Urinary incontinence (UI) is the complaint of involuntary loss 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. Normal bladder emptying occurs with a decrease in urethral resistance concomitant with a volitional contraction of the bladder or detrusor muscle.
Acetylcholine is the neurotransmitter that mediates both volitional and involuntary contractions of the bladder. 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 antimuscarinic therapy is anti-M3 based.
UI occurs as a result of overfunctioning or underfunctioning 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 overactivity is known as urge UI (UUI) and is associated with increased urinary frequency, urgency, and urge incontinence. The detrusor muscle is overactive and contracts inappropriately during the filling phase.
Urethral overactivity 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 overactivity include benign prostatic hypertrophy ; prostate cancer and, in women, cystocele formation or surgical overcorrection after UI surgery.
Mixed incontinence includes the combination of bladder overactivity and urethral underactivity.
Functional incontinence is not caused by bladder- or urethra-specific factors but rather occurs in patients with conditions such as cognitive or mobility deficits.
Signs and symptoms of UI depend on the underlying pathophysiology. Patients with SUI generally complain of urinary leakage with physical activity, whereas those with UUI complain of nocturia and nocturnal incontinence.
Urethral overactivity and/or bladder underactivity 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.
Patients should undergo complete medical history with assessment of symptoms, 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.
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. Urinalysis and urine culture should be performed to rule out urinary tract infection.
For urethral overactivity and/or bladder underactivity, digital rectal exam or transrectal ultrasound should be performed to rule out prostate enlargement. Renal function tests should be performed to rule out renal failure.
Nonpharmacologic treatment (e.g., life-style modifications, scheduling regimens, pelvic floor muscle rehabilitation) is the chief form of UI management at the primary care level.
Surgery rarely plays a role in the initial management of UI but can be required for secondary complications (e.g., skin breakdown or infection). Otherwise, the decision to surgically treat symptomatic UI requires that lifestyle compromise warrants an elective operation and that nonoperative therapy be proven undesirable or ineffective.
Stress Urinary Incontinence (SUI)
The goal of treatment of SUI is to improve urethral closure by stimulating Î±-adrenergic receptors in the 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.
Many open trials support the use of a variety of Î±-receptor agonists in SUI. Combining an Î±-receptor agonist with an estrogen yields somewhat superior clinical and urodynamic responses compared with monotherapy with either agent alone.
Contraindications to Î±-receptor agonists 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 expected to become first-line therapy for SUI. 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.
To avoid drug interactions, clinicians should be careful when administering duloxetine with substrates or inhibitors of cytochrome P450 (CYP450) isoenzymes 2D6 and 1A2.
The adverse-event profile might make adherence problematic. Adverse events include nausea, headache, insomnia, constipation, dry mouth, dizziness, fatigue, somnolence, vomiting, and diarrhea.
Urge Urinary Incontinence (UUI)
The pharmacotherapy of first choice for UUI is anticholinergic/antispasmodic drugs, which antagonize muscarinic cholinergic receptors.
Oxybutynin immediate-release (IR) has been the drug of first choice for UUI and the â€œgold standardâ€ against which other drugs are compared. Financial considerations favor generic oxybutynin IR.
Approximately 25% of patients discontinue oxybutynin IR because of adverse effects due to antimuscarinic effects (e.g., dry mouth, constipation, vision impairment, confusion, cognitive dysfunction, and tachycardia), Î±-adrenergic inhibition (e.g., orthostatic hypotension), and histamine H1 inhibition (e.g., sedation, and weight gain).
Oxybutynin IR is best tolerated when the dose is gradually escalated from less than or equal to 2.5 mg twice daily to 2.5 mg three times daily after 1 month. Oxybutynin IR can be further increased in 2.5-mg/day increments every 1 to 2 months until the desired response, maximum recommended dose of 5 mg three times daily, or maximum tolerated dose is attained.
Oxybutynin extended-release (XL) is better tolerated than oxybutynin IR and is as effective in reducing the number of UI episodes, restoring continence, decreasing the number of micturitions per day, and increasing urine volume voided per micturition. Oxybutynin XL has some efficacy and safety advantages over tolterodine long-acting (LA); however, these findings are based on open-label studies.
The maximum benefit of oxybutynin XL is not realized for up to 4 weeks after starting therapy or escalating the dose.
Oxybutynin transdermal system (TDS) 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.
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 decreasing the number of daily micturitions and increasing the volume voided per micturition. However, most studies have not shown a decrease in the number of daily UI episodes as compared with placebo.
Tolterodine undergoes hepatic metabolism involving CYP450 2D6 and 3A4 isoenzymes. Therefore, elimination can be impaired by CYP450 3A4 inhibitors including fluoxetine, sertraline, fluvoxamine, macrolide antibiotics, imidazoles, and grapefruit juice.
Tolterodine’s most common adverse effects are dry mouth, dyspepsia, headache, constipation, and dry eyes. Tolterodine is better tolerated than oxybutynin IR, and dry mouth occurs less often with tolterodine LA than with tolterodine IR.
Other Pharmacologic Therapies for UUI
Trospium chloride, a quaternary ammonium anticholinergic, is superior to placebo and is equivalent to oxybutynin IR and tolterodine IR. However, clinical studies are limited by their focus on cystometric rather than clinical endpoints, small absolute benefits compared with placebo, and lack of comparisons with LR formulations.
Trospium chloride causes the expected anticholinergic adverse effects. The positive electrical charge could prevent trospium chloride from crossing the blood-brain barrier, but there are no data supporting the hypothesis that the drug is less neurotoxic than non-quaternary ammonium anticholinergics.
Solifenacin succinate and darifenacin are antagonists of M1, M2, and M3 muscarinic cholinergic receptors. These antagonists do not offer significant advances over other anticholinergics despite being â€œuroselectiveâ€ in preclinical studies. Both behave like nonselective anticholinergic in humans, causing dry mouth and other anticholinergic effects.
Drug interactions are possible if CYP450 inhibitors are given with solifenacin succinate (metabolized by 3A4 isoenzyme) or darifenacin (metabolized by 2D6 and 3A4 isoenzymes).
Other agents including tricyclic antidepressants, propantheline, flavoxate, hyoscyamine, and dicyclomine hydrochloride are less effective, not safer, or have not been adequately studied.
Patients with UUI and elevated postvoid residual urine volume should be treated by intermittent self-catheterization along with frequent voiding between catheterizations.