Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder

Abstract

1. The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2. Muscarinic M3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3. Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4. This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.

Figure 1

The role of the M3 receptor in detrusor contraction. Acetylcholine (ACh), produced in the presynaptic terminal by the action of choline acetyl transferase (ChAT) on choline and acetyl coenzyme A (acetyl-CoA), is released by exocytosis. ACh is metabolized by acetyl cholinesterase (AChE) to release choline. Detrusor contraction is mediated by the binding of ACh on postjunctional membrane muscarinic M₃ receptors (M₃), resulting in activation of the contractile proteins within the detrusor muscle (Effects). Prejunctional M₂ and M₄ receptors inhibit, whereas prejunctional M₁ receptors facilitate the release of ACh. The M₂ receptor also appears to have an indirect functional role in detrusor contractility, and possibly a minor direct effect, but the mechanism remains unclear. Atropine inhibits contraction by blockade of muscarinic receptors.

Figure 2

Mean plasma concentration versus time profiles of available antimuscarinic agents (Olsson & Szamosi, 2001; Prescribing Information (Sanctura), 2004; Product Information, Ditropan/Ditropan XL, 2004; Smulders et al., 2004; Product Information, Enablex (US), 2005). ^*Median serum concentration of active metabolite (5-hydroxymethyl) in healthy volunteers identified as extensive metabolizers. ^†Mean plasma concentration of R-oxybutynin.

Figure 3

Mean plasma concentration versus time profiles of immediate release and extended release versions of (a) oxybutynin and (b) tolterodine (extensive and poor metabolizers) (Gupta & Sathyan, 1999; Olsson & Szamosi, 2001; Appell et al., 2003). ^*Oral tablet administration. (a) (Upper figure). Reproduced with permission from Gupta S.K. & Sathyan G. Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate release oxybutynin. J. Clin. Pharmacol. 1999; 39: 289–296. Copyright 2006, Reprinted by permission of Sage Publication Inc. (Lower figure). Reproduced with permission from Appell RA et al. Pharmacokinetics metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy subjects. Mayo. Clin. Proc. 2003; 78: 696–702. (b) Reproduced with permission from Olsson B et al. Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine. Clin. Pharmacokinet. 2001; 40: 227–235.