Role of prokinetics in acid reflux disease

The role of prokinetic drugs in adult acid reflux disease is probably less important than in the past, due to the development of potent and safe acid suppressors. Nevertheless, prokinetic agents are still prescribed in infants and children where clinicians are more reluctant to embark in long-term acid suppression. In the future, the development of new compounds (e.g. CCK1 antagonists or GABAb agonists) that are capable of inhibiting transient lower esophageal sphincter relaxations could represent a significant progress in a field of active pharmacological research and competition.

Several prokinetic agents have been used for the management of acid reflux disease. Examples of ancillary prokinetics include: 

Bethanechol, a cholinergic agent has been shown effective in reducing symptoms and lesions of esophagitis in both adults and children. However, it also stimulates gastric acid secretion and is responsible for several side-effects. Similarly, metoclopramide (a 5HT3-antagonist), although effective on refiux symptoms at relatively large doses (at least 40 mg/day) is frequently responsible for adverse effects such as drowsiness, bowel disturbance, dizziness or even severe extrapyramidal manifestations.

Domperidone is a more recently developed dopamine antagonist related to butyrophenones that has nearly the same pharmacodynamic actions as metoclopramide on esophageal and gastric motility.

Although domperidone does not cross the blood–brain barrier and seldom causes extrapyramidal effects, it may, however, produce symptoms related to hyperprolactinaemia (galactorrhoea, or amenorrhoea). Results similar to those obtained with metoclopramide would be expected in acid reflux disease, with domperidone being better tolerated. Although metoclopramide and domperidone are still used in indigestion and other gastrointestinal motility-related disorders, they have been virtually abandoned for the treatment of acid reflux disease since the development of cisapride.

Cisapride is a prokinetic drug without an antidopaminergic effect. It is an agonist of 5-HT4 receptors and releases acetylcholine in the myenteric plexus of the gut. Cisapride increases the amplitude of esophageal body contractions, increases lower esophageal sphincter pressure (especially in reflux patients with a low tone at baseline) and accelerates gastric emptying. Nevertheless, cisapride does not change the rate of transient lower esophageal sphincter relaxations.

Although cisapride has indirect cholinomimetic effects, it does not affect gastric acid secretion. Cisapride administration (10 or 20 mg, four times a day) enhances salivary secretion in asymptomatic volunteers. This effect may contribute to esophageal clearance and benefit patients with acid reflux disease.

The efficacy of cisapride has been established beyond doubt, both in adults and children. In the short term, cisapride (10 mg four times daily or 20 mg twice daily) is more effective than placebo and equally effective as H2-receptor antagonists for symptom relief and healing of esophagitis. Large placebo-controlled trials have shown that maintenance treatment with cisapride (10 or 20 mg twice daily or 20 mg nocte) significantly reduces the 6- and 12-month relapse rate of esophagitis. The therapeutic gain, however, is mainly limited to patients with mild or moderate esophagitis.

Cisapride is usually well-tolerated, the most frequent side effects being mild diarrhoea, abdominal pain and headache. However, exceptional but lethal cardiac complications (i.e. torsades de pointes) have recently been reported. This adverse effect may reduce the role of cisapride considerably in the treatment of acid reflux disease since safe, effective, well-tolerated drugs are now available. The clinician should also be aware of the interaction between cisapride and several other drugs, such as spiramycin and ketoconazole; their concurrent use is absolutely contraindicated. The production licence for cisapride has recently been withdrawn in several countries in Europe and the USA because of life-threatening cardiac side-effects.