in early 2003. These agents appear to be most useful in male patients with BPH whose prostates are very large (40 mL or larger), who have low urinary flow rates, and whose condition is related primarily to hormone-stimulated overgrowth of glandular tissue. A four-year study completed in 1998 found that finasteride reduced the need for surgery (5% for the finasteride group vs. 10% for the placebo group) and the incidence of urinary retention (3% vs. 7%) in men with enlarged prostate glands who had moderate to severe symptoms. This agent has not been shown to be as beneficial in men with normal or moderately enlarged prostate glands and whose BPH symptoms are caused primarily by muscle-cell overgrowth.Finasteride has been shown to be effective in reducing urinary tract bleeding, an occasional complication of benign prostatic hyperplasia.

The normal course for finasteride is once daily for up to six months, at which time lessening of symptoms should be clearly noted. Both finasteride and dutasteride are substrates for the CYP-3A3/-3A4 isoenzyme system and thus have the potential for drug­drug interactions with inhibitors of this pathway such as the “azole” antifungals, erythromycin, and cyclosporine. The effects of inhibition may lead to the worsening of adverse effects. The manufacturer has not reported any clinically significant untoward effects with finasteride on drug­drug interactions. Induction of this metabolic pathway with phenytoin or phenobarbital, for example, may lead to treatment failure. Finasteride has been associated with sexual dysfunction, including low sexual drive and impotence. Less common side effects include abdominal pain, back pain, decreased volume of ejaculate, diarrhea, dizziness, and headache.

Finasteride may reduce prostate specific antigen levels, which can mask the presence of prostate cancer. This was seen rather consistently in patients groups of various races. In one study, serum levels of free and total PSA were measured at baseline and for as long as nine months of treatment. In the finasteride group, mean total PSA levels declined from 3.0 ng/mL at baseline to 1.5 ng/mL after six months of treatment (50% decrease, p<0.01). In the placebo group, with similar baseline prostate specific antigen levels, no significant change was observed. Prostate specific antigen density declined significantly in finasteride-treated men (p<0.01), but not in patients on placebo. The mean percent free PSA (13% to 17% at baseline) was not significantly altered by finasteride or placebo. Patients taking finasteride should be advised that doubling their prostate specific antigen value would provide a more accurate number for assessing their cancer risk.

Finasteride has been shown to reduce the need for surgery in patients with moderate-to-severe symptoms. In one four-year study, patients on finasteride demonstrated a significant decrease in the need for surgery and in the incidence of acute urinary retention.

Other Agents

Gonadotropin-releasing hormones have been used in managing benign prostatic hyperplasia but have been associated with a reduction in sexual drive and are likely to cause impotence. Flutamide may be an alternative to surgery in certain patients with BPH who have physical or mental disorders. Patients with chronic conditions are often tempted to try alternative treatments, including herbs and other nontraditional therapies. These may be of benefit, but they should not be recommended without the patient first consulting with his physician. Until scientific studies determine actual benefits, proper doses, and side effects of unregulated herbal products, the patient is at risk for ineffective or even harmful treatment.

The berry of the plant Serenoa repens, commonly known as saw palmetto, contains certain chemicals that appear to improve benign prostatic hyperplasia symptoms. These chemicals appear to inhibit production of dihydrotestosterone, although there has been little scientific research conducted to validate this effect. Saw palmetto may aggravate chronic gastrointestinal diseases, such as peptic ulcers, gastroesophageal reflux disease, and ulcerative colitis. Until further research is conducted, pharmacists should be cautious in their recommendation of saw palmetto for patients with benign prostatic hyperplasia.

Combination Therapy

As new information comes to light, a growing area of interest is progression of BPH. Evidence is mounting that the combination of an alpha-blocker with a 5-alpha-reductase inhibitor in selected patients will significantly delay clinical progression of symptoms. The results of a multicenter National Institutes of Health clinical trial presented at the May 2002 American Urological Association meeting indicated that combination therapy may be more effective than monotherapy in managing BPH. The Medical Therapy of Prostatic Symptoms (MTOPS) Trial found that combining finasteride with doxazosin reduced the risk of benign prostatic hyperplasia progression by 67% vs. placebo. This compares favorably versus using each agent singularly, as finasteride alone reduced the rate of progression by 34% and doxazosin alone reduced the rate of progression by 39%.

MTOPS studied over 3,000 men with benign prostatic hyperplasia age 50 and over for an average of 4.5 years. Patients were divided into one of four treatment groups: those taking 5 mg of finasteride, those taking 4 mg or 8 mg of doxazosin, those taking both drugs, and those taking placebo. Endpoints for the trial included preventing BPH progression (defined as a >=4-point increase in symptom score), urinary tract infections, urinary retention, incontinence, and the need for invasive therapy.

Compared to placebo, the risk of urinary retention was reduced by 79% for patients on combination therapy, 67% for patients on finasteride alone, 31% on doxazosin alone, and 28% on placebo. The risk for necessary invasive therapy was reduced by 69% in patients on combination therapy, 64% in patients on finasteride, 8% in patients on doxazosin, and 6% in patients on placebo. The study results also clearly delineated which patients were at increased risk of progression and those most likely to benefit from treatment.

Conclusion

The trend today in managing mild to moderate benign prostatic hyperplasia is pharmacotherapy, with surgery reserved for men with the most severe symptoms. Nonselective alpha-blockers have been the prototype pharmacologic treatment modality; however, it may be prudent to avoid these agents in elderly patients at risk for cardiovascular disease. Selective alpha-blockers offer an effective alternative with more tolerable side effect profiles. The use of combination therapy with alpha-blockers and 5-alpha-reductase inhibitors has been shown to be beneficial in men with moderately to severely enlarged prostates and acute urinary retention.

Related posts:

1. Management of Benign Prostatic Hyperplasia (BPH): Pharmacotherapy Pharmacologic agents designed to relax prostatic smooth muscle (alpha-adrenergic blockers) and reduce prostatic size (androgen suppression) have been reported to be safe and effective in treating benign prostatic hyperplasia (BPH). The selective alpha-1 blockers doxazosin and terazosin, and the 5-alpha reductase inhibitor finasteride, have...
2. The management of benign prostatic hyperplasia: Behavioral Modifications Certain lifestyle changes can help relieve symptoms and are particularly important for patients who choose to avoid surgery or drug therapy. It is important for patients with benign prostatic hyperplasia (BPH) to urinate on a regular basis and not just in response to an...
3. The management of benign prostatic hyperplasia: Signs and Symptoms of BPH The most common sequelae of benign prostatic hyperplasia (BPH) include lower urinary tract symptoms (LUTS), such as hesitancy, interrupted weak urine stream, urgency and leaking or dribbling, and more frequent urination, especially at night (Table 1). The size of the prostate does not always...
4. The management of benign prostatic hyperplasia: Treatment Approaches to BPH Because benign prostatic hyperplasia (BPH) rarely causes serious complications, men usually have a choice between seeking treatment for BPH or opting for watchful waiting. The primary goals of treatment for benign prostatic hyperplasia are to improve urinary flow and to reduce symptoms. Many treatment...
5. Benign prostatic hyperplasia. Part 7: Treatment Alternative surgical treatment Many alternative procedures have been tried, including transurethral incision of prostate (TUIP), which is less likely to produce retrograde ejaculation and may have lower morbidity rates but higher re-operative rates (up to 20% at 10 years). Balloon dilatation is less invasive,...

Tags: Benign Prostatic Hyperplasia (BPH), Drugs, Pharmacotherapy, Treatment
Posted in: Benign Prostatic Hyperplasia