Urinary incontinence is a common problem among elderly individuals. The updated (March 1996) Agency for Health Care Policy and Research (AHCPR) guidelines on managing acute and chronic urinary incontinence indicate that for persons over the age of 60 living in the community, the prevalence of urinary incontinence can be as high as 15%-35%. Women are twice as likely as men to suffer from the condition.1
Caregivers of the homebound elderly report that approximately 53% are incontinent, with urinary incontinence ranking as one of the 10 leading diagnoses for homebound individuals. This condition ranks first in total charges to Medicare for nursing services per person served in home care programs.
Also, urinary incontinence is a leading cause of institutionalization among the elderly, with at least 50% of nursing facility admissions listing a diagnosis of incontinence.1
In addition to the obvious psychological effects on the resident, care of these patients requires additional staff time and training. Consequences of urinary incontinence, including immobility and the development of pressure ulcers, may result in hospitalization or other added costs.
In fact, the latest AHCPR guidelines put the direct cost of caring for incontinence in nursing facility patients at $5.2 billion.1 It is, therefore, of primary importance that the consultant pharmacist have a thorough understanding of the various types of incontinence, the drugs that may cause or exacerbate incontinence, and the appropriate pharmacologic management of this problem.
In order to understand the effects of medications used in treating the various types of urinary incontinence, it is necessary to understand the innervation of the bladder and urethral sphincters. The detrusor muscle of the bladder contracts due to parasympathetic stimulation via acetylcholine, and relaxes due to sympathetic stimulation of beta-adrenergic receptors. Sympathetic stimulation of alpha-adrenergic receptors by norepinephrine causes contraction of the internal involuntary urethral sphincter.
The external urethral sphincter, innervated by the somatic nervous system, allows for the voluntary control of urination. As the bladder fills, signals are sent to the cortical center of the brain, creating the urge to urinate. Urination begins when the cortical center of the brain triggers inhibition of sympathetic impulses and stimulates the parasympathetic system, so that the internal and external sphincters relax and the detrusor muscle of the bladder contracts.2,3
Aging causes a number of changes in urinary tract physiology, all of which can affect continence. These changes include:
In addition, with age, the kidneys become less efficient at concentrating urine, causing an increase in urine volume (See Table 1).2,3
| TABLE 1. Age-Associated Changes in Bladder Functiona Decreased bladder capacity Shorter time between awareness of the need to void and symptomatic urgency Incomplete emptying and increased residual volume Decreased flow rate Increased number of involuntary bladder contractions (detrusor instability) Decreased strength of pelvic support muscles Atrophic changes in urethral lining and bladder trigone in postmenopausal women2 aAdapted from reference 2. |
Urinary incontinence is especially prevalent in women. This is due in part to the presence of estrogen receptors throughout the urethra and bladder. In postmenopausal women, estrogen deficiency causes atrophy of the urethral epithelium, resulting in decreased efficiency of the urethral sphincters. In addition, age-related loss of tone in the pelvic floor muscles (which also may result from factors such as childbirth and obesity) can contribute to incontinence in women.
Because of the manner in which the urinary tract is innervated, any medication that affects alpha-adrenergic, beta-adrenergic, or cholinergic receptors may also affect continence. (Table 2) lists drugs the consultant pharmacist should suspect as potential iatrogenic causes of incontinence.
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Table 2. Drugs Associated with Urinary Incontinencea Alpha-adrenergic agonists (sympathomimetic decongestants) Alpha-adrenergic antagonists (prazosin, terazosin, phenoxybenzamine) Anticholinergics and agents with anticholinergic activity Antipsychotics/neuroleptics Bromocriptine Calcium-channel blockers Clonazepam Diuretics Ethanol Lithium Metoclopramide Misoprostol Phenytoin Sedatives/hypnotics Skeletal muscle relaxants (baclofen, dantrolene) Sympatholytics (methyldopa, reserpine, guanethedine) aAdapted from reference 3. |
Stress incontinence is caused by the inability of the internal urethral sphincter to remain closed in response to increased intra-abdominal pressures such as those that occur with coughing or sneezing. In postmenopausal women, in whom intrinsic sphincter deficiency is the suspected cause of stress incontinence, estrogen replacement therapy (ERT) may be a useful first-line approach to management of this problem. It should be noted, however, that it may take 6 to 12 weeks for the patient to experience the positive effects of ERT.
Alpha-adrenergic agonists, such as phenylpropanolamine and pseudoephedrine, may also prove useful in increasing muscle tone in the bladder and urethra.
Conversely, stress incontinence may be exacerbated in patients taking alpha-adrenergic blockers. The concomitant use of phenylpropanolamine and estrogen may produce a synergistic effect, as estrogen increases the number and/or responsiveness of alpha-adrenergic receptors in the bladder.2,3
| Table 3. Pharmacologic Treatment of Urge and Stress Incontinence | |
|---|---|
AgentUrge Incontinence Oxybutynin Propantheline Dicyclomine hydrochloride Flavoxate Imipramine and doxepin Calcium-channel blockers Stress Incontinence Phenylpropanolamine Estrogens Equivalent |
Dose2.5-5 mg t.i.d.-q.i.d. 7.5-30 mg 3-5 times/day, on an empty stomach; higher doses may be required for greater efficacy 10-25 mg t.i.d. N/A Initial 10-25 mg q.d.-t.i.d.; total daily dose 25-100 mg. Less frequent use possible. N/A 25-75 mg b.i.d. in sustained-release form Equivalent to 0.3-1.25 mg of conjugated estrogen; orally or up to 1.25 mg of estrogen topically |
Urge incontinence, the most common type of incontinence, results from the instability or hypermotility of the detrusor muscle. Premature detrusor contractions may occur spontaneously or be triggered by coughing or sneezing. This similarity to stress incontinence can make an accurate diagnosis of urge incontinence difficult. In addition, several conditions, including tumors, diverticulitis, and fecal impactions, cause increased irritability of the bladder.
Caffeine, beta-blockers, and cholinergic agents are also causes of increased bladder irritability. Because the premature detrusor contractions may also be due to disturbances of cerebral cortical control mechanisms, dosages of sedatives, hypnotics, and neuroleptics should also be reduced, if possible.2,3
Medications frequently used for the treatment of urge incontinence are listed in (Table 3). Drugs with a combination of anticholinergic and antispasmodic properties, such as oxybutynin and dicyclomine, are the most widely used agents and improve continence in the majority of patients. Because these agents have a rapid onset of action, their use should be considered a therapeutic failure if no improvement is seen within the first few days of therapy.
The antidepressants doxepin and imipramine have anticholinergic effects, as well as alpha- and beta- adrenergic stimulant effects. Benefit from these agents may take several weeks. Current research indicates that calcium channel blockers and beta agonists (such as terbutaline) may be useful, as well. However, anticholinergic effects of many of these medications may limit their use in the elderly. In addition, these agents should be used cautiously in patients with dementia, as they can increase confusion.2
Overflow incontinence may be caused either by hypotonicity of the detrusor muscle or obstruction of the bladder outlet. Pharmacologic treatment for detrusor hypotonicity is relatively ineffective, although the cholinergic agonist bethanechol and beta-blockers have proven effective in some patients. More important, medications with anticholinergic effects or beta-adrenergic effects can exacerbate overflow incontinence due to hypotonicity and should be discontinued if possible.
| Table 4. Clinical
Pharmacokinetics/ Pharmacology of Tolterodinea Half-life: 2-3 hours Systemic clearance: 30 liters/hour Volume of distribution: 110 liter Major metabolite: hydroxylation of the 5-methyl group, mediated by cytochrome P450 2D6; results in active metabolite aAdapted from reference 4. |
Currently in development are two new agents for the treatment of incontinence: tolterodine (Detrusitol), being developed by Pharmacia & Upjohn; and duloxetine, under development by Eli Lilly. Tolterodine has been shown to be a bladder-selective muscarinic receptor antagonist that can be used to treat urge incontinence. Because of its selectivity for the bladder, it has been postulated that tolterodine will prove beneficial in decreasing uncontrolled detrusor contractions without the classic anti-muscarinic side effects of the agents (such as oxybutynin) currently in use.4 Table 4 lists some of the pharmacokinetic data available for tolterodine. Pharmacia & Upjohn submitted a new drug application to the Food and Drug Administration in March of this year. This NDA is based on clinical trials involving more than 2,600 patients in the United States, Canada, Australia, and Europe.
Eli Lilly's new agent, duloxetine, is currently in Phase II trials for the treatment of stress and urge incontinence. Duloxetine is reported to inhibit reuptake of serotonin and norepinephrine, thereby increasing bladder storage capacity. If clinical trials continue at the current pace, it is expected that duloxetine will undergo Phase III trials in 1998.