Gary G. Kay

Antimuscarinic agents are the predominant pharmacological treatment for patients with overactive bladder (OAB). These drugs are thought to act primarily through antagonism at muscarinic M ₃ receptors located at neuromuscular junctions in the human bladder detrusor muscle. Several of these drugs have been shown to be efficacious in ameliorating the symptoms of OAB in older patients, but most currently available agents lack selectivity for the M ₃ receptor subtype, and interaction with other muscarinic receptor subtypes throughout the body may adversely affect a variety of physiological functions and result in unwanted side effects, including cognitive dysfunction. With the recent availability of antimuscarinic agents that show increased selectivity for M ₃ receptors relative to other muscarinic subtypes, an invitational expert panel meeting was convened to review not only the mechanisms by which antimuscarinic agents could affect cognitive function, but also the published literature on cognitive adverse events. A review of the literature shows that the cholinergic system in the central nervous system (CNS) exerts a major influence on cognitive processes, in particular memory via M ₁ cholinergic receptors. In addition, recent evidence suggests a role for M ₂ receptors in mediating cognitive function. Thus, cognitive dysfunction (including memory loss) during treatment with nonselective antimuscarinic agents for OAB is of growing concern, particularly in older patients and those with mild cognitive impairment or dementia. Increased blood–brain barrier permeability, which can occur with advanced age and certain comorbidities, may also facilitate CNS access of antimuscarinic agents (regardless of their physiochemical properties) and add to antimuscarinic burden. On the basis of available evidence, antimuscarinic agents with selectivity for M ₃ over M ₁ and M ₂ receptors, limited CNS penetration, or both may therefore offer a favorable balance of efficacy in treating OAB together with a reduced risk of adverse cognitive events in the older population.