Personalized therapeutics of α₁-blockers in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia

Dear editor

We read with great interest the multicenter, prospective, comparative cohort study by Zhang et al¹ who suggested that patients with uncontrolled or untreated hypertension and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH/LUTS) should be warned about a decrease in blood pressure on initiation of alfuzosin 10 mg therapy alone or concomitantly with antihypertensive medication. Here we discuss and share our perspectives on this issue.

α₁-blockers are the most frequently prescribed medical therapy in the treatment of BPH/LUTS. A number of α₁-blockers (alfuzosin, doxazosin, terazosin, tamsulosin, naftopidil, silodosin) have been approved for the treatment of BPH throughout the world; however, they exhibit different selectivity toward α₁-adrenoceptor (AR) subtypes. Three types of α₁-AR subtypes (α_1A, α_1B, and α_1D) are found in human tissue. The α_1A subtype is located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra, and mediates contraction of the smooth muscle in these tissues. In addition to α_1A-ARs, α_1D-ARs are also present to a significant extent in the human prostate, and α_1B-ARs are thought to mediate contraction of human arteries.²

The early α₁-blockers (alfuzosin, doxazosin, terazosin) were nonselective for subtype and were associated with blood pressure-related adverse effects, such as orthostatic hypotension.³ Sato et al compared the binding affinity of tamsulosin for human α₁-AR subtypes with that of other α₁-blockers, ie, silodosin, terazosin, alfuzosin, and naftopidil.⁴ Tamsulosin has relative selectivity for the α_1A-subtype and α_1D-subtype (α_1A = α_1D > α_1B), and naftopidil has relative selectivity for the α_1D-subtype (α_1D ≥ α_1A > α_1B). The affinity of tamsulosin for the human α_1A-AR was, respectively, 5-fold, 120-fold, 280-fold, and 400-fold higher than that of silodosin, terazosin, alfuzosin, and naftopidil, respectively. However, the α_1B-AR binding affinity of silodosin was shown to be much lower than that of tamsulosin in vitro.⁵ The selectivity of silodosin towards the α_1A-AR subtype versus the α_1B-AR subtype (α_1A > α_1D > α_1B) was reported to be 38-fold higher than that of tamsulosin in studies using transgenic Chinese hamster ovary cells.^6,7 The selectivity ratio (α_1A/α_1B) for terazosin, doxazosin, alfuzosin, tamsulosin, and silodosin was 0.3, 0.4, 0.5, 6.3, and 166, respectively.⁸ The unique AR selectivity profile of silodosin minimizes the propensity for blood pressure-related adverse effects caused by α_1B-AR blockade.⁹ Regarding the efficacy of subtype-selective α₁-blockers in the management of BPH, expression of α₁-AR subtype mRNA was observed as a predictor. Tamsulosin hydrochloride was more effective in patients with dominant expression of the α_1A-AR subtype, whereas naftopidil was more effective in those with dominant expression of the α_1D-AR subtype.¹⁰

With respect to the indications for α₁-blockers, doxazosin and terazosin are currently indicated for the treatment of both hypertension and BPH/LUTS, and are more likely to impair safety-relevant physiological blood pressure control in normotensives with LUTS than are tamsulosin and silodosin.^11,12 Alfuzosin is only indicated for treatment of BPH/LUTS. The study by Zhang et al demonstrated that alfuzosin 10 mg has no clinically important effects on blood pressure when used to treat BPH/LUTS in men who were physiologically normotensive or had hypertension controlled by antihypertensive medication. The relevance of their finding is that it provides reassurance for clinicians when prescribing alfuzosin 10 mg for a patient who is already on antihypertensive therapy, without the need to worry about the risk of hypotensive episodes. However, alfuzosin 10 mg significantly decreased blood pressure in patients with uncontrolled or untreated hypertension, indicating that such patients require careful evaluation before initiating alfuzosin therapy.¹ The study by Zhang et al further indicates that the clinical selectivity and cardiovascular safety of α₁-blockers are related to patient-treatment interactions (comedication and comorbidity), and their finding will enrich our knowledge about the personalized therapeutics of α₁-blockers in the treatment of BPH/LUTS.¹ However, the vasodilatory adverse events of alfuzosin are related to dose, dosage interval, and formulation, ie, they are less frequent with once-daily, sustained-release alfuzosin 10 mg than with the three times daily 2.5 mg formulation (6.3% versus 9.4%, respectively).¹³ Therefore, clinicians should be cautious about extrapolating the finding of the study by Zhang et al to treatment of BPH/LUTS with an immediate-release formulation of alfuzosin.¹

Acknowledgment

This work was supported by the Zhejiang Provincial Bureau of Health (2012KYA090).

Disclosure

The authors report no conflicts of interest in this work.

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References

1.		Zhang LT, Lee SW, Park K, et al. Multicenter, prospective, comparative cohort study evaluating the efficacy and safety of alfuzosin 10 mg with regard to blood pressure in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia with or without antihypertensive medications. Clin Interv Aging. 2015;10:277–286.
2.		Sohn JT, Ding X, McCune DF, Perez DM, Murray PA. Fentanyl attenuates alpha1B-adrenoceptor-mediated pulmonary artery contraction. Anesthesiology. 2005;103:327–334.
3.		Schwinn DA, Roehrborn CG. Alpha1-adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol. 2008;15:193–199.
4.		Sato S, Hatanaka T, Yuyama H, et al. Tamsulosin potently and selectively antagonizes human recombinant α(1A/1D)-adrenoceptors: slow dissociation from the α(1A)-adrenoceptor may account for selectivity for α(1A)-adrenoceptor over α(1B)-adrenoceptor subtype. Biol Pharm Bull. 2012;35:72–77.
5.		Yamada S, Ito Y, Tsukada H. α1-Adrenoceptors and muscarinic receptors in voiding function – binding characteristics of therapeutic agents in relation to the pharmacokinetics. Br J Clin Pharmacol. 2011;72:205–217.
6.		Yoshida M, Kudoh J, Homma Y, Kawabe K. Safety and efficacy of silodosin for the treatment of benign prostatic hyperplasia. Clin Interv Aging. 2011;6:161–172.
7.		Schwinn DA, Price DT, Narayan P. Alpha1-adrenoceptor subtype selectivity and lower urinary tract symptoms. Mayo Clin Proc. 2004;79:1423–1434.
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9.		Lepor H, Kazzazi A, Djavan B. α-blockers for benign prostatic hyperplasia: the new era. Curr Opin Urol. 2012;22:7–15.
10.		Kojima Y, Sasaki S, Kubota Y, et al. Expression of alpha1-adrenoceptor subtype mRNA as a predictor of the efficacy of subtype selective alpha1-adrenoceptor antagonists in the management of benign prostatic hyperplasia. J Urol. 2008;179:1040–1046.
11.		de Mey C. Alpha(1)-blockers for BPH: are there differences? Eur Urol. 1999;36 Suppl 3:52–63.
12.		Capitanio U, Salonia A, Briganti A, Montorsi F. Silodosin in the management of lower urinary tract symptoms as a result of benign prostatic hyperplasia: who are the best candidates? Int J Clin Pract. 2013;67:544–551.
13.		van Kerrebroeck P, Jardin A, Laval KU, van Cangh P. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol. 2000;37:306–313.

Authors’ reply

Li Tao Zhang,¹ Sung Won Lee,² Kwangsung Park,³ Woo Sik Chung,⁴ Sae Woong Kim,⁵ Jae Seog Hyun,⁶ Doo Geon Moon,⁷ Sang-Kuk Yang,⁸ Ji Kan Ryu,⁹ Dae Yul Yang,¹⁰ Ki Hak Moon,¹¹ Kweon Sik Min,¹² Jong Kwan Park¹

¹Department of Urology, Chonbuk National University, Medical School and Biomedical Research Institute and Clinical Trial Center for Medical Devices of Chonbuk National University Hospital, Jeonju, ²Department of Urology, College of Medicine, Sungkyunkwan University, Seoul, ³Department of Urology, College of Medicine, Chonnam National University, Gwangju, ⁴Department of Urology, College of Medicine, Ihwa University, ⁵Department of Urology, College of Medicine, Catholic University, Seoul, ⁶Department of Urology, College of Medicine, Kyungsang National University, Jinju, ⁷Department of Urology, College of Medicine, Korea University, Seoul, ⁸Department of Urology, Chungju Hospital, College of Medicine, Konkuk University, Chungju, ⁹Department of Urology, College of Medicine, Inha University, Incheon, ¹⁰Department of Urology, College of Medicine, Hallym University, Seoul, ¹¹Department of Urology, College of Medicine, Youngnam University, Daegu, ¹²Department of Urology, College of Medicine, Inje University, Busan, Republic of Korea

Correspondence: Jong Kwan Park, Department of Urology, Chonbuk National University, Medical School and Biomedical Research Institute and Clinical Trial Center for Medical Devices of Chonbuk National University Hospital, Jeonju 561-712, Republic of Korea, Tel +82 063 250 1510, Fax +82 063 250 1564, Email [email protected]

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Dear editor

Alpha₁-adrenergic receptor antagonists (α₁-blockers) were initially developed as cardiovascular drugs for the treatment of arterial hypertension, but are no longer considered first-line antihypertensive drugs, with more favorable medications now available for use in clinical practice.¹ However, α-blockers have remained first-line agents in the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), producing rapid and sustained symptomatic relief irrespective of prostate size.² The American Urological Association recommends α-blockers as safe and efficacious pharmacological treatment options for patients suffering from LUTS/BPH.^3,4

Alpha₁-receptors are abundant in the smooth muscle of the prostate and bladder, and α₁-blockers produce a reduction in smooth muscle tone.⁵ Of the three α-blocker subtypes (α_1A, α_1B, and α_1D), α_1A is considered to be the major regulator of smooth muscle tone in the prostate and bladder neck.^6,7 In contrast, the α_1B subtype regulates blood pressure via arterial smooth muscle relaxation,⁷ while the α_1D subtype is associated with relaxation of the bladder muscle as well as innervation of the sacral spinal cord.^7,8

The currently available α₁-blockers (alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin) differ in their safety profiles but share similar efficacy.^4,9 Older α₁-blockers (doxazosin and terazosin), which are used to treat both hypertension and LUTS/BPH, are associated with a greater incidence of symptomatic hypotension while silodosin is associated with a higher prevalence of anejaculation ascribed to its selectivity for the α_1A adrenergic receptor at the seminal vesicle and vas deferens.^4,9–11 The orthostatic hypotension by α₁-blocker was not frequently but diversely occurred, although the patient took the very low dosage of the medication, which had highly uroselectivity.As such, the concept of a uroselective α_1A adrenergic receptor antagonist has been proposed to reflect the ratio of beneficial urinary effects versus cardiovascular adverse effects such as orthostatic hypotension. Alfuzosin, a novel uroselective antagonist devoid of cardiovascular adverse effects, have been successfully developed in recent years. It is presently available in three formulations: immediate-release alfuzosin 2.5 mg taken three times a day,¹² sustained-release alfuzosin 5 mg taken twice a day,¹³ and prolonged-release alfuzosin 10 mg taken once a day.¹⁴

As early as 2000 years, the cardiovascular safety of alfuzosin 10 mg had never been investigated in patients aged older than 50 years.¹⁵ In the current study, 335 patients were recruited for assessment in daily clinical practice, and it was found that antihypertensive comedication does not affect its cardiovascular tolerability when taken once daily. This more favorable safety profile is attributed to the pharmacokinetic properties of the 10 mg formulation because the time to peak plasma concentration is 9 hours versus1 hour for alfuzosin 2.5 mg and 3 hours for alfuzosin 5 mg, as reviewed in Oelke et al.¹⁶ Therefore, this novel formulation implied the uroselectivity of alfuzosin 10 mg, which is clinically effective in the treatment of LUTS without adverse cardiovascular events.

Disclosure

The authors report no conflicts of interest in this work.

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References

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6.		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.
7.		Chapple CR. A comparison of varying alpha-blockers and other pharmacotherapy options for lower urinary tract symptoms. Rev Urol. 2005;7 Suppl 4:S22–S30.
8.		Schwinn DA, Michelotti GA. Alpha1-adrenergic receptors in the lower urinary tract and vascular bed: potential role for the alpha1d subtype in filling symptoms and effects of ageing on vascular expression. BJU Int. 2000;85 Suppl 2:6–11.
9.		Keating GM. Silodosin: a review of its use in the treatment of the signs and symptoms of benign prostatic hyperplasia. Drugs. 2015;75:207–217.
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11.		Andersson KE, Wyllie MG. Ejaculatory dysfunction: why all alpha-blockers are not equal. BJU Int. 2003;92:876–877.
12.		Hofner K, Jonas U. Alfuzosin: a clinically uroselective alpha1-blocker. World J Urol. 2002;19:405–412.
13.		Andersson KE. The concept of uroselectivity. Eur Urol. 1998;33 Suppl 2:7–11.
14.		McKeage K, Plosker GL. Alfuzosin: a review of the therapeutic use of the prolonged-release formulation given once daily in the management of benign prostatic hyperplasia. Drugs. 2002;62:633–653.
15.		van Kerrebroeck P, Jardin A, Laval KU, et al. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol. 2000;37:306–313.
16.		Oelke M, Gericke A, Michel MC. Cardiovascular and ocular safety of alpha1-adrenoceptor antagonists in the treatment of male lower urinary tract symptoms. Expert Opin Drug Saf. 2014;13:1187–1197.