Reviews for Primary Care - Fall 2007 - (Page 3) Alpha Blockers for BPH Treatment alpha blockers. The clinical benefit of alpha blockers has consistently been shown to be independent of baseline prostate volume,17,18 which is further evidence for the limited relevance of prostate volume to LUTS. Another fundamental question is whether the severity of LUTS depends on BOO. The observation that urinary flow rate decreases and LUTS increases with age provides the rationale for linking LUTS and BOO.4 The fact that alpha blockers and transurethral resection of the prostate relieve both BOO and LUTS supported the assumption that LUTS was caused by the BOO. The first indication that the severity of LUTS is not related to BOO was derived from the previously discussed epidemiological studies of men with BPH and in the general community. These studies showed that the severity of BOO and LUTS were only weakly correlated.11,12 If the mechanism for improving LUTS in men receiving alpha blockers and undergoing transurethral resection of the prostate is due to the relief of BOO, then there should be a strong correlation between the changes in urinary flow rate and the changes in LUTS following intervention. The fact that these relationships were not observed provides compelling evidence that neither the pathophysiology nor the mechanism for symptom improvement following these interventions is primarily related to relief of BOO.17,19 The recent observation that phosphodiesterase inhibitors improve LUTS without having any effect on urinary flow rate is further evidence that symptom improvement is not dependent upon BOO.15 posed of stromal and epithelial elements, respectively.20 Half of the stromal hyperplasia is composed of smooth-muscle elements.21 For decades, it was assumed that the enlarged hyperplastic prostate caused BOO via both dynamic and static mechanisms.22 The dynamic obstruction was thought to be the result of smooth-muscle hyperplasia causing a functional obstruction and static obstruction arising from the bulk enlargement of the hyperplastic process encroaching upon the prostatic urethra. Marco Caine demonstrated in 1975 that strips of human prostate contracted in response to norepinephrine.23 The norepinephrine-induced contractions were inhibited by pretreatment with phenoxybenzamine, a subtype.27 Subsequent studies by the same group using both autoradiography28 and immunohistochemistry29 localized the alpha 1a subtype to the prostatic stroma. Functional studies demonstrated that the alpha 1a subtype mediated human prostate contraction.30 (Note: Alpha 1a was originally called alpha 1c.) If one assumes that the efficacy of alpha blockers is mediated by prostate smooth-muscle relaxation, then there would be a compelling reason to develop alpha 1a subtype selective inhibitors for the treatment of BPH. Presumably, some of the adverse events associated with non-selective alpha 1 blockade are mediated by the alpha 1b and alpha 1d adrenoceptor subtypes. These adverse events would be minimized or eliminated by adminis- Functional studies suggested that it was the alpha 1 adrenoceptor subtype that mediated prostate muscle contraction. non-selective inhibitor of alpha adrenoceptor. These studies implicated the alpha adrenoceptor as the mediator of prostate smooth-muscle contraction. Lepor and Shapiro were the first investigators to characterize both alpha 1 and 2 adrenoceptors in the human prostate using radioligand binding studies.24,25 An abundance of both alpha 1 and alpha 2 adrenoceptors were identified. Functional studies suggested that it was the alpha 1 adrenoceptor subtype that mediated prostate muscle contraction.26 trating an alpha 1a selective antagonist. There is now abundant evidence that alpha 1 blockers relieve LUTS via mechanisms unrelated to prostate smooth-muscle relaxation.4 Therefore, it is conceivable that an alpha 1a subtype selective antagonist would retain its modest impact on relieving BOO while failing to relieve LUTS if the therapeutic effect on LUTS is mediated by alpha 1b or alpha 1d subtypes. The developments of several alpha 1a subtype selective antagonists were terminated due to lack of any clinical advantage. Rationale for Developing Alpha 1 Subtype Selective Blockers for BPH Three subtypes of the alpha 1 adrenoceptor (alpha 1a, alpha 1b, alpha 1d) have been cloned and pharmacologically characterized. Lepor and associates demonstrated that the predominant alpha 1 adrenoceptor subtype in the human prostate was the alpha 1a Development of Alpha Blockers for the Treatment of BPH Nonselective Alpha Antagonists In 1976, phenoxybenzamine was the first alpha blocker reported to be effective for the treatment of BPH.31 Two years later, the therapeutic benefit of phenoxybenzamine was confirmed by a randomized, placebo-controlled Rationale for Alpha Blockers and BPH The relative degree of stromal and epithelial hyperplasia is highly variable. Overall, approximately 80% and 20% of the hyperplastic volume is com- VOL. 1 NO. 1 2007 REVIEWS FOR PRIMARY CARE 3
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