Can Bladder Anticholinergics Be Used Long Term?

Karen Shapiro, PharmD, BCPS

Disclosures

April 23, 2009

Question

What are the concerns related to using long-acting or extended-release anticholinergic agents over long time periods? Are other medications available that would better ameliorate urinary incontinence?

Response from Karen Shapiro, PharmD, BCPS
Clinical Pharmacist, Arcadian Health Plan, San Dimas, California

Bladder anticholinergic agents tolterodine and oxybutynin work by blocking the binding of acetylcholine at bladder muscarinic receptors. Acetylcholine stimulates muscarinic receptors, resulting in contraction of the bladder detrusor muscle and a sudden urge to urinate.[1] Bladder anticholinergics are used both short and long term, but many studies have found high rates of patient discontinuation.[2] With longer use, the discontinuation rate increases.[3] The reasons for discontinuation require further investigation[3] but may be related to side effects or cost.[4] Clinicians should consider these factors in addition to advanced age, comorbidities, and potential drug-drug interactions when prescribing long-term bladder anticholinergics for their patients.

Anticholinergic side effects are common with these agents and include dry mouth, constipation, headache, and blurred vision. Clinicians should ensure that patients are counseled regarding measures to prevent or relieve these side effects.

A primary concern with long-term use of bladder anticholinergics is their effect on cognitive function, which typically declines with age and with neurologic disease such as dementia. Concurrent use of drugs such as the bladder anticholinergics can intensify this decline. Regrettably, the cholinesterase inhibitors (CIs) used to treat dementia can also worsen incontinence,[5] requiring treatment with both classes of drugs.[6] A recent study showed a more rapid functional decline in higher-functioning dementia patients taking both a CI, such as donepezil, with oxybutynin or tolterodine vs those taking a CI alone.[6]

In addition, drug-drug interactions may occur with the anticholinergic agents. When entering a prescription for an anticholinergic agent for urinary incontinence, the medication profile should be scanned for drugs with anticholinergic properties that the patient is already taking. These include benzodiazepines, psychiatric agents (including antipsychotics, hypnotics, and normal-to-high doses of tricyclic antidepressants), skeletal muscle relaxants, antihistamines, and anticonvulsants. In addition, the profile should be screened for agents that cause constipation (such as opioid analgesics, verapamil, and iron supplements) and agents required for volume control (such as diuretics) that could possibly be reduced or discontinued. When this is not possible, the risk for additive side effects should be evaluated. Centrally acting anticholinergics (such as benztropine and trihexyphenidyl) are sometimes used for psychiatric conditions and to treat early (tremor-predominant) Parkinson's disease, except in the elderly, for whom they are considered "do-not-use" drugs. Using an anticholinergic approved for incontinence along with one of the centrally acting agents would be considered polypharmacy and present an unreasonable risk to the patient.

With long-term use, changes in the patient's organ function may necessitate a dose adjustment of the bladder anticholinergic agent. For example, the maximum recommended dose of tolterodine is 2 mg/day in the presence of significant hepatic or renal dysfunction.[7] The clinician should monitor hepatic and renal function closely and adjust doses as necessary.

Immediate-release oxybutynin is available as a generic product and is a frequent choice of formularies. The longer-acting oral formulation of oxybutynin (Ditropan XL®, often included in formularies) and the transdermal patch (Oxytrol®, Ortho-McNeil Pharmaceutical, Inc., Titusville, New Jersey) have simpler dosing regimens and cause fewer side effects.[2] The flip side is that they are more expensive. The longer-acting formulation of tolterodine (Detrol® LA, Pfizer, New York, NY) has fewer side effects than the shorter-acting version,[2] but pricing is not much different. Generic tolterodine will not be available in the United States until at least 2012.

Three new anticholinergics, solifenacin, darifenacin, and trospium, have different side effect profiles and may be alternatives to tolterodine and oxybutynin. The M3 receptor-specific agents, darifenacin and solifenacin, may have the least effect on cognitive function. Unfortunately, the M3 receptor is also prevalent in the mouth and gut wall, which is why dry mouth and constipation remain side effects. Darifenacin is contraindicated in the presence of severe constipation, ulcerative colitis, and myasthenia gravis.[8]

There are no other drug classes for the treatment of urinary incontinence. Pelvic floor muscle training is often recommended for the management of incontinence. Some women will improve with pelvic exercise alone; others require both drugs and exercises to control urge incontinence. Pelvic floor exercises are easy to do the wrong way. Patients must be instructed to perform these exercises with proper technique. The Mayo Clinic Website[9] has simple instructions for both exercises and bladder training, which may also be helpful. Scheduled toilet trips, every 2-4 hours, can reduce incontinence episodes. Avoiding acidic foods, which can cause bladder irritation, and reducing caffeine and alcohol intake may also help.

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