**5.1 Metoclopramide**

The most commonly used prokinetic agent, metoclopramide, can be used to treat gastrointestinal motility disorders [40, 41]. Not only is metoclopramide a central dopamine D2 receptor antagonist, but the medication also blocks the dopamine D2 receptor in peripheral nerve endings and promotes the release of acetylcholine. This leads to increasing gastrointestinal motility, gastric emptying, and LES tone [40, 41].

Metoclopramide comes in oral and parenteral formulations for GERD use, with the dosing frequency summarized in **Table 4**. The onset of action for the oral formulation is 30–60 minutes, 1–3 minutes for intravenous, and 10–15 minutes for intramuscular injections [42, 43]. All formulations have a 1–2 hour duration with rapid


### **Table 4.**

*Dosing and duration of metoclopramide [42–44].*

absorption [42, 43]. It is hepatically metabolized through oxidation, glucuronide, and sulfate conjugation [42, 43]. This results in the formation of monomethyl metoclopramide, which is an oxidative metabolite formed through CYP2D6 [42, 43].

Metoclopramide use is limited due to the central nervous system side effects such as agitation, irritability, depression, drowsiness, dystonic reactions, and tardive dyskinesia [45]. The most common side effects reported are dysgeusia, fatigue, restlessness, and drowsiness in more than 10% of patients taking metoclopramide. Severe side effects that may occur with metoclopramide are visual impairment, tardive dyskinesia, suicidal ideation, serotonin syndrome, seizures, porphyria, angioedema, and agranulocytosis [42, 43].

Metoclopramide should not be administered with atypical antipsychotics due to the increased risk of tardive dyskinesia, other extrapyramidal symptoms, and neuroleptic malignant syndrome [42, 43]. If atypical antipsychotics have to be used with this medication, patients must be monitored closely for movement disorders and CNS effects [42, 43]. Atypical antipsychotics should be discontinued upon first signs of dyskinesia [42, 43]. Due to the increased risk of tardive dyskinesia, treatment is not recommended beyond 12 weeks with metoclopramide use [44]. Populations with characteristics such as diabetes, geriatric, female, renal dysfunction, pediatric, or more than 12 weeks of metoclopramide use have all been associated with an increased risk of tardive dyskinesia and symptoms are often irreversible [42–44].

According to guidelines for the management of GERD, metoclopramide does not have a role in therapy unless gastroparesis is present [4]. Metoclopramide monotherapy is generally considered in patients refractory to conventional, acid-suppressive therapy [4]. Although PPIs are regarded as first-line, using a PPI alone is insufficient in approximately 30% of GERD patients [46, 47]. Prokinetic drugs have been used in clinical settings as a second-line option despite the fact that their benefits for GERD management are not well established [46, 47].

Although insufficient evidence is available regarding combination therapy with PPIs, the evidence for metoclopramide and H2RA combination therapy use did not show a clear benefit compared to monotherapy [4].
