Abstract
Alpha-blockers are the mainstay of lower urinary tract symptoms (LUTS) in relation with benign prostatic obstruction (BPO). Their use is extensively recommended in men with LUTS as a firstline therapy with LUTS/BPO in case of voiding symptoms, alone or mixed with storage symptoms, based on level 1 evidence. The main hypothesis regarding their mechanism of action is the relaxation of smooth muscle cells in the bladder neck and inside the prostate. While alpha-blockers have the ability to improve symptoms of the voiding phase (and the filling phase in some cases), there is poor and limited evidence regarding the fact that these drugs improve flow rate, decrease obstruction, or modify urodynamic parameters. The most frequent adverse events include hypotension and ejaculatory dysfunction, and evaluation of efficacy and tolerance is mandatory in the short and long term. Whereas some patients with stay under alpha-blocker therapy for the rest of their life, some will require additional drugs and/or surgery related to disease progression.
Keywords
Alpha-blockers, Voiding symptoms, Benign prostatic hyperplasia
Introduction
Lower urinary tract symptoms (LUTS)/benign prostatic obstruction (BPO) are very common in men over 50 years of age and their management is a daily issue for every physician (not only urologists). Treatment of nonneurogenic male LUTS depends mainly on the initial clinical picture, as extensively detailed in current clinical guidelines [ ]. While some patients with moderate, slightly bothersome symptoms are eligible for active surveillance, most patients with bothersome symptoms and decreased quality of life require introduction of pharmacological therapy in addition to conservative measures. Firstline surgical treatment is only indicated for complicated disease [ ].
Alpha-blockers have been introduced around 25 years ago for LUTS/BPO management and this class of medications includes now several molecules, not all available on the market in every country. Current epidemiological studies have shown that alpha-blockers are the most prescribed “BPH drug” (benign prostatic hyperplasia) in Europe (before phytotherapy, 5-alpha-reductase inhibitors, phosphodiesterase type 5 inhibitors, antimuscarinics, and others) [ ]. Detailed epidemiological data show that alpha-blockers are mainly prescribed by family physicians rather than by urologists, including for treatment initiation.
This article dedicated on the medical management of LUTS/BPO by alpha-blockers will focus on (i) the underlying physiology and mechanism of action of the drugs, (ii) clinical data about its efficacy and adverse events, and (iii) indications (as a single or combined prescription).
Pathophysiology and Mechanisms of Action of Alpha-Blockers in BPH
Pathophysiology of LUTS/BPH/BPO: Reviewing Alpha-Adrenoreceptors as a Valuable Therapeutic Target
Since the introduction of alpha-blockers, knowledge about the pathophysiology of LUTS in men in association with BPH has dramatically improved. While in the early 1990s, BPH was very closely associated to urinary symptoms (through the word “prostatism”), the first paradigm shift was to consider LUTS as a clinical picture, and BPH as a histological disease [ ].
Once recognized, LUTS have then been further categorized in storage symptoms and voiding symptoms. Nocturia was also more and more considered as a specific symptom, with specific etiologies (such as nocturnal polyuria), but is still included in the field of storage symptoms [ ]. At the same time, in the 1990s, American Urological Association (AUA) score (the so-called International Prostatic Symptom Score (IPSS)) has become the standard for clinical assessment of LUTS [ ].
From the pathophysiological point of view, the bladder has been recognized as mainly responsible for storage symptoms (primarily of secondarily to chronic bladder obstruction) [ ] and voiding symptoms are currently attributed to bladder outlet obstruction (BOO) (possibly related to BPO, or another etiology such as stenosis or detrusor sphincter dyssynergia) and/or underactive bladder, a concept still immature remaining under scrutiny [ ].
Thus, the modern view of medical treatment of LUTS in a context of BPH is to analyze whether a potential therapeutic target can
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Improve voiding symptoms by relieving BOO due to the prostate (BPO), or improving bladder contraction.
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Improve storage symptoms by acting on the detrusor, the urothelium, or another part of the bladder wall.
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Improve specifically nocturia by influencing a specific underlying mechanism different from the above.
Potential Action of Alpha-Blockers on BPO
LUTS in the context of BPH/BPO are correlated with BOO which is caused by static and dynamic component. Static obstruction is due to the enlargement itself of the prostate that narrow the urethra lumen, while bladder neck and prostatic smooth muscle cells contraction lead to an additional dynamic obstruction. This is supported by histological studies that revealed a higher expression of smooth muscle cells in the prostate of patients with BPH [ ].
These prostatic and bladder neck contraction are mediated through endogenous adrenergic stimulation of alpha- and beta-adrenergic receptors (α-ARs and β-ARs). Although α2-ARs are more frequently represented in the lower urinary tract, the main receptor responsible for prostatic and bladder neck smooth muscle contraction is the α1 receptor [ ]. In 1990, Kawabe et al. [ ] found that alpha-adrenoreceptors were situated more in the adenoma than in the prostatic capsule, but they failed to identify any correlation between the density of alpha-adrenoreceptors and the volume of the enucleated prostate. in vitro studies showed human prostatic stromal cell contraction with α1-AR agonists [ ], while systemic injection of α1-adrenoreceptor agonist such as phenylephrine leads to an increase in intraurethral pressure in conscious dogs [ ]. However, these findings suggest an important role of alpha-adrenoreceptors in BOO physiopathology. Three subtypes of A1-ARs were identified, α1a, α1b, and α1d. Of these, genomic analysis showed that only α1a and α1d were expressed in the urethra and the human prostate with a ratio of 70% and 30%, respectively [ ]. These subtypes are, therefore, the main target of pharmacological molecules.
The affinity of the molecule for this subunit defines the uroselectivity of the drug therapy. A1-AR blocking agent decreases voiding dysfunction by inducing a smooth muscle cell relaxation at the prostatic and bladder neck level. Other subunits, located in blood vessels, in central nervous system, and other smooth muscle cells, lead to adverse events.
Potential Effects of Alpha-Blockers on Storage Symptoms and Bladder Function
Alpha-blockers may have an effect on the detrusor function that could explain partly their positive effect on LUTS in the context of BPH. Some studies have found that naftopidil could have an inhibitory effect on afferences through C-fibers and could explain improvement of bladder capacity during the storage phase [ ]. Furthermore, Miyazato et al. have found that α(1)-AR facilitates the micturition reflex in the spinal cord, and that terazosin could inhibit this effect, thus explaining the impact of alpha-blockers in the genesis of overactive bladder [ , ]. Finally, Goi et al. [ ] found that silodosin may have a positive effect on bladder blood flow and thus have a positive effect on detrusor function.
Potential Effects of Alpha-Blockers on Nocturia
Comprehensive reviews have been published about the definition of nocturia, its etiologies, and relevant therapeutic options. Nocturia is defined by the symptom of waking up at night with the desire to pass urine, and is at best evaluated through a bladder diary. The origins of nocturia belong to one (or more) of the four following contexts: nocturnal polyuria, sleep disorders, 24 h polyuria, and/or reduced bladder capacity (anatomic or functional) [ ]. Therapeutic options must be chosen after adequate exploration of bladder diaries (3 to 7 days being the gold standard). Alpha-blockers can only impact nocturia through its action on BOO (see hereunder). Actually, there is very low inconsistent evidence that alpha-blockers can improve nocturia because all studies have considered nocturia as a secondary outcome, and measured it through IPPS question 7, and not a frequency volume chart [ ].
Types of Alpha-Adrenergic Blockers: Family Members
A lot of alpha-adrenergic blockers have been developed that differs on their selectivity to α receptors and their serum half-life elimination (see Table 8.1 ).
| Drug Name | Half-Life (h) | Selectivity |
|---|---|---|
| Phenoxybenzamine | 24 | α1 and α2 |
| Alfuzosin | 9.1 | α1a, α1b, α1d |
| Doxazosin | 22 | α1a, α1b, α1d |
| Prazosin | 4 to 7 | α1a, α1b, α1d |
| Silodosin | 13.3 | α1a |
| Tamsulosin | 10 to 13 | α1a, α1d |
| Térazosine | 12 | α1a, α1b, α1d |
Phenoxybenzamine was the first alpha-AR antagonist to be developed. It was a nonselective alpha-blocker that blocked either α1 or α2 receptors. If the efficacy was the same than nonuroselective alpha-blocker, its affinity for α2 receptors led to much more side effects and a lower tolerance profile that conducted to abandon this drug for BPH [ ].
All other alpha-AR antagonists are only specific toward α1 receptors. Nonetheless, alpha1-bockers were originally developed to treat hypertension and were subsequently used for LUTS. Therefore, prazosin, doxazosin, and terazosin show high affinity for all subtypes of alpha-androgen receptors (α1a, α1b, α1d) [ ] and are called nonselective alpha-blockers. α1-ARs subtypes are also located in the blood vessels, especially α1b that has been implicated in blood pressure regulation in in vivo studies [ ]. This is why research is focused on therapy with low affinity toward α1b-ARs subtype in order to inhibit side effects related to hypotension.
Uroselective alpha-blockers have higher affinity for subtypes α1a and α1d which are the most predominant receptors in the bladder neck and the prostate. Each agent currently used to treat BPH has had their affinity for all subtypes of α1 receptors, determined in in vivo and in vitro studies [ , ]. The selectivity of tamsulosin toward α1d is equivalent to its selectivity for α1a which is 10-fold greater than its selectivity for α1b [ ]. Alfuzosin was the first agent originally administered for LUTS that was not initially used as an antihypertensive treatment. Even if alfuzosin showed high affinity for all α1-ARs subtypes, it was 1.5 to 3.0 times more uroselective than prazosin in animal models. This was supported by in vitro studies that showed a poor penetration of the alfuzosin through the blood-brain barrier. Moreover, blood and prostatic alfuzosin concentration of 12 men undergoing BPH surgery revealed that prostate and blood concentration of the alfuzosin were significantly correlated with a prostate-blood ratio of 2.4 ± 0.7 reflecting the high diffusion of the drug into the prostatic tissue [ ].
As the functional role of α1d-ARs remains unclear, new therapeutics have focused on α1a receptors in order to increase uroselectivity and lower hypotension. Silodosin is a selective α1a-ARs antagonist with an affinity at least 50- to 160-fold higher for this subtype than toward α1b- and α1d-ARs [ ]. in vivo analysis showed that intravenous administration of silodosin decreased intraurethral pressure with less hypotensive effect than tamsulosin [ ].
Although the effect of alpha-blockers is quick, within 6–48 h after treatment initiation, A1-AR blockers are fully effective after a few weeks [ ]. However, one the main defects of the early drugs was their short serum elimination half-life. Prazosin, intermediate-release alfuzosin, and indoramin had a short half-life elimination that require, therefore, at least, twice-daily dosing. New drugs were further developed with longer serum half-life elimination. Terazosin, doxazosin, tamsulosin, silodosin, and extended-release alfuzosin are long-acting alpha-adrenergic blockers that require only one take a day and have been shown to be effective in the treatment of BPH-related symptoms.
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