Muscarinic Blocking Drugs: Mechanism of Action

MECHANISM OF ACTION

Antimuscarinic drugs are competitive antagonists of the binding of ACh to muscarinic receptors. The seven trans-membrane helices of these receptors have a ringlike or-ganization in the cell membrane that forms a narrow central cleft where ACh binds. At least seven amino acids from four transmembrane helices have been im-plicated in agonist binding to the muscarinic receptors. Some of these residues, particularly a negatively charged aspartate, interact electrostatically with the positively charged quaternary ammonium moiety of ACh, whereas other residues are required for binding to the ester moiety. Although the tertiary amine and qua-ternary ammonium groups of antimuscarinic drugs bind to the same anionic site on the receptor that agonists occupy, these drugs do not fit into the narrow cleft and consequently cannot activate the receptor.

Dicyclomine (Bentyl), oxybutynin (Ditropan), and tolterodine (Detrol) are nonselective smooth muscle re-laxants that produce relatively little antagonism of mus-carinic receptors at therapeutic concentrations. The mechanism of relaxation is not known. Finally, some other classes of drugs can act in part as muscarinic an-tagonists. For example, the antipsychotics and antide-pressants produce antimuscarinic side effects (e.g., dry mouth).