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9 - Renal and Urologic Disorders |
227
through their mouth. Autonomic reflexes decline
with age, diminishing the vasomotor response
to heat.
1
Measurement of serum sodium is
an important part of an assessment of hydra-
tion status because changes in serum sodium
concentration usually reflect either an excess or
deficit of water.
Sodium and Water Imbalance in the
Elderly
Hypernatremia (serum sodium >145 mEq/L)
is a hypertonic condition that is usually due to
a deficit of water and is most common in the
elderly with an impaired thirst sensation and or a
lack of access to water. Older patients with dehy-
dration usually present with a change in mental
status such as lethargy, increasing confusion,
and postural hypotension.
1
Treatment should
focus on the repletion of water and sodium at a
rate that is slow enough to allow for equilibration
of water into the brain. Fluid replacement that is
too rapid may cause cerebral edema and brain
toxicity, leading to seizures and death.
23
Fluid
replacement with intravenous normal saline (or
less concentrated solutions) should not exceed
approximately 150–200 mL/hr to restore the intra-
vascular volume, and then at slower rates, with
half-normal saline solutions, to correct the water
deficit.
1,23
In older persons, hypernatremia and
dehydration have often developed gradually;
therefore, the correction of this condition should,
likewise, be in a slow and cautious manner.
Changes in serum sodium should not exceed
6–8 mEq/L over 24 hours.
23
When rehydration
therapy is underway, monitoring of the patient is
needed. This can include laboratory assessment
with serum electrolytes as well as clinical signs
of improvement in the patient, such as moistness
of mucus membranes, skin turgor, concentration
of urine, and mental status.
Hyponatremia (serum sodium <135 mEq/L)
is a common disorder and an independent
predictor of mortality in community-dwelling and
hospitalized older people.
1
Chronic mild hypona-
tremia in the elderly is associated with an increase
in falls, osteoporosis, and bone fractures.
1,24
Evaluation of data from the National Health
and Nutrition Examination Survey (NHANES
III) reveals a linear relationship between serum
sodium and femoral neck bone mineral density,
suggesting that for each 1 mmol/L decrease
in serum sodium a loss of 0.037 g/cm
2
in bone
mineral density of the femoral neck occurs.
25
In
the older person, hyponatremia is usually due
to fluid excess, often from an overcorrection of
dehydration with isotonic fluid.
1,23
Evaluation of
the serum osmolality will help determine whether
or not the patient has an isotonic, hypertonic, or
hypotonic variety of hyponatremia. Hypotonic
hyponatremia is more common, and further eval-
uation of the urine sodium concentration will help
determine whether the patient is hypovolemic
(generally due to thiazide diuretics), hypervol-
emic (generally due to congestive heart failure,
cirrhosis, or overcorrection with isotonic fluids),
or euvolemic (generally due to low sodium
intake, polydipsia, or the syndrome of inappro-
priate ADH secretion).
23
In a patient with hypona-
tremia, knowledge of the volume status guides
therapy.
Thiazide diuretics are a frequent cause of
hypotonic hyponatremia because they block
sodium reabsorption in the distal tubules of the
renal cortex, which increases sodium and water
excretion by the kidney. Arginine vasopressin
or ADH is released to counter the decrease in
plasma volume, which increases the reabsorp-
tion of free water, resulting in a hyponatremia that
is due to a net loss more of sodium than water.
23
Treatment of hypovolemic hyponatremia
should begin by addressing the cause (such
as discontinuation of the thiazide diuretic) and
replacement of the sodium and fluid deficit in
a manner consistent with the severity of symp-
toms in the patient. The sodium deficit can be
calculated by subtracting the desired serum
sodium value from the patient’s observed
sodium and multiplying by the patient’s total
body water. Estimates of total body water for
older men equal 0.5 L/kg × weight (kg) and
for older women 0.45 L/kg × weight (kg). For
example, total body water for an 80-year-old,
60-kg woman is 27 L. If this woman had a serum
sodium of 120 mEq/L and a desired value
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| Fundamentals of Geriatric Pharmacotherapy
of 125 mEq/L, her sodium deficit would be
135 mEq ([125 – 120] × 27). One liter of
normal saline contains 154 mEq of sodium.
In patients with severe central nervous system
(CNS) symptoms, such as coma or seizures,
normal saline in small amounts to slowly raise
the serum sodium by 6–8 mEq/L over 24 hours
is a treatment goal.
23
Ringer’s lactate may be a
preferable replacement solution because normal
saline solutions have relatively more chloride in
comparison to the plasma and may lead to a
hyperchloremic acidosis.
1
For patients with hypervolemic hypona-
tremia, treatment is focused on achieving a
negative water balance by increasing water
excretion and limiting oral fluid intake to <1,000
mL/day. If congestive heart failure is the cause
for this condition, optimal treatment for the heart
failure should be instituted.
Drugs can be a cause of euvolemic hypo-
natremia. Although the overall incidence of
syndrome of inappropriate ADH is relatively
low, it is higher in the elderly. In addition, many
classes of drug therapy can cause drug-induced
syndrome of inappropriate ADH, and drug
regimen review is recommended for older indi-
viduals with signs of hyponatremia. Commonly
reported drug-induced causes include anti-
depressants (many agents but older women
are especially at risk with selective serotonin
reuptake inhibitors [SSRIs]), antipsychotics,
anticonvulsants, and antineoplastic agents.
Drug-induced syndrome of inappropriate ADH
secretion has also been reported with analge-
sics such as fentanyl and ibuprofen, antipar-
kinson medications, clonidine, ACE inhibitors,
amiodarone, and theophylline. Discontinuation
of the offending agent is recommended.
26
Hypomagnesemia occurs with long-term
use of proton pump inhibitors due to a reduc-
tion in passive absorption of magnesium in the
intestines.
27
It is estimated that about one-third
of the elderly take proton pump inhibitors, so
this adverse drug effect will be more common
in the elderly. Low magnesium concentrations
are associated with cardiovascular disease and
with cardiovascular complications in patients
with CKD. Symptoms of mild to moderate hypo-
magnesemia include muscle cramping, nausea,
vomiting, fatigue, and weakness. The use of
proton pump inhibitors and magnesium levels
was evaluated in a cohort study of elderly people
admitted to a hospital over a 6-month period.
These individuals averaged 84 years of age;
42% were taking a proton pump inhibitor, and
33% were male. Two-thirds of the study partici-
pants had been taking the proton pump inhibitor
for longer than 12 months. Elderly participants
who were receiving a proton pump inhibitor and
who had an estimated GFR of <60 mL/min had
magnesium levels that were lower than other
comparison groups.
27
Pharmacists should care-
fully monitor patients for this adverse effect and
confirm the need for continued therapy with the
proton pump inhibitor.
U D
Urinary Incontinence
Urinary incontinence (UI) is defined as invol-
untary urine loss and is a condition that is not
always recognized or reported.
28-31
Individuals
may be reticent to self-report UI to their health
providers due to embarrassment, yet it can nega-
tively impact dignity and contribute to increased
social isolation. Approximately 30% of older
adults within the community and almost 60% of
individuals residing in long-term care facilities
are affected by UI.
28,29,31
Although the prevalence
of UI increases with age, it is not considered a
normal part of aging.
28,29
The incidence in men
is about one third that of women, but at the age
of 80, men and women have similar rates of
UI.
28,29,31
This disorder is expensive, with annual
direct costs in the United States approaching
$20 billion. An estimated 70% of the cost is due
to routine incontinence protective items such as
pads, diapers, and skin care products, but the
cost of institutional care significantly contributes
to this figure.
28
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229
Before classifying the various types of UI,
review of the anatomy and physiology of the
aging bladder is needed. The lower urinary
tract is composed of the bladder (including the
detrusor muscle), urethra, urinary sphincter,
and nearby musculofascial components
including nerves, connective tissue, and blood
vessels.
32
Urination is controlled by the CNS, the
spinal cord, and the peripheral nerves. The para-
sympathetic nervous system (PNS), the sympa-
thetic nervous system (SNS), and the somatic
nervous system all work together to execute
proper bladder control.
33
Overall, bladder physiology and mictu-
rition are regulated by the action of various
neurotransmitters and nervous systems (Figure
9-1).
33
Acetylcholine is the major neurotransmitter
responsible for bladder contraction and inter-
acts with muscarinic receptors on the detrusor
muscle.
34
Of the five known muscarinic subtypes
M
1
–M
5
, M
2
subtypes predominate on the bladder
smooth-muscle cholinergic receptors. The M
3
receptors are responsible for both the emptying
contraction associated with urination as well as
involuntary bladder contractions that can lead to
UI. M
3
receptors appear to be the most clinically
relevant within the human bladder, and many
antimuscarinic drug therapies are targeted at
blocking this receptor subtype.
31,34
Disturbances
in the neural regulation of micturition at any point
(pelvic nerves, spinal cord, or brain) may result
in UI due to changes in lower tract function.
32
Sensory receptors in the bladder are stimu-
lated as it fills with urine, and signals are sent to
the brain indicating bladder fullness. Variability
exists within older adults, but approximately
100–200 mL of urine is required before the brain
will sense bladder fullness. Stimulation of the
SNS and inhibition of the PNS occur during low
bladder volume, and this leads to bladder filling
Figure 9-1. Basic bladder anatomy and physiology.
Source: Reprinted with permission from DeMaagd G, Geibig JD. An overview of overactive bladder and its
pharmacological management with a focus on anticholinergic drugs. PT. 2006;31:462-471.
Brain (Micturition center)
Spinal cord
(Thoracic and lumbar re
gions)
External sphincter
(Sacral regions)
Parasympathetic
nervous system (PNS)
(Cholinergic receptors)
Bladder
Detrusor muscle
Sympathetic nervous system (SNS)
Beta-adrenergic receptors
SNS
inhibition
Somatic (pudendal) nerve
Internal sphincter (Alpha-adrenergic)
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| Fundamentals of Geriatric Pharmacotherapy
by contraction of the internal sphincter and relax-
ation of the detrusor muscle. Inhibitory signals by
the brain are replaced by impulses that stimulate
the PNS when the bladder is full and micturition
is necessary. Detrusor contraction results as well
as relaxation of the internal sphincter and inhi-
bition of the SNS. Urinary flow will occur when
intravesical pressure is greater than the resis-
tance within the urethra. Once the bladder has
emptied and is ready to be filled again, the brain
signals parasympathetic inhibition and sympa-
thetic stimulation, resulting in detrusor relaxation
and contraction of the internal sphincter.
33-35
Specific age-related physiological changes
occur within the urinary tract including decreases
in bladder elasticity and bladder capacity, as
well as more frequent voiding. The detrusor
muscle may contract spontaneously; in addition,
reduced muscle strength can lead to incomplete
bladder emptying. There is also a decrease in
the urethral closing pressure and difficulty in
postponing urination.
28,31,32
Sex-specific changes
also occur. Up to 70% of women affected by
UI attribute symptom onset with menopause.
Women experience a decline in bladder outlet
and urethral resistance due to the decreased
circulating estrogen levels in the genitourinary
tract and the effect on the pelvic musculature.
Diminished estrogen levels can lead to atrophic
vaginitis and urologic complications including
dysuria, urgency, and the development of UTIs.
Age-related loss of tone in the muscles of the
pelvic floor due to childbirth and/or obesity
can also contribute to incontinence. UI is less
common in men and carries a later and more
sudden onset than in women. Prostate enlarge-
ment can lead to decreased urinary flow rates,
instability of the detrusor muscle, and overflow
incontinence.
28,36
UI can be categorized by the duration of
symptoms, clinical presentation, or physiologic
abnormalities. In addition, transient causes of UI
are a special consideration in older adults and
should be differentiated from established incon-
tinence secondary to urinary tract dysfunction.
The following mnemonic (spells DIAPPERs with
an extra “p”) is used to identify some of these
reversible causes: delirium, infection, atrophic
vaginitis and urethritis, pharmacological agents,
psychiatric disorders, excessive urine output,
restricted mobility, and stool impaction.
30,31
Table
9-1 highlights some of the medication
classes
often implicated in causing or worsening incon-
tinence.
28,32,34,35
Types of Urinary Incontinence
Stress incontinence typically occurs when the
urinary sphincter is compromised and no longer
Table 9-1. Medication Classes that Can Affect Urinary Tract Function or UI
28,32,34,35
Drug Class Result
ACE inhibitor Occurrence of cough can increase intra-abdominal
pressure and aggravate stress incontinence
Acetylcholinesterase inhibitor Polyuria, frequency
α-adrenergic agonist Increases internal sphincter tone
α-adrenergic blocker Decreases internal sphincter tone
Anticholinergic Decreases detrusor muscle contraction, possible
urinary retention
Calcium-channel blocker Decreases detrusor muscle contraction, possible
urinary retention
Diuretic Increases bladder filling, polyuria
Opioid Decreases detrusor muscle contraction; possible
urinary retention, fecal impaction, and sedation
Sedative/hypnotic Confusion, functional incontinence
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231
able to resist the urine flow from the bladder,
especially during physical activity. Transient
increases in intra-abdominal pressure can lead to
losses of small volumes of urine when laughing,
sneezing, coughing, bending, or lifting. This is
the most common type of incontinence in women
and risk factors include pregnancy, childbirth,
menopause, cognitive impairment, age, and
obesity. Hormonal factors play a role because
the prevalence increases after menopause with
estrogen deficiency. Men also can experience
stress incontinence, but usually only as a result
of internal sphincter damage from urological
procedures, including prostate surgery.
32-34
Urge urinary incontinence (UUI) and over-
active bladder (OAB) are associated with
detrusor muscle overactivity. The terms over-
active bladder, urge urinary incontinence, and
detrusor over-activity are used synonymously
at times but need to be differentiated. OAB is a
symptom complex that involves urinary urgency
with or without UUI, urinary frequency (more than
eight voiding episodes in a 24-hour period), and
nocturia (two or more nighttime awakenings to
void).
35
It is important to recognize that OAB can
result with or without the features of UUI.
33
Indi-
viduals with UUI experience detrusor overactivity
that leads to forceful, early detrusor contractions
before the bladder is full and results in urinary
urgency and frequency.
34
KEY POINT:
Detrusor overactivity is a
specic diagnosis obtained by urodynamic
testing that identies involuntary detrusor
contractions during the lling phase.
OAB, in contrast, does not require invasive
urodynamic testing and is diagnosed
primarily by report of patient symptoms.
ese terms should not be interchanged,
because the denitions are distinct.
The cause of UUI and OAB is most
commonly idiopathic. Risk factors include
normal aging, neurological disease, or bladder
outlet obstruction. The underlying pathology
for UUI and OAB may either be neurogenic
or myogenic, and differing theories exist. The
mechanism for the neurogenic hypothesis
implies that disease-related changes within the
peripheral nervous system or the CNS lead to
UUI and OAB. The myogenic hypothesis states
that these conditions occur as a result of smooth
muscle changes within the bladder wall. In prac-
tice, these etiologies are often related, so it is
difficult to differentiate.
32,35
Overflow incontinence occurs as a result
of urethral overactivity and/or bladder underac-
tivity. The bladder is at maximum capacity and
distended but is unable to empty, and this leads
to the leakage of urine.
32,34
Individuals usually
present with symptoms of dribbling, weak
urinary stream, hesitancy, or incomplete voiding.
Causes can be neurogenic, such as diabetes
mellitus, spinal cord injuries, or multiple sclerosis
.
Anticholinergic medications, conditions causing
detrusor muscle underactivity, or denervation
of the bladder wall musculature are
examples
of other potential causes. In men, obstructed
urinary outflow due to BPH or prostate cancer is
another common cause of overflow incontinence
and an important consideration.
29,34
Individuals with functional incontinence are
unable to reach the toilet in time, either due to
physical (e.g., impaired mobility, poor vision) or
cognitive issues (i.e., dementia, confusion, medi-
cation side effects). There are no defects within
the urinary tract, related to a primary disease (e.g.,
dementia, postoperative orthopedic surgery).
29,32
Mixed types of incontinence exist and diag-
nosis can be confusing because of the overlap of
symptoms. The combination of bladder overac-
tivity and urethral sphincter underactivity is one
common form of mixed incontinence. Another
mixed form characterized by bladder overac-
tivity (instability) and impaired bladder contrac-
tility may also occur in elderly men, leading to a
mixed condition known as detrusor hyperactivity,
with impaired contractility.
29,32,36
Signs and symp-
toms of the mixed conditions are typical of the
forms of incontinence that make up the individual
diagnoses.
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| Fundamentals of Geriatric Pharmacotherapy
Neurogenic bladder, a type of overflow
incontinence, involves the loss of voluntary
control of bladder function due to spinal cord
injury or neurological conditions. This type of
incontinence is managed by intermittent cath-
eterization or placement of a suprapubic tube.
Elderly patients may be vulnerable to inappro-
priate use of catheters for other types of incon-
tinence, which can lead to complications from
chronic catheter use.
31
Treatment
When treatment options are considered for UI,
goals must be identified along with a plan that
will be suitable for the individual, whether at
home, residing in a long-term care facility, or any
other living situation. These goals should target a
reduction in the frequency and severity of incon-
tinence episodes and should minimize related
complications. Frequently, these complications
are overlooked, and clinicians cannot underes-
timate the importance of weighing the risks and
benefits of treatment options. Potential complica-
tions of not treating UI include skin breakdown,
UTIs, increased risk of falls, sleep disturbances,
psychological effects including depression,
isolation from activities, and changes in dignity
relating to embarrassment.
29-31
Treating the
underlying cause(s) is desirable but not always
an option due to the individual’s overall condition,
treatment preferences, and functional ability.
29
In
some cases, behavioral therapy is appropriate,
and nondrug therapies may be the only choice
for individuals if drugs or surgery are not desir-
able. However, multiple pharmacological agents
are now available with a variety of mechanisms
and profiles that may suit specific needs.
Regardless of the type of UI an individual
experiences, it may be necessary to use incon-
tinence undergarments as a means to avoid the
soiling of clothing from a wetting episode. For
some individuals with occasional or minor symp-
toms, incontinence shields or adult briefs may be
the sole intervention chosen. These products may
also be used in combination with drug therapy,
because wetting episodes may still occur. In
very frail or functionally dependent patients,
adult briefs with regular changing and personal
cleansing are a mainstay of incontinence care.
For those individuals who are dependent on a
caregiver for all toileting and personal hygiene
activities, especially those with significant cogni-
tive impairment, the decision is often made to
discontinue pharmacological intervention for
incontinence. If drug therapy does not result in a
reduction of wetting episodes, urge discomfort,
or the need for adult briefs, the side effect profile
may outweigh the benefit in these individuals.
Nondrug erapy and Behavioral/
Muscle Rehabilitation
Individuals with OAB or detrusor overactivity
often respond to behavioral therapy. According to
the American Urological Association, this should
be implemented before any pharmacological
treatment.
28,37
One method focuses on altering
bladder function by modifying habits to include
delayed voiding.
Behavioral training is another
approach that targets the bladder outlet; this
includes pelvic floor muscle training to improve
urge suppression.
37
Bladder training is a general
term that refers to a combination of patient
education, voiding schedules, urge suppres-
sion techniques, and pelvic muscle exercises.
Toileting assistance protocols are helpful in
patients with cognitive or mobility impairment.
35
Using routine toileting, prompted voiding, and
habit-training schedules will empty the bladder
regularly to minimize leaking.
37
In addition to
OAB and UUI, behavioral techniques are often
used for stress and mixed incontinence.
32
Bladder training involving urge control
strategies works well in individuals with higher
cognition, ability to toilet, and motivation to coop-
erate with a training program. To retrain bladder
habits, scheduled toiletings are adjusted for
longer or shorter times, depending on the indi-
vidual voiding pattern. This may be an option
for individuals who are cognitively or physically
impaired and need reminders or assistance with
the process. Overflow incontinence can also be
managed by instructing individuals to void on a
regular schedule (i.e., every 2 hours) to avoid
increased volume and bladder distention.
29,32,38
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Pelvic muscle rehabilitation and exercises
can be effective in stress, urge, and mixed
incontinence. Examples include biofeed-
back, vaginal weight training, and Kegel exer-
cises. Most effective in motivated individuals
with adequate cognition, proper technique is
required to contract the pelvic floor muscles
during Kegel exercises without the use of acces-
sory muscles.
32
The exercises strengthen the
periurethral and pelvic floor muscles and must
be performed regularly to be effective.
32,34
Kegel
exercises or other forms of pelvic floor muscle
rehabilitation may be used in combination with
bladder training. Several studies in women show
the combination to be more effective than either
alone.
39
Older adults with cognitive impairment
face additional challenges with these tech-
niques. They may require regular reminders to
urinate and dryness checks to enhance bladder
training. Keeping a bed pan or commode near
the bed may also prevent potential falls and
subsequent injuries.
Drug erapy
Drug therapy for UI becomes necessary when
the symptoms are not sufficiently managed
with nonpharmacological therapies. Often, the
combination of drug therapy with behavioral
or muscle rehabilitation is utilized for optimal
results.
31
Pharmacological interventions have the
potential to reduce the number of incontinence
episodes experienced per day while increasing
the volume of urine that the bladder can hold.
Medications target specific underlying abnor-
malities, and it is imperative to identify the type
of incontinence before beginning pharmacolog-
ical treatment.
29
Table 9-2 summarizes possible
pharmacologic options for treating various forms
of UI.
28,29,32,33,43,53,54
Drug erapy for Stress Incontinence
There are currently no Food and Drug Administra-
tion (FDA)–approved agents to treat stress urinary
incontinence (SUI). Alpha-adrenergic agonists
such as pseudoephedrine lack selectivity for
the urethral alpha adrenoreceptors and cardio-
vascular safety concerns exist. Imipramine and
estrogen are options with limited efficacy.
40
In addi-
tion, data from the Heart and Estrogen/Progestin
Replacement Study demonstrated an increased
risk of stress and urge incontinence in women who
were randomly assigned to receive estrogen alone
or the combination of estrogen and progesterone
41
Using oral hormone
therapy for the treatment of stress incontinence is
generally not recommended; however, the Euro-
pean Association of Urology (EAU) does endorse
the use of intravaginal estrogen as a Grade A
level recommendation for the improvement of
vaginal and urinary symptoms in postmenopausal
women.
42,43
Supporting evidence is based on
the fact that besides an improvement in vaginal
atrophy, local estrogen therapy may reduce UI
and also the frequency and urgency associ-
ated with OAB. Local estrogens demonstrated a
greater effect than placebo at improving UI and
reducing frequency. The EAU recommends to
offer topical estrogens to postmenopausal women
with UI (stress, mixed, and urgency), although the
preferred method of delivery or duration of therapy
has not yet been determined.
43
Duloxetine hydrochloride is a selective reup-
take inhibitor of serotonin and norepinephrine.
It is not currently approved for SUI in the United
States, but it is approved by the regulatory agency
in the European Union. In women, it may result in
stronger urethral contractions, with an improve-
ment in sphincter tone during urine storage and
physical stress.
40
Randomized, placebo-controlled
trials of duloxetine have been published demon-
strating significant benefits in SUI; however, the
emergence of adverse events such as nausea,
dry mouth, and fatigue within the trials can be
problematic for many healthy, nondepressed indi-
viduals. Initial manufacturer recommended doses
were poorly tolerated and left clinicians with a
negative perception.
32,40,44
Another weakness with
the available evidence is the general under-repre-
sentation of older adults within the study popula-
tions. Although a varied age range has been eval-
uated across many studies, the findings cannot
clearly be applied to older adults.
45,46
The overall safety and efficacy, and place
within therapy remains undetermined, but the
EAU does recommend duloxetine for SUI or
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| Fundamentals of Geriatric Pharmacotherapy
Table 9-2. Drug Treatment of UI
28,29,32,33,43,53,54
Type of
Incontinence Drug Treatment Class Specific Agent(s) Comments
Urge or OAB Antimuscarinic/
anticholinergic agents
β
3
-adrenergic agonist
Neuromuscular blocker
Darifenacin,
oxybutynin,
solifenacin,
tolterodine,
trospium
Mirabegron
OnabotulinumtoxinA
Anticholinergic agents are generally
first-line therapy. Various forms
exist: short-acting, long-acting,
and oxybutynin patch and gel.
Differences in muscarinic receptor
blocking exist.
Hypertension, headache, and urinary
tract infection are potential adverse
effects.
Injected via cystoscopy; used in OAB
for adults who cannot use or do not
respond to antimuscarinic agents.
Stress
incontinence
α-adrenergic agonists
Local estrogens
Serotonin/
norepinephrine
reuptake inhibitor
Pseudoephedrine,
phenylephrine
Conjugated
estrogen, vaginal
cream, or estradiol
vaginal insert/ring
Duloxetine
Avoid use with hypertension,
cardiac arrhythmia. Other side
effects include tremor, anxiety, and
agitation.
Intravaginal estrogen recommended
by the European Association of
Urology. Improves vaginal and
urinary symptoms in SUI, MUI, and
UUI.
Not FDA approved for SUI; side
effects (including nausea, dry
mouth, fatigue) may limit its
usefulness.
Overflow
incontinence
α-adrenergic
antagonists
5α-reductase inhibitors
Antimuscarinic agents
Alfuzosin,
tamsulosin,
silodosin,
doxazosin,
terazosin
Finasteride,
dutasteride
Tolterodine
Side effects vary depending on
selectivity to receptors in the
bladder and/or prostate (alfuzosin,
tamsulosin, and silodosin are more
specific).
For advanced BPH or refractory
symptoms.
Must weigh risk of urinary retention
with improvement in lower urinary
tract symptoms.
Functional
incontinence
Remove barriers and
obstacles, provide
schedules or
prompted toileting,
assistance may be
required to transfer
on/off commode
Consider therapy to remove any
potential cause
MUI Focus on symptoms that
dominate
Consider treatments for individual
components (i.e., stress and urge)
MUI, mixed urinary incontinence.
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9 - Renal and Urologic Disorders |
235
mixed UI for temporary improvement when more
effective treatments such as surgery are not
an option.
43
Doses of 80 mg daily are gener-
ally used, and individuals may experience
symptom relief as long as they are willing and
able to tolerate the side effects. Duloxetine is not
recommended for individuals with a CrCl <30
mL/min. It is advised to be used with caution in
the elderly within the 2012 American Geriatrics
Society Beers Criteria due to the potential for
hyponatremia or the increased risk of syndrome
of inappropriate antidiuretic hormone.
28,32,40,43,44,47
Drug erapy for Overactive Bladder
Muscarinic antagonists are the most commonly
prescribed drugs available for the treatment of
UUI. The anticholinergic agents used to treat
OAB vary in their pharmacokinetic proper-
ties, dosing, and tolerability profiles. There are
differences in muscarinic receptor affinities, but
efficacy as reported in clinical trials appears to
be similar. Oxybutynin is a lipophilic, nonspe-
cific muscarinic antagonist that is available
as an immediate-release, extended-release
transdermal, or gel formulation. It is effective in
reducing UUI symptoms; however, it is associ-
ated with high incidence of anticholinergic side
effects. Dry mouth, blurred vision, constipa-
tion, sedation, and cognitive impairment are all
concerns in the older patient. Despite similar
efficacy among these formulations, it has been
theorized that extended-release transdermal or
gel formulations are preferable based on toler-
ability considerations. For extended-release
oral formulations, this is based on the idea that
slow release of drug into the bloodstream avoids
spikes in serum concentration associated with
intermittent doses. For the transdermal formu-
lation, this is based on lower concentrations of
the active metabolite N-desethyloxybutynin by
avoidance of first-pass metabolism in the liver.
The oxybutynin gel formulation also bypasses
first-pass metabolism. Data from clinical trials
does suggest a reduction in adverse events;
however, this was primarily for dry mouth.
28,48
Tolterodine is also available in both imme-
diate-release and long-acting formulations
and has comparable efficacy to oxybutynin
for improvement of OAB symptoms. It is also a
nonselective muscarinic antagonist but is less
lipophilic than oxybutynin and, therefore, theo-
rized to result in poor distribution into the CNS,
resulting in fewer side effects. Comparisons of
extended-release tolterodine to either imme-
diate-release or extended-release oxybutynin
did show a lower incidence of adverse effects;
however, again, this was primarily limited to
reduced incidence of dry mouth.
48
When discussing the use of extended-
release or immediate-release preparations, both
can be offered as therapy, and there are many
factors to consider. In some cases, there may be
insurer issues that determine product selection
that the prescriber must acknowledge in addi-
tion to recognizing improved adherence with
once-daily formulations. If immediate-release
preparations are unsuccessful or intolerable,
then extended-release agents may be consid-
ered. If individuals are having sufficient symptom
control without side effects, then a change may
be unnecessary.
37,43
There are two agents that are more selective
for the M
3
receptor, solifenacin and darifenacin,
which are both available in formulations for once-
daily dosing. In one study comparing solifenacin
to tolterodine, solifenacin significantly improved
symptoms of urgency and UI versus tolterodine;
however, this study has been criticized because
dose escalation was allowed in the solifenacin
group but not in the tolterodine group.
48
Agents
with high M
3
selectivity are thought to be associ-
ated with relatively higher rates of constipation,
but discontinuation rates due to adverse events
were not different between the two groups. The
potential sparing of M
1
receptor-mediated cogni-
tive impairment has only been minimally inves-
tigated. Darifenacin’s effect on cognitive func-
tion was compared to oxybutynin ER in healthy
subjects over the age of 60. Darifenacin-treated
subjects scored similar to placebo subjects on
delayed recall tests, while subjects receiving
oxybutynin ER experienced memory deteriora-
tion estimated to be comparable to brain aging
of 10 years. This study has limitations such as
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236
| Fundamentals of Geriatric Pharmacotherapy
short duration, dropouts, differences in baseline
characteristics between groups, and questions
about dose equivalence.
48,49
Trospium is different from other muscarinic
antagonists because it is a quaternary ammo-
nium compound and is, therefore, thought to
penetrate poorly into the CNS. Trospium is similar
in efficacy to oxybutynin IR; dry mouth is reported
to occur less often.
48
In general, clinicians should
not use antimuscarinic agents in individuals with
narrow-angle glaucoma unless approved by
the treating ophthalmologist, and these agents
should also be used very cautiously in the pres-
ence of impaired gastric emptying or history
of urinary retention. In these situations, benefit
versus risk must be carefully considered.
37
One recent systematic review evaluated
the pharmacological treatment of UI in women,
focusing on darifenacin, fesoterodine, oxybu-
tynin, solifenacin, tolterodine, and trospium. The
evaluation identified 94 randomized trials of drug
efficacy or comparative effectiveness and exam-
ined adverse effects and treatment discontinu-
ation secondary to adverse effects. Pharmaco-
logical agents were more effective than placebo
in improving UI and achieving continence
with a low magnitude of benefit. There was a
<20% absolute risk difference in continence
for all drugs. Pharmacological agents resulted
in adverse effects more often than placebo,
leading to higher discontinuation rates. None of
the agents showed clear superiority compared
to one another.
50
The FDA approved transdermal oxybutynin
from prescription-only dispensing to over the
counter (OTC) in 2013. This change involved
significant controversy. There were three study
types conducted to present information to the
FDA to gain approval: a label comprehension
study, a self-selection study, and an actual-use
study. Based on the results of these studies,
the OTC oxybutynin product is only approved
to be used by women over 18 years of age for
OAB. According to the product label, it should
only be used only when symptoms are present
for more than 3 months, and individuals should
discontinue and speak with a provider if the
condition does not improve within 2 weeks.
28,51
Now that this product is available OTC without
a prescription for women, it is important that
patients understand when it is appropriate to
use and how to monitor for tolerability and effi-
cacy. It is not approved for men, based on the
potential issues of differentiating UI causes from
BPH.
28
When considering product marketing and
packaging, it is clear that this agent is targeting
women.
Mirabegron is the first beta-3 adrenergic
antagonist approved in the United States. It is a
once-daily treatment indicated for OAB in adults
with symptoms of UUI, urgency, and urinary
frequency.
32,52,53
Mirabegron 25- and 50-mg
daily doses significantly reduced the number
of daily incontinence episodes compared to
placebo. The starting dose is 25 mg, and if
sufficient response is not seen at 8 weeks it can
be increased to 50 mg. Patients with reduced
CrCl of 15–29 mL/min or moderate liver disease
should not receive more than 25 mg. Increases
in blood pressure have been reported, and it is
not recommended for use in patients with severe
uncontrolled hypertension (systolic and diastolic
blood pressure exceeding 180 mmHg or 110
mmHg, respectively). Mirabegron is a moderate
CYP2D6 inhibitor and may interact with 2D6
substrates, especially agents with a narrow ther-
apeutic index.
28,52,53
Mirabegron appears to demonstrate
moderate efficacy in treating OAB. Because
there are no anticholinergic properties, this is
an advantage, but urinary retention, elevations
in blood pressure, and drug interactions may
occur. There is limited information regarding
long-term safety data.
52,53
Another addition to drug therapy involves
FDA approval of onabotulinumtoxinA for the
treatment of UI in adults due to detrusor overac-
tivity associated with neurological conditions and
intolerance or insufficient response to anticholin-
ergic therapy. In 2013, it was also approved for
adults in OAB with symptoms of UUI, urgency,
and frequency. Upon injection of onabotulinum-
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