Urinary incontinence (UI) is the complaint of involuntary leakage of urine. The urethral sphincter, a combination of smooth and striated muscles within and external to the urethra, maintains adequate resistance to the flow of urine from the bladder until voluntary voiding is initiated.
Volitional and involuntary bladder contractions are mediated by acetylcholine. Bladder smooth muscle cholinergic receptors are mainly of the M2 variety; however, M3 receptors are responsible for both emptying contraction of normal micturition and involuntary bladder contractions, which can result in UI. Therefore, most pharmacologic anti-muscarinic therapy is anti-M3 based.
UI occurs as a result of over functioning or under functioning of the urethra, bladder, or both. Urethral underactivity is known as stress UI (SUI) and occurs during activities such as exercise, lifting, coughing, and sneezing. The urethral sphincter no longer resists the flow of urine from the bladder during periods of physical activity.
Bladder over activity is known as urge UI (UUI) and is associated with increased urinary frequency and urgency, with or without urge incontinence. The detrusor muscle is overactive and contracts inappropriately during the filling phase.
Urethral over-activity and/or bladder underactivity is known as overflow incontinence. The bladder is filled to capacity but is unable to empty, causing urine to leak from a distended bladder past a normal outlet and sphincter. Common causes of urethral over-activity include benign prostatic hyperplasia; prostate cancer; and, in women, cystocele formation or surgical over-correction after SUI surgery.
Mixed incontinence includes the combination of bladder over-activity and urethral under-activity. Functional incontinence is not caused by bladder- or urethra-specific factors but rather occurs in patients with conditions such as cognitive or mobility deficits. Many medications can aggravate voiding dysfunction
Signs and symptoms of UI depend on the underlying pathophysiology. Patients with SUI generally complain of urine leakage with physical activity, whereas those with UUI complain of frequency, urgency, high-volume incontinence, and nocturia and nocturnal incontinence.
Urethral over-activity and/or bladder under-activity is a rare but important cause of UI. Patients complain of lower abdominal fullness, hesitancy, straining to void, decreased force of stream, interrupted stream, and sense of incomplete bladder emptying. Patients can also have urinary frequency, urgency, and abdominal pain.
A complete medical history, physical examination (i.e., abdominal examination to exclude distended bladder, pelvic examination in women looking for evidence of prolapse or hormonal deficiency, and genital and prostate examination in men), and brief neurologic assessment of the perineum and lower extremities are recommended.
• For SUI, the preferred diagnostic test is observation of urethral meatus while the patient coughs or strains.
• For UUI, the preferred diagnostic tests are urodynamic studies. Perform urinalysis and urine culture to rule out urinary tract infection.
• For urethral over-activity and/or bladder under-activity, perform digital rectal examination or trans-rectal ultrasound to rule out prostate enlargement. Perform renal function tests to rule out renal failure.
Goals of Treatment: Restoration of continence, reduction in the number of UI episodes, and prevention of complications.
Non pharmacologic treatment
Non-pharmacologic, nonsurgical treatment (e.g., lifestyle modifications, toilet scheduling regimens, and pelvic floor muscle rehabilitation) is first-line treatment for UI.
Surgery rarely plays a role in initial management of UI but can be required for secondary complications (e.g., skin breakdown or infection). The decision to surgically treat symptomatic UI requires that lifestyle compromise warrant an elective operation and that non-operative therapy be proven undesirable or ineffective.
Bladder Over activity: Urge Urinary Incontinence
The pharmacotherapy of first choice for UUI is anticholinergic/antispasmodic drugs, which antagonize muscarinic cholinergic receptors.
Oxybutynin immediate-release (IR) is the drug of first choice for UUI and the “gold standard” against which other drugs are compared. Financial considerations favor generic oxybutynin IR. Many patients discontinue oxybutynin IR because of adverse effects due to ant muscarinic effects (e.g., dry mouth, constipation, vision impairment, confusion, cognitive dysfunction, and tachycardia), α-adrenergic inhibition (e.g., orthostatic hypotension), and histamine H1 inhibition (e.g., sedation and weight gain).
Optimize tolerability of oxybutynin IR by initiating therapy with no more than 2.5 mg twice daily and increasing 2.5 mg three times daily after 1 month. Titrate in 2.5 mg/day increments every 1 to 2 months until the desired response, maximum recommended dose, or maximum tolerated dose is attained.
Oxybutynin extended-release (XL) is better tolerated than oxybutynin IR and as effective in clinical outcomes. Maximum benefits seen up to 4 weeks after starting therapy or dose escalation.
Oxybutynin transdermal system (TDS) has similar efficacy but is better tolerated than oxybutynin IR presumably because this route avoids first-pass metabolism in the liver, which generates the metabolite thought to cause adverse events, especially dry mouth.
Oxybutynin gel is also available for daily use. No data are available comparing it with an active control.
Tolterodine, a competitive muscarinic receptor antagonist, is considered first-line therapy in patients with urinary frequency, urgency, or urge incontinence. Controlled studies demonstrate that tolterodine is more effective than placebo and as effective as oxybutynin IR in efficacy outcomes with lower drug discontinuation rates.
Tolterodine undergoes hepatic metabolism involving cytochrome (CYP) 2D6 and 3A4 isoenzymes. Therefore, elimination may be impaired by CYP 3A4 inhibitors, including fluoxetine, sertraline, fluvoxamine, macrolide antibiotics, azole antifungals, and grapefruit juice.
Tolterodine’s most common adverse effects include dry mouth, dyspepsia, headache, constipation, and dry eyes. The maximum benefit of tolterodine is not realized for up to 8 weeks after starting therapy or dose escalation.
• Tolterodine long acting (LA) offers once-daily dosing and may also take up to 8 weeks after starting therapy or dose escalation to see maximum benefit.
• Fesoterodine fumarate is a prodrug for tolterodine and is considered an alternative first-line therapy for UI in patients with urinary frequency, urgency, or urge incontinence.
• Trospium chloride IR, a quaternary ammonium anticholinergic, is superior to placebo and is equivalent to oxybutynin IR and tolterodine IR. It causes the expected anticholinergic adverse effects with increased frequency in patients 75 years or older. An extended-release product is also available. Take on an empty stomach.
• Solifenacin succinate and darifenacin are second-generation antimuscarinic agents. Both have been shown to improve quality-of-life domains. Drug interactions are possible if CYP 3A4 inhibitors are given with solifenacin succinate or CYP 2D6 or 3A4 inhibitors with darifenacin.
• Mirabegron is a β3-adrenergic agonist alternative to anticholinergic/antimuscarinic drugs for managing UUI. It has modest efficacy as compared with placebo. Hypertension, nasopharyngitis, urinary tract infection, and headache were the most common adverse effects reported. It is a moderate inhibitor of CYP2D6.
Use of other agents, including tricyclic antidepressants, propantheline, flavoxate, hyoscyamine, and dicyclomine hydrochloride, is not recommended. They are less effective, not safer, or have not been adequately studied. Selection of initial drug therapy depends on side-effect profile, comorbidities, concurrent drug therapy, and patient preference in drug delivery methods
Botulinum toxin A temporarily paralyzes smooth or striated muscle. It is approved for the treatment of refractory UUI associated with neurogenic detrusor overactivity. It is recommended by the American Urological Association as third-line in patients with idiopathic overactive bladder as an off-label use.
Adverse effects of botulinum toxin A include dysuria, hematuria, urinary tract infection, and urinary retention (up to 20%). Therapeutic and adverse effects are seen 3 to 7 days after injection and subside after 6 to 8 months. Patients with UUI and elevated postvoid residual urine volume should be treated by intermittent self-catheterization along with frequent voiding between catheterizations.
Urethral Underactivity: Stress Urinary Incontinence
Treatment of SUI is aimed at improving urethral closure by stimulating α-adrenergic receptors in smooth muscle of the bladder neck and proximal urethra, enhancing supportive structures underlying the urethral epithelium, or enhancing serotonin and norepinephrine effects in the micturition reflex pathways.
Historically, local and systemic estrogens have been the mainstays of pharmacologic management of SUI. In open trials, estrogens were administered orally, intramuscularly, vaginally, or transdermally. Regardless of the route, estrogens exerted variable effects on urodynamic parameters, such as maximum urethral closure pressure, functional urethral length, and pressure transmission ratio.
Results of four placebo-controlled comparative trials have not been as favorable, finding no significant clinical or urodynamic effect for oral estrogen compared with placebo.
α-Adrenergic receptor agonist
Many open trials support the use of a variety of α-adrenergic receptor agonists in SUI. Combining an α-adrenergic receptor agonist with an estrogen yields somewhat superior clinical and urodynamic responses compared with monotherapy.
Contraindications to these agents include hypertension, tachyarrhythmias, coronary artery disease, myocardial infarction, cor pulmonale, hyperthyroidism, renal failure, and narrow-angle glaucoma.
Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake indicated for depression and painful diabetic neuropathy, is approved in many countries for the treatment of SUI, but not in the United States. Duloxetine is thought to facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase.
Six placebo-controlled studies showed that duloxetine reduces incontinent episode frequency and the number of daily micturitions, increases micturition interval, and improves quality-of-life scores. These benefits were statistically significant but clinically modest.
Monitor patients taking concurrent CYP 2D6 and 1A2 substrates or inhibitors closely. The adverse event profile might make adherence problematic. Adverse events include nausea, headache, insomnia, constipation, dry mouth, dizziness, fatigue, somnolence, vomiting, and diarrhea.
Overflow incontinence secondary to benign or malignant prostatic hyperplasia may be amenable to pharmacotherapy