New Developments in Prokinetic Therapy for Gastric Motility Disorders

Abstract

Prokinetic agents amplify and coordinate the gastrointestinal muscular contractions to facilitate the transit of intra-luminal content. Following the institution of dietary recommendations, prokinetics are the first medications whose goal is to improve gastric emptying and relieve symptoms of gastroparesis. The recommended use of metoclopramide, the only currently approved medication for gastroparesis in the United States, is for a duration of less than 3 months, due to the risk of reversible or irreversible extrapyramidal tremors. Domperidone, a dopamine D2 receptor antagonist, is available for prescription through the FDA’s program for Expanded Access to Investigational Drugs. Macrolides are used off label and are associated with tachyphylaxis and variable duration of efficacy. Aprepitant relieves some symptoms of gastroparesis. There are newer agents in the pipeline targeting diverse gastric (fundic, antral and pyloric) motor functions, including novel serotonergic 5-HT4 agonists, dopaminergic D2/3 antagonists, neurokinin NK1 antagonists, and ghrelin agonist. Novel targets with potential to improve gastric motor functions include the pylorus, macrophage/inflammatory function, oxidative stress, and neurogenesis. In the current review, we discuss the use of pharmacological approaches with potential to enhance motor functions in the management of gastroparesis.

Gastroparesis

“…123 Supplementary Table 2 lists current 117,120-136 and investigational 137 prokinetic drugs for gastric motility disorders, as summarized recently. 138 Two pharmacological approaches pursued to reverse pyloric dysfunction. First is reversal of the reduced neuronal NOS expression and decreased guanosine 3 0 ,5 0 -cyclic monophosphate content with the phosphodiesterase-5 inhibitor, sildenafil.…”

“…NOTE. From Camilleri and Atieh,138 reproduced with permission. DG, diabetic gastroparesis; FD, functional dyspepsia; GA, gastric accommodation; GE, gastric emptying; GP, gastroparesis; IG, idiopathic gastroparesis.…”

Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders

“…Prokinetic medications can amplify muscular contractions in the gut to help enhance peristaltic movements of the gut; therefore, accelerating transit of intra-luminal contents ( Acosta and Camilleri, 2015 ). Prokinetic medications can act in a generalized fashion, affecting multiple regions of the gut, or in a more specific manner, only affecting certain areas of the gut based on the location of the receptor targets ( Camilleri and Atieh, 2021 ). 5-HT4R agonists, 5-HT3R antagonists, 5-HT1AR agonists, ghrelin receptor agonists, dopamine-2 receptor antagonists, and muscarinic receptor antagonists are all prokinetic agents that have been demonstrated to restore altered gut motility in patients with gut motility disorders and FGIDs ( Simren and Tack, 2018 ; Grover et al, 2019 ; Ghoshal, 2020 ; Camilleri and Atieh, 2021 ).…”

“…Based on previous clinical trials and meta-analyses, prokinetics have been recommended to treat gastroparesis, FD, IBS-C, and chronic constipation ( Simren and Tack, 2018 ; Carbone et al, 2019 ; Grover et al, 2019 ; Camilleri and Atieh, 2021 ; Sharma et al, 2021 ). The pharmacological classes of prokinetics include serotonin 5-HT4R agonists, 5-HT1AR agonists, ghrelin receptor agonists, dopamine-2 receptor antagonists, and muscarinic receptor antagonists.…”

Management of dysphagia and gastroparesis in Parkinson’s disease in real-world clinical practice – Balancing pharmacological and non-pharmacological approaches

“…Other compounds are also known to have prokinetic effects ( Ramprasad et al, 2018 ; Camilleri and Atieh, 2021 ). Erythromycin and azithromycin increase gastric antral contractions and enhance gastric emptying.…”