Editing Functional: Pharmacological Management of LUTS (section)

=== Decreasing Outlet Resistance at the Level of the Smooth Sphincter ===

==== α1-blockers (alpha-1-adrenoreceptor antagonists) ====

===== Mechanism of action =====
*'''<span style="color:#ff0000">Capable of reducing smooth muscle tone in the bladder outlet in both men and women and in the prostatic muscle.</span>'''
** Facilitate urine release in conditions of functionally increased urethral resistance, such as with BOO secondary to prostatic enlargement and bladder neck dysfunction
* '''<span style="color:#ff0000">Urethral tone and intraurethral pressure are influenced by α-adrenergic receptors</span>'''
** Hypogastric nerve stimulation and α-adrenergic agonists raise intraurethral pressure, which is blocked by α1-adrenergic antagonists.
** '''α1 and α2 adrenoceptors have been shown in the urethra'''
*** '''α2 receptors'''
**** '''More common than α1'''
*** '''α1 receptors'''
**** '''More important for adrenergically induced lower urinary tract smooth muscle contraction and prostate smooth muscle contraction.'''
**** '''<span style="color:#ff0000">Subtypes (3): α1A, α1B, and α1D</span>'''
***** '''<span style="color:#ff0000">Structurally and pharmacologically distinct and have different tissue distributions</span>'''
***** All mediate blood vessel dilation
***** A 4th subtype, α1L, also found in human prostate is derived from the same gene as the α1A subtype, but α1L and α1A receptors have different pharmacologic properties.
***** '''<span style="color:#ff0000">α1A adrenoceptor is the major subtype expressed in urethral smooth muscle and prostate and mediates their contraction</span>'''
****** '''Although the α1A adrenoceptor is the major subtype in the prostate and urethra, highly selective α1A-adrenoceptor antagonists (e.g., RS-17053) do not alter LUTS scores in men with BPH, but are effective at relaxing prostate smooth muscle and increasing urine flow'''
****** '''In contrast, <span style="color:#ff0000">α1-adrenoceptor antagonists that contain α1D-adrenoceptor blocking activity improve bladder-based symptoms, suggesting the important role of the α1D-adrenoceptors for storage symptoms associated with BOO, and receptors potentially located at the bladder or the spinal cord</span>'''
******* The contribution of α1D receptors to DO observed in a variety of pathologic conditions, including obstructive uropathy and incontinence, still needs to be established
****** '''An individual’s response to the different α1-AR antagonists may vary based on the expression level of α1-AR subtype mRNA in their prostate'''
**** '''<span style="color:#ff0000">The α1-blockers vary in their selectivity for the different subtypes</span>'''
***** '''Selectivity for α1B-AR has been considered disadvantageous from a cardiovascular point of view'''
***** '''<span style="color:#ff0000">Non-selective (3)[https://pubmed.ncbi.nlm.nih.gov/27752927/]:</span> <span style="color:#0000ff">TAD</span>'''
*****# '''<span style="color:#0000ff">T</span><span style="color:#ff0000">erazosin</span>'''
*****# '''<span style="color:#0000ff">A</span><span style="color:#ff0000">lfuzosin</span>'''
*****# '''<span style="color:#0000ff">D</span><span style="color:#ff0000">oxazosin</span>'''
***** '''<span style="color:#ff0000">Selective (3):</span>'''
*****# '''<span style="color:#ff0000">Silodosin: (most selective) α1A > α1D > α1B</span>'''
*****# '''<span style="color:#ff0000">Tamsulosin: α1A = α1D > α1B</span>'''
*****# Naftopidil: 1d ≥ 1a > 1b)
* '''<span style="color:#ff0000">Considered effective for treatment of both storage and voiding symptoms in men with LUTS associated with bladder outlet obstruction secondary to benign prostatic enlargement.</span>'''
** However, in a study in which tamsulosin was given alone or together with tolterodine to patients with male LUTS and OAB symptoms, monotherapy with the drug was not effective.
* '''<span style="color:#ff0000">In females, treatment of OAB symptoms with α1-blockers seems to be ineffective and may produce stress incontinence</span>'''
* '''<span style="color:#ff0000">Comparing different alpha-blockers:</span>'''
** In a trial comparing silodosin 8-mg to tamsulosin 0.4-mg to placebo, silodosin overall efficacy was not inferior to tamsulosin.
** Only silodosin showed a significant effect on nocturia over placebo.

===== Adverse events =====

* '''<span style="color:#ff0000">Most common (5):</span>'''
# '''<span style="color:#ff0000">Dizziness</span>''' (most common, 2-10%)
#* '''<span style="color:#ff0000">Highest rates for terazosin and doxazosin</span>'''
#** '''<span style="color:#ff0000">Terazosin and doxazosin require dose titration and blood pressure monitoring</span>'''
# '''<span style="color:#ff0000">Orthostatic hypotension</span>'''
# '''<span style="color:#ff0000">Headache</span>'''
# '''<span style="color:#ff0000">Nasal congestion</span>'''
# '''<span style="color:#ff0000">Retrograde ejaculation</span>'''
#* '''<span style="color:#ff0000">Most often reported with silodosin and tamsulosin.</span>'''
#** '''<span style="color:#ff0000">Silodosin is associated with higher rates of ejaculatory dysfunction (14%)</span> compared to tamsulosin (2%).''' However, only 1.3% of silodosin-treated patients discontinued treatment because of this adverse event.

===== Contraindications =====

* '''Absolute (1)[https://www.ncbi.nlm.nih.gov/books/NBK556066/ §]'''
** '''Hypersensitivity to alpha-blockers or any other component of the drug formulation'''
* '''<span style="color:#ff0000">Caution (4):</span>'''
*# '''<span style="color:#ff0000">Planned cataract surgery[https://pubmed.ncbi.nlm.nih.gov/34384237/ ★]</span>'''
*#* Can complicate cataract surgery by inducing sudden iris prolapse and pupil constriction during the surgery, known as "intraoperative floppy iris syndrome[https://www.ncbi.nlm.nih.gov/books/NBK556066/ §]
*#** Tamsulosin has the highest risk for IFIS (40x that of alfusozin), but all alpha blockers increase the risk of IFIS to some degree.[https://pubmed.ncbi.nlm.nih.gov/34384237/ §]
*#** For every 255 men receiving tamsulosin in the immediate preoperative cataract surgical period, one serious complication (e.g., retinal detachment, lost lens or lens fragment, endophthalmitis) would result.[https://pubmed.ncbi.nlm.nih.gov/34384237/ §]
*#* '''<span style="color:#ff0000">When initiating alpha blocker therapy, patients with planned cataract surgery should be informed of the associated risk of intraoperative floppy iris syndrome risk and be advised to discuss these risks with their ophthalmologists, ideally with delay of medication initiation until after planned procedures.[https://pubmed.ncbi.nlm.nih.gov/34384237/ ★]'''
*#* '''Discontinuation of tamsulosin 4 to 7 days prior to cataract surgery is routine practice, but it does not completely eliminate intraoperative floppy iris syndrome risk.[https://pubmed.ncbi.nlm.nih.gov/34384237/ ★]'''
*# '''<span style="color:#ff0000">Patients on several antihypertensives, or with orthostatic hypotension[https://pubmed.ncbi.nlm.nih.gov/34384237/ ★]</span>'''
*#* '''When treating patients on several antihypertensives, or with orthostatic hypotension, it is best to select an alpha blocker that exhibits minimal impact on blood pressure (eg, the highly selective alpha 1a blocker silodosin)[https://pubmed.ncbi.nlm.nih.gov/34384237/ §]'''
*#'''<span style="color:#ff0000">Concomitant use of a PDE5[https://pubmed.ncbi.nlm.nih.gov/34384237/ ★]</span>'''
*#*'''<span style="color:#ff0000">The hypotensive effects of terazosin and doxazosin can be potentiated by concomitant use of a PDE5, such as sildenafil or vardenafil.[https://pubmed.ncbi.nlm.nih.gov/34384237/ ★]</span>'''
*#*'''Tamsulosin at a dose of 0.4 mg/day, however, does not appear to significantly potentiate the hypotensive effects of sildenafil.[https://pubmed.ncbi.nlm.nih.gov/34384237/ §]'''
*#*'''Regardless, patients utilizing both these medications should be counselled appropriately regarding the risk for drops in blood pressure and symptoms associated with this.[https://pubmed.ncbi.nlm.nih.gov/34384237/ §]'''
*#'''<span style="color:#ff0000">With tamsulosin, caution may be required in patients with serious sulfonamide allergy[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831305/ §]</span>'''