Urinary incontinence (UI) Niazy B Hussam Aldin PhD Clinical Pharmacy

Defination Urinary incontinence (UI) is the complaint of involuntary leakage of urine

Pathophysiology 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 opening of the urethra concomitant with a volitional bladder contraction. • 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.

Diagnosis DIAGNOSIS • Patients should undergo a 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.

NONPHARMACOLOGIC TREATMENT • Nonpharmacologic treatment (e.g., lifestyle modifications, toilet 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 non operative therapy be proven undesirable or ineffective.

PHARMACOLOGIC TREATMENT • The choice of pharmacologic therapy (Table 84-3) depends on the type of UI. • Pharmacologic therapies should be combined with non pharmacologic therapies.

Urethral Underactivity: Stress Urinary Incontinence • The goal of treatment of SUI is to improve urethral closure by stimulating α-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.

Estrogens • Historically, local and systemic estrogens have seen 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.

α-Adrenergic Receptor Agonists • 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 • 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.

Bladder Overactivity: Urge Urinary Incontinence • The pharmacotherapy of first choice for UUI is anticholinergic/antispasmodic drugs, which antagonize muscarinic cholinergic receptors. Oxybutynin • Oxybutynin immediate-release (IR) has been 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 antimuscarinic 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).

Tolterodine • 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 micturition 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.

Other Pharmacologic Therapies for Urge Urinary Incontinence • 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.

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 “uroselective” in preclinical studies

Other agents, including tricyclic antidepressants, propantheline, flavoxate, hyoscyamine, and dicyclomine hydrochloride, are less effective, not safer, or have not been adequately studied

EVALUATION OF THERAPEUTIC OUTCOMES Total elimination of UI signs and symptoms may not be possible. Therefore, realistic goals should be established for therapy. • In the long-term management of UI, the clinical symptoms of most distress to the individual patient need to be monitored. • Survey instruments used in UI research along with quantitating the use of ancillary supplies (e.g., pads) can be used in clinical monitoring