BPH: Focus on Medication Management

Benign prostatic hyperplasia (BPH)is the most common benign neoplasmin American men. Theprostate itself is a male accessory sexgland with minimal physiologic use—secretion of an alkaline fluid thatbecomes part of the semen during ejaculation.¹ Its impact on quality of life,especially in elderly patients, can bequite profound, however. Usually at thecrux of the problem is a gradual changein prostate size, which can begin when aman is in his 30s or 40s. The symptomsbegin to manifest and become especiallytroubling in later years. For example, 90%of men between 70 and 90 years of agehave significant BPH symptoms.¹

Presentation

Patients who present with lower urinarytract symptoms (LUTS) associatedwith BPH tend to worsen over time. Thegrowth of prostate tissue causes amechanical obstruction during the earlyphase of BPH by decreasing the urethrallumen size. Obstructive symptoms arepresent, including difficulty initiating urinationor having a weak stream. Somepatients even push on their bladder toinitiate urination. Other symptoms includeinvoluntary postvoid dripping and asensation of having a full bladder with aninability to void completely.¹

Next, irritative symptoms indicative ofthe late phase of BPH begin to emerge.Unvoided urine can cause the bladder tobecome hypersensitive to even smallamounts of urine.^2,3 As a result, patientsare likely to experience increased frequency."Toilet mapping" involves patientsalways locating the nearest bathroom.² Patients also haveincreased urgency and nocturiaand may keep a bedpanin the bedroom. Finally,if patients present with BPHcomplications—such ashydronephrosis, hematuria,renal insufficiency, or frequenturinary tract infections—they should bereferred to a urologist.

The clinician should notassume that symptoms callfor a definitive diagnosis ofBPH by themselves. Otherdisease states usually areruled out first, includingprostate cancer, prostatitis,and urinary tract infections.⁴The digital rectal examination(DRE) and the prostatespecificantigen (PSA) laboratorytest are helpful in thisregard.

The Symptom Score Index (SSI) questionnaireis a very useful tool to establisha baseline of symptom severity and efficacyof treatment. The tool consists of 7questions, with increased LUTS representedby an increased score (Table⁵).Mild, moderate, and severe BPH is indicatedby scores of 0 to 7, 8 to 19, and 20or greater, respectively.⁶ Although thequestionnaire was designed for patientself-administration, the clinician mayneed to define terms for better comprehension.Also, the same interviewershould conduct the questionnaire tomaintain consistency throughout thepatient's therapy.

The designations of mild, moderate,and severe BPH are based on an arbitrarypoint system and may not necessarilyindicate the efficacy of the medication.The degree of increase or decreasein the score from baseline ismore reliable. Patients detect a "slight"or "moderate" improvement when thescore decreases by 3 to 4 points or 5 to7 points, respectively.⁴

Treatment Options

The goals of treatment for BPH are toimprove symptoms, to halt disease progression,and to prevent complicationsresulting from untreated or undertreatedBPH.⁷ Because quality of life is an importantconsideration, a patient's choice oftherapy should take precedence, oncethe SSI is completed. Therefore, anappropriate treatment for a patient withmild symptoms and no treatmentrequest would include watchful waiting,annual PSA and DRE monitoring, andlifestyle changes (eg, stopping consumptionof coffee or diuretics at bedtime).Patients with moderate-to-severe symptomsshould be offered either pharmacologicor surgical intervention.⁶

Of the choices for moderate symptoms,BPH medications usually are preferred,including alpha₁-receptor inhibitorsand 5-alpha-reductase inhibitors.alpha₁-receptor inhibitors decreasesmooth muscle tone in the prostate tissue,bladder neck, and urethra. Thisaction is quick, compared with that of 5-alpha-reductase inhibitors, thus makingthem the drugs of choice for patientsneeding immediate symptom relief.⁸

All of the alpha₁-receptor inhibitorsare equally efficacious because theydecrease the SSI score by an averageof 5 to 7 points, when compared withplacebo.² These drugs can be stratifiedinto 3 classes, however, depending ontheir adverse-event profile, degree ofreceptor and subreceptor selectivity,and chronology of discovery.

Phenoxybenzamine was the firstalpha-receptor inhibitor tried for BPH, butit caused severe cardiovascular adverseeffects and is no longer used.

The 2nd-generation alpha₁-receptorinhibitors include doxazosin and terazosin.Because they reduce blood pressure,they are FDA-approved for bothhypertension and BPH. Therefore, sittingand standing blood pressure should bechecked to determine whether thepatient can tolerate doxazosin or terazosin.Also, patients should use themonly at bedtime to avoid orthostasis ordizziness.⁹ These effects are more pronouncedwhen one of these drugs iscombined with other blood pressuremedications.

Finally, these medications must bestarted at a low dose and titratedupward slowly. A feasible titration schedulewould be to start with a 1-or 2-mgdose of either of these medications. Theprescriber can double the dose every 2to 4 weeks until the maximum dose isreached (8 mg and 10 mg for doxazosinand terazosin, respectively), adverseeffects occur, or LUTS are alleviated.Onset of symptom relief occurs at 1 to 2weeks and peaks at 2 to 4 weeks afterdose titration.⁶

The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) revealed someintriguing results with these medications.¹⁰ The doxazosin arm was discontinuedearly because that drug had noeffect on reducing coronary heart diseaseor total mortality for patients withhypertension, and there was an 80%increased risk for developing heart failure.Therefore, 2nd-generation alpha₁-receptor inhibitors should not be used assingular therapy for the dual treatment ofBPH and hypertension. Additional antihypertensiveswith doxazosin or terazosinare recommended for patients with bothdisease states.

The 3rd-generation alpha₁-receptorinhibitors, tamsulosin and alfuzosin, areuroselective because they act onprostate tissue without decreasing bloodpressure. Thus, they are not FDA-approvedfor hypertension. Tamsulosin isavailable in 0.4-mg doses, and alfuzosinis available in 10-mg doses. Both aredosed once daily, but these drugs shouldbe given after the same meal each dayrather than at bedtime. Also, they relievesymptoms more quickly (1 day for onsetand 1 week for peak relief), comparedwith the 2nd-generation alpha₁-receptorinhibitors.⁶ Waiting 2 to 4 weeks afterstarting these medications to evaluateefficacy ensures a peak response, however.The adverse effects of tamsulosinand alfuzosin include dizziness, asthenia,and, in the case of tamsulosin, abnormalejaculation.¹¹

The 5-alpha-reductase inhibitors, finasterideand dutasteride, shrink prostate tissueby apoptosis and inhibit the enzymethat converts testosterone to dihydrotestosterone.^12,13 Finasteride and dutasterideare available in 5-and 0.5-mgdosage forms, respectively, and areadministered once daily regardless ofmeals or time of day. Because the mechanismof action relies on shrinking theprostate tissue, symptom relief takes upto 6 months after starting daily use. Also,these medications should be reserved inmost cases for patients with enlargedprostates (>40 g), since studies have consistentlyshown that patients with smallerprostate sizes do not experience significantsymptom relief.^12,13 On the positiveside, these drugs have been proven toattenuate disease progression, includingthe need for surgical intervention or thedevelopment of acute urinary retention.¹⁴These 5-alpha-reductase inhibitors areteratogenic. Also, adverse effects includeerectile dysfunction, decreased libido, andejaculatory disorder.

If the maximum titration of an alpha₁-receptor inhibitor does not yield significantrelief of LUTS, a 5-alpha-reductaseinhibitor may be added. The MedicalTherapy of Prostatic Symptoms (MTOPS)trial showed increased efficacy in relief ofsymptoms and reduction of disease progressionwhen using both classes, comparedwith either class alone. Adverseeffects are significantly increased, however,when using both classes together,and a benefit is most likely for patientswith enlarged prostates.¹⁴ Finally, if symptomsare moderate or severe despitemaximum use of medications, surgery isan option that should be discussed witha urologist.⁶

A word of caution is needed concerningherbal therapies: although they representattractive alternatives for men seekingrelief from LUTS, they should not berecommended for most patients. Studiescomparing herbal versus prescriptionmedications are inhibited by a lack ofstandardization for symptom scores andthe general use of an open label.¹⁵Clinically, if patients exhibit symptomssevere enough to request relief (ie, moderate-to-severe BPH), they should beoffered prescription-strength medicationrelief rather than herbal therapy.⁶

BPH Management in Primary CarePractice

The patient's need for symptomaticrelief, degree of prostate enlargement,and tolerability of the medication shouldall be considered when using BPH medications.Because 2nd-generation alpha₁-receptor inhibitors can cause significantblood pressure reduction—and thisreduction is increased proportional tothe dose—these medications should beused for men who can tolerate doseadjustment for full symptom relief. Also,the elderly may be susceptible to fallsfrom the adverse effects of dizziness andsyncope. Thus, 3rd-generation alpha₁-receptor inhibitors may be a betterchoice for patients with baselinehypotension or orthostasis.²

Other factors also contribute toincreased LUTS. Stopping or decreasingthe dose of certain concomitant medicationscould alleviate LUTS. For example,nasal decongestants such as pseudoephedrinestimulate prostate alphareceptors, and anticholinergics such as antihistamines and tricyclic antidepressantsincrease urination frequency. Also,patients who use twice-daily diureticscould combine their daily dose intomorning administration only, thus preventingsignificant nocturia. Finally, cliniciansshould talk to patients about commonsensemeasures, such as eliminatingwater, coffee, and tea consumption aftertheir evening meals.²

Conclusion

The impact of untreated or undertreatedLUTS on quality of life is enormous.Thus, this disease state should be treatedas thoroughly as other chronic diseasestates. A baseline SSI can be measuredagainst subsequent scores throughouttherapy. By selecting the mostappropriate medication therapy andmaintaining a vigilant examination onsuccessive patient visits, the clinician cansignificantly reduce LUTS and considerablyimprove patients' quality of life.

Dr. Sherman is an associate professorof pharmacy practice at University ofLouisiana at Monroe College ofPharmacy.

References

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14.McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin,finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. NEngl J Med. 2003;349:2387-2398.

15.Dvorkin L, Song KY. Herbs for benign prostatic hyperplasia. Ann Pharmacother.2002;36:1443-1452.