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Abstract

Overactive bladder syndrome, urge syndrome or urgency–frequency syndrome is defined as ‘urgency with or without urge incontinence, usually with frequency and nocturia’. Although this definition indicates that these symptoms are suggestive of detrusor overactivity (the observation of involuntary detrusor contractions during the filling phase of cystometry), a urodynamic demonstration of detrusor overactivity is not necessary in order to make the diagnosis. Nevertheless, patients with overactive bladder syndrome represent a substantial proportion of patients suffering with urinary symptomatology, and approximately a third of individuals with overactive bladder suffer from incontinence. Furthermore, as compared with those patients with stress urinary incontinence, women with urge incontinence have a poorer overall quality of life, perhaps related to both the volume of urine lost as well as the unpredictable nature of the leakage. When combined with behavioral modification, antimuscarinic pharmacotherapy remains the mainstay of treatment for this condition. A number of these agents are available for the treatment of overactive bladder-related incontinence, each with unique pharmacokinetic and pharmacodynamic properties. In order to optimize therapy for patients suffering from this type of incontinence, it is necessary to understand the mechanism of action of these agents, as well as to be familiar with the differences between them with respect to efficacy, safety and tolerability.

Keywords

antimuscarinic detrusor overactivity overactive bladder syndrome urinary incontinence women

Overactive bladder (OAB) syndrome, urge syndrome or urgency–frequency syndrome is defined as ‘urgency with or without urge incontinence, usually with frequency and nocturia’ [1]. Patients with OAB represent a substantial proportion of patients suffering with urinary symptomatology, and approximately a third of individuals with OAB suffer with incontinence [2]. Furthermore, as compared with those patients with stress urinary incontinence (UI), women with urge incontinence have a poorer overall quality of life, perhaps related to both the volume of urine lost as well as the unpredictable nature of the leakage [3 –5].

Multiple classes of drugs are potentially useful to decrease bladder contractility or decrease sensation and thereby treat OAB (Box 1), but very few have been utilized clinically [6]. Antimuscarinic agents have repeatedly demonstrated their efficacy in managing this disorder in many placebo-controlled trials and remain the most commonly prescribed treatment for this condition. Since Diokno and Lapides described the properties and application of oxybutynin chloride in the therapy of urinary dysfunction almost 30 years ago, antimuscarinic therapy has remained the mainstay of therapy for detrusor overactivity and, more recently, the symptom complex known as OAB [6 –9].

For many years, widely available agents for OAB in the USA included oxybutynin, tolterodine, propantheline, dicyclomine and hysocyamine. Recently, several new antimuscarinic agents have become available. This article will attempt to highlight some of the existing clinically available antimuscarinic therapies for the pharmacological treatment of OAB and related incontinence.

Uroselectivity

Most of the neurohumoral stimulus for physiological bladder contraction, both volitional and involuntary, is from acetylcholine (ACh)-induced stimulation of autonomic, postganglionic, parasympathetic muscarinic–cholinergic receptor sites on bladder smooth muscle. The majority of current pharmacotherapy for OAB is therefore directed toward muscarinic receptors. Since autonomic innervation, receptors and receptor content are ubiquitous throughout the human body's organ systems, there are no agents in clinical use whose actions are purely selective for the lower urinary tract (LUT); that is, uroselective. Thus, the majority of side effects attributed to drugs facilitating bladder storage or emptying are the collateral effects on organ systems that share some of the same neurophysiological or neuropharmacological characteristics as the LUT. The problems are how to affect bladder function without interfering with the function of other organ systems (uroselectivity) and how to eliminate overactivity without disturbing normal micturition [10].

Box 1.

Potential pharmacological therapy for overactive bladder.

Anticholinergic agents

Musculotropic relaxants

Calcium antagonists

Potassium-channel openers

Calcium-channel modulators

Prostaglandin inhibitors

β-adrenergic agonists

α-adrenergic antagonists

Tricyclic antidepressants

Dimethyl sulfoxide

Phosphodiesterase inhibitors

Modulators of:

– Serotonin

– Nitric oxide

– Calcitonin gene-related peptide

– Vasoactive intestinal polypeptide

– Neuropeptide Y

– Endothelins

– Bradykinins

– γ-aminobutyric acid

– Enkephalins

– Nociceptin

– Polysynaptic inhibitors

– Tachykinin receptor antagonists

– Purinergic antagonists

Adapted from [6].

In general, drug therapy for all LUT dysfunction is hindered by a lack of uroselectivity, which may explain problems with efficacy and tolerability in OAB pharmacotherapy [11]. Many of the drugs described are highly effective agents; however, dose-dependent systemic adverse effects can often limit the ability of the physician to exploit a given drug's therapeutic effects. Escalating dosages may lead to increasing unwanted effects on other organ systems, which may result in the failure to reach a therapeutic dose. Nevertheless, improvements in uroselectivity can be approached in a number of ways, including:

Receptor selectivity

Organ selectivity

Alterations in drug delivery, metabolism and distribution

Receptor selectivity may be of little use unless the receptor is not expressed in other organs, or unless a receptor subtype exists that is specific for the organ being treated or its neurological connections. Organ specificity may indeed be the ‘magic bullet’ of drug therapy. The ideal organ-selective drug for the LUT would exert desirable effects only on the bladder and/or urethra, thus eliminating side effects. Theoretically, the concept of organ specificity is very attractive, but practically and clinically it is very difficult to achieve. Alternate drug-delivery systems may be helpful by increasing the target concentration of an agent (e.g., intravesical therapy) or changing the metabolism of a drug to lower the concentration of a metabolite particularly productive of side effects. Certain drugs or their metabolites may be prevented from gaining access to a potentially troublesome site of activity (e.g., across the blood–brain barrier) either by virtue of their innate characteristics or by alteration. Given our current state of imperfection in this area, it is important to distinguish potential laboratory effects from real clinical effects, both beneficial and adverse. Commercial or marketing claims of the superiority of one agent based on organ or receptor selectivity, or alternative mechanisms of drug delivery, should be subject to strong scrutiny and be supported by both laboratory and clinical data. In the absence of such data, these claims have little scientific merit and are more theoretical than real.

Mechanism of action & properties of antimuscarinics

The primary motor input to the detrusor muscle of the bladder is along the pelvic nerves emanating from spinal cord segments S2–S4. Parasympathetic impulses travel to the bladder along the efferent fibers of the pelvic nerves. The impulses pass through ganglia situated in the bladder wall before reaching their target. ACh appears to be the primary neurotransmitter at the neuromuscular junction in the human LUT. Both volitional and involuntary contractions of the detrusor muscle are mediated, at least in part, by the activation of postsynaptic muscarinic receptors by ACh. Of the five known subtypes of muscarinic receptors, bladder smooth-muscle cholinergic receptors are mainly of the M₂ variety. However, M₃ receptors are responsible for the emptying contraction of normal micturition, as well as involuntary bladder contractions (IBCs), which may result in UI [10]. Thus, most pharmacological antimuscarinic therapy is primarily anti-M₃ receptor based.

Antimuscarinic agents such as atropine inhibit normal and IBCs [12,13]. For many years, all of these agents were thought to act pharmacologically as competitive antagonists of ACh at the level of the postganglionic muscarinic receptor, at the neuromuscular synapse on the efferent side of the micturition reflex. While it is widely accepted that there is little or no sacral parasympathetic activity to the bladder during normal filling, it is clinically apparent that antimuscarinic drugs increase bladder capacity, and it has been suggested that anti-cholinesterase inhibitors and cholinomimetics decrease bladder capacity [14]. In fact, it is not well understood how, during this phase of the micturition cycle (filling and storage), antimuscarinic agents exert their favorable effects despite the apparent lack of parasympathetic activity. Andersson and Yoshida have proposed that one potential mechanism by which these drugs act during bladder filling to reduce detrusor overactivity is via an effect on afferent activity [15]. Antimuscarinic drugs seem to affect the sensation of urgency during filling, suggesting ongoing ACh-mediated stimulation of detrusor tone. Furthermore, a basal release of ACh has been demonstrated from non-neuronal (perhaps urothelial), as well as neuronal sources in the human bladder, which may be related to the stretching of the bladder wall as it fills [16]. If this is the case, agents that inhibit ACh release or activity during bladder filling could contribute to bladder relaxation or maintenance of low bladder tone during this phase of the micturition cycle, with a consequent decrease in symptomatology unrelated to the occurrence of an IBC.

The designations M₁–M₅ are used to describe the pharmacological and molecular subtypes of muscarinic ACh receptors [17]. Human urinary bladder smooth muscle contains a mixed population of M₂ and M₃ subtypes, with a predominance of M₂ receptors (80% of the total muscarinic receptor population) [18]. While the minor population of M₃ receptors is believed to be primarily responsible for mediating bladder contraction [19], experimental evidence suggests that M₂ receptors are also involved in bladder contractility in some species and in certain types of LUT dysfunction [20 –23]. As mentioned, available antimuscarinic agents are limited by a lack of selectivity for the LUT, and this property is responsible for their classic anticholinergic side effects elsewhere in the body. As increasing doses are utilized for their desirable clinical effects on the LUT, unfavorable collateral effects may be observed in other organ systems (e.g., xerostomia and constipation). Although M₃-selective agents have the potential to eliminate some of these side effects, the M₃ receptors in LUT tissues appear identical to those elsewhere in the body [24]. However, if some of the as yet undefined heterogeneity among M₃ receptors in various tissues is uncovered, it may be reasonable to develop a uroselective agent acting only on the muscarinic receptors in the LUT.

The potential side effects of all antimuscarinic agents include inhibition of salivary secretion (leading to xerostomia or dry mouth), blockade of the sphincter muscles of the iris and the ciliary muscle of the lens to cholinergic stimulation (blurry vision), tachycardia, drowsiness, cognitive dysfunction, inhibition of gut motility (constipation) and inhibition of sweat-gland activity. Agents that possess ganglionic-blocking activity may also cause orthostatic hypotension and erectile dysfunction at the high doses generally required for the manifestation of nicotinic activity. In general, antimuscarinic agents are contraindicated in patients with narrow-angle glaucoma and should be used with caution in patients with significant bladder-outlet obstruction.

Specific antimuscarinic agents

Antimuscarinics can be broadly divided into drugs with pure antimuscarinic properties and those with mixed actions. In addition to their antimuscarinic properties, the latter group of drugs induce multiple in vitro actions, including an independent musculotropic or antispasmodic action directly on smooth muscle. This effect occurs at a site that is metabolically distal to the cholinergic or other contractile-receptor mechanisms and is possibly related to calcium channel blockade. In vitro, their direct smooth-muscle relaxant effects are reportedly 500-times weaker than their antimuscarinic effects [13]. These drugs may also possess some local anesthetic properties which, like the direct musculotropic relaxant effects, may only be relevant when given intravesically. When administered orally, the clinical relevance of these actions is unclear [13,18]. However, if any of these agents exerted a clinically significant direct inhibitory effect independent of their antimuscarinic action, there would be a therapeutic rationale for combination therapy with a relatively pure anticholinergic agent.

Relatively pure antimuscarinic agents

Atropine sulfate

This agent is rarely used to treat OAB due to its adverse systemic effects [25]. The pharmacologically active portion of the racemic mixture of atropine is L-hyoscyamine. This agent and hyoscyamine sulfate are reported to produce anticholinergic actions and side effects similar to other belladonna alkaloids. Hyoscyamine sulfate is also available in a sublingual formulation, which offers a theoretical advantage with respect to absorption and metabolism. However, controlled studies of its effects on bladder hyperactivity are lacking [25].

Propantheline bromide

This is a nonselective antimuscarinic agent which, as a quaternary ammonium compound, has a low and varying biological availability [13]. It is metabolized quickly to inactive metabolites. The usual adult dose is 15–30 mg every 4–6 h, but titration is often necessary and higher doses are sometimes required. Limited evaluable data on the drug's effectiveness in treating OAB are available. The Agency for HealthCare Policy and Research (AHCPR) Urinary Incontinence Guideline Panel reviewed five randomized, controlled trials of propantheline [26]. Of the total number of patients enrolled, 82% were female. Reports of cure ranged from 0–5% (all figures refer to percentage effect in those receiving drug minus percentage effect in those receiving placebo), reductions in urge incontinence ranged from 0–53%, side effects ranged from 0–50% and dropouts ranged from 0–9%.

Tolterodine tartrate

Developed specifically for the treatment of OAB, this drug is not muscarinic-receptor specific but demonstrates some selectivity for the bladder over the salivary gland in certain experimental models [27 –29]. Clinically, it appears to have a favorable side-effect profile, not only with respect to dry mouth but also bowel and CNS effects [18,30]. The immediate-release (IR) formulation of tolterodine is available in 1 and 2 mg tablets and is dosed twice-daily. The drug is primarily metabolized by the liver, with the primary hepatic metabolite possessing near equivalent antimuscarinic potency.

Appell reported on a pooled analysis of 1120 patients in whom tolterodine (1 or 2 mg twice-daily) was compared with oxybutynin IR (5 mg three-times daily) or placebo [31]. Compared with placebo, both active drugs significantly decreased the number of incontinent episodes and micturitions occurring in 24 h and increased the volume voided per micturition. Mean episodes of urge UI decreased from 40 to 60%, and frequency of urination decreased by approximately 20% compared with baseline. The 2-mg dose of tolterodine (twice-daily) and the 5-mg dose of oxybutynin (three-times daily) were equally efficacious, but tolerance was significantly better with tolterodine when adverse events such as dry mouth (frequency and intensity), dose reductions and patient withdrawals were considered.

Chancellor and colleagues conducted a large, double-blind study comparing tolterodine (2 mg twice-daily) with placebo [32]. Tolterodine reduced urge incontinence episodes and also produced significant reductions in micturition frequency and pad-use compared with placebo. Of tolterodine-treated patients, 2% reported severe dry mouth and 10% reported moderate dry mouth, compared with 0 and 2% of placebo patients, respectively. Mild dry mouth was reported by 18% of drug-treated patients and 6% of placebo-treated patients. Constipation was reported by 7% of tolterodine recipients and 4% of placebo recipients. The profile and frequency of other adverse events in the two treatment groups were similar. CNS adverse events were not significantly different between the tolterodine and placebo groups.

Kreder and colleagues studied the effects of tolterodine IR in patients with pure urge UI versus those with urge-predominant mixed UI [33]. At the end of the 16-week trial, there was no statistical difference between the two groups with respect to reductions in total UI episodes, patient-reported cure rate or reduction in pad use (67 vs 75%, 39 vs 44% and 21 vs 27%, mixed UI vs pure urge UI, all differences not significant; p < 0.05). The reported incidence of side effects in this trial was similar to that previously reported in other studies.

Tolterodine is available in an extended-release (ER), once-daily formulation. The pharmacokinetic profile and dosing of tolterodine ER can be seen in Tables 1 & 2, respectively. Von Kerrebroeck and colleagues compared this agent with the twice-daily formulation and placebo as part of the largest trial ever performed in patients with OAB [34]. In this pivotal study, the median number of urge incontinence episodes in patients receiving the once-daily formulation, the twice-daily formulation and placebo were reduced by 71, 60 and 33%, respectively. Both preparations were statistically superior to placebo, and the once-daily preparation was statistically more effective than the twice-daily formulation using this outcome indicator. Statistically significant improvements in all other micturition diary variables were recorded for both formulations over placebo. The incidence of dry mouth was 23% for once-daily tolterodine, 30% for twice-daily tolterodine and 8% for placebo. Khullar and colleagues compared tolterodine ER with placebo in an 8-week, double-blind, randomized, controlled trial involving 854 women with urge-predominant mixed UI. Tolterodine ER significantly reduced weekly urge UI episodes (−12.3) and daily micturition frequency (−2.1), and increased the median volume voided/micturition (+34 ml) compared with placebo (−8.0, −1.3 and +19 ml, respectively; p < 0.0001) [35].

Table 1.

Selected pharmacokinetics of commonly used antimuscarinic OAB agents in the USA.

Agent	Bioavailability (%)	T_max (h)	T_1/2 (h)	Protein bound (%)	Excreted unchanged in urine (%)	Active metabolites	Metabolism	Effect of food on pharmacokinetics
Tolterodine ER*	10–74	2–6	8.4	>96	<1% (<14% including active metabolite)	Yes	Liver: CYP2D6 and CYP3A4	No
Oxybutynin ER*	156–187 > IR form (g~6)	11.8–12.7	12.4–13.2	n/a	<0.1%	Yes	Liver: CYP3A4	No
Solifenacin*	90	3–8	45–68	96	<15%	Minimal	Liver: CYP3A4	No
Darifenacin*	15–19	5.2–7.6	12–19.95	98	<3%	No	Liver: CYP2D6 and CYP3A4	No
Trospium*	4–16.1	5.3	18.3	50–85	60	No	Not well defined, but eliminated at least in part by active tubular (renal) secretion	Yes
Oxybutynin patch*	n/a	10–48	7–8*	n/a	<0.1%	Yes	CYP3A4	no

From PI (Prescribing Information/Product Label).

Following removal of the patch.

ER: Estrogen receptor; IR: Immediate-release; n/a: Not available; OAB: Overactive bladder; T_max: Time to maximum serum concentration; T_1/2: Terminal elimination half-life; CYP: Cytochrome P450.

Table 2.

Recommended dosing of commonly utilized antimuscarinic agents in the USA.

Drug	Available doses	Dose range	Regimen
Tolterodine extended-release	2 and 4 mg tablet	2–4 mg	Daily
Oxybutynin extended-release	5, 10 and 15 mg tablet	5–30 mg	Daily
Darifenacin	7.5 and 15 mg tablet	7.5–15 mg	Daily
Solifenacin	5 and 10 mg tablet	5–10 mg	Daily
Trospium	20 mg tablet	20 mg	Twice-daily
Oxybutynin patch	3.9 mg/day patch	3.9 mg/day patch	Every 3 days

Furthermore, the overall efficacy of tolterodine ER does not seem to be markedly different between those who have severe UI at baseline compared with those who have less severe UI. In a post hoc analysis from the Von Kerrebroeck study mentioned previously, Landis and colleagues compared those with severe UI (>20 episodes of UI/week) with those with less severe UI (<21 episodes of UI/week), and found that the improvement in UI episodes was no different between the two groups (71 vs 68%, severe vs nonsevere, not significant; p < 0.05) [36].

Using an evidence-based approach, the pharmacology subcommittee from the Proceedings of the 3rd International Consultation on Incontinence characterized tolterodine as safe and effective for the treatment of urge UI [37].

Trospium chloride

Trospium chloride is an antimuscarinic agent with atropine-like effects. It possesses no selectivity for muscarinic receptor subtypes M₁–M₅. In contrast to other agents, it contains a highly charged quarternary ammonium group, which may limit penetration across the blood–brain barrier [38]. This may explain why few, if any, central anticholinergic effects have been reported with administration of the drug [39,40]. The pharmacokinetic profile and dosing for trospium can be seen in Box 1 & Table 2, respectively.

The exact metabolic pathway for trospium is not well defined, but approximately 5–10% of an oral dose undergoes absorption and subsequent metabolism by the cytochrome P450 system in the liver. A total of 60% of this absorbed dose of the drug is excreted in the urine as the active, unaltered, unmetabolized compound. The presence of the unaltered, unmetabolized drug in the urine following oral dosing has been hypothesized to be responsible for some of the favorable effects on the bladder relative to those seen on the salivary gland [41]. In support of this, it is known that the muscarinic receptor density in the urothelium is significantly greater than that seen in the detrusor muscle and that the urothelium may modulate the activity of the underlying smooth muscle of the detrusor [42]. It is interesting to speculate whether these urothelial muscarinic receptors may have a role in bladder overactivity and, if so, whether any role exists for direct muscarinic blockade of the urothelium in the treatment of symptoms of OAB. On the negative side of this argument, however, is the fact that there is no evidence for an augmented efficacy of this agent over others that do not achieve a significant urinary concentration.

Results from two large, multicenter, double-blind, placebo-controlled studies have been published, involving a total of 1181 patients with OAB [43,44]. In both studies, patients were randomized to trospium chloride 20 mg twice-daily or placebo for 12 weeks. Symptoms were recorded in a voiding diary and patients assessed the severity of their urgency symptoms using the validated Indevus Urgency Severity Scale (IUSS). In both studies, trospium was associated with significantly greater reductions in urinary frequency, number of urge incontinence episodes, IUSS scores and significantly greater increases in average volume voided/void compared with placebo (p < 0.001). Treatment effects were apparent early in the study, with improvement in all assessment parameters by week 1 (p < 0.005).

Trospium has been compared with other antimuscarinic agents such as oxybutynin and tolterodine. In one study, trospium was as effective as oxybutynin in patients with hyper-reflexia due to spinal cord injury, but had fewer adverse effects [38]. Halaska and colleagues reported on the long-term results (52 weeks) of 358 patients with urge syndrome treated with either trospium 20 mg twice-daily or oxybutnin 5 mg twice-daily [45]. There were statistically significant improvements with both drugs in diary parameters such as micturition frequency, UI episodes and urge episodes, as well as urodynamic outcome measures including cystometric capacity. The risk of dry mouth during the study was greater with oxybutynin, suggesting a favorable tolerability profile for trospium. Reported in abstract form only, trospium was compared with tolterodine IR 2 mg twice-daily in a placebo-controlled study. The efficacy and safety profiles of the two agents were similar and both reduced urinary frequency relative to placebo [46].

The International Consultation on Incontinence (ICI) subcommittee on pharmacology concluded that trospium is an effective and safe option for the treatment of urge UI based on rigorous clinical trials [25].

Darifenacin

Darifenacin is a once-daily, relatively selective M₃ receptor antagonist. The potential implications of the high degree of M₃ selectivity of this agent are interesting. It is well established that activation of the M₃ receptor in the detrusor is responsible for both normal volitional bladder emptying and the involuntary bladder contractions responsible for the symptoms related to OAB. Thus, although it is possible to speculate that highly selective blockade of the M₃ receptor would be beneficial in maximally reducing symptoms of OAB, while sparing blockade of the other muscarinic subtypes throughout the body, it is unclear whether such an agent would also result in improved tolerability given its likely systemic effects on M₃ receptors elsewhere, including those in the salivary glands, gut and CNS. In addition, it is possible to consider that this particular agent may have fewer collateral effects on end organs possessing a significant density of muscarinic receptors other than the M₃ subtype, such as the heart (M₂) and brain (M₁, M₂, M₄ and M₅), due to its relative lack of selectivity for other muscarinic receptor subtypes, thus providing an additional margin of safety. The pharmacokinetic profile and dosing of darifenacin can be seen in Tables 1 & 2, respectively. Organ selectivity for the bladder over the salivary glands has been demonstrated in some animal models [47,48], but the clinical importance of this finding has not been established [25].

Small, early studies proved the efficacy of this drug; but in small doses that did not cause salivary problems, darifenacin was no more effective than placebo [49,50]. Haab and colleagues reported on a multicenter, placebo-controlled trial of darifenacin [51]. A total of 561 patients were randomized to three different doses of active drug (3.75, 7.5 and 15 mg) and treated for 12 weeks. At the higher doses (7.5 and 15 mg), median reductions in UI episodes/week were statistically significant compared with placebo (−67.7, −72.8 and −55.9% for the 7.5 and 15 mg doses and placebo, respectively) and comparable to those reported in other trials of antimuscarinic compounds in patients with OAB. Statistically significant improvements in urinary frequency, mean volume/void, number of urgency episodes/day and severity of urgency were also reported. Dry mouth was reported by 18.8, 31.3 and 8.5% of patients in the 7.5, 15 mg and placebo groups, respectively, but there were no patient withdrawals due to this adverse event. Constipation was noted in 14.4, 13.9 and 6.7% of patients in the 7.5, 15 mg and placebo groups, respectively, but only 0.9% of patients discontinued the active drug due to this event. CNS and cardiac safety profiles were comparable to placebo.

Steers and colleagues compared darifenacin with placebo in a large, multicenter, randomized, controlled trial involving 398 patients with OAB [52]. Efficacy was evaluated at 2 and 12 weeks for the primary end point (change in incontinence episodes from baseline) and secondary end points, which included frequency and urgency episodes/day, bladder capacity, urgency severity, nocturia and number of significant leaks/week. Dose escalation from 7.5 to 15 mg was permitted in the darifenacin arm, and 59% of patients opted for the higher dose. Overall, there was a significant reduction in the median number of incontinence episodes in the darifenacin-treated group compared with the placebo-treated group (−62.9 vs −48.1%, drug vs placebo, respectively; p = 0.035). Darifenacin also achieved statistically significant improvements in the secondary efficacy variables of significant leaks/week, frequency, bladder capacity, urgency and urge severity.

Cardozo and Dixon evaluated a novel efficacy parameter in a multicenter, double-blind, randomized, controlled trial with a primary end point of change in warning time [53]. Warning time was defined as the time from the first sensation of urgency to voluntary micturition or incontinence. Treatment resulted in significant improvements in warning time when compared with placebo, with a median increase of 4.3 min in the darifenacin-treated patients (at a dose of 30 mg) compared with placebo (p = 0.003). In theory, increasing warning time would extrapolate to improvements in symptoms and a decrease in incontinence episodes, but these were not extensively assessed as additional variables, nor has a change in warning time been correlated with a change in symptoms. There was a statistically significant reduction in the severity of urgency versus placebo in the clinical setting (p = 0.035), but not at home.

As mentioned, cognitive impairment with antimuscarinic agents may be due to interaction with other cholinergic receptors, including the M₁ receptors. It has been postulated that darifenacin, with its M₃ selectivity, might be associated with fewer unwanted CNS effects. Lipton and colleagues assessed the cognitive effects of darifenacin on unimpaired/minimally impaired elderly patients in a double-blind, three-period, crossover trial [54]. Darifenacin formulations used in the study were the IR tablets (5 mg three-times daily) and sustained-released tablets (3.75, 7.5 or 15 mg daily) in addition to a placebo arm. Patients were randomized to three of these five treatments for 2 weeks at a time, with a 7-day washout between treatments. There was no statistical difference compared with placebo for the mean change from baseline of word recognition sensitivity, speed of choice reaction time and memory-scanning sensitivity. Likewise, no effect was seen on simple reaction time, digit vigilance speed or accuracy, or word-recognition speed. This also held true for memory-scanning speed, except with the 3.75 mg dose, which led to a decrease in this cognitive parameter when compared with placebo. Finally, there was no effect on self-rated alertness or contentment but, interestingly, the 15 mg dose showed a decrease in self-rated calmness while the 3.75 mg dose demonstrated improvement (p = 0.007 and p = 0.046, respectively).

The 3rd International Consultation on Incontinence has deemed darifenacin efficacious and safe based on strong, good-quality, randomized, controlled trials [37].

Solifenacin

Solifenacin is a novel, once-daily antimuscarinic agent. It is an isoquinolone carboxylate derivative that may demonstrate organ selectivity for the bladder versus salivary glands in some animal models [55 –57]. The half-life of the drug is quite long at almost 60 h; however, the clinical significance of this unusual pharmacokinetic property is unclear. Other pharmacokinetic parameters are outlined in Table 2.

Cardozo and colleagues randomized 911 patients to receive either 5 or 10 mg solifenacin or placebo in a 12-week multicenter trial [58]. The primary outcome variable was change in urinary frequency. Secondary efficacy variables assessed included urinary urgency, nocturia, volume voided, total incontinence episodes and urge UI episodes. Compared with placebo (−1.59), micturitions/24 h were statistically significantly decreased with solifenacin 5 mg (−2.37; p = 0.0018) and 10 mg (−2.81; p = 0.0001). The 5 mg solifenacin dose showed an improvement in the reduction of the number of nocturia episodes compared with placebo, but this did not reach statistical significance. All other treatment effects reached statistical significance. Based on a 3-day voiding diary, 50.3 and 49.7% of patients treated with 5 and 10 mg solifenacin, respectively, had no incontinence at the conclusion of the study; however, the percentage of dry patients in the placebo arm was not reported. Side effects were more prominent in the 10 mg group, but both doses were well tolerated when compared with placebo.

Solifenacin has been compared with tolterodine in several studies. Chapple and colleagues randomized 225 patients to four different doses of solifenacin (2.5, 5, 10 or 20 mg daily), tolterodine IR (2 mg twice-daily) or placebo [59]. The primary efficacy variable was urinary frequency (mean number of micturitions/24 h). The 5, 10 and 20 mg dosages of solifenacin showed statistically significant reductions in urinary frequency compared with placebo (mean reductions: −2.21, −2.47 and −2.75 daily voids for the 5, 10 and 20 mg doses, respectively vs −1.03 with placebo); however, the groups receiving the 2.5 mg dose of solifenacin and tolterodine did not (mean reductions −1.45 and −1.79 for 2.5 mg solifenacin and tolterodine, respectively). Notably, there were no statistically significant differences observed between solifenacin and tolterodine compared with placebo in two other secondary outcome variables (mean reduction in incontinence episodes and urgency episodes). Dry mouth was reported by 2.6% of patients in the placebo group compared with 14, 14 and 38% receiving the 5, 10 and 20 mg doses of solifenacin, respectively, and 24% in the tolterodine group.

In another study by Chapple, solifenacin 5 and 10 mg was compared with tolterodine IR (2 mg twice-daily) and placebo in 1033 patients [60]. The 5 and 10 mg doses of solifenacin demonstrated statistically significant decreases in urge UI episodes, total incontinence episodes and urgency episodes compared with placebo, but tolterodine did not. All three active treatments showed statistically significant improvements in mean volume voided/void and micturition frequency. Dry mouth was reported by 18.6% of patients in the tolterodine group, compared with 4.9% in the placebo group and 14 and 21.3% of patients receiving the 5 and 10 mg doses of solifenacin, respectively.

A recent double-blind, double-dummy, prospective, randomized trial compared solifenacin 5 and 10 mg with the ER formulation of tolterodine [61]. In an interesting study design, patients were initially randomized to therapy with 5 mg of solifenacin or 4 mg of tolterdine ER. After 4 weeks, patients were given the option to request a higher dose. Consistent with the product labeling, patients in the solifenacin arm were titrated to the 10 mg dose, whereas those in the tolterodine arm were given a dummy titration but remained at the 4 mg dose. Overall, dose titration was requested by 51% of the tolterodine group and 48% of the solifenacin group. The study was designed as a ‘noninferiority trial’ and, with respect to the primary outcome variable of micturition frequency, there was no difference between the agents in the per protocol set analysis of 1049 patients (reduction of 2.45 vs 2.25 voids/24 h, in solifenacin and tolterodine, respectively; p = 0.0004 for noninferiority). Secondary end points including reduction in urge incontinence episodes, overall incontinence episodes and reduction in urgency, all favored solifenacin. Of patients with incontinence at study entry, 59% of those receiving solifenacin and 49% of those receiving tolterodine were continent at the end of the trial. Dry mouth of any severity was noted by 30% of the solifenacin-treated patients and 24% of patients in the tolterodine group. Constipation rates were likewise higher in the solifenacin group (6.4 vs 2.5%, in solifenacin and tolterodine, respectively), but overall, the number of individuals discontinuing trial medication due to adverse events was low and comparable between the drugs (3.5 vs 3%, solifenacin vs tolterodine, respectively).

As with darifenacin, the 3rd International Consultation on Incontinence characterized solifenacin as effective, with an acceptable adverse-event profile, based on strong, good-quality randomized, controlled trials [37].

Anticholinergic agents with mixed actions

Oxybutynin chloride

This agent is a potent muscarinic receptor antagonist with some degree of selectivity for M₃ and M₁ receptors. In human tissues, it has a higher affinity for muscarinic receptors in the parotid gland than it does for those in the bladder [18]. Oxybutynin was originally developed to treat gastrointestinal (GI) hypermotility disorders. Diokno and Lapides first reported on its urological applications in 1972 [7]. This agent is a well-absorbed tertiary amine that undergoes extensive first-pass metabolism. The pharmacological properties of its active metabolite are similar to those of the parent compound, but occur at concentrations six-times higher. The major metabolite is also thought to cause the majority of adverse effects observed with this agent [62,63]. Reducing the extent of first-pass metabolism by intravesical administration, GI absorption outside the portal system, or transdermal or rectal administration are potential avenues to improve tolerability [62,64 –73]. Oxybutynin's side effects are antimuscarinic and dose related. An additional theoretical consideration is its physiochemical composition, which might permit relatively greater penetration into the CNS through the blood–brain barrier. The agent is relatively small, uncharged and lipophilic. This may account for some of the reports of adverse CNS effects observed with this agent, especially in the geriatric population [74,75].

Initial reports documented the success of the agent in depressing detrusor overactivity in patients with neurogenic bladder dysfunction; subsequent reports also documented its success in inhibiting other types of bladder hyperactivity [12]. The recommended oral adult dose of the IR formulation is 5 mg three- or four-times daily, although lower doses have been suggested. No antimuscarinic drug has yet been objectively demonstrated to be more efficacious at relieving OAB symptoms than oxybutynin IR, and it remains the most inexpensive agent in its class. However, given the multiple alternative agents now available, the inconvenient dosing regimen, and the relatively unfavorable antimuscarinic side-effect profile, the IR form of this agent has limited usage. The AHCPR Urinary Incontinence Guideline Panel reviewed six randomized clinical trials of oxybutynin IR [26]. Reports of cure ranged from 28–44%, reductions in urge incontinence from 9–56%, side effects from 2–66% and dropouts from 3 to 45%. In a review of 15 randomized, controlled trials of 476 patients treated with oxybutynin, Thüroff and colleagues reported a mean decrease in incontinence of 52% and a mean reduction in frequency of micturitions/24 h of 33% [76]. The overall ‘subjective improvement’ rate was 74% (range 61–100%). Side effects were reported by a mean of 70% (range 17–93%) of patients.

The once-daily formulation of oxybutynin considerably improved the convenience and tolerability of this agent compared with the IR tablet. Oxybutynin ER uses an innovative osmotic drug delivery system to release the drug at a controlled rate over 24 h. This formulation overcomes the marked peak-to-trough fluctuations in plasma levels of both the drug and its metabolites, which occurs with oxybutynin IR [72]. The pharmacokinetic profile of the ER formulation is shown in Table 1. A trend towards a lower incidence of dry mouth with oxybutynin ER was attributed to reduced first-pass metabolism and the maintenance of lower and less fluctuating plasma levels of the drug. Clinical trials of oxybutynin ER have concentrated primarily on comparing this drug with oxybutynin IR, although trials comparing it with both tolterodine IR [77] and tolterodine ER [78] have been published. Anderson and colleagues reported on a multi-center, randomized, double-blind study of 105 patients with urge incontinence or mixed incontinence with a clinically significant urge component, treated with oxybutynin ER. All had been prior positive responders to oxybutynin IR [79]. This was a dose-titration study and patients were taken to the highest possible dose or until intolerable side effects were encountered. The number of weekly urge incontinence episodes decreased from 27.4 to 4.8 after oxybutynin ER and from 23.4 to 3.1 after oxybutynin IR, and total incontinence episodes decreased from a mean of 29.3 to 6 and from 26.3 to 3.8, respectively. Dry mouth of any severity was reported by 68 and 87% of the ER and IR groups, respectively, and moderate or severe dry mouth occurred in 25 and 46%, respectively. The high rate of dry mouth reported in this study is generally attributed to the dose-titration study design. Curiously, a statistically greater percentage increase in voiding frequency was observed in the ER patients (54%) than in the IR patients (17%). The reason for the increase in urinary frequency observed in this study is unclear and is at odds with nearly all other antimuscarinic studies in which urinary frequency was measured as an outcome parameter. Another study included 226 patients with urge incontinence [80]. These were prior responders to anticholinergic therapy and had seven or more urge incontinence episodes/week. Reductions in urge UI episodes from baseline to the end of treatment were 18.6 to 2.9/week (83% mean decrease) and 19.8 to 4.4/week (76% mean decrease) in the ER and IR oxybutynin groups, respectively (nonsignificant difference). The incidence of dry mouth increased with dose in both groups, but there was no statistically significant difference in dry mouth rates between the groups: 47.7 and 59.1% for the ER and IR groups, respectively. However, a significantly lower proportion of patients receiving oxybutynin ER had moderate-to-severe dry mouth or any dry mouth compared with those receiving oxybutynin IR.

Appell and colleagues compared oxybutynin ER with tolterodine IR [77]. Of 378 patients enrolled, 332 completed the 12-week study. Compared with baseline, weekly urge incontinence episodes were reduced (25.6–6.1 vs 24.1–7.8, oxybutynin ER and tolterodine IR groups, respectively), as was urinary frequency (91.8–67.1 vs 91.6–71.5 episodes/week). There was a statistically significant difference between the two drugs, favoring oxybutynin in both outcome parameters.

Diokno and colleagues directly compared the ER formulations of oxybutynin and tolterodine in patients with severe urge UI and found no difference in efficacy with respect to reducing incontinence episodes [78]. At the conclusion of the 12-week study, there was no difference between the two agents with respect to the reduction of urge UI episodes from baseline (87 vs 81% reduction in patients receiving oxybutynin and tolterodine, respectively; p < 0.05); however, more patients gained complete continence with oxybutynin (23 vs 17% in patients receiving oxybutynin and tolterodine, respectively). Dry mouth was the most commonly reported adverse event, noted in 30 versus 22% of patients receiving oxybutynin and tolterodine, respectively.

Other alternative methods of drug administration for oxybutynin have been investigated, with the notion that a reduction in hepatic metabolism (reduced first-pass effect) will result in decreased formation of metabolites and an improvement in overall tolerability. Rectal administration has been reported to have fewer adverse effects than the conventional tablets [65,73], as has intravesical instillation [81,82].

The 3rd International Consultation on Incontinence Pharmacology Committee characterized oral oxybutynin as safe and effective for the treatment of urge UI, based on good-quality studies [83].

Transdermal oxybutynin chloride

A transdermal delivery system for oxybutynin was recently introduced. The patch is applied for 3 days and then replaced. The potential advantages of this delivery method include patient dosing convenience, as well as steady serum drug levels with reduced portal delivery and, thus, a reduction in the hepatic metabolite. Davila and colleagues reported the results of a randomized, double-blind, double-dummy, dose-escalation study comparing a transdermal delivery system with oral oxybutynin IR for urodynamically confirmed urge UI [84]. All patients had previously been diagnosed with motor urge incontinence and had demonstrated symptomatic improvement with anticholinergic therapy. Compared with baseline, daily incontinence episodes decreased significantly in both groups (66 vs 72%, in the patch vs oral groups, respectively). There was no significant difference in reduction in incontinence episodes between the two groups (p = 0.39). Dry mouth of any type was noted in 38 and 94% of patients in the patch and oral groups, respectively. A total of 39% of patients in the active transdermal patch group had some degree of erythema at the patch site, compared with 22% in the placebo group. The transdermal patch was also evaluated by Dmochowski and colleagues in patients with OAB and urge or mixed incontinence [69]. Patients were randomized to 12 weeks of double-blind daily treatment with a total of 1.3, 2.6 or 3.9 mg of oxybutynin delivered via a transdermal delivery system or a placebo patch administered twice weekly, followed by a 12-week, open-label, dose-titration period to assess efficacy and safety further. Compared with placebo, the 3.9 mg patch significantly reduced the number of weekly incontinence episodes (−19.5 vs −14.5 episodes/week in patch vs placebo groups; p = 0.0165, respectively), reduced daily urinary frequency (−2.3 vs −1.7 micturitions/day in patch vs placebo groups, respectively; p = 0.0457) and increased average voided volume (24 vs 6 cc/void in patch vs placebo groups, respectively; p = 0.0063). Other than a significant increase in volume voided with the 2.6 mg patch compared with placebo, there were no other differences between placebo and the 1.3 or 2.6 mg patch in any of the outcomes reported in the double-blind portion of the study. In the open-label, dose-titration portion of the study, a sustained reduction of almost three incontinence episodes/day was noted in all groups. Overall, dry mouth was reported by 4.6, 6.8 and 9.6% of patients in the 1.3, 2.6 and 3.9 mg patch groups, respectively, compared with 8.3% of patients receiving placebo. This difference was not statistically significant. The most commonly reported treatment-related adverse event was erythema at the patch site.

The transdermal delivery system (3.9 mg patch) was also compared with sustained-release tolterodine (4 mg daily) in 361 patients with urge or mixed UI [85]. Median reductions in UI episodes and micturition frequency were similar between the two agents. Dry mouth of any type was reported by 7.3, 4.1 and 1.7% of patients in the tolterodine, patch and placebo groups, respectively. Patch-site reactions of any type (e.g., erythema or pruritis) were noted in 5.7, 26.4 and 6.9% of patients in the tolterodine, patch and placebo groups, respectively.

Overall, the patch is well tolerated and may offer an alternative for some patients with OAB. It does not appear to be more efficacious than either oxybutynin IR or tolterodine. However, some patients may experience local reactions at the patch site. Patch-site reactions are generally mild and self limited. Some patients may use topical corticosteroids to relieve local symptoms at the patch site.

Dicyclomine hydrochloride

This agent is reported to possess a direct relaxant effect on smooth muscle in addition to an antimuscarinic action. However, it is not widely used to treat OAB. The ICI rated this drug as effective based on pharmacological and physiological evidence, but clinical evidence from good-quality, randomized, controlled trials is lacking [83]. The ICI failed to recommend dicyclomine for use.

Flavoxate hydrochloride

This compound was originally thought to be a weak anticholinergic agent but, in addition, to possess a direct inhibitory action. Some authors have suggested that the agent demonstrates no anticholinergic effects but does have moderate calcium antagonist activity, local anesthetic properties and the ability to inhibit phosphodiesterase [18]. Overall, favorable clinical effects have been reported in some series of patients with frequency, urgency and incontinence, and in patients with urodynamically documented detrusor hyper-reflexia [86]. However, Briggs and colleagues reported essentially no effect on neurogenic detrusor overactivity in an elderly population [87]. A similar conclusion was reached by Chapple and associates in a double-blind, placebo-controlled, crossover study of idiopathic detrusor overactivity [88]. Reported side effects are few. The drug failed to achieve a ‘recommended’ assessment by the ICI, which noted that cogent evidence of pharmacological or physiological efficacy (or both) was lacking for this agent, as well as evidence for its efficacy from good-quality, randomized, controlled trials [83].

Conclusion

Notwithstanding suggestions to the contrary, none of the existing pharmacotherapies for OAB-related UI are either absolutely selective for the bladder or universally efficacious. Dose-dependent side effects, such as dry mouth and constipation, limit the utility of the oral antimuscarinic agents in particular. Furthermore, although statistically significant and well-documented reductions in frequency, urgency and UI episodes have been noted in published randomized, double-blind, placebo-controlled studies, complete cure of OAB is not commonly seen clinically [61,77]. A recent comprehensive systematic review of currently available anticholinergic medications by the Cochrane group concluded the following: “The use of anticholinergic drugs by people with OAB syndrome results in statistically significant improvement in symptoms. However, the clinical significance of these differences is uncertain… Dry mouth is a common side effect of therapy” [89]. Given this statement, it is hoped that ongoing and promising investigations into the etiology and therapy of OAB and urge UI will lead to further improvements in the pharmacological treatment of this highly prevalent condition.

Future perspective

Currently available antimuscarinic agents for the treatment of OAB and associated urge incontinence are not ideal. Although significant reductions in incontinence episodes have been clinically documented, cure rates for urge UI are quite low, ranging from 0–50% of treated patients. Furthermore, although these agents are generally well tolerated, dry mouth, constipation and CNS effects may limit therapy in some individuals. Current clinical data indicate that no particular agent has an overwhelming advantage with respect to efficacy, despite attempts at dose titration. Why are we unable to cure more individuals with antimuscarinic therapy? Have we reached a therapeutic ceiling with respect to this class of drugs?

Executive summary

Antimuscarinic therapy for female urge incontinence

Drug therapy for urge incontinence and overactive bladder is, at present, directed towards competitive antagonism of the muscarinic receptor.

Current antimuscarinic therapy is not uroselective. Collateral effects on other organs throughout the body are the result of antagonism of muscarinic receptors elsewhere, resulting in side effects such as dry mouth and constipation.

Expected median reduction in urge incontinence episodes across all agents ranges from approximately 20–60#x0025; above placebo.

This range is highly variable due to differences in study design, including inclusion/exclusion critieria and the length of voiding diary utilized, among other factors. Cure rates in studies using these agents are also quite variable.

Although generally well tolerated, side effects from antimuscarinic therapy include dry mouth, constipation and CNS effects.

Specific agents: tolterodine

A nonselective muscarinic receptor antagonist originally developed for the treatment of overactive bladder.

It is available in two dosages, as well as immediate-release (twice-daily) and once-daily formulations.

Specific agents: darifenacin

A highly M₃ muscarinic subtype-selective agent available in two dosages.

It is unclear whether this degree of muscarinic selectivity is advantageous or a liability with respect to efficacy or tolerability.

It is available as an extended-release, once-daily formulation.

Current studies comparing the clinical efficacy of this agent with other antimuscarinic agents are, at present, lacking.

Specific agents: solifenacin

A once-daily antimuscarinic agent available in two different dosages.

A very long half-life may offer some potential advantages and disadvantages.

Specific agents: trospium

A nonspecific muscarinic receptor antagonist that has been available for many years in Europe.

It is currently available in the USA as a twice-daily formulation.

It has a quaternary ammonium structure that reduces absorption in the gastrointestinal tract and results in variable systemic levels, especially if taken with food.

Minimal drug-drug interactions due to a lack of significant metabolism by the liver.

Unmetabolized drug in the urine may confer some local effects on the bladder urothelium.

Specific agents: oxybutynin

Originally utilized for the therapy of irritable bowel syndrome, this was the first oral antimuscarinic agent utilized for urge incontinence.

This agent is moderately selective for the M₁ and M₃ muscarinic subtypes and may be classified as a mixed agent, in that it may have smooth muscle relaxant properties independent of its antimuscarinic properties.

It is available as an immediate-release formulation, as well as a once-daily tablet.

The immediate-release formulation is comparatively inexpensive and widely available, although it requires multiple daily doses to maintain efficacy and is associated with significant adverse effects.

Specific agents: oxybutynin patch

A transdermal delivery system for oxybutynin, this formulation is dosed twice weekly.

Its efficacy is similar to the other antimuscarinics.

Reactions at the patch application site may include pruritis and erythema; however, this antimuscarinic is generally well tolerated.

Are there other mechanisms underlying OAB and urge incontinence for which other classes of as yet undiscovered pharmacological therapy may be effective?

The ideal or optimal pharmacological treatment for OAB would be universally efficacious in relieving or curing the symptoms of OAB, completely without side effects, adverse events, effects on other organs or interactions with other drugs, would have no contraindications and, finally, could be administered conveniently, easily and inexpensively. Unfortunately, none of the existing antimuscarinic agents meet all of these criteria. Recent advances in the understanding of the pathophysiology of OAB and urge incontinence and the multiple, non-autonomic mechanisms that may be responsible for the clinical manifestations of the condition promise to provide a whole new array of pharmacological options. Other potential (and in some cases theoretical) therapies that are not yet near clinical application include genetic manipulation, tissue engineering, characterization and manipulation of purinergic pathways, including modulation of the P2X receptor, phosphodiesterase inhibitors, tachykinin receptor antagonists (neurokinin antagonists) and alteration of central dopaminergic, γ-amino-butyric acid (GABA)-ergic and enkephalinergic pathways [90,91].

Footnotes

Dr Rovner acknowledges the following potential conflicts of interest:

Pfizer: Consultant/Advisor, Investigator in a Scientific Study, Speakers Bureau; Astellas: Consultant, Speakers Bureau; Novartis: Consultant, Speakers Bureau; Q-Med: Investigator in a Scientific Study.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

Abrams

Cardozo

Fall

: The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol. Urodyn. 21, 167–178 (2002).

Definitive article regarding the terminology referable to the lower urinary tract

Stewart

Van Rooyen

Cundiff

: Prevalence and burden of overactive bladder in the United States. World J. Urol. 20, 327–336 (2003).

One of the original studies looking at the epidemiology of overactive bladder (OAB) in the USA

DuBeau

Levy

Mangione

: The impact of urge urinary incontinence on quality of life: importance of patients' perspective and explanatory style. J. Am. Geriatr. Soc. 46, 683–692 (1998).

Kobelt

Kirchberger

Malone-Lee

: Quality-of-life aspects of the overactive bladder and the effect of treatment with tolterodine. BJU Int. 83, 583–590 (1999).

Simeonova

Milsom

Kullendorff

: The prevalence of urinary incontinence and its influence on the quality of life in women from an urban Swedish population. Acta Obstet. Gynecol. Scand. 78, 546–551 (1999).

Andersson

Wein

: Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol. Rev. 56, 581–631 (2004).

10.

Comprehensive review of the pharmacology of the lower urinary tract

11.

Diokno

Lapides

: Oxybutynin: a new drug with analgesic and anticholinergic properties. J. Urol. 108, 307–309 (1972).

12.

Rovner

Wein

: Modern pharmacotherapy of urge urinary incontinence in the USA: tolterodine and oxybutynin. BJU Int. 86(Suppl. 2), 44–53 (2000).

13.

Rovner

Wein

: Pharmacologic management of urinary incontinence in the female. Minerva Ginecol. 56, 327–347 (2004).

14.

Andersson

: The overactive bladder: pharmacologic basis of drug treatment. Urology 50, 74–84 (1997).

15.

Andersson

: The concept of uroselectivity. Eur. Urol. 33(Suppl. 2), 7–11 (1998).

16.

Andersson

: Current concepts in the treatment of disorders of micturition. Drugs 35, 477–494 (1988).

17.

Andersson

: Advances in the pharmacological control of the bladder. Exp. Physiol. 84, 195–213 (1999).

18.

Andersson

: Changes in bladder tone during filling: pharmacological aspects. Scand. J. Urol. Nephrol. 201, 67–72 (1999).

19.

Andersson

Yoshida

: Antimuscarinics and the overactive detrusor – which is the main mechanism of action? Eur. Urol. 43, 1–5 (2003).

20.

Interesting ideas which conflict with some of the classical theories on the mechanism of action of antimuscarinic agents

21.

Yoshida

Inadome

Murakami

: Effects of age and muscle stretching on acetylcholine release in isolated human bladder smooth muscle. J. Urol. 167, 40 (2002) (Abstract).

22.

Caulfield

: Muscarinic receptors – characterization, coupling and function. Pharmacol. Ther. 58, 319–379 (1993).

23.

Chapple

: Muscarinic receptor antagonists in the treatment of overactive bladder. Urology 55, 33–46 (2000).

24.

Fetscher

Fleichman

Schmidt

: M(3) muscarinic receptors mediate contraction of human urinary bladder. Br. J. Pharmacol. 136, 641–643 (2002).

25.

Braverman

Legos

Young

: M₂ receptors in genitourinary smooth muscle pathology. Life Sci. 64, 429–436 (1999).

26.

Braverman

Ruggieri

Pontari

: The M₂ muscarinic receptor subtype mediates cholinergic bladder contractions in patients with neurogenic bladder dysfunction. J. Urol. 165, 36 (2001).

27.

Chapple

Yamanishi

Chess-Williams

: Muscarinic receptor subtypes and management of the overactive bladder. Urology 60, 82–88 (2002). • Concise review of antimuscarinics and their role in the treatment of OAB.

28.

Pontari

Braverman

Ruggieri

: The M2 muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R874–R880 (2004).

29.

Caulfield

Birdsall

: International Union of Pharmacology XVII. Classification of muscarinic acetylcholine receptors. Pharmacol. Rev. 50, 279–290 (1998).

30.

Andersson

Appell

Cardozo

: Pharmacological treatment of urinary incontinence. In: Incontinence. Abrams

(Ed.) Heath Publication Ltd., Plymouth, UK, 447–486 (1999).

31.

Comprehensive evidence-based review on the pharmacotherapy of urinary incontinence

32.

Agency for Healthcare Policy and Research: Urinary Incontinence Guideline Panel: Urinary Incontinence in Adults: Clinical Practice Guidelines. (AHCPR publication 92–0038). US Department of Health & Human Services, Public Health Service, Rockville, MD, USA (1992).

33.

Nilvebrant

Sundquist

Gilberg

: Tolterodine is not subtype (M1–M5) selective but exhibits functional bladder selectivity in vivo. Neurourol. Urodyn. 15, 310–311 (1996).

34.

Nilvebrant

Andersson

Gillberg

: Tolterodine – a new bladder-selective antimuscarinic agent. Eur. J. Pharmacol. 327, 195–207 (1997).

35.

Nilvebrant

Hallen

Larsson

: Tolterodine – a new bladder selective muscarinic receptor antagonist: preclinical pharmacological and clinical data. Life Sci. 60, 1129–1136 (1997).

36.

Todorova

Vonderheid-Guth

Dimpfel

: Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J. Clin. Pharmacol. 41, 636–644 (2001).

37.

Appell

: Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology 50, 90–96 (1997).

38.

Chancellor

Freedman

: Tolterodine, an effective and well-tolerated treatment for urge incontinence and other overactive bladder symptoms. Clin. Drug Invest. 19, 83–91 (2000).

39.

Kreder

Brubaker

Mainprize

: Tolterodine is equally effective in patients with mixed incontinence and those with urge incontinence alone. BJU Int. 92, 418–421 (2003).

40.

Van Kerrebroeck

Kreder

Jonas

: Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 57, 414–421 (2001).

41.

This remains the largest study ever carried out on OAB pharmacotherapy to date

42.

Khullar

Hill

Laval

: Treatment of urge-predominant mixed urinary incontinence with tolterodine extended release: a randomized, placebo-controlled trial. Urology 64, 269–274 (2004).

43.

Landis

Kaplan

Swift

: Efficacy of antimuscarinic therapy for overactive bladder with varying degrees of incontinence severity. J. Urol. 171, 752–756 (2004).

44.

Post hoc review suggesting that baseline severity of OAB-related incontinence does not impact on response to tolterodine

45.

Andersson

: Pharmacological treatment of urinary incontinence. In: Incontinence (3rd Edition). Abrams

Cardozo

Khoury

(Eds). Heath Publication Ltd., Plymouth, UK, 819 (2005).

46.

Madersbacher

Stohrer

Richter

: Trospium chloride versus oxybutynin: a randomized, double-blind, multicentre trial in the treatment of detrusor hyper-reflexia. Br. J. Urol. 75, 452–456 (1995).

47.

Pietzko

Dimpfel

Schwantes

: Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers. Eur. J. Clin. Pharmacol. 47, 337–343 (1994).

48.

Todorova

Vonderheid-Guth

Dimpfel

: Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J. Clin. Pharmacol. 41, 636–644 (2001).

49.

Hofner

Oelke

Machtens

: Trospium chloride – an effective drug in the treatment of overactive bladder and detrusor hyperreflexia. World J. Urol. 19, 336–343 (2001).

50.

Hawthorn

Chapple

Cock

: Urothelium derived inhibitory factor(s) influences on detrusor muscle contractility in vitro. Br. J. Pharmacol. 129, 416–419 (2000).

51.

Zinner

Gittelman

Harris

Susset

Kanelos

Auerbach

, Trospium Study Group: Trospium chloride improves overactive bladder symptoms: a multicenter Phase III trial. J. Urol. 171, 2311–2315 (2004).

52.

Rudy

: A multicenter, randomized, placebo-controlled trial of trospium chloride in overactive bladder patients. International Continence Society Annual Meeting. Paris, France (2004) (Abstract).

53.

Halaska

Ralph

Wiedemann

: Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability World J. Urol. 20, 392–399 (2003).

54.

Juneman

: Efficacy and tolerability of trospium chloride and tolterodine in 234 patients with urge syndrome. Neurourol. Urodyn. 19, 488–490 (2000) (Abstract).

55.

Newgreen

Anderson

DWP

Carter

: Darifenacin: a novel bladder-selective agent for the treatment of urge incontinence. Neurourol. Urodyn. 14, 95 (1995) (Abstract).

56.

Wallis

Napier

: Muscarinic antagonists in development for disorders of smooth muscle function. Life Sci. 64, 395–401 (1999).

57.

Rosario

Cutinha

Chapple

: The effects of single-dose darifenacin on cystometric parameters and salivary flow in patients with urge incontinence secondary to detrusor instability. Eur. Urol. 30, 240 (1996) (Abstract).

58.

Rosario

Smith

Radley

: Pharmacodynamics of anticholinergic agents measured by ambulatory urodynamic monitoring: a study of methodology. Neurourol. Urodyn. 18, 223–233 (1999).

59.

Haab

Stewart

Dwyer

: Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur. Urol. 45, 420–429 (2004).

60.

Pivotal study demonstrating the efficacy of darifenacin over placebo

61.

Steers

Corcos

Foote

: An investigation of dose titration with darifenacin, an M3-selective receptor antagonist. BJU Int. 95, 580–586 (2005).

62.

Cardozo

Dixon

: Increased warning time with darifenacin: a new concept in the management of urinary urgency. J. Urol. 173, 1214–1218 (2005).

63.

Lipton

Kolodner

Wesnes

: Assessment of cognitive function of the elderly population: effects of darifenacin. J. Urol. 173, 493–498 (2005).

64.

Hegde

Mammen

Jasper

: Antimuscarinics for the treatment of overactive bladder: current options and emerging therapies. Curr. Opin. Investig. Drugs 5, 40–49 (2004).

65.

Ikeda

Kobayashi

Suzuki

: M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland. Naunyn Schmiedebergs Arch. Pharmacol. 366, 97–103 (2002).

66.

Kobayashi

Ikeda

Miyata

: Comparison of in vitro selectivity profiles of solifenacin succinate (YM905) and current antimuscarinic drugs in bladder and salivary glands: a Ca2+ mobilization study in monkey cells. Life Sci. 74, 843–853 (2004).

67.

Cardozo

Lisec

Millard

: Randomized, double-blind placebo-controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J. Urol. 172, 1919–1924 (2004).

68.

Chapple

Arano

Bosch

: Solifenacin appears effective and well-tolerated in patients with symptomatic idiopathic detrusor overactivity in a placebo-and tolterodine-controlled Phase 2 dose-finding study. BJU Int. 93, 71–77 (2004).

69.

Chapple

Rechberger

Al Shukri

: Randomized, double-blind placebo-and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int. 93, 303–310 (2004).

70.

Chapple

Martinez-Garcia

Selvaggi

: A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur. Urol. 48, 464–470 (2005).

71.

Buyse

Waldeck

Verpoorten

: Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism. J. Urol. 160, 892–896 (1998).

72.

Hughes

Lang

Lazare

: Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application to pharmacokinetic studies in young, elderly and frail elderly volunteers. Xenobiotica 22, 859–869 (1992).

73.

Chandiramani

Peterson

Duthie

: Urodynamic changes during therapeutic intravesical instillations of capsaicin. Br. J. Urol. 77, 792–797 (1996).

74.

Collas

Malone-Lee

: The pharmacokinetic properties of rectal oxybutynin – a possible alternative to intravesical administration. Neurourol. Urodyn. 16, 346–350 (1997).

75.

Lehtoranta

Tainio

Lukkari-Lax

: Pharmacokinetics, efficacy, and safety of intravesical formulation of oxybutynin in patients with detrusor overactivity. Scand. J. Urol. Nephrol. 36, 18–24 (2002).

76.

Lose

Norgaard

: Intravesical oxybutynin for treating incontinence resulting from an overactive detrusor. BJU Int. 87, 767–773 (2001).

77.

Saito

Watanabe

Tabuchi

: Urodynamic effects and safety of modified intravesical oxybutynin chloride in patients with neurogenic detrusor overactivity: 3 years experience. Int. J. Urol. 11, 592–596 (2004).

78.

Dmochowski

Davila

Zinner

: Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence. J. Urol. 168, 580–586 (2002).

79.

Dmochowski

Staskin

: Advances in drug delivery: improved bioavailability and drug effect. Curr. Urol. Rep. 3, 439–444 (2002).

80.

Gupta

Sathyan

Mori

: New perspectives on the overactive bladder: pharmacokinetics and bioavailability. Urology 60, 78–80 (2002).

81.

Gupta

Sathyan

: Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J. Clin. Pharmacol. 39, 289–296 (1999).

82.

Winkler

Sand

: Treatment of detrusor instability with oxybutynin rectal suppositories. Int. Urogynecol. J. 9, 100–102 (1998).

83.

Donnellan

Fook

McDonald

: Oxybutynin and cognitive dysfunction. Br. Med. J. 315, 1363–1364 (1997).

84.

Katz

Sands

L P

Bilker

: Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride. J. Am. Ger. Soc. 46, 8–13 (1998).

85.

Thuroff

Bunke

Ebner

: Randomized, double-blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J. Urol. 145, 813–816 (1991).

86.

Appell

Sand

Dmochowski

: Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study. Mayo Clin. Proc. 76, 358–363 (2001).

87.

Diokno

Appell

Sand

: Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin. Proc. 78, 687–695 (2003).

88.

Anderson

Mobley

Blank

: Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group. J. Urol. 161, 1809–1812 (1999).

89.

Versi

Appell

Mobley

: Dry mouth with conventional and controlled-release oxybutynin in urinary incontinence. The Ditropan XL Study Group. Obstet. Gynecol. 95, 718–721 (2000).

90.

Brendler

Radebaugh

Mohler

: Topical oxybutynin chloride for relaxation of dysfunctional bladders. J. Urol. 141, 1350–1352 (1989).

91.

O'Flynn

Thomas

: Intravesical instillation of oxybutynin hydrochlorixe for detrusor hyperreflexia. Br. J. Urol. 723, 566–570 (1993).

92.

Andersson

K-E

Appell

Cardozo

: Pharmacological treatment of urinary incontinence. In: Incontinence. Abrams

Khoury

Wein

(Eds). Heath Publication Ltd., Plymouth, UK, 447–486 (1999).

93.

Davila

Daugherty

Sanders

: A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J. Urol. 166, 140–145 (2001).

94.

Dmochowski

Sand

Zinner

: Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 62, 237–242 (2003).

95.

Jonas

Petri

Kissel

: Effect of flavoxate on uninhibited detrusor muscle. Eur. Urol. 5, 106–109 (1979).

96.

Briggs

Castleden

Asher

: The effect of flavoxate on uninhibited detrusor contractions and urinary incontinence in the elderly. J. Urol. 123, 665–666 (1980).

97.

Chapple

Parkhouse

Gardener

: Double-blind placebo-controlled crossover study of flavoxate in the treatment of idiopathic detrusor instability. Br. J. Urol. 66, 491–494 (1990).

98.

Hay-Smith

Herbison

Ellis

: Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst. Rev. CD003781 (2002).

99.

Summary of the Cochrane group's evidence-based evaluation of OAB pharmacotherapy

100.

Sellers

Chapple

Chess-Williams

: Potential therapeutic targets for treatment of the overactive bladder. World J. Urol. 19, 307–311 (2001).

101.

Yoshimura

Chancellor

: Current and future pharmacological treatment for overactive bladder. J. Urol. 168, 1897–1913 (2002).

Antimuscarinic Drugs for the Treatment of Female Urinary Incontinence

Abstract

Keywords

Uroselectivity

Mechanism of action & properties of antimuscarinics

Specific antimuscarinic agents

Relatively pure antimuscarinic agents

Atropine sulfate

Propantheline bromide

Tolterodine tartrate

Trospium chloride

Darifenacin

Solifenacin

Anticholinergic agents with mixed actions

Oxybutynin chloride

Transdermal oxybutynin chloride

Dicyclomine hydrochloride

Flavoxate hydrochloride

Conclusion

Future perspective

Footnotes

References