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9 - Renal and Urologic Disorders |
237
toxinA by cystoscopy—an endoscopic proce-
dure to view the bladder and urethra via a thin,
lighted instrument—the bladder relaxes and
the storage capacity is increased, reducing
episodes of UI. There are many risks associated
with this agent, including urinary retention and
UTIs.
28,54,55
Besides OAB, clinical studies with onabotu-
linumtoxinA in older adults are limited. In the
approval studies for OAB, about 40% of the
subjects were over 65, and 15% were 75 or
above. UTI and urinary retention were more
common in individuals over 65 in both placebo
and treatment group. The safety profile was
similar for both younger and older subjects.
28,54
The recommended dose of onabotulinumtoxinA
for OAB is 100 units injected via cystoscope. The
needle should be inserted 2 mm into the detrusor,
and 20 injections (0.5 mL each) are spaced
approximately 1 cm apart. Patients should be
observed for at least 30 minutes after the injec-
tions and until a spontaneous void has occurred.
It is important to note that individuals may be
considered for reinjection when the effect of the
previous injection has lessened, but not sooner
than 12 weeks from the previous bladder injec-
tion. The median duration of response based
on patient qualification for retreatment was
19–24 weeks when receiving the 100-unit dose
according to product labeling.
54
In general, no single agent has emerged as
the product of choice for treating UUI or OAB.
48,49
Drug selection is based on the perceived side
effect profile, and all patients should be care-
fully monitored for symptom response and emer-
gence of adverse effects. At this time, there is
no clear clinical advantage of the newer versus
older agents, and there is a lack of head-to-head
clinical trials to determine any one particular
agent as superior. Choosing an agent based on
uroselective properties has not been demon-
strated to be an accurate predictor of successful
therapy.
28
Tolerability, individual preference, or
formulary considerations may be the deciding
factor in determining the appropriate agent.
33
Antimuscarinics should begin to work within the
first month of initiating therapy, and mirabegron
25 mg is generally effective within 8 weeks. It
is important to ensure appropriate follow-up to
assess potential adverse effects as well as effi-
cacy.
28,53
Drug erapy for Overow Incontinence
The drug therapy for this type of incontinence will
be discussed in the Benign Prostatic Hyperplasia
section. Although women can experience this
type of incontinence, and there are limited data
describing the use of alpha antagonists such as
terazosin and doxazosin in these circumstances,
the majority of the clinical data in this area have
been evaluated in men with urinary symptoms
associated with BPH.
Special Considerations for the Use of
Drug erapy
There are many factors to consider prior to initi-
ating drug therapy for UI. Comorbid conditions
such as dementia, constipation, orthostatic
hypotension, history of falling, or other condi-
tions may influence the choice of drug therapy.
Other medications that the patient is taking may
interact with an agent intended to treat incon-
tinence. For example, adding anticholinergic
medications for incontinence to a regimen that
includes other anticholinergic medications can
result in added side effects. Conversely, the
concurrent use of acetylcholinesterase inhibitors
with some of the anticholinergic drugs to treat UI
may alter the efficacy of each drug and cause
undesirable side effects due to a potential state
of pharmacological opposition. Acetylcholines-
terase inhibitors increase acetylcholine levels
in the neural cleft in patients with dementia, and
incontinence agents target the muscarinic recep-
tors to decrease acetylcholine. Previous studies
demonstrate that bladder anticholinergic agents
are associated with cognitive impairment in indi-
viduals with dementia, but literature describing
concurrent use of acetylcholinesterase inhibitors
and anticholinergics is limited to case reports
and small observational studies.
In a prospective cohort of nursing home
residents, the addition of either tolterodine or
oxybutynin to patients already receiving an
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| Fundamentals of Geriatric Pharmacotherapy
acetylcholinesterase inhibitor was evaluated. In
individuals with higher levels of baseline func-
tioning, the rate of decline in function (activities of
daily living and cognition) was 50% faster when
bladder anticholinergics were combined with
acetylcholinesterase inhibitors than when acetyl-
cholinesterase inhibitors were used alone.
56
Progression of dementia can exacerbate UI, and
this is a challenge for caregivers. Caution should
be exercised when anticholinergics are added
to a pharmacotherapy regimen in a patient with
dementia, as the risk for cognitive and functional
decline may not outweigh any improvement in
continence. These individuals should be closely
monitored when therapy is initiated and on an
ongoing basis.
28
It is important to evaluate the safety and
efficacy of newer agents in the older adult and
elderly population to determine the best choice
for pharmacotherapy. Although some of the
newer agents may offer better side effect profiles,
no clear improvement in efficacy has been
demonstrated. Cost is another issue for some
older adults, as many of the older agents are
available generically, and there may be formu-
lary and insurance restrictions. A sufficient trial
should be given, at least 1–2 months, to deter-
mine how well any agent is working. Monitor
carefully for side effects, objective evidence of
incontinence frequency, and patient satisfac-
tion with therapy. If an agent has not produced
an adequate response in 2 months, consider
discontinuing the drug or switching to another
agent in the appropriate category.
29
Surgery
Utilizing surgery as an option for the treatment
of UI is a consideration when behavioral modi-
fications, pelvic muscle rehabilitation, and/or
drug therapy have not been successful. Surgical
procedures to treat stress incontinence are
intended to correct urethral closure deficiencies
and to improve urethrovesical junction support.
Examples in women include bladder neck
needle suspension, anterior vaginal repair, or
suburethral sling procedures. There are poten-
tial adverse outcomes and risks with surgery,
including urge incontinence, voiding difficul-
ties, or pelvic organ prolapse.
39
In men, surgical
options for SUI include collagen or an artificial
urinary sphincter.
32
For patients with overflow incontinence,
there are not any effective surgical options for
bladder underactivity. After reversible causes
are excluded, self-catheterization by the patient
or a caregiver several times a day is one effec-
tive management strategy to empty the bladder.
Urethral overactivity is typically caused by some
type of anatomic obstruction. In men, this is often
explained by benign prostatic enlargement.
32
Benign Prostatic Hyperplasia
BPH is a common condition affecting older men
and a cause for significant urinary symptoms that
alter a man’s quality of life. Age is the predomi-
nant factor in establishing the prevalence and
histopathologic significance of BPH. Prostatic
hypertrophy develops typically after age 40, with
a 50% prevalence by age 60 and a prevalence
approaching 90% by age 85. Autopsy studies
show that an estimated 80% of elderly men
have microscopic changes consistent with BPH.
Approximately half the individuals with these
changes experience moderate to severe lower
urinary tract symptoms.
57-59
The prostate gland is surrounded by a
dense fibrous capsule composed of smooth
muscle cells, glandular cells, and supportive
stromal cells.
60
Alpha reductase is also found
within the prostate and facilitates the conversion
of testosterone to dihydrotestosterone (DHT).
At birth, prostate size resembles that of a pea,
growing during puberty to reach an adult size
by ages 25–30. A second growth spurt occurs
around age 40, and growth continues through the
seventh or eighth decades. The exact etiology of
BPH is unknown; however, age-related hormonal
changes, type II 5-alpha reductase, and circu-
lating androgens such as DHT are involved. The
pathogenesis of BPH is due to static factors,
including glandular enlargement of the prostate,
as well as to dynamic factors such as excessive
alpha-adrenergic tone of the stromal compo-
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9 - Renal and Urologic Disorders |
239
nent of the prostate gland, bladder neck, and
posterior urethra. This leads to the narrowing of
the urethral lumen by contraction of the pros-
tate gland surrounding the urethra. Ultimately,
anatomic enlargement of the prostate gland
and narrowing of the urethral lumen results in
obstructed urinary outflow.
57,60
Individuals with BPH often experience a
wide range of signs and symptoms of disease
that are classified as obstructive or irritative.
Obstructive symptoms, known as bladder
outlet obstruction (BOO) or prostatism, result
from decreased bladder emptying and include
hesitancy, urinary stream weakness, intermit-
tency, and the sensation of incomplete bladder
emptying. Irritative symptoms, which occur in
50% to 80% of patients with BPH, typically occur
later in the disease process and can be attrib-
uted to long-standing bladder neck obstruc-
tion. These symptoms often result in frequency,
nocturia, and urgency. Symptoms of BPH are
highly variable and may improve, worsen, or
remain stable; it is not necessarily a progressive
condition in all men.
57,60
An individual’s ability to
tolerate symptoms is often the motivation to seek
treatment.
Men with troubling lower urinary tract symp-
toms (LUTS) should be evaluated to assess
severity and the potential for causes other than
BPH, such as prostatitis and bladder or prostate
cancer. It is important to establish that symptoms
are truly due to BPH and not to other diagnoses
of LUTS.
59,60
The American Urological Associa-
tion Symptom Index (AUA-SI) for BPH and the
Disease-Specific Quality of Life Question is a
validated tool that can be used to objectively
determine BPH severity in men seeking treat-
ment (see Figure 9-2) and is superior to an
unstructured interview in quantifying the severity
and frequency of symptoms.
59
Refer to Figure
9-3 for an algorithm for diagnosis and treatment
from the American Urological Association.
59
Most recent guidelines from the American
Urological Association include two algorithms
for approaching the evaluation and treatment
of LUTS (see Figures 9-3 and 9-4). The first
describes basic management and classifies
diagnostic tests as either recommended (should
be performed on every patient during the initial
evaluation) or optional (test of proven value in the
evaluation of select patients). Optional tests are
generally performed during a detailed evalua-
tion by a urologist. If the initial evaluation reveals
LUTS associated with results of a digital rectal
exam suggesting prostate cancer, hematuria,
abnormal prostate-specific antigen levels, recur-
rent UTI, palpable bladder, history/risk of urethral
stricture, and/or a neurological disease raising
the likelihood of a primary bladder disorder,
patients should be referred to a urologist for
follow-up before initiation of treatment.
If initial evaluation finds the presence of
LUTS only, with or without mild prostate enlarge-
ment, treatment is not warranted, and the patient
can be seen again when symptoms become
bothersome. However, if the LUTS are both-
ersome to the patient, there may be several
causes, including benign prostatic obstruction,
OAB, and nocturnal polyuria. If nocturnal poly-
uria is the predominant symptom, and the patient
awakens two or more times nightly to void, guide-
lines recommend that a frequency volume chart
be completed by the patient. Nocturnal polyuria
is diagnosed when >33% of the 24-hour total
urine output occurs at night. On diagnosis, fluid
intake should be reduced and pharmacologic
agents (i.e., desmopressin) may be considered.
When symptoms persist, the patient should be
treated as having no significant nocturia, and
medical and pharmacological treatments should
be employed as necessary. Initial interventions
of modifiable factors should include decreased
nocturnal fluid intake, increased activity, and
avoidance of excess alcohol and other irritating
foods.
Basic management of patients with both-
ersome LUTS includes alteration of modifiable
factors and lifestyle advice, such as increasing
activity. Modifiable factors include concomi-
tant drugs, excess fluid intake at night, excess
alcohol intake, and highly seasoned or irritating
foods.
61
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240
| Fundamentals of Geriatric Pharmacotherapy
Figure 9-2. The American Urological Association Symptom Index for benign prostatic hyperplasia and the
Disease-Specific Quality of Life Question.
Source: Roehrborn CG, McConnell JD, Barry MJ, Benaim E, Bruskewitz RC, Blute ML, Holtgrewe, HL, Kaplan
SA, Lange JL, Lowe FC, Roberts RG, Stein BS: AUA Guideline on the Management of Benign Prostatic Hyper-
plasia: Diagnosis and Treatment Recommendations. American Urological Association Education and Research,
Inc., ©2003. http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=bph.
AUA-BPH Symptom Score
Not at
all
Less
than I
time
in 5
Less
than
half
the
time
About
half
the
time
More
than
half the
time
Almost
always
I . Over the past month, how often have you
had a sensation of not emptying your
bladder completely after you finished
urinating?
0 J 2 3 4 5
2. Over the past month, how often have you
had to urinate again less than 2 hours
after you finished urinating?
0 I 2 3 4 5
3. Over the past month, how often have
you found you stopped and started again
several times when you urinated?
0 I 2 3 4 5
4. Over the past month, how often have you
found it difficult to postpone urination?
0 I 2 3 4 5
5. 0ver the past month, how often have you
had a weak urinary stream?
0 I 2 3 4 5
6. Over the past month, how often have you
had to push or strain to begin urination?
0 I 2 3 4 5
None I time 2 times 3 times 4 times 5 or more
times
7. Over the past month, how many times did
you most typically get up to urinate from
the time you went to bed at night until the
time you got up in the morning?
0 I 2 3 4 5
Total Symptom Score
The Disease-Specific Quality of Life Question
The International Prostate Symptom Score uses the same seven questions as the AUA Symptom
Index
(presented above), with the addition of the following Disease-Specific Quality of Life
Question (bother score),
scored on a scale from 0 to 6 points (delighted to terrible):
“If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel
about that?”
Patient Name: DOB: ID: Date of assessment:
Initial Assessment ( ) Monitor during:
Therapy ( ) after: Therapy/surgery ( )
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241
Figure 9-3. Basic management of lower urinary tract symptoms (LUTS) in men.
AUA-SI, American Urological Association Symptom Index; DRE, digital rectal exam; PSA, prostate-specific
antigen.
Source: Reprinted from Abrams P, Chapple C, Khoury, S, et al. Evaluation and treatment of lower urinary tract-
symptoms in older men. J Urol. 2003 Jan;189:S93-S101. With permission from Elsevier.
Polyuria
1. Polyuria 24-hr output ≥3 L
Lifestyle and fluid intake is to be reduced
4
2. Nocturnal polyuria ≥33% output at night
Fluid intake to be reduced—consider
other causes
LUTS cause
little or no
bother
Reassurance
and follow-up
Complicated LUTS
• Suspicious DRE
• Hematuria
• Abnormal PSA
• Pain
• Infection
3
• Palpable bladder
• Neurological disease
Predominant significant
nocturia
Frequency-volume chart
1. When life expectancy is >10 yr and if the
diagnosis of prostate cancer can modify the
management. For the AUA PSA Best Practice
Statement: 2009 Update, see: www.uaunet.
org.
2.
When significant nocturia is a predominant
symptom.
3. Assess and start treatment before referral.
4. In practice, advise patients with symptoms to
aim for a urine output of a
bout 1 L/24 hr.
5. See Figure 9-4.
Recommended tests:
• Relevant medical history
• Assessment of LUTS
• Severity and bother (i.e., AUA-SI)
• Physical examination including DRE
• Urinalysis
• Serum PSA
1
• Frequency/volume chart
2
Bothersome LUTS
No polyuria
Standard treatment
• Alter modifiable factors
- Drugs
- Fluid and food intake
• Lifestyle advice
DRUG TREATMENT
5
FAILURE
Success in relieving
bothersome LUTS:
Continue therapy
DETAILED MANAGEMENT
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242
| Fundamentals of Geriatric Pharmacotherapy
Figure 9-4. Detailed management for persistent bothersome LUTS after basic management.
Source: Reprinted from Abrams P, Chapple C, Khoury, S, et al. Evaluation and treatment of lower urinary tract-
symptoms in older men. J Urol. 2003 Jan;189:S93-S101. With permission from Elsevier.
BOO: Bladder outlet obstruction
MIST: Minimally invasive surgical
treatment
OAB: Overactive bladder
PSA: Prostate-specific antigen
PVR: Post-void residual
Rx: Treatment
1
Consider checking PVR prior to
initiation
2
PSA < 1.5 ng/mL
3
PSA > 1.5 ng/mL
OAB
(Storage Symptoms)
No evidence of BOO
• Lifestyle intervention
• Behavioral therapy
• Antimuscarinics
1
Recommended tests:
• Validated questionnaires
• FVC (frequency/volume chart)
Optional tests:
• Flow rate recording
• Residual urine
Evidence of BOO
• Discuss RX options
• Shared decision
MIST
or surgery options
flow rate
(if not previously
used)
Medical therapy option
FAILURE
Mixed OAB
and BOO
Predominant BOO
Reassess and consider
invasive therapy of OAB
(i.e., Neuromodulation)
Antimuscarinics
1
and α-blocker
Small gland/and/or
low PSA
2
α-blocker
Larger gland and/or higher
PSA
3
α-blocker and/or
5α-reductase inhibitor
FAILURE
Offer MIST or surgery to patient
Evaluation clearly suggestive of
obstruction? (Omax<10 mL/s)
YES
NO
Pressure-flow studies
NO Obstruction
YES
Treat appropriately. If
interventional therapy
is pursued, patients
need to be informed of
possibly higher failure
rates
Proceed with selected
techniques
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243
Many pharmacological agents must be
avoided in men with BPH, because of the poten-
tial to worsen symptoms. Alpha-adrenergic
agonists used as decongestants (oral or intra-
nasal) can lead to muscle contraction secondary
to alpha-adrenergic receptor stimulation in the
prostate. Bladder emptying may be affected
because of changes to the urethral lumen.
Examples include pseudoephedrine, ephed-
rine, or phenylephrine. In general, drugs with
anticholinergic properties have the potential
to decrease contractility of the urinary bladder
detrusor muscle. This is especially problematic
in patients with BPH with a narrowed urethral
lumen and an enlarged prostate gland. This loss
of effective detrusor contraction can result in
urinary retention. Example agents include anti-
histamines, tricyclic antidepressants, antipsy-
chotics, or muscle relaxants. Despite this, anti-
cholinergic drugs must be used carefully when
LUTS persist despite traditional interventions.
In addition, opiates may impair autonomic func-
tion, and diuretics may lead to polyuria. Theoreti-
cally, testosterone replacement regimens used
in primary or secondary hypogonadism should
be used cautiously, as these agents can be
metabolized by the prostate to DHT.
57-69
If symp-
toms persist despite all of the above, pharma-
cologic therapy can be considered, and follow-
up assessment is recommended to assess
response to therapy. Time to follow-up is variable
depending on the agent chosen. Successful
treatment can be re-evaluated annually.
59
Treatment of BPH
Traditionally, the primary treatment goal has
been to alleviate bothersome LUTS. More
recently, treatment has addressed the preven-
tion of disease progression.
62
However, because
BPH is a disease characterized by symptoms,
treatment continues to be focused on deter-
mining the severity of the symptoms and the
individual’s desire to relieve those symptoms.
Generally, pharmacologic therapy focuses on
reducing the dynamic factor via agents that
relax prostatic smooth muscle, reducing the
static factor via agents that interfere with testos-
terone’s stimulatory effect on prostate gland
enlargement, or a combination of both. Treat-
ment and management options include watchful
waiting, drug therapy, and surgical interventions.
The American Urology Association Guidelines
on the Management of BPH are a primary tool
governing treatment decisions in the United
States. Within this guideline, the AUA-SI and
Quality of Life questionnaire shown in Figure 9-2
is used to survey patients to identify their total
symptom score. Disease severity is classified as
mild, moderate, or severe based on the score
(mild is ≤7, moderate is 8–19, and severe is ≥20).
According to the guidelines, patients with either
mild symptoms or those with moderate-severe
scores who are not bothered by their LUTS should
be managed using watchful waiting. Generally,
these individuals will not benefit from therapy
because symptoms do not have a significant
impact on the quality of life.
59
Watchful waiting
involves annual visits for reassessment and
education about behavioral strategies that may
assist with symptom management (i.e., avoiding
medications that can exacerbate BPH).
57-59
Individuals with bothersome moderate to
severe symptoms and a score ≥8 have several
treatment options available, including medical
watchful waiting, medical therapies (alpha-
adrenergic blockers/antagonists or 5-alpha
reductase inhibitors [5ARIs]), minimally inva-
sive therapies (transurethral microwave heat
treatments or transurethral needle ablation), or
surgical therapies (transurethral resection of the
prostate or open prostatectomy). The risks and
benefits of each option should be discussed
with the patient to allow the most individual-
ized therapy. If a patient’s LUTS are bother-
some despite basic management strategies, a
urologist should be consulted. If drug therapy
is considered, agents should be chosen based
on coexisting OAB symptoms and prostate
size/prostate-specific antigen (PSA) levels (see
Figure 9-4).
59
Coexisting OAB symptoms and prostate
size (or serum PSA levels) can help to deter-
mine what kind of drug therapy is most appro-
priate. When a patient has BOO in addition to
OAB symptoms, a combination of alpha-adren-
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| Fundamentals of Geriatric Pharmacotherapy
ergic blockade and anticholinergic therapy is
warranted. However, when BOO symptoms are
more significant, alpha-adrenergic blockers
(AABs) are the first line. When the prostate is
enlarged, alpha blockers alone, 5ARIs alone,
and/or a combination of the two have shown to
be most efficacious.
59
Current drug treatment options for BPH
generally include AABs (also known as alpha-
adrenergic antagonists), 5-alpha reductase
inhibitors (5ARIs), or a combination of the two
classes. Ideally, drug therapy should be initiated
with a single agent before combination. Gener-
ally, AABs are the preferred first agent because
they have a faster onset and are more effective
than 5ARIs. AABs are also effective in reducing
LUTS independent of prostate size, have no
effect on PSA, and are associated with less
sexual side effects compared to 5ARIs. However,
if a patient has a significantly enlarged prostate
(>40 g) and cannot tolerate the cardiovascular
effects of AABs, 5ARIs are recommended. For
patients at high risk of developing complica-
tions associated with BPH (prostate gland >40 g
and PSA ≥1.4 ng/mL), combination therapy with
both AABs and 5ARIs is appropriate.
62,63
In these
patients, combination therapy quickly relieves
symptoms, delays disease progression, and
reduces the need for surgical intervention.
57
Short-term improvements, including the
relief of BPH symptoms and an increased urinary
flow, have been demonstrated with both AABs
and 5ARI therapy. No clear evidence is avail-
able to prove that AABs alone can reduce the
need for future prostate surgical procedures,
but 5ARIs have shown reductions in the need
for surgical interventions.
66
Overall, drug therapy
is not as efficacious as surgical interventions;
however, this option may offer symptomatic
relief, with fewer and less severe associated
adverse events.
59
AABs relieve symptoms in men suffering
from moderate to severe BPH. Smooth muscles in
the prostate gland contract in response to stimu-
lation by alpha receptors, leading to constriction
of the prostatic urethra. AABs improve LUTS by
encouraging smooth muscle relaxation. AABs
used in the treatment of BPH include alfuzosin,
doxazosin, tamsulosin, terazosin, and silodosin.
With the emergence of newer, more convenient,
and safer options, older AABs such as phenoxy-
benzamine and prazosin are not currently recom-
mended in the treatment of BPH.
59
Tamsulosin
and silodosin are third-generation AABs, and
the remaining are second-generation. In addi-
tion to prostate effects, doxazosin and terazosin,
considered to be nonselective alpha
1
adrenergic
antagonists, also decrease blood pressure by
their effect on vascular smooth muscle and carry
an FDA labeling for hypertension. However,
AABs are not preferred as single-drug therapy
for treatment of both BPH and hypertension in a
patient.
57
Due to their mechanism of action and
peak onset, immediate-release formulations of
doxazosin and terazosin should be administered
at bedtime.
57
Tamsulosin, alfuzosin, and silodosin are
newer agents that treat constriction of prostate
smooth muscle.
59,64,69
Tamsulosin is a selec-
tive antagonist of alpha
1a
adrenoreceptors
of the prostate, whereas alfuzosin and silo-
dosin are selective antagonists of postsynaptic
alpha
1
adrenoreceptors located in the prostate,
bladder base, bladder neck, prostatic capsule,
and prostatic urethra.
67,68
Alpha blockers may
cause orthostatic hypotension, and nonselective
agents must be started at a low dose and titrated
to efficacy; dose titration is not required for alfu-
sozin.
68
By targeting the lower urinary tract and
prostatic smooth muscles, tamsulosin and alfu-
zosin appear to have favorable safety profiles;
however, warnings for syncope and orthostatic
hypotension remain in the product labeling.
66,67
The incidence of orthostatic hypotension is
increased when alpha blockers are combined
with drugs that can exacerbate hypotension, and
caution must be exercised in these situations.
58
Alfuzosin, doxazosin, tamsulosin, and tera-
zosin are recommended as appropriate treat-
ment options for LUTS secondary to BPH, and,
according to the most recent AUA Guideline,
all are equally efficacious in the management
of LUTS secondary to BPH.
59
There are differ-
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9 - Renal and Urologic Disorders |
245
ences among these drugs regarding adverse
event profiles, but in terms of clinical effective-
ness the drugs are similar. Treated patients can
expect a 30% to 40% improvement in AUA-SI
within 2–6 weeks, depending on the need for
up-dose titration.
57
Time to peak effect for BPH
symptoms differs among the agents: tamsulosin
and alfuzosin generally will peak within several
days, whereas doxazosin and terazosin may
take several weeks.
57
Methodically sound trials
that compare these agents against each other
are needed to show superiority for any particular
one.
59
Numerous trials document that doxazosin,
terazosin, alfuzosin, and tamsulosin are effec-
tive as single agents in both symptom relief and
increased urine flow when compared to placebo.
Doxazosin monotherapy has also demonstrated
decreased long-term complications of BPH,
including UI, urinary retention, and renal insuf-
ficiency.
57
Unlike tamsulosin, silodosin, the most
recently approved AAB, requires dosage adjust-
ment for renal impairment (50% of normal dosing
for CrCl <50 mL/min, contraindicated in CrCl
<30 mL/min) and hepatic impairment (contra-
indicated with Child-Pugh ≥10), has increased
potential for drug interactions, and limited expe-
rience in clinical practice. Due to these factors,
tamsulosin is currently the preferred third-gener-
ation AAB.
79
DHT is an androgenic hormone that
stimulates growth of the prostate. The 5ARIs,
finasteride and dutasteride, inhibit the conver-
sion of testosterone to DHT.
58
These medications
offer more benefit when the prostate volume is
>40 mL.
65
One meta-analysis suggested that
finasteride is more effective in men with large
versus small prostate size.
69
Alpha reductase inhibitors are appropriate
and effective options for individuals with pros-
tate enlargement and LUTS and have been
shown to modify the clinical disease course
and potentially reduce the risk of urinary reten-
tion and surgical interventions.
59,70
PSA levels
are decreased with 5ARI therapy, so it is recom-
mended to obtain baseline PSA levels prior to
beginning treatment. Although the guidelines
suggest that cancer detection is not masked, it is
recommended to perform PSA and rectal exams
annually, and any increases in PSA should be
evaluated for medication noncompliance and/or
prostate cancer.
57,59
Differences exist between finasteride and
dutasteride. Finasteride competitively inhibits
type II 5-alpha reductase and lowers intrapros-
tatic DHT by 80% to 90% and serum DHT by
70%. On the other hand, dutasteride is a dual
nonselective inhibitor of type I and II 5-alpha
reductase. Intraprostatic DHT production is
quickly and completely suppressed, and serum
DHT is decreased by about 90% with dutaste-
ride. Despite these pharmacodynamic differ-
ences, direct comparison trials have not shown
any advantage of these actions in favor of dutas-
teride, and both agents have demonstrated
comparable efficacy in reducing prostate size.
57
One important consideration is that 5ARIs
are not as effective as an alpha blocker in
improving LUTS. These agents are not an
appropriate treatment recommendation for
men without prostate enlargement.
59
Alpha-
reductase inhibitors do not provide immediate
symptom relief; 6 months of therapy is generally
required to achieve clinical benefit.
71
Overall, an
evidence-based review determined that 5ARI
therapy partially relieves symptoms but is less
effective for symptom control than alpha blocker
therapy. However, due to the more progressive
disease in men with larger prostate glands or for
those with higher PSA values, 5ARIs have a role
in modifying BPH and its clinical course that is
not found with alpha blockers.
59,72
There are instances when combination
therapy with alpha blockers and 5ARIs may be
beneficial, especially in men with larger pros-
tate size and elevated PSA.
59,62,73
These patients
appear to be at increased risk for disease
progression, highlighted by worsening symp-
toms and complications of disease.
57
Combina-
tion therapy makes sense theoretically in that the
alpha blocker will begin to work for symptomatic
relief until the finasteride can begin to reduce
prostate size. Combination therapy with finaste-
ride and doxazosin has been most investigated.
59
Recent studies have been conducted involving
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246
| Fundamentals of Geriatric Pharmacotherapy
dutasteride and tamsulosin, and this prompted
FDA approval for dutasteride and tamsulosin in
combination for the treatment of symptomatic
BPH in men with an enlarged prostate.
73,74
Two
large studies, the MTOPS and the ComBAT, eval-
uated combination drug therapy versus mono-
therapy using either doxazosin and finasteride
or dutasteride and tamsulosin. Although there
were baseline differences between the MTOPS
and ComBAT study groups, the results of the two
studies support the use of combination therapy
in men with prostate enlargement and moderate
to severe LUTS in achieving further symptomatic
benefit.
74-77
Alpha blockers, 5ARIs, or even surgery
(discussed below) may all improve bladder
emptying or urinary flow. However, there is a
potential role for the addition of an anticholin-
ergic agent such as oxybutynin or tolterodine
to improve irritative voiding symptoms (e.g.,
frequency and urgency associated with BPH).
57
LUTS, BPH, and OAB are related, but the mech-
anisms linking them are not well understood.
One theory is that BOO may lead to OAB.
78
Anticholinergic agents can reduce detrusor
contractions by blocking muscarinic receptors in
the detrusor muscle. Because older adults are
especially sensitive to the CNS adverse effects
and dry mouth of anticholinergic drugs, they
must be chosen carefully and used with extreme
caution, as discussed in the Types of Urinary
Incontinence section of this chapter. The current
AUA Clinical Practice Guideline suggests that
the use of anticholinergic agents in combination
with AABs is appropriate in patients with mixed
OAB and BOO.
70
Use of anticholinergic agents
in individuals with BPH may also lead to acute
urinary retention or increased postvoid residual
(PVR) urine volume.
57,78
Therefore, baseline PVR
is recommended before initiation of anticholin-
ergic therapy.
70
Emerging erapies
Phosphodiesterase (PDE) inhibitors increase the
concentration and prolong the activity of intracel-
lular cGMP, hereby reducing smooth muscle tone
of the detrusor, prostate, and urethra. Until now,
11 different PDEs have been identified, of which
PDE 4 and PDE 5 are predominant in the tran-
sition zone of the human prostate, bladder, and
urethra.
80,81
Nitric oxide might also be involved in
the micturition cycle by inhibiting reflex pathways
in the spinal cord and neurotransmission in the
urethra, prostate, or bladder.
82
Sildenafil, tadalafil,
and vardenafil have been studied in recent trials
both alone and with AABs. These trials demon-
strated that all PDE 5 inhibitors (PDE5Is) signifi-
cantly and consistently reduced International
Prostate Symptom Scores by approximately 17%
to 35%. Both bladder storage and voiding symp-
toms decreased equally during treatment with
PDE5Is.
83-90
However, trials were conducted on a
limited number of patients for a very short dura-
tion (maximum 12 weeks) and, therefore, PDE5Is
are not currently recommended for use in LUTS.
91
Although tadalafil gained FDA approval for BPH,
current guidelines do not recommend it as first-
line therapy.
59,91
Dietary Supplements
In addition to pharmacological agents, alter-
native therapies may be considered by some
patients. Saw palmetto plant extract (Serenoa
repens) has been used to manage the LUTS of
BPH. The mechanism of action of saw palmetto
is unknown in the management of BPH. Possible
proposed mechanisms include preventing the
conversion of testosterone to DHT, potential anti-
inflammatory activity, or prostate epithelial invo-
lution similar to effects noted with other 5ARIs.
91
This proposed mechanism of saw palmetto
suggests a possible drug interaction between
this product and standard drug therapy for BPH.
Individuals should be counseled and warned
about this combination. There have been mixed
opinions regarding the value of saw palmetto.
Although trials and meta-analyses exist that
clearly demonstrate the efficacy of Serenoa
repens in improving symptom scores and
maximum flow rate, current practice guidelines
do not recommend saw palmetto or other forms
of phytotherapy for BPH, because of the lack of
long-term studies.
59,92-95
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