A prokinetic agent (also gastroprokinetic agent, gastrokinetic agent or propulsive) is a type of

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

which enhances

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...

by increasing the frequency or strength of

contraction Contraction may refer to: Linguistics * Contraction (grammar), a shortened word * Poetic contraction, omission of letters for poetic reasons * Elision, omission of sounds ** Syncope (phonology), omission of sounds in a word * Synalepha, merged ...

s, but without disrupting their rhythm. They are used to treat certain gastrointestinal symptoms, including

abdominal discomfort Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...

bloating Abdominal bloating (or simply bloating) is a short-term disease that affects the gastrointestinal tract. Bloating is generally characterized by an excess buildup of gas, air or fluids in the stomach. A person may have feelings of tightness, press ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

heart burn Heartburn, also known as pyrosis, cardialgia or acid indigestion, is a burning sensation in the central chest or upper central abdomen. Heartburn is usually due to regurgitation of gastric acid (gastric reflux) into the esophagus. It is the ma ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

, and

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

; and certain

gastrointestinal disorders Gastrointestinal diseases (abbrev. GI diseases or GI illnesses) refer to diseases involving the gastrointestinal tract, namely the oesophagus, stomach, small intestine, large intestine and rectum, and the accessory organs of digestion, the live ...

, including

irritable bowel syndrome Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...

gastritis Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...

gastroparesis Gastroparesis (gastro- from Ancient Greek γαστήρ – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis"), also called delayed gastric emptying, is a medical disorder consisting of weak muscular contractions (peristalsis) ...

, and

functional dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier t ...

. Most prokinetic agents are grouped under the

Anatomical Therapeutic Chemical Classification System The Anatomical Therapeutic Chemical (ATC) Classification System is a drug classification system that classifies the active ingredients of drugs according to the organ or system on which they act and their therapeutic, pharmacological and chemical ...

(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. Other prokinetic drugs may increase

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

concentrations by stimulating the M₁ receptor which causes acetylcholine release, or by inhibiting the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...

which metabolizes acetylcholine. Higher acetylcholine levels increase gastrointestinal

peristalsis Peristalsis ( , ) is a radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an anterograde direction. Peristalsis is progression of coordinated contraction of involuntary circular muscles, which ...

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 Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...

and

pathophysiology Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is the ...

of GI tract motility. Therefore, 5-HT₄ receptors have been identified as potential therapeutic targets for diseases related to GI dysmotility such as chronic

. Some of these prokinetic agents, such as

mosapride 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 gastroin ...

and

cisapride 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 incr ...

, classic

benzamides Benzamide is a organic compound with the chemical formula of C6H5C(O)NH2. It is the simplest amide derivative of benzoic acid Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benze ...

, 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 (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...

uman ether-a-go-go K⁺channels) contributes to its potential to cause

cardiac arrhythmias Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

Prucalopride Prucalopride, brand names Resolor and Motegrity among others, is a drug acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements. Pruca ...

, a first in class

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 i ...

, is a selective, high affinity

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

(5-HT₄) receptor

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

that stimulates colonic mass movements, which provide the main propulsive force to

defecation Defecation (or defaecation) follows digestion, and is a necessary process by which organisms eliminate a solid, semisolid, or liquid waste material known as feces from the digestive tract via the anus. The act has a variety of names ranging f ...

.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.

SSRIs Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellul ...

have been found to have prokinetic actions on the small intestine. Other molecules, including macrolides such as mitemcinal and

erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used duri ...

, have affinity for the motilin receptor where they act as agonists resulting in prokinetic properties.

Research

Animal research has found that supplementation with the probiotics ''

Lactobacillus rhamnosus ''Lacticaseibacillus rhamnosus'' (previously ''Lactobacillus rhamnosus'') is a bacterium that originally was considered to be a subspecies of ''L. casei'', but genetic research found it to be a separate species in the ''L. casei'' clade, which a ...

'' and '' Bifidobacterium lactis'' enhances the speed and strength of phase III of the

migrating motor complex 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 w ...

in the small intestine resulting in reduced

small intestinal bacterial overgrowth 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 (or large bowel), which is r ...

and

bacterial translocation Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows ...

. 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. ''Bifidobacterium bifidum'' in combination with ''Lactobacillus acidophilus'' accelerated small intestine transit in rats. Research into the prokinetic effects of probiotics on the gastrointestinal tract has also been conducted in humans. '' Lactobacillus reuteri'' in infants and ''

Lactobacillus casei ''Lacticaseibacillus casei ''is an organism that belongs to the largest genus in the family ''Lactobacillaceae'', a lactic acid bacteria (LAB), that was previously classified as ''Lactobacillus casei-01''. This bacteria has been identified as facu ...

'' and ''

Bifidobacterium breve ''Bifidobacterium breve'' is a bacterial species of the genus ''Bifidobacterium'' which has probiotic properties. ''Bifidobacteria'' are a type of bacteria that live symbiotically in the intestines of humans. They have been used to treat a number ...

'' in children have been found to be effective in the treatment of constipation. ''

Lactobacillus plantarum ''Lactiplantibacillus plantarum'' (formerly ''Lactobacillus arabinosus'' and ''Lactobacillus plantarum'') is a widespread member of the genus ''Lactiplantibacillus'' and commonly found in many fermented food products as well as anaerobic plant ma ...

'', in adults has been found to increase defecation frequency.

Pharmacodynamics

Research

Examples

Notes and references

Further reading