Effect of Itopride on Esophageal Motility and Lower Esophageal Sphincter Function

Introduction

Itopride is an antagonist of dopamine D₂ receptors and an inhibitor of the enzyme acetylcholinesterase, thereby activating the release of acetylcholine and inhibiting its degradation. Previous studies focused on functional dyspeptic disorders of the upper type have demonstrated its effect on accelerating gastric evacuation. In patients suffering from gastroesophageal reflux disease (GERD), itopride has been shown to reduce esophageal exposure to acidic gastric juices through a not entirely understood mechanism.

The pathophysiology of GERD is multifactorial and includes several known mechanisms − one of the most important is transient relaxation of the lower esophageal sphincter triggered by the vagovagal reflex in response to stomach distension. Pharmacological inhibition of transient relaxation of the lower esophageal sphincter is one of the primary therapeutic goals in GERD. A clinical study on healthy individuals evaluated the effect of itopride on esophageal motility and lower esophageal sphincter function through esophageal manometry.

Study Methodology

A double-blind crossover study involved 12 healthy volunteers (5 men and 7 women with an average age of 32.6 ± 2 years and a BMI of 22.2 ± 0.9 kg/m²). None of the participants had symptoms or a positive history of upper gastrointestinal tract disorders. Participants were randomized to receive itopride at a dose of 50 mg/day, itopride at a dose of 100 mg/day, or placebo; according to the crossover design, all participants underwent all variants sequentially, with a minimum interval of 1 week between cycles.

After a 3-day premedication, participants underwent esophageal manometry and pH-metry following a 12-hour overnight fasting. After probe insertion, a 20-minute stabilization interval in a seated position was followed by the participants drinking 10 sips of water and then swallowing the assigned medication. After 60 minutes, they were given a standardized liquid meal in the form of a nutritional drink, followed by a 120-minute measurement interval. During the entire measurement, participants swallowed 10 sips of water every 30 minutes and evaluated gastrointestinal and overall symptoms on a visual analog scale every 15 minutes.

Results

At the beginning of the measurement, lower gastric pressure was observed in persons taking itopride compared to placebo, but other parameters were identical. No significant difference was observed between modalities in the tone of the lower esophageal sphincter, amplitude, and duration of esophageal peristaltic contractions, pH measured in the distal esophagus, or symptom assessment.

In subjects on itopride, a significant difference was observed in food-induced transient relaxations of the lower esophageal sphincter. With placebo, a significant increase in transient relaxation of the lower esophageal sphincter was observed 60 and 120 minutes after food intake (p < 0.001). In the 50 mg itopride group, there was no significant increase in relaxation for 60 minutes after food intake, and compared to placebo, this rate was significantly lower (p < 0.05). In the 100 mg itopride group, there was no significant increase observed at 60 or 120 minutes, and compared to placebo, the relaxation rate was significantly lower at both time intervals (p < 0.05).

Conclusion

The study results indicated that administration of itopride compared to placebo significantly reduces the incidence of transient relaxations of the lower esophageal sphincter without significantly differing effects on esophageal motility and postprandial lower esophageal sphincter pressure. This mechanism could explain the positive effect of itopride on gastroesophageal reflux symptoms. Postprandial pH values in the distal esophagus were not significantly affected by itopride compared to placebo, which may be because the study was conducted on healthy individuals without a history of GERD.

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Source: Scarpellini E., Vos R., Blondeau K. et al. The effects of itopride on oesophageal motility and lower oesophageal sphincter function in man. Aliment Pharmacol Ther 2011; 33 (1): 99–105, doi: 10.1111/j.1365-2036.2010.04487.x.