Dopamine Antagonists

Metoclopramide is both an antiemetic through centrally acting dopamine D2 receptor antagonist and 5-HT4 receptor agonist in the brain and prokinetic through 5-HT4 receptor agonist in the gut. Currently, metoclopramide remains the only FDA-approved medication for gastroparesis and is available in oral, oral dissolving tablet, liquid, intranasal, and parenteral formulations that may be administered intravenously, intramuscularly, or subcutaneously. However, its use is associated with significant extrapyramidal motor dysfunction including acute dystonias, Parkinson-type movements, and tardive dyskinesia [24, 25]. The tardive dyskinesia which occurs in <1% and is not always reversible has led to a FDA black box warning to limit its use to 12 weeks. Guidelines recommend starting at lowest effective dose (i.e., 5 mg TID before meals, maximum 40 mg/day) and dose reduction and/or drug holidays as able. Recently a nasally administered form of the agent was introduced and was similar in efficacy compared with the oral version of the drug [26]. In a post hoc analysis of a placebo-controlled trial in diabetic patients, gastroparesis-like symptoms showed marginal superiority over placebo. It should be noted that this finding was limited to female patients [27].

Motilin Agonists

After earlier descriptions about its effect on motilin receptors and the resulting changes in gastrointestinal motility [31], clinical studies first described the prokinetic effect of erythromycin in patients with diabetic gastroparesis nearly 30 years ago [32]. Subsequent studies confirmed the accelerated emptying, which seemed to decline over time but remained significant compared to baseline with an associated improvement of symptom scores [33]. However, the reported benefits of motilin agonists were transient, likely due to receptor desensitization, and the observed symptomatic improvements were not superior to placebo [34]. Subsequent development of other motilin agonists without antibiotic effects similarly showed no benefit over placebo [35, 36]. The originally described approach with intravenous administration of erythromycin is still used in clinical practice when significant gastric retention or even bezoar formation contribute to acute worsening of symptoms, which is a rare but frustrating scenario for patients and physicians alike. Erythromycin may be given at 3 mg/kg IV every 8 hours in the inpatient setting and 50–100 mg before meals in the outpatient setting. However, interactions with many commonly used medications and development of tachyphylaxis limit its role for the agent in the chronic management of gastroparesis. See Table 4.2.

Ghrelin Agonist

The discovery of ghrelin, a peptide hormone produced in the stomach and acting on the growth hormone secretagogue receptor, triggered significant interest as it stimulates appetite, food intake, and a positive energy balance; it also acutely accelerates gastric emptying through vagally mediated pathways [37]. Acute administration of the ghrelin agonist TZP-101 indeed accelerated gastric emptying and improved symptoms [38, 39]. However, a follow-up investigation with an oral agent did not show benefit over placebo at 12 weeks of treatment [10, 11]. Relamorelin , another ghrelin agonist with greater potency and stability, administered subcutaneously improved symptoms of gastroparesis and enhanced gastric emptying in two large randomized trials but worsened diabetic control in about 15% of the patients [9, 40]. Phase III studies are underway with relamorelin in diabetic gastroparesis. Considering the fact that ghrelin signals through vagal pathways and that we likely face a high prevalence of autonomic neuropathy in patients with diabetic gastroparesis, it is possible that ghrelin agonists will have additional beneficial effects in patient groups with other causes of impaired gastric function.

Serotonin

Considering the importance of serotonin (5-HT) in gastrointestinal signaling and function, agents targeting these receptors have been tried in gastroparesis and in functional dyspepsia. The most commonly used drugs block the 5-HT₃ receptor and play an important role as antiemetics. Their beneficial effect is likely due to a central effect on vagal pathways. In contrast, tegaserod and cisapride had agonistic properties on 5-HT₄ receptors and stimulated contractions, resulting in accelerated gastric emptying [41]. Clinical studies indeed confirmed increased antral contractility and enhanced gastric emptying, but inconsistent symptomatic benefit [42–44]. Concerns about serious adverse events with cardiac arrhythmias due to QT prolongation or myocardial infarctions prompted the withdrawal of these agents from the market though cisapride is available for compassionate use. Tegaserod was just reapproved by the FDA for the treatment of irritable bowel syndrome in females 65 years and younger without a history of ischemic CV disease. Finally, another oral 5-HT4 agonist prucalopride was also recently FDA-approved for chronic constipation and has been shown to improve symptoms and gastric emptying in patients with idiopathic gastroparesis in recent small pilot study [45].

The 5-HT_1a receptor agonist buspirone can mediate relaxation of the proximal stomach and thus enhances the accommodation after a meal. This property led to detailed mechanistic studies in patients with functional dyspepsia who often complain about significant postprandial fullness and discomfort. A small proof-of-concept study indeed confirmed the improved accommodation, which correlated with delayed emptying and decreased symptoms [46]. Buspirone use has not been formally studied in patients with gastroparesis, but may be useful in patients with postprandial fullness or bloating.