What are the respective advantages of the different prokinetic agents at the disposal of the gastroenterologist?
D. Couturier (Paris)
Generally, prokinetic agents influence gastrointestinal motility through one or more of the following pathways:
- Promoting cholinergic tone;
- Antagonizing inhibitory neurotransmitters (e.g., serotonin, dopamine);
- Mimicking nonadrenergic noncholinergic compounds that increase motility (e.g., motilin) .
Direct cholinergic agonists
Bethanechol is an ester derivative of choline and acts at muscarinic receptors. It enhances the amplitude of contractions throughout the gastrointestinal tract and increases the lower esophageal sphincter (LES) pressure . Side effects from bethanechol have to be taken into account in the treatment of esophageal disease, mainly gastroesophageal reflux (GER). They result from secretion of saliva and gastric acid and from enhancement of parasympathetic tone causing abdominal cramps, diarrhea, salivation, flushing and bradycardia.
These drugs are derivatives of para-aminobenzoic acid. Metoclopramide and cisapride have been extensively evaluated.
Although the clinical benefits of metoclopramide (methoxy-2-chloro-5-procainamide) are restricted to the upper intestinal tract, experimental studies demonstrate a significant effect on intestinal smooth muscle. Metoclopramide has both peripheral and central dopamine receptor antagonist effects. The action on the gastrointestinal tract appears to be dependent on the release of acetylcholine from intrinsic cholinergic neurons: atropine antagonizes its effect on the LES. Vagotomy does not reduce the effect of metoclopramide. Metoclopramide has no effect on gastrin acid secretion and serum gastrin level. Metoclopramide's central antidopaminergic effects explain the effective antiemetic action, this benefit in counterpart by some extrapyramidal side effects (akathisia, dyskinesia), more common in children and the elderly.
This drug promotes gastrointestinal motility by indirectly stimulating cholinergic nerves. It causes the release of acetylcholine from enteric neurons, an effect that is antagonized by both tetrodotoxin and corticholinergics. Cisapride acts through several other pharmacological mechanisms whose effects are difficult to evaluate on the esophagus. In clinical trials, a transient increase in stool frequency was the only side effect, which does not limit the use in clinical practice.
Domperidone is a benzimidazole derivative that specifically antagonizes the inhibitory effects of dopamine, which seems to be an important inhibitory transmitter. It has no
cholinergic activity and is not inhibited by atropine. Domperidone has limited ability to cross the blood-brain barrier and therefore acts primarily as a peripheral antagonist. Thus, in contrast to metoclopramide, domperidone rarely causes dystonic or extrapyramidal symptoms and it may increase prolactin levels and occasionally female patients may develop galactorrhea.
Recent studies in humans, rabbits and dogs have demonstrated that erythromycin and certain other macrolides stimulate gastrointestinal contractions. The more specific action has been described on small bowel motility. It appears that erythromycin acts through motilin receptors and produces similar motor effects as motilin.
Although gastroesophageal reflux disease (GERD) is often considered a peptic ulcer disease, most of the factors that contribute to the development of reflux esophagitis depend on disorders of esophagus and gastric motility, which produce incompetent LES and impaired esophageal clearance. Incompetent LES may manifest as intermittent inappropriate relaxations or chronically low basal pressure. Effective clearance is dependent on orderly peristaltic contractions with appropriate velocity, duration and amplitude, whose decrease correlates best with delayed acid clearance . On the other hand, delayed gastric emptying also contributes to the risk of reflux.
In theory, prokinetic drugs should be the most recommended agents for the treatment of GERD and esophagitis .
Bethanechol increases sphincter pressure and esophageal contractions in a dose-dependent fashion. Some studies suggest that bethanechol reduces reflux symptoms and improves endoscopic findings [5,6]. The overall utility of bethanechol in the treatment of GERD is limited by side effects and concurrent stimulation of acid secretion. Side effects seen in about 15% of patients include abdominal cramps, blurred vision, fatigue and increased micturition.
Metoclopramide has been shown to be more effective than placebo in the treatment of the symptoms of GER [7,8], and as effective as are H2 antagonists and antiacids . A dose of 10 mg orally in an adult is insufficient to improve LES pressure consistently. Although metoclopramide provides symptomatic relief from acid reflux its effectiveness in healing esophagitis lesion is less convincing . The mechanism by which metoclopramide improves symptoms is mainly a dose-dependent increase in LES pressure . Sphincter pressure begins to rise within 20-30 min and peaks approximately 1 h after oral administration.
Cisapride improves both subjective and objective evidence of esophagitis and is at least as effective as either ranitidine or metoclopramide . It is also effective in reducing the duration of acid exposure . In a pediatric series, cisapride appears to be effective in improving endoscopic findings . Cisapride increases the LES pressure, the amplitude of contractions in the distal esophagus, and it enhances the rate of gastric emptying as well. The LES pressure increase is dose-dependent and occurs whether the drug is administered orally or intravenously [14,15].
Domperidone has been shown to be equivalent to ranitidine and superior to
placebo in reducing the symptoms of GER and in promoting endoscopic evidence of esophagitis . The effect of domperidone on the motor function of esophagus is inconsistent, and the benefit on esophageal function may be less than that seen with prokinetic agents.
Trials using erythromycin as treatment for gastroesophageal reflux have not yet been reported. Erythromycin significantly increases LES pressure and the duration of peristaltic contractions, acting by stimulation of cholinergic nerves . It has been shown to increase LES pressure in patients with esophageal involvement by systemic sclerosis .
Finally, among the available prokinetics drugs, the benefit from treatment with cisapride is well documented. Cisapride improves subjective symptoms as well as endoscopic evidence of mucosal inflammation. The indication of a treatment with metoclopramide is confined to the treatment of nonulcer dyspepsia with or without GER symptoms. Since direct cholinergic agonists increase gastric secretion which is implicated in the pathophysiology of esophagitis, although they have been shown efficient, their clinical use is limited.
Clinical trials, using erythromycin and other motilin-like agonists, are needed as treatment for GER.
12. Rode H, Stunden RJ, Millar AJW et al. Esophageal pH assessment of gastroesophageal reflux in 18 patients and the effects of two prokinetic agents: cisapride and metoclopramide. J Pediatr Surg 1987:22:931-934.
15. Smout AJPM, Bogaard JW, Grade AC. Effects of cisapride, a new gastrointestinal prokinetic substance on interdigestive and postprandial motor activity of the distal oesophagus in man. Gut 1985:16:246-251.
16. Masci E, Testoni PA, Pasaretti S et al. Comparison of ranitidine, domperidone maleate and ranitidine and domperidone maleate in the short-term treatment of reflux esophagitis. Drugs Exp Clin Res 1985;19:l-6.
17. Chaussade S, Michopoulos S, Guerre J, Couturier D. Erythromycin (ERY), a motilin agonist, increases the human lower esophageal sphincter pressure (LES) by stimulation of cholinergic nerves. Gastroenterology 1990:98:A335.
18. Chaussade S, Michopoulos S, Samama J et al. Erythromycin, a motilin agonist, increases the human lower esophageal sphincter pressure in patients with systemic sclerosis. Gastroenterology 1991;100:A428.