Prostate Cancer and Prostatic Diseases (1999) 2, 110±119 ß 1999 Stockton Press All rights reserved 1365±7852/99 $15.00 http://www.stockton-press.co.uk/pc Review Alpha-1-adrenoceptor blockade in the treatment of benign prostatic hyperplasia F Lowe1* 1Department of Urology, St. Luke's-Roosevelt Hospital Center, 425 West 59th Street, New York, NY 10019 In light of the growing interest in the concept of `uroselectivity' and in the increased worldwide use of alpha-blockers for benign prostatic hyperplasia (BPH), this review evaluates the relative bene®ts of various alpha-blocking agents in the treatment of BPH. The pharmacological and physiological selec- tivity as well as the clinical ef®cacy and safety of alfuzosin, doxazosin (Car- dura1), tamsulosin (Flomax1), and terazosin (Hytrin1) are compared. In reviewing ef®cacy and safety, emphasis is given to 17 placebo-controlled, double- blind trials of these alpha-blockers published in peer-reviewed journals. This review also considers long-term data, effects on blood pressure, costs, and dose ranges. Keywords: benign prostatic hyperplasia; alfuzosin; doxazosin; tamsulosin; terazosin Introduction The primary goal of alpha-blocker therapy for BPH is to relieve lower urinary tract symptoms. These symptoms As the management of symptomatic benign prostatic are believed to be caused mainly by bladder outlet hyperplasia (BPH) has evolved, alpha-blockers have obstruction secondary to enlargement of the prostate, to become the ®rst choice for medical therapy. They are a increased smooth muscle tone in the prostate, and to the safe and effective noninvasive alternative to transurethral detrusor response to prolonged voiding against a rela- resection of the prostate (TURP), the traditional `gold- tively obstructed outlet. Recently, however, this view has standard' BPH therapy. Alpha-blockers have been recom- been challenged by evidence that bladder outlet obstruc- mended as a ®rst-line therapy for BPH most recently by tion is a weak predictor of symptom severity, and that the International Consultation on BPH1 and previously in prostate size is a very weak predictor of symptom sever- the American Health Care Policy and Research (AHCPR) ity and bladder outlet obstruction.10 ± 12 guidelines.2 Factors that have led to the increasing popularity of alpha-blockade are patient preference for noninvasive Rationale for the use of alpha-blockers 3 treatment, the signi®cant morbidities and high initial The presumed mechanism of action of alpha-blockade in 2 costs of TURP, accumulating long-term data on the BPH is the relaxation of prostatic smooth muscle, which 4±7 ef®cacy and safety of alpha-blockers, and the superior accounts for 40% of the area density of BPH tissue.13 8,9 ef®cacy of alpha-blockers relative to ®nasteride. Finas- However, in light of the fact that men respond to alpha- teride, a 5-alpha-reductase inhibitor, is now considered an blockers even in the absence of bladder outlet obstruc- appropriate treatment option for the subset of BPH tion,14 and that there is a weak correlation between the patients who have moderate or severe symptoms and severity of lower urinary tract symptoms and bladder very large sized prostates ( 40 g). outlet obstruction,15 it has been suggested that other mechanisms such as neurological pathways and sensory *Correspondence: Dr F Lowe, Department of Urology, St. Luke's- innervation of the prostate may be responsible for alpha- Roosevelt Hospital Center, 425 West 59th Street, New York, NY blocker ef®cacy.11,12 Only further elucidation of the patho- 10019 physiology of BPH will help to clarify the mechanism (or Received 4 January 1999; revised 15 February 1999; accepted mechanisms) of action of alpha-blockers. 15 March 1999 Alpha-1-adrenoceptor blockade in BPH F Lowe 111 Alpha-blockers and uroselectivity In the 20 years since Caine et al16 reported that the prostatic capsule is responsive to alpha adrenergic stimu- lation, developments in alpha-blockers have centered on the facts that alpha-1 adrenoceptors predominate in the prostate17 and are responsible for mediating smooth muscle tone.18 These ®ndings in¯uenced the development of the alpha-blockers indicated for BPH, from the non- selective alpha-1 and alpha-2 antagonist phenoxybenza- mine, to the short-acting selective alpha-1 antagonists alfuzosin, prazosin, and indoramin, to the long-acting Figure 1 Pharmacological selectivity of alfuzosin, doxazosin, tamsulosin, selective alpha-1 antagonists doxazosin (Cardura1), tam- and terazosin.31 sulosin (Flomax1), and terazosin (Hytrin1). In recent years, subtypes of the alpha-1 adrenoceptor have been characterized as alpha-1A, -1B, and -1D.19 In the prostate, the alpha-1A subtype predominates, accounting for 70% of the total mRNA; the alpha-1B and alpha-1D subtypes account for the remaining 30%.20 Outside of the prostate, the alpha-1A subtype has been found to be ubiquitous,21 ± 23 the alpha-1B sub- type is present in the vasculature and spleen,24,25 and the alpha-1D subtype is present in the vasculature and, as recent evidence suggests, in the bladder detrusor (accounting for 60±70% of the total mRNA).26 The predominance of the alpha-1A subtype in the prostate, and indications that this subtype may play a prime role in prostatic contraction, has led to research of alpha-1A-selective compounds and to the concept of Figure 2 Physiological selectivity of alfuzosin, doxazosin, tamsulosin, and terazosin. In vivo derived pseudo pA2 values indicate the relative drug `uroselectivity' or prostate selectivity. In the past few effect on the reduction of intraurethral pressure (IUP) or mean arterial years, there has been ongoing research for uroselective blood pressure (MABP).31 agents that act preferentially on prostate smooth muscle (alpha-1A) with little effect on the vasculature (alpha-1B and -1D) and central nervous system (CNS) in an attempt reported that none of these alpha-blockers produced a to improve clinical ef®cacy and curtail side effects. greater reduction in urethral pressure than in blood Pharmacological selectivity is assessed in vitro by mea- pressure in the anesthetized dog model (Figure 2); this suring the relative af®nities for the alpha-1A vs the -1B was similar to tamsulosin data reported by Shibasaki et and -1D subtypes. Physiological or functional selectivity al.34 Recently, Hancock et al 39 demonstrated in vivo in a is assessed in vivo by measuring the relative phenyleph- conscious dog model that doxazosin, tamsulosin, and rine-induced reductions in urethral pressure versus blood terazosin lowered mean arterial blood pressure in a pressure: An ideal agent that demonstrates pharmacolo- dose-dependent manner. While an early report suggested gical and physiological selectivity would then clinically in that alfuzosin may preferentially reduce urethral pressure BPH patients be expected to provide superior ef®cacy, vs blood pressure,32 there have been no subsequent minimal CNS± and blood-pressure±related side effects, studies to con®rm this. and minimal hypotension. If the agent demonstrates In terms of uroselectivity, simply demonstrating phar- optimal ef®cacy with minimal side effects, then this macological selectivity for only the alpha-1A receptor agent would be considered clinically uroselective. may not be suf®cient for achieving clinical uroselectivity The pharmacological and physiological selectivities of (that is, optimizing ef®cacy and minimizing blood-pres- alfuzosin, doxazosin, tamsulosin, and terazosin have been sure±related effects). Firstly, alpha-1A receptors exist out- reported in a number of published analyses.27 ± 34 While side of the prostate and therefore may contribute to some analyses indicate that tamsulosin is weakly selective undesired nonurologic effects. Secondly, alpha-1B and for the alpha-1A subtype vs alpha-1B,29,33 others report alpha-1D subtypes may be as necessary as the alpha-1A that none of the four agents has subtype selectivity.27,28,31 subtype in achieving optimal ef®cacy;11 these subtypes The consensus opinion of the Alpha-Blocker Committee exist in the prostate, and their presence in other tissues at the 4th International Consultation on BPH was that may also contribute to ef®cacy. The alpha-1D receptor none of these agents has any distinct selectivity for alpha- predominates in the bladder detrusor, and this may help 1-adrenoceptor subtypes nor for the prostate that could be confer optimal ef®cacy. Thirdly, an additional alpha-1 indicative of clinical selectivity.1 Regarding in vitro phar- subtype, alpha-1L, has been de®ned in functional but macological selectivity, data ®rst reported by Kenny et not molecular studies, and has been proposed to mediate al.31 and cited in a recent review of alpha-blockers by contraction of human lower urinary tract tissues.36 Kirby35 demonstrated that none of these alpha-blockers Finally, selectivity observed pharmacologically and was selective for the alpha-1A subtype (Figure 1). Regard- physiologically in preclinical in vitro and animal-model ing in vivo physiological selectivity, Kenny et al 31 also settings will not necessarily play out in humans.21 In fact, Alpha-1-adrenoceptor blockade in BPH F Lowe 112 to date, two compounds demonstrating a high degree of able ef®cacy and safety.38 In a pilot study of doxazosin pharmacological selectivity in vitro for the alpha-1A sub- (4 mg) and terazosin (5 mg) evaluating morning and type failed to produce suf®cient ef®cacy in men with evening dosing regimens, these two alpha-blockers pro- BPH.37 With these unanswered questions, de®nitive con- duced comparable ef®cacy and safety, with evening clusions cannot be made about the particular alpha-1 dosing resulting in fewer side effects than morning subtypes that should and should not be blocked in the dosing for both agents.39 A single-blind study of tamsu- treatment of BPH.1 losin and terazosin ef®cacy and safety has been pub- lished40 but limitations of the study design undermine the conclusions and relevance of the comparison.