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Management of benign prostatic hyperplasia (BPH)

Posted by admin on June 3rd, 2010 No Comments

The National Prescribing Centre (NPC) [UK]

Summary

Symptoms of benign prostatic hyperplasia (BPH) are common in older men. They result from hyperplasia of glandular tissue and increased smooth muscle tone. Many men accept these symptoms as a normal part of the ageing process, and do not seek treatment.

As BPH is not always a progressive condition, and the incidence of complications is low, ‘watchful waiting’ is appropriate for men whose symptoms are mild.

Men suffering severe symptoms, or who develop complications of benign prostatic hyperplasia such as acute urinary retention or recurrent urinary tract infection, should be referred to a urologist for consideration of surgical treatment.

Transurethral resection of the prostate is the most commonly used surgical procedure. It is more effective than drug therapy, but is occasionally associated with complications such as impotence and incontinence.

Alphaj-adrenoceptor blocking drugs reduce smooth muscle tone in the prostatic tissue and bladder neck, decreasing resistance to urinary flow. They can produce cardiovascular side-effects, such as hypotension.

Tamsulosin (Flomax MR, capsules, 400 micrograms) is an inhibitor of the α1A-receptor subtype, which is thought to be predominant in the prostate. No convincing evidence exists that this results in fewer adverse effects compared to other α1-blockers.

Finasteride (Proscar, tablets, 5mg) inhibits 5α-reductase, resulting in shrinkage of prostatic glandular tissue. There is evidence that finasteride also reduces the risk of acute urinary retention and need for surgery, although such events are relatively uncommon.

Patients should be informed of the advantages and disadvantages of all treatment options, and should participate in the choice of therapy.

What is benign prostatic hyperplasia?

BPH is a benign enlargement of the prostate gland which occurs as a consequence of ageing. This leads to narrowing of the urethra, which may result in difficulty in passing urine. Prostatic enlargement is believed to be the result of two processes:

• hyperplasia of glandular tissue, under the stimulus of dihydrotestosterone (DHT); and

• increased smooth muscle tone, both within the prostate and in the bladder neck, under the control of α1-adrenoceptors.

Medical treatment of benign prostatic hyperplasia aims to alter these processes, either by inhibiting 5α-reductase, the enzyme responsible for the formation of DHT, or by blockade of α1-adrenoceptors.

Patients suffering from BPH may present with a variety of the following symptoms, which may be classified as:

• ‘filling’ symptoms: such as frequency, urgency, and nocturia; or

• ‘voiding’ symptoms: e.g. poor urinary stream, intermittent stream, hesitancy and terminal dribbling.

Symptoms from either or both categories may occur. While they may be irritating, these symptoms do not in themselves have serious consequences. However, on some occasions, bladder outflow obstruction resulting from benign prostatic hyperplasia may lead to recurrent urinary tract infection (UTI) and pyelonephritis, or chronic urinary retention and hydronephrosis.

How common is it?

Symptoms of BPH may be found in a large number of men over the age of 60, and the prevalence rises with age. There is a lack of consensus on an exact definition for the condition; differences in criteria for the diagnosis of benign prostatic hyperplasia have led to varying estimates of prevalence in studies.

One study determined the prevalence rates of BPH in a population of 502 men aged 55 to 74 using several different case definitions. Prevalence rates in men aged 60-64 varied from 2% to 22%, depending on the parameters used. In this study, the prostate volume used as the main cut-off for diagnosis of BPH was 30cm. However, in a study using a prostate weight of 20g as the cut-off, prevalence of benign prostatic hyperplasia in men aged 60-69 was 43%.

Added to this uncertainty is the fact that many men who admit to suffering symptoms of BPH when questioned, say their symptoms are not particularly bothersome. Many men accept symptoms of benign prostatic hyperplasia as a normal part of the ageing process, and may not be prompted to seek treatment.

What are the treatment options?

Treatment options for benign prostatic hyperplasia range from no active treatment (’watchful waiting’), through various medical interventions, to surgical treatment. Each option is associated with a different balance of risks, benefits, and level of uncertainty about the long-term outcome. Treatment of BPH is directed at improving patients’ symptoms and quality of life rather than towards prevention of the serious morbidity or mortality which may rarely result. For these reasons, it is essential that patients are actively involved in the decision on which treatment they receive.

Non-drug treatment

Benign prostatic hyperplasia is not always a progressive condition. A review article summarising the results of five studies of the natural history of BPH, concluded that, of men with moderate symptoms followed for five years, 40% would improve, 45% remain unchanged and only about 15% deteriorate. One study randomly assigned 556 men with moderate symptoms of BPH to transurethral surgery or watchful waiting and followed them for almost three years. It found that only 7% of those assigned to the watchful waiting group required surgery for ‘treatment failure’. Watchful waiting is, therefore, considered a valid treatment option for men with mild to moderate symptoms.

Transurethral resection of the prostate (TURP) is considered to be the gold standard treatment for benign prostatic hyperplasia. It produces significant improvements for many men in symptoms and in objective measures, such as peak urinary flow rate. Complications which have been attributed to TURP include retrograde ejaculation, impotence, and some degree of urinary incontinence. However, the study mentioned above found no difference in rates of incontinence or impotence between men assigned to transurethral resection of the prostate and those assigned to watchful waiting.

Drug treatment

Alpha1-adrenoceptor blocking drugs act by reducing smooth muscle tone in the prostatic tissue and bladder neck, thereby decreasing resistance to urinary flow. Six agents are available in the UK; these are alfuzosin (Xatral, tablets, 2.5mg; Xatral SR, tablets, 5mg), doxazosin (Cardura, tablets, 2mg/4mg), indoramin (Doralese, tablets, 20mg), prazosin (Hypovase, tablets, 2mg; Prazosin, tablets, 2mg), tamsulosin (Flomax MR, capsules) and terazosin (Hytrin BPH, tablets, 5mg/10mg).

A review of twenty-nine clinical trials of α1-blockers stated that the average improvement in maximum urine flow rate (Qmax) with these compounds was 1.5ml/s. Overall symptom scores decreased by 14% and residual urine volume decreased by 29%. Some tolerance to the effects on urinary flow rate was noted in a proportion of patients after six months of therapy. However, the improvement in symptom scores was maintained long-term.

Side-effects associated with the α1-blockers include hypotension, particularly after the first dose, sedation, and dizziness. Therapy is usually begun with a low dose taken at bedtime and titrated upwards over a few weeks.

Tamsulosin is an agent which is more selective than other alpha1-blockers; it is said to act on the α1A-receptor subtype, which is thought to be predominant in prostatic tissue. Theoretically, such a selective action might avoid some of the cardiovascular effects seen with other agents.

Tamsulosin has been compared to alfuzosin and terazosin in clinical trials. When compared to alfuzosin in 245 men with benign prostatic enlargement and lower urinary tract symptoms suggestive of benign prostatic hyperplasia, tamsulosin produced comparable improvements in O and symptom scores over twelve weeks. Although tamsulosin had significantly less effect on both systolic and diastolic blood pressure than alfuzosin, no difference in the rate of adverse events associated with the hypotensive effects of α1-blockers was observed.

In the second study, which was single-blind, involved 72 patients and lasted for nine weeks, tamsulosin and terazosin were similarly effective in improving both subjective and objective measures of BPH. The incidence of adverse cardiovascular effects was higher in the terazosin group. It is difficult to assess how relevant the results of this study are to the UK, as it was conducted in Korea and the dose of tamsulosin was much lower than that used here.

Finasteride is a specific inhibitor of the enzyme 5a-reductase, which is responsible for the metabolism of testosterone to dihydrotestosterone, a more potent androgen. DHT stimulates prostatic growth and the development of benign prostatic hyperplasia. Treatment with 5mg finasteride for twelve months has been shown to reduce prostate volume by 19%, increase maximum urinary flow rate by 1.6ml/s, and decrease total urinary-symptom scores by 21%.

Two recent studies investigated the effects of finasteride on the incidence of acute urinary retention and the need for surgical treatment. The first study was a pooled analysis of three randomised, double-blind, multicentre studies comparing finasteride 5mg daily to placebo over 24 months in 4,222 patients with moderate symptoms of BPH. Finasteride therapy was associated with a statistically significant reduction in both acute urinary retention and rates of surgical intervention.

The second study compared 5mg of finasteride to placebo over four years in a randomised, double-blind trial. A total of 3,040 men with enlarged prostates and moderate to severe urinary symptoms were recruited from 95 centres. The primary end-point of the study was the symptom score; need for prostate surgery and development of acute urinary retention were secondary end-points.

Symptom scores decreased by a mean of 3.3 points out of 35 (9.4%) in the finasteride group, compared to a mean of 1.3 points (3.7%) in the placebo group. The risks of surgery and acute urinary retention (AUR) were both significantly reduced by finasteride. However, the absolute reduction in the risk of surgery or AUR was only 6.6%, meaning that 15 men would have to be treated with finasteride for four years in order to avoid one episode of acute urinary retention or surgery.

A recent meta-analysis of six trials comparing finasteride with placebo examined whether there was any relationship between measures of disease severity at the start of treatment and the response to finasteride. It concluded that improvements in peak urinary flow rate and symptom scores were significant only in men whose prostate volume was measured (by ultrasound or magnetic resonance imaging) at greater than 40cm3.

Adverse effects associated with finasteride include decreased libido, decreased ejaculate volume and impotence. Finasteride reduces serum concentrations of prostate specific antigen (PSA), a marker for prostate cancer, by an average of 50%.

Finasteride was compared to terazosin, combination therapy, and placebo in 1,229 men in a double-blind study lasting 52 weeks. This study found that terazosin was significantly more effective than finasteride and placebo in improving symptom scores and urinary flow rate. It also found that the combination of terazosin and finasteride was no more effective than terazosin monotherapy, even though finasteride reduced prostate size. Finasteride alone was not significantly different to placebo.

This study has been criticised on the basis of its inclusion criteria, which were based on symptoms rather than prostate size. The average prostate volume in the study population was only 37cm. An accompanying editorial suggested that men with larger prostates might respond differently to finasteride.

How should patients be managed?

The following investigations are recommended before any course of action is decided:

• full medical history,

• urinary symptom review,

• digital rectal examination (DRE),

• urine analysis, and

• serum creatinine.

Routine measurement of serum prostate specific antigen (PSA) levels is controversial. This is due to uncertainty over whether moderately raised levels are indicative of benign prostatic hyperplasia or prostate cancer. GPs should discuss policies on the use of PSA levels with local urology departments.

Symptom severity is not directly related to prostate size. Use of a validated symptom score, such as the International Prostate Symptom Score (IPSS), can help to categorise the severity of BPH, and monitor response to therapy.

Referral to a urologist for further investigations (such as ultrasound and urinary flow rate studies) and management may be considered for patients with moderate to severe symptoms, as well as those with complications such as haematuria or recurrent urinary tract infection. Clinical suspicion of prostate malignancy should also prompt immediate referral.

Alpha1-blockers may be effective regardless of the size of the prostate. Full clinical response often occurs after 4-6 weeks, while finasteride may take 6 months or more to produce maximal effects. An α1-blocker may, therefore, be an appropriate first choice therapy for many men, with finasteride reserved for those who do not tolerate α1-blockade, fail to gain relief of symptoms, or whose prostates are known to be particularly enlarged. There is no convincing evidence that any α1-blocker is more effective than another.

Conclusions

Although benign prostatic hyperplasia is common in older men, many consider the symptoms to be a normal part of the ageing process, and do not seek medical treatment. Given the variation in the natural history of the condition, and the uncertainty over the risks and benefits of most of the available interventions, there is no reason to encourage men who do not find their symptoms bothersome to seek medical intervention.

For those men whose symptoms are significantly bothersome, the use of a symptom scoring system in conjunction with clinical assessment will help to categorise severity. Those suffering from severe BPH should be offered the option of surgery, most likely by TURP. Those who decline surgery, or for whom it is not an option, may be offered drug therapy. Patients should be fully informed of the potential side-effects of all therapies, and should participate in the decision about which approach is taken.

Posted in Benign Prostatic Hyperplasia

UroXatral: Drug for Treatment of BPH

Posted by admin on April 3rd, 2010 No Comments

Trade Name Drug: UroXatral

Generic Name Drug: Alfuzosin HCl

Company: Sanofi-Synthelabo

Indication / Use: Benign prostatic hyperplasia

Approval Date / FDA Class: 12 06 2003 / 1S

Development and Mechanism of Action:Benign prostatic hyperplasia (BPH) is defined histologically. Clinically, it is characterized by lower urinary tract symptoms (urinary frequency, urgency, a weak and intermittent stream, needing to strain, a sense of incomplete emptying, and nocturia) and can lead to complications, including acute urinary retention. The mechanisms by which BPH causes symptoms and complications are unclear, although obstruction of the bladder outlet is an important factor. The best documented risk factors are increasing age and functioning testes. Estimates of the prevalence of symptomatic BPH indicate that approximately 50% of men ages 51 to 60 have benign prostatic hyperplasia. Community- and practice-based studies suggest that men with lower urinary tract symptoms can expect slow progression of the symptoms. However, symptoms can wax and wane without treatment. In men with symptoms of BPH, rates of acute urinary retention range from 1% to 2% a year. The objective of drug therapy of BPH is to reduce or alleviate lower urinary tract symptoms, to prevent complications, and to minimize adverse effects of treatment.

Table 1. Pharmacokinetics of Alpha1-Blockers
Parameter Alfuzosin
(UroXatral)		 Prazosin
(Minipress)		 Terazosin
(Hytrin)		 Doxazosin
(Cardura)		 Tamsulosin
% Oral bioavailability 49% (fed) ND ND ~ 65 > 90 (fasting)
Tmax, h ~ 8 ~ 3 ~ 1 ~ 2 ­ – 3 4 – 5 (fasting)
6 – 7 (fed)
% Protein binding ~ 90 High 90 – 94 ~ 98 94 – 99
Metabolism CYP3A4 oxidation,
O-demethylation,
N-dealkylation		 Extensive via a demethylation
and conjugation		 ND Extensive via
O-demethylation
and hydroxylation		 CYP450
Elimination T /2, h 3 – 9 2 – 3 ~ 12 ~ 22 9 – 15
Excretion Urine (10%)
Feces (75 ­ 91%)		 Bile and feces Urine (~ 40%)
Feces (~ 60%)		 Urine (~ 9%)
Feces (~ 63%)		 Urine (76%)
Feces (21%)

Pharmacotherapy for benign prostatic hyperplasia includes the 5-alpha-reductase inhibitor finasteride (Proscar), and alpha1-adrenoceptor antagonists. Finasteride reduces prostate volume and symptom scores, while increasing peak urinary flow rates. The main problem with finasteride treatment is that it increases the incidence of ejaculation disorders. Androgen receptor antagonists are of no value in BPH because of their adverse effects. Smooth muscle tone in the prostate and bladder neck is regulated by alpha1-adrenergic receptors. Blockade of these receptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of benign prostatic hyperplasia. Currently available alpha1-adrenoceptor antagonists appear to possess very similar clinical efficacy producing a 15% to 25% increase in maximum flow rate with a significant improvement in 30% to 40% of patients. The non­tissue selective alpha1-blockers (prazosin, terazosin, and doxazosin) can elicit postural symptoms related to orthostatic hypotension and they may cause episodes of dizziness and somnolence as a result of distribution to and action in the CNS. Uroselective alpha1-blockers dosed on a once-daily schedule, tamsulosin (Flomax) and, most recently, alfuzosin, have been developed to address the drawbacks of the nonselective agents.

Alfuzosin (UroXatral), a tetrahydroquinazoline derivative, differs from the non­tissue selective alpha1-blockers as a result of replacement of the piperazine heterocycle in the latter with a propylenediamine moiety in the structure of the new drug. Alfuzosin is not selective for any of the alpha1-adrenoceptor subtypes (A, B, or D) but has been shown to possess a high selectivity for receptors in the lower urinary tract. At doses three to 10 times higher than those required to induce significant urethral relaxation in animal models, alfuzosin shows the lowest and shortest-lasting hypotensive activity compared to doxazosin, tamsulosin, and terazosin. Pharmacokinetics: A comparison of selected pharmacokinetic parameters of the alpha1-adrenoceptor antagonists is provided in table 1. The oral absorption of alfuzosin is significantly aided by the presence of food. The drug is extensively cleared by hepatic metabolism primarily involving the 3A4 isoform. Excretion of the drug and metabolites occurs mainly in the feces.

While there is no relationship between peak plasma concentrations of alfuzosin and age, trough levels are positively correlated with age. The concentrations in subjects 75 and older are approximately 35% greater than in those below age 65. Relative to subjects with normal renal function, the mean Cmax and AUC values for alfuzosin are increased by approximately 50% in patients with mild, moderate, or severe renal impairment. Clearance of alfuzosin is reduced in patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), leading to threefold to fourfold higher plasma concentrations of the drug in these patients compared to healthy subjects. Therefore, alfuzosin is contraindicated in patients with moderate to severe hepatic impairment.

UroXatral: Clinical Profile

Alfuzosin (UroXatral) is officially indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. Clinical efficacy data for alfuzosin from placebo-controlled trials have demonstrated efficacy compared to placebo in urinary flow improvement and in improvement in urinary symptoms without the need for dose titration. A randomized controlled clinical trial in 256 men compared tamsulosin against alfuzosin while a second trial in 103 men compared alfuzosin against prazosin in the treatment of BPH. These trials found no significant difference in symptom score among a-blockers tested. A clinical trial in 1,051 men comparing alfuzosin against finasteride against both drugs combined over six months found that alfuzosin compared with finasteride significantly decreased the mean international prostate symptom score from baseline, and found no significant difference between alfuzosin alone and combination therapy.

Adverse Reactions

In the clinical trials, the most common adverse effects occurring more frequently than with placebo were dizziness, upper respiratory tract infection, headache, and fatigue. Withdrawals attributed to adverse events have been found to be similar for alfuzosin, tamsulosin (0.4-mg dose), and placebo. However, a higher withdrawal rate was found with doxazosin, terazosin, and tamsulosin (0.8-mg dose). There was little observable difference between the number of men experiencing dizziness with alfuzosin or tamsulosin compared with placebo. However, more men experienced dizziness after terazosin and doxazosin than placebo. Comparison of tamsulosin versus alfuzosin found similarities in the incidence of common adverse effects including dizziness (7%), asthenia (2%), and postural hypotension (2%).

As with other a-blockers, some patients may experience postural hypotension or syncope. If symptoms of angina pectoris should appear or worsen, the use of alfuzosin should be discontinued. Caution should be exercised when alfuzosin is administered in patients with severe renal insufficiency. Consideration should be given in deciding to prescribe alfuzosin for patients with a known QT prolongation or who are taking medications known to prolong QT, although there has been no signal of torsades de pointes in extensive postmarketing experience with alfuzosin outside the United States.

Drug Interactions

Clearance of alfuzosin (UroXatral) via CYP3A4 metabolic pathways results in interactions between the new drug and other drugs that either inhibit or induce this enzyme. Repeated administration of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin Cmax 2.3-fold and AUC increased 3.2-fold following a single 10-mg dose of alfuzosin. Therefore, alfuzosin should not be coadministered with potent inhibitors of CYP3A4, eg, ketoconazole, itraconazole, or ritonavir, because exposure is increased. Coadministration of alfuzosin with antihypertensive medications may enhance the effects of the latter on blood pressure.

Dosage and Administration

UroXatral (alfuzosin) hydrochloride is formulated as a 10-mg extended release tablet. The recommended dosage is one 10-mg extended-release tablet daily to be taken immediately after the same meal each day. The tablets should not be chewed or crushed.

Posted in Drugs: α-blockers

Pharmacotherapy for BPH (Benign Prostatic Hyperplasia)

Posted by admin on March 3rd, 2010 No Comments

Mechanisms of Obstruction and Rationale for Pharmacotherapy

Current pharmacotherapy for Benign Prostatic Hyperplasia (BPH) is based on agents that relax the smooth muscles of prostatic urethra and stroma and those that deprive acinar cells of androgen.

Various agents have been tried in the treatment of BPH (Table). They may be broadly grouped into those affecting the dynamic component of urethral obstruction, namely the smooth muscle and prostatic stroma, and those affecting the glandular elements by androgen deprivation. The mechanism of action of many agents claimed to be useful in Benign Prostatic Hyperplasia is not clearly understood.

TABLE — Drugs That Have Been Tried in the Medical Management of Benign Prostatic Hyperplasia
(Some agents act by more than one mechanism)
Drug Class Drug (Code Designation) Trade Name
α1-Adrenergic antagonists
Prazosin HCl Minipress
Terazosin HCl Hytrin
Doxazosin mesylate Cardura
Phentolamine mesylate
YM-617
Nicergoline Sermion
Indoramin Baratol
Ketanserin
Yohimbine HCI
Antiandrogens
Selective
5α-Reductase inhibitors Finasteride Proscar
Epristeride
Agents blocking androgen uptake and causing receptor blockade Flutamide Eulexin
Cyproterone acetate
Nilutamide Nilandron
Oxendolone Prostetin
Gestonorone caproate Depostat
Casodex (10176,334)
Nonselective
Gn-RH analogues Nafarelin acetate Synarel
Leuprolide acetate Lupron
Goserelin acetate Zoladex
Estrogens Diethylstilbestrol
Chlorotrianisene TACE
Progestational agents Megestrol acetate Megace Primostat
Hydroxyprogesterone acetate
Hydroxyprogesterone caproate
Medrogestone
Aromatase inhibitors Testolactone Teslac
Atamestane
Steroidogenesis inhibitors Aminoglutethimide
Ketoconazole Nizoral
Prolactin inhibitor Bromocriptine mesylate
Miscellaneous agents Candicidin
Sitoglustde (WA184)
Probucol
Cimetidine Tagamet
Physosterols
Extract of the plant Serenoa repens Permixon
Spironolactone Aldactone
Tamoxifen citrate
Bazoton
Fluorouracil
Gn-RH – gonadotropin-releasing hormone, HCl – hydrochloride

Caine has suggested that obstruction due to Benign Prostatic Hyperplasia occurs because of two factors: a dynamic component is thought to occur as a result of the contraction of smooth muscles of the prostate and prostatic urethra and is mediated mostly by adrenergic receptors; and a mechanical component of obstruction is related to the presence of a mass of hyperplastic acinar or stromal tissue that compresses and narrows the urethral lumen. There is some evidence that the presence and density of stromal content in BPH may relate to the severity of obstruction.

Current understanding of the biologic mechanisms of obstruction is limited and does not extend to two common clinical facts. The first is that the size of the prostate does not always correlate with the severity of symptoms or objective signs of obstruction. The second is the discrepancy between the histologic changes of BPH and the presence and severity of symptoms. From a physiologic standpoint, five conditions in patients with symptoms of “BPH” may exist singly or in combination. These are prostatic urethral obstruction, impaired detrusor contractility, detrusor instability, sensory urgency, and primary vesical neck obstruction. All these conditions likely result from varying combinations of prostatic enlargement and subtle neurologic dysfunction, all due to age-related central nervous system degeneration. Alternatively, a hyperplastic prostate during growth may disrupt normal sphincteric function. Thus, it is not surprising that prostatectomy fails to relieve symptoms of prostatism in about 20% of patients because the symptoms may be caused by poorly understood deficits in neurosensory pathways regulating micturition and sphincteric function.

Transurethral prostatectomy is the most common surgical procedure currently performed for the treatment of Benign Prostatic Hyperplasia. Outcome analyses have questioned the results of transurethral resection of the prostate (TURP). Patients undergoing TURP have been reported to be at greater risk from cardiovascular death than patients undergoing open prostatectomy. Recently these findings were disputed, and it was reported that transurethral resection for BPH does not increase long-term mortality and that comorbid illnesses and older age probably account for the apparent increase in long-term mortality after TURP. The morbidity of the procedure remains unchanged, however. In a review in 1962, the morbidity after transurethral resection of the prostate was reported to be 18% and the mortality 2.5%. More recently, the American Urological Association (AUA) cooperative study of 3,885 patients after the procedure revealed an overall complication rate of 18% and 0.2% mortality. Thus, the search for alternative therapies has been prompted by patients’ preferences for less invasive forms of treatment without prohibitive side effects. Apart from pharmacotherapy, other methods undergoing trials for the treatment of Benign Prostatic Hyperplasia include laser ablation, microwave hyperthermia, and prostatic stents. Ultimately, the role of surgical treatment and newer modalities must be based on relative effectiveness, cost, morbidity, effect on quality of life, expectations, and treatment preferences of patients.

Posted in Pharmacotherapy

Management of Benign Prostatic Hyperplasia (BPH): Pharmacotherapy

Posted by admin on February 14th, 2010 No Comments

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 been approved by the FDA for the treatment of BPH. Patients with clinically significant BPH are candidates for pharmacotherapy unless they are experiencing severe symptomatology (e.g., serious urinary retention). These agents are reported to improve symptoms of benign prostatic hyperplasia (BPH) with minimal morbidity at a substantial cost savings relative to TURP.

Pharmacotherapy: Alpha-Adrenergic Blockers

Alpha-1 adrenergic blockers prazosin (Minipress), terazosin (Hytrin) and doxazosin (Cardura) have all been extensively studied in patients with benign prostatic hyperplasia (BPH). These agents relax smooth muscle at the bladder neck and prostatic urethra, offering symptomatic improvement in a relatively short period of time.

Although prazosin has demonstrated efficacy in patients with BPH, it has fallen out of favor since it is short-acting, requiring multiple daily dosing. Terazosin has been studied extensively and has consistently demonstrated efficacy. Patients on terazosin, frequently titrated to doses of 10 mg once daily, show an increase in peak urinary flow rate (PUFR) and a decrease in their symptoms. Doxazosin, although not studied as extensively as terazosin, has also demonstrated similar efficacy in this patient population. Similar agents studied outside the United States, such as tamsulosin and alfuzosin, have demonstrated some efficacy.

The long-acting alpha-1 blockers terazosin and doxazosin are frequently used to treat common comorbid disease states such as hypertension. Occasionally, however, the maximum dose of an alpha-1 blocker necessary to treat benign prostatic hyperplasia (BPH) in normotensive men cannot be achieved due to the risk of hypotension developing. However, studies have demonstrated that alpha-1 blockade will significantly lower blood pressure in patients with BPH who are hypertensive; yet in normotensive BPH patients, the blood pressure is not significantly decreased. Common dosages employed for alpha-1 antagonists in BPH and hypertension can be found in Table 3. Additionally, alpha-1 blockers have a favorable effect on the lipoprotein profile by slightly lowering LDL and VLDL, and increasing HDL, thereby decreasing the risk for coronary artery disease.

Table 3 Common Dosages Utilized for Alpha-1
Antagonists in BPH and Hypertension
Drug Dose for BPH Dose for Hypertension
Prazosin 2 mg BID to TID 6 mg to 15 mg divided 2 to 3 times daily
Doxazosin 2 mg to 8 mg QD 2 mg to 16 mg QD
Terazosin 5 mg to 10 mg QD 2 mg to 5 mg QD

Approximately 10%–15% of patients receiving an alpha-1 blocker develop a clinically significant adverse event. Side effects such as dizziness, headache, asthenia, syncope and hypotension have been reported, especially after the first dose. In order to minimize this “first dose” effect, it is important to take the once-daily dose at bedtime, titrating upwards slowly.

Posted in Management

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