Review article: An analysis of the pharmacological rationale for selecting drugs to inhibit vomiting or increase gastric emptying during treatment of gastroparesis

Abstract

Background: Drugs which can inhibit nausea/vomiting and/or increase gastric emptying are used to treat gastroparesis, mostly 'off-label'. Within each category, they act at different targets and modulate different physiological mechanisms.Aims: Address the questions: In gastroparesis, why should blocking one pathway causing vomiting, be more appropriate than another? Why might increasing gastric emptying via one mechanism be more appropriate than another? Methods: Drugs used clinically were identified via consensus opinions and reviews, excluding the poorly characterised. Their pharmacology was defined, mapped to mechanisms influencing vomiting and gastric emptying, and rationale developed for therapeutic use. Results:Vomiting: Rationale for 5-HT 3 , D 2 , H 1 or muscarinic antagonists, and mirtazapine, amitriptyline, nortriptyline, are poor. Arguments for inhibiting central consequences of vagal afferent transmission by NK 1 antagonism are complicated by doubts over effects on nausea. Gastric emptying: Confusion emerges because of side-effects of drugs increasing gastric emptying: Metoclopramide (5-HT 4 agonist, D 2 and 5-HT 3 antagonist; also blocks some emetic stimuli and causes tardive dyskinesia) and Erythromycin (high-efficacy motilin agonist, requiring low doses to minimise side-effects). Limited trials with selective 5-HT 4 agonists indicate variable efficacy.Conclusions: Several drug classes inhibiting vomiting have no scientific rationale. NK 1 antagonism has rationale but complicated by limited efficacy against nausea. Studies must resolve variable efficacy of selective 5-HT 4 agonists and apparent superiority over motilin agonists. Overall, lack of robust activity indicates a need for novel approaches targeting nausea (e.g., modulating gastric pacemaker or vagal activity, use of receptor agonists or new targets such as GDF15) and objective assessments of nausea.

An assessment of the effects of neurokinin1receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development

“…It is self‐evident that blockade of vagal afferent activation at a peripheral site or vagal afferent transmission to the mNTS would only contribute to the anti‐vomiting effects of NK 1 RAs when the primary stimulus activates the vagus (e.g., acute phase of CINV, possibly gastroparesis 163 ). Therefore, a vagal site of action would not account for block of stimuli acting only either via the AP or the vestibular system so additional site(s) of action need to be considered.…”

“…This question is relevant to both CINV and gastroparesis where abdominal vagal afferents are implicated in genesis of nausea and vomiting 8,163 . Regardless of whether NK 1 RAs reduce vagal afferent firing by acting peripherally (e.g., 153 ) or centrally (e.g., 160 ), the degree of activation, and the pattern, frequency and duration of abdominal vagal afferent activity required for induction of nausea as compared to vomiting is unknown.…”

“…The electroceutical approaches to treatment of gastrointestinal symptoms, including nausea, 197,198 may provide a route by which this system may be controlled but further study is needed to determine the pathways and cell types involved. A final approach is to target the abdominal vagal afferents at a peripheral site but this would only be applicable when a peripheral release of SP has been demonstrated and when the original signal originates from disordered upper digestive tract function (e.g., gastroparesis 163 ). Research into the development of anti‐nausea drugs is further hampered by the paucity of human volunteer studies using stimuli other than motion.…”

Domperidone vs Metoclopramide: Comparative Evaluation of Efficacy in Treating Diabetic Gastroparesis

“…Domperidone primarily acts as a dopamine receptor antagonist, exerting prokinetic effects by blocking inhibitory impulses in the gastrointestinal tract. In contrast, metoclopramide functions as a dopamine receptor antagonist and a serotonin receptor agonist with additional antiemetic properties (3). Various prokinetic agents, such as dopamine D2 antagonists like metoclopramide and domperidone, the cholinomimetic cisapride, and macrolide antibiotics like erythromycin, have been employed with varying success in diabetic gastroparesis (DG) treatment (4).…”

Editorial: empirical pharmacological management of gastroparesis—a cautionary tale

“…The insightful review by Sanger and Andrews 7 provides a clear rationale for the failure of prokinetic and conventional antiemetic therapy in the management of symptomatic gastroparesis. An unequivocal message is that therapy should ideally target the relevant underlying abnormalities, potentially addressing more than one pathway in the case of multiple dysfunctions.…”