Prokinetic agent
Encyclopedia
A gastroprokinetic agent, gastrokinetic, or prokinetic, is a type of drug
which enhances gastrointestinal motility
by increasing the frequency of contraction
s in the small intestine
or making them stronger, but without disrupting their rhythm. They are used to relieve gastrointestinal symptoms such as abdominal discomfort, bloating
, constipation
, heart burn, nausea
, and vomiting
. They are used to treat a number of gastrointestinal disorders, including irritable bowel syndrome
, gastritis
, acid reflux disease
, gastroparesis
, and functional dyspepsia.
Most of these drugs are grouped under ATC code A03F.
concentrations by antagonizing the M1 receptor which inhibits 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.
The 5-HT4 receptor
is thought to play a significant role in both the physiology
and pathophysiology
of GI tract motility. 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
.
Other molecules, including macrolides such as mitemcinal
and Erythromycin
, appear to have high 5-HT4 affinity as well, although limited data exists as this property was an unexpected outcome of off-label use in the clinic.
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
which enhances gastrointestinal motility
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...
by increasing the frequency of contraction
Contraction
Contraction may refer to:In physiology:* Muscle contraction, one that occurs when a muscle fiber lengthens or shortens** Uterine contraction, contraction of the uterus, such as during childbirth* Contraction, a stage in wound healing...
s in the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
or making them stronger, but without disrupting their rhythm. They are used to relieve gastrointestinal symptoms such as abdominal discomfort, bloating
Bloating
Bloating is any abnormal general swelling, or increase in diameter of the abdominal area. As a symptom, the patient feels a full and tight abdomen, which may cause abdominal pain sometimes accompanied by increased borborygmus or more seriously the total lack of borborygmus.-Symptoms:The most common...
, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, heart burn, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. They are used to treat a number of gastrointestinal disorders, including irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
, gastritis
Gastritis
Gastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic...
, acid reflux disease
Gastroesophageal reflux disease
Gastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...
, gastroparesis
Gastroparesis
Gastroparesis, also called delayed gastric emptying, is a medical condition consisting of a paresis of the stomach, resulting in food remaining in the stomach for a longer period of time than normal. Normally, the stomach contracts to move food down into the small intestine for digestion. The...
, and functional dyspepsia.
Most of these drugs are grouped under ATC code A03F.
Pharmacodynamics
These drugs may increase acetylcholineAcetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
concentrations by antagonizing the M1 receptor which inhibits acetylcholine release, or by inhibiting
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
which metabolizes acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
. Higher acetylcholine levels increase gastrointestinal peristalsis
Peristalsis
Peristalsis is a radially symmetrical contraction and relaxation of muscles which propagates in a wave down the muscular tube, in an anterograde fashion. In humans, peristalsis is found in the contraction of smooth muscles to propel contents through the digestive tract. Earthworms use a similar...
and further increase pressure on the lower esophageal sphincter, thereby stimulating gastrointestinal motility, accelerating gastric emptying, and improving gastro-duodenal coordination.
The 5-HT4 receptor
5-HT4 receptor
5-hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.- Location :The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system ....
is thought to play a significant role in both the physiology
Physiology
Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system. The highest honor awarded in physiology is the Nobel Prize in Physiology or...
and pathophysiology
Pathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
of GI tract motility. Therefore, 5-HT4 receptors have been identified as potential therapeutic targets for diseases related to GI dysmotility such as chronic constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
. Some of these prokinetic agents, such as mosapride
Mosapride
Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist which accelerates gastric emptying and is used for the treatment of acid reflux, irritable bowel syndrome and functional dyspepsia....
and cisapride
Cisapride
Cisapride is a gastroprokinetic agent, a drug which 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...
, 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
HERG
hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
[human ether-a-go-go K+] channels) contributes to its potential to cause cardiac arrhythmias. Prucalopride
Prucalopride
Prucalopride is a drug acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalising bowel movements...
, a first in class benzofuran
Benzofuran
Benzofuran is the heterocyclic compound consisting of fused benzene and furan rings. This colourless liquid is a component of coal tar. Benzofuran is the "parent" of many related compounds with more complex structures. For example, psoralen is a benzofuran derivative that occurs in several...
, is a selective, high affinity serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-HT4) receptor agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
that stimulates colonic mass movements, which provide the main propulsive force to defecation
Defecation
Defecation is the final act of digestion by which organisms eliminate solid, semisolid or liquid waste material from the digestive tract via the anus. Waves of muscular contraction known as peristalsis in the walls of the colon move fecal matter through the digestive tract towards the rectum...
.
Other molecules, including macrolides such as mitemcinal
Mitemcinal
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...
and Erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, appear to have high 5-HT4 affinity as well, although limited data exists as this property was an unexpected outcome of off-label use in the clinic.
Further reading
- Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill, 2001. ISBN 0-07-135469-7.