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Figure 109-1 Neurologic bladder control.

Age-Related Changes

Aging affects the lower urinary tract in several ways (Table 109-1), including both

structural and functional changes. Bladder capacity, the ability to postpone voiding,

urethral and bladder compliance, maximal urethral closure pressure (the maximal

difference between the urethral and the intravesical pressure), and urinary flow rate

all are reduced with normal aging.

2,3 For women, these changes are correlated with

the postmenopausal decline of estrogen production. Estrogen has trophic effects on

the epithelium and on tissues lining and surrounding the urethra, bladder outlet, and

vagina. Atrophy of these tissues can result in friability, inflammation, susceptibility

to infection, diminished periurethral blood flow, and prolapse of pelvic structures.

All of these effects can precipitate symptoms of urinary incontinence. For men, the

age-related changes in the prostate gland are responsible for many of the changes in

urination. The most common age-related change, in both women and men, is

involuntary bladder contractions (detrusor motor instability). These involuntary

bladder contractions occur in up to 20% of asymptomatic, neurologically normal,

continent elderly patients.

4–7

Table 109-1

Age-Related Changes in Urologic Function

↓ Bladder capacity

↑ Residual urine

↑ Uninhibited bladder contractions

↑ Nocturnalsodium and fluid excretion

↓ Urethral resistance in women

↑ Urethral resistance in men

Weakness of pelvic floor muscles in women

Table 109-2

Causes of Incontinence

Mnemonic: DIPPERS

D Delirium

I Infection

P Psychological

P Pharmaceuticals

E Excess urine output

R Reduced mobility

S Stool impaction (and other factors)

Source: Wagg A et al. Urinary incontinence in frail elderly persons: report from the 5th International Consultation

on Incontinence. Neurourol Urodyn. 2015;34(5):398–406.

Each of these changes predisposes people to incontinence, but none alone

precipitates it. This predisposition to incontinence, together with the increased

likelihood that an older person will be subjected to additional pathologic,

physiologic, or pharmacologic insults, underlies the higher incidence of incontinence

in the elderly. The onset or exacerbation of incontinence in an older person is likely

to be caused by a precipitating factor outside the lower urinary tract.

8 Common

treatable causes of urinary incontinence in the elderly can be described with the

mneumonic DIPPERS (Table 109-2).

9 Correspondingly, reversal of the precipitating

factor may be sufficient to restore continence without correction of the underlying

urologic abnormality.

Loss of bladder control in the elderly was reported in 36.7% of short-term

residents and 70.3% of long-term residents in nursing homes.

10 Moderate, severe, and

very severe levels of bladder incontinence were identified in 24.0% of

noninstitutionalized elderly patients.

10

Incontinence has economic costs, and medical

(e.g., cystitis, urosepsis, pressure sores, perineal rashes, falls) and psychosocial

(e.g., embarrassment, isolation, depression, predisposition to institutionalization)

consequences. Nevertheless, incontinence often is a neglected condition. Patients

may not report incontinence to their primary-care providers because of

embarrassment or misconception regarding treatment. Incontinence is not an

inevitable consequence of aging. It is a pathologic condition that, when rationally

approached, usually can be ameliorated or cured, often without invasive tests or

surgery and almost invariably without an indwelling catheter.

11,12

Classification

Urinary incontinence can be classified in several different ways. The two most basic

types of urinary incontinence are (a) acute

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( o r transient) and reversible and (b) chronic and persistent. Persistent urinary

incontinence (PUI), which refers to incontinence that is not acute and occurs for a

long time, can be classified further into four subgroups: (a) urge, (b) stress, (c)

overflow, and (d) functional.

ACUTE INCONTINENCE

Urinary incontinence that is of relatively recent onset or associated with an acute

medical problem should prompt a review for reversible factors. These include the

following: (a) cystitis, atrophic vaginitis, and urethritis; (b) heart failure; (c) polyuria

from diabetes; (d) delirium and acute confusional states; (e) immobility; and (f)

medication side effects (discussed subsequently). The management of acute forms of

urinary incontinence depends on the identification and elimination of the reversible

factor.

For women with urethritis and atrophic vaginitis with irritative voiding symptoms,

estrogen replacement can be very helpful. An intravaginal estrogen cream is

administered nightly for 7 days, followed by at least once-a-week application.

13

In

keeping with the Women’s Health Initiative trial, serious risks, including breast

cancer and cardiovascular disease, appear to outweigh long-term benefits of

systemic combination of hormone therapy. Therefore, topical therapy is preferred.

14

Drug-Induced Urinary Incontinence

Several medications are associated with acute-onset urinary incontinence, including

diuretics, α-adrenergic agonists (e.g., pseudoephedrine), α-adrenergic antagonists

(e.g., terazosin), anticholinergics, and neuroleptics.

Reports of female stress incontinence from α1

-adrenergic receptor antagonists,

which have a relaxant effect on urethral smooth muscle, have appeared in the medical

literature.

15–17

In one study, the incidence of genuine stress incontinence was

significantly higher in women taking prazosin (86.2%) than in the group without

prazosin (65.7%; p <0.01). In 55% of the women contacted in the prazosin group,

urinary incontinence was reduced or cured by prazosin withdrawal.

18 There was a

significant increase in functional urethral length, maximal urethral closure pressure,

and abdominal pressure transmission to the urethra after prazosin withdrawal. In one

case report, switching from doxazosin to enalapril briefly reduced the female

patient’s stress incontinence; however, she experienced a persistent dry cough (from

the enalapril) that continued to cause episodic stress incontinence. Her cough and

stress incontinence resolved when she was switched to amlodipine.

19

PERSISTENT URINARY INCONTINENCE

Urge Incontinence

Urge incontinence, the most common form of incontinence affecting the elderly,

occurs when involuntary voiding is preceded by a warning of a few seconds to a few

minutes. Urge PUI is characterized by precipitous urine leakage, most often after the

urge to void is perceived. Urge PUI can be caused by a variety of genitourinary and

neurologic disorders. It most often, but not always, is associated with detrusor motor

instability (involuntary contraction of the bladder) or detrusor hyper-reflexia

(detrusor motor instability caused by a neurologic disorder). The most common

causes are local genitourinary conditions, such as cystitis, urethritis, tumors, stones,

bladder diverticula, and outflow obstruction. Neurologic disorders, such as stroke,

dementia, parkinsonism, and spinal cord injury, can be associated with urge PUI.

8

Overactive bladder is a medical syndrome defined by symptoms of urgency, with or

without urge urinary incontinence, usually with frequency and nocturia. By definition,

overactive bladder is a syndrome and not a diagnosis.

Stress Incontinence

Stress incontinence is the involuntary leakage of urine that occurs when an abrupt

increase in intra-abdominal pressure (“stress,” e.g., coughing, sneezing, laughing,

lifting) overcomes urethral resistance. Stress incontinence is common in elderly

women but uncommon in men (unless the sphincter has been damaged during a

transurethral resection of the prostate [TURP] or a prostatectomy). Typical stress

PUI is characterized by daytime loss of small-to-moderate amounts of urine,

infrequent nocturnal incontinence, and a low postvoid residual volume in the absence

of a large cystocele. Stress incontinence can be diagnosed by the “tissue test” in

which a tissue is placed just below the urethra and the patient is asked to cough,

resulting in the loss of a small amount of urine. The usual cause of stress PUI is

urethral hypermobility owing to weakness and laxity of pelvic floor musculature, but

other conditions, such as sphincter incompetence, urethral instability, or stressinduced detrusor instability, occasionally are responsible.

2 Obesity or TURP in men

also can predispose individuals to stress incontinence. Many factors have been

suggested to contribute to the development of urinary stress incontinence in women,

including estrogen deficiency and a genetic defect in the connective tissue in such

patients. The prevalence of urinary stress incontinence among first-degree relatives

of patients with urinary incontinence is 3 times (p < 0.005) that of matched control

groups of women without micturition disorders.

20

Overflow Incontinence

Overflow incontinence occurs when the weight of urine in a distended bladder

overcomes outlet resistance. Leakage of small amounts of urine (dribbling) is

common throughout the day and night. The patient may complain of hesitancy,

diminished and interrupted flow, a need to strain to void, and a sense of incomplete

emptying. The bladder usually is palpable, and the residual urine volume is large.

Overflow incontinence results from an anatomic outlet obstruction or an

acontractile (or atonic) bladder.

8 Common causes are benign prostatic hyperplasia

(BPH), urethral stricture, bladder sphincter dyssynergia, diabetic neuropathy, fecal

impaction, and anticholinergic medication use. If the cause is neurologically

mediated, control of the perianal sphincter may be impaired.

21

Functional Incontinence

Functional incontinence occurs when a continent individual is unable or unwilling to

reach the toilet to urinate. Common causes are musculoskeletal disorders, muscle

weakness, impaired mental status, use of physical restraints, psychological

impairment, environmental barriers, and medications (e.g., sedatives, neuroleptics).

Clinical Presentation and Evaluation

CASE 109-1

QUESTION 1: H.K., an 83-year-old female resident of a nursing facility with moderate dementia, had urinary

incontinence 3 years before admission. She has been managed with adult diapers (briefs) and bladder training.

What objective and subjective data are needed to determine the pathophysiology (and hence the classification)

of H.K.’s urinary incontinence?

The rationale for the clinical evaluation of H.K. is to classify the imbalance

between bladder pressure and bladder sphincter resistance and, as a result, institute

appropriate medical or surgical management of her urinary incontinence.

Documentation of H.K.’s urinary incontinence is accomplished most easily by

keeping an incontinence record. Observations should be recorded every 2 hours

regarding whether she is wet or dry, as well as associated symptoms or

circumstances. A record maintained for 3 to 4 days will facilitate assessment of the

voiding pattern. Knowledge of the voiding pattern can be used to design

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bladder training programs and to detect iatrogenic causes (e.g., diuretic ingestion,

use of restraints). Successful bladder training relies on estimating when the bladder

is full.

Physical examination, including a neurologic assessment, of H.K. is needed to

determine the cause and classification of her urinary incontinence. Clinical findings

may identify specific pathophysiologic abnormalities. H.K. should have a thorough

pelvic examination to determine the contribution of atrophic vaginitis, uterine

prolapse, and bladder anatomy. Funneling of the bladder neck suggests stress

incontinence, and palpation of the bladder suggests overflow incontinence. The

presence of physical restraints or musculoskeletal disability would suggest functional

incontinence.

H.K.’s bladder should be catheterized immediately after urination to determine

residual urine volume. Alternatively, if a bladder ultrasound is available, the volume

can be measured noninvasively. Volumes in excess of 50 to 100 mLin the elderly are

abnormal and may indicate retention due to obstruction or an adynamic detrusor

muscle. If urinary retention is chronic, the patient may require clean intermittent selfcatheterization. Although urodynamic studies are widely recommended and used,

little evidence suggests that these produce clinically useful data for institutionalized

geriatric patients. A urinalysis, blood chemistries, renal function, and postprandial

glucose tests should be performed. An abnormal urinalysis may suggest pathology

(e.g., infection) that can be managed medically. Urinary tract infection is common in

the incontinent patient.

Treatment options exist for each type of urinary incontinence (Table 109-3).

Proper evaluation should guide the clinician in choosing the optimal course of drug

therapy. Drug therapy should be based on sound principles of neurophysiology,

urology, and pharmacology. Drug therapy is directed at decreasing bladder

contractility (detrusor instability) or increasing bladder outlet resistance (bladder

neck and proximal urethra).

Table 109-3

Drug Therapy of Persistent Urinary Incontinence

Type Treatment With Initial Doses

Urge Oxybutynin 2.5 mg every day to TID; 5–30 mg XL every day

Oxybutynin transdermal patch 3.9 mg/24 hour 1 patch 2×/week

Oxybutynin 10% topical gel 100 mg/g every day

Oxybutynin 3% topical gel 84 mg (3 pumps) every day

Tolterodine 1–2 mg every day; 2–4 LA every day

Trospium 20 mg BID; 60 mg ER every day

Darifenacin 7.5 mg every day

Solifenacin 5 mg every day

Fesoterodine 4 mg every day

Stress Pseudoephedrine 15–30 mg BID–TID

Imipramine 25 mg every day

Vaginal estrogen cream 0.5–1.0 g 2 to 3 times/week

Duloxetine 40–80 mg every day divided in one or two doses

Overflow Terazosin 1–5 mg every day (usually at bedtime)

Doxazosin 1–8 mg every day

Tamsulosin 0.4–0.8 mg every day

Alfuzosin 10 mg every day

Silodosin 4–8 mg every day

Bethanechol 10 mg TID

Functional None

BID, 2 times daily; LA, long acting; TID, 3 times daily; XL, extended release.

CASE 109-1, QUESTION 2: The incontinence record maintained by the nursing staff indicates that H.K. has

urinary urges quite frequently, resulting in urine leakage. Throughout the day and night, H.K. urinates 4 to 5

times. Physical examination reveals atrophic vaginitis, no funneling of the bladder neck, and no bladder

distension. H.K. does have a history of stroke. The urinalysis is normal, as are the blood chemistries.

Postvoiding bladder scan revealed a residual urine volume of 30 mL. What is the pathophysiology and

classification of H.K.’s incontinence?

Most neuropathic disease processes can change bladder function. As illustrated by

H.K., a cerebrovascular accident is commonly associated with bladder dysfunction

and incontinence in the elderly. Neurologic injury above the level of the micturition

center in the spinal cord, in most cases, results in bladder spasticity. Sacral reflexes

are intact, but loss of inhibition from higher CNS centers results in spastic bladder

and inappropriate sphincter behavior. The degree of spasticity varies between the

bladder and sphincter, as well as from patient to patient with the same CNS lesions.

H.K. has a spastic detrusor muscle resulting from an unchecked sacral reflex. H.K.’s

bladder dysfunction is classified as urge urinary incontinence of the persistent type.

Nonpharmacologic Therapy

A number of nonpharmacologic options are available that may help improve the

symptoms of PUI. The first step is to educate patients about bladder function,

appropriate fluid intake, and avoidance of caffeine and other bladder irritants. The

patient can then keep a bladder diary in which they record their fluid intake, voiding

pattern, and incontinence episodes. Bladder training refers to scheduled voiding,

urge-suppression techniques, and pelvic muscle exercises. Scheduled voiding can be

used in both cognitively intact and impaired individuals. The patient is instructed to

void on a schedule (e.g., every 2 hours), thereby minimizing the volume of urine in

the bladder and making incontinence episodes less likely. The same principle can be

used in cognitively impaired patients by prompting them to toilet. Urge-suppression

techniques can be used to retrain the bladder; the scheduled toiletings are adjusted

for longer or shorter times, depending on the patient’s voiding pattern. The goal is to

achieve an interval during which the patient is continent and does not need to void. In

most patients, this is approximately 2 hours. Pelvic floor muscle exercises, also

known as Kegel exercises, work by increasing the strength and tone of the pelvic

floor muscles. In randomized trials, incontinence episodes were reduced by 54% to

75% compared with 6% to 16% with no treatment.

22 The patient should receive

adequate instruction on how to identify the pelvic floor muscles and then practice

these exercises 3 times a day.

CASE 109-1, QUESTION 3: What nonpharmacologic therapy should be recommended for H.K.?

H.K. should have a comprehensive review of her medications completed to

determine any temporal relationship between medications and incontinence episodes.

She should then be placed on a toileting schedule in which she is prompted to void

every 2 hours. The nursing staff should continue to keep a bladder diary in which they

record fluid intake and when she is wet and dry. This information can be used to

tailor her toileting schedule to make sure H.K. has the best outcome while at the same

time being practical, based on staffing at the institution. Because of H.K.’s moderate

dementia, the teaching of pelvic floor muscle exercises may not be feasible.

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Drug Therapy

ANTICHOLINERGIC AGENTS

CASE 109-1, QUESTION 4: What drug therapy should be prescribed for H.K.?

H.K. has detrusor instability that may respond to anticholinergic drug therapy if

nonpharmacologic measures do not produce desired results. The major

neurohormonal stimulus for physiologic bladder muscle contraction is acetylcholineinduced stimulation of postganglionic parasympathetic cholinergic receptor sites on

bladder smooth muscle. Atropine and atropine-like substances depress true

involuntary bladder contractions of any etiology by the interaction at the muscarinic

receptor.

23 Of the five known muscarinic subtypes (M1

through M5

), M3 appears to be

the most clinically relevant in the human bladder. M2 muscarinic receptors are the

predominant subtype (comprising about 80% of all muscarinic receptors); however,

contraction of smooth muscle, including muscles in the urinary bladder, is mediated

mainly by M3

receptors. M3

receptors are also involved in contraction of the

gastrointestinal smooth muscle, saliva production, and iris sphincter function.

24

Inhibition of the muscarinic receptors in the urinary bladder results in decreased

urinary bladder contraction, increased residual urine volume, and decreased detrusor

muscle pressure.

Oxybutynin Chloride

Oxybutynin is available as an oral immediate-release tablet, an extended-release

tablet, a transdermal system, and a topical gel. Oxybutynin has been described as a

strong independent smooth muscle relaxant with local anesthetic activity and

anticholinergic effects.

23,25 This agent has been used successfully to depress

uninhibited detrusor contractions in patients with and without neurogenic bladder

dysfunction. Oxybutynin improves symptoms, total bladder capacity, neuropathic

voiding dysfunction, and bladder filling pressure.

26–28 The oral dosage of oxybutynin

chloride suggested for the elderly is 2.5 mg up to 3 times a day; in some cases, the

dosage may need to be increased to 5 mg 3 times a day. Because oxybutynin is a

tertiary-amine anticholinergic compound and also blocks central M1

receptors, the

potential for CNS toxicity increases as the dose is increased. Once-daily, controlledrelease oxybutynin at doses of 5 to 30 mg reduced the number of incontinence

episodes.

29,30 Maximal benefit was demonstrated by maintenance week 4 and was

sustained as long as the patient continued therapy.

31

The transdermal system is available both in a prescription and over-the-counter

version and contains 36 mg of active drug and delivers 3.9 mg of oxybutynin per day

when dosed twice a week.

32 The transdermal system should be protected from

moisture and humidity. Common side effects from the transdermal system at the

application site are pruritus (14%) and redness (8.3%). A comparison study of

immediate-release oxybutynin and the transdermal system indicated that patients

using the transdermal system experienced fewer side effects. Dry mouth was reported

in 38% of the oxybutynin transdermal system users in contrast to 94% of those who

used immediate-release tablets.

33 Oxybutynin is also available as a 10% topical gel

in 1-g unit dose sachets. One sachet delivers 100 mg and is applied per day to the

abdomen, thigh, upper arm, or shoulder. It is also available as a 3% gel in a multidose container. The dose is three pumps (84 mg) daily. Application site reactions

were reported in 5.4% of patients, and dry mouth was reported in 6.9% of patients.

34

Tolterodine Tartrate

Tolterodine is a competitive muscarinic receptor antagonist that is relatively

selective for M2 and M3

receptors. It is indicated for the treatment of overactive

bladder symptoms of urinary frequency or urge incontinence. At doses of 1 to 2 mg

twice a day, compared with a placebo, the number of urinary voids per 24 hours

decreased (p = 0.0045), the volume of urine per void increased (p < 0.001), and the

mean number of incontinence episodes decreased by 50% (p < 0.19).

35 Although

tolterodine can modestly prolong the QT interval, no clinical or electrocardiographic

evidence was seen of significant cardiac adverse events in the group studied.

35,36 The

onset of pharmacologic action of tolterodine is less than 1 hour, and therapeutic

efficacy is maintained during long-term treatment.

Despite short terminal half-lives of 2 to 3 hours and 3 to 4 hours for tolterodine

and its active 5-hydroxy metabolite, respectively, twice-daily dosing is effective

because of the drug’s long pharmacodynamic effects.

37 Dosage adjustment is

recommended in the presence of renal or hepatic impairment and during concurrent

therapy with drugs that inhibit cytochrome P-450 (CYP) 2D6 and CYP3A4 isozymes.

The usual dose for the elderly is 1 to 2 mg twice daily of the immediate release or 2

to 4 mg once daily of the long-acting formulation. The incidence of dry mouth with

the long-acting formulation is 23%.

36

Fesoterodine

Fesoterodine is an antimuscarinic prodrug that is converted into the same active

metabolite as that of tolterodine. The efficacy and safety of fesoterodine appear

comparable to those of tolterodine.

38 The recommended starting dosage of

fesoterodine is 4 mg once daily and may be increased to 8 mg in patients with an

insufficient response. Patients with severe renal impairment (creatinine clearance

<30 mL/minute) or those taking a strong CYP3A4 inhibitor should not take more than

4 mg/day.

Trospium Chloride

Trospium is a quaternary ammonium antimuscarinic agent with relative selectivity for

M2 and M3

receptors. It is used for the management of overactive bladder and urge

incontinence. The hydrophilic properties of trospium minimize the passage of the

drug through the blood–brain barrier, thereby causing fewer CNS and cognitive

adverse events.

39 No significant differences were found in urodynamic outcomes

between trospium and oxybutynin in a 52-week study.

40 The reduction in 24-hour

micturition frequency and urgency episodes at 26 and 52 weeks of treatment was also

not significant. However, the incidence of dry mouth and gastrointestinal adverse

events was significantly lower in the trospium group. The medication should be

administered at a dose of 20 mg twice daily or 60 mg of the extended-release product

once daily. For patients with severe renal insufficiency (creatinine clearance <30

mL/minute), the dose should be reduced to 20 mg once daily. Trospium has no CYPrelated drug interactions and should be taken on an empty stomach to avoid

decreasing absorption.

Darifenacin

Darifenacin is a selective M3 muscarinic receptor antagonist indicated for the

treatment of overactive bladder with symptoms of urinary incontinence, urgency, and

frequency. A pooled analysis of three 12-week, double-blind, placebo-controlled

trials (n = 1,059) demonstrated that darifenacin reduced the median number of

incontinence episodes per week (p < 0.01) versus placebo.

41 Dry mouth and

constipation were the most common reasons for discontinuation. The recommended

starting dose is 7.5 mg once daily. Based on the individual response, the dose may be

increased to 15 mg daily after 2 weeks.

Solifenacin

Solifenacin is a competitive muscarinic receptor antagonist that is selective for M3

receptors. It is used for the treatment of overactive bladder with symptoms of urinary

incontinence. In clinical trials, solifenacin showed significant reduction in the

symptoms

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of urinary frequency, urgency, and urge incontinence compared with placebo.

42,43

Safety concerns with solifenacin include an increased risk of QT interval

prolongation in patients with a known history of QT interval prolongation or patients

who are taking medications known to prolong the QT interval. The recommended

dose of solifenacin is 5 mg once daily, which can be increased to 10 mg once daily if

needed. However, in those with renal and hepatic impairment or on CYP3A4

inhibitors, the dose should not exceed 5 mg once daily.

β-ADRENERGIC AGENTS

Mirabegron is a first in class β3

-adrenergic agonist approved for use in overactive

bladder. The human bladder muscle has β1,2,3

-adrenergic receptors; however, β3

-

adrenergic receptors account for 95% of the β-receptors and are most likely

responsible for detrusor relaxation.

44 Compared to placebo, mirabegron was able to

reduce the mean number of incontinence episodes per 24 hours by –0.44 (95 %

confidence interval (CI) –0.59 to –0.29, p <0.00001).

45 The efficacy of mirabegron is

sustained at 12 months, and its safety is notable for significantly less dry mouth and

constipation compared to antimuscarinics.

46 Although mirabegron has not been

studied in patients with dementia, clinical trials have not reported any CNS adverse

effects with mirabegron. Mirabegron can be used alone or in combination with

antimuscarinics for those who cannot tolerate an increase in the antimuscarinic dose

or are already on a maximum dose. Mirabegron is initiated at 25 mg once daily and

can be titrated up to 50 mg once daily in 2 to 4 weeks. Patients with renal or hepatic

impairment should not receive doses higher than 25 mg once daily. Blood pressure

increases have been reported with mirabegron (>10%) particularly in patients with

uncontrolled hypertension and thus warrant careful monitoring.

47 Mirabegron is also

a CYP2D6 inhibitor, and drugs that are CYP2D6 substrates taken concomitantly may

require dose adjustments.

Although any of the aforementioned drugs may be useful for H.K., a careful

consideration of adverse event profile should be considered before prescribing an

anticholinergic agent. The rate of decline in activities of daily living and cognition in

patients with dementia was 50% faster when anticholinergic medications were

combined with acetylcholinesterase inhibitors than when acetylcholinesterase

inhibitors were used alone.

48 Even though H.K. is not treated with an

acetylcholinesterase inhibitor, she does have moderate dementia and would likely

have pronounced anticholinergic side effects. In addition, the limited efficacy of

anticholinergic medications needs to be carefully considered before starting

treatment in H.K. A comprehensive review of placebo-controlled trials of

anticholinergic medications for overactive bladder estimated that, as a class, even

long-acting agents have a very limited effect on symptoms, with approximately one

fewer incontinent episode and one fewer voiding episode per 48 hours.

49 Given the

potential for side effects and the limited efficacy, it would be prudent to use

nonpharmacologic measures (i.e., prompted voiding) to manage H.K. If the desired

end points are not achieved, a trial of an anticholinergic medication could be

considered. Mirabegron may potentially be a safe option in patients with dementia;

however, future studies to promote its use over anticholinergics in this population

would be beneficial. All agents in this group should be prescribed for a 2-week trial

period with careful monitoring for efficacy and side effects.

INCREASING BLADDER OUTLET RESISTANCE

CASE 109-2

QUESTION 1: M.K., a 68-year-old woman, has been diagnosed with urinary stress incontinence. What

therapy would be appropriate for this type of PUI?

M.K. should initially be educated on pelvic floor muscle or Kegel exercises.

Several methods have been effectively used to help patients identify and correctly

exercise the pelvic floor muscles, including self-help books, biofeedback, electrical

stimulation, and verbal feedback during physical examination by a physician.

22 Once

the pelvic floor muscles have been identified, M.K. should empty her bladder and sit

or lie down. She should contract her pelvic floor muscles, holding the contraction for

5 seconds, and then relax for 5 seconds. This should be repeated 5 times with a goal

of 10-second contractions for M.K. She should practice these exercises 3 times a

day.

CASE 109-2, QUESTION 2: M.K. has incomplete resolution of her stress incontinence symptoms. Physical

examination indicates urogenital atrophy. What are the pharmacologic options for stress incontinence?

Imipramine Hydrochloride

The pharmacologic mechanism of tricyclic antidepressants (TCAs) in treating PUI at

best is speculative.

50 All the TCAs have some degree of anticholinergic effect, both

centrally and peripherally, but not at all sites. Imipramine has significant systemic

anticholinergic effects, but it has weak anticholinergic effects at the detrusor

muscle.

51

Imipramine has a significant inhibitory effect on the detrusor muscle that is

mediated by neither anticholinergic nor adrenergic mechanisms. Its detrusor

inhibitory effect may be the result of peripheral blockade of norepinephrine reuptake.

The ability of imipramine to increase bladder outlet resistance is believed to be

attributable to enhanced α-adrenergic effects in the smooth muscle of the bladder

base and proximal urethra, where α-receptors outnumber β-receptors. The significant

anticholinergic side effects associated with imipramine make it a poor treatment

option in the elderly.

α-Adrenergic receptor stimulation at the detrusor muscle and proximal urethra will

increase the maximal urethral closure pressure.

52 However, α-adrenergic agonists,

such as pseudoephedrine, have a minimal role in the treatment of stress urinary

incontinence because the risk of adverse events exceeds the limited benefit it is likely

to provide.

Duloxetine

Duloxetine is a serotonin and norepinephrine reuptake inhibitor that has shown

efficacy in patients with stress incontinence. Duloxetine also treats depression, and

though not FDA-approved for the treatment of stress incontinence, it could be a

reasonable option for a woman with both depression and stress incontinence. A

meta-analysis of nine trials including 3,063 women predominately with stress

incontinence showed duloxetine-treated patients had a reduction in the incontinence

episode frequency by approximately 50%; however, the absolute reduction (10.8%

vs. 7.7%) in incontinence episodes was small, suggesting that any benefits would be

modest. Adverse effects were common, with 71% of duloxetine-treated patients

reporting side effects and approximately one in eight patients discontinuing

treatment.

53 The most common adverse effect with duloxetine is nausea, which tends

to resolve with time. The dose of duloxetine that has been studied for stress

incontinence is 40 to 80 mg/day in one or two doses. The clinical effects of

duloxetine appear to be modest and need to be weighed against the risk of adverse

events.

Estrogens

Estrogens affect many aspects of uterine smooth muscle, including excitability,

receptor density, and transmitter metabolism, especially adrenergic nerves.

54 The

detrusor and urethra are embryologically related to the uterus, and significant work

has been done on estrogenic hormone effects on the lower urinary tract.

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α-Adrenergic stimulation of the urethra is estrogen dependent,

55 and several studies

have demonstrated the relationship of estrogen with α-adrenergic receptor density in

the lower urinary tract.

56 Estrogen therapy, in the form of vaginal suppositories (10

mcg/day), facilitates urinary storage in some postmenopausal patients by increasing

urethral outlet resistance, and it has an additive effect with α-adrenergic therapy.

15

Additional preparations of estrogen include a vaginal ring that is inserted into the

vagina and removed after 90 days. The ring releases 7.5 mcg of estradiol each day

over a 90-day period. The use of estrogen in the treatment of stress PUI requires

further study. The use of long-term estrogen treatment must be considered carefully in

light of the controversy about whether estrogen therapy predisposes to the

development of endometrial carcinoma. If estrogen is combined with α-adrenergic

agonist therapy, the lowest effective maintenance dose should be prescribed.

M.K.’s incomplete resolution of stress incontinence symptoms is probably caused

by urogenital atrophy. She would respond well to an intravaginal estrogen cream,

which will improve local blood flow and dryness. An estrogen cream such as

estradiol should be prescribed at a dose of 0.5 g of cream 3 times a week. The

combination of local estrogen therapy and pelvic floor muscle exercises should

eliminate M.K.’s symptoms.

DECREASING BLADDER OUTLET RESISTANCE

Overflow incontinence in female patients resulting from outlet obstruction or weak

detrusor muscle is now being treated with α1A-blockers by many urologists. Most

α1A-receptors are found in prostate tissue; however, these same receptors are also

located in the spinal cord, bladder neck, urethra, and periurethral tissue in women.

57

The urinary symptoms suggestive of prostatism are not sex-specific. Well-controlled,

randomized, crossover studies are needed to determine the efficacy of α1A-blockers

in overflow incontinence. If detrusor underactivity is the known cause of overflow

incontinence, bethanechol can be considered. As a cholinergic agent, bethanechol

increases bladder muscle tone causing contractions that initiate urination. Common

adverse effects with bethanechol include flushing, tachycardia, abdominal cramps,

and malaise.

BENIGN PROSTATIC HYPERPLASIA

Benign prostatic hyperplasia (BPH), a common cause of urinary dysfunction

symptoms in elderly men, results from proliferation of the stromal and epithelial cells

of the prostate gland.

58,59 There is both a static and a dynamic component to prostate

enlargement. The static component increases the prostate size by smooth muscle cell

proliferation in the prostate stroma, whereas the dynamic component contributes to an

enlarged prostate through an increase in smooth muscle tone in the prostate and

bladder neck. The term benign prostatic hypertrophy often is used inappropriately

because the prostate gland pathology results from hyperplasia rather than

hypertrophy. BPH rarely is detected in men younger than 40 years of age. After age

40, the prevalence of BPH is age dependent.

60 Approximately 75% of men who live

to the age of 70 exhibit clinical symptoms of BPH that are sufficiently severe to

necessitate medical attention, and approximately 90% of octogenarians have

evidence of BPH. Essentially, all men will experience BPH if they live long enough.

The microscopic incidence of BPH is fairly constant among several Western and

developing countries,

61 suggesting that the initiation of BPH may not be

environmentally or genetically influenced. Although BPH and prostatic cancer often

coexist, no compelling evidence indicates that BPH predisposes patients to the

development of prostate cancer.

62 The appearance of atypical prostatic hyperplasia

correlates, however, with the presence of latent prostatic carcinoma.

63

The cause of BPH is unclear; however, most hypotheses are based on hormonal

and aging processes. This is because intact, normally functioning testes are essential

for BPH to develop,

64 and castration before puberty prevents the development of

BPH. The prostate is dependent on androgens both for embryologic development and

for maintenance of size and function in the mature male.

65 Testosterone, the major

circulating androgen, is metabolized to dihydrotestosterone (DHT) by 5α-reductase.

The two isoenzymes of 5α-reductase are designated as type 1 and type 2. Type 2 is

found predominantly in the prostate and other genital tissues, whereas type 1 is found

throughout the body, as well as in the prostate.

66 For testosterone to be active in the

prostate, it must be converted to DHT; therefore, DHT is the obligate androgen

responsible for normal and hyperplastic prostate growth. Within the prostate, DHT

initiates RNA synthesis, protein synthesis, and cell replication. The exact role of

testosterone may be only to initiate fibroadenomatous hyperplasia, eventually

resulting in glandular enlargement.

Stromal hyperplasia in the prostate periurethral glands is one of the earliest

microscopic findings in men with BPH.

61 As men increase in age, testosterone serum

concentrations decrease and the peripheral conversion of testosterone to estrogen

increases. At one time, estrogens were thought to initiate stromal hyperplasia, which

in turn induces epithelial hyperplasia. It is now known, however, that estrogens do

not have a direct effect on the development of BPH and prostatic carcinoma, but

progesterone does play a role in their pathogenesis. Progesterone receptors have

been shown to exist in prostate stromal cells, whereas estrogen receptors were

essentially nonexistent.

67

Pathophysiology and Clinical Presentation

CASE 109-3

QUESTION 1: G.M., a 72-year-old man, presents to the emergency department with severe lower abdominal

discomfort of 4 days’ duration. His history consists of having increasing difficulty initiating urination, a

significant decrease in the force of his urinary stream, occasional midstream stoppage, and postvoid dribbling.

Physical examination is unremarkable except for the abdominal and rectal examination. Abdominal examination

reveals distension, tenderness, and increased dullness in the hypogastrium with a large mass, believed to be the

bladder. On rectal examination, the prostate is found to be severely enlarged, firm, and rubbery without nodules

or undue hardness. G.M. gives a history of nocturia (approximately 4 to 5 times a night) and daytime urinary

frequency (8 to 10 times a day). G.M. indicates that when he is able to urinate he has a weak stream and

difficulty maintaining flow, and does not feel relieved. Laboratory findings are as follows:

Blood urea nitrogen (BUN), 45 mg/dL

Serum creatinine (SCr), 3.2 mg/dL

Serum prostatic acid phosphatase, 3 units/L

Serum prostate-specific antigen (PSA), 7.1 ng/mL

A urethral catheter was inserted, and 900 mL of urine was obtained. G.M. subsequently was scheduled for a

urologic workup. What is the pathophysiologic basis for G.M.’s symptoms?

Symptoms of BPH can be both obstructive and irritative, and descriptions of the

symptoms need a frame of reference for standardization. The Boyarsky index, a

questionnaire consisting of nine questions to quantify the severity of BPH, has been

developed.

68 Five questions are designed to assess obstructive symptoms and

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four to assess irritative symptoms. Although some limitations to the use of this

questionnaire (Table 109-4) may exist, it is one of the most common measures used

to quantify symptoms in BPH studies, and it correlates well with the pathophysiology

of BPH.

61 The format of the Boyarsky index is designed to help the clinician educate

the patient about the obstructive and irritative symptoms of BPH. The Boyarsky index

was the first of three patient questionnaires developed to quantitatively assess BPH

and the effectiveness of individual treatment.

65 As such, this questionnaire has been

used in numerous clinical trials to measure the outcome of interventions. The

Boyarsky index is not useful in comparing different treatment therapies among BPH

patients because it has not been sufficiently validated for this purpose; rather, it is

useful in evaluating an individual’s response to therapy.

The Multidisciplinary Measurements Committee of the American Urologic

Association (AUA) also has published a urinary symptom index for prostatism.

69 The

index is useful to assess the baseline severity of prostatism, disease progression, and

effectiveness of different therapies. The AUA symptom index allows comparison

among therapies and is the preferred questionnaire for BPH research. It has been

validated through internal consistency reliability, constructive reliability, test–retest

reliability, and criterion reliability.

65 The AUA index, however, may not be BPH

specific.

70 When 101 men and 96 women between the ages of 55 and 79 used the

AUA index, urinary symptoms and severity of urinary symptoms were similar in both

groups. Therefore, symptoms associated with prostatism can be associated with

aging as well as BPH. The National Institutes of Health convened a chronic

prostatitis workshop to come to consensus on a new classification system for the

diagnosis and management of prostatitis.

71 This group developed a symptom index

that provides a valid outcome measure for men with prostatitis. This index attempts

to quantify the pain and discomfort associated with prostatism and should help

differentiate prostatism from prostatic hyperplasia. The symptom index is selfadministered.

CASE 109-3, QUESTION 2: What objective findings in G.M. are associated with BPH?

G.M. presents with obstructive symptoms consistent with BPH as follows: (a) a

history of difficulty in initiating urination (hesitancy), (b) a decrease in urinary force,

(c) occasional midstream stoppage, (d) postvoid dribbling, and (e) a feeling of

incomplete bladder emptying. The common obstructive symptom of decreased force

and size of urine stream is caused by urethral compression from prostate gland

hyperplasia. Hesitancy, another obstructive symptom, is the result of the bladder

detrusor muscle taking a longer time to generate the initial increased pressure to

overcome urethral resistance. Urinary stream intermittency is caused by the inability

of the bladder detrusor muscle to sustain the increased pressure until the end of

voiding. Terminal dribbling and incomplete emptying occur for the same reason, but

also may be caused by obstructive prostatic tissue at the bladder neck, causing a

“ball-valve” effect.

G.M. also has a history of classic irritative symptoms that are consistent with BPH

as follows: (a) nocturia approximately 4 to 5 times a night and (b) daytime urinary

frequency of 8 to 10 times a day. Incomplete emptying of the bladder results in

shorter intervals between voiding, explaining the complaint of frequency. Also, a

large prostate gland provokes the bladder to trigger a voiding response more

frequently. This response is more pronounced if the prostate is growing

intravesically and compromising the bladder volume. The bladder detrusor muscle

becomes hypertrophied as a result of the greater bladder residual urine volume,

which can result in increased detrusor muscle excitability. Clinically, this

excitability may result in bladder instability. The symptoms of urinary frequency are

more pronounced at night because cortical inhibitions are lessened and bladder

sphincter tone is more relaxed during sleep. Obstructive symptoms are associated

more with an enlarged prostate, and the predominance of irritative symptoms could

suggest voiding dysfunctions in addition to those of BPH.

Table 109-4

Benign Prostatic Hyperplasia Symptom Scoring System (Boyarsky Index)

a

Nocturia

0 Absence of symptoms

1 Urinates 1 time/night

2 Urinates 2–3 times/night

3 Urinates ≥4 times/night

Daytime Frequency

0 Urinates 1–4 times/day

1 Urinates 5–7 times/day

2 Urinates 8–12 times/day

3 Urinates ≥13 times/day

Hesitance (lasts ≥1 minute)

0 Occasional (≤20% of the time)

1 Moderate (20%–50% of the time)

2 Frequent (≥50% of the time)

3 Always present

Intermittency (lasts ≥1 minute)

0 Occasional (≤20% of the time)

1 Moderate (20%–50% of the time)

2 Frequent (≥50% of the time)

3 Always present

Terminal Dribbling (at end of voiding)

0 Occasional (≤20% of the time)

1 Moderate (20%–50% of the time)

2 Frequent (≥50% of the time)

3 Always present (may wet clothes)

Urgency

0 Absence

1 Occasionally difficult to postpone urination

2 Frequently difficult to postpone urination

3 Always difficult to postpone urination

Impairment of Size and Force of Urinary Stream

0 Absence

1 Impaired trajectory

2 Most of the time size and force are restricted

3 Urinates with great effort and stream is interrupted

Dysuria

0 Absence

1 Occasional burning sensation during urination

2 Frequent (>50% of the time) burning sensation

3 Frequent and painful burning sensation during urination

Sensation of Incomplete Voiding

0 Absence

1 Occasionalsensation

2 Frequent (>50% of the time) sensation

3 Constant and urgent sensation, no relief on voiding

aSymptom scoring provides the clinician with a tool to measure the relative need for, and efficacy of, different

interventions. No specific score is associated with the need for a specific intervention. A low symptom score in

the absence of significant urine retention generally indicates that medical management can be attempted before

considering surgical intervention.

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Figure 109-2 Flow of urine is interrupted by compression from a prostate that has enlarged from normalsize. In

this diagram, the ureters and bladder are dilated by backed-up urine.

Urinary incontinence is not a common symptom of BPH. With advanced BPH, a

large residual volume of urine in the bladder weakens the bladder sphincter and

allows the escape of small amounts of urine when the bladder is full. Because the

residual bladder volume increases, the ureters will dilate, resulting in stasis of urine

in the ureters. The end result may be ascending hydronephrosis caused by the

transmission of high pressure to nephrons, which produces renal damage (Fig. 109-

2). This can account for abdominal discomfort and flank pain during voiding and

ascending urinary tract infections.

Acute urinary retention in BPH can occur as a result of increasing size of the

prostate gland. Independent of gland size, drugs may precipitate acute urinary

retention. Drugs, such as alcohol, anticholinergic agents, α-adrenergic agents, and

neuroleptics, all have been associated with acute urinary retention in men with BPH.

Commonly, when advanced BPH is present, acute urinary retention is exacerbated if

the patient does not void at the first sign of urgency. G.M. is not taking any drugs

commonly associated with urinary retention.

Clinical Findings

G.M. presents with classic symptoms of BPH. The increasingly severe symptoms

culminated in an episode of acute urinary retention as evidenced by inability to void

and lower abdominal discomfort. Objective symptoms associated with G.M.’s BPH

include (a) abdominal tenderness with increased dullness in the hypogastrium; (b) the

finding of an enlarged bladder; (c) an enlarged, firm, and rubbery prostate gland; and

(d) a return of 900 mL of urine via urinary catheter. The normal serum acid

phosphatase, slightly elevated PSA, and digital rectal examination of the prostate

suggest that G.M. does not have prostatic carcinoma at this time (see the ProstateSpecific Antigen section later in this chapter). The elevated BUN and SCr may

suggest hydronephrosis as a result of his BPH.

CASE 109-3, QUESTION 2: What objective findings in G.M. are associated with BPH?

URINALYSIS

Because patients with BPH also may have a urinary tract infection, a urinalysis with

microscopic examination is essential. It is mandatory that G.M. gives a urine

specimen for urinalysis before the digital rectal examination of the prostate gland

because examination of the prostate causes prostatic secretions to be expelled into

the urethra, which may contaminate the urine specimen and make it difficult to

determine the source of an infection. The presence of white blood cells and bacteria

in the urine necessitates a workup for infection. Similarly, hematuria requires a

workup for urinary tract pathology other than BPH. Because BPH also can cause

hydronephrosis, renal function and serum electrolytes should be evaluated.

DIGITAL RECTAL EXAMINATION

A serum PSA followed by a digital rectal examination of the prostate remains a

fundamental part of evaluating a man with prostatism. The prostate examination

should determine the size, shape, consistency, and nodularity of this gland. Prostatic

hyperplasia results in a large, palpable prostate with a smooth mucosal surface

rectally. The discernment of the right and left prostate lobes is lost in BPH. The

digital rectal examination of a patient with BPH commonly finds asymmetry of the

prostate, with one side being larger than the other. Prostatic enlargement can be in

both an anteroposterior and a superoinferior direction. As a result, on digital rectal

examination, the upper extent of prostate hyperplasia is not palpable. Occasionally,

the degree of enlargement felt by digital rectal examination may be misleading

because a substantial portion of enlargement may be intravesicular. The consistency

of the gland may be soft or firm, depending on the predominance of glandular or

fibromuscular elements.

72 The presence of firm-to-hard nodules, irregularities,

induration, or a stony, hard prostate suggests possible prostate cancer. In those cases

in which the prostate gland size or shape may be questioned, the patient should have

a transrectal ultrasound (TRUS) to determine the gland volume.

PROSTATE-SPECIFIC ANTIGEN

PSA is a glycoprotein enzyme (molecular weight, 33,000) that is secreted in the

cytoplasm of the prostatic cells; it aids in the liquefaction of semen. Some claim that

this enzyme is specific for prostate origin, although a few isolated instances of

elevation in nonprostate tumors have been reported. PSA correlates reasonably well,

on average, with prostate weight owing to benign prostate glandular hyperplasia.

73

Prostate cancer, however, produces approximately 10 times the amount of PSA on a

tissue volume basis than does BPH.

74 Men 50 years of age or older have been

encouraged to have an annual measurement of serum PSA and a digital rectal

examination as a basic screen for prostate cancer and to monitor the growth of the

prostate gland. Several investigators have proposed age-adjusted PSA reference

ranges, which reflect the size of the prostate gland (Table 109-5).

75–77 Studies have

resulted in several formulas that try to adjust the PSA for the effect of BPH. The bestknown formula for predicting the PSA level (PSA serum density) is as follows

78

:

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Table 109-5

Age-Adjusted Prostate-Specific Antigen Values

Age Range (years) PSA Density

PSA Upper Limit (ng/mL) 40–49 2.5 0.08

50–59 3.5 0.10

60–69 4.5 0.11

70–79 6.5 0.13

PSA, prostate-specific antigen.

The PSA result for G.M. is slightly above the upper limit for his age. As such, he

should have a TRUS to determine the prostate gland volume and, hence, the PSA

density. Once the prostate gland volume is determined, the significance of his PSA

level of 7.1 ng/mL can be determined.

Drug Therapy

α1-ADRENERGIC RECEPTOR ANTAGONISTS

CASE 109-3, QUESTION 4: What drug therapy should be prescribed to treat G.M.’s prostatic hyperplasia?

G.M. most likely will be scheduled for a TURP, because he presents with acute

urinary retention and hydronephrosis owing to a moderately enlarged prostate gland

(i.e., >40 g and <80 g). He should be started and maintained on an α1

-adrenergic

receptor antagonist to reduce the tension of the bladder neck, the prostate adenoma,

and the prostatic capsule. Similarly, he should receive a 5α-reductase inhibitor to

induce atrophy of the prostate gland and halt progression of the disease.

The prostatic capsule and hyperplastic prostate have plentiful α1A-adrenergic

receptors. The three known subtypes of the α1

-adrenergic receptor are α1A, α1B, and

α1D. Inhibiting the α1A-adrenergic receptors can reduce the smooth muscle tone of the

prostatic urethra, thereby reducing the functional component of urethral constriction

and obstruction.

Terazosin

Terazosin, a long-acting α1

-adrenergic receptor antagonist, has significantly reduced

obstructive symptoms and improved urinary flow rates at doses of 1 to 5 mg/day.

65,79

The α1

-blockade alone does not account for the long-term clinical responses exerted

by this drug in the treatment of BPH. Terazosin has been shown to induce prostate

smooth muscle cell apoptosis, resulting in reduced urinary symptoms. Terazosin (and

doxazosin) has a quinazoline nucleus, which may account for this effect. Tamsulosin,

which is not a quinazoline, does not induce prostate smooth muscle cell apoptosis.

80

In most patients, the dose of terazosin should be started at 1 mg once daily at

bedtime and titrated over several weeks to 5 to 10 mg once daily to obtain desired

results. Orthostatic hypotension may occur in the beginning days of therapy or during

dosage adjustment periods. In patients who stop their terazosin therapy for 2 or more

days, therapy should be reinstituted cautiously to avoid the “first-dose” adverse

effect of syncope.

Terazosin has demonstrated sustained improvement in BPH symptom scores for a

30-month period. Only 10% of the patients experienced treatment failure.

65

In this

long-term study, the systolic blood pressure in normotensive and hypertensive

patients was decreased by 4 and 18 mm Hg, respectively. Apparently, terazosin

typically only lowered the blood pressure significantly in the hypertensive patients.

Doxazosin

Doxazosin, another quinazoline derivative, is a long-acting α1

-adrenergic receptor

antagonist structurally related to prazosin and terazosin (Table 109-3). Prazosin has a

relatively short half-life and is not recommended for use in BPH. Doxazosin

originally was prescribed primarily for hypertension and currently is not considered

a first-line antihypertensive agent. (For a discussion of the current use of α-blockers

in hypertension, see Chapter 14, Essential Hypertension.) Hypertension and BPH are

linked by the sympathetic nervous system. As with terazosin, doxazosin improves

urinary flow rates and symptoms in patients with BPH. These effects have been

demonstrated in controlled clinical studies, within weeks, and for the long-term.

Doxazosin should be started at 1 mg/day. After 1 to 2 weeks, the dose can be

increased over several weeks to 8 mg/day. As with other long-acting α1

-adrenergic

receptor antagonists, the first dose should be taken at bedtime to minimize

lightheadedness and syncope (the first-dose effect), and the blood pressure of the

patient should be monitored periodically during therapy. Most patients require

between 4 and 8 mg/day for effective control of the urinary symptoms of BPH.

Dosages greater than 4 mg/day are associated with a greater frequency of dizziness,

orthostatic hypotension, and syncope.

79,81

Tamsulosin

Tamsulosin, a nonquinazoline, is a long-acting selective α1A-adrenergic receptor

antagonist similar to doxazosin, terazosin, and prazosin. Tamsulosin and its

metabolites are more specific for the prostatic α1A-adrenergic and less specific for

the vascular α1A-adrenergic receptors responsible for orthostatic hypotension.

Consequently, no need exists to titrate tamsulosin to the recommended daily dose

range of 0.4 to 0.8 mg. Coadministration of tamsulosin with antihypertensive agents

does not require dosage adjustment of the antihypertensives. Tamsulosin is very

effective in treating bladder outlet obstruction associated with BPH.

82,83

More than 90% of tamsulosin is absorbed after oral administration of a 0.4-mg

dose under fasting conditions. Administration with food decreases the bioavailability

by 30% and increases time to peak plasma concentration. Tamsulosin is hepatically

metabolized by CYP3A4 and CYP2D6.

84

Impaired renal function increases the total

tamsulosin plasma concentration by approximately 100% during steady state.

However, active unbound drug levels are not affected; thus, renal dose adjustment is

not required.

85 Tamsulosin appears to reduce mean ejaculatory volume in 90% of

patients.

86 As with all α1

-adrenergic receptor antagonists, tamsulosin does not affect

the PSA and must be taken indefinitely to maintain its therapeutic effect.

87