A prokinetic agent (also prokineticin, gastroprokinetic agent, gastrokinetic agent or propulsive) is a type of drug 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 tract is the largest of the body's systems, after the cardiovascular system. ...

motility Motility is the ability of an organism to move independently using metabolism, metabolic energy. This biological concept encompasses movement at various levels, from whole organisms to cells and subcellular components. Motility is observed in ...

by increasing the frequency or strength of contractions, but without disrupting their rhythm. They are used to treat certain gastrointestinal symptoms, including abdominal discomfort,

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, pressu ...

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

, heart burn,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, and

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

; and certain gastrointestinal disorders, including

irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...

, gastritis,

gastroparesis Gastroparesis (gastro- from Ancient Greek – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis") is a medical disorder of ineffective neuromuscular contractions (peristalsis) of the stomach, resulting in food and l ...

, and functional dyspepsia. 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 chemi ...

(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 compound 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. Par ...

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

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, 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 th ...

which metabolizes acetylcholine. Higher acetylcholine levels increase gastrointestinal

peristalsis Peristalsis ( , ) is a type of intestinal motility, characterized by symmetry in biology#Radial symmetry, radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an wikt:anterograde, anterograde dir ...

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 science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...

and

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

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 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 uman ether-a-go-go K⁺channels) contributes to its potential to cause cardiac arrhythmias. Prucalopride, 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 structural nucleus (parent compound) of many related compounds with more complex stru ...

, is a selective, high affinity

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

(5-HT₄) receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

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

defecation Defecation (or defaecation) follows digestion and is the necessary biological process by which organisms eliminate a solid, semisolid, or liquid metabolic waste, waste material known as feces (or faeces) from the digestive tract via the anus o ...

.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 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 ...

, 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'' 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. 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''. This bacteria has been identified as fac ...

'' 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 numbe ...

'' in children have been found to be effective in the treatment of constipation. '' Lactobacillus plantarum'', in adults has been found to increase defecation frequency.

Pharmacodynamics

Research

Examples

Notes and references

Further reading