UROLOGY
`
`VOLUME 51, NUMBER 2A
`
`SUPPLEMENT TO FEBRUARY 1993
`
`URINARY INCONTINENCE:
`THE SCOPE OF THE PROBLEM—THE SOLUTIONS ON THE HORIZON
`Guest Editor‘ ALAN], WEIN, M_D.
`
`Introduction: Urinary Incontinence;
`The Scope of the Problern—.The Solutions on the Horizon
`
`Epidemiology, Pathophysiology, and Evaluation ofUrinary Incontinence and
`Overactive Bladder
`
`Outcome Measures for Urinary Incontinence
`
`Special Considerations in Elderly Individuals With Urinary Incontinence
`
`Electrical Stimulation for the Treatment oi Urinary Incontinence
`
`Surgery for the Treatment of Overactive Bladder
`
`Behavioral Intervention for Comrnunity—Dwellin_g Individuals With Urinary Incontinence
`
`Biofeedback for Communiry—Dwelling Individuals With Urinary Incontinence
`
`Behavioral Modification for Institutionalized Individuals With Urinary Incontinence
`
`Phannacologic Options for the Overactive Bladder
`
`UNIV OF SOUTHERN CALIF.
`
`FEB 2 7 1998
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`NORRIS MEDICAL LIBRARY
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`ELSEVIER
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`SEIR
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`PHARMACOLOGIC OPTIONS FOR THE
`OVERACTIVE BLADDER
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`ALAN_].WElN
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`1__:____:__
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`ABSTRACT
`Objectives. To review the current pharmacoiogic options for treatment of the overactive bladder and to
`describe potential therapies on the horizon.
`Methods. The literature on the clinical efficacy and safety of the currently available agents is described.
`Results. According to the guidelines issued by the Agency for Health Care Policy and Research [AHCPR),
`anticholinergic agents should be the first~line pharmacologic therapy for patients with detrusor instability.
`Oxybutynin is the anticholinergic of choice for this indication, whereas propantheline is the second-line
`therapy. Although calcium antagonists have been investigated,
`the one such drug introduced for the
`treatment of overactive bladder [terodiline] was withdrawn from the market because of a risk of cardiac
`arrhythmia. Studies of potassium channel openers have found either a lack of clinical efficacy or an
`unacceptable level of side effects. Alpha—adrenergic antagonists may be useful for decreasing bladder
`overactivity in patients who have autonomous bladders as the result of conditions such as spinal cord injury.
`Tricyclic antidepressants (particularly irnipramine) may be effective in decreasing bladder contractiiity,
`although the AHCPR guidelines caution that these drugs should be reserved for use in carefully evaluated
`patients. Future developments in the treatment of detrusor overactivity are likely to occur in 3 categories:
`drugs that affect peripheral excitatory mechanisms, drugs that inhibit afferent mechanisms, and drugs that
`affect more central actions at either the ganglionic. spinal cord, or supraspinal level.
`Conclusions. Although pharmacoiogic management of the overactive bladder has progressed little in the
`past 10 years, the future may hoid the promise of more effective therapies. UROLOGY 51 (Suppl 2A]:
`43-47, I998. © 1998, Elsevier Science Inc. All rights reserved.
`
`
`D espite disagreements regarding the details of
`neurophysiology, neuropharmacology, and
`neuromorphology, all observers would agree that
`bladder filling and urine storage require the follow-
`ing: 1) accommodation of increasing volumes of
`urine at a low intrav esical pressure and with appro~
`priate sensation; 2) a bladder outlet that is closed at
`rest and remains so during increases in intra-ab-
`dominal pressure; and 3) an absence ofinvoluntary
`bladder contractions.‘ All
`types of therapy for
`urine storage disorders, whether neuropathic or
`nonneuropathic in etiology, can be classified
`within a functional scheme derived from this sim~
`ple concept. Therapy to improve urine storage may
`be directed toward inhibiting bladder contractility,
`
`_jm.j__.
`
`From the Division afUrolog_y, University 0fPcnns_ylvam'a Medi-
`cal Center, Philadclpliia, Pcnnsylvcmia
`Reprint requests.‘ Alan]. Wcin, MD, Division of Urology, Uni-
`versity of Penns_ylvanin Medical Ct’.iIl(’I', First Floor, Rhodes Pa-
`vilion, .3400 Spruce Street, Pliilaclclpliici, PA l9l04
`
`© 1998, ELHEVIER Scitirtct INC.
`ALL i't[GHl'5 i2i:.~Ei2vi;o
`h._
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`decreasing sensory (afferent) input, or increasing
`bladder capacity.
`
`ANTICHOLINERGIC AGENTS
`
`Most of the neurohumoral stimulus for bladder
`contraction consists
`of
`acetylcholine-induced
`stimulation of postganglionic parasympathetic
`cholinergic receptors on bladder smooth muscle.
`Atropine and atropine-like anticholinergic agents
`inhibit the binding of acetylcholine to the cholin-
`ergic receptor,
`thereby suppressing involuntary
`bladder contractions of any etiology?-3 These
`drugs increase the volume of the first involuntary
`bladder contraction, decrease the amplitude of the
`involuntary bladder contraction, and may increase
`total bladder capacity.” However,
`involuntary
`contractions are not entirely inhibited. in several
`animal models, atropine only partially antagonizes
`the response of the whole bladder to pelvic nerve
`stimulation and the response of bladder muscle
`strips to field stimulation. This so-called atropine
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`to the cholinergic receptor in the smooth muscle
`cell membrane. However, they all have an atro-
`pine~lil<e effect, and questions remain regarding
`the degree to which the clinical, as opposed to the
`laboratory, efficacy of these drugs is attributable to
`this atropine-like effect. Most have some in vltro
`local anesthetic properties as well.
`Oxybutynin is a moderately potent anticholin.
`ergic agent that has strong, independent muscular
`tropic relaxant activity and local anesthetic activ-
`ity. The 1996 AHCPR guidelines
`state that
`oxybutynin is the anticholinergic of choice when
`pharrnacologic therapy is to be used for patients
`with detrusor instability? The recommended oral
`adult dosage is 2.5 to 5 mg 3 or 4 times daily.
`Several studies have found this drug to be effective
`in the management of various types of bladder
`overactivity.7r‘° For example,
`in a randomized,
`double-blind, placebo—controlled trial. Moisey er
`al. found that 17 of 23 patients with detrusor insta-
`bility experienced symptomatic improvement with
`5 mg oxybutynin 3 times daily and 9 had evidence
`of urodynamic improvement
`(primarily an in-
`crease in maximal bladder capacity) .7 Thiiroff et al.
`compared oxybutynin, propantheline, and placebo
`in patients with symptoms of instability and either
`detrusor instability or hyperreflexiaw Oxybutynin
`(5 mg 3 times daily) was most effective, although
`propanthcline was used at a relatively low dose of
`15 mg 3 times daily. The authors pointed out that
`their 67% rate of good or excellent results with
`oxybutynin compared favorably with the 61% to
`86% range calculated from other studies. The po-
`tential side effects are antimuscarinic in nature and
`cause a considerable number of patients to discon-
`tinue this medication.
`Flavoxate is another drug that has a direct inliib-
`itory action on smooth muscle, as well as having
`anticholinergic and local analgesic effects.” How-
`ever, this agent has questionable clinical efficacy
`and is not recommended for the treatment of de-
`trusor instability, according to the AHCPR guide-
`lines.“
`
`CALCIUM ANTAGONISTS
`
`resistance may be caused by the release of a non-
`cholinergic excitatory neurotransmitter.3 The exis-
`tence of atropine resistance in normal human blad-
`der muscle has not been confirmed and may exist
`only in abnormal states. This hypothesis may ex-
`plain why it is difficult to abolish involuntary blad-
`der contractions with anticholinergic therapy
`alone. Anticholinergic agents do not increase the
`warning time (the time between the perception
`that an involuntary contraction is about to occur
`and its actual occurrence). Therefore, urgency and
`incontinence will continue to occur unless such
`treatment is used in combination with a timed
`voiding or toileting regimen.
`According to the 1996 practice guidelines issued
`by the Agency for Health Care Policy and Research
`(AHCPR), anticholinergic agents should be con-
`sidered first-line pharmacologic therapy for pa-
`tients with detrusor instability.“ Propantheline
`bromide is the traditional oral agent used to pro-
`duce an antimuscarinic effect in the lower urinary
`tract (LUT). The AHCPR guidelines state that pro-
`pantheline should be the second-line anticliolin-
`ergic agent for the treatment of detrusor instability
`in patients who can tolerate the full dosage (the
`first-line agent being oxybutynin, as discussed un-
`der musculotropic relaxants below). The recom-
`mended dosage of propantheline is 7.5 to 30 mg
`administered 3 to 5 times per day, although higher
`dosages (15 to 60 mg 4 times daily) may be re-
`quired. There appear to be few differences between
`the antimuscarinic effects of propantheline on
`bladder smooth muscle and those of other anti-
`muscarinic agents (for instance, glycopyrrolate,
`isopropamide, hyoscyamine, anisotropine, and
`methylbromide).
`The ideal anticholinergic agent would be one
`that inhibits only the muscarinic receptor subtype
`responsible for bladder contraction. However,
`it
`has been very difficult, either experimentally or
`clinically, to identify a compound that would affect
`only bladder contractility and not the salivary se-
`cretory glands. All antimuscarinic agents have the
`potential to inhibit salivary secretion (causing dry
`mouth), block the ciliary muscle of the lens to cho-
`linergic stimulation (causing blurred vision for
`nearby objects), and cause tachycardia, drowsi-
`ness, and inhibition of gut motility. Drugs that
`have some ganglionic blocking activity may also
`cause orthostatic hypotension and, at high doses,
`impotence.
`
`
`
`
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`
`
`The dependence of contractile activity on
`changes in cytosolic calcium varies from tissue to
`tissue, as do the characteristics of the calcium
`channels involved. Nonetheless, interference with
`the inflow or intracellular release of calcium is ‘A
`mechanism by which bladder smooth muscle re-
`laxation may be achieved.” An agent that com-
`bines calcium antagonistic activity with anticho-
`linergic activity may therefore offer
`improved
`clinical efficacy. The calcium antagonist terodiline
`was found effective in several clinical studies coir
`ducted during the 19803 and early l99OS.”“j
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`UROLOGY 51 (Supplement 2A}, Febrticiiy I998
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`MUSCULOTROPIC RELAXANTS
`
`Agents classified as musculotropic relaxants or
`antispasmodics are all said to have an inhibitory
`effect on bladder smooth muscle contraction met-
`abolically distal to the attachment of acetylcholine
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`However, this agent was withdrawn from the mar-
`ket following reports of the potential for cardiac
`arrhythmia (specifically, torsade de pointes).”"”
`
`POTASSIUM CHANNEL OPENERS
`
`Potassium channel openers relax various types of
`smooth muscle by increasing potassium efflux and
`causing membrane hyperpolarization.” Such
`agents also abolish spontaneous contractile activ-
`ity in normal and hypertrophied preparations and
`will inhibit contractions caused by carbachol (an
`acetylcholine agonist) and electrical sti1nulation.l“’
`Theoretically, a potassium channel opener would
`have the advantage of not affecting the contractile
`power of a normal micturition. However, assess-
`ments of these agents have found a lack of clinical
`efficacy or an unacceptable level of side effects.1°~31
`
`ALPHA-ADRENERGIC ANTAGONISTS
`
`Alpha—adrenergic antagonists have been used to
`decrease bladder overactivity with some success in
`patients who have so-called decentralized or au-
`tonomous bladders as the result of myelodysplasia,
`spinal cord injury, or radical pelvic surgery.“
`
`TRICYCLIC ANTIDEPRESSANTS
`
`The tricyclic antidepressants are a complex
`group of drugs that have central and peripheral
`anticholinergic effects, as well as sedative effects,
`and block the active reuptake of norepinephrine
`and serotonin. However, the exact mechanisms by
`which these drugs act in the LUT remain a matter
`of debate.
`
`The 1996 AHCPR guidelines caution that tricy-
`clic antidepressants should be reserved for use in
`carefully evaluated patients.“ The guidelines state
`that the usual oral dosage ofimipramine is 10 to 25
`mg initially administered 1 to 3 times per day, but
`less-frequent adtninistration is often possible be.-
`cause ofthe long half-lives of these drugs. The total
`daily dosage is typically 25 to 100 mg.
`ltnipramine, in particular, is useful for facilitat-
`ing urine storage by decreasing bladder contractil-
`ity and increasing outlet resistance.23"37 In a study
`by Castelden et al., elderly patients with detrusor
`instability began therapy with a single 25 mg night-
`time dose of imipramine." The dose was increased
`by 25 mg every third day until the patient either
`achieved continence, experienced side effects, or
`reached a dose of 150 mg. Of 10 patients, 6 became
`continent. Among those who underwent repeat
`cystometry, bladder capacity increased by a mean
`of 105 mL, bladder pressure at capacity decreased
`by a mean of 18 cm H20, and maximum urethral
`pressure increased by a mean of 30 cm H20. In our
`experience, imipramine and atropine—like agents
`
`UROLOGY 51 (Supplcincnt ZA), February 1998
`
`often have additive effects on the LUT. Therefore, a
`
`combination of imipramine and an antiinuscarinic
`or antispasrriodic drug may be useful for decreas-
`ing bladder contractility. However, the side effects
`may be additive as well.
`Doxepin is another tricyclic antidepressant that
`has been evaluated for the treatment of U1. In a
`randomized, double—blind, cross-over study by
`Lose et al, women with involuntary bladder con-
`tractions and either frequency, urgency, or urge Ul
`received either a single 50 mg dose of doxepin at
`bedtime or this dose plus an additional 25 mg in
`the 1norning.33 Doxepin produced a significant de-
`crease in nighttime frequency and nighttime in-
`continence episodes. This treatment also resulted
`in a nearly statistically significant decrease in urine
`loss and in cystometric measurements of first sen-
`sation and maximum bladder capacity.
`If a tricyclic antidepressant is prescribed for the
`treatment of voiding dysfunction, the patient must
`be informed that this is not the usual indication for
`the drug and that side effects may occur. At the
`generally larger doses used to achieve antidepres-
`sant effects, the most frequent side effects of the
`tricyclic antidepressants are those attributable to
`the systemic anticholinergic activity of
`these
`drugs.2‘-W’ Central nervous system (CNS) side ef-
`fects and postural hypotension may also occur.
`Imipramine is contraindicated in patients receiv-
`ing monoainine oxidase inhibitors because severe
`CNS toxicity may develop.
`In addition,
`these
`agents can produce arrhythmias and should there-
`fore be used with caution in patients with cardio-
`vascular disorders?“ Side effects such as weakness,
`fatigue, and orthostatic hypotension may be espe-
`cially marked in elderly patients.
`
`PROSTAGLANDIN INHIBITORS AND
`BETA-ADRENERGIC AGONISTS
`
`Some laboratory evidence is available to suggest
`that prostaglandin inhibitors or beta—adrenergie
`agonists should be effective in decreasing bladder
`contractility. However, these lines of investigation
`have not proved fruitful in the clinical setting.
`
`FUTURE DEVELOPMENTS
`
`Future developments in the treatment of detru-
`sor overactivity are apt to occur in 3 categories.
`The first category consists of drugs that affect pe-
`ripheral excitatory mechanisms. Such therapies
`could take the form of more specific receptor an-
`tagonists, drugs that affect membrane phenomena,
`or drugs that affect excitation contraction cou-
`pling. The second category includes drugs that in-
`hibit afferent (sensory) mechanisms. The third cat-
`egory consists of drugs that affect more central
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`actions at either the ganglionic, spinal cord, or su-
`praspinal level.
`At the 1997 meeting of the American Urological
`Association, the category of agents that affect affer-
`ent mechanisms was the most commonly men-
`tioned of the newer treatment strategies. A total of
`9 abstracts were presented on capsaicin, an irritant
`and algogenic compound obtained from hot red
`peppers.-3‘-3° One abstract dealt with a new potas-
`sium channel opener (YM-934),“° and one with a
`phosphodiesterase-1
`inhibitor
`(vinpocetine}.“
`Two abstracts described work with tolterotline, a
`selective muscarinic antagonist that has less of an
`effect on salivary gland smooth muscle than on
`detrusor smooth 11’1LlSClE.“l1:'l3
`
`CONCLUSIONS
`
`At present, anticholinergic agents remain the
`most common pharmacologic therapy for the over-
`active bladder. According to the AHCPR guide-
`lines, oxybutynin is the anticholinergic of first
`choice, followed by propantheline. Alpha-adrener-
`gic antagonists may be useful for the treatment of
`patients with decentralized bladders. The AHCPR
`advises that
`tricyclic antidepressants should be
`used only in carefully evaluated patients. lmipra-
`mine, in particular, can help decrease bladder con-
`tractility.
`Although the pharmacologic management of
`overactive bladder has progressed little in the past
`10 years, the future may hold the promise of more
`effective therapies. Among the promising treat-
`ments on the horizon are agents designed to affect
`peripheral excitatory mechanisms, inhibit afferent
`mechanisms, or affect more central actions at ei-
`ther the ganglionic, spinal cord, or supraspinal
`level.
`
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`
`UROLOGY 51 (5t.tpplt‘mt'nt ZA), Ft'lJt1tnry 1998
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`47
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`Patent Owner, UCB Pharma GmbH — Exhibit 2031 - 0006