Editing Functional: Pharmacological Management of LUTS (section)

== Pharmacologic therapy to facilitate bladder emptying ==

=== 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>'''

=== Decreasing Outlet Resistance at a Site of Anatomic Obstruction ===

==== 5α-reductase inhibitors ====

===== Mechanism of action =====

*'''<span style="color:#ff0000">5α-reductase converts testosterone to DHT</span>'''
** '''<span style="color:#ff0000">Type 1 5α-reductase is expressed primarily in the non-genital skin and liver, and to a lesser extent in the prostate, testis, and brain</span>'''
** '''<span style="color:#ff0000">Type 2 5α-reductase is expressed predominantly in the prostate epithelium and other genital tissues such as the epididymis, genitalia, seminal vesicle, testis, but also in liver, uterus, breast, hair follicles, and placenta</span>'''
** '''<span style="color:#ff0000">Finasteride inhibits type 2, dutasteride inhibits both type 1 and 2</span>'''

===== Landmark studies =====

*'''<span style="color:#ff00ff">Finasteride Study Group</span>'''
** 895 men with some symptoms of urinary obstruction, an enlarged prostate gland on digital rectal examination, and maximal urinary-flow rates of less than 15 ml per second (with a voided volume of 150 ml or more).
** Randomized to 3 arms: 1mg finasteride vs. 5mg finasteride vs. placebo once daily for 12 months
** Results
*** The mean serum dihydrotestosterone concentrations decreased significantly in the two finasteride-treated groups (P<0.001) during the first two weeks of treatment and did not change thereafter 
**** The decrease in serum dihydrotestosterone concentrations among the men who received 5 mg of finasteride daily was significantly greater than that among the men who received 1 mg of finasteride daily
*** In both finasteride-treated groups, serum testosterone concentrations increased approximately 8 to 10 percent after two weeks of treatment, and they remained increased thereafter.
**** Despite the increases, all values were within the normal range at all times.
*** Serum luteinizing hormone concentrations increased in all three groups during the first two months. However, the increases in both finasteride-treated groups were significantly higher than those in the placebo group
*** the men in both finasteride-treated groups had significant reductions in serum prostate-specific antigen for the comparison with the placebo group) at all times from month 3 through month 12 of treatment
**** The median decrease was 50 percent among the men who received 5 mg of finasteride and 48 percent among those who received 1 mg of finasteride.
*** Men treated with 5 mg of finasteride had a '''significant decrease in total symptom scores'''. The men treated with 1 mg of finasteride had no significant changes in the symptom scores.
*** During the 12 months of treatment, the '''maximal urinary-flow rates increased''' progressively in both finasteride-treated groups, but not in the group given placebo
*** During the first six months, the median size of the prostate decreased progressively in both finasteride-treated groups, after which it did not change significantly, and it was significantly smaller in both finasteride-treated groups than in the placebo group at all times. After 12 months of treatment, the '''prostate had shrunk by 19 percent from base line''' in the group given 5 mg of finasteride, by 18 percent in the group given 1 mg of finasteride, and by 3 percent in the group given placebo
** [https://pubmed.ncbi.nlm.nih.gov/1383816/ Gormley, Glenn J., et al."The effect of finasteride in men with benign prostatic hyperplasia." ''New England Journal of Medicine'' 327.17 (1992): 1185-1191.]

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

*'''Most common (4):'''
*# '''<span style="color:#ff0000">Reduced volume of ejaculate</span>''' (absolute risk difference 4%)
*# '''<span style="color:#ff0000">Erectile dysfunction</span>''' (4%)
*# '''<span style="color:#ff0000">Loss of libido</span>''' (3%)
*# '''<span style="color:#ff0000">Gynecomastia</span>''' (2%)

===== Other benefits of 5-ARIs (4): =====
# '''Improves sensitivity of PSA and DRE for prostate cancer detection'''
# '''Reduced risk of prostatitis'''
# '''Reduced risk of acute urinary retention'''
# '''Reduced risk of BPH-related surgical intervention'''
=== Decreasing Outlet Resistance at the Level of the Striated Sphincter ===
* '''No class of pharmacologic agents that will selectively relax the striated musculature of the pelvic floor.''' 
*'''Injection of botulinum toxin into the striated sphincter has been used with some clinical success, especially in patients with neurologic striated sphincter dyssynergia'''. 
**The potential for spread to nearby structures is greater than with intravesical therapy, and distant effects can also occur, but these are rare

=== Increasing Intravesical Pressure and Bladder Contractility ===
* '''Currently no effective drug for the treatment of detrusor underactivity or underactive bladder'''
* '''Parasympathomimetic agents'''
** ACh, which stimulates bladder contraction, cannot be used for therapeutic purposes because of its action at both muscarinic and nicotinic receptors and it is rapidly hydrolyzed by cholinesterases.
** Many ACh-like drugs exist, but only bethanechol chloride exhibits a relatively selective in vitro action on the urinary bladder and gut with little or no nicotinic action.
*** '''Bethanechol''' 
****'''Cholinesterase resistant'''
****'''Causes an in vitro contraction of smooth muscle from all areas of the bladder.''' 
****'''Little evidence of its efficacy'''
**** At least in a "denervated" bladder, an oral dose of 200 mg is required to produce the same urodynamic effects as a subcutaneous dose of 5 mg.
* Prostaglandins
** Synthesized both locally in bladder muscle and mucosa
*** Synthesis initiated by various physiologic stimuli such as detrusor muscle stretch, mucosal injury, and neural stimulation; directly by adenosine triphosphate; and by mediators of inflammation.
** Have been variably reported to be useful in facilitating bladder emptying with intravesical administration. Possible roles include:
**# Neuromodulators of efferent and afferent transmission
**# Sensitization
**# Activation of certain sensory nerves
**# Potentiation of acetylcholine (but not ATP) release from cholinergic nerve terminals through prejunctional prostanoid receptors.
** Initial reports of the use of intravesical prostanoids producing lasting favorable clinical effects have not been confirmed.

=== Phosphodiesterase Inhibitors ===
* '''Mechanism''': drugs acting through the nitric oxide (NO)/cGMP system, such as PDE5 inhibitors, can '''relax the smooth muscle of the bladder outflow region and may improve urinary bladder blood perfusion'''
* '''<span style="color:#ff0000">As monotherapy, PDE5 inhibitors significantly improve IPSS and International Index of Erectile Function (IIEF) scores, but not Qmax, when compared with placebo.</span>'''
** '''PDE inhibitors seem to improve subjective measurements but not objective ones, eg. Qmax'''
** '''The mechanism behind the beneficial effect of the PDE inhibitors on LUTS and OAB and their site(s) of action largely remain to be elucidated.'''
** Combination of PDE5 inhibitors and α-blockers led to significant improvements of the IPSS and IIEF scores as well as Qmax when compared with the use of α-blockers alone.
* As of the time of Campbell’s writing, only tadalafil has been approved for the treatment of LUTS caused by benign prostatic obstruction (BPO)
* There is insufficient information is available on the combination of PDE5 inhibitors with other LUTS medications such as 5α-reductase inhibitors.

=== Phytotherapy ===

==== Saw palmetto ====
* RCT
** 225 men age >49 with moderate-to-severe symptoms of benign prostatic hyperplasia
** Randomized to to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo.
** Primary outcome: changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate.
** Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values, and the rate of reported adverse effects.
** Results
*** '''No significant difference between the saw palmetto and placebo groups in the change in AUASI scores, maximal urinary flow rate, prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen'''
** [https://pubmed.ncbi.nlm.nih.gov/16467543/ Bent, Stephen, et al."Saw palmetto for benign prostatic hyperplasia." New England Journal of Medicine 354.6 (2006): 557-566.]