Comparison of selective M₃ and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans

Abstract

Although in vitro studies show that muscarinic M(3) receptors primarily mediate the effects of acetylcholine on gastrointestinal contractility, the muscarinic receptor subtypes regulating gastrointestinal motor activity and transit in humans in vivo are unclear. We hypothesized that muscarinic M(3)-specific but not nonspecific receptor antagonists would delay gastrointestinal and colonic transit in humans. In this parallel-group study, gastric emptying, small intestinal transit, and colonic transit were assessed by scintigraphy on days 4-6 in 72 healthy subjects (49 women) who received placebo (n = 16), the M(3) antagonist darifenacin ER [7.5 mg (n = 20) or 15 mg daily (n = 17)], or the nonspecific antagonist tolterodine [4 mg daily (n = 19)] for 6 days. Bowel habits were recorded by daily diaries. Both doses of darifenacin substantially delayed [P < 0.01 vs. placebo (for both doses), P < 0.01 vs. tolterodine (for 15 mg)] small intestinal transit, i.e., colonic filling at 6 h (placebo [59.6 +/- 6.4%, mean +/- SE], 7.5 mg ER [34.4 +/- 6.1%], 15 mg ER [20.4 +/- 6.3%)]. Darifenacin (15 mg) also delayed (P < 0.01 vs. placebo and tolterodine) half-time for ascending colonic emptying [placebo (12.0 +/- 1.5 h), 7.5 mg (18.6 +/- 1.9 h), 15 mg (22.9 +/- 2.6 h)] and colonic transit (geometric center) at 24 [placebo (2.8 +/- 0.2), 7.5 mg (2.4 +/- 0.2), 15 mg (1.9 +/- 0.2)] but not 48 h. Darifenacin did not affect gastric emptying and tolterodine did not affect bowel habits or gastrointestinal transit. With muscarinic antagonists used at clinically approved doses, these findings demonstrate that muscarinic M(3) receptors regulate small intestinal and colonic transit in humans; colonic effects are more pronounced in the right than left colon. At doses that affect small and large intestinal transit, M(3) antagonists do not affect gastric emptying in humans. The efficacy of darifenacin in diarrhea-predominant irritable bowel syndrome should be evaluated.

Systemic Absorption of Cyclopentolate and Adverse Events After Retinopathy of Prematurity Exams

“…32,33 Historically cyclopentolate has been described as a non-specific muscarinic antagonist, but there is no evidence supporting the nonspecificity at muscarinic receptors.…”

“…17,39 Genes that influence the metabolism of anticholinergics have been identified, and it is possible that one or more of these candidate genes may contribute to our findings. 20,32,40–43 …”

Clinical features and disturbances of gastrointestinal transit in patients with rapid gastric emptying

“…In a previous study, 25 of 60 patients (40%) with non‐organic diarrhea had rapid GE . Patients with rapid small intestinal and/or colonic transit may benefit from treatment with muscarinic cholinergic or serotonin 5‐HT 3 receptor antagonists …”

Pharmacological agents currently in clinical trials for disorders in neurogastroenterology

“…Darifenacin retarded human small bowel and colonic transit (44), otilonium reduced rectal sensations (45), and hyoscine reduced enterocyte secretion (46). Therefore, this class of agents can counteract three mechanisms that contribute to chronic diarrhea.…”