THE OVERACTIVE BLADDER
From the New York University Symposium on Surgical, Pharmacologic, and Technologic Advances in Adult and
Pediatric Urology
| PHAMACOLOGIC TREATMENT OPTIONS—Paul Abrams, MD, Professor of Urology, Bristol Urological Institute,
Southmead Hospital, Westbury-on-Trym, Bristol, UK
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| Introduction: overactive bladder (OAB)—characterized by urgency (key symptom) and/or urgency incontinence
(ie, ≈50% of patients have urgency and urgency incontinence); patients usually experience frequency and nocturia
(ie, frequency can occur in absence of OAB); diagnosed during initial office visit; occurs in women as part of spectrum
of potential incontinence and lower urinary tract storage disorders (problems range from stress and mixed urinary
incontinence to dry OAB detected in younger patients with symptomatic problem, good pelvic floor control,
and no urgency incontinence); detrusor overactivity (DO)—urodynamic diagnosis; characterized by involuntary
detrusor contractions; evaluated by measuring bladder pressures during filling; interaction between OAB and
DO—patient with urgency incontinence probably experiences involuntary detrusor contractions; in patient with
urgency or frequency and nocturia, involuntary contractions less likely
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| Overactive bladder: etiology poorly understood; can be managed but not cured; conservative options—education
about appropriate fluid intake (can markedly improve symptoms in many patients); pelvic floor exercises; bladder
training; intermittent catheterization in patients with multiple sclerosis; pharmacologic therapy (treatment mainstay);
point—every patient should receive spectrum of treatment
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| Drugs with antimuscarinic and mixed activity used to manage DO: concern exists that drugs may pass
blood-brain barrier (BBB) and affect short-term memory and concentration in children and elderly individuals;
tolterodine (Detrol)—safe and effective; once-daily formulation associated with lower side-effect profile and precludes
need for dose titration; trospium—quaternary ammonium compound that theoretically will not cross BBB;
administered on bid basis; effective; has fewer side effects than oxybutynin; oxybutynin—effective; patch formulation
reduces side-effect profile, but can cause skin irritation; propiverine—effective; has possible calcium antagonist
mechanism (potential cardiotoxic effect unsubstantiated by clinical data); provides second possible means of
controlling idiopathic DO; darifenacin—developed to manage irritable bowel syndrome; theoretically, may cause
fewer side effects; bowel symptoms theoretically possible in response to drug’s specificity for M3 muscarinic receptors;
solifenacin—new drug; efficacy good; administered as 5-mg or 10-mg daily dose; specific to M2 and M3
muscarinic receptors; has long half-life (theoretically, side effects can last ≈1 wk once treatment stopped); problems
associated with use of antimuscarinic agents—intolerance to classic side effects of dry mouth and difficulty
in visual accommodation; need to titrate dose of many agents; central nervous system (CNS) side effects (monitor
patients carefully)
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| Additional drug options: imipramine—pharmacologically “dirty,” with several areas of activity, ie, acts as α-agonist
and local anesthetic; desmopressin (1-damino-8-arginine vasopressin [DDAVP])—antidiuretic hormone
(ADH) analogue; can reduce urine output and alter nocturnal symptoms; reduces urinary incontinence when taken
during day; one daily dose permits normal voiding
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| Lower urinary tract symptoms (LUTS) in older men: erroneously blamed on prostate alone (many other
causes of symptomatology must be considered); OAB—incidence similar in older men and women; common
cause of storage-related symptoms of urgency and urgency incontinence; combination of DO-induced OAB and
prostatic obstruction—often develops with increasing age; traditionally, treatment has focused on administering
α-blockers to address prostatic problems; involuntary detrusor contractions and symptoms of OAB more bothersome
to older men than slow urine stream and should become focus of overall management approach; antimuscarinic
therapy—treatment of choice in otherwise normal patients with OAB; concern over urinary retention
has prevented use of therapy in older men
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 | Double-blind study randomizing men with symptomatic OAB, DO, and bladder outlet obstruction (BOO) to placebo
or tolterodine therapy: designed to determine whether antimuscarinic therapy places men with high-pressure,
low-flow systems at increased risk for urinary retention; when compared to placebo group, men receiving
tolterodine experienced—no change in maximum urine flow rate; no statistically significant change in bladder
pressure at maximum flow; improvement in urine volume at first involuntary contraction that could produce sensations
of urgency or urgency incontinence; improvement in maximum cystometric capacity (ie, finding shows
drug effective during storage phase of mic-turition); became slightly less obstructed (unexplained benefit attributed
to tolterodine); no change in bladder contractility or voiding efficiency; small increase in residual urine;
mild-to-moderate episode of dry mouth; clinically insignificant increase in postvoid residual; no increase in adverse
urinary events; data suggest antimuscarinic therapy—safe; does not increase risk for urinary retention in
older men; can be considered when α-blockade ineffective, inadequate, or when symptoms of OAB predominate
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| Speculations on physiology
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| OAB: may have neurogenic and/or myogenic etiology; efficacy of antimuscarinic therapy thought to be modulated
via blockade of muscarinic receptors located in detrusor muscle; autonomous rhythmic bladder contractions during
filling and storage—emerging paradigm; may be required for sensory monitoring of bladder volume; CNS
may exert control through autonomic nerves, ie, increasing rhythmic contractions via parasympathetic nerves
and decreasing contractions via sympathetic nerves
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| Antimuscarinic drugs: exert effects during filling/storage phase of micturition, ie, bladder capacity increases, urgency
decreases; questions exist as to whether antimuscarinic drugs have multiple sites of activity
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| Sensory pathways in bladder control: afferent signals originate in urothelium, suburothelium, and detrusor smooth
muscle; filling and distention may be detected through volume and tension sensors; sensory signals can be modulated
by—tachykinins; purinergic agonists; vanilloid agonists; acetylcholine (ACh)
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| Sensory pathways in OAB: sacral parasympathetic nerves usually inactive during bladder filling and storage; basal
level of ACh release in human bladder—non-neuronal leakage (originates in urothelium and suburothelium); neuronal
leakage (spontaneous release enhanced by nerve damage, obstruction, ischemia, and age); increased ACh release
during filling—may contribute to OAB by increasing bladder afferent activity during storage; may be
blocked by drugs like tolterodine (drug activity can produce beneficial effect on filling against OAB symptoms; activity
may explain why tolterodine does not affect voiding phase during release of large amount of ACh)
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| BOTULINUM TOXIN FOR THE TREATMENT OF BLADDER AND DETRUSOR OVERACTIVITY —Victor
W. Nitti, MD, Associate Professor and Vice-Chairman, Department of Urology, New York University School of
Medicine, New York
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| Botulinum toxin: not approved by Food and Drug Administration (FDA) for managing OAB and DO; polypeptide
consists of light and heavy chains bound by disulfide bond; depending on specific toxin, metalloproteases and nonhemagglutinins
can be attached to structure; options—botulinum toxin type A (BOTOX [vacuum dried]);
Clostridium botulinum type A toxin-haemagglutinin complex [Dysport]; botulinum toxin type B (Myobloc);
point—concentrations and therapeutic doses differ with form of botulinum toxin; toxin—blocks ACh to inhibit
contraction of striated and smooth muscle; probably blocks other neurotransmitters leading to afferent stimulation;
works on intracellular soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) complex or protein
to prevent ACh and other neurotransmitters from leaving nerve terminal and stimulating receptors (ie, different
toxins work on different components of SNARE complex)
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| Mechanism by which botulinum toxin disrupts entry of ACh into synaptic space: once toxin becomes
endocytized into cell, cell membrane becomes depolarized when light chain of—toxin type A cleaves synaptosome-associated
protein of 25 kDa (SNAP-25); toxin type B cleaves vesicle associated membrane protein
(VAMP); subsequent to toxin activity—depolarized membrane prevents neurotransmitter (ACh) from leaving cell;
terminal nerve sprouting takes place; over months, sprouts regress and normal nerve terminals take over
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| Botulinum toxin and urinary function: biopsy data obtained from patients with OAB—determined that receptors
involved with afferent control prevalent in patients with neurogenic and idiopathic DO (these receptors showed
reduced activity following botulinum toxin injection); suggested that botulinum toxin may play role in achieving
afferent control in bladder mechanism (toxin activity may be more complex than just stopping muscle contraction
through inhibition of ACh release); in lower urinary tract, botulinum toxin—injected into external sphincter
blocks muscle contraction at parasympathetic level; may exert effect on somatic and sensory function; points—
data support concept that botulinum toxin can help adults with neurogenic and idiopathic DO refractory to alternative
medical therapy; requirement for general anesthesia in children may render approach impractical in pediatric
patients
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| Botulinum toxin therapy: BOTOX—used in United States; comes crystallized in 100-U vials; must be refrigerated
or frozen; costs $466 to $650 per vial, ie, many patients may have to pay for toxin themselves; ideal method for reconstitution
has not been worked out; 100 U of BOTOX dissolved in 10 mL of solvent—preferred dilution; provides
better coverage when injected into detrusor; concentration used in studies achieving most favorable results;
patient selection—individuals who have failed standard therapy receive botulinum toxin injections or InterStim
therapy; toxin injection easier for patient but expensive if not covered by insurance or Medicare; to reduce costs of
procedure—give patient prescription for BOTOX to fill on their own; administer BOTOX in office
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| Pointers on technique: obtain urinalysis to rule out urinary tract infection; administer local anesthetic; catheterize patient
and empty bladder; instill 40 mL of 1% lidocaine and 2% lidocaine gel into urethra (wait 20 min; bladder should
be empty of lidocaine before starting injections; risk for interaction between BOTOX and lidocaine unknown); use
flexible or rigid scope—in men, flexible scope may be more comfortable (rigid scope more difficult to use under local
anesthetic; if patient uncomfortable, some bleeding from prostate may develop); rigid scope preferred in women
and can be used to perform faster, more precise injections; points—ideal injection template has not been determined;
number of injection sites has not been standardized, ie, most studies inject 20 to 30 sites, with injections into trigone
being optional; some studies inject trigone only; injections—intramuscular; performed in office using local anesthetic;
place initial injection behind ureteral orifices; perform intradetrusor injection; go across bladder base; place
subsequent injections across bladder to achieve reasonable coverage; as injections get closer to bladder dome, needle
does not penetrate as deeply; following procedure—monitor voiding; administer prophylactic antibiotics for 3 days;
check postvoid residual at 10 days; let patients know it takes ≈2 wk for injections to take effect
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| Complications: immediate postinjection problems, eg, difficulty voiding, marked hematuria, fever, and chills rare;
elevated residuals—unusual; patient should be aware of risk; if postinjection evaluation shows postvoid residual
higher than previous functional bladder capacity, intermittent catheterization may be necessary; problem appears
to be associated with higher doses of botulinum toxin, ie, in patients of concern, limit dose of botulinum
toxin to 100 U; transient weakness—rare; reported with Dysport, not BOTOX
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| In future, clinicians must determine: ideal injection protocol; total number of units and concentration of botulinum
toxin that should be administered; location and number of injection sites; patients most likely to respond to
therapy
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| Conclusions about current management options: medical therapy—effectively treats ≈60% of patients with
OAB and DO; associated with compliance problems and side effects; second-line surgical options—effective; associated
with marked morbidity; botulinum toxin injections— promising therapeutic option
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Educational Objectives
| The goal of this program is to educate the listener about medical options for treating bladder and detrusor overactivity.
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Review pharmacologic agents currently used to manage overactive bladder (OAB) and detrusor overactivity
(DO).
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| 2. Determine the role of antimuscarinic agents in older men.
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| 3. Describe biochemical characteristics of botulinum toxin.
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| 4. Assess the potential merits of using botulinum toxin to manage OAB and neurogenic and idiopathic DO.
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| 5. Evaluate current techniques used to inject botulinum toxin into the bladder.
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Discussed on This Program
Botulinum toxin type A [Botox, Botox Cosmetic]
Botulinum toxin type B [Myobloc]
Clostridium botulinum type A toxin-haemagglutinin complex [Dysport]
Darifenacin HBr (Enablex)
Desmopressin acetate (1-deamino-8-D-arginine vasopressin) [DDAVP, Stimate]
Imipramine HCl [Tofranil]
Lidocaine HCl (several trade names and preparations)
Oxybutynin chloride [Ditropan, Ditropan XL, Osytrol]
Propiverine hydrochloride [Detrunorm]
Resiniferatoxin [RTX] (investigational)
Solifenacin succinate [VESIcare]
Tolterodine tartrate [Detrol, Detrol LA]
Trospium chloride [Sanctura]
Suggested Reading
Andersson KE, Yoshida M: Antimuscarinics and the overactive detrusor. Which is the main mechanism of action?
Eur Urol, 43:1, 2003; Appell RA: Clinical efficacy and safety of tolterodine in the treatment of overactive bladder:
a pooled analysis. Urology 50:90, 1997; Chapple CR et al: Randomized, double-blind placebo- and
tolterodine-controlled trial of the once-daily antimuscarinic agent Solifenacin in patients with symptomatic overactive
bladder. BJU 93:303, 2004; Roehrborn CG et al: Efficacy and tolerability of tolterodine extended-release in
men with overactive bladder and urgency urinary incontinence. BJU 97:1003, 2006; Schmid DM et al: Experience
with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome
refractory to anticholinergics. J Urol 176:177, 2006; Schurch B: Botulinum toxin for the management of
bladder dysfunction. Drugs 66:1301, 2006; Staskin DR, MacDiarmid SA: Using anticholinergics to treat overactive
bladder: the issue of treatment tolerability. Am J Med 119:9, 2006; Woodhouse JB et al: Botulinum toxin and
the overactive bladder. Br J Hosp 67:460, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Abrams is affiliated with American Medical Systems, Ferring Pharmaceuticals, Novartis
Pharmaceuticals Corp., Pfizer Inc., Plethora, and Schwarz-Pharma.
Drs. Abrams and Nitti gave their scientific lectures at Surgical, Pharmacological, and Technological Advances in
Adult and Pediatric Urology: State of the Art, presented December 8-10, 2005 in New York, NY, by New York University
School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation
in the production of this program.
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