Overactive Bladder?More than a Nuisance

People who have it call it a nuisance, or worse. Overactive bladder (OAB) is a symptom syndrome of urgency with or without urge incontinence. It usually includes frequency and nocturia, which suggest lower-urinary- tract dysfunction. The OAB symptom combination suggests urodynamically demonstrable detrusor (bladder muscle) overactivity, but it can be due to other forms of urethrovesical dysfunction. The term OAB generally is used when no infection or other obvious pathology exists. OAB is not urinary incontinence, although many pharmacists believe otherwise.¹

In elderly patients, OAB often dominoes into significant social, psychological, occupational, domestic, physical, and sexual problems. Affected individuals fear lingering urine odor or accidental leakage. Low self-esteem, truncated social interaction, and infrequent sexual activity follow. As a result of OAB, many elders limit fluid intake, which concentrates urine and inadvertently compounds the problem.

Estimates of the prevalence of OAB in the United States range from 17 million to 33 million cases,^2,3 with women affected twice as often as men.4 Among community-dwelling elders, roughly 17% to 55% of women and 11% to 34% of men older than 59 years have OAB.⁴ Risk factors are listed in the Table.

Drug Treatment

Many drugs have been tried for OAB. Agents such as anticholinergic drugs or tricyclic antidepressants have side effects that are undesirable in elders (dry mouth, constipation, impaired cognitive function, electrocardiograph changes, and postural hypotension). Today, 2 agents represent first-line therapy?oxybutynin and tolterodine. Patients curious about these drugs must consider several factors:

• Symptom severity
• Success or failure with behavioral interventions
• Previous experience with particular medications
• Potential adverse effects
• Cost

Unfortunately, little evidence-based information exists to guide the decision-making process, especially if comorbidities and polypharmacy are present. Before initiating drug treatment, clinicians should identify and treat any possible or probable underlying causes of bladder dysfunction (eg, diabetes, infection, constipation). Most important, patients must realize that neither drug will cure the problem? behavioral modification is a necessary adjunct.

Oxybutynin

Oxybutynin, used to treat bladder instability for more than 30 years, inhibits acetylcholine?s muscarinic action and exerts a direct antispasmodic effect on smooth muscle, relaxing the bladder?s smooth muscle. Oxybutynin targets the bladder?s M1, M2, and M3 muscarinic receptors. Its higher affinity for muscarinic receptors in the parotid gland than in the bladder produces dry mouth, however.⁵

Oxybutynin dosage forms include an immediate-release 5-mg tablet and a 5-mg/mL syrup (various generics); extended- release (ER) tablets in 5, 10, or 15 mg (Ditropan XL, Alza); and a 3.9-mg patch (Oxytrol, Watson). The ER tablets are as effective as the immediate-release tablets but have fewer side effects.⁶ Regardless, patients may prefer the immediate- release tablets for several reasons:

• Use for intermittent dosing (eg, for symptoms only at night or prior to venturing out)
• If the patient is already stabilized on and prefers the immediate-release tablets
• If the patient cannot tolerate the side effects from the ER form
• If cost is a factor, because they are less expensive than the other forms

The immediate-release form is dosed initially at 2.5 mg up to 4 times a day. Frail patients can begin with 2.5 mg 2 to 3 times a day.⁵

The ER form of the drug is started at 5 mg once daily, increased by 5 mg after 1 to 4 weeks until the response is acceptable. The maximum dose is 30 mg/day. Patients should be counseled not to chew or crush the ER form.⁵

Oxybutynin is contraindicated in patients with urinary and gastric retention or uncontrolled narrow-angle glaucoma. Hepatic or renal impairment, gastrointestinal (GI) obstructive disorders, bladder outflow obstruction, ulcerative colitis, intestinal atony, myasthenia gravis, and gastroesophageal reflux are reasons for caution.⁵

Oxybutynin?s side effects are usually dose-related, with dry mouth reported most often. One study randomized 226 patients (mean age, 58.8 years) to receive ER oxybutynin or immediaterelease oxybutynin. The study found that target symptom improvement was comparable, but patients taking ER oxybutynin were less likely to complain of moderate-to-severe dry mouth.⁶ Constipation, somnolence, dizziness, tachycardia, blurred vision, and worsening of gastroesophageal reflux also are common. Oxybutynin may worsen cognitive impairment.⁵

The Patch

The newly developed oxybutynin patch delivers the drug continuously over 3 to 4 days. Patients should be advised to apply the patch to clean, smooth, dry skin on the buttocks, abdomen, or hip every 3 to 4 days, rotating sites. The patch causes fewer systemic side effects than oral oxybutynin. Common adverse events include application pruritus (16.8%), dry mouth (9.6%), application-site erythema (5.6%), and vesicles (3.2%). In addition, 2% to 4% of patients have reported diarrhea, dysuria, constipation, and abnormal vision.⁷

Tolterodine

Tolterodine (Detrol, Pharmacia), a muscarinic receptor antagonist released in 1998, inhibits detrusor muscle contraction without muscarinic- receptor-subtype specificity.⁸ Tolterodine targets bladder muscarinic receptors, with less binding affinity to parotid gland receptors. It reduces incontinence and micturition frequency, and it increases the urine volume voided per micturition.^9,10

Available in a 1- or 2-mg tablet (Detrol) or as a 2- or 4-mg ER capsule (Detrol LA), the manufacturer recommends 2 mg twice daily for the immediate- release drug, or 4 mg of the ER once daily. Patients with significant renal impairment (creatinine clearance between 10 and 30 mL/min) or hepatic insufficiency should start at half the dose. Advise patients to take ER tolterodine with liquids and to swallow it whole; it can be taken without regard to food.⁸

Tolterodine is contraindicated in patients with urinary or gastric retention or uncontrolled narrow-angle glaucoma. It should be used with caution in patients with clinically significant bladder outflow obstruction or GI disorders, or patients currently being treated for narrow-angle glaucoma. Although safe with most drugs, including diuretics and warfarin, tolterodine has 2 significant interactions:

• If CYP3A4 inhibitors (ie, azole antifungals, macrolide antibiotics, cyclosporine, and vinblastine) are given concurrently, the tolterodine dose should be reduced by 50%
• Fluoxetine, a CYP2D6 inhibitor, can increase tolterodine levels^8,11,12

Tolterodine?s adverse effects also are dose-related, with dry mouth occurring in approximately 23% of patients taking ER tolterodine and about 30% of patients taking immediate-release tolterodine. Constipation, dyspepsia, and dry eyes are common. Patients sometimes report fatigue, vision abnormalities, somnolence, anxiety, sinusitis, and dysuria with both dosage forms. Worsening of cognitive impairment and delirium can occur.^11,12

Future Directions

Current drugs to treat OAB are nonselective. Two investigational agents currently in clinical trials, darifenacin and solifenacin, specifically antagonize the M3 receptor and may be bladder-selective.¹³ With all agents, current and future, dosing should be individualized.

Editor?s Note: Dr. Wick?s book, Supervision: A Pharmacy Perspective, was published in March 2003. This book is available from the American Pharmacists Association on-line (www.pharmacist. com) or via a toll-free telephone call (800- 878-0729).

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