Basic and clinical pharmacology of new motility promoting agents

Abstract

Recent research has provided new information about drugs that could be used to treat functional motility disorders. Promotility drugs accelerate gastric emptying or colonic transit and these properties may contribute to their efficacy in treating symptoms associated with gastroparesis, functional dyspepsia or constipation. 5-Hydroxytryptamine4 receptors are targets for drugs (tegaserod, renzapride) that treat symptoms in constipated irritable bowel syndrome patients and in gastroparesis. Drugs acting at motilin (erythromycin) and cholecystokinin-1 (dexloxiglumide) receptors accelerate gastric emptying. Dexloxiglumide might be useful in the treatment of functional dyspepsia particularly that associated with lipid intake. Alvimopan is a mu-opioid receptor antagonist that does not cross the blood brain barrier. Alvimopan is effective in treating postsurgical ileus and perhaps opiate-induced bowel dysfunction. Successes and failures of recent efforts to develop promotility agents revealed opportunities and challenges for developing new promotility drugs. The pharmacological properties of partial agonists might be exploited to develop effective promotility drugs. However, opposing actions of promotility agents on motility (increased contraction vs decreased accommodation) limit the clinical efficacy of drugs with these opposing actions. Selection of appropriate patient populations for evaluation of new drugs is also critical.

Effects of Corydaline from Corydalis Tuber on Gastric Motor Function in an Animal Model

“…Prokinetics, such as cisapride and mosapride, are a group of drugs that stimulate smooth muscle contraction to enhance GE and intestinal transit. 20,21) Recent studies have demonstrated that impaired gastric accommodation in FD may contribute to symptom generation. 22) Matsueda et al showed that acotiamide, a fundus-relaxing drug that acts via blockade of the M1/M2 muscarinic receptor, significantly improves the symptoms of FD and is more effective in reducing symptoms in patients with the postprandial distress syndrome of FD than in patients with epigastric pain syndrome.…”

Physiological Modulation of Intestinal Motility by Enteric Dopaminergic Neurons and the D2Receptor: Analysis of Dopamine Receptor Expression, Location, Development, and Function in Wild-Type and Knock-Out Mice

“…Domperidone (Barone, 1999;Drolet et al, 2000) and tegaserod are both used therapeutically as prokinetic agents, although domperidone is often thought to be more effective on the proximal gut (Longo and Vernava, 1993;Jost, 1997) and so has been used to relieve the symptoms of dyspepsia and gastroparesis (Horowitz and Fraser, 1995;Tonini et al, 2004), whereas tegaserod is used to treat chronic constipation and constipation-predominant irritable bowel syndrome (Prather et al, 2000;Muller-Lissner et al, 2001;Johanson, 2004;Galligan and Vanner, 2005). Domperidone and DA, however, have both been shown to exert effects on the colon and rectum as well as on the upper bowel (Wiley and Owyang, 1987), whereas tegaserod accelerates gastric emptying (Degen et al, 2001;James et al, 2004;Crowell et al, 2005) and has also been useful in treating dyspepsia and gastroparesis (Banh et al, 2005;Galligan and Vanner, 2005;Zuberi et al, 2005). The acceleration by D 2 knock-out of total gastrointestinal and colonic motility suggests that D 2 receptors are important at all levels of the gut and are not restricted in their function to the proximal † † …”

Gavage-Related Reflux in Rats

“…Cholecystokinin, a neuropeptide secreted by endocrine cells of the duodenum, is released in response to the presence of lipids and/or fatty acids in the duodenal lumen. Circulating CCK inhibits gastric emptying (via vagal afferents) and gastric acid secretion (Cakir et al 2007;Shillabeer and Davison 1987) by activation of CCK1-type receptors in the stomach (localized to gastric smooth muscle cells and to peripheral terminals in the vagal afferent fibers) as well as in the central nervous system (Galligan and Vanner 2005).…”