While a range of drugs have been used in the past for the management of overactive bladder—from smooth muscle relaxants to tricyclic antidepressants—antimuscarinic agents now form the mainstay in the armamentarium used to control the symptoms associated with this condition. Conventional wisdom
12 holds that antimuscarinics act by blocking the muscarinic receptors on the detrusor muscle (which are normally stimulated by acetylcholine released from parasympathetic nerves) thereby diminishing the intensity of involuntary detrusor muscle contractions. Emerging research,
12 however, suggests that anti-muscarinic agents mainly act during the storage phase, decreasing urge and increasing bladder capacity, during which time there is normally no activity in the parasympathetic nerves. Studies
12-14 are now focusing on the ability of antimuscarinics to modulate afferent impulses as a means of effectiveness.
Antimuscarinic agents differ at the structural and molecular level, resulting in different metabolism, absorption, potency, and selectivity profiles, as follows:
An understanding of these differences—particularly in how they impact the efficacy and safety of the agents—is important and allows physicians to make informed decisions about the most suitable treatment option for their patients' needs.
15-20 A summary of these features is provided in
Figure 2.
There are currently five antimuscarinic agents available in the United States for the treatment of overactive bladder: oxybutynin, tolterodine tartrate, darifenacin, solifenacin (all tertiary amines), and trospium (a quaternary amine). The tertiary amines are predominantly metabolized by the cytochrome P-450 enzymes in the liver with little active compound being excreted in the urine. Of administered doses, <0.1%, <1%, and <15% of unchanged oxybutynin, tolterodine, and solifenacin, respectively, is excreted in the urine.
22-24 For darfenacin, 3% of the dose excreted in urine is unchanged.
25 By contrast, trospium (quaternary amine) is minimally metabolized in the liver, with the majority (60%) of the absorbed compound being excreted in its active form.
26 The different pharmacologic profiles of these antimuscarinic agents
22-27 may contribute to the differences in safety and efficacy seen in clinical practice studies (
Table).
28-34
Oxybutynin has been available for the treatment of overactive bladder for more than 30 years and is effective in a range of patients. It is available as immediate- and extended-release oral tablets (oxybutynin chloride) and as a transdermal patch.
30,35 The most commonly reported adverse event for extended-release oral oxybutynin is dry mouth, experienced by up to 68% of patients and causing some patients to discontinue therapy.
36 Transdermal oxybutynin results in a far lower incidence of dry mouth (<10%) but is associated with local skin reactions such as pruritis.
30 This lower incidence of dry mouth is believed to result from the lack of presystemic metabolism to form an active metabolite with similar properties to the parent compound (N-desethyl-oxybutynin).
Certain attributes of oral oxybutynin, such as its relatively small size, highly lipophilic nature, and its neutral charge, make it more likely to cross the blood-brain barrier than other antimuscarinic agents available for the treatment of overactive bladder. Therefore, central anticholinergic effects, which could result in cognitive impairment, are a concern in patients (particularly elderly patients) taking oxybutynin.
37
Tolterodine, which is orally administered, has been available in the United States since 1998. Originally launched as an immediate-release formulation, tolterodine is now available as an extended-release formulation. Initiated and maintained at a dose of 4 mg once daily, tolterodine extended-release formulation is efficacious in the treatment of overactive bladder.
38 Tolterodine has comparable efficacy to oxybutynin, but with a reduced incidence of adverse events (eg, dry mouth).
37,39,40 Although preliminary reports
41,42 have drawn an association between tolterodine and impaired cognitive functioning, tolterodine is less lipophilic than oxybutynin and is therefore less likely to cross the blood-brain barrier.
43
Newer oral antimuscarinic agents darifenacin (7.5 mg and 15 mg) and solifenacin (5 mg and 10 mg) were approved for the treatment of overactive bladder and urge incontinence by the FDA in 2003 and 2004, respectively. Both agents are well-tolerated and substantially reduce urge incontinence episodes, frequency, and urgency, and increase the volume of urine voided.
44-47 The most commonly reported adverse events for both darifenacin and solifenacin are dry mouth and constipation. Darifenacin has little affinity for the M
1 muscarinic subtype receptor, a feature that is proposed to minimize cognitive effects that might arise if the compound were to cross the blood-brain barrier. Accordingly, adverse cognitive effects have not been reported for darifenacin.
48 Solifenacin is a nonselective muscarinic antagonist that binds to the M
1, M
2, and M
3 muscarinic receptors—though with slightly greater affinity for M
1 and M
3 receptors than M
2 receptors.
49 Animal studies
27,49 suggest that solifenacin has the highest degree of bladder selectivity compared with oxybutynin, tolterodine, and darifenacin. In a recent head-to-head trial,
50 a flexible dosing regimen with solifenacin was found to be superior to extended-release tolterodine for the majority of efficacy variables investigated. However, because this trial
50 was designed to show non-inferiority, these results should be viewed with caution.
Trospium, an antimuscarinic agent approved by the FDA in 2004 for the treatment of overactive bladder, has been available in Europe for more than 20 years. The safety and efficacy of trospium have been demonstrated in clinical trials involving over 3000 patients in the United States and Europe and have been further demonstrated with postmarketing studies involving over 10,000 patients.
13 Trospium is unique among the new antimuscarinic agents for several reasons: it has the least selectivity and the highest overall affinity for the muscarinic receptor subtypes; it is a positively charged quaternary amine, which prevents transfer across the blood-brain barrier; and it is minimally metabolized by cytochrome P-450 enzymes, with approximately 60% of the absorbed dose being excreted in the urine in active form. In addition, this agent demonstrates a rapid onset of effect, reducing frequency and urge incontinence within the first few days of treatment.
15,34
Trospium also has comparable efficacy to oral oxybutynin and tolterodine, but with fewer adverse events.
51 The lack of cognitive adverse effects may result from the inability of trospium to transfer across the blood-brain barrier. The lack of adverse drug-drug interactions is a result of the lack of metabolism by cytochrome P-450 enzymes. Evidence supporting the possible additional benefits of a compound that is active in the urine was provided by a recent study
14 in which urine from individuals who had ingested a variety of antimuscarinic agents was injected into the bladders of rats. The results of the study
14 showed that, in accordance with its activity in urine, trospium has a local inhibitory effect on detrusor overactivity.