What is the role of erythromycin derivatives as part of the medical treatment of esophagitis?
M. Delvaux (Toulouse)
Prokinetic agents have been considered for a while as a main part of the medical treatment of gastroesophageal reflux disease (GERD). Their beneficial action in patients with GERD includes an increase in the tone of the lower esophageal sphincter (LES) as well as a stimulatory effect on esophageal peristalsis and gastric motility and emptying .
Erythromycin and its derivatives, the motilides, mimic the effects of motilin on the motility of the gut, which are mainly comparable to those of prokinetics . Motilin has a wide variety of actions on the different segments of the gastrointestinal tract. Motilin plasma level raises during phases II and III of the gastrointestinal migrating motor complex (MMC) and it has been shown that this increase in plasmatic motilin is synchronous with phasic and tonic contractile activity of the LES [3, 4]. Moreover, the esophageal and gastric components of the MMC are absent in the absence of plasma motilin variations . In the opossum, the increase in LES pressure starts between 40 and 60% (phase II of the MMC), and continues till it is 95% and the development of phase III activity in the duodenum . In this study, exogenous motilin elicited a contractile response in the LES that mimicked the spontaneous phase III pattern of LES contractions. This effect of motilin was blocked by hexamethonium and partially inhibited by atropine, suggesting that motilin acts on the LES by the preganglionic stimulation of cholinergic nerves. In the dog, it was recently shown that motilin was responsible for type II (non-peristaltic) contractions of the esophagus that occur simultaneously with phase III of the MMC, in the interdigestive state . In man, motilin, administered intravenously, initiates a MMC and increases the LES pressure . On the contrary, no correlation was observed between plasma motilin levels and changes in esophageal motility induced by physical exercise .
Motilin seems thus to be involved in the control of the esophageal MMC, that is a component of the gastrointestinal MMC and is mainly characterized by an increase in tone or basal pressure of the LES. The effects of motilin on esophageal motility are less clear.
As motilin does, in man, erythromycin has been shown to increase LES pressure at the dose of 3.5 mg/kg orally, in the fed state [9, 10]. However, in both studies, erythromycin did not alter the LES relaxation, nor did it modify the peristalsis of the esophagus. The effect of erythromycin on the LES pressure is mediated through the activation of cholinergic nerves since in healthy volunteers, the effect of erythromycin on the LES was fully blocked by atropine . In this study, erythromycin also reduced the velocity of peristaltic waves in the esophagus but did not affect their amplitude. Up to now, no study has evaluated the effects of new motilides on the LES.
Considering the effects of motilin and erythromycin on LES function and the observation that LES pressure is frequently decreased in patients with GERD, it appears meaningful to evaluate the possible benefit of erythromycin or its derivatives as a treatment of reflux. Actually, very few studies have been published. In a manometric study, 10 patients with GERD were evaluated before and during an intravenous infusion of 500 mg erythromycin . In these patients who had a normal low LES basal pressure, erythromycin incresased it by 100%. It also increased the duration of the peristaltic waves in the esophagus without affecting their other characteristics. However, erythromycin has been disappointing in treating patients with GERD. In a study evaluating the effect of erythromycin on symptoms and pH metry recording, it failed to improve the score of symptoms and did not decrease the number of pathological reflux episodes .
Finally, erythromycin increases the tone of the LES but it seems not to improve GERD-related symptoms. Moreover, the pharmacokinetics of erythromycin preclude its use in daily practice, because of poor absorption by the oral route and the risk of tachyphylaxis, as shown for the treatment of gastric emptying disorders.
11. Chaussade S, Michopoulos S, Sogni P, Guerre J, Couturier D. Motilin agonist erythromycin increases human lower esophageal sphincter pressure by stimulation of cholinergic nerves. Dig Dis Sci 1994;39:381-384.
12. Pennathur A, Tran A, Cioppi M, Fayad J, Sieren GL, Little AG. Erythromycin strengthens the defective lower esophageal sphincter in patients with gastroesophageal reflux disease. Am J Surg 1994;167:169-173.