Pathophysiology of Benign Prostatic Hyperplasia: Insights From Medical Therapy for the Disease

Advances in the Pharmacologic Treatment of BPH

5. RIU0_S0002_12-14.qxd 12/14/09 4:10 PM Page S9 ADVANCES IN THE PHARMACOLOGIC TREATMENT OF BPH Pathophysiology of Benign Prostatic Hyperplasia: Insights From Medical Therapy for the Disease Herbert Lepor, MD Department of Urology, New York University School of Medicine, New York, NY The medical treatment of benign prostatic hyperplasia (BPH) has its roots in the early 1970s. During this era, the first clinical trials investigating -blockade and androgen deprivation therapy were reported for men with clinical BPH. The observation that clinical BPH was improved following administration of both -blockers and androgen deprivation therapy supported the evolving paradigm that clinical BPH resulted from dynamic and static pathways. During the past several decades, the evolution of -blockers for the treatment of BPH has been impacted by innovations targeted to simplify the administration and improve tolerability while maintaining their effectiveness. [Rev Urol. 2009;11(suppl 1):S9–S13 doi: 10.3909/riu11S1S0002] © 2009 MedReviews®, LLC Key words: -Adrenoceptors • -Blockers • Benign prostatic hyperplasia • Bladder outlet obstruction • Lower urinary tract symptoms • Selectivity he medical treatment of benign prostatic hyperplasia (BPH) has its roots in the early 1970s. During this era, the first clinical trials investigating -blockade1 and androgen deprivation therapy2 were reported for men with clinical BPH. Although these preliminary studies enrolled a small number of subjects and did not use validated self-administered questionnaires and uroflowmetry to assess symptom improvement and relief of bladder outlet obstruction (BOO), they did yield evidence suggesting clinical benefit. The observation that clinical BPH was improved following administration of both -blockers and androgen deprivation therapy supported the evolving paradigm that clinical BPH resulted from dynamic and static pathways.3 In this paradigm of clinical BPH, the dynamic T VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S9 5. RIU0_S0002_12-14.qxd 12/14/09 4:10 PM Page S10 Pathophysiology of BPH: Insights From Medical Therapy continued component of BOO was mediated by the tension of prostate smooth muscle via -adrenoceptors. The static component of BOO was attributed to the anatomic obstruction resulting from bulk enlargement of the prostate, which was under the regulation of androgens. Because the proliferative process of BPH involved both smooth muscle and epithelial hyperplasia,4 it was reasonable to assume that both histologic elements contributed to the underlying pathophysiology of BOO and the disease.5 Beginning in the 1990s, the first multicenter, randomized, doubleblind, placebo-controlled studies confirmed the clinical effectiveness of blockade6 and androgen deprivation therapy7 for the treatment of BPH. In these studies, -blockade and androgen deprivation therapies were achieved using selective long-acting 1-blockers and 5-reductase inhibitors (5ARIs), respectively. The agents represented a significant advancement over the drugs used in the early 1970s to achieve -blockade and androgen deprivation, due primarily to better drug tolerance and ease of administration. The amelioration of side effects was a fundamental step forward because the pharmacologic improvement of quality of life via improvement of lower urinary tract symptoms (LUTS) mandated drugs with exceptionally favorable tolerability. The Veterans Affairs (VA) Cooperative Trial8 was the first study to compare the effectiveness of -blockers, 5ARIs, the combination of these drugs, and placebo in a cohort of men with clinical BPH. The study demonstrated that effectiveness (symptom improvement and increase in peak urinary flow rate) was only observed in the -blockade and combination arms. There were no significant differences in efficacy between placebo and the 5ARI groups or the -blocker S10 VOL. 11 SUPPL. 1 2009 and combination groups. These studies were interpreted to show that in men designated as having clinical BPH, 5ARIs exhibit no effectiveness and simply act as a placebo. A second multicenter study using a different blocker confirmed the results of the VA Cooperative Trial.9 How does one resolve the apparent contradiction of the literature as it relates to 5ARIs? The answer is quite simple. All of the phase III BPH studies enrolled the subset of men with exceptionally large prostates, whereas the VA Cooperative Trial8 and the Prospective European Doxazosin and Combination Therapy (PREDICT) trial9 enrolled all men with clinical BPH. 5ARIs exhibit clinical effectiveness only in men with “large” prostates, which represents a relatively small subset of men classified as having clinical BPH; therefore, only those studies enrolling men with “large” prostates demonstrated the clinical effectiveness of 5ARIs.10 During the past 35 years, the evolution of -blockers for the treatment of BPH has been impacted by innovations targeted to simplify the administration and improve tolerability while maintaining effectiveness.11 This has been achieved primarily by the development of formulations with slow-release properties and new agents with unique selectivities for and cardiovascular side effects are minimal.12 The clinical implications of -blocker selectivity is discussed in greater detail below. -Adrenoceptors In the early 1970s, -adrenoceptors were further classified into 1 and 2 subtypes.13 Both 1- and 2adrenoceptors were subsequently identified in the prostate using radioligand binding techniques.14,15 Prostatic 1-adrenoceptors were more predominant than 2-adrenoceptors and were observed to directly mediate the tension of prostate smooth muscle.16 Localization studies revealed that the 1-adrenoceptors were associated primarily with prostatic smooth muscle, which is consistent with their mode of action.17 Because the bladder neck also contained a high density of 1-adrenoceptors and the bladder body was essentially devoid of these receptors,18 the composite clinical effect of -blockers on micturition is to facilitate bladder emptying by reducing outlet resistance without diminishing detrusor contractility. 1-Adrenoceptors were subsequently classified as 1A, 1B, and 1D subtypes.19 Using radioligand binding studies in transfected mouse tissue membranes expressing each of these individual receptor subtypes, 1Aadrenoceptors were shown to be the Silodosin, the most recently US Food and Drug Administration-approved -blocker, is administered once daily and cardiovascular side effects are minimal. inhibition the 3 -adrenoceptor subtypes. Phenoxybenzamine, the first blocker used for the treatment of BPH, was administered twice daily and caused severe side effects, including orthostatic hypotension.1 Silodosin, the most recently US Food and Drug Administration (FDA)–approved -blocker, is administered once daily REVIEWS IN UROLOGY dominant subtype in the human prostate.20 Immunohistochemical studies revealed that the 1A-adrenoceptor localized to the prostate smooth muscle.21 A negligible density of 1B- and 1D-adrenoceptors were observed in the prostate. In vitro muscle isometric tension studies subsequently demonstrated that the 5. RIU0_S0002_12-14.qxd 12/14/09 10:31 PM Page S11 Pathophysiology of BPH: Insights From Medical Therapy 1A subtype mediated prostate smooth muscle contraction.20 Although different blood vessels express different proportions of the 1-adrenoceptor subtypes, the 1B subtype is dominant in the vascular system.22 These studies in the 1990s provided the rationale to develop highly selective 1A antagonists for the treatment of BPH because efficacy of -blockers was felt to be mediated by relaxing prostate smooth, whereas the side effects including orthostatic hypotension, asthenia, and dizziness were attributed to relaxation of blood vessels.23 Although all of the commercially available -blockers have been consistently shown to improve LUTS and relieve BOO, the evidence linking commonality of mechanism for these outcomes is tenuous.24 For example, men who experience the greatest symptom improvement on -blockers do not exhibit the greatest improvement in BOO.10 In addition, men with LUTS and no evidence of BOO experience improvement of their LUTS without changes in their BOO.25 There is also evidence that dizziness and asthenia associated with administration of -blockers are not attributable to effects on the vasculature,26 indicating that a drug devoid of 1B effects may not eliminate side effects in a meaningful way. These clinical observations question the wisdom of developing an 1A subtype-selective antagonist for BPH that would only target relaxation of BOO. There is increasing evidence that targets other than BOO are responsible for the clinical benefit of -blockers on LUTS secondary to BPH (Figure 1). These targets include sensory afferents located within the bladder and spinal cord, which appear to be mediated by the 1D-adrenoceptor subtype.27,28 Collectively, these clinical observations suggest that an -blocker with a unique profile for relative inhibition Figure 1. New concepts in drug development of -blockers. AR, androgen receptor; BOO, bladder outlet obstruction; LUTS, lower urinary tract symptoms. Data from Roehrborn CG and Schwinn DA28 and Schwinn DA and Roehrborn CG.19 ␣1-ARs and Human LUTS Prostate Spinal Cord Detrusor Vessels ␣1A ␣1D ␣1D ␣1B > ␣1A • ↓BOO – ␣1A ARs in bladder neck and prostate • ↓LUTS – ␣1A in bladder neck and prostate smooth muscle – ␣1D in bladder – ␣1D in sensory afferents and central nervous system • ↓Vascular interaction – ␣1B in blood vessels of the 3 -adrenoceptor subtypes may also have unique clinical properties for the treatment of BPH. -Adrenoceptor Selectivity -Adrenoceptor selectivity has been defined on the basis of pharmacologic, urologic, and clinical selectivity (Table 1). Pharmacologic selectivity is defined simply on the basis of binding affinities for the 3 subtypes of the 1-adrenoceptor. Uroselectivity has been defined using in vitro and in vivo methodologies. The in vitro methodology involves comparing the relative affinity of the -blocker to inhibit prostate with vascular smooth muscle, whereas in vivo selectivity is based on relative potency for inhibiting prostatic urethral versus blood pressures. Clinical selectivity is based on the relative efficacy and side effects of the different agents. Ultimately, the only relevant selectivity is clinical selectivity. Uroselectivity presumes that efficacy and adverse events are mediated by prostate and vascular smooth muscle. If this were the case, this model would be superb for screening blockers respectively, which is not a valid assumption. Pharmacologic Selectivity Tatemichi and colleagues29 examined the pharmacologic selectivity of 3 different -blockers—prazosin, tamsulosin, and silodosin—for the 1A-, 1B-, and 1D-adrenoceptors expressed in mouse LM (TK-) cells. The pKi values and relative selectivity for the 1 subtypes are shown in Table 2. Table 1 -Adrenergic Selectivity of BPH Drugs Study Type Assessment Pharmacologic Receptor binding studies Uroselectivity Relative potency for inhibiting prostate vs vascular smooth muscle (in vitro studies) Clinical Efficacy vs adverse events in RCT BPH, benign prostatic hyperplasia; RCT, randomized, controlled trial. VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S11 5. RIU0_S0002_12-14.qxd 12/14/09 4:10 PM Page S12 Pathophysiology of BPH: Insights From Medical Therapy continued Table 2 Pharmacologic Selectivity: Receptor Binding Studies Human 1-Adrenergic Receptor Subtypes Expressed in the Mouse LM (TK-) Cell Line Selectivity to 1A pKi 1A 1B 1D Relative to 1B Relative to 1D Silodosin 10.4 8.19 8.66 162 55 Tamsulosin 10.9 9.92 10.5 9.55 2.51 Prazosin 9.91 10.6 10.1 .204 .646 Ratio expressed as the relative concentration. Data from Tatemichi S et al.29 Table 3 Uroselectivity: Inhibition of Phenylephrine-Mediated Smooth Muscle Contraction pA2 Compound 1A: Prostate 1B: Mesenteric Artery 1A/1B Silodosin 9.64  .12 7.47  .12 .068 Prazosin 8.48  .04 9.15  .08 4.675 Tamsulosin 9.78  .09 9.36  .24 .379 Data from Murata S et al.30 Table 4 Uroselectivity: Inhibition of Phenylephrine-Mediated Responses in Anesthetized Rats (n  5-8) Uroselectivity The uroselectivity of -blockers, when defined using in vitro techniques, represents the relative affinity to inhibit phenylephrine-mediated contractions in fresh tissue preparations of prostate and vascular smooth muscle. The relative potency of prazosin, tamsulosin, and silodosin to inhibit prostatic and vascular smooth muscle is shown in Table 3.30 In vivo techniques have also been used to define the uroselectivity of -blockers by measuring inhibition of phenylephrine-mediated increases in intraurethral and blood pressure. Phenylephrine in this model may be injected via an intravenous or intraduodenal route. The relative potency of prazosin, tamsulosin, silodosin, and terazosin using these in vivo models is shown in Table 4.31 Clinical Selectivity Clinical uroselectivity is defined in the clinical setting by comparing clinical outcomes relative to side effects. Silodosin's pharmacologic and urinary selectivities may explain its unique clinical properties. References Urethral Pressure (ID50) (/kg) Blood Pressure (ED15) (/kg) Uroselectivity (BP/UP) Silodosin 1.4 12 8.6 Tamsulosin .67 .70 1.0 Prazosin 4.8 1.4 .3 Terazosin 49 7.3 .15 Intravenous Injection 1. 2. 3. 4. Intraduodenal Injection Silodosin 54 870 16.1 Tamsulosin 19 61 3.2 Prazosin 48 24 .5 Terazosin — — — 5. 6. BP, blood pressure; ED15, dose required to reduce BP by 15%; ID50, dose required to inhibit the increase in intraurethral pressure by 50%; UP, urethral pressure. Data from Akiyama K et al.31 S12 VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY Caine M, Pfau A, Perlberg S. The use of alphaadrenergic blockers in benign prostatic obstruction. Br J Urol. 1976;48:255-263. Caine M, Perlberg S, Gordon R. The treatment of benign prostatic hypertrophy with flutamide (SCH 13521): a placebo-controlled study. J Urol. 1975;114:564-568. Caine M. The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol. 1986;136:1-4. Shapiro E, Becich MJ, Lepor H. The relative proportion of stromal and epithelial hyperplasia as related to the development of clinical BPH. J Urol. 1992;147:1293-1297. Shapiro E, Hartanto V, Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate. 1992;21:297-307. Lepor H, Auerbach S, Puras-Baez A, et al. A multicenter fixed-dose study of the safety and efficacy of terazosin in the treatment of the symptoms of benign prostatic hyperplasia. J Urol. 1992;148:1467-1474. 5. RIU0_S0002_12-14.qxd 12/14/09 4:10 PM Page S13 Pathophysiology of BPH: Insights From Medical Therapy 7. 8. 9. 10. 11. 12. 13. 14. 15. Finasteride Study Group. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. Prostate. 1993;22:291-299. Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group. N Engl J Med. 1996;335:533-539. Kirby R, Jens EA, Bartsch G, et al. Results of the PREDICT (prospective European doxazosin and combination therapy) trial [abstract 1027]. J Urol. 1999;16(suppl 4):266. Lepor H, Williford WO, Barry MJ. The impact of medical therapy on bother due to symptoms, quality of life and global outcome and factors predicting response of medical therapy: an analysis of the V.A. study of BPH. J Urol. 1998;160:1358-1367. Lepor H. The evolution of alpha-blockers for the treatment of benign prostatic hyperplasia. Rev Urol. 2006;8(suppl 4):S3-S9. Lepor H, Lepor NE, Hill LA, Trohman RG. The QT interval and selection of alpha-blockers for benign prostatic hyperplasia. Rev Urol. 2008;10:85-91. Langer SZ. Presynaptic regulation of catecholamine release. Biochem Pharmacol. 1974;23:1793-1800. Lepor H, Shapiro E. Characterization of the alpha1 adrenergic receptor in human benign prostatic hyperplasia. J Urol. 1984;132: 1226-1229. Shapiro E, Lepor H. Alpha2 adrenergic receptors in hyperplastic human prostate: identification 16. 17. 18. 19. 20. 21. 22. 23. and characterization using [3H] rauwolscine. J Urol. 1986;135:1038-1042. Lepor H, Gup DI, Baumann M, Shapiro E. Laboratory assessment of terazosin and alpha1 blockade in prostatic hyperplasia. Urology. 1988; 32(6 suppl):21-26. Kobayashi S, Tang R, Shapiro E, Lepor H. Characterization of human alpha1 adrenoceptor binding sites using radioligand receptor binding on slide-mounted tissue section. J Urol. 1993;150: 2002-2006. Lepor H, Shapiro E. Alpha1 adrenergic receptors in the lower genitourinary tissues: insight into development and function. J Urol. 1987;138: 979-983. Schwinn DA, Roehrborn CG. Alpha1-adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol. 2008;15:193-199. Forray C, Bard JA, Wetzel JM, et al. The alpha1 adrenergic receptor that mediates smooth muscle contraction in human prostate has pharmacologic properties of the cloned human alpha1c subtype. Mol Pharmacol. 1994;45:703-708. Walden PD, Gerardi C, Lepor H. Localization and expression of the 1A, 1B and 1D -adrenoceptors in hyperplastic and non-hyperplastic human prostate. J Urol. 1999;161:635-640. Hatano A, Takahashi H, Tamaki M, et al. Pharmacological evidence of distinct alpha 1-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery. Br J Pharmacol. 1994;113:723-728. Lepor H. Alpha1 adrenoceptor subtype: clinical 24. 25. 26. 27. 28. 29. 30. 31. or theoretical benefit? Br J Urol. 1995;76(suppl 1): 57-61. Shapiro E, Lepor H. Pathophysiology of clinical benign prostatic hyperplasia. Urol Clin North Am. 1995;22:285-290. Lepor H, Nieder A, Dixon CM, et al. The effectiveness of terazosin in men with normal and abnormal peak flow rates. Urology 1997;49:476-480. Lepor H, Jones K, Williford W. The mechanism of adverse events associated with terazosin: an analysis of the veteran’s affairs cooperative study. J Urol. 2000;163:1134-1137. Kirby R, Andersson KE, Lepor H, Steers WD. alpha1-Adrenoceptor selectivity and the treatment of benign prostatic hyperplasia and lower urinary tract symptoms. Prostate Cancer Prostatic Dis. 2000;3:76-83. Roehrborn CG, Schwinn DA. Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol. 2004;171:1029-1035. Tatemichi S, Kobayashi K, Maezawa A, et al. [Alpha1-adrenoceptor subtype selectivity and organ specificity of silodosin (KMD-3213)]. Yakugaku Zasshi. 2006;126:209-216. Murata S, Taniguchi T, Takahashi M, et al. Tissue selectivity of KMD-3213, an alpha(1)-adrenoreceptor antagonist, in human prostate and vasculature. J Urol. 2000;164:578-583. Akiyama K, Hora M, Tatemichi S, et al. D-3213, a uroselective and long-acting alpha(1a)adrenoceptor antagonist, tested in a novel rat model. J Pharmacol Exp Ther. 1999;291:81-91. Main Points • Beginning in the 1990s, studies confirmed the clinical effectiveness of -blockade and androgen deprivation therapy for the treatment of benign prostatic hyperplasia (BPH). • During the past several decades, the evolution of -blockers for the treatment of BPH has been impacted by innovations targeted to simplify their administration and improve tolerability while maintaining their effectiveness. • Although all of the commercially available -blockers have been consistently shown to improve lower urinary tract symptoms (LUTS) and relieve bladder outlet obstruction (BOO), the evidence linking commonality of mechanism for these outcomes is tenuous. • The VA Cooperative study compared the effectiveness of -blockers, 5-reductase inhibitors, the combination of these drugs, and placebo in men with BPH. The study demonstrated that effectiveness (symptom improvement and increase in peak urinary flow rate) was only observed in the -blockade and combination arms. The results of this study were confirmed in the subsequent PREDICT trial. • In the early 1970s, the -adrenoceptors were further classified into 1 and 2 subtypes. Both 1- and 2-adrenoceptors were subsequently identified in the prostate using radioligand binding techniques. Prostatic 1-adrenoceptors were more predominant than 2-adrenoceptors and were observed to directly mediate the tension of prostate smooth muscle. • The composite clinical effect of -blockers on micturition is to facilitate bladder emptying by reducing outlet resistance without diminishing detrusor contractility; however, there is increasing evidence that targets other than BOO are responsible for the clinical benefit of -blockers on LUTS secondary to BPH. • Clinical selectivity is based on the relative efficacy and side effects of the different agents; ultimately, the only relevant selectivity is clinical selectivity. Silodosin is the only -blocker that has a unique selectivity profile that may have clinical implications. VOL. 11 SUPPL. 1 2009 REVIEWS IN UROLOGY S13