{{short description|Medication to promote gastrointestinal emptying}} A '''prokinetic agent''' (also '''prokineticin''', '''gastroprokinetic agent''', '''gastrokinetic agent''' or '''propulsive''') is a type of drug which enhances gastrointestinal motility by increasing the frequency or strength of contractions, but without disrupting their rhythm.<ref>{{Cite journal |vauthors=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 |date=November 2023 |editor-last=Touyz |editor-first=Rhian |editor-link=Rhian Touyz |title=Therapeutic Potential of Targeting Prokineticin Receptors in Diseases |journal=Pharmacological Reviews |language=en |volume=75 |issue=6 |pages=1167–1199 |doi=10.1124/pharmrev.122.000801 |issn=0031-6997 |pmc=10595023 |pmid=37684054}}</ref> 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,<ref name="urlAcid Reflux Symptoms">{{cite web |url=http://www.acidrefluxsymptomse.com/acid-reflux-symptoms.html |title=Acid Reflux Symptoms |access-date=2011-06-23 |archive-url=https://web.archive.org/web/20110615110241/http://www.acidrefluxsymptomse.com/acid-reflux-symptoms.html |archive-date=2011-06-15 |url-status=dead }}</ref> 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.<ref name="Dickson-2010">{{Cite journal | last1 = Dickson | first1 = EJ. | last2 = Heredia | first2 = DJ. | last3 = Smith | first3 = TK. | title = 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 | url = http://ajpgi.physiology.org/content/299/1/G144 | journal = Am J Physiol Gastrointest Liver Physiol | volume = 299 | issue = 1 | pages = G144–57 |date=Jul 2010 | doi = 10.1152/ajpgi.00496.2009 | pmid = 20413719 | pmc=2904117}}</ref>

Other prokinetic drugs may increase acetylcholine concentrations by stimulating the M<sub>1</sub> 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|date=October 2013}}

The 5-HT<sub>4</sub> receptor is thought to play a significant role in both the physiology and pathophysiology of GI tract motility.<ref>{{cite journal | last1 = Gershon | first1 = MD | last2 = Tack | first2 = J | year = 2007 | title = The serotonin signaling system: from basic understanding to drug development for functional GI disorders | journal = Gastroenterology | volume = 132 | issue = 1| pages = 397–414 | doi=10.1053/j.gastro.2006.11.002 | pmid=17241888| doi-access = free }}</ref> Therefore, 5-HT<sub>4</sub> 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 5HT<sub>4</sub> 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<sup>+</sup>] channels) contributes to its potential to cause cardiac arrhythmias. Prucalopride, a first in class benzofuran, is a selective, high affinity serotonin (5-HT<sub>4</sub>) receptor agonist that stimulates colonic mass movements, which provide the main propulsive force to defecation.<ref>SmPC. Summary of product characteristics Resolor (prucalopride)October, 2009:'''1-9.'''</ref><ref>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.</ref> SSRIs have been found to have prokinetic actions on the small intestine.<ref name="pmid8174987">{{cite journal |vauthors=Gorard DA, Libby GW, Farthing MJ |title=5-Hydroxytryptamine and human small intestinal motility: effect of inhibiting 5-hydroxytryptamine reuptake |journal=Gut |volume=35 |issue=4 |pages=496–500 |date=April 1994 |pmid=8174987 |pmc=1374798 |doi=10.1136/gut.35.4.496}}</ref>

Other molecules, including macrolides such as mitemcinal and erythromycin, have affinity for the motilin receptor where they act as agonists resulting in prokinetic properties.<ref name="Takanashi-2009">{{Cite journal | last1 = Takanashi | first1 = H. | last2 = Cynshi | first2 = O. | title = Motilides: a long and winding road: lessons from mitemcinal (GM-611) on diabetic gastroparesis | journal = Regul Pept | volume = 155 | issue = 1–3 | pages = 18–23 |date=Jun 2009 | doi = 10.1016/j.regpep.2009.03.011 | pmid = 19345243 }}</ref><ref name="Berthet-2010">{{Cite journal | last1 = Berthet | first1 = S. | last2 = Charpiat | first2 = B. | last3 = Mabrut | first3 = JY. | title = Erythromycin as a prokinetic agent: risk factors | journal = Journal of Visceral Surgery| volume = 147 | issue = 2 | pages = e13–8 |date=Apr 2010 | doi = 10.1016/j.jviscsurg.2010.06.001 | pmid = 20655290 | doi-access = }}</ref><ref name="Depoortere-2001">{{Cite journal | last1 = Depoortere | first1 = I. | title = Motilin and motilin receptors: characterization and functional significance | journal = Verh K Acad Geneeskd Belg | volume = 63 | issue = 6 | pages = 511–29 | year = 2001 | pmid = 11813507 }}</ref>

==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.<ref name="Lesniewska-2006">{{Cite journal | last1 = Lesniewska | first1 = V. | last2 = Rowland | first2 = I. | last3 = Laerke | first3 = HN. | last4 = Grant | first4 = G. | last5 = Naughton | first5 = PJ. | title = Relationship between dietary-induced changes in intestinal commensal microflora and duodenojejunal myoelectric activity monitored by radiotelemetry in the rat in vivo | url = http://ep.physoc.org/content/91/1/229.long | journal = Exp Physiol | volume = 91 | issue = 1 | pages = 229–37 |date=Jan 2006 | doi = 10.1113/expphysiol.2005.031708 | pmid = 16263800 | doi-access = free }}</ref>

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.<ref name="Lesniewska-2006"/> ''Bifidobacterium bifidum'' in combination with ''Lactobacillus acidophilus'' accelerated small intestine transit in rats.<ref name="Husebye-2001">{{Cite journal | last1 = Husebye | first1 = E. | last2 = Hellström | first2 = PM. | last3 = Sundler | first3 = F. | last4 = Chen | first4 = J. | last5 = Midtvedt | first5 = T. | title = Influence of microbial species on small intestinal myoelectric activity and transit in germ-free rats | journal = Am J Physiol Gastrointest Liver Physiol | volume = 280 | issue = 3 | pages = G368–80 |date=Mar 2001 | doi = 10.1152/ajpgi.2001.280.3.G368 | pmid = 11171619 }}</ref>

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.<ref name="Wu-2013">{{Cite journal | last1 = Wu | first1 = RY. | last2 = Pasyk | first2 = M. | last3 = Wang | first3 = B. | last4 = Forsythe | first4 = P. | last5 = Bienenstock | first5 = J. | last6 = Mao | first6 = YK. | last7 = Sharma | first7 = P. | last8 = Stanisz | first8 = AM. | last9 = Kunze | first9 = WA. | title = Spatiotemporal maps reveal regional differences in the effects on gut motility for Lactobacillus reuteri and rhamnosus strains | journal = Neurogastroenterol Motil | volume = 25 | issue = 3 | pages = e205–14 |date=Mar 2013 | doi = 10.1111/nmo.12072 | pmid = 23316914 | doi-access = free }}</ref>

== Examples == {{Columns-list|colwidth=30em| * Cisapride * Domperidone * Itopride * Mosapride<ref name="Mozaffari-2013">{{Cite journal | last1 = Mozaffari | first1 = S. | last2 = Nikfar | first2 = S. | last3 = Abdollahi | first3 = M. | title = Metabolic and toxicological considerations for the latest drugs used to treat irritable bowel syndrome | journal = Expert Opin Drug Metab Toxicol | volume = 9 | issue = 4 | pages = 403–21 |date=Apr 2013 | doi = 10.1517/17425255.2013.759558 | pmid = 23330973 | s2cid = 37740247 }}</ref> * Metoclopramide * Prucalopride<ref name="Mozaffari-2013"/> * Renzapride * Tegaserod * Mitemcinal * Levosulpiride * Cinitapride * Linaclotide }}

== Notes and references== {{reflist|30em}}

== Further reading == {{refbegin}} * {{cite book |editor1-last=Gilman |editor1-first=A. G. |editor1-link=Alfred G. Gilman |editor2-last=Rall |editor2-first=T. W. |editor3-last=Nies |editor3-first=Alan S. |editor4-last=Taylor |editor4-first=Palmer |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=8th |publisher=Pergamon Press |location=New York |year=1991 |isbn=0-08-040296-8}} {{refend}}

{{Propulsives}} {{Portal bar|Medicine}}

Category:Motility stimulants