Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder.
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.
Abrams
Paul
P
Bristol Urological Institute, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB. paul_abrams@bui.ac.uk
Andersson
Karl-Erik
KE
Buccafusco
Jerry J
JJ
Chapple
Christopher
C
de Groat
William Chet
WC
Fryer
Alison D
AD
Kay
Gary
G
Laties
Alan
A
Nathanson
Neil M
NM
Pasricha
Pankaj Jay
PJ
Wein
Alan J
AJ
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011976:Receptors, Muscarinic / Q000378:metabolism* / Q000502:physiology*; D014018:Tissue Distribution; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*
D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic