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.
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]
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]
Laxatives, purgatives, or aperients are substances that loosen stools and increase bowel movements. They are used to treat and prevent constipation.
Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the heterocyclic nitrogen). The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others. Tryptamine has been shown to activate trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems. In the human gut, symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility. Multiple tryptamine-derived drugs have been developed to treat migraines, while trace amine-associated receptors are being explored as a potential treatment target for neuropsychiatric disorders.
Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system. It has been sold under the trade names Prepulsid (Janssen-Ortho) and Propulsid (in the United States). It was discovered by Janssen Pharmaceuticals in 1980. In many countries, it has been either withdrawn from the market or had its indications limited due to incidence of serious cardiac side-effects. Propulsid was linked to children's deaths.
Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction. The word 'ileus' is from Ancient Greek eileós. The term 'subileus' refers to a partial obstruction.
Small intestinal bacterial overgrowth (SIBO), also termed bacterial overgrowth, or small bowel bacterial overgrowth syndrome (SBBOS), is a disorder of excessive bacterial growth in the small intestine. Unlike the colon, which is rich with bacteria, the small bowel usually has fewer than 100,000 organisms per millilitre. Patients with bacterial overgrowth typically develop symptoms which may include nausea, bloating, vomiting, diarrhea, malnutrition, weight loss and malabsorption, which is caused by a number of mechanisms.
Motilin is a 22-amino acid polypeptide hormone in the motilin family that, in humans, is encoded by the MLN gene.
Enterochromaffin (EC) cells are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal regulation, particularly intestinal motility and secretion. They were discovered by Nikolai Kulchitsky.
Renzapride is a prokinetic agent and antiemetic which acts as a full 5-HT4 agonist and partial 5-HT3 antagonist. It also functions as a 5-HT2B antagonist and has some affinity for the 5-HT2A and 5-HT2C receptors.
Migrating motor complex, also known as migrating myoelectric complex, migratory motor complex, migratory myoelectric complex and MMC, is a pattern of electrical activity observed in the gastrointestinal tract in a regular cycle during fasting. MMC was discovered and characterized in fasting dogs in 1969 by Dr. Joseph H. Szurszewski at the Mayo Clinic. He also showed that this activity stops upon eating a meal, and suggested that it induces a motor activity that acts as a "interdigestive housekeeper" in the small intestine. These motor complexes trigger peristaltic waves, which facilitate transportation of indigestible substances such as bone, fiber, and foreign bodies from the stomach, through the small intestine, past the ileocecal sphincter, and into the colon. MMC activity varies widely across individuals and within an individual when measured on different days. The MMC occurs every 90–230 minutes during the interdigestive phase and is responsible for the rumbling experienced when hungry. It also serves to transport bacteria from the small intestine to the large intestine and to inhibit the migration of colonic bacteria into the terminal ileum; an impairment to the MMC typically results in small intestinal bacterial overgrowth.
Intestinal pseudo-obstruction (IPO) is a clinical syndrome caused by severe impairment in the ability of the intestines to push food through. It is characterized by the signs and symptoms of intestinal obstruction without any lesion in the intestinal lumen. Clinical features mimic those seen with mechanical intestinal obstructions and can include abdominal pain, nausea, abdominal distension, vomiting, dysphagia and constipation depending upon the part of the gastrointestinal tract involved.
The gastrocolic reflex or gastrocolic response is a physiological reflex that controls the motility, or peristalsis, of the gastrointestinal tract following a meal. It involves an increase in motility of the colon consisting primarily of giant migrating contractions, or migrating motor complexes, in response to stretch in the stomach following ingestion and byproducts of digestion entering the small intestine. Thus, this reflex is responsible for the urge to defecate following a meal. The small intestine also shows a similar motility response. The gastrocolic reflex's function in driving existing intestinal contents through the digestive system helps make way for ingested food.
A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.
Motilin receptor is a G protein-coupled receptor that binds motilin. It was first cloned in 1999 by Merck Laboratories. and scientists have since been searching for compounds to modify its behavior.
Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist. The major active metabolite of mosapride, known as M1, additionally acts as a 5HT3 antagonist, which accelerates gastric emptying throughout the whole of the gastrointestinal tract in humans, and is used for the treatment of gastritis, gastroesophageal reflux disease, functional dyspepsia and irritable bowel syndrome. It is recommended to be taken on an empty stomach (i.e. at least one hour before food or two hours after food).
Itopride (INN; brand name Ganaton) is a prokinetic benzamide derivative. These drugs inhibit dopamine and acetylcholine esterase enzyme and have a gastrokinetic effect. Itopride is indicated for the treatment of functional dyspepsia and other gastrointestinal conditions. It is a combined D2 receptor antagonist and acetylcholinesterase inhibitor.
Mitemcinal is a motilin agonist derived from the macrolide antibiotic, erythromycin. It was discovered in the labs of Chugai Pharma. Mitemcinal is orally administered and it is believed to have strong promotility effects. Promotility drugs relieve symptoms of reflux by speeding the clearance of acid from the oesophagus and stomach. The parent compound, erythromycin, has these characteristics, but mitemcinal lacks the antibiotic properties of erythromycin.
Prucalopride, sold under brand names Resolor and Motegrity among others, is a medication acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements. Prucalopride was approved for medical use in the European Union in 2009, in Canada in 2011, in Israel in 2014, and in the United States in December 2018. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.
Cinitapride (trade names Cintapro, Pemix) is a gastroprokinetic agent and antiemetic agent of the benzamide class which is marketed in India, Mexico, Pakistan and Spain. It acts as an agonist of the 5-HT1 and 5-HT4 receptors and as an antagonist of the 5-HT2 receptors.
Velusetrag (INN, USAN; previously known as TD-5108) is an experimental drug candidate for the treatment of gastric neuromuscular disorders including gastroparesis, and lower gastrointestinal motility disorders including chronic idiopathic constipation and irritable bowel syndrome. It is a potent, selective, high efficacy 5-HT4 receptor serotonin agonist being developed by Theravance Biopharma and Alfa Wassermann. Velusetrag demonstrates less selectivity for other serotonin receptors, such as 5-HT2 and 5-HT3, to earlier generation 5-HT agonists like cisapride and tegaserod.
CJ-033466 is a drug which acts as a potent and selective 5-HT4 serotonin receptor partial agonist. In animal tests it stimulated gastrointestinal motility with 30 times the potency of cisapride, and with lower affinity for the hERG channel.
