Category:Prokinetics

A prokinetic is a medicine that increases gastrointestinal motility, particularly in the upper gastrointestinal tract (oesophagus, stomach, small intestine), by enhancing the propulsive contractions that move luminal contents through the gut. The category is used clinically for gastroparesis (the delayed gastric emptying of diabetes, post-surgical states, scleroderma, and idiopathic causes), for functional dyspepsia with predominant postprandial-distress symptoms, for gastroesophageal reflux disease refractory to acid suppression, for postoperative ileus, and for chronic idiopathic constipation when the colonic motility is the principal target.

The pharmacological history of the prokinetics is dominated by serotonin and dopamine. The serotonergic enteric nervous system was elucidated through the 1960s and 1970s by Michael Gershon at Columbia, who termed the enteric nervous system "the second brain"; the recognition that approximately 95 percent of body serotonin resides in the gut and that multiple serotonin-receptor subtypes (5-HT1, 5-HT2, 5-HT3, 5-HT4) regulate gut motility, secretion, and sensation provided the mechanistic foundation for an entire class of medicines.

The first prokinetic in routine clinical use was metoclopramide (Reglan, introduced 1964 by Justin-Besançon and Laville at Delagrange in France). Metoclopramide combines D2 dopamine-receptor antagonism (central antiemetic effect and peripheral upper-GI prokinetic effect through removal of dopaminergic inhibition of motility) with 5-HT4 receptor agonism (direct stimulation of acetylcholine release from enteric motor neurons) with weak 5-HT3 antagonism. The medicine has held a place in upper-GI prokinetic use for sixty years; its dose-related extrapyramidal-symptom profile (acute dystonia, akathisia, parkinsonism, the most-feared tardive dyskinesia after months of use) has restricted long-term use, with the 2009 FDA boxed warning limiting routine continuous use to under 12 weeks and the 2014 European Medicines Agency restriction of single doses to 10 mg every 8 hours and total duration to 5 days. The medicine remains useful for acute diabetic gastroparesis flares, for postoperative ileus, and for chemotherapy-induced nausea (low-dose intravenous, with corticosteroid and 5-HT3 antagonist).

The related D2-only domperidone (Janssen 1974, available in Europe, Canada, and many other markets but not in the United States) avoids central effects by virtue of its quaternary-amine structure that does not cross the blood-brain barrier in clinically meaningful concentrations. Domperidone produces no extrapyramidal symptoms and has the additional indication of lactation enhancement through prolactin elevation. Its U.S. non-availability reflects an FDA concern over the QT-prolongation signal and arrhythmia risk that led to refusal of approval in 1989 and to a 2004 FDA warning against compounded domperidone use; the medicine remains accessible in the U.S. only through compassionate-use programmes.

The 5-HT4 receptor agonists are a distinct prokinetic class. Cisapride (Propulsid, Janssen 1993), the prototype, was withdrawn worldwide between 2000 and 2002 after a series of fatal arrhythmia events attributed to QT prolongation from hERG-channel blockade by the medicine. The selective second-generation 5-HT4 agonists with reduced hERG affinity were developed to recover the prokinetic benefit without the cardiac risk: tegaserod (Zelnorm, Novartis 2002 for IBS-C, withdrawn 2007 for cardiovascular signal, reintroduced 2019 for women under 65 with low cardiovascular risk), and the more highly selective prucalopride (Resotran/Resolor in Europe and Canada 2009, Motegrity in U.S. 2018) which has been used for chronic idiopathic constipation across millions of patient-years without the cardiovascular signal of its predecessors. The newer selective agents velusetrag and naronapride are in development for selected gastric and colonic motility indications.

The macrolide antibacterial erythromycin is a prokinetic by a different mechanism: at sub-antibacterial doses (250 mg intravenously or orally before meals), it agonises the motilin receptor on gastric and small-bowel smooth muscle, triggering powerful contractile complexes resembling the interdigestive migrating motor complex. The medicine is used for acute diabetic gastroparesis flare and for ICU-related gastroparesis, but tachyphylaxis develops within a few days of continuous use and limits its chronic role. The selective motilin-receptor agonists (the macrolide-derivative camicinal and the non-macrolide motilides in trial) are being developed for the indication where erythromycin has proved useful but inadequate.

For lower-GI motility, the chloride-channel activator lubiprostone, the guanylate-cyclase-C agonists linaclotide and plecanatide, the sodium-hydrogen exchanger inhibitor tenapanor, and the 5-HT4 agonist prucalopride are described in detail under IBS treatments and at the chronic-constipation pages; they are listed here insofar as they affect motility, although the chloride-channel and guanylate-cyclase mechanisms are secretory rather than motility in the conventional sense.

The peripheral mu-opioid antagonists for opioid-induced constipation (methylnaltrexone, naloxegol, naldemedine) reverse opioid-mediated inhibition of gut motility without affecting the central analgesic effect of the opioid; they are used in chronic-opioid-using patients with refractory constipation and are mechanistically distinct from the prokinetic category proper but are sometimes grouped with it.

By mechanism:

• D2 dopamine-receptor antagonists (cross-indexed under dopamine D2 antagonists):
  • Metoclopramide (Reglan; gastroparesis, postoperative ileus, antiemetic)
  • Domperidone (Motilium; peripheral D2 only; not U.S.)
  • Itopride (Japan, India; D2 antagonist + acetylcholinesterase inhibitor)
• 5-HT4 receptor agonists:
  • Prucalopride (Motegrity/Resolor; selective; chronic idiopathic constipation)
  • Tegaserod (Zelnorm; restricted to women under 65)
  • Cisapride (Propulsid; withdrawn 2000)
  • Velusetrag, naronapride (in trial)
• Motilin receptor agonists:
  • Erythromycin (sub-antibacterial doses for acute use; tachyphylaxis limits chronic use)
  • Camicinal (in trial)
• Acetylcholinesterase inhibitors (selected use for severe gastroparesis):
  • Pyridostigmine (off-label for chronic intestinal pseudo-obstruction)
  • Neostigmine (intravenous for acute colonic pseudo-obstruction, Ogilvie syndrome)
• Ghrelin-receptor agonists (in trial for gastroparesis):
  • Relamorelin, ulimorelin (development stalled)
• Peripheral mu-opioid antagonists (for opioid-induced constipation; mechanistically distinct):
  • Methylnaltrexone (Relistor), naloxegol (Movantik), naldemedine (Symproic)

The boundary of this category is "medicine that increases the propulsive contractions of the gastrointestinal tract." The chloride-channel activators (lubiprostone), guanylate-cyclase-C agonists (linaclotide, plecanatide), and SNH inhibitors (tenapanor) increase intestinal fluid secretion rather than motility per se and are listed under IBS treatments; their effect on perceived gut function does overlap with that of the prokinetics. The osmotic laxatives, stimulant laxatives, stool softeners, and bulk-forming agents are categorised under osmotic laxatives, stimulant laxatives, and stool softeners respectively. The antispasmodics are the opposite-direction medicines (smooth-muscle relaxation) and are listed under that category.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.