Gastroparesis, metoclopramide, and tardive dyskinesia: Risk revisited

Abstract

Background Metoclopramide is primarily a dopamine receptor antagonist, with 5HT3 receptor antagonist and 5HT4 receptor agonist activity, and used as an antiemetic and gastroprokinetic since almost 50 years. Regulatory authorities issued restrictions and recommendations regarding long‐term use of the drug at oral doses exceeding 10 mg 3‐4 times daily because of the risk for development of tardive dyskinesia. The aim of our study was to review mechanism(s) of action and pharmacokinetic‐pharmacodynamic properties of metoclopramide, as well as the risk of metoclopramide‐induced tardive dyskinesia, factors that may change drug exposure in humans, and to summarize the clinical context for appropriate use of the drug. Methods A PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: drug‐drug interaction, gastroparesis, metoclopramide, natural history, pharmacokinetics, pharmacodynamics, drug‐drug interaction, outcome, risk factors, tardive dyskinesia. Key results Data show that the risk of tardive dyskinesia from metoclopramide is low, in the range of 0.1% per 1000 patient years. This is far below a previously estimated 1%‐10% risk suggested in treatment guidelines by regulatory authorities. High‐risk groups are elderly females, diabetics, patients with liver or kidney failure, and patients with concomitant antipsychotic drug therapy, which reduces the threshold for neurological complications. Conclusions & Inferences The risk of tardive dyskinesia due to metoclopramide is far below approximated numbers in treatment guidelines. This risk and the influence of known risk factors should be considered when starting a course of metoclopramide for treatment of gastroparesis.

Impaired Clearance From the Brain Increases the Brain Exposure to Metoclopramide in Elderly Subjects

“…Metoclopramide is considered a weak P‐gp substrate, which shows appreciable brain distribution despite being transported by P‐gp at the BBB 4 . This is supported by the occurrence of central nervous system (CNS) side effects associated with the use of metoclopramide (i.e., extrapyramidal movement disorders), which are mediated through antagonism at dopamine D 2 receptors in the basal ganglia 2 . The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) restricted the long‐term use of metoclopramide because of the risk for development of tardive dyskinesia, a potentially irreversible serious movement disorder 2 .…”

Drug-induced tardive dyskinesia

“…Гр у п п ы Л С , а с с о ц и и р о в а н н ы х с р а з в и т и е м Т Д Противорвотные средства. Наиболее часто ТД возникает на фоне применения метоклопрамида [24] [28,29] риск ТД составлял лишь 0,1% (на 1000 пациенто-лет). Авторы отмечают, что пожилые люди, пациенты, страдающие сахарным диабетом, болезнями печени и/или почек, а также одновременно с лечением основного заболевания получающие антипсихотики, относятся к группе высокого риска развития ТД.…”

Domination of Gastric Complications Among Diabetic Patients

“…Metoclopramide acts on several different receptors; primarily as a dopamine receptor antagonist, both peripherally improving gastric emptying, and centrally resulting in an anti-emetic effect [26,27] . Metoclopramide side effects, mostly related to its ability to cross the blood-brain barrier, include drowsiness, restlessness, hyperprolactinemia, and tardive dyskinesia (TD) (when taken more than 12 wk), a movement disorder that may be irreversible [28][29][30] . Other groups of medication, such as 5-HT3 receptor antagonists, phenothiazines, and muscarinic cholinergic receptor antagonist, have been used off-label for symptomatic relieve but they do not have effect of gastric motility.…”