Editing Functional: Pharmacological Management of LUTS (section)

=== Increasing bladder storage ===

==== Anti-cholinergics ====

* '''Also known as muscarinic receptor antagonists, anti-muscarinics, etc.'''

===== Mechanisms of action (3): =====
# '''<span style="color:#ff0000">Decrease the activity in AFFARENT nerves (both C and Aδ fibers) from the bladder</span>'''
#* '''<span style="color:#ff0000">Primary mechanism; anti-cholinergics act mainly during the storage phase (rather than the voiding phase)</span>'''
#** '''During the storage phase'''
#*** '''ACh is released''' from both neuronal and non-neuronal sources (e.g., the urothelium and suburothelium) '''and''' '''directly or indirectly''' (by increasing detrusor smooth muscle tone) '''excites afferent nerves in the suburothelium and within the detrusor'''
#*** '''Normally no parasympathetic input to the LUT.'''
#* '''Since they act during the storage phase, they can be safely administered in men with bladder outlet obstruction as they do not alter urinary flow rate, voiding pressure, or incidence of urinary retention.'''
#** '''Caution should be used in large PVRs'''
# '''<span style="color:#ff0000">Blocking the muscarinic receptors on the detrusor muscle,</span>''' which are otherwise stimulated by ACh released from activated cholinergic (parasympathetic) nerves.
#* '''Less significant effect than reducing AFFARENT activity'''
# '''<span style="color:#ff0000">Reduce the micromotions caused by the release of small packets of Ach</span>'''
* '''<span style="color:#ff0000">In patients with involuntary bladder contractions (detrusor overactivity) of any cause, anti-cholinergics (5):</span>'''
*# '''<span style="color:#ff0000">Increase the volume to the first detrusor overactivity</span>''' (affarent)
*# '''<span style="color:#ff0000">Increase the total bladder capacity</span>''' (affarent)
*# '''<span style="color:#ff0000">Increase mean voided volume</span>''' (affarent)
*# '''<span style="color:#ff0000">Decrease urgency</span>''' (affarent)
*# '''<span style="color:#ff0000">Decrease the amplitude of the contraction</span>''' (efferent)
* '''Do not affect detrusor or abdominal leak point pressure'''
* '''Produce only partial inhibition due to secondary release of a transmitter other than Ach'''
** This is known as atropine resistance and is the most common hypothesis explaining the difficulty of curing detrusor overactivity with anti-cholimergic agents alone, and supports the rationale of combined treatment of detrusor overactivity with agents of different mechanisms of action. The importance or unimportance of an atropine-resistant component to detrusor contraction in the treatment of detrusor overactivity in humans remains to be established.

===== Pharmacology =====
*'''<span style="color:#ff0000">Anti-cholinergics can be classified as tertiary vs. quaternary amines</span>'''
** '''<span style="color:#ff0000">Tertiary amines</span>'''
*** '''<span style="color:#ff0000">Oxybutynin, tolterodine, fesoterodine, solifenacin, darifenacin,</span>''' atropine, imidafenacin, and propiverine
*** '''Well absorbed from the GI tract'''
*** '''Theoretically able to pass into the central nervous system (CNS)'''
**** '''Factors that increase the likelihood of an anti-cholinergic passing through the blood-brain barrier (3):'''
****# '''High lipophilicity'''
****# '''Small molecular size'''
****# '''Low electrical charge'''
** '''<span style="color:#ff0000">Quaternary amines</span>'''
*** '''<span style="color:#ff0000">Trospium and propantheline</span>'''
*** '''Not well absorbed from the GI tract'''
*** '''<span style="color:#ff0000">Pass into the CNS to a limited extent, and have a low incidence of CNS side effects</span>'''
* '''<span style="color:#ff0000">Metabolism</span>'''
** '''<span style="color:#ff0000">Many metabolized by the P450 enzyme system to active and/or inactive metabolites.</span>'''
*** Most commonly involved P450 enzymes are CYP2D6 and CYP3A4
*** Metabolic conversion creates '''a risk for drug-drug interactions; coadministration of a potent inhibitor of this enzyme (e.g., ketoconazole) may lead to an increase in the circulating drug'''

===== Contraindications (7): =====
# '''<span style="color:#ff0000">Untreated narrow-angle glaucoma</span>'''
#* Can induce or precipitate acute angle-closure glaucoma due to their antagonistic actions on M3 and M5 receptors in the eye
# '''<span style="color:#ff0000">GI obstruction</span>'''
# '''<span style="color:#ff0000">Myasthenia gravis</span>''' (some sources)
# '''<span style="color:#ff0000">Dialysis dependent</span>''' (solifenacin product monograph)
# '''<span style="color:#ff0000">History of urinary retention</span>'''
# '''<span style="color:#ff0000">Cognitive impairment (doses of 20mg oxybutynin)</span>''' (CUA OAB Guidelines)
# '''<span style="color:#ff0000">Hypersensitivity</span>'''

===== Adverse events =====
* The clinical usefulness of available antimuscarinic agents is limited by their lack of selectivity
* '''The low persistence with prescribed anti-cholinergic therapy for OAB is due to lack of efficacy and adverse effects.'''
** '''The longest persistence has been reported for solifenacin'''
* '''<span style="color:#ff0000">Common side effects include:</span>'''
*# '''<span style="color:#ff0000">Dry mouth</span>''' (30% medication vs. 8% placebo)
*# '''<span style="color:#ff0000">Constipation</span>'''
*# '''<span style="color:#ff0000">Blurred vision</span>'''
*# '''<span style="color:#ff0000">CNS side effects (cognitive dysfunction, memory impairment, dizziness, fatigue, and headache)</span>'''
* '''<span style="color:#ff0000">Potential serious side effects are cardiac and include:</span>'''
*# '''<span style="color:#ff0000">Increases in heart rate</span>'''
*# '''<span style="color:#ff0000">Arrhythmia</span> (QT prolongation and induction of polymorphic ventricular tachycardia (torsades de pointes)'''
*#* '''QT prolongation is not related to muscarinic blockade''' but rather linked to inhibition of the hERG potassium channel in the heart. '''Some anti-cholinergic drugs may cause this, but this is not a class effect.'''

===== Frequently used anti-cholinergics for LUTS =====
* None of the anti-cholinergic drugs in clinical use is ideal as a first-line treatment for all OAB patients. Optimal treatment should be individualized.
* '''Site and speed of anti-cholinergic metabolism has profound effects in terms of clinical efficacy and side effects'''; '''therapeutically, it is more important to be tissue selective than subtype selective'''
** Oral immediate-release (IR) oxybutynin has higher risk of dry mouth than tolterodine
** IR preparations have higher risk of dry mouth than extended release (ER) preparations of oxybutynin or tolterodine
** IR tolterodine has lower efficacy and higher risk of dry mouth than solifenacin
** Fesoterodine has higher efficacy but also higher risk of widhdrawal becaue of adverse events in general, in particular a higher risk of dry mouth compared to ER tolterodine

====== Oxybutynin (Ditropan) ======
* '''Mechanism of action:'''
*# '''Blocks muscarinic receptors''' (main effect when given systemically)
*# '''Direct muscle relaxant'''
*# '''Local anesthetic effects'''
*#* The latter 2 may be of importance when the drug is administered intravesically, but probably play no role when it is given orally.
* '''Metabolism: Undergoes extensive upper gastrointestinal and first-pass hepatic metabolism via the cytochrome P450 system (CYP3A4) into multiple metabolites.'''
** '''The primary metabolite, N-desethyloxybutynin, has been implicated as the major cause of the troublesome side effect of dry mouth associated with oxybutynin.'''
* Selectivity: slightly higher affinity for M1 and M3 receptors than for M2 receptors
* Dosing: Immediate release and extended release formulations available, as well as a transdermal patch and gel formulations.
** '''Transdermal delivery''' also alters oxybutynin metabolism, reducing N-desethyloxybutynin production to an even greater extent than OXY-ER, and is associated with '''much less dry mouth. Side effects include application site reaction pruritus and erythema'''
* '''Adverse events:'''
** '''Immediate release has high incidence of side effects (dry mouth, constipation, drowsiness, blurred vision)'''
** Extended release version was developed to decrease liver metabolite formulation of N-desethyloxybutynin with the presumption that it would result in decreased side effects
** A significant dose-response relationship for both urgency incontinence episodes and dry mouth.
** '''Studies show no effect on ECG'''
** '''May have negative effects on cognitive function, particularly in the elderly population but also in children'''
*Estimated cost per month: 10$ USD[https://www.goodrx.com/]

====== Tolterodine (Detrol) ======
* '''Metabolism: extensively metabolized by the liver (cytochrome P450) into its major active metabolite 5-HMT''' 
** '''5-HMT has''' '''a similar pharmacologic profile as the mother compound and significantly contributes to the therapeutic effect of tolterodine.'''
**'''5-HMT is metabolized in the liver, but a significant part of 5-HMT is excreted renally without additional metabolism'''
* '''Selectivity:''' tissue selective (has selectivity for the bladder compared with the salivary gland) but no selectivity for muscarinic receptor subtypes.
* Dosing: Available in immediate release and extended release formulations. The extended release form seems to have advantages over the immediate release form in terms of both efficacy and tolerability
* Outcomes: significant improvement in frequency and incontinence episodes
* Adverse events:
** No effect on QT interval
** '''Low incidence of cognitive effects''' (relatively low lipophilicity of tolterodine and even lesser one of 5-HMT imply limited propensity to penetrate into the CNS)
*Estimated cost per month: 35$ USD[https://www.goodrx.com/]

====== Fesoterodine (Toviaz) ======
* '''Metabolism: an orally active prodrug that is converted to the active metabolite 5-hydroxymethyl tolterodine (5-HMT)'''
** All of the effects of fesoterodine are thought to be mediated via 5-HMT.
* Selectivity: no selectivity for muscarinic receptor subtypes
* '''Dosing: Recommended doses are 4 and 8 mg/day,''' with the 8-mg dose having a greater effect at the expense of a higher rate of dry mouth.
** The suggested starting dose, 4 mg/day, can be used in patients with moderately impaired renal or hepatic function because of the '''combination of renal excretion and hepatic metabolism of 5-HMT'''
* Adverse events:
** Most common side effects are dry mouth, headache, and constipation
** No effect on QT interval
*Estimated cost per month: 50$ USD[https://www.goodrx.com/]

====== Darifenacin (Enablex) ======
* '''Metabolism: extensively metabolized by the liver (cytochrome P450)'''
* '''Selectivity: relatively selective muscarinic M3-receptor antagonist;''' not necessarily tissue selective, because salivary glands and other tissues also contain M3 muscarinic receptors
* Dosing: Developed as a '''controlled'''-release formulation, which allows '''once-daily administration; recommended doses are 7.5 and 15 mg/day'''
* Outcomes: improves frequency, urgency, and incontinence episodes, but no improvement in nocturia
* '''Adverse events:'''
** Most common side effects are dry mouth and constipation
** '''No effect on cognition, QT interval, or heart rate'''
* Symptoms improve as early at 6 to 8 days from initiation
*Estimated cost per month: 60$ USD[https://www.goodrx.com/]

====== Solifenacin (Vesicare) ======
* '''Metabolism: significantly metabolized by the liver (cytochrome P450)'''
* Selectivity: Modest selectivity for M3 over M2 (and M1) receptors
* Dosing: 5 or 10 mg/day
*'''Outcomes: reduces nocturia'''; most of the effect is observed 2 weeks after treatment initiation
* Adverse events:
** Most common side effects are dry mouth and constipation
** '''No effect on cognitive function''' or heart rate. 30-mg dose may increase QT interval
*Estimated cost per month: 30$ USD[https://www.goodrx.com/]

*

====== Tropsium (Trosec) ======
* '''<span style="color:#ff0000">Metabolism: mainly eliminated unchanged in the urine; not metabolized by the cytochrome P450 enzyme</span>'''
** Darifenacin, solifenacin, fesoterodine, tolterodine, and oxybutynin, are all actively metabolized in the liver by the cytochrome P450 enzyme system. Trospium chloride is not metabolized to any significant degree in the liver
* '''Selectivity:''' no selectivity for muscarinic receptor subtypes.
* Dosing: Extended release formulation available
* '''Outcomes: reduces nocturia'''
* Adverse events:
** Most common side effects are dry mouth, constipation, and headache
** '''No negative cognitive effects (quaternary amines are expected to cross the blood-brain barrier to a limited extent)'''
*Estimated cost per month: 25$ USD[https://www.goodrx.com/]

====== Propiverine (Mictoryl) ======
* '''Mechanism of action: combined anti-cholinergic and calcium antagonistic actions.'''
** The importance of the calcium antagonistic component for the drug’s clinical effects has not been established.
* Selectivity: no selectivity for muscarinic receptor subtypes.
* Dosing: Extended release formulation available
* Adverse events:
** May have equal efficacy and fewer side effects than oxybutynin
** No significant effect on QT interval
* Approved for use in Canada, but not US (at time of Campbell’s writing)

====== Other ======
*Atropine
** Rarely used for treatment of OAB or DO because of its systemic side effects
* Imidafenacin
** Seems to be effective and have acceptable tolerability. However, limited data on its use; not yet available in the Western countries
* Propantheline
** Seems to be effective and to have acceptable tolerability. However, limited data on its use
* Flavoxate
** The main mechanism of flavoxate’s effect on smooth muscle has not been established.
** Limited data on its use

==== β3-adrenoreceptor agonists ====

* '''<span style="color:#ff0000">3 β-ARs subtypes (β1, β2, and β3) have been identified in the detrusor and urothelium.</span>'''
** Stimulation of β2- and β3-adrenergic receptors results in the direct relaxation of the detrusor smooth muscle
** '''<span style="color:#ff0000">β3-adrenergic receptor is the most highly expressed subtype</span>''' among α- and β-adrenoceptor subtypes at the mRNA level in human bladder

===== Mechanism of action =====
* '''Stimulates β3-adrenoceptor causing activation of adenylyl cyclase with the subsequent formation of cAMP, resulting in detrusor relaxation'''
** Recall that in erectile physiology, activation of guanyl cyclase results in increased cGMP, resulting in arterial wall smooth muscle relaxation
* '''Inhibits filling induced activity in both mechanosensitive Aδ and C-fiber primary bladder afferents,''' at least in an animal model.

===== Mirabegron =====

====== Metabolism ======
* Rapidly absorbed
* '''Metabolized in the liver via multiple pathways, mainly by cytochrome P450'''
** '''Subject to clinically relevant drug-drug interactions;''' should be used with caution in patients who are taking ketoconazole or other potent CYP3A4 inhibitors.
** Metabolites are inactive

====== Outcomes ======
* '''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'''

====== Contraindications(3):[https://www.astellas.com/ca/system/files/pdf/Myrbetriq_PM_EN.pdf §] ======
# '''<span style="color:#ff0000">Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg.</span>'''
# '''<span style="color:#ff0000">Pregnancy</span>'''
# '''<span style="color:#ff0000">Hypersensitivity</span>'''

====== Dosage ======
* '''Starting dose of 25 mg and increasing to 50 mg, if needed, is recommended.'''
* '''Lowest dose is also recommended for renal and hepatic impairment'''

====== <span style="color:#ff0000">Adverse events[https://www.astellas.com/ca/system/files/pdf/Myrbetriq_PM_EN.pdf §]</span> ======
* '''<span style="color:#ff0000">≥1% (5)</span>'''
*# '''<span style="color:#ff0000">Hypertension</span>'''
*#* 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.
*#* 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 ====

===== Botulinum toxin =====
* '''A neurotoxin produced by''' '''gram-positive Clostridium botulinum'''
* '''7 subtypes; subtype A has the longest duration of action, making it the most relevant clinically.'''
** Subtype A is available in different forms''':''' 
***'''OnabotulinumtoxinA''' (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.
* '''<span style="color:#ff0000">Mechanisms of action (4):'''
*# '''<span style="color:#ff0000">Inhibits release of acetylcholine from pre-synaptic cholinergic motor nerve endings by cleaving SNAP 25 and rendering the SNARE complex inactive, resulting in muscle paralysis'''
*#* '''Acts on both striated muscle and smooth muscle'''
*#** '''Striated muscle paralysis recovers within 2-4 months'''
*# '''<span style="color:#ff0000">Terminal axonal degeneration due to accumulation of neurotransmitter-containing synaptic vesicles'''
*# '''<span style="color:#ff0000">Inhibits the release of other neurotransmitters including ATP and neuropeptides such as substance P'''
*# '''<span style="color:#ff0000">Reduces afferent activity from bladder'''
* Efficacy
** RCTs have documented the clinical effects of onabotulinumtoxinA both in neurogenic detrusor overactivity and idiopathic detrusor overactivity, wherein the drug decreases incontinence episodes, frequency, and urgency and improves QoL.
** '''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
* '''<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">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">Unwillingness or inability to self-catheterize</span>'''
*# '''<span style="color:#ff0000">Hypersensitivity</span>'''
* '''<span style="color:#ff0000">Adverse events:</span>'''
**'''<span style="color:#ff0000">Most common (3):</span>'''
**#'''<span style="color:#ff0000">Bladder pain</span>'''
**#'''<span style="color:#ff0000">Gross hematuria (usually mild)</span>'''
**# '''<span style="color:#ff0000">Urinary tract infection</span>'''
**'''<span style="color:#ff0000">Most serious (2):</span>''' 
**#'''<span style="color:#ff0000">Urinary retention and a transient necessity to perform CIC (≈5%)</span>'''
**#*<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'''
**#*'''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.
**#'''Paralysis of the striated musculature caused by circulatory leakage of the toxin'''
**#* '''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'''

===== Capsaicin and resiniferatozin (vanilloids) =====
* Cause an initial excitation followed by a long-lasting blockade.
* Resiniferatoxin is 1000 times more potent than capsaicin for desensitization and a few hundred times more potent for excitation
* Not commonly used; there have been positive and negative trials with RTX.