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PUBLISHED JUNE 19, 2007

Urinary Incontinence
Treatment Update with a Focus on Pharmacological Management

George DeMaagd, PharmD, BCPS

Professor of Pharmacy Practice, Ferris State University
Big Rapids, Michigan

US Pharm. 2007;32(6):34-44.

Urinary incontinence (UI) is best defined as a variety of abnormalities of the urinary

tract that result in the inability to experience normal micturition, leading to involuntary
loss of bladder control. Approximately 40% of community-dwelling elderly and
hospitalized patients are afflicted with this disorder.1-3 Sixty percent of nursing home
patients experience this disorder, and it is often the reason for their admittance.4 Due
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to the social stigma associated with UI, the actual incidence in the community may
be underestimated. Urinary incontinence may be associated with significant medical
complications, creating issues for both patients and caregivers.1,5,6 The economic
impact that results from UI influences both direct and indirect costs, placing a
significant burden on the health care system.7,8

CAUSES OF URINARY INCONTINENCE

The causes of urinary incontinence are numerous and may involve age-related
changes in the bladder and urethra, including declines in outlet resistance in females
and prostate enlargement in males. Causes may also be secondary to a variety of
cerebral insults or diseases, including cerebrovascular disease (strokes), spinal cord
lesions, Alzheimer's disease, and Parkinson's disease. Reversible causes are
numerous and include urinary tract infections, stool impaction, and numerous other
triggers, described by the acronym DIAPPERS in Table 1.9-14 Numerous medication
and medication classes can cause or exacerbate an existing incontinence and are
described in Table 2 .12,13 Pharmacists should be aware of these potential disease–
drug interactions when monitoring their patients' drug therapy.

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OVERVIEW OF THE ANATOMY AND PHYSIOLOGY OF THE BLADDER

A basic understanding of the bladder's anatomy and pathophysiology is important in
order to understand the various UI types and their pharmacological
management.11,14 Figure 1 describes the anatomy and physiology associated with
bladder function, including the detrusor muscle in the bladder body and the internal
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and external sphincters, along with their nervous system connections. The bladder
fills when sympathetic nervous system control results in a relaxed detrusor muscle
and closed sphincters at the bladder outlet. When the bladder reaches a certain
volume (200-400 mL), signals move from the spinal cord to brain centers, resulting in
the sensation of urge. During voiding, the parasympathetic nervous system releases
acetylcholine, which acts on the bladder detrusor smooth muscle to create
contractions, and, concurrently, the sympathetic nervous system and somatic
systems allow the sphincters to open. The result of these complex processes is the
release of urine (micturition) from the bladder. 14-18

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DIAGNOSIS AND TREATMENT OVERVIEW

The evaluation and diagnosis of UI requires a complete medical examination to rule
out reversible causes and may require the participation of physicians trained in
urological evaluation.13 Correct diagnosis is important since drugs utilized for one
incontinence type may exacerbate other types. 18,19 From a pharmacist's perspective,
a good understanding of the medications used to treat incontinence and the
medications (Table 2) that may exacerbate this disorder are important.9-13 In

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addition, since many urinary incontinent patients are elderly, drug use can be
challenging and requires an understanding of the pharmacokinetic and
pharmacodynamic changes that occur in this population.20
CLASSIFICATION OF INCONTINENCE
The various types of UI include those listed in Table 3, although many patients may
experience mixed etiologies. This article will provide an overview of the three major
types of UI and their treatments, including urge, stress, and overflow types.6,13,21-26

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URGE INCONTINENCE
Urge UI is the most common cause of incontinence in the elderly and is best
described by features of urgency that result in loss of urine. Urge incontinence is
often referred to as overactive bladder (OAB), although an important distinction
needs to be made from OAB since approximately two thirds of patients with OAB are
not incontinent of urine.13,27-30 The pathophysiology is primarily due to detrusor
muscle overactivity, resulting in uncontrolled, uninhibited, or involuntary bladder
muscle contractions. 30-32a Clinically, patients describe a sudden desire to urinate,
which is difficult to defer and results in leakage of urine occurring at various times
during the day and night.6,29,30 The causes may be secondary to neurogenic insults
including stroke, trauma, and neurologic diseases in addition to reversible causes
such as drugs and infections.6,9-13,26 The treatments for urge incontinence include
bladder training, behavioral treatments, pelvic floor exercises (Kegels), pads for
temporary support, surgery, and pharmacotherapy.33-35

Pharmacotherapy with Anticholinergic Drugs

The basis of pharmacotherapy for urge incontinence is controlling bladder detrusor
muscle overactivity with drugs that act as acetylcholine (cholinergic) antagonists on
bladder muscarinic (M) receptors, specifically the M2 and M3. The result is a
reduction in urgency symptoms and improvements in bladder control.36 Since
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muscarinic receptors are also located in other organ systems throughout the body
and since these antimuscarinic drugs are nonselective, numerous other effects
and/or adverse effects may result from their use.
Anticholinergic or antimuscarinic side effects include both peripheral and central
adverse reactions as noted in Table 4 . These adverse effects, including confusion,
delirium, constipation, and urinary retention, are especially concerning in the more
vulnerable elderly population.11,36,41,42 Contraindications to these agents are
documented elsewhere and include narrow-angle glaucoma, urinary/gastric
obstructive disorders, and dementia. Drug interactions include other anticholinergic
drugs, acetylcholinesterase inhibitors, and numerous other agents. All of the
antimuscarinic agents discussed below, except trospium, are metabolized by the
cytochrome P-450 (CYP-450) system, and inhibitors of this system can potentiate
their side-effect profiles.11,36 Monitoring for anticholinergic side effects, drug
interactions, and potential contraindications, especially in patients who are taking
multiple drugs with these properties, is essential for all health care professionals,
including pharmacists.

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A number of anticholinergic drugs are utilized in the treatment of urge incontinence.

Older agents such as propantheline, dicyclomine, and flavoxate are still available but
are rarely used because of their questionable efficacy and side-effect profiles. The
tricyclic antidepressants (TCAs), including imipramine, have been used in urge
incontinence and may have a role in mixed forms of stress and urge due to their duel
antimuscarinic and alpha-adrenergic properties.36,43-47 The major agents used today
in the treatment of urge incontinence include oxybutynin chloride (OBC), tolterodine
(TD), and the three newest agents--trospium chloride (TC), darifenacin (DAF), and
solifenacin (SFA)--along with a transdermal formulation of oxybutynin. Results from
two large meta-analyses reported similar clinical efficacy among the available agents
measured as reductions in episodes of urgency, frequency, daily micturitions,

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nocturnal awakenings, increase volume per void, and patient satisfaction. 44,48
Comparison trials with these agents are limited, however, and will be discussed
below in a brief overview.49-51
Oxybutynin chloride: Oxybutynin chloride is the oldest of the agents presently used
for urge incontinence and is available in regular-release and long-acting oral
products, in addition to a patch formulation. Clinical trials indicate similar efficacy to
other agents in the class, and the significance of OBC's proposed additional muscle
relaxation properties is not clear.52 The oral extended-release formulation and patch
formulations may offer improved tolerability, due to less formation of the active
metabolite desethyloxybutynin (DES).53-57 The adverse effects include dose-related
anticholinergic effects as described above, along with the addition of erythema and
pruritus associated with the transdermal patch. Dry mouth with this agent is reported
to be as high as 50% to 70% and may be due to greater binding to the parotid
gland.52-57 Drug interactions include the expected additive side effects when used
with other anticholinergic agents. In addition, CYP-450 2D6 and 3A4 pathway
inhibitors (e.g., fluconazole and erythromycin) may potentiate its side-effect profile.
Monitoring and reviewing patients' medication profiles are important when
oxybutynin is prescribed with other agents.36,52,57

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Tolterodine (Detrol, Detrol LA): Tolterodine is available in both regular-release tablets

and long-acting products, and they may offer improved tolerability versus regular-
release oxybutynin, with similar efficacy and tolerability to the other available
agents.57,58 Tolterodine's bioavailability (BA) and elimination is dependent on the
CYP-450 2D6 metabolism phenotype, with extensive metabolizers having a lower BA
and less excretion of drug in the urine. Drug interactions are similar to those reported
with oxybutynin, above.59-62

Newer Agents Released in 2004

The search for drugs with improved tolerability led to the development, approval, and
release of three new drugs in 2004.49-51 Although these agents appear equal in
efficacy to oxybutynin and tolterodine, they may have some individual advantages in
pharmacokinetic profile and/or tolerability, although there is limited evidence to
support a clinical advantage.63-65

Trospium (Sanctura): The first of the new agents, trospium chloride, has a quaternary
amine structure resulting in a hydrophilic molecule, with less blood–brain barrier
penetration and a reduced potential for central nervous system (CNS) side effects.
The BA of this agent is poor, and administration should be on an empty stomach.
Hepatic metabolism is limited, resulting in lack of CYP-450 involvement and
associated drug interactions. Elimination is via tubular secretion, requiring dose
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adjustments in patients with creatinine clearances (CrCl) less than 30

mL/minute.51,64,65 Trospium's efficacy is reported to be similar to other drugs in the
class, although it may be better tolerated in some patients. 64,66-68 Drug interactions
may involve competition for tubular secretion (metformin, digoxin) and drugs with an
additive anticholinergic side-effect profile. Contraindications are similar to those of
other anticholinergic agents as discussed above.51,69-71

Solifenacin (VESIcare): Solifenacin, another of the new antimuscarinics, is dosed

once daily and has excellent BA. Solifenacin is metabolized primarily by CYP-450 3A4
and has some dependence on renal clearance, requiring adjustments in patients with
a CrCl less than 30 mL/minute.50,72 Efficacy is reported to be similar to that of the
other available anticholinergic agents,72-76 with one trial reporting fewer micturitions
per 24 hours with solifenacin versus tolterodine.63 Adverse effects are similar to
those of the other agents, along with reports of prolonged QTc intervals at higher
doses, suggesting caution with patients at risk for this adverse event. As noted with
oxybutynin and other drugs mentioned above, drug interactions, adverse effects, and
contraindications are similar along with the added QTc concern. 50,77

Darifenacin (Enablex): Darifenacin, the third of the newer agents released in 2004, is
also dosed once daily. Darifenacin's BA is poor and depends on the CYP-450 2D6
metabolism phenotype. Extensive metabolizers have a lower BA and more
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dependence on the CYP-450 3A4 pathway. Dosage adjustments are recommended in

patients with hepatic impairment, and caution is suggested in patients with renal
disease. 49,78
Darifenacin is reported to have a higher affinity for bladder M3 receptors, suggesting
greater selectivity and tolerability, although clinical evidence of this advantage is
lacking.78-80 Clinical trials with darifenacin have reported similar efficacy to the other
agents, with improved tolerability versus oxybutynin.81-84 As noted with oxybutynin
and the others above, metabolism involves the CYP-450 system, and adverse effects
and contraindication are also similar.49
Summary
The anticholinergic/muscarinic drugs described above have a role in the
management of urge incontinence. Doses should be started low, especially in elderly
patients, and titrated slowly with careful monitoring for adverse effects and drug
interactions. An adequate trial of four to eight weeks is recommended, with no clear
advantage in terms of efficacy between the five agents discussed, although
tolerability differences may exist.47,48,81,82 Patient counseling when dispensing these
agents should include a review of potential side effects, drug interactions, and
education on dosing and onset of action.

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STRESS INCONTINENCE
Stress incontinence, the most common form of UI in elderly women, is primarily a
problem with bladder sphincter function, resulting in urine leakage at inappropriate
times. Risk factors are numerous, including aging changes, multiple childbirths,
medications (Table 2), obesity, trauma, or neurogenic problems.13,26,59,85-88 Although
the economic costs are high, the social costs and impact on elderly women are also
significant. 89-91 Clinically, patients describe involuntary loss of urine triggered by
coughing, sneezing, or rising quickly. Patients with pure stress incontinence may lack
urgency and nocturia, although many of these patients may have mixed forms of
incontinence with features of urgency.87,88,92,93 The treatment of stress incontinence
includes temporary pads for social situations, behavioral interventions, and Kegel
exercises, along with a number of surgical options.37,94-99 There are limited agents
and data available for the pharmacological management of pure stress incontinence.
Unlabeled uses of alpha-adrenergic agonists (e.g., pseudoephedrine and
phenylephrine) are based on the urethral smooth-muscle response to alpha
stimulation, resulting in improved control of the internal sphincter and reduced urine
loss. Lack of proven efficacy with these agents and concerns with adverse effects
including insomnia, anxiety, hypertension, arrhythmias, and stroke limits their
utility.13,26,59,100-102 The tricyclic antidepressant imipramine has been used in the

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treatment of stress or mixed incontinence, due to its alpha-adrenergic agonist and

anticholinergic properties. Low doses may provide relief in some patients, especially
if they have a mixed disorder with stress and urgency symptoms. With its
anticholinergic side-effect profile, the use of this agent in elderly patients may be
problematic.11,26,36,85,86

Although the loss of estrogen in postmenopausal woman may contribute to

symptoms of stress incontinence due to estrogen's influence on sphincter control,
there is limited clinical evidence to support its use. Estrogen therapy has been
proposed to increase urethral resistance via stimulation of estrogen receptors. If
treatment is utilized, local or topical treatments are recommended and include
creams (Table 3), vaginal tablets, or elastomer ring formulations, which may be
beneficial for improving irritative symptoms and discomfort in some patients.
85,86,103-107
The use of oral estrogen for stress incontinence is not recommended due
lack of benefit, along with the small but significant increased risk of other
comorbidities.108
The most recent agent being evaluated for stress incontinence is duloxetine, a dual
norepinephrine (NE) and serotonin (5HT) reuptake blocker approved for depression.
The proposed mechanism in this disorder is through duloxetine's action on receptors

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in the Onuf's nucleus of the spinal cord and on the pudendal bladder nerve to improve
urethral sphincter muscle contractions and tone.109

OVERFLOW INCONTINENCE
Overflow incontinence is best described as an overfilled bladder secondary to
obstruction, bladder prolapse, or alignment problems, most commonly seen in males
with benign prostatic hyperplasia (BPH).11,13,26,110 Men with BPH are usually found to
have an enlarged prostate on physical exam, and in some cases further evaluation
may be warranted to rule out prostate cancer or other obstructions.110 The clinical
presentation of overflow incontinence is described by lower urinary tract symptoms
including difficulty starting urination and/or having a weak urine stream, a sense of
incomplete emptying, nocturia, and dribbling. A complicating feature of this disorder
is that two thirds of patients with BPH may also have urgency symptoms, which can
make diagnosis and treatment challenging.110,111 Treatment for overflow
incontinence caused by BPH may include watchful waiting and eliminating potential
triggers, including alcohol and/or caffeine. Surgical options may include transurethral
resection of the prostate (TURP) or newer, less-invasive laser procedures.110,112-116

Drug therapy for the treatment of overflow incontinence secondary to BPH includes
the peripheral alpha-adrenergic blockers and the 5-alpha-reductase inhibitors.110,112
The alpha-adrenergic blockers include the older, nonselective agents originally
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approved to treat hypertension and the newer prostate selective agents, which have
minimal effects on blood pressure.117-119 The alpha-adrenergic blockers are usually
the choice therapy in early mild disease due to their faster onset of action, usually
within six weeks.118-121 Their mechanism of action is through their blocking action at
the prostate alpha 1A receptor, resulting in improved urine outflow and relief of the
symptoms described above.

These agents are metabolized by the hepatic CYP-450 system, and monitoring for
drug interactions is necessary. Adverse effects include dizziness, peripheral edema,
sedation, ejaculatory dysfunction, flulike symptoms, headaches, and gastrointestinal
effects. Contraindications include heart failure, hypotension, and the potential to
exacerbate stress incontinence in females. Individual differences between these
agents include selectivity, dosing frequency, and cost issues related to brand name
products. The selective agents may be better choices in patients without
hypertension or in elderly patients at risk for orthostatic hypotension. The
nonselective agents may be appropriate choices in younger BPH patients with
concurrent hypertension. Patient counseling when dispensing these agents should
include a review of potential side effects, especially effects on blood pressure,
sedation, and dizziness.110,112,118

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Alpha-Reductase Inhibitors
The alpha-reductase inhibitors finasteride and dutasteride are also used to treat
overflow incontinence secondary to BPH. Their mechanism of action is through
inhibiting the conversion of testosterone to dihydrotestosterone, resulting in reduced
androgenic prostate stimulation and leading to reduced gland size and improved
urine outflow. Although usually considered a second-line therapy, they may be used
first-line in patients with contraindications to the alpha-blockers (hypotension or
heart failure) or in combination with alpha-blockers in progressive or more moderate-
to-severe disease, e.g., large glands. Although effective in treating the symptoms of
BPH, their side-effect profile (e.g., decreased libido, impotence, dry sex, and
gynecomastia) and slower onset of action, which may take up to six to 12 months,
limits their use in mild disease.110,112,118,122-124 Similar efficacy for both agents has
been reported in clinical trials, and potential differences in selectivity for reductase
enzymes have not been demonstrated clinically.125 Although these agents are not
indicated in women, they are classified as pregnancy category X, and avoidance of
drug contact by any potential route (handling broken tablets, semen transfer) with
pregnant women or those seeking to become pregnant is recommended. 110,112,118

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Other therapies that have been utilized in the management of overflow incontinence
secondary to BPH include the herbal saw palmetto, which is reported to have 5-alpha-
reductase inhibitor activity and the cholinergic agonist bethanechol, which may be
used for acute management after TURP procedures11,36 Investigational therapies
include combinations of anticholinergic drugs with alpha-blockers for patients who
have urgency associated with their BPH symptoms.111,126 The use of the erectile
dysfunction drugs (e.g., phosphodiesterase inhibitors [sildenafil] and botulinum toxin)
are also being evaluated in the treatment of overflow incontinence secondary to
BPH.127,128 As noted in Table 3, other types of incontinence include functional
incontinence secondary to patients' inability to reach the bathroom due to a physical
disability and atonic bladder, where complete loss of bladder innervation and control
secondary to various diseases or insults, including stroke or diabetes, requires the
use of intermittent catheterizations. Mixed UI may occur in up to 20% to 30% of
patients and, due to the various clinical presentations and symptoms, may require
extensive evaluation and therapeutic trials to determine appropriate
therapies.6,11,13,18,24-26,59,88

CONCLUSION
The pharmacological management of UI requires appropriate evaluation by qualified
clinicians. Pharmacists can offer educational support to patients by questioning and
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monitoring the effectiveness and tolerability of the various pharmacotherapies.

Taking time to get to know your patients in the ambulatory and clinical settings
allows the pharmacist the opportunity to provide valuable education, intervention,
and recommendations to improve patient care outcomes in the management of this
complex disorder.

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