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.

Prokinetic Medications

Some reports have shown that patients with acid reflux have abnormally high pyloric sphincter pressures. This has lead to the concept of “pyloric spasm” and the idea that therapies aimed at relaxing the pyloric sphincter could improve gastric emptying. Prokinetic Therapy which enhances forward gastrointestinal motility, have been proposed to address this particular pathophysiology.

Dopamine Antagonists
Metoclopramide (Reglan) is the most commonly used prokinetic drug and the agent that we employ as first line therapy. It is a central and peripheral dopamine receptor (D2) antagonist and a powerful antiemetic at the chemoreceptor trigger zone level while also being effective in improving gastric emptying by increasing antral contractions and decreasing receptive relaxation of the proximal stomach. However, as many as 40% of patients cannot tolerate metoclopramide because of central nervous system (CNS) side effects. If tolerated orally, the usual dose is 10 to 20 mg 30 minutes before meals and bedtime. One strategy for patients who do tolerate this agent orally is to also use it subcutaneously (sc) during periods of worse nausea or vomiting. Metoclopramide sc can be given by the patient (2 mL [10 mg] 2 or 3 times daily) with oral medication during and after hospitalizations while stepping down to oral therapy alone or as a bolus supplement at home to control intermittent breakthrough nausea. For patients that have intolerable side effects on metoclopromide or continued symptomatology, other agents can be used. We frequently substitute Domperidone (Motilium) for metoclopramide. It is a very effective dopamine2 antagonist, like metoclopramide, and shares its effect on upper gastrointestinal (GI) motility. It is a potent antiemetic at the chemoreceptor trigger zone but does not cross the bloodbrain barrier and, therefore, has no CNS side effects. Unfortunately, however, it is not available in the United States despite the fact that its effectiveness and safety have been established in clinical trials. Domperidone can be obtained from some compounding pharmacies in the United States and from pharmacies in other countries but is not usually covered by health insurance providers. Domperidone, at doses from 10 mg to 30 mg by mouth (po) 4 times daily (qid) (also given 30 minutes before meals and bedtime), has been shown to significantly reduce acid reflux symptoms, enhance quality of life, and accelerate gastric emptying of a solid meal. Domperidone does cause increased serum prolactin levels, and the most commonly reported side effects are gynecomastia in men and breast enlargement and lactation in women. These events occur in approximately 5% of treated patients.

Motilin Agonists
Erythromycin is a useful adjunctive therapy that can be added to metoclopramide or domperidone if symptoms persist despite maximal tolerated doses of these agents. It attaches to the motilin receptor and stimulates enteric contractility. It is not an antiemetic and concomitant agents to address nausea must also be initiated with this agent. Both intravenous and oral forms have been shown to improve gastric emptying rates, but this therapy can be complicated by cramping and abdominal pain. Low doses in a liquid (syrup) form are best to treat gastroparesis (eg, 125 mg 2 or 3 times daily). A potential concern with this agent is that it loses effectiveness over time due to down regulation of the motilin receptor.
GM611 (Mitemcinal, Chugai Pharmaceutical Company) is a macrolide that, like erythromycin, binds to the motilin receptor and stimulates enteric contractility, but does not have antimicrobial properties. It is currently in phase II trials and has been shown to increase gastric motility and gastric emptying.
Results of these treatment trials on acid reflux will be available in the near future.


5Hydroxytryptamine Agonists
Cisapride (Propulsid) is the original agent in this class and works by stimulating the stomach via 5hydroxytryptamine (5HT4) receptors. It is relatively free of CNS side effects and has been shown to improve gastric emptying of solids and liquids. Unfortunately, the unacceptably high rate of potentially fatal cardiac arrhythmias seen with this drug prompted the US Food and Drug Administration to restrict its use. Consequently, we rarely use this drug outside of special circumstances.
Mosapride (Takeda Pharmaceutical Company) is an investigational agent and is a 5HT4 agonist. It has been shown to have stimulatory effects throughout the human GI tract and has less potential for cardiac arrhythmia than its predecessor, Propulsid. It may become a useful agent in the treatment of gastroparetic patients and gastroesophageal reflux and these trials are currently being conducted.

Tegaserod (Zelnorm) (Novartis Pharmaceutical Company) is the most recently approved prokinetic agent. It has recently been FDA approved for treatment of women with constipation predominant irritable bowel syndrome (IBS). It is a partial and selective 5HT4 receptor agonist that possesses GI stimulatory effects from the esophagus to the rectum. Studies have shown
stimulatory motor effects throughout the digestive tract, and it has been shown to accelerate orocecal transit in patients with IBS. There are data showing improved gastric emptying times in patients with acid reflux and clinical trials in this subgroup of patients are ongoing. Dosing is recommended as 6 mg po twice daily but in our experience dosing up to 4 times daily is well tolerated without loose stools. This therapy is especially indicated for patients who complain of constipation in addition to their symptoms of gastroparesis. Tegaserod does not have antiemetic properties, and, therefore,would need to be given in combination with standard antiemetics.

Somatostatin (Octreotide) is used for patients with concomitant small bowel motility problems (eg, diarrhea and bacterial overgrowth). Somatostatin works by initiating a migration motor complex beginning in the small bowel, which agitates the gut, moving the bacteria further downstream and helps to sterilize the small intestine. It should be given as 50 to 100 microgram sc at night before bed. However,metronidazole or other antibiotics should be given during the day to further address bacterial overgrowth. Somatostatin actually inhibits gastric emptying and hence daytime use would require concomitant prokinetics and administration should not directly precede meals. It can be very effective for treating dumping syndrome when given preprandially in this specific clinical setting usually observed postvagotomy or gastric surgery.