Editing Functional: Pharmacological Management of LUTS (section)

===== 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