Download Hyperlipidemia for Family Doctors

Preventing Those “Most
Embarrassing” Moments:
Understanding
Overactive Bladder
Craig V. Comiter, M.D.
Associate Professor, Urology
Chief, Section of Urology
Urology Residency Program Director
University of Arizona HSC
Typical Case
• 52 y.o female
• LUTS
–
–
–
–
urinary frequency q 1 hour
Nocturia x 3
Min SUI, mod UUI
3 ppd
History
• PMH
– TVH 3 years ago for bleeding
• Ovaries left in place
– G3P3V3, 1 prolonged labor
• Meds
– HMG-CoA reductase inhibitor
• Social
– 2 cups coffee in AM
– 1 glass wine in PM
– 1 soda per day
Physical Exam and Labs
• Normal appearing
• Trace LE edema
• Pelvic exam
– Mild atrophic vaginitis
– Grade 1 cystocele
– Some leakage with cough
• Urinalysis = negative
• Post-void residual urine = 125 ml
What would you do now?
1. Pelvic floor exercises and behavioral
modification
2. Antimuscarinics
3. Refer to urology
4. Surgery
5. Estrogen replacement
Lower Urinary Tract Symptoms
(LUTS)
•
•
•
•
•
•
•
Frequency
Urgency
Nocturia
Dysuria
Hesitancy
Straining
Double voiding
• Stress Incontinence
• Urgency Incontinence
• Other
–
–
–
–
Hematuria
Urinary tract infections
Dysparunia
Coital incontinence
Urinary Incontinence
•
•
•
•
•
•
Stress versus Urge
Neurogenic versus Myogenic
Vesicogenic versus Sphinteric
Environmental
Psychogenic
Idiopathic
A better system to evaluate the
patient
• Inability to store
– Because of the bladder
– Because of the outlet
• Inability to empty
– Because of the bladder
– Because of the outlet
STORE
STORE
EMPTY
STORE
B
L
A
D
D
E
R
EMPTY
STORE
B
L
A
D
D
E
R
O
U
T
L
E
T
EMPTY
B
L
A
D
D
E
R
O
U
T
L
E
T
STORAGE
EMPTYING
OVERACTIVE
UNDERACTIVE
“URGE”
“RETENTION”
PRESSURE
‘TOO MUCH’
PRESSURE
‘TOO LITTLE’
UNDERACTIVE
OVERACTIVE
“STRESS”
“OBSTRUCTION”
RESISTANCE
‘TOO LITTLE’
RESISTANCE
‘TOO MUCH’
B
L
A
D
D
E
R
O
U
T
L
E
T
STORAGE
OVERACTIVE
“URGE”
PRESSURE= ‘TOO MUCH’
EMPTYING
“RETENTION”
UNDERACTIVE
PRESSURE= ‘TOO LITTLE’
SYMPTOMS:
frequency, urge, nocturia
urge inc.
SYMPTOMS:
hesitancy, nocturia, straining,
overflow incontinence
UNDERACTIVE
“STRESS”
RESISTANCE= ‘TOO LITTLE’
OVERACTIVE
“OBSTRUCTION”
RESISTANCE= ‘TOO MUCH’
SYMPTOMS:
cough, laugh, sneeze
stress incontinence
SYMPTOMS:
hesitancy, straining,
incomplete emptying,
nocturia
overflow incontinence
Normal Storage
• If you leak, you leave a trail
• If you leave a trail, you get eaten by the
predator
• Store at low pressure (keeps kidneys safe)
– No unpleasant sensation
– No unstable contractions
• Keep your mind off your bladder
STORAGE
Bladder
ACCOMODATES URINE
AT
LOW INTRAVESICAL PRESSURE
Outlet
INCREASED
RESISTANCE
The organism is quite
vulnerable during voiding…
Coaptive evolution
• If we must void, (to eliminate waste)
• And if we are vulnerable during voiding…
• Let’s see how else voiding can be useful
As a sign of dominance
Marking One’s Territory
• Void on command
– Urge voiding abnormal
• Voluntarily stop voiding
– Pelvic floor/sphincter contraction
– Reflex relaxation of detrusor
• This is why Kegel exercises help
• Void on next tree
As a sign of disrespect
Emptying
COORDINATED CONTRACTION
Bladder
Outlet
UNOBSTRUCTED
OUTLET
Micturition Reflexes
3 major functions:
 Amplification: amplify weak smooth muscle
signal from bladder to help emptying
 efficient contraction
 Coordination: coordinates bladder and sphincter
function
 Timing: initiate voluntary voiding at different
volumes
Detrusor
Parasympathetic
Sympathetic
Internal Sphincter
Somatic
(Pudendal nerve)
External Sphincter
Courtesy – Michael Chancellor, MD
Bladder-Bladder Reflex
• Bladder afferent nerves synapse with
interneurons in sacral cord
• Interneurons synapse with bladder
preganglionic (parasympathetic) nerves
• Positive reflex
– Activates the full bladder
Bladder-Urethra Reflex
• Interneurons activated by bladder afferents
also synapse with urethral efferent
(parasympathetic) neurons
• Inhibitory reflex
– Proximal urethral SM relaxes
– Urethral outlet opens reflexively
– Remember the bladder-bladder positive reflex
Positive Feedback Mechanism:
a potential liability
In pathologic conditions…
– Emergence of bladder hyperactivity and
incontinence.
– Loss of central inhibition/sensitization of
bladder afferents can lead to “unmasking”of
involuntary voiding
Aδ vs C fiber afferents
• A δ (myelinated) fibers
– Mechanoreceptors
• Fullness, tension
• C (unmyelinated) fibers
– Nociceptors
• Pain, temperature, irritation, chemical
• Reflex to trigger voiding
Role of non-myelinated C-fibers
(afferent hypersensitivity)
•
•
•
•
Normally afferent C-fiber nociceptors silent
Subepithelial, lamina propria, SM
Insensitive to normal bladder distention
Become mechanosensitive with decreased
activation threshold in response to
– Inflammation
– Obstruction
– Chemical stimuli
C-fibers
• Enhanced transmission to sacral cord
– And within cord
– Reflex trigger -- voiding
• Causes sx of:
–
–
–
–
Frequency
Urgency
Pain
Urge incontinence
Functions of the Urothelium
Barrier
 Exchange
 Secretion


K-E Andersson, 2005
Signaling
Muscarinic Receptors
in the Urothelium/Suburothelium
Receptor binding studies:
 High density of muscarinic receptors in the
urothelium/suburothelium (“mucosa”)
 Both M2 receptors (75%), and M3 receptors
(25%) can be demonstrated
Mansfield et al. Br J Pharmacol. 2005;144(8):1089.
The Urothelium:
Not Your Ordinary Lining
• Not just a barrier for toxic substances
– Also is a highly metabolic active tissue
– May take an active part in both storage and voiding
phases of micturition cycle
– ATP may be involved in sensory signaling in the urinary
bladder
– ATP acts on P2x3 receptors on subepithelial sensory
nerves to convey information to the CNS
– Effects of ATP inhibited by L-arginine and by
neurokinin-2–receptor antagonist
• Suggesting that both nitric oxide and tachykinins
could interfere with actions of ATP
Andersson K-E, et al. Urology. 2002;60(suppl 5A):13-21.
Ferguson DR, et al. J Physiol. 1997;505:503-511.
Interstitial Cells and OAB
• Exaggerated spontaneous phasic activity in the bladder could
be etiological factor in the development of OAB
– Interstitial cells (myofibroblasts) in ureter, urethra, and
bladder body
– Heterogenous cell population
• Suburothelial interstitial cells
– Gap junctions, electrically active
– Increase intracellular calcium levels in response to ATP
• Detrusor interstitial cells
– May act by modifying signal transmission
Drake MJ, et al. J Urol. 2003;170:276-279.
Kumar V, et al. Curr Opin Urol. 2005;15:222-226.
Myofibroblasts
• Spindle cells, vimentin positivie
– Suburothelial cells in lamina propria
•
•
•
•
Close appositions with bare nerve endings
Functional syncytium via gap junctions
Activated by s t r e t c h
Mechanoreceptors
A Functional Syncytium
• Urothelium, reacting to stretch, releases transmitters (ATP,
NO)
• Afferent nerves nearby react
• Some of these receptors are located on a network of
interlinked cells, or interstitial cells
• This network may integrate signals and responses in the
bladder wall (pH, infection, K+)
• The next decade will see major advances in our
understanding of bladder sensation and pathogenesis
when the system is dysfunctional
N Cl
-
+
HO
O
O
Urothelium
PGs+
IC
ACh+
ATP+
URGENCY
NO -
Basal membrane
TKs+
VIP-
PACAP-
Lamina propria
N Cl
-
+
IC
Detrusor
Ad fiber
IC = interstitial cells
K-E Andersson, 2005
Muscularis mucosae
HO
O
O
C-fiber
C-fiber
Possible Role of the Urothelium in
the Overactive Bladder
Summary
 The urothelium, interstitial cells, and suburothelial
afferent nerves appear to be a functional unit
 Substances released from the urothelium can alter
the excitability of bladder afferent nerves
 Acetylcholine released from nerves and urothelium
during the filling of the bladder may stimulate
afferent nerve activity and contribute to OAB
B
L
A
D
D
E
R
O
U
T
L
E
T
STORAGE
EMPTYING
OVERACTIVE
UNDERACTIVE
“URGE”
“RETENTION”
PRESSURE
‘TOO MUCH’
PRESSURE
‘TOO LITTLE’
UNDERACTIVE
OVERACTIVE
“STRESS”
“OBSTRUCTION”
RESISTANCE
‘TOO LITTLE’
RESISTANCE
‘TOO MUCH’
OAB -- Definition
• Syndrome characterized by
– Urgency
– With or without urge incontinence
– Often with frequency and nocturia
OAB Is an Underreported
Condition
• Many patients do not seek help because they believe
no effective treatment is available
• 73% of patients who seek treatment are currently
not on medication
• 2 of every 3 patients report that symptoms affect
daily living
• Many patients self-manage OAB by voiding
frequently, reducing fluid intake, and wearing pads
Milsom I, et al. BJU Int. 2001;87:760-766.
Prevalence of
Chronic Conditions in the US
40
35
30
25
Population 20
(millions)
15
Dry
10
5
Wet
0
*Adams PF, et al. Vital Health Statistics 10. 1999; No 200:93-94.
†Stewart WF, et al. World J Urol. 2003;20:327-336.
Estimated Costs* of OAB
Total costs of OAB in
2000 were ≈ $12 billion
Breakdown of costs among
community residents
Lost
productivity
• Community residents in
the United States
– $9.17 billion
• Institutionalized costs
– $2.85 billion
• Annual spending for
patients with OAB is 5-fold
higher compared to
patients without the
Health-related
condition
consequences
– $5018 vs. $1767
*US dollars for year 2000
Diagnosis
Treatment
Routine care
Hu TW, et al. Urology. 2003;61:1123-1128.
Mullins C, et al. Am J Manag Care. 2005;11:S101-S102.
Costs Associated With OAB
Comorbidities
$1,000
Cost per patient
$900
$800
$700
$600
11,556 adult patients with OAB,
11,556 controls,
matched on propensity score
P < 0.0001
$500
$400
$300
$200
$100
$0
Vulvovaginitis
Skin
infections
Depression
UTIs
Overactive bladder
Control
Adapted from Darkov T, et al. Pharmacotherapy. 2005;25:511-519.
Falls and
fractures
Prevalence of OAB by Age
35
Men
Women
Prevalence (percent)
30
25
20
15
10
5
0
<25
25-34
35-44
45-54
55-64
Age (years)
Adapted from Stewart W et al. WHO/ICI. 2001. Poster.
65+
Prevalence of OAB With
Incontinence by Age
Prevalence (percent)
25
Men
Women
20
15
10
5
0
<25
25-34
35-44
45-54
55-64
Age (years)
Adapted from Stewart W et al. WHO/ICI. 2001. Poster.
65+
Pelvic Floor Dysfunction
• Urgency and UI due to combined defects
– bladder and pelvic floor
• Female wet with 10-15 cm H2O contractions
• Male dry with 40-50 cm H2O contractions
• First patient unable to inhibit the instability
due to weak pelvic floor muscles
Neurogenic Mechanisms
Changes in Peripheral and Central Neural Pathways
Could Lead to OAB
• Reduction in peripheral or central inhibition
• Enhancement of excitatory transmission in
micturition reflex pathway
• Increased primary afferent input from LUT
• Emergence of un-inhibitable bladder reflexes
• Examples
– Suprapontine and spinal cord lesions
de Groat WC. Urology. 1997;50(Suppl 6A):36-52.
Myogenic Mechanism for OAB
Changes in Electrical Conductivity
• Abnormal spontaneous mechanical activity
(fused tetanic contractions)
• Increased gap junctions on EM
• Changes in the electric coupling between muscle cells
– May lead to uncontrolled spread of muscle contraction
over the whole bladder (urgency, incontinence)
German K, et al. J Urol. 1995;153:1678-1673.
Elbadawi A, et al. J Urol. 1993;150:1657-1667.
Sethia KK, et al. J Urol. 1990;143:1243-1246.
Staskin DR. Drugs Aging. 2005;22:1013-1028.
Diagnosis of Overactive
Bladder
• Most cases of overactive bladder can be
diagnosed based on:
– patient history, symptom assessment
– physical examination
– Urinalysis
– (post void residual urine volume)
• Initiation of noninvasive treatment does not
require an extensive further workup
Patient History
• Which urinary problems does the patient have?
– Duration, most bothersome symptoms
– Triggering factors or events (cough, sneeze)
• Irritants of the bladder/lifestyle
– Tea, coffee, alcohol intake
– Spicy or acidic foods
• Voiding diary to determine average number of symptom episodes, number
of pads used
– Associated frequency, urgency, dysuria, pain with a full bladder, and
history of urinary tract infections
• Causes that may aggravate symptoms
– Heart failure on diuretics
– Surgical history (spinal, pelvic)
– Bowel function (irritable bowel syndrome association)
– Alzheimer treatment with acetylcholinesterase inhibitors
Staskin D, et al. ICS Standard Committee. Chapter 9;Committee 5:485-517.
Available at: http://cms.clevelandclinic.org/urology/body.cfm?id=120. Accessed 1/12/06.
Patient History (cont.)
• Gynecological/obstetric history
– eg, incontinence during intercourse, difficult deliveries,
grand multiparity, forceps use, large babies, history of pelvic
surgery, hysterectomy
• Quality of life
– Is it affecting daily activities? (sleep, work)
• Concomitant symptoms of fecal incontinence or pelvic organ
prolapse
– Pelvic pressure, chronic constipation, urinary hesitancy
Staskin D, et al. ICS Standard Committee. Chapter 9;Committee 5:485-517.
Medication History Is Important
Some medications may contribute to
lower urinary tract dysfunction
• Diuretics
• Antidepressants
• -agonist
• -antagonist
• -antagonist
• Sedatives
• Anticholinergics
• Analgesics
• Fluid output
• Bladder contractility
• Outlet response
Key Points of
Physical Examination
• Beginning examination
– Patient instructed to come in with full bladder
– Take note of obesity patients
• Predisposes to diabetes mellitus
• Which leads to neuropathy  neurogenic incontinence
– Medications
• Neurologic examination
– Survey of mental status
– Observation of gait (CNS, spinal cord, PNS disease)
• Urinalysis and culture
– Rule out urinary tract infections; stones
• Post void residual urine (if possible)
Julian TM. Clin Obstet Gynecol. 1998;41:663-671.
Radiography: a valuable
extension of the physical
examination
Relax
Strain
Diagnosis: Rule Out
Other Causes of Symptoms
• Local pathology
–
–
–
–
–
infection
bladder stones
bladder tumors
interstitial cystitis
outlet obstruction
• Metabolic factors
– diabetes
– polydipsia
• Medications
–
–
–
–
–
diuretics
antidepressants
antihypertensives
sedatives
narcotics
• Other factors
– pregnancy
– psychological factors
Rule out other causes…
• Patient had abdominal
hysterectomy
• Developed incontinence postop
• “seen by” 3 separate
physicians, dx’d with OAB
OAB ?
Urethral
Diverticulum
Urethral diverticulum with stone!
Urethral diverticulum
With stone
Reversible Causes of
Incontinence
•
•
•
•
•
•
•
•
Delirium
Infection
Atrophic vaginitis
Pharmaceuticals
Prostate
Excess urine
Restricted mobility
Stool impaction
Treatments for overactive
bladder
•
•
•
•
•
Behavioral
Pharmacological
Neuromodulatory
Surgical
Intravesical
Behavioral Modifications for OAB
•
•
•
•
Fluid and dietary modifications
Scheduled (timed) voiding
Bladder retraining drill
Pelvic floor re-education and exercise
Bladder
Basis of urge control:
Normal reflex arc inhibits
detrusor by voluntary
contraction of distal
urethral sphincter
Pelvic floor muscles
Andersson KE, et al. Pharmacol Rev. 2004;56:581-631.
Evidence-Based CME Recommendation:
Pelvic floor muscle training may be helpful in the
treatment of urinary stress incontinence in
women.
AAFP-Approved Source:
Cochrane Database of Systematic Reviews
Website where evidence is sited:
http://www.cochrane.org/reviews/en/ab005654.html
Strength of Evidence:
A systematic review of thirteen trials involving 714
women (375 PFMT, 339 controls).
Behavioral Modifications
Benefits and Limitations
Benefits
•
Scheduled or prompted voiding
– Can increase interval between voids
•
Physical therapy
– Kegel exercises, weighted vaginal cones
– Can help rehabilitate pelvic floor musculature
•
Biofeedback
– Can help the patient isolate the correct muscles to exercise
Limitations
•
Long-term compliance
– Proper execution is labor- and time-consuming, costly
– Requires active patient participation, intact mental status
– Gradual results, dry rate 25%-35%
Borello-France D, et al. Clin Obstet Gynecol. 2004;47:70-82.
Rosenberg MT, et al. Cleve Clin J Med. 2005;72:149-156.
Combined Behavioral Modifications
and Pharmacologic Therapy
Enhanced therapeutic effects
Mean reduction in UI (%)
Behavioral
modifications
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
Combined
therapy
Drug
therapy
Combined
therapy
-57.5
-72.7
-88.5
P = 0.034
UI: urge incontinence
-84.3
P = 0.001
Burgio KL, et al. J Am Geriatr Soc. 2000;48:370-374.
“Typical” OAB Case
•
•
•
•
Mild – moderate symptoms
Urine clean
Not retaining a significant volume
No significant prolapse
What would you do now?
1. Pelvic floor exercises and behavioral
modification – first line treatment for mildmoderate sx
2. Antimuscarinics
3. Refer to urology
4. Surgery
5. Estrogen replacement
Pharmacologic Treatment of
OAB
• Reduce or inhibit physiologic mechanisms involved in
bladder smooth muscle contraction
–antimuscarinics
–Ca++ channel blockers
–K+ channel openers
–tricyclic antidepressants
–alpha-adrenergic blockers
–afferent blockade
–B-agonists
–prostaglandin inhibitors
Pharmacologic Therapy for the
Treatment of OAB
• Antimuscarinic agents are the mainstay for
treating OAB
• OAB symptoms relieved by
– inhibition of involuntary bladder contractions
– increased bladder capacity
• Treatment can be limited by side effects such
as dry mouth, GI effects (eg, constipation),
and CNS effects
Evidence-Based CME Recommendation:
The use of anticholinergic drugs in individuals with
overactive bladder syndrome results in statistically
significant improvement of symptoms.
AAFP-Approved Source:
Cochrane Database of Systematic Reviews
Website where evidence is sited:
http://www.cochrane.org/reviews/en/ab003781.html
Strength of Evidence:
Systematic review of 51 randomized or quasi-randomized
trials, 32 parallel designs and 19 crossover designs were
included (6,713 adults).
Distribution of Muscarinic Receptors in
Target Organs of the Parasympathetic
Nervous System
CNS
Iris/ciliary body
Lacrimal gland
Salivary
glands
Heart
Gallbladder
Stomach
Muscarinic receptors are
also located in the CNS.
Colon
Bladder (detrusor muscle)
Abrams P, Wein AJ. The Overactive Bladder—A Widespread and Treatable Condition. 1998.
Antimuscarinics: Mechanism of
Action
• Stabilizing effect on bladder muscle
• increases bladder capacity
• diminishes frequency of involuntary
contractions
• delays initial urge to void
• does not change warning time
– must combine with timed voiding/toileting
Role of Postjunctional Muscarinic
Receptors in the Bladder
• Human bladder smooth muscle contains
primarily M2 (70% to 80%) and M3 (20% to
30%) receptor subtypes
• Activation of M3 receptors evokes direct
smooth muscle contraction (primary stimulus
for bladder contraction)
• Stimulation of M2 receptors may reverse
sympathetically mediated smooth muscle
relaxation
Wang P. J Pharmacol Exp Ther. 1995;273:959-966.
Chapple CR. Urology. 2000;55:33-46.
Pre- and Postjunctional Receptors
in Bladder Smooth Muscle
ACh
ACh
+
-
NE
ACh
NE
+
Bladder smooth muscle
M3 receptor activation
results in bladder contraction
NE
-
Bladder
smooth
muscle
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
NE
NE
ACh
NE
+
-
ACh
Bladder
smooth
muscle
M3 receptor activation
results in bladder contraction
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
NE
NE
ACh
NE
+
-
ACh
Bladder smooth muscle
M3 receptor activation
results in bladder contraction
Bladder
smooth
muscle
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
NE
NE
ACh
NE
+
-
ACh
Bladder
smooth
muscle
M3 receptor activation
results in bladder contraction
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
NE
NE
ACh
NE
+
-
ACh
Bladder
smooth
muscle
M3 receptor activation
results in bladder contraction
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
-
+
ACh
+
-
Bladder
smooth
muscle
Adrenergic receptor activation
results in bladder relaxation
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
ACh
-
+
Bladder smooth muscle
Adrenergic receptor activation
results in bladder relaxation
Bladder
smooth
muscle
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
ACh
-
+
Bladder smooth muscle
Bladder smooth
muscle
Adrenergic receptor activation
results in bladder relaxation
Bladder
smooth
muscle
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
ACh
-
+
Bladder smooth muscle
Adrenergic receptor activation
results in bladder relaxation
Bladder
smooth
muscle
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
ACh
-
+
ACh
Bladder smooth muscle
M2 receptor activation
may reverse bladder relaxation
Bladder
smooth
muscle
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
ACh
-
+
ACh
Bladder smooth muscle
Bladder smooth muscle
M2 receptor activation
may reverse bladder relaxation
Bladder
smooth
muscle
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
ACh
-
+
ACh
Bladder smooth muscle
M2 receptor activation
may reverse bladder relaxation
Bladder
smooth
muscle
Pre- and Postjunctional Receptors in
Bladder Smooth Muscle
ACh
ACh
+
-
ACh
-
+
ACh
Bladder smooth muscle
M2 receptor activation
may reverse bladder relaxation
Bladder
smooth
muscle
More complex patient…
•
•
•
•
Failed
Failed
Failed
Failed
fluid restriction
pelvic floor exercises
caffeine restriction
timed voiding
What would you do now?
1. Pelvic floor exercises and behavioral
modification
2. Antimuscarinics plus continued
behavioral modification
3. Refer to urology
4. Surgery
5. Estrogen replacement
Antimuscarinics: The Players
•
•
•
•
•
•
•
Oxybutynin IR (Ditropan)
Oxybutynin ER (Ditropan XL)
Oxybutynin patch (Oxytrol)
Tolterodine BID or ER (Detrol LA)
Trospium BID (Sanctura)
Darifenacin QD (Enablex)
Solifenacin QD (Vesicare)
Other players
• Not FDA approved for OAB
• Often used with anecdotal success
• Estrogen or Estradiol (Estrace)
– Local, not systemic
– No real data to support estrogen replacement…
• Tricyclic antidepressants
– Imipramine
•
•
•
•
•
Smooth muscle relaxant
Anticholinergic
Alpha agonist
Primary metabolite (desipramine) is a Ca++ channel blocker
Often in conjunction with antimuscarinic
An Urgent Word About Urgency
• A good history can differentiate between SUI
and UUI
• Not all urgency is the same
• Urgency does not equate with detrusor
instability
• Urgency may be a symptom of
stress incontinence
The “Funny” Story
• Daytime urgency/incontinence, but no
nocturia
• Mixed incontinence, leaks with minimal
activity
• Mixed incontinence, floridly positive Marshall
test
• Mixed incontinence with terrible urgency, no
improvement at all with cholinolytics
Sensation of Imminent Micturition
ISD -- leakage in posterior urethra
gives patient a sense of urgency
Who Should Manage OAB?
•
•
•
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Internist
Family practitioner
General practitioner
Nurse practitioner
Physician’s assistant
Urologist
Gynecologist
Urogynecologist
Reasons to Refer Patients to
Specialists
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Difficulty emptying
Recurrent UTI’s
Hematuria
Prior treatment
Neurologic problem
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Radical pelvic surgery
Symptomatic prolapse
Prostate problems
Surgery planned
Failed initial treatment
• Behavioral modification and pelvic floor
exercises
• Darifenacin 7.5 mg daily x 4 weeks
• Darifenacin 15 mg daily x 4 weeks
What would you do now?
1. Pelvic floor exercises and behavioral
modification
2. Antimuscarinics
3. Refer to urology – for consideration of
neuromodulation
4. Surgery
5. Estrogen replacement
What if pills/injections fail?
Check X-Ray
Sacral Neuromodulation
Implant Procedure
Failed initial treatment
• Behavioral modification and pelvic floor
exercises
• Darifenacin 7.5 mg daily x 4 weeks
• Darifenacin 15 mg daily x 4 weeks
• Trial of sacral neuromodulation
What would you do now?
1. Pelvic floor exercises and behavioral
modification
2. Antimuscarinics
3. Neuromodulation
4. Surgery – augmentation cystoplasty
5. Estrogen replacement
What if SNS fails?
Is there a standard treatment before
moving onto investigational
treatments?
• Augmentation cystoplasty
– Intestinal segment
– Attached to opened bladder
– Increases volume of sphere
U-SHAPE CONFIGURATION
DETUBULARIZATION
CREATION OF ILEAL PATCH
POSTERIOR U INCISION
ANTERIOR FLAP
BLADDER ANASTOMOSIS
BLADDER TO BOWEL ANASTOMOSIS
Patients are searching for
answers
Intravesical Drugs
Vanilloids
(investigational)
• Activate nociceptive sensory nerve fibers
through an ion channel known as vanilloid
receptor subtype 1 (VR1)
• VR1 is located on C-fiber bladder afferent
nerves, and activation of the receptors
excites then desensitizes C fibers
– Many pathologic conditions
• Spinal cord injury
• Chronic bladder irritation
• Result in overall increase in C-fiber
activity causing bladder overactivity
Chancellor M. Rev Urol. 2002;4(suppl 4):S50-S56.
Ouslander JG. N Engl J Med. 2004;350:786-799.
“Derived from
plants in pepper
family”
Botulinum Toxins (BTX)
Possible Applications in Urology
• Neurogenic and idiopathic detrusor overactivity
• OAB without detrusor overactivity
• Detrusor/sphincter dyssynergia
• Motor and sensory urge
• Urinary retention/voiding dysfunction
• Pelvic pain/chronic prostatic pain/interstitial cystitis
• 3 phase II studies under way
Moore C, et al. Curr Urol Rep. 2005;6:419-423.
http://www.clinicaltrials.gov. Accessed 1/24/06.
Botulinum toxin is not yet approved
by the FDA for use in urology
Investigational Drugs
Botulinum Toxin A
Botulinum toxin blocks ACH fusion and release
Presynaptic Nerve
Terminal
ACH
Muscle
- Botulinum toxin
- Acetylcholine (ACH) vesicles
-
Inhibited ACH results in decreased muscle contractility and muscle
atrophy at site of injection
-
In a study by Smith et al, its effectiveness was investigated
comparing a 40-injection technique versus a 10-injection technique,
which may be used in an office setting
Smith C, et al. J Endourol. 2005;19:880-882.
Adapted from Chancellor M. Rev Urol. 2002;4(suppl 4):S50-S56.
Botulinum Toxin Type A and
Idiopathic OAB (investigational)
OAB patients refractory to antimuscarinics:
– Efficacy of (100 units) BTX-A injections into the
detrusor muscle
100
P < 0.001
Improvement
after 1-2 weeks
of treatment (%)
•
90
88
80
80
76
70
60
50
Overall bladder function
Urgency
Incontinence
• Decrease of micturitions/day (14 to 7) and nocturia (4 to 1.5)
• Improvement of urodynamics
(reflex volume, maximum bladder capacity, detrusor compliance)
n = 100 (mean age, 57 years)
Schmid DM, et al. Poster #547. AUA Meeting 2005.
Electromagnetic Stimulation
• Trans-sacral nerve stimulation of S3 and S4 roots via
electromagnetic pulses
– Hypothesis: change in electric potentials may increase
inhibitory neuronal impulses to the bladder detrusor
muscle
• Prospective, double-blind, randomized, controlled trial:
– Portable device/sham unit; 20-minute pulse intervals for
12 weeks
• Stimulation has no effect on OAB symptoms in women
– Frequency, nocturia, leakage, quality of life, no placebo
effects
O’Reilly B, et al. Abstract #53. ICS Meeting 2005.
n = 63
Drugs With Potential
to Treat OAB
Investigational
blockers1
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Calcium-channel
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Potassium-channel openers1
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Prostaglandin inhibitors1
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Direct-acting smooth muscle
relaxants1
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Serotonergic agents1
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Neuromuscular-junction
acetylcholine inhibitors1
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Centrally acting muscle
relaxants1
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Vanilloids/afferent nerve
inhibitors1
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-Adrenoceptor antagonists2
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-Adrenoceptor antagonists2
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Antidiuretic agents3
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Estrogens1,3
•
Tachykinin antagonists2
1. Ouslander JG. N Engl J Med. 2004;350:786-799.
2. Sellers DJ, et al. World J Urol. 2001;19:307-311.
3. Nygaard IE, et al. Clin Obstet Gynecol. 2004;47:83-92.
If you treat OAB successfully
in your patients…
They will be dancing…
… and singing your praises….
Thank you.
Craig V. Comiter, M.D.
Chief, Section of Urology
University of Arizona, HSC
520-694-4032