Prokinetic agent

A prokinetic agent (also prokineticin, gastroprokinetic agent, gastrokinetic agent or propulsive) is a type of small peptide drug which enhances gastrointestinal motility by increasing the frequency or strength of contractions, but without disrupting their rhythm.^[1] They are used to treat certain gastrointestinal symptoms, including abdominal discomfort, bloating, constipation, heart burn, nausea, and vomiting; and certain gastrointestinal disorders, including irritable bowel syndrome, gastritis,^[2] gastroparesis, and functional dyspepsia.

Most prokinetic agents are grouped under the Anatomical Therapeutic Chemical Classification System (a World Health Organization drug classification system), as ATC code A03F.

Pharmacodynamics

Activation of a wide range of serotonin receptors by serotonin itself or by certain prokinetic drugs results in enhanced gastrointestinal motility.^[3]

Other prokinetic drugs may increase acetylcholine concentrations by stimulating the M₁ receptor which causes acetylcholine release, or by inhibiting the enzyme acetylcholinesterase which metabolizes acetylcholine. Higher acetylcholine levels increase gastrointestinal peristalsis and further increase pressure on the lower esophageal sphincter, thereby stimulating gastrointestinal motility, accelerating gastric emptying, and improving gastro-duodenal coordination.^{[citation needed]}

The 5-HT₄ receptor is thought to play a significant role in both the physiology and pathophysiology of GI tract motility.^[4] Therefore, 5-HT₄ receptors have been identified as potential therapeutic targets for diseases related to GI dysmotility such as chronic constipation. Some of these prokinetic agents, such as mosapride and cisapride, classic benzamides, have only moderate affinity for 5HT₄ receptors. In recent years, it has become clear that the selectivity profile is a major determinant of the risk-benefit profile of this class of agent. As such, the relatively poor selectivity profile of cisapride versus other receptors (especially hERG [human ether-a-go-go K⁺] channels) contributes to its potential to cause cardiac arrhythmias. Prucalopride, a first in class benzofuran, is a selective, high affinity serotonin (5-HT₄) receptor agonist that stimulates colonic mass movements, which provide the main propulsive force to defecation.^[5][6] SSRIs have been found to have prokinetic actions on the small intestine.^[7]

Other molecules, including macrolides such as mitemcinal and erythromycin, have affinity for the motilin receptor where they act as agonists resulting in prokinetic properties.^[8][9][10]

Research

Animal research has found that supplementation with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis enhances the speed and strength of phase III of the migrating motor complex in the small intestine resulting in reduced small intestinal bacterial overgrowth and bacterial translocation.^[11]

Research in rats has found that supplementation with Lactobacillus acidophilus and Bifidobacterium bifidum increases small intestinal motility with a measurable decrease in the duration of migrating motor complex cycles. A further study found that in rats supplemented with a diet of Lactobacillus rhamnosus and Bifidobacterium lactis, the number and velocity of phase iii of the migrating motor complex increased. These effects make the small intestine more effective at propelling food, bacteria and luminal secretions into the colon.^[11] Bifidobacterium bifidum in combination with Lactobacillus acidophilus accelerated small intestine transit in rats.^[12]

Research into the prokinetic effects of probiotics on the gastrointestinal tract has also been conducted in humans. Lactobacillus reuteri in infants and Lactobacillus casei and Bifidobacterium breve in children have been found to be effective in the treatment of constipation. Lactobacillus plantarum, in adults has been found to increase defecation frequency.^[13]

Examples

• Benzamide
• Cisapride
• Domperidone
• Itopride
• Mosapride^[14]
• Metoclopramide
• Prucalopride^[14]
• Renzapride
• Tegaserod
• Mitemcinal
• Levosulpiride
• Cinitapride
• Linaclotide

Notes and references

1. Vincenzi M, Kremić A, Jouve A, Lattanzi R, Miele R, Benharouga M, Alfaidy N, Migrenne-Li S, Kanthasamy AG, Porcionatto M, Ferrara N, Tetko IV, Désaubry L, Nebigil CG (November 2023). Touyz R (ed.). "Therapeutic Potential of Targeting Prokineticin Receptors in Diseases". Pharmacological Reviews. 75 (6): 1167–1199. doi:10.1124/pharmrev.122.000801. ISSN 0031-6997. PMC 10595023. PMID 37684054.
2. . Archived from the original on 2011-06-15. Retrieved 2011-06-23.
3. Dickson, EJ.; Heredia, DJ.; Smith, TK. (Jul 2010). "Critical role of 5-HT1A, 5-HT3, and 5-HT7 receptor subtypes in the initiation, generation, and propagation of the murine colonic migrating motor complex". Am J Physiol Gastrointest Liver Physiol. 299 (1): G144–57. doi:10.1152/ajpgi.00496.2009. PMC 2904117. PMID 20413719.
4. Gershon, MD; Tack, J (2007). "The serotonin signaling system: from basic understanding to drug development for functional GI disorders". Gastroenterology. 132 (1): 397–414. doi:10.1053/j.gastro.2006.11.002. PMID 17241888.
5. SmPC. Summary of product characteristics Resolor (prucalopride)October, 2009:1-9.
6. Bouras EP, Camilleri M, Burton DD, McKinzie S. Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans. Gut. May 1999;44(5):682-686.
7. Gorard DA, Libby GW, Farthing MJ (April 1994). "5-Hydroxytryptamine and human small intestinal motility: effect of inhibiting 5-hydroxytryptamine reuptake". Gut. 35 (4): 496–500. doi:10.1136/gut.35.4.496. PMC 1374798. PMID 8174987.
8. Takanashi, H.; Cynshi, O. (Jun 2009). "Motilides: a long and winding road: lessons from mitemcinal (GM-611) on diabetic gastroparesis". Regul Pept. 155 (1–3): 18–23. doi:10.1016/j.regpep.2009.03.011. PMID 19345243.
9. Berthet, S.; Charpiat, B.; Mabrut, JY. (Apr 2010). "Erythromycin as a prokinetic agent: risk factors". Journal of Visceral Surgery. 147 (2): e13–8. doi:10.1016/j.jviscsurg.2010.06.001. PMID 20655290.
10. Depoortere, I. (2001). "Motilin and motilin receptors: characterization and functional significance". Verh K Acad Geneeskd Belg. 63 (6): 511–29. PMID 11813507.
11. Lesniewska, V.; Rowland, I.; Laerke, HN.; Grant, G.; Naughton, PJ. (Jan 2006). "Relationship between dietary-induced changes in intestinal commensal microflora and duodenojejunal myoelectric activity monitored by radiotelemetry in the rat in vivo". Exp Physiol. 91 (1): 229–37. doi:10.1113/expphysiol.2005.031708. PMID 16263800.
12. Husebye, E.; Hellström, PM.; Sundler, F.; Chen, J.; Midtvedt, T. (Mar 2001). "Influence of microbial species on small intestinal myoelectric activity and transit in germ-free rats". Am J Physiol Gastrointest Liver Physiol. 280 (3): G368–80. doi:10.1152/ajpgi.2001.280.3.G368. PMID 11171619.
13. Wu, RY.; Pasyk, M.; Wang, B.; Forsythe, P.; Bienenstock, J.; Mao, YK.; Sharma, P.; Stanisz, AM.; Kunze, WA. (Mar 2013). "Spatiotemporal maps reveal regional differences in the effects on gut motility for Lactobacillus reuteri and rhamnosus strains". Neurogastroenterol Motil. 25 (3): e205–14. doi:10.1111/nmo.12072. PMID 23316914.
14. Mozaffari, S.; Nikfar, S.; Abdollahi, M. (Apr 2013). "Metabolic and toxicological considerations for the latest drugs used to treat irritable bowel syndrome". Expert Opin Drug Metab Toxicol. 9 (4): 403–21. doi:10.1517/17425255.2013.759558. PMID 23330973. S2CID 37740247.

Further reading

• Gilman, A. G.; Rall, T. W.; Nies, Alan S.; Taylor, Palmer, eds. (1991). Goodman & Gilman's The Pharmacological Basis of Therapeutics (8th ed.). New York: Pergamon Press. ISBN 0-08-040296-8.