Abstract
Background:Antimuscarinic agents used in the treatment of overactive bladder (OAB) differ in their potential to impair cognitive function. It is hypothesised that low brain concentrations and relatively low selectivity for the M1 muscarinic receptor may reduce the potential for adverse central nervous system (CNS) effects with darifenacin, compared with other antimuscarinics, particularly oxybutynin.Methods:Cognitive function studies evaluating darifenacin, oxybutynin, tolterodine, solifenacin and/or trospium were identified from publications databases (Medline, Biosis and Embase) and congress abstracts. Preclinical studies and randomised controlled trials in adults were reviewed.Results:Five randomised, double-blind, multiple-dose studies of cognitive function were identified. Oxybutynin was consistently associated with cognitive deficit (four studies), whereas darifenacin did not impair cognition (three studies). These findings were supported by data from sleep/attention and EEG studies. Tolterodine data were limited to one small study with each formulation. For solifenacin and trospium, there were no human studies evaluating memory, the cognitive function most vulnerable to CNS anticholinergics.Conclusions:There is compelling evidence of cognitive impairment with oxybutynin, whereas darifenacin stands out by demonstrating no impairment of memory or other cognitive functions in three randomised, controlled trials. This may be attributed to the differences in physicochemical properties, efflux mechanisms and relative M1 muscarinic receptor sparing. The risk of CNS impairment is of particular concern for vulnerable populations such as the elderly (a substantial proportion of the OAB population), and CNS-compromised neurogenic bladder patients such as those with multiple sclerosis or Parkinson’s disease.
Highlights
Overactive bladder (OAB) is a common condition, comprising a symptom complex that includes urinary urgency, frequency and in one-third of patients, urgency-associated incontinence [1]
An important factor for consideration is whether the choice of antimuscarinic therapy can influence central nervous system (CNS) outcomes, and evidence is accumulating for differences between antimuscarinic drugs in their potential to adversely affect memory and other aspects of cognitive function
Other antimuscarinic agents were consistently found to be relatively non-selective for M3 receptors, with ratios of binding for M3 over M1 receptors ranging from 0.5 to 2.5 across all studies [31,32,33,34,35,36,37,38,39,40]. These findings suggest that the potential for negative cognitive effects among all currently available OAB drugs is likely to be the highest for oxybutynin, which demonstrates a high propensity for CNS penetration and accumulation coupled with a 2008 The Authors Journal compilation a 2008 Blackwell Publishing Ltd Int J Clin Pract, November 2008, 62, 11, 1792–1800 non-selectivity for M3 receptors over the M1 receptor subtype
Summary
Antimuscarinic agents used in the treatment of overactive bladder (OAB) differ in their potential to impair cognitive function. Conclusions: There is compelling evidence of cognitive impairment with oxybutynin, whereas darifenacin stands out by demonstrating no impairment of memory or other cognitive functions in three randomised, controlled trials. This may be attributed to the differences in physicochemical properties, efflux mechanisms and relative M1 muscarinic receptor sparing. Message for the Clinic Antimuscarinics used in the treatment of overactive bladder differ in their potential to affect cognitive function. Darifenacin and tolterodine stand out as having been shown to not cause impairment of memory or other cognitive functions in randomised clinical trials
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