BJU International (1999), 84, 923–947
`
`REVIEW
`
`The pharmacological treatment of urinary incontinence
`K.-E. ANDERSSON, R. APPELL 1 , L.D. CARDOZO2 , C. CHAPPLE 3 , H.P. DRUTZ 4 , A.E. FINKBEINER 5 ,
`F. HAAB 6 and R. VELA NAVARRETE 7
`The Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden, 1Department of Urology, The Cleveland Clinic
`Foundation, Cleveland, Ohio, USA, 2King’s College Hospital, London, UK, 3Department of Urology, Royal Hallamshire Hospital,
`SheBeld, UK, 4Service Urologie, Hopital Tenon University of Toronto, Mount Sinai Hospital, Ontario, Canada, 5Department of
`Urology, University of Arkansas for Medical Sciences, Little Rock, USA, 6Urogynecology Unit, Paris, and 7Department of Urology,
`Universidad Autonoma, Madrid, Spain
`
`Introduction
`The bladder and urethra constitute a functional unit
`which is controlled by a complex interplay between the
`central and peripheral nervous systems and local regulat-
`ory factors [1,2]. Malfunction at various levels may
`result in micturition disorders, which roughly can be
`classified as disturbances of storage or of emptying.
`Failure to store urine may lead to various forms of
`incontinence (mainly urge and stress incontinence), and
`failure to empty can lead to urinary retention, which
`may result in overflow incontinence. Theoretically, a
`disturbed storage function can be improved by agents
`that decrease detrusor activity, increase bladder capacity
`and/or increase outlet resistance. Many drugs have been
`tried, but the results are often disappointing, partly
`through poor treatment eBcacy and side-eCects [3]. The
`development of pharmacological treatment has been
`slow, and the use of some of the currently prescribed
`agents is founded more on tradition than on evidence
`based on results from controlled clinical trials [4–8].
`In the present review of drugs in current use for the
`treatment of urinary incontinence, agents specifically
`used to treat urinary tract infections and interstitial
`cystitis have not been included. The currently used
`terminology conforms with the recommendations of the
`ICS. Drugs have been evaluated using diCerent types of
`evidence (Table 1). Evidence of pharmacological and/or
`physiological eBcacy means that a drug has been shown
`to have desired eCects in relevant preclinical experiments
`or in healthy volunteers (or in experimental situations
`in patients); the present clinical drug recommendations
`are based on evaluations made using a modification of
`the grading of evidence found in the Agency for Health
`Care Policy and Research (AHCPR) guidelines (Table 2).
`
`Accepted for publication 31 August 1999
`
`© 1999 BJU International
`
`Table 1 Types of evidence
`
`Type
`
`Pharmacodynamic
`
`Pharmacokinetic
`
`Physiological
`
`Clinical
`
`Condition
`
`In vitro
`In vivo
`Absorption
`Distribution
`Metabolism
`Excretion
`Animal models
`Clinical phase I
`Trials
`‘practice’
`
`Bladder contraction
`
`Normal bladder contraction in humans is mediated
`mainly through stimulation of muscarinic receptors in
`the detrusor muscle. Atropine resistance, i.e. contraction
`of isolated bladder muscle in response to electrical nerve
`stimulation after pretreatment with atropine, has been
`shown in most animal species, but seems to be of little
`importance in normal human bladder muscle [1].
`However, atropine-resistant
`(nonadrenergic, nonchol-
`inergic, NANC) contractions have been reported in
`normal human detrusor and may be caused by ATP
`[9–11]. A significant degree of atropine resistance may
`exist in morphologically and/or functionally changed
`bladders, and has been reported to occur in hypertrophic
`bladders [12,13], interstitial cystitis [14], and in neuro-
`genic bladders [15]. The importance of the NANC compo-
`nent to detrusor contraction in vivo, normally, and in
`diCerent micturition disorders, remains to be established.
`
`Drugs used to treat bladder hyperactivity
`
`Studies have documented a 33–61% prevalence of an
`overactive bladder in the elderly over the age of 65 years
`
`923
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`
`924 K.-E. ANDERSSON et al.
`
`Drug
`
`Bladder hyperactivity
`Antimuscarinic drugs
`Atropine, hyoscyamine
`Propantheline
`Emepronium
`Trospium
`Tolterodine
`(Darifenacin)
`Drugs acting on membrane channels
`Calcium antagonists
`Potassium-channel openers
`Drugs with mixed actions
`Oxybutynin
`Dicyclomine
`Propiverine
`Flavoxate
`(Terodiline)
`a-adrenoceptor antagonists
`Alfuzosin
`Doxazosin
`Prazosin
`Terazosin
`Tamsulosin
`b-Adrenoceptor agonists
`Terbutaline
`Clenbuterol
`Salbutamol
`Antidepressants: Imipramine
`Prostaglandin synthesis inhibitors
`Indomethacin
`Flurbiprofen
`Vasopressin analogue: Desmopressin
`Other drugs
`Baclofen
`Capsaicin
`Resiniferatoxin
`Stress incontinence
`a-Adrenoceptor agonists
`Ephedrine
`Norephedrine (phenylpropanolamine)
`Other drugs
`Imipramine
`Clenbuterol
`(Duloxetine)
`Hormones: Oestrogens
`Overflow incontinence
`a-adrenoceptor antagonists
`Alfuzosin
`Doxazosin
`Prazosin
`Terazosin
`Tamsulosin
`(Phenoxybenzamine)
`Muscarinic receptor agonists
`Bethanechol
`
`Evidence*
`
`Pharmacological/
`physiological
`
`Clinical
`
`Assessment
`
`Table 2 Drugs used in the treatment of
`bladder hyperactivity, stress and overflow
`incontinence
`
`E
`E
`E
`E
`E
`Under investigation
`
`C
`A
`A/B
`A
`A
`
`Under investigation
`Under investigation
`
`E
`E
`E
`U
`E
`
`U
`U
`U
`U
`U
`
`U
`U
`U
`E
`
`U
`U
`E
`
`E
`E
`Under investigation
`
`E
`E
`
`A
`B
`A
`B/C
`A
`
`B/C
`B/C
`B/C
`B/C
`B/C
`
`B/C
`B/C
`C
`A
`
`B
`B
`A
`
`C
`B
`
`B/C
`B
`
`U
`U
`Under investigation
`E
`
`C
`B
`
`–
`
`E
`E
`E
`E
`E
`E
`
`E
`
`B
`B
`B
`B
`B
`A/B
`
`B/C
`
`–
`R
`R
`R
`R
`
`R
`–
`R
`–
`–
`
`–
`–
`–
`–
`–
`
`–
`–
`–
`R
`
`–
`–
`R
`
`–
`–
`
`–
`–
`
`–
`–
`
`–
`
`–
`–
`–
`–
`–
`–
`
`–
`
`© 1999 BJU International 84, 923–947
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`Table 2 (Cont’d)
`
`PHARMACOLOGICAL TREATMENT OF URINARY INCONTINENCE
`
`925
`
`Drug
`
`Evidence*
`
`Pharmacological/
`physiological
`
`Carbachol
`Anticholinesterase inhibitor: Distigmine
`Other drugs
`Baclofen
`Benzodiazepines
`Dantrolene
`
`E
`E
`
`E
`E
`E
`
`Clinical
`
`Assessment
`
`B/C
`B/C
`
`B
`C
`C
`
`–
`–
`
`–
`–
`–
`
`*E, eCective; U, unproven; A, good quality RCT; B, clinical studies; C, ‘expert’ opinion;
`R, recommended.
`
`[15–17]. It appears that detrusor hyperactivity may be
`the result of several diCerent mechanisms, both myogenic
`[18] and neurological [19]. Most probably, both factors
`contribute to the genesis of the hyperactive bladder.
`An abundance of drugs has been used for the treat-
`ment of the hyperactive detrusor (Table 2). However, for
`many of them, clinical use is based on the results of
`preliminary, open studies rather than randomized, con-
`trolled clinical trials (RCTs). It should be stressed that in
`many trials on both detrusor instability and detrusor
`hyper-reflexia,
`there has been such a high placebo
`response that meaningful diCerences between placebo
`and active drug cannot be detected. However, drug
`eCects in individual patients may be both useful and
`important.
`
`Antimuscarinic (anticholinergic) drugs
`
`Muscarinic receptors mediate not only normal bladder
`contraction, but also the principal contractions of over-
`active bladders, and antimuscarinic drugs are able to
`produce an almost complete paralysis of the normal
`bladder when injected parenterally. Several studies sug-
`gest that detrusor contractions can also be blocked in
`patients with bladder hyperactivity [20–23]. On the
`other hand, there are several reports of
`insuBcient
`eBcacy for antimuscarinic drugs given orally to patients
`with unstable detrusor contractions [24–27].
`It
`is
`unclear to what extent this can be attributed to low
`bioavailability, side-eCects limiting the dose that can be
`given, or to atropine resistance.
`Atropine and related antimuscarinic drugs are tertiary
`amines. They are well absorbed from the gastrointestinal
`tract and pass easily into the CNS; side-eCects on the CNS
`may therefore limit their use. Quaternary ammonium
`compounds are not well absorbed, pass into the CNS to
`a limited extent, and have a lower incidence of CNS side-
`eCects [28]. They still produce well-known peripheral
`antimuscarinic side-eCects, e.g. accommodation paral-
`
`© 1999 BJU International 84, 923–947
`
`ysis, constipation, tachycardia and dryness of mouth.
`All antimuscarinic drugs are contraindicated in patients
`with narrow-angle glaucoma.
`Antimuscarinic agents are still the most widely used
`treatment for urge and urge incontinence [8]. However,
`currently used drugs lack selectivity for the bladder [29]
`and eCects on other organ systems (Fig. 1) may result
`in side-eCects which limit their usefulness. Theoretically,
`drugs with selectivity for the bladder may be obtained,
`if the receptor subtype(s) mediating bladder contraction,
`and those producing the main side-eCects of antimuscar-
`inic drugs, were diCerent. One way of avoiding many of
`the antimuscarinic side-eCects is to administer the drugs
`intravesically. However, this is practical only in a limited
`number of patients.
`Several subpopulations of muscarinic receptors have
`been identified, and five diCerent subtypes (m1-m5) have
`been cloned. Pharmacologically, five diCerent subtypes
`(M1-M5) have been defined [29–31], all with a wide
`distribution in the body. The subtypes that can be
`detected in the human bladder and those responsible for
`bladder contraction have been studied using various
`approaches. Cultured human detrusor cells expressed M3
`receptors linked to phosphoinositide hydrolysis [32], and
`an important role for M3 receptors is widely accepted
`(Fig. 2). M1, M2, and M3 receptor subtypes were detected
`in human detrusor muscle by receptor binding; there
`was a distinct predominance of M3 receptors [33].
`However, Yamaguchi et al. [34] were able to show the
`presence of mRNA encoding the m2 and m3 subtypes,
`but not the m1, m4 and m5 subtypes in the human
`bladder. Using subtype-specific immunoprecipitation,
`Wang et al. [35] detected only m2 and m3 subtypes in
`human and rabbit detrusor membranes,
`the ratio
`of m25m3 being 351. Despite a predominance of m2
`receptors in the detrusor of several species, it has been
`found that the pharmacologically defined M3 receptor
`mediates bladder contraction [35,36]. However, recently,
`at least in the rat, M2 receptors were also shown to be
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`926 K.-E. ANDERSSON et al.
`
`Fig. 1. The eCects of antimuscarinic drugs
`in diCerent target organs.
`
`able to mediate bladder contraction in vitro as well as in
`vivo by reversing b-adrenoceptor-mediated relaxation
`[37]. What this means for the human bladder is unclear.
`Future studies with muscarinic receptor antagonists
`with a selectivity for M3 receptors, such as darifenacin
`[38,39], vamicamide [40] and zamifenacin [41], will
`reveal whether or not the principle of selective M3
`receptor antagonism oCers therapeutic advantages. As
`M3 receptors are located not only in the bladder but also
`in the salivary glands and the intestine, this could mean
`that two of the most common side-eCects, dry mouth
`and constipation, will not be avoided.
`Atropine (dL-hyoscyamine)
`is rarely used to treat
`detrusor hyperactivity because of its systemic side-eCects,
`which preclude its use. However,
`in patients with
`
`intravesical atropine may be
`detrusor hyper-reflexia,
`eCective for increasing bladder capacity without causing
`any systemic adverse eCects, as shown in open pilot
`trials [42,43].
`The pharmacologically active antimuscarinic half of
`atropine is l-hyoscyamine. Although widely used, few
`clinical studies are available to evaluate the antimuscar-
`inic activity of l-hyoscyamine sulphate.
`Propantheline bromide is a quaternary ammonium com-
`pound, not selective for muscarinic receptor subtypes,
`which has a low (5–10%) and individually varying
`biological availability [4]. It is usually given in a dose of
`15–30 mg four times daily, but to obtain an optimal
`eCect, individual titration of the dose is necessary, and
`often a higher dosage. Using this approach in 26 patients
`
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`PHARMACOLOGICAL TREATMENT OF URINARY INCONTINENCE
`
`927
`
`Fig. 2. Bladder contraction is mediated by
`the stimulation of muscarinic M2 and M3
`receptors.
`
`with uninhibited detrusor contractions, Blaivas et al.
`[22],
`in an open study, obtained a complete clinical
`response in all patients but one, who did not tolerate
`more than propantheline 15 mg four times daily. The
`range of dosages varied from 7.5 to 60 mg four times
`daily. In contrast, Thu¨ roC et al. [44] comparing the
`eCects oxybutynin 5 mg×3, propantheline 15 mg×3
`and placebo in a randomized, double-blind, multicentre
`trial on the treatment of frequency, urgency and inconti-
`nence related to detrusor hyperactivity (154 patients
`with idiopathic detrusor instability or detrusor hyper-
`reflexia), found no diCerences between the placebo and
`propantheline groups. In another randomized compara-
`tive trial with crossover design (23 women with idio-
`pathic detrusor instability), and with dose titration,
`Holmes et al. [45] found no diCerences in eBcacy between
`oxybutynin and propantheline. Leys [46] found no sig-
`nificant diCerences in the eCect on enuretic children
`comparing propantheline 15–45 mg×4 to placebo.
`Propantheline has a documented eCect on detrusor
`hyperactivity and may,
`in individually titrated doses,
`be clinically useful.
`
`© 1999 BJU International 84, 923–947
`
`Emepronium bromide or carrageenate is a quaternary
`ammonium compound lacking selectivity for muscarinic
`receptor subtypes. It has a low biological availability
`(5–10%) which varies markedly between individuals
`[47]. The dosage must be kept in the range 200 mg 3–4
`times daily or higher. To obtain an optimal eCect,
`individual titration of the drug is necessary; the dose is
`increased until
`incontinence is eliminated or until
`untoward side-eCects preclude further increase. Positive
`eCects in patients with urge incontinence have been
`shown in controlled clinical trials, e.g. [48,49]. Massey
`and Abrams [49] studied the eCects of emepronium
`carrageenate in women with detrusor instability in a
`double-blind, placebo-controlled, randomized crossover
`trial. Dosages were individually titrated; of 72 patients
`entering the study, five were withdrawn during the
`titration phase, 24 were treated with 1200 mg daily and
`43 with 1600/2000 mg daily. There was a dose-
`dependent improvement of both symptoms and mictur-
`ition values. However, some investigators have shown
`emepronium to exert no significant eCects on the bladder
`when administered orally [50].
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`
`928 K.-E. ANDERSSON et al.
`
`The eCect of emepronium bromide has often been
`attributed to a ganglionic blocking action, and it has
`been suggested that such an eCect would contribute to
`a favourable and selective eCect on the detrusor.
`However, this has never been documented clinically and
`there is no experimental evidence that the drug has a
`selective eCect on the detrusor.
`Emepronium has a documented eCect in detrusor
`hyperactivity and may, in individually titrated doses, be
`clinically useful. Emepronium bromide has been with-
`drawn because of the high incidence of oesophageal/oral
`ulceration. In countries where emepronium is available,
`it is marketed as emepronium carrageenate.
`Trospium chloride is a quaternary ammonium com-
`pound with antimuscarinic actions, but also with eCects
`on ganglia [51]. It has no selectivity for muscarinic
`receptor subtypes. Its biological availability is low, at
`#5% [52]. Several open studies have indicated that the
`drug may be useful in the treatment of detrusor hyper-
`activity [53–55]. In a placebo-controlled, double-blind
`study on patients with detrusor hyper-reflexia [55], the
`drug was given twice daily in a dose of 20 mg over a
`3-week period.
`It
`increased maximum cystometric
`capacity, decreased maximal detrusor pressure and
`increased compliance in the treatment group, whereas
`no eCects were noted in the placebo group. Side-eCects
`were few and comparable in both groups. In a ran-
`domized, double-blind multicentre trial in patients with
`spinal cord injuries and detrusor hyper-reflexia [56],
`trospium and oxybutynin were equally eCective; how-
`ever,
`trospium seemed to have fewer
`side-eCects.
`Trospium chloride has a documented eCect in detrusor
`hyperactivity.
`Tolterodine is a new potent and competitive antagonist
`at muscarinic receptors, intended for the treatment of
`urinary urgency and urge incontinence [57–59]. The
`drug has no selectivity for muscarinic receptor subtypes,
`but still shows some selectivity for the bladder over the
`salivary glands in an animal model [57], and possibly
`in man [60]. Tolterodine has a major active metabolite
`with a similar pharmacological profile [61]. This metab-
`olite significantly contributes to the therapeutic eCect of
`tolterodine [62,63]. Tolterodine is rapidly absorbed and
`has a half-life of 2–3 h, but the eCects on the bladder
`seem to be more long-lasting than could be expected
`from the pharmacokinetic data. The main metabolite
`also has a half-life of 2–3 h [63]. In healthy volunteers,
`orally given tolterodine in a high dose (6.4 mg) had a
`powerful
`inhibitory eCect on micturition and reduced
`stimulated salivation 1 h after administration of the drug
`[60]. However, 5 h after administration, the eCects on
`the urinary bladder were maintained, whereas no sig-
`nificant eCects on salivation could be detected.
`Several randomized, double-blind, placebo-controlled
`
`studies, both on patients with idiopathic detrusor insta-
`bility and detrusor hyper-reflexia, have documented
`a
`significant
`reduction in micturition frequency
`and number of
`incontinence episodes
`[59,64–66].
`Tolterodine seems to be well tolerated when used in the
`dosage range 1–4 mg a day. In a placebo-controlled
`study, comparing tolterodine (2 mg×2) and oxybutynin
`(5 mg×3) in 293 patients with detrusor instability, both
`drugs were found to be equally eCective in reducing the
`frequency of micturition and number of incontinence
`episodes. However, tolterodine appeared to have a better
`eBcacy/tolerability profile [67]. These findings were
`largely confirmed in another study on 240 patients
`with bladder hyperactivity [68]. Tolterodine has a well
`documented eCect in detrusor hyperactivity and the
`side-eCect profile seems acceptable.
`Darifenacin is a highly selective muscarinic M3 receptor
`antagonist [69]. In some animal models, there is a
`marginal selectivity for the urinary bladder over the
`salivary gland [38,70], but the clinical importance of
`this finding has not been established. In a pilot study on
`patients with detrusor instability, the drug was found to
`reduce the total number, maximum amplitude, and
`duration of unstable bladder contractions [71]. The drug
`is being further evaluated clinically for the treatment of
`bladder hyperactivity, but published clinical results do
`not allow an evaluation of its eCects.
`
`Drugs acting on membrane channels
`
`Calcium antagonists
`
`The activation of detrusor muscle, both through muscar-
`inic receptor and NANC pathways, seems to require the
`
`influx of extracellular Ca2+ through Ca2+ channels, as
`well as via mobilization of intracellular Ca2+ [1]. The
`antagonists, blocking l-type Ca2+ channels, and theoreti-
`
`influx of extracellular calcium can be blocked by calcium
`
`inhibiting
`cally this would be an attractive way of
`detrusor hyperactivity [72]. However, there have been
`few clinical studies of the eCects of calcium antagonists
`in patients with detrusor hyperactivity. In an open study,
`Rud et al. [73] found that nifedipine reduced the fre-
`quency and amplitude of unstable detrusor contractions,
`increased bladder capacity and gave symptomatic relief.
`These results could not be confirmed by Laval and
`Lutzeyer [74], who found that nifedipine had no signifi-
`cant eCect on unstable detrusor contractions.
`In a
`double-blind placebo-controlled study, Palmer et al. [75]
`found that flunarizine caused both symptomatic and
`urodynamic improvement in women with urge inconti-
`nence. Unfortunately, their results could not be con-
`firmed by several other investigators [4]. Faustini et al.
`[76] found in an open urodynamic study of patients
`
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`PHARMACOLOGICAL TREATMENT OF URINARY INCONTINENCE
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`929
`
`with detrusor hyperactivity that diltiazem 60 mg×3 for
`10 days significantly increased bladder capacity, lowered
`bladder pressure and maximum detrusor pressure, and
`raised the threshold of the second sensation of mictur-
`ition. The number of nocturnal micturitions and episodes
`of
`incontinence were decreased. No side-eCects were
`reported.
`instillation of verapamil was found to
`Intravesical
`increase bladder capacity and decrease the degree of
`leakage during cystometry in patients with detrusor
`hyper-reflexia [77]. The eCect was less pronounced in
`patients with non-neurogenic hyperactivity [78].
`Available information does not suggest that systemic
`therapy with calcium antagonists is an eCective way to
`treat detrusor hyperactivity, but controlled clinical trials
`are lacking. However, the possibility that intravesical
`therapy with these drugs could be useful should not be
`ignored, nor that calcium antagonists may enhance the
`eCects of antimuscarinic agents [79].
`
`Potassium-channel openers
`
`Opening of K+ channels and the subsequent eAux of
`K+ will produce hyperpolarization of various smooth
`decrease in Ca2+ influx by reducing the opening prob-
`ability of Ca2+ channels, with subsequent relaxation or
`
`muscles,
`
`including the detrusor [80]. This leads to a
`
`inhibition of contraction. Theoretically, such drugs may
`be active during the filling phase of the bladder, abol-
`ishing bladder hyperactivity with no eCect on normal
`
`bladder contraction. K+-channel openers, such as pinaci-
`
`dil and cromakalim, have been eCective in animal models
`[80], but clinically the eCects have not been encouraging.
`
`The first generation of openers of ATP-sensitive K+-
`
`channels, such as cromakalim and pinacidil, were found
`to be up to 200 times more potent as inhibitors of
`vascular preparations than of detrusor muscle [81,82].
`In clinical trials performed with these drugs, no bladder
`eCects have been found at doses already causing lowering
`of blood pressure [83,84]. However, new drugs with
`KATP-channel opening properties have been described,
`which may be useful for the treatment of bladder hyper-
`activity [85,86].
`
`K+-channel opening is an attractive way of treating
`
`bladder hyperactivity, as it would make it possible to
`eliminate undesired bladder contractions without aCect-
`ing normal micturition. If bladder eCects can be detected
`in man, with no cardiovascular actions, the principle of
`
`K+-channel opening may represent a promising way of
`
`treating bladder hyperactivity. However, at present there
`is no evidence from controlled clinical trials to sug-
`
`gest that K+-channel openers represent a treatment
`
`alternative.
`
`© 1999 BJU International 84, 923–947
`
`Drugs with ‘mixed’ actions
`
`Some drugs used to block bladder hyperactivity have
`been shown to have more than one mechanism of
`action. They all have a more or less pronounced antimus-
`carinic eCect and an often poorly defined ‘direct’ action
`on bladder muscle. For several of
`these drugs,
`the
`antimuscarinic eCects can be detected at much lower
`drug concentrations than the direct action, which may
`
`involve blockade of voltage-operated Ca2+ channels.
`
`Most probably, the clinical eCects of these drugs can be
`explained mainly by an antimuscarinic action. Among
`the drugs with mixed actions was terodiline, which was
`withdrawn from the market because it was suspected to
`cause polymorphic ventricular tachycardia (torsade de
`pointes) in some patients [87,88].
`Oxybutynin has several pharmacological eCects, some
`of which seem diBcult to relate to its eCectiveness in the
`treatment of detrusor hyperactivity.
`It has both an
`antimuscarinic and a direct muscle-relaxant eCect, and
`local anaesthetic actions. The latter eCect may be import-
`ant when the drug is administered intravesically, but
`probably plays no role when it is given orally. In vitro,
`oxybutynin was 500 times weaker as a smooth muscle
`relaxant than as an antimuscarinic agent [89]. Most
`probably, when given systemically, oxybutynin acts
`mainly as an antimuscarinic drug. Oxybutynin has a
`high aBnity for muscarinic receptors in human bladder
`tissue and eCectively blocks carbachol-induced contrac-
`tions [90,91]. The drug was shown to have higher
`aBnity for muscarinic M1 and M3 receptors than for M2
`receptors [92,93], but the clinical significance of this
`is unclear.
`Oxybutynin is a tertiary amine that is well absorbed,
`but undergoes an extensive first-pass metabolism (bio-
`logical availability 6% in healthy volunteers). The plasma
`half-life of the drug is #2 h, but with wide inter-
`individual variation [94,95]. Oxybutynin has an active
`metabolite, N-desethyl oxybutynin, which has pharma-
`cological properties similar to those of the parent com-
`pound [91], but which occurs
`in much higher
`concentrations [95]. Considering this, it seems reason-
`able to assume that the eCect of oral oxybutynin is
`largely exerted by the metabolite. The occurrence of an
`active metabolite may also explain the lack of correlation
`between the plasma concentration of oxybutynin and
`side-eCects in geriatric patients, reported by Ouslander
`et al. [96].
`Several studies, both open and controlled, have shown
`that oxybutynin is eCective in controlling detrusor hyper-
`activity [97]. In a randomized, double-blind, crossover
`trial of 30 patients with detrusor instability, Moisey et al.
`[98] compared oxybutynin 5 mg ×3 with placebo. The
`study was completed by 23 patients; five withdrew
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`930 K.-E. ANDERSSON et al.
`
`because of severe side-eCects. Of the patients who com-
`pleted the trial, 17 (69%) had symptomatic improvement
`and nine had improvement on urodynamic assessment.
`The eCect of oxybutynin in the management of idiopathic
`detrusor instability in women was studied by Cardozo
`et al. [99] in a double-blind, fixed-dose (5 mg) placebo-
`controlled trial. Oxybutynin was significantly better than
`placebo in improving LUTS and urodynamic values.
`However, eight of 20 women receiving oxybutynin
`stopped medication because of side-eCects and of those
`completing active therapy, 80% suCered significant side-
`eCects, e.g. dry mouth or dry skin. This highlights the
`diBculty of conducting double-blind studies with this
`drug because of the severe side-eCects obtained with
`active treatment, which makes it diBcult to blind the
`study. Similar results were shown in other placebo-
`controlled trials of patients with detrusor hyperactivity,
`including hyper-reflexia [44,98,100–105].
`significantly
`Also
`oxybutynin
`7.5–15 mg/day
`improved the quality of life of patients with an overactive
`bladder in a large open multicentre trial. In this study,
`the patients’ compliance was 97% and side-eCects
`(mainly dry mouth) were reported by only 8% of the
`patients [106].
`Holmes et al. [45] compared oxybutynin and propan-
`theline, using a patient-regulated variable-dose approach
`in a randomized, cross-over trial including 23 women
`with detrusor instability. The daily doses of oxybutynin
`were 7.5–30 mg and those of propantheline bromide
`45–145 mg. There were no diCerences in eCectiveness
`between the drugs. On the other hand, Thu¨ roC et al.
`[44], using a fixed-dose protocol and a parallel-group
`design, compared the eCects oxybutynin 5 mg×3, pro-
`pantheline 15 mg×3 and placebo in a randomized,
`double-blind multicentre trial
`including 154 patients
`(149 women, five men) with detrusor hyperactivity
`(including detrusor hyper-reflexia). The mean grade of
`improvement was significantly higher with oxybutynin
`(58%) than with propantheline (45%) or placebo (43%).
`Also, the rate of possible adverse eCects was significantly
`higher for oxybutynin (63%) than for propantheline
`(44%) and placebo (33%).
`Iselin et al. [107] conducted a double-blind, placebo-
`controlled study on 53 patients with BPH to evaluate
`the symptomatic and urodynamic eCects of oxybutynin
`(5 mg×3) on irritative micturitional symptoms during
`the first week after TURP. Compared with placebo,
`oxybutynin significantly decreased frequency, urgency
`and detrusor pressure at first sensation of filling, but had
`no eCect on detrusor instability and did not change the
`maximal bladder capacity. Dryness of the mouth was
`reported in 13% of placebo-treated patients and in 65%
`of those receiving oxybutynin.
`In 75 nursing home residents, Ouslander et al. [108]
`
`found that oxybutynin did not add to the clinical eCec-
`tiveness of prompted voiding in a placebo-controlled,
`double-blind, cross-over trial. In another controlled trial
`in 57 elderly subjects, oxybutynin with bladder training
`was found to be superior to bladder training alone [109].
`Several open studies in patients with spinal cord
`injuries have suggested that oxybutynin, given orally or
`intravesically, can be of therapeutic benefit [110,111].
`Administered intravesically, oxybutynin has in several
`studies been shown to increase bladder capacity and
`produce clinical improvement with few side-eCects, both
`in hyper-reflexia and in other types of bladder hyper-
`activity, and both in children and adults [112–120],
`although adverse eCects may occur [121,122].
`Forms of oxybutynin other than the conventional
`tablet have been introduced; rectal administration [123]
`was reported to have fewer adverse eCects than the
`conventional tablets. A controlled-release preparation,
`administered once daily, was found to be as eCective as
`the conventional tablet given twice daily, and with a
`similar number of adverse events during treatment
`[124]. OROSA oxybutynin, another controlled-release
`preparation given once daily, was tested in an open
`study on 257 patients, and was reported to produce
`fewer side-eCects than conventional forms of oral admin-
`istration [125].
`The therapeutic eCect of oxybutynin on detrusor hyp-
`eractivity is associated with a high incidence of side-
`eCects (up to 80% with oral administration). These are
`typically antimuscarinic
`(dry mouth,
`constipation,
`drowsiness, blurred vision) and are often dose-limiting
`[126,127]. The eCects on the electrocardiogram of
`oxybutynin were studied in elderly patients with urinary
`incontinence [128]; no changes were found. It cannot
`be excluded that the commonly recommended dose of
`5 mg×3 is unnecessarily high in some patients, and
`that a starting dose of 2.5 mg×2 with following dose-
`titration would reduce the number of adverse eCects
`[106,129].
`Oxybutynin has well-documented eBcacy in the treat-
`ment of detrusor hyperactivity and is probably, despite
`its adverse eCect profile, the drug of first choice in
`patients with this disorder.
`Dicyclomine has been described as having both a direct
`relaxant eCect on smooth muscle and an antimuscarinic
`action [130]. Favourable results in detrusor hyperactivity
`have been reported in several studies [131–134]. In 43
`patients with detrusor hyperactivity, Beck et al. [131]
`compared the eCects of three times daily administration
`of dicyclomine 10 mg, propantheline 15 mg or placebo
`for 3 weeks. In the placebo group, 20% were cured or
`improved; the corresponding values for propantheline
`bromide and dicyclomine were 73% and 62%, respect-
`ively. In a preliminary study, Awad et al. [132] reported
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`PHARMACOLOGICAL TREATMENT OF URINARY INCONTINENCE
`
`931
`
`that dicyclomine 20 mg×3 caused a resolution or sig-
`nificant improvement of symptoms in 24 of 27 patients
`with uninhibited bladder contractions. Side-eCects were
`few, mainly antimuscarinic, and did not necessitate
`withdrawal from the study. In another preliminary study
`of 14 patients with uninhibited neurogenic bladder,
`Fischer et al. [133] reported that 11 patients showed a
`significant blockade of uninhibited bladder contractions
`when given dicyclomine as a single 20 mg oral dose.
`Even if published experiences of the eCect of dicyclo-
`mine on detrusor hyperactivity are favourable, the drug
`is not widely used, and controlled clinical trials docu-
`menting its eBcacy and side-eCects are scarce.
`Propiverine has been shown to have combined anticho-
`linergic and calcium antagonistic actions [135–138].
`The drug is rapidly absorbed, but has a high first-pass
`metabolism. Several active metabolites are formed [139],
`whose pharmacological characteristics do not seem to
`have been studied in detail. It seems most probable that
`these metabolites contribute to the clinical eCects of
`the drug.
`Propiverine has been shown to have beneficial eCects
`in patients with detrusor hyperactivity in several investi-
`gations
`[140–142] and in children with enuresis
`[143,144]. Most of the studies have been open and are
`preliminary.