Delayed gastric emptying, or gastroparesis, is a condition that impairs the normal movement of food from the stomach into the small intestine. It often presents with symptoms such as nausea, vomiting, bloating, and early satiety. This condition can significantly affect quality of life, as well as medical care, and is commonly associated with diabetes, post-surgical complications, and certain neurological disorders. In some cases, however, several drug classes known to increase gastric emptying through various mechanisms may be used to clinically manage gastroparesis.

Prokinetic agents are among the most commonly prescribed drugs for improving gastric emptying. Metoclopramide, a dopamine D2 receptor antagonist and serotonin 5-HT4 agonist, enhances gastric contractions and accelerates gastric transit. Despite its effectiveness, long-term use is limited due to central nervous system side effects, including extrapyramidal symptoms and tardive dyskinesia. Domperidone, another D2 antagonist, offers similar benefits without crossing the blood-brain barrier, thereby reducing the risk of neurological complications. However, its association with QT prolongation and potential cardiac arrhythmias has led to restricted use in some regions.

Serotonin receptor modulators, particularly those targeting the 5-HT4 receptor, have also been explored for their prokinetic effects. Cisapride, once a widely used 5-HT4 agonist, was withdrawn in many countries due to its cardiac risks. Prucalopride, a newer 5-HT4 agonist developed for chronic constipation, has shown promise in small studies for improving gastric emptying and alleviating symptoms in patients with overlapping gastrointestinal disorders. These agents act by enhancing cholinergic transmission in the enteric nervous system, thereby stimulating coordinated GI motility.

Motilin receptor agonists represent another class of drugs used to increase gastric emptying. Erythromycin, a macrolide antibiotic, mimics the action of motilin, a gastrointestinal hormone that stimulates the migrating motor complex. At low, sub-antimicrobial doses, erythromycin effectively increases gastric emptying, especially in diabetic gastroparesis. However, its benefits are often short-lived due to tachyphylaxis, and long-term use raises concerns about antibiotic resistance. Newer agents like mitemcinal aim to retain prokinetic effects without antibiotic activity, although they are not yet widely available.

Ghrelin receptor agonists are a newer therapeutic option showing potential in clinical trials. Ghrelin, known for stimulating appetite, also enhances gastric motility. Relamorelin, a synthetic ghrelin receptor agonist, has demonstrated the ability to increase gastric emptying and reduce vomiting in patients with diabetic gastroparesis. Its mechanism involves the activation of pathways that coordinate gastric and intestinal motility. Although still under investigation, ghrelin agonists may represent a significant advancement in the pharmacologic treatment of gastroparesis.

Several pharmacologic agents are available to increase gastric emptying, each with distinct mechanisms and safety profiles. Traditional agents like metoclopramide and erythromycin remain in use, but their limitations have driven the development of newer options targeting serotonin, motilin, and ghrelin pathways. Individualized treatment, considering the patient’s underlying condition, symptom profile, and the drug’s potential side effects, remains essential. Continued research into novel prokinetic therapies may provide safer and more effective options for managing this challenging condition.

References

1. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108(1):18–37. doi: 10.1038/ajg.2012.373.
2. Tack J, Janssen P. Gastroparesis—symptoms and new treatment options. Nat Rev Gastroenterol Hepatol. 2010;7(8):465–471.
3. Friedenberg FK, Palit A, Parkman HP. The use of erythromycin as a prokinetic agent in the treatment of gastroparesis. Aliment Pharmacol Ther. 2008;27(8):741–752.
4. Lembo AJ, Camilleri M, McCallum RW, et al. Relamorelin reduces vomiting frequency and severity in patients with diabetic gastroparesis. Gastroenterology. 2016;151(1):87–96.e6. doi: 10.1053/j.gastro.2016.03.038.
5. Van der Ploeg R, Soeters MR, Bogaards SJ, et al. Safety and tolerability of prucalopride in patients with chronic constipation: pooled data from four randomized, controlled trials. Am J Gastroenterol. 2009;104(7):1799–1807. doi: 10.1007/s10620-016-4147-9.