A Pharmacist's Guide to Treatment of Urinary Incontinence

Urinary incontinence (UI) can be defined as an involuntary loss of urine that results in physical, hygienic, or psychological distress.⁽¹⁾ In this country, UI occurs in 10% to 35% of adults and in about half of all of nursing home residents.⁽²⁾ Annually, more than $16 billion are spent treating an estimated 13 million Americans affected by UI.⁽³⁾ Up to 50% of patients with UI do not discuss the disorder with their physicians, despite the existence of effective treatments.^(4,5) Incontinence is both a medical and psychosocial disorder with serious complications for the patient and the family. These include a loss of independence, low self-esteem, and impairment of social and sexual activities.

Types of UIUI may be broadly classified as acute or persistent (chronic) incontinence. Acute incontinence is defined as a sudden onset of urine leakage due to an acute precipitating condition,⁽⁴⁾ such as epilepsy, delirium, acute infection, sudden immobility, and urinary retention with overflow. Certain drugs have been associated with UI, including diuretics, sedative/hypnotics and paradoxically, phenothiazines (eg, thi-oridazine).⁽⁴⁾ Other factors associated with polyuria may contribute to UI, including excessive caffeine, fluid, and alcohol intake, and hyperglycemia.

Persistent IncontinenceUrge incontinence (?overactive bladder?) is the most common type of incontinence in the elderly.⁽³⁾Associated with an involuntary loss of urine and a strong sensation to void, its symptoms include urgency, frequency, dysuria, and nocturia. It is caused by detrusor instability, hyperactivity, and involuntary sphincter relaxation.

Stress incontinence is caused by urethral hypermobility with anatomic changes and defects, as well as intrinsic urethral sphincter deficiency. It is common in middle-aged, post-menopausal women, and is associated with urethral sphincter failure with increased abdominal pressure. Symptoms often include a small amount of urine loss during coughing, sneezing, or physical activity, with a continuous leaking at rest or with minimal exertion.

Overflow incontinence is caused by hypotonic detrusor muscle, benign prostatic hyperplasia, urethral strictures, urogenital prolapse, and surgical overcorrection of urethral stricture. It is common in men with overflow tract obstruction due to prostatic hyperplasia or in women with large cystoceole with perineal sensation and sacral reflexes intact. It is associated with bladder distension. Symptoms in clude frequent dribbling, urge, stress symptoms, urgency, and frequency.

Detrusor hyperflexia with impaired bladder contractility (DHIC) has the same symptoms as urge inconti nence, but with a large postvoid resid ual urine volume.

Reflex incontinence is caused by a decreased bladder compliance with a risk of vesicouretral reflux. This may occur secondary to radiation, inflam matory cystitis, and pelvic surgery Some signs include postvoid inconti nence and continual incontinence with bladder hypersensitivity.

Functional incontinence is due to an inability to get to the bathroom on time because of a physical or cognitive impairment.

Iatrogenic incontinence is sometimes seen in elderly patients given a new prescription for a diuretic; this may lead to urge incontinence. Similarly, alcohol, caffeine, and lithium may be associated with polyuria and con tribute to UI.

Treatment Overview

The capacity of the urinary bladder usually is between 300 and 500 mL The goal of drug therapy is to help increase the volume of urine at low intravesical pressure and prevent invol untary bladder contractions with maintenance of bladder function. Drug therapy will decrease the outflow obstruction, inhibit bladder contractil ity, decrease sensory input, and increase bladder capacity.

Drugs can be used with behavioral treatment, such as bladder training and exercises to manage stress, urge, and mixed incon tinence, as well as with a voiding schedule. Exercises help build pelvic muscle strength to reduce symptoms Premenopausal women who have UI can use weights and pelvic muscle exercises to treat the symptoms Urological consultation and surgery is appropriate in patients with UI secondary to anatomic abnormalities.

Several classes of drugs have been used to treat UI, including antichol-inergics (eg, tolterodine) and tricyclic antidepressants (eg, imipramine). Cholinergic stimulation causes the urge to void by contracting the bladder through the cholinergic reflex arc of the sacral micturition center.

Anticholinergics should be used as first-line therapy for UI secondary to detrusor instability. Oxybutynin (Ditropan) and tolterodine (Detrol) are the most widely used agents. Other agents, such as propantheline (Pro-Banthine), tricyclic antidepres-sants, and dicyclomine (Bentyl), can be used as alternative treatments. Estrogen can be beneficial for post-menopausal women with UI. While phenylpropanolamine (PPA) has previously been used to treat stress incontinence, the FDA has recommended the removal and discontinued marketing of PPA products due to a public health advisory concerning the risk of hemorrhagic stroke associated with its use. Some physicians use pseudoephedrine in patients with stress incontinence and urethral sphincter weakness as an alternative to PPA; however, there is little evidence to support its efficacy. Other drugs with questionable and unproven efficacy in UI include nifedi-pine and indomethacin.

Anticholinergic DrugsPharmacologic treatment of UI targets peripheral, muscarinic receptors involved in the control of bladder contraction with agents such as oxybu-tynin and tolterodine. Frequency and urgency are usually caused by uncontrolled bladder contractions during the filling phase due to detrusor instability mediated by muscarinic receptors. Anticholinergic drugs suppress involuntary bladder contractions in urinary retention by inhibiting the binding of acetylcholine to the muscarinic receptors in the detrusor muscle of the bladder. These muscarinic receptors are also found in the salivary glands. Therefore, anticholinergics can decrease saliva production causing dry mouth, which can lead to secondary oral mucosal disease and may interfere with compliance with prescribed medications.

Since muscarinic receptors exist in the central nervous system (CNS), anti-cholinergic drugs that cross the blood-brain barrier cause cognitive impairment and other CNS side effects.

Tolterodine is a muscarinic receptor antagonist with the same potency as oxybutynin at receptors located in the bladder; it is eight times less potent at the parotid gland.⁽¹⁾ In a recent meta-analysis of four clinical trials, Harvey, et al compared the efficacy and safety of tolterodine with oxybutynin in patients with urge UI.⁽¹⁾ The doses compared in these trials were tolterodine 2 mg bid or oxybutynin 2.5 to 5 mg tid. This analysis demonstrated that oxy-butynin was slightly more effective than tolterodine in decreasing the number of daily incontinent episodes and increasing the mean urine volume per micturition. However, tolerability was better with tolterodine. Tolterodine was also associated with fewer treatment withdrawals due to adverse effects.⁽¹⁾ Other studies have demonstrated that 18% of patients treated with antimuscarinic agents for overactive bladder remain on treatment after 6 months.⁽⁶⁾ The most common reason for stopping treatment is because of adverse anticholinergic effects, such as dry mouth.

A study done by Malone-Lee et al compared the efficacy and tolerability of 10-week treatment with tolterodine and oxybutynin in patients 50 years and older with overactive bladder and symptoms of UI.⁽⁷⁾ The study showed that tolterodine was as effective as oxybutynin with respect to urgency, frequency, and urge incontinence, but the tolerability of tolterodine was greater than oxybutynin. Both oxybu-tynin and tolterodine are tertiary amines that cross the blood-brain barrier. However, tolterodine is 30 times less lipophilic than oxybutynin, and its CNS activity is limited; other clinical trials have confirmed this.⁽⁸⁾ A study by Chancellor et al compared the saliva output (measurement of dry mouth) with oxybutynin (both immediate release [IR] and extended release [ER]) vs tolterodine.⁽⁹⁾ ER oxybu-tynin and tolterodine were shown to have less effects on saliva output than the IR formulations. Both ER oxybu-tynin and tolterodine are better tolerated than IR oxybutynin.

The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study compared the efficacy and tolerability of 12-week treatment with tolterodine or ER oxybu-tynin in patients with overactive bladder.⁽¹⁰⁾ ER oxybutynin was shown more effective on urge incontinence, total incontinence, and micturition frequency episodes. Both treatment groups had similar rates of dry mouth and other anticholinergic side effects. ER tolterodine given once daily was effective and well tolerated for the treatment of overactive bladder.⁽¹¹⁾ In a double-blind, randomized, placebo-controlled trial, patients received tolterodine ER 4 mg qd (n = 507), tolterodine IR 2 mg bid (n = 514), or placebo (n = 508). Both tolterodine ER and IR significantly reduced the mean number of urge incontinence episodes per week when compared to placebo. Decreases in micturition and pad usage were also significant for both formulations when compared to placebo. The most common side effects of both formulations included dry mouth and constipation.

Tolterodine is metabolized by cytochrome P-450 and isoforms 2D6 and 3A4. In patients deficient in the 2D6 isozyme, the clearance of toltero-dine decreased by 60% when keto-conazole, an enzyme inhibitor, was coadministered.⁽¹²⁾ Thus, caution should be exercised when patients receiving tolterodine are prescribed potentially interacting drugs, such as itraconazole, miconazole, erythromycin, clarithro-mycin, and cyclosporine. This includes monitoring patients for excessive dry mouth and urinary retention.

EstrogenIn a meta-analysis, Fantl et al concluded that estrogen therapy subjectively improves UI in postmeno-pausal women.⁽¹³⁾ However, considerable variability exists with respect to diagnostic criteria, therapeutic interventions, and outcome assessments used in these studies.

Tricyclic Antidepressants

While no antidepressants are FDA-approved for UI, imipramine can be considered as an alternative to anti-cholinergic agents. It has been modestly effective at 25 to 75 mg/day in elderly patients and in women with UI associated with spontaneous unstable detrusor contraction.(14)Doxepin has also been used.⁽³⁾

Patient Counseling

Pharmacists involved in the care of patients with UI should take a thorough medication history to rule out any iatrogenic causes, such as diuretic use and excessive alcohol, caffeine, or fluid intake. Patients should be reassured of the safety and efficacy of drug therapy for UI, especially anticholin-ergic agents. Help patients understand the symptoms of overactive bladder, which include urinary urgency (a strong and sudden desire to urinate), frequent urination day and night, and urge incontinence (accidental loss of urine caused by a sudden and unstoppable urge to urinate). Patients receiving tolterodine or oxybutynin can be counseled to expect the development of dry mouth as the main side effect. The long-acting formulations of these drugs increase patient compliance and decrease the chance for anti-cholinergic side effects. Patients also can be referred for bladder training, and they should be counseled that exercises help build pelvic muscle strength to reduce symptoms. A variety of information and help is also available. Refer patients to one or more of the resources listed in Table 1. Patients who do not respond to adequate trials of anticholinergic drugs at therapeutic dosages should be referred to a urologist for further evaluation and management.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. E. McCardell, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: emccardell@pharmacytimes.com.