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6.30.5.1.3 Modulators of cholinergic neurotransmission

Cholinergic mechanisms are critical to excitatory enteric neurotransmission. It is therefore perhaps unsurprising that modulation of this system, either through receptor agonism, antagonism, or through the inhibition of metabolism of endogenous neurotransmitters, has profound effects of GI motor function.

Both direct receptor agonism with bethanechol (21) or indirect receptor agonism through the inhibition of cholinesterase activity with neostigmine (22) have substantial historical precedent as strategies to increase GI motility. However, their claims as true prokinetic agents are less straightforward. Given the extensive preclinical data supporting the motility-enhancing and prokinetic effects of these agents, an historical perspective is beyond the scope of this chapter. However, studies of gastric emptying in healthy volunteers demonstrated that bethanechol increases gastric contractile activity, particularly in the antrum.62 However, this effect was not accompanied by increases in gastric emptying. This lack of a true prokinetic effect in the stomach has been observed previously, where bethanechol even appeared to increase gastric residence time.63 In the large bowel of healthy volunteers, bethanechol stimulated phasic contractile activity but failed to increase colonic transit.64 Thus it appears that bethanechol, while able to stimulate contractile activity throughout the GI tract, is unable to stimulate propulsive motility.

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