Alpha-1 Adrenergic Receptor Antagonists, The Preferred Treatment For BPH

Benign prostatic hyperplasia (BPH) is a nonmalignant adenomatous overgrowth of the prostate gland commonly seen in aging men. Alpha-1 adrenergic receptor blockers are the most prescribed pharmacotherapy for the treatment of BPH and associated lower urinary tract symptoms. This article overviews the significant role of alpha-1 adrenergic receptor blockers in the management of BPH. The previous article describes the existing treatment modalities for benign prostatic hyperplasia. Click here to read more. BPH is associated with obstructive and irritative lower urinary tract symptoms (LUTS) such as hesitancy, frequent urination, feeling of incomplete urination, weak urinary stream, and nocturia which have a negative impact on patient’s quality of life. Severe complications associated with BPH include urinary tract infection, acute urinary retention, bladder stones, renal insufficiency, and renal failure. Furthermore, recent research findings have associated BPH with various comorbid conditions like hypertension, cardiovascular disease, and erectile dysfunction. The prevalence of BPH is age dependent. Approximately 50% aged above 60 years and 75% of men aged above 70 years are diagnosed with BPH and/or have symptoms linked to BPH. Considering the increase in the life expectancy of the aging population, the treatment of BPH poses a substantial social-economic burden to the healthcare systems worldwide. Although several pharmacological treatment options such as phosphodiesterase-5 enzyme (PDE-5) inhibitors, 5-alpha reductase inhibitors (5ARIs), etc. are available for BPH, alpha-1 adrenergic receptor blockers are the first-line of treatment for LUTS associated with BPH.   Alpha-1 Adrenergic Receptor Blockers The rationale behind alpha-1 adrenergic receptor blockers (or alpha-1 blockers) being the most preferred therapy for BPH mainly depends on the role of activated alpha-1 adrenergic receptors in increased prostatic smooth muscle tone with urethral constriction and impaired flow of urine, which are the major factors in the pathophysiology of symptomatic BPH. There are three alpha-1 adrenergic receptor subtypes: alpha-1A, alpha-1B, and alpha-1D. The alpha-1A subtype specifically regulates the smooth muscle contraction of the prostate and bladder neck whereas the alpha-1B subtype regulates blood pressure through vascular smooth muscle contraction and alpha-1D subtype is associated with bladder muscle contraction and sacral spinal cord innervation. Mechanism of action Alpha-1 adrenergic receptor blockers reduce the tension of smooth muscles in blood vessel walls and relax the smooth muscle tone of the prostate and the bladder neck. Based on their receptor subtype selectivity and the duration of serum elimination half-lives, the alpha-1 blockers can be categorized as follows: Nonselective alpha-blockers (e.g. Phenoxybenzamine) Selective long-acting alpha-1 blockers – (e.g. Terazosin, Doxazosin, slow-release-Alfuzosin) Selective short-acting alpha-1 blockers (e.g. Prazosin, Alfuzosin, and Indoramin) Alpha-1A subtype-selective blockers– (e.g. Tamsulosin and Silodosin) Clinical evidence Numerous Phase II and Phase III clinical trials of drugs used for the treatment of BPH have been conducted. According to several reports, alpha-1 adrenergic receptor blockers represent a safe and well-tolerated strategy in the management of BPH. A recent meta-analysis that evaluated the effectiveness and safety of available therapies for BPH demonstrated that alpha-1 blockers were more effective compared to 5ARIs and PDE-5 inhibitors, with doxazosin and terazosin appearing to be the most effective agents. However, it implicated that all drug therapies for BPH are generally safe and well-tolerated, with no major difference regarding the overall safety. Likewise, another prospective, double-blind, placebo-controlled trial revealed that doxazosin was highly effective in improving urinary symptoms and urinary flow rate in men with BPH and was more effective than finasteride (a 5ARI) alone or placebo. Approximately, 1095 men aged 50 to 80 years were randomized to treatment for 52 weeks with doxazosin, finasteride, the combination of doxazosin and finasteride, or placebo. Furthermore, in a 4-year Combination of Avodart and Tamsulosin (CombAT) study that enrolled 4844 men 50 years or older with moderate-to-severe BPH symptoms, prostate volume of 30 mL or greater, and a PSA level of 1.5-10 ng/mL, combination therapy with dutasteride (5ARI) and tamsulosin reported improved symptoms, urinary flow, and quality of life better than monotherapy with either drug. According to an open randomized clinical study that compared the short-term efficacy and safety of 3 alpha-1 blockers, prazosin, terazosin and tamsulosin, found that both the efficacy and safety profiles were different among the alpha-1 blockers at standard doses and further recommended that a particular alpha-1 blocker and its optimal dose should be selected on the basis of the baseline characteristics of the patients with symptomatic BPH. Moreover, alpha-1 blockers such as prazosin and tamsulosin have also demonstrated their efficacy, in combination therapies, for the treatment of comorbid conditions such as hypertension and other cardiovascular diseases with BPH. However, appropriate selection of alpha-1 blocker is important as the majority of elderly men with BPH take multiple medications that, in combination, may exacerbate the adverse events and lead to subsequent morbidity and mortality. Overall, the primary aim of treating BPH includes relief from the symptoms and signs, and prevent the progression of the disease. Clinical evidence suggests that most of the alpha-1 adrenergic receptor blockers are effective, well tolerated and cost-effective. Further research into the underlying mechanism and minimizing the side effects will help clinicians to choose an appropriate alpha-1 blocker depending on patient-specific factors. Which factors do you consider while prescribing Alpha-1 blockers as the first-line therapy for BPH and associated LUTS?  References Woodard, T., Manigault, K., McBurrows, N., Wray, T. and Woodard, L. (2016). Management of Benign Prostatic Hyperplasia in Older Adults. The Consultant Pharmacist, 31(8), pp.412-424. Yuan, J., Mao, C., Wong, S., Yang, Z., Fu, X., Dai, X. and Tang, J. (2015). Comparative Effectiveness and Safety of Monodrug Therapies for Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia. Medicine, 94(27), p.e974. Fine, S.R., Ginsberg, P. (2008). Alpha-adrenergic receptor antagonists in older patients with benign prostatic hyperplasia: issues and potential complications. J Am Osteopath Assoc. 108:333-337. Lepor, H., Kazzazi, and Djavan, B. (2012). α-Blockers for benign prostatic hyperplasia. Current Opinion in Urology, 22(1), pp.7-15. Kirby, R., Roehrborn, C., Boyle, P., Bartsch, G., Jardin, A., Cary, M., Sweeney, M. and Grossman, E. (2003). Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology, 61(1), pp.119-126. Kaplan, S. (2011). Re: The Effects of Combination Therapy With Dutasteride and Tamsulosin on Clinical Outcomes in Men With Symptomatic Benign Prostatic Hyperplasia: 4-Year Results From the CombAT Study. The Journal of Urology, 185(4), pp.1384-1385. Tsujii, T. (2000). Comparison of prazosin, terazosin and tamsulosin in the treatment of symptomatic benign prostatic hyperplasia: A short-term open, randomized multicenter study. International Journal of Urology, 7(6), pp.199-205.

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