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.

Acid Reflux Diet

Typically it has been presumed that there are two mechanisms that provoke heartburn via food intake. First, some foods with a more acidic pH, such as citrus fruits, have been shown to directly irritate the lining of the esophagus and produce heartburn, and, second, some foods have
been shown to decrease the lower esophageal sphincter (LES) pressure, thereby predisposing to gastroesophageal (GE) reflux. Data with regard to the effect of a high fat meal are conlicting; however, there appears to be a consensus that chocolate does decrease the LES pressure.
Peppermint, garlic, and onions are food constituents that clinically appear to induce heartburn
in many patients. These compounds have a similar derivation and are often categorized as carminatives. In a clinical study to directly test one of these constituents (ie, raw onions), and its effect on postprandial reflux. In this study, individuals had to eat a hamburger with and without a large raw onion. In the onion condition it was shown that there was a significant postprandial increase in esophageal acid contact. Peppermint has also been shown to induce GE reflux, but this may be confounded by the fact that dissolving a peppermint may have the salubrious effect of enhancing salivation, which will facilitate acid clearance. Chewing gum may also induce increased salvation with similar effects on esophageal acid clearance.
Heartburn and esophageal irritation are common experiences in individuals with an acid sensitive esophagus who ingest citrus fruit juices. A recently published survey showed a significant correlation between the acidity of the citrus juices and heartburn score.
On this basis, it would seem reasonable to advise patients to avoid chocolate, citrus fruits, and fruit juices, as well as carminatives, such as onions and garlic.
Data with regard to high fat content on LES pressure are equivocal, but it would seem rational to advise individuals to avoid high fat foods, at least with regard to their effect on delayed gastric emptying and GE reflux.
Carbonation and caffeine.
There's no differences between carbonated water, caffeine-free Pepsi, or regular Pepsi, the LES changes are due to gas rather than caffeine level or pH. The difference between regular coffee and decaffeinated coffee, It has been found that decaffeinated coffee indeed did reduce the per-
cent of acid contact time in the esophagus.
Gastric Distention
An obvious and inexorable effect of eating is gastric distention. Because evidence is now clear that gastric distention does induce transient lower esophageal sphincter relaxations (TLESR), it would seem that food ingestion alone would predispose to reflux via the mechanism of TLESR. Again, although no randomized control trial exists to document the efficacy of this measure, it would seem prudent to advise patients to avoid large volume meals as well as carbonation.