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Functional: Pharmacological Management of LUTS: Difference between revisions

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===== Mirabegron =====
===== Mirabegron =====
* '''Metabolism'''
 
** Rapidly absorbed
====== Metabolism ======
** '''Metabolized in the liver via multiple pathways, mainly by cytochrome P450'''
* Rapidly absorbed
*** '''Subject to clinically relevant drug-drug interactions;''' should be used with caution in patients who are taking ketoconazole or other potent CYP3A4 inhibitors.
* '''Metabolized in the liver via multiple pathways, mainly by cytochrome P450'''
*** Metabolites are inactive
** '''Subject to clinically relevant drug-drug interactions;''' should be used with caution in patients who are taking ketoconazole or other potent CYP3A4 inhibitors.
* '''Outcomes:'''
** Metabolites are inactive
** '''Increases bladder capacity, improves frequency, urgency, incontinence episodes'''
 
** '''Does not adversely affect flow rate, detrusor pressure at maximum flow rate, bladder contractile index, or residual volume'''
====== Outcomes ======
* '''<span style="color:#ff0000">Contraindications</span>''' (drug monograph) '''(3):'''
* '''Increases bladder capacity, improves frequency, urgency, incontinence episodes'''
*# '''<span style="color:#ff0000">Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg.</span>'''
* '''Does not adversely affect flow rate, detrusor pressure at maximum flow rate, bladder contractile index, or residual volume'''
*# '''<span style="color:#ff0000">Pregnancy</span>'''
 
*# '''<span style="color:#ff0000">Hypersensitivity</span>'''
====== Contraindications(3):[https://www.astellas.com/ca/system/files/pdf/Myrbetriq_PM_EN.pdf §] ======
* '''Dosage'''
# '''<span style="color:#ff0000">Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg.</span>'''
** '''Starting dose of 25 mg and increasing to 50 mg, if needed, is recommended.'''
# '''<span style="color:#ff0000">Pregnancy</span>'''
** '''Lowest dose is also recommended for renal and hepatic impairment'''
# '''<span style="color:#ff0000">Hypersensitivity</span>'''
* '''<span style="color:#ff0000">Adverse events</span>'''
 
** '''<span style="color:#ff0000">Common side effects</span>''' (drug monograph)''':'''
====== Dosage ======
*** '''<span style="color:#ff0000">Hypertension</span>'''
* '''Starting dose of 25 mg and increasing to 50 mg, if needed, is recommended.'''
**** The mean increase (compared with placebo) in systolic and diastolic blood pressure after therapeutic doses of mirabegron once daily was ≈0.5-1 mm Hg and was reversible on discontinuation of treatment.
* '''Lowest dose is also recommended for renal and hepatic impairment'''
**** In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for mirabegron 50 mg was ≈1 beat/min and reversible on discontinuation of treatment.
 
*** '''<span style="color:#ff0000">Headache, dizziness</span>'''
====== <span style="color:#ff0000">Adverse events[https://www.astellas.com/ca/system/files/pdf/Myrbetriq_PM_EN.pdf §]</span> ======
*** '''<span style="color:#ff0000">UTI</span>'''
* '''<span style="color:#ff0000">≥1% (5)</span>'''
*** '''<span style="color:#ff0000">Constipation, dry eyes, blurry vision</span>'''
*# '''<span style="color:#ff0000">Hypertension</span>'''
*** '''Does not cause increase QT interval'''
*#* The mean increase (compared with placebo) in systolic and diastolic blood pressure after therapeutic doses of mirabegron once daily was ≈0.5-1 mm Hg and was reversible on discontinuation of treatment.
** '''Even if the cardiovascular effects of mirabegron observed in clinical studies have been minimal and clinically not relevant, effects on HR and blood pressure need to be monitored when the drug is prescribed'''
*#* In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for mirabegron 50 mg was ≈1 beat/min and reversible on discontinuation of treatment.
*# '''<span style="color:#ff0000">Tachycardia</span>'''
*#'''<span style="color:#ff0000">Nasopharyngitis</span>'''
*#'''<span style="color:#ff0000">Urinary tract infection</span>'''
*#'''<span style="color:#ff0000">Headache</span>'''
*#'''<span style="color:#ff0000">Constipation</span>'''
*'''Does not cause increase QT interval'''
* '''Effects on HR and blood pressure need to be monitored when the drug is prescribed''', even if the cardiovascular effects of mirabegron observed in clinical studies have been minimal and clinically not relevant


==== Toxins ====
==== Toxins ====
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* '''A neurotoxin produced by''' '''gram-positive Clostridium botulinum'''
* '''A neurotoxin produced by''' '''gram-positive Clostridium botulinum'''
* '''7 subtypes; subtype A has the longest duration of action, making it the most relevant clinically.'''
* '''7 subtypes; subtype A has the longest duration of action, making it the most relevant clinically.'''
** Subtype A is available in 4 different forms''': onabotulinumtoxinA''' (onabotA), abobotulinumtoxinA (abobotA), and incobotulinumtoxinA (incobotA) for '''Botox''', Dysport, and Xeomin, respectively.
** Subtype A is available in different forms''':'''
*** Although the toxin is the same, it is wrapped by different proteins that modify the relative potency of each brand.
***'''OnabotulinumtoxinA''' (onabotA) - '''Botox'''
*** Most of the information available about intravesical application of BoNTA derives from the use of onabotA (Botox).
***'''AbobotulinumtoxinA''' (abobotA) - '''Dysport'''
***IncobotulinumtoxinA (incobotA) - Xeomin
**** Although the toxin is the same, it is wrapped by different proteins that modify the relative potency of each brand.
**** Most of the information available about intravesical application of BoNTA derives from the use of onabotA (Botox).
****Dysport associated with higher rates of need for clean intermittent self-catheterization
** Clinical dose conversion studies for the LUT do not exist.
** Clinical dose conversion studies for the LUT do not exist.
* '''<span style="color:#ff0000">Mechanisms of action (4):'''
* '''<span style="color:#ff0000">Mechanisms of action (4):'''
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** '''Shown to be effective in patients with OAB.'''
** '''Shown to be effective in patients with OAB.'''
*** '''Successful OAB treatment with BoNTA does not appear to be related to the existence of DO.''' No differences in outcomes were found between those with and those without baseline DO
*** '''Successful OAB treatment with BoNTA does not appear to be related to the existence of DO.''' No differences in outcomes were found between those with and those without baseline DO
* '''<span style="color:#ff0000">Contraindications (4):</span>'''
* '''<span style="color:#ff0000">Dosing: FDA-approved dose of 200U for neurogenic OAB</span>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649594/ §][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739988/ §]'''
*# '''<span style="color:#ff0000">Active UTI</span>'''
**'''<span style="color:#ff0000">Not FDA-approved in non-neurogenic OAB patients, 100U typically used</span>'''
*'''<span style="color:#ff0000">Contraindications (4):</span>'''
*# '''<span style="color:#ff0000">Active urinary tract infection</span>'''
*# '''<span style="color:#ff0000">Acute urinary retention</span>'''
*# '''<span style="color:#ff0000">Acute urinary retention</span>'''
*# '''<span style="color:#ff0000">Unwillingness or inability to self-catheterize</span>'''
*# '''<span style="color:#ff0000">Unwillingness or inability to self-catheterize</span>'''
*# '''<span style="color:#ff0000">Hypersensitivity</span>'''
*# '''<span style="color:#ff0000">Hypersensitivity</span>'''
* '''<span style="color:#ff0000">Adverse events:</span>'''
* '''<span style="color:#ff0000">Adverse events:</span>'''
** '''<span style="color:#ff0000">Most common: bladder pain and urinary infections. Hematuria, usually mild, may also occur'''
**'''<span style="color:#ff0000">Most common (3):</span>'''
** '''Most serious: paralysis of the striated musculature caused by circulatory leakage of the toxin'''
**#'''<span style="color:#ff0000">Bladder pain</span>'''
*** Has never been reported.
**#'''<span style="color:#ff0000">Gross hematuria (usually mild)</span>'''
**** '''Caution should be used in treating high-risk patients, including:'''
**# '''<span style="color:#ff0000">Urinary tract infection</span>'''
****# '''Children'''
**'''<span style="color:#ff0000">Most serious (2):</span>'''
****# '''Patients with low pulmonary reserve'''
**#'''<span style="color:#ff0000">Urinary retention and a transient necessity to perform CIC (≈5%)</span>'''
****# '''Patients with myasthenia gravis'''
**#*<span style="color:#ff0000">'''Patient must be able and willing to return for frequent post-void residual evaluation and able and willing to perform self-catheterization if necessary'''
*** '''Transient muscle weakness''' was reported with abobotA application
**#*'''The proportion of patients who initiate CIC at any time during treatment cycle 1 was 6.1%''' versus none in the placebo group; for over half the patients who initiated CIC, the duration of CIC was 6 weeks or less.
** '''Most feared in patients with voluntary voiding: urinary retention and a transient necessity to perform CIC.'''
**#'''Paralysis of the striated musculature caused by circulatory leakage of the toxin'''
*** '''The proportion of patients who initiate CIC at any time during treatment cycle 1 was 6.1%''' versus none in the placebo group; for over half the patients who initiated CIC, the duration of CIC was 6 weeks or less.
**#* '''Has never been reported.'''
**#** '''Caution should be used in treating high-risk patients, including:'''
**#**# '''Children'''
**#**# '''Patients with low pulmonary reserve'''
**#**# '''Patients with myasthenia gravis'''
**#* '''Transient muscle weakness''' was reported with abobotA application
**'''<span style="color:#ff0000">Other:</span>'''
**#'''<span style="color:#ff0000">Dry mouth</span>'''
**#'''<span style="color:#ff0000">Dysphagia</span>'''
**#'''<span style="color:#ff0000">Impaired vision</span>'''
**# '''<span style="color:#ff0000">Eyelid weakness</span>'''
**#'''<span style="color:#ff0000">Arm weakness</span>'''
**#'''<span style="color:#ff0000">Leg weakness</span>'''
**# '''<span style="color:#ff0000">Torso weakness</span>'''  
** '''Aminoglycosides should be avoided during BoNTA treatment because they might block motor plates and therefore enhance BoNTA effect'''
** '''Aminoglycosides should be avoided during BoNTA treatment because they might block motor plates and therefore enhance BoNTA effect'''


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#* '''<span style="color:#ff0000">Most often reported with silodosin and tamsulosin.</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.
#** '''<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 ===
=== Decreasing Outlet Resistance at a Site of Anatomic Obstruction ===
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# '''Reduced risk of BPH-related surgical intervention'''
# '''Reduced risk of BPH-related surgical intervention'''
=== Decreasing Outlet Resistance at the Level of the Striated Sphincter ===
=== Decreasing Outlet Resistance at the Level of the Striated Sphincter ===
* '''There is no class of pharmacologic agents that will selectively relax the striated musculature of the pelvic floor. However, 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
* '''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'''.  
=== Phosphodiesterase inhibitors ===
**The potential for spread to nearby structures is greater than with intravesical therapy, and distant effects can also occur, but these are rare
* '''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.


=== Increasing Intravesical Pressure and Bladder Contractility ===
=== Increasing Intravesical Pressure and Bladder Contractility ===
* '''There is currently no effective drug for the treatment of detrusor underactivity or underactive bladder'''
* '''Currently no effective drug for the treatment of detrusor underactivity or underactive bladder'''
* '''Parasympathomimetic agents'''
* '''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.
** 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.
** 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 is cholinesterase resistant and causes an in vitro contraction of smooth muscle from all areas of the bladder. However, there is little evidence of its efficacy.'''
*** '''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.
**** 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
* Prostaglandins
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**# Potentiation of acetylcholine (but not ATP) release from cholinergic nerve terminals through prejunctional prostanoid receptors.
**# 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.
** 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 ===
=== Phytotherapy ===
* '''Saw palmetto'''
 
** RCT
==== Saw palmetto ====
*** 225 men age >49 with moderate-to-severe symptoms of benign prostatic hyperplasia
* RCT
*** Randomized to to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo.
** 225 men age >49 with moderate-to-severe symptoms of benign prostatic hyperplasia
*** Primary outcome: changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate.
** Randomized to to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo.
*** 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.
** Primary outcome: changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate.
*** Results
** 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.
**** '''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'''
** Results
*** [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.]
*** '''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.]


== Other drugs ==
== Other drugs ==


* '''Desmopressin'''
=== Desmopressin ===
** '''Mechanism of action:'''
* '''Mechanism of action:'''
*** '''Analogue of the endogenous hormone''' '''vasopressin (also known as antidiuretic hormone).'''
** '''Analogue of the endogenous hormone''' '''vasopressin (also known as antidiuretic hormone).'''
**** Vasopressin
*** Vasopressin
***** Functions (2):
**** Functions (2):
*****# Causes contraction of vascular smooth muscle
****# Causes contraction of vascular smooth muscle
*****# Stimulates water reabsorption from the collecting ducts
****# Stimulates water reabsorption from the collecting ducts
***** Release stimulated by:
**** Release stimulated by:
****** Hyperosmolality
***** Hyperosmolality
****** Hypovolemia
***** Hypovolemia
****** Stress
***** Stress
****** Nausea
***** Nausea
****** Pregnancy
***** Pregnancy
****** Hypoglycemia
***** Hypoglycemia
****** Nicotine
***** Nicotine
****** Morphine
***** Morphine
****** Other drugs
***** Other drugs
***** Release inhibited by:
**** Release inhibited by:
****** Hypoosmolality
***** Hypoosmolality
****** Hypervolemia
***** Hypervolemia
****** Ethanol
***** Ethanol
****** Phenytoin
***** Phenytoin
** '''Pharmacology'''
* '''Pharmacology'''
*** '''More powerful and longer-lasting antidiuretic action than vasopressin/anti-diuretic hormone''' due to selectivity for antidiuretic over vasopressor effects.
** '''More powerful and longer-lasting antidiuretic action than vasopressin/anti-diuretic hormone''' due to selectivity for antidiuretic over vasopressor effects.
*** '''Fast onset of action, with urine production decreasing within 30 minutes of oral administration'''
** '''Fast onset of action, with urine production decreasing within 30 minutes of oral administration'''
*** Available in formulations for oral, parenteral, and nasal administration.
** Available in formulations for oral, parenteral, and nasal administration.
**** '''Because symptomatic hyponatremia with water intoxication,''' which is the only serious adverse event reported in children, '''occurred after intranasal or intravenous administration of desmopressin,''' the FDA and the European Medicines Agency (EMA) '''removed the indication for the treatment of primary nocturnal enuresis from all intranasal preparations of desmopressin.''' '''An oral lyophilisate formulation (MELT) requiring no concomitant fluid intake is currently available'''
*** '''Because symptomatic hyponatremia with water intoxication,''' which is the only serious adverse event reported in children, '''occurred after intranasal or intravenous administration of desmopressin,''' the FDA and the European Medicines Agency (EMA) '''removed the indication for the treatment of primary nocturnal enuresis from all intranasal preparations of desmopressin.''' '''An oral lyophilisate formulation (MELT) requiring no concomitant fluid intake is currently available'''
** '''Efficacy'''
* '''Efficacy'''
*** '''Nocturia'''
** '''Nocturia'''
**** '''Desmopressin is the most common vasopressin analogue used to treat nocturia in children and adults.'''
*** '''Desmopressin is the most common vasopressin analogue used to treat nocturia in children and adults.'''
***** '''Decreased vasopressin levels are believed to be important in the pathophysiology of some forms of polyuria, specifically nocturnal polyuria.'''
**** '''Decreased vasopressin levels are believed to be important in the pathophysiology of some forms of polyuria, specifically nocturnal polyuria.'''
**** '''Results in significant improvements in reducing nocturnal voids and increasing the hours of undisturbed sleep'''.
*** '''Results in significant improvements in reducing nocturnal voids and increasing the hours of undisturbed sleep'''.
**** '''Generally well tolerated in all the studies on nocturia.'''
*** '''Generally well tolerated in all the studies on nocturia.'''
*** '''Enuresis'''
** '''Enuresis'''
**** In children, effective in reducing bedwetting. However, there was no effect after discontinuation of treatment, indicating that '''desmopressin suppresses the symptom of enuresis but does not cure the underlying cause.'''
*** In children, effective in reducing bedwetting. However, there was no effect after discontinuation of treatment, indicating that '''desmopressin suppresses the symptom of enuresis but does not cure the underlying cause.'''
***** In addition, not all children responded sufficiently to desmopressin monotherapy.
**** In addition, not all children responded sufficiently to desmopressin monotherapy.
***** '''The combination of desmopressin and an enuresis alarm resulted in a greatly improved short-term success rate and decreased relapse rates'''
**** '''The combination of desmopressin and an enuresis alarm resulted in a greatly improved short-term success rate and decreased relapse rates'''
** '''Contraindications (drug monograph):'''
* '''Contraindications (drug monograph):'''
*** '''Patients with type IIB or platelet-type (pseudo) Willerbrand disease, because of the risk of platelet aggregation and thrombocytopenia'''
** '''Patients with type IIB or platelet-type (pseudo) Willerbrand disease, because of the risk of platelet aggregation and thrombocytopenia'''
*** '''Any condition associated with impaired water excretion, such as:'''
** '''Any condition associated with impaired water excretion, such as:'''
**** '''Hyponatremia'''
**** '''Severe liver disease'''
**** '''[Hydro]nephrosis'''
**** '''Cardiac insufficiency'''
**** '''Chronic renal insufficiency'''
**** '''Congestive heart failure'''
**** '''Habitual or psychogenic polydypsia'''
*** '''Any medical conditions which lead to sodium losing states such as:'''
**** '''Vomiting'''
**** '''Diarrhea'''
**** '''Bulimia'''
**** '''Anorexia nervosa'''
**** '''Adrenocortical insufficiency'''
**** '''Salt losing nephropathies'''
*** '''Lactose intolerance/allergies'''
** '''Adverse events'''
*** '''Hyponatremia'''
*** '''Hyponatremia'''
**** '''Can lead to a variety of adverse events ranging from mild headache, anorexia, nausea, and vomiting to loss of consciousness, seizures, and death'''
*** '''Severe liver disease'''
**** '''Usually occurs soon after treatment is initiated'''
*** '''[Hydro]nephrosis'''
**** '''Risk factors:'''
*** '''Cardiac insufficiency'''
****# '''Increasing age'''
*** '''Chronic renal insufficiency'''
****# '''Female gender'''
*** '''Congestive heart failure'''
****# '''Cardiac disease'''
*** '''Habitual or psychogenic polydypsia'''
****# '''Increasing 24-hour urine volume'''
** '''Any medical conditions which lead to sodium losing states such as:'''
** '''Dosing'''
*** '''Vomiting'''
*** '''Females demonstrate increased sensitivity to demopression; recommended efficacious doses are 25 μg MELT for females and 50 to 100 μg MELT for males'''
*** '''Diarrhea'''
*** '''Prior to initiation, a serum sodium should be obtained at baseline, then again after initiation. Serum sodium should be assessed regularly, at least every 6 months with long-term desmopressin administration'''
*** '''Bulimia'''
*** '''Initiation of desmopressin is currently not indicated for patients age ≥ 65''' (different than CUA guidelines, see below)
*** '''Anorexia nervosa'''
*** '''2018 CUA MLUTS Guidelines'''
*** '''Adrenocortical insufficiency'''
**** '''While the risk of hyponatremia is low in men with normal baseline serum sodium, sodium must be checked at baseline and 4–8 days as well as 30 days after initiation of treatment in (2):'''
*** '''Salt losing nephropathies'''
****# '''All men taking desmopressin melts'''
** '''Lactose intolerance/allergies'''
****# '''Men ≥65 years taking 50 μg oral disintegrating tablet'''
* '''Adverse events'''
***** Note that these guidelines are for male LUTS and therefore recommendations for females are not provided.
** '''Hyponatremia'''
* '''Dimethyl sulfoxide (DMSO)'''
*** '''Can lead to a variety of adverse events ranging from mild headache, anorexia, nausea, and vomiting to loss of consciousness, seizures, and death'''
** Has been used as an industrial solvent for many years
*** '''Usually occurs soon after treatment is initiated'''
** '''Used in a 50% solution to improve symptoms in interstitial cystitis'''
*** '''Risk factors:'''
** Has not been shown to be useful in the treatment of:
***# '''Increasing age'''
*** Neurogenic detrusor overactivity
***# '''Female gender'''
*** Idiopathic detrusor overactivity
***# '''Cardiac disease'''
*** Any patients with urgency or frequency but without interstitial cystitis
***# '''Increasing 24-hour urine volume'''
* '''Baclofen'''
* '''Dosing'''
** Mechanism of action: depresses monosynaptic and polysynaptic excitation of motor neurons and interneurons in the spinal cord by activating GABAB receptors.
** '''Females demonstrate increased sensitivity to demopression; recommended efficacious doses are 25 μg MELT for females and 50 to 100 μg MELT for males'''
** Has been tried in idiopathic detrusor overactivity but with poor efficacy
** '''Prior to initiation, a serum sodium should be obtained at baseline, then again after initiation. Serum sodium should be assessed regularly, at least every 6 months with long-term desmopressin administration'''
* Cyclooxygenase inhibitors
** '''Initiation of desmopressin is currently not indicated for patients age ≥ 65''' (different than CUA guidelines, see below)
** Although there are theoretic mechanisms by which prostaglandin synthesis inhibitors could affect filling and storage symptoms, clinical evidence for this is scarce. The interest in the use of selective COX-2 inhibitors was tempered by concerns about long-term cardiovascular toxicity with these drugs.
** '''2018 CUA MLUTS Guidelines'''
* Calcium antagonists
*** '''While the risk of hyponatremia is low in men with normal baseline serum sodium, sodium must be checked at baseline and 4–8 days as well as 30 days after initiation of treatment in (2):'''
** Activation of detrusor muscle seems to require influx of extracellular Ca2+ through Ca2+ channels as well as via mobilization of intracellular Ca2+. The influx of extracellular calcium can be blocked by calcium antagonists, blocking L-type Ca2+ channels, and theoretically this would be an attractive way of inhibiting DO and regulating detrusor smooth muscle tone. Although these in vitro data suggest a possible role for calcium channel inhibitors, in the treatment of DO and incontinence, only limited clinical studies are available
***# '''All men taking desmopressin melts'''
* Potassium channel openers
***# '''Men ≥65 years taking 50 μg oral disintegrating tablet'''
** Potassium channels contribute to the membrane potential of smooth muscle cells and hence to the regulation of smooth muscle tone. Despite promising preclinical efficacy data, potassium channel openers at present are not a therapeutic option and may never become one owing to a lack of selectivity for bladder over cardiovascular tissues
**** Note that these guidelines are for male LUTS and therefore recommendations for females are not provided.
 
=== Phenazopyridine ===
 
* Trade name: Pyridium
* '''Mechanism of action'''
** Unknown
* '''Pharmacology'''
** Rapidly excreted in the urine
* '''Efficacy'''
** Considered a “grandfathered” drug that lacks both the safety and efficacy data required for Food and Drug Administration approval[https://pubmed.ncbi.nlm.nih.gov/31006341/]
*** Marketed prior to the Food, Drug, and Cosmetic Act of 1938
* '''Contraindications (2)[https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=165d01d4-a9f7-2293-e054-00144ff8d46c&type=pdf]'''
** Hypersensitivity
** Renal insufficiency
* '''Adverse events[https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=165d01d4-a9f7-2293-e054-00144ff8d46c&type=pdf]'''
** Most common
*** Headache
*** Rash
*** Pruritis
*** Skin or sclera discoloration
**** A yellowish tinge of the skin or sclera may indicate accumulation due to impaired renal excretion and the need to discontinue therapy
*** Urine discoloration
**** Patients should be informed that phenazopyridine produces a reddish-orange discoloration of the urine and may stain fabric.
*** GI disturbance
** Rare but serious: methylglobinemia, hemolytic anemia, thrombocytopenia, neutropenia, nephrotoxicity, and hepatotoxicity, usually at overdosage levels
* '''Dosing'''
** 200 mg three times daily after meals
** Duration of treatment
*** When used concomitantly with an antibacterial agent for the treatment of a urinary tract infection, the administration of Phenazopyridine HCl should not exceed 2 days.'''[https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=165d01d4-a9f7-2293-e054-00144ff8d46c&type=pdf]'''
***American Hospital Formulary Service states that therapy may be extended for up to 15 days in non-infectious scenarios[https://pubmed.ncbi.nlm.nih.gov/31006341/]
***Another study found no difference in adverse drug reactions among patients receiving phenazopyridine for >14 days compared to a matched comparator group[https://pubmed.ncbi.nlm.nih.gov/31006341/]
***
 
=== Dimethyl sulfoxide (DMSO) ===
* Has been used as an industrial solvent for many years
* '''Used in a 50% solution to improve symptoms in interstitial cystitis'''
* Has not been shown to be useful in the treatment of:
** Neurogenic detrusor overactivity
** Idiopathic detrusor overactivity
** Any patients with urgency or frequency but without interstitial cystitis
 
=== Baclofen ===
* Mechanism of action: depresses monosynaptic and polysynaptic excitation of motor neurons and interneurons in the spinal cord by activating GABAB receptors.
* Has been tried in idiopathic detrusor overactivity but with poor efficacy
 
=== Cyclooxygenase inhibitors ===
* Although there are theoretic mechanisms by which prostaglandin synthesis inhibitors could affect filling and storage symptoms, clinical evidence for this is scarce. The interest in the use of selective COX-2 inhibitors was tempered by concerns about long-term cardiovascular toxicity with these drugs.
 
=== Calcium antagonists ===
* Activation of detrusor muscle seems to require influx of extracellular Ca2+ through Ca2+ channels as well as via mobilization of intracellular Ca2+. The influx of extracellular calcium can be blocked by calcium antagonists, blocking L-type Ca2+ channels, and theoretically this would be an attractive way of inhibiting DO and regulating detrusor smooth muscle tone. Although these in vitro data suggest a possible role for calcium channel inhibitors, in the treatment of DO and incontinence, only limited clinical studies are available
 
=== Potassium channel openers ===
* Potassium channels contribute to the membrane potential of smooth muscle cells and hence to the regulation of smooth muscle tone. Despite promising preclinical efficacy data, potassium channel openers at present are not a therapeutic option and may never become one owing to a lack of selectivity for bladder over cardiovascular tissues


== Combinations ==
== Combinations ==


=== '''Alpha-blockers and 5-ARIs''' ===
=== Alpha-blockers and 5-ARIs ===
* '''<span style="color:#ff00ff">MTOPS</span>'''§
* '''<span style="color:#ff00ff">MTOPS</span>'''§
** '''Population: 3047 men age ≥ 50 with IPSS 8-30, PSA ≤ 10 ng/mL, Qmax ≥4 but ≤15 ml/s with minimum voided volume ≥125 ml'''
** '''Population: 3047 men age ≥ 50 with IPSS 8-30, PSA ≤ 10 ng/mL, Qmax ≥4 but ≤15 ml/s with minimum voided volume ≥125 ml'''
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