Editing Functional: Pharmacological Management of LUTS (section)

=== Increasing outlet resistance ===

* Many factors seem to be involved in the pathogenesis of SUI: urethral support, vesical neck function, and function of the nerves and musculature of the bladder, urethra, and pelvic floor. Anatomic factors cannot be treated pharmacologically. However, women with SUI have lower resting urethral pressures than age-matched continent women
* '''The pharmacologic treatment of SUI aims at increasing intraurethral closure forces by increasing the tone in the urethral smooth and striated muscles but relative lack of efficacy and/or side effects have limited their clinical use'''.
* '''Antidepressants'''
** '''Imipramine'''
*** '''Tricyclic antidepressant (TCA)'''
*** '''Mechanism of action:''' complex pharmacologic effects, including '''strong systemic anti-cholinergic activity and blockade of the reuptake of serotonin and noradrenaline''', but its mode of action in DO has not been established; theoretically facilitates urine storage, both by '''decreasing bladder contractility and by increasing outlet resistance'''
*** '''Contraindications:'''
**** '''Concomitant use of monoamine oxidase inhibitors'''
***** Severe CNS toxicity can be precipitated, including hyperpyrexia, seizures, and coma
*** '''If any of the TCAs are prescribed for the treatment of voiding dysfunction, the patient should be thoroughly informed of the fact that this is not the usual indication for this drug and that potential side effects exist.'''
**** '''Imipramine is the only drug that has been widely used clinically to treat storage symptoms without good-quality RCTs that support is effectiveness'''
**** Has been known for a long time that imipramine can have favorable effects in the treatment of nocturnal enuresis in children.
*** '''Adverse events:'''
**** '''Most frequent side effects of TCAs are those attributable to their systemic anti-cholinergic activity'''
**** '''Therapeutic doses of TCAs may cause serious toxic effects on the cardiovascular system (orthostatic hypotension, ventricular arrhythmias).'''
***** '''Imipramine prolongs QTc.'''
***** Children seem particularly sensitive to the cardiotoxic action of TCAs.
****** It should be noted that data in the literature refer to therapeutic doses of these medications for depression and not the smaller (in comparison) doses of imipramine used for the treatment of voiding dysfunction.
**** '''Other adverse events include weakness, fatigue, hepatic dysfunction, allergic phenomena (including rash), obstructive jaundice, and agranulocytosis'''
**** Reports of significant side effects (severe abdominal distress, nausea, vomiting, headache, lethargy, and irritability) after abrupt cessation of high doses of imipramine in children would suggest that the drug '''should be discontinued gradually, especially in patients receiving high doses'''.
** '''Duloxetine'''
*** '''MOA: serotonin-noradrenaline reuptake inhibitor (SNRI)'''
*** In a cat model, significantly increases sphincteric muscle activity during the filling and storage phase of micturition, and increased bladder capacity.
*** Lipophilic, well absorbed, and extensively metabolized by the liver
*** Has been shown to improve storage symptoms, but trials are lacking; may result in subjective more than objective improvements
*** Currently, duloxetine is licensed in the European Union for women with moderate to severe SUI. It is approved in the United States for treatment of a variety of disorders, but was withdrawn from the approval process for the treatment of SUI.
* α-adrenergic agonists (e.g. ephedrine)
** Hypogastric nerve stimulation and α-adrenergic agonists raise intraurethral pressure. These findings provide the rationale for use of α-adrenergic agonists to promote urine storage by increasing urethral resistance.
** The use of peripheral α-adrenergic agonists has largely been abandoned because of the adverse effects associated with these agents and the weak evidence of efficacy compared with placebo
*** Phenylpropanolamine is associated with significantly increased risk of stroke in women
* β-AR agonists and antagonists
** Paradoxically, there are theoretic rationales for using both β-AR agonists and antagonists for treatment of SUI
*** β-AR stimulation is generally conceded to decrease urethral pressure, but β2-AR agonists have been reported to increase the contractility of striated muscle fibers.
*** Conversely, the blockade of urethral β-ARs by β-AR antagonists may enhance the effects of NA on urethral α-ARs.
*** There are few data suggesting significant efficacy.
* '''There is currently no effective drug for male SUI'''.
** Duloxetine has been evaluated in this context but usage of duloxetine for SUI in men is universally off-label.
** A drug is needed for male SUI.