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 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.
OVERVIEW OF THE ANATOMY AND PHYSIOLOGY OF THE
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 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.
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 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
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 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
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,
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 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
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
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
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, 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.
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 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.
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
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
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 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 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 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
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
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.
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
The pharmacological management of UI requires appropriate evaluation by
qualified clinicians. Pharmacists can offer educational support to patients by
questioning and 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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