Prokinetic Drugs

Gastrointestinal Prokinetic Drugs (Monogastric)

The enteric nervous system of the GI tract can function independently of the CNS to control bowel function. Because there are no nerve fibers that actually penetrate the intestinal epithelium, the enteric nervous system uses enteroendocrine cells such as the enterochromaffin cells as sensory transducers. More than 95% of the body's serotonin is located in the GI tract, and >90% of that store is in the enterochromaffin cells scattered in the enteric epithelium from the stomach to the colon. The remaining serotonin is located in the enteric nervous system, where 5-HT acts as a neurotransmitter. From the enterochromaffin cells, serotonin is secreted into the lamina propria in high concentrations, which overflow into the portal circulation and intestinal lumen. The effect of serotonin on intestinal activity is coordinated by 5-HT receptor subtypes. The 5-HT1P receptor initiates peristaltic and secretory reflexes, and so far no drugs have been developed to target this specific receptor. The 5-HT3 receptor activates extrinsic sensory nerves and is responsible for the sensation of nausea and induction of vomiting from visceral hypersensitivity. Therefore, specific 5-HT3 antagonists such as ondansetron and granisetron are very effective for treatment of vomiting seen with chemotherapy. Stimulation of the 5-HT4 receptor increases the presynaptic release of acetylcholine and calcitonin gene-related peptide, thereby enhancing neurotransmission. This enhancement promotes propulsive peristaltic and secretory reflexes. Specific 5-HT4 agonists such as cisapride enhance neurotransmission and depend on natural stimuli to evoke peristaltic and secretory reflexes. This makes these drugs very well tolerated, because they do not induce perpetual or excessive motility. It is also the reason for the limitations of these drugs, because they are not effective if enteric nerves have degenerated or become nonfunctional (as in cats with end-stage megacolon).

A gastroprokinetic agent, gastrokinetic, or prokinetic, is a type of drug which enhances gastrointestinal motility by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm. They are used to relieve gastrointestinal symptoms such as abdominal discomfort, bloating, constipation, heart burn, nausea, and vomiting. They are used to treat a number of gastrointestinal disorders, including irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.

Prokinetic (promotility) drugs, in the past, formed the mainstay of treatment for dysmotilities (chronic intestinal pseudo-obstruction, slow-transit constipation, and gastroparesis). As well, they historically formed the backbone of treatment for acid reflux (gastroesophageal reflux disease, or GERD) along with acid suppression medications. Promotility drugs are drugs that enhance the emptying of the stomach and/or gut and enhance the contractions/co-ordination of the gut.

            In a healthy human esophagus, swallowing induces primary peristalsis. This begins the process of moving food through the digestive tract. In turn, gastroesophageal reflux provokes a second wave of muscular contractions that clears the esophagus, pushing food down through the lower esophageal sphincter (LES) and into the stomach.

However, in some people, the LES either relaxes or opens spontaneously, allowing stomach contents—including acids—to re-enter the esophagus. This is called acid reflux and may lead to symptoms like heartburn.

            Prokinetic agents, or prokinetics, are medications that help control acid reflux. Prokinetics help strengthen the lower esophageal sphincter (LES) and cause the contents of the stomach to empty faster. This allows less time for acid reflux to occur.

            Today, prokinetics are typically used with other gastroesophageal reflux disease (GERD) or heartburn medications, such as proton pump inhibitors (PPIs) or H2 receptor blockers. Unlike these other acid reflux medications, which all generally are safe, prokinetics may have serious or even dangerous side effects. They’re often only used in the most serious cases of GERD.

            For example, prokinetics might be used to treat patients who also have insulin-dependent diabetes, or infants and children with significantly impaired bowel emptying or severe constipation that doesn’t respond to other treatments.  

            They are defined as drugs that initiate or enhance peristalsis and facilitate bolus transport. These drugs act primarily through enteric neurons since peristalsis is based on neural reflexes. They also improve sphincteric function by increasing its resting pressures. Drugs that act directly on the smooth muscle such as bethanechol (cholinergic agent) do not initiate peristalsis and may facilitate bolus transport by increasing the force or amplitude of existing peristaltic contractions. For unknown reasons their therapeutic effects appear to be more effective on the motility of the esophagus and stomach than in the small intestine and colon. These prokinetic drugs stimulate esophageal clearance and gastric emptying and increase resting lower esophageal sphincter pressures.

There are three types of prokinetic drugs available:

1) Dopamine antagonists such as metoclopramide and domperidone. They are classified as such because they block the effects of dopamine in the central nervous system and at the chemoreceptor zone. Because of this last action they are effective anti-emetics. They stimulate peristalsis by releasing acetylcholine since their actions are antagonized by atropine, a muscarinic blocker. About 20% of patients, however, treated with metoclopramide complain of adverse effects and therefore its use is confined to patients with hypomotility disorders associated with nausea.

2) The substituted benzamides such as cisapride and mosapride seem to release acetylcholine by acting on 5HT4 receptors. Their actions are also blocked by atropine. They are being used in the treatment of mild to moderate gastroesophageal reflux, gastroparesis and some forms of pseudo-obstruction. Adverse effects are mild and relatively infrequent.

3) Motilides such as erythromycin which enhance peristalsis by acting on motilin receptors or by releasing motilin. Their actions appear to be mediated by acetylcholine since they are also blocked by atropine.

Thus effective treatment of gastrointestinal hypomotility disorders with these drugs requires the presence of some degree of neural and muscle function. Prokinetic drugs increase the movement of ingested material through the GI tract. They are useful in the treatment of motility disorders, because they induce coordinated motility patterns. Unfortunately, some prokinetic drugs may produce a number of serious adverse effects that complicate their use.

Pharmacodynamics

            Activation of a wide range of serotonin receptors by serotonin itself or by certain prokinetic drugs results in enhanced gastrointestinal motility. Other prokinetic drugs may increase acetylcholine concentrations by stimulating the M₁ receptor which causes acetylcholine release, or by inhibiting the enzyme acetylcholinesterase which metabolizes acetylcholine. Higher acetylcholine levels increase gastrointestinal peristalsis and further increase pressure on the lower esophageal sphincter, thereby stimulating gastrointestinal motility, accelerating gastric emptying, and improving gastro-duodenal coordination.

            The 5-HT₄ receptor is thought to play a significant role in both the physiology and pathophysiology of GI tract motility. Therefore, 5-HT₄ receptors have been identified as potential therapeutic targets for diseases related to GI dysmotility such as chronic constipation. Some of these prokinetic agents, such as mosapride and cisapride, classic benzamides, have only moderate affinity for 5HT₄ receptors. In recent years, it has become clear that the selectivity profile is a major determinant of the risk-benefit profile of this class of agent. As such, the relatively poor selectivity profile of cisapride versus other receptors (especially hERG [human ether-a-go-go K⁺] channels) contributes to its potential to cause cardiac arrhythmias. Prucalopride, a first in class benzofuran, is a selective, high affinity serotonin (5-HT₄) receptor agonist that stimulates colonic mass movements, which provide the main propulsive force to defecation. SSRIs have been found to have prokinetic actions on the small intestine.

            Other molecules, including macrolides such as mitemcinal and erythromycin, have affinity for the motilin receptor where they act as agonists resulting in prokinetic properties.

            Symptomatic gastroesophageal reflux is a complex syndrome resulting from various defects. In some patients it may be a primary defect of the defense mechanisms of the mucosa, but it is more likely that primary motor disorders of the upper gastrointestinal tract are the main cause. Several motor defects are proposed to play a major role in the pathophysiology of reflux disease. The most important are:

1) mechanisms leading to frequent gastroesophageal reflux such as, a defective basal lower esophageal sphincter pressure (LESP), an increased frequency of transient lower esophageal sphincter relaxations (TLESR's) and delayed gastric emptying;

2) mechanisms leading to slow esophageal clearance due to esophageal body motor dysfunctions such as disrupted peristaltic contractions with low velocity, duration and amplitude.

            Recent excellent reviews give extensive information on gastrointestinal prokinetic agents. The purpose of this short communication is to summarize and update the latest results concerning the investigations on the mode of action of established and possible new esophagoprokinetic molecules in gastroesophageal reflux disease.

            The pharmacological substances which, theoretically, have the potential to correct the above-mentioned motor defects and which may be clinically effective in gastroesophageal reflux disease can be divided into four groups.

            1. The direct cholinergic agonist bethanechol increases LESP when given orally or subcutaneously. It also increases the amplitude and duration of the esophageal peristaltic contractions. A major disadvantage of bethanechol is that it increases antropyloroduodenal motility in a non-coordinated way. The consequence of this is that it has only little effect on gastric emptying in patients with gastroesophageal reflux disease. There are also conflicting studies on the possible beneficial effect of bethanechol by increasing salivary flow. Bethanechol increases parasympathetic tone which results in enhanced gastric secretion and side effects such as abdominal cramps, flushing, bradycardia, diarrhea and blurred vision.

            2. Antidopaminergics (metoclopramide, domperidone) increase LESP. Metoclopramide and domperidone have no convincing effects on esophageal peristalsis and also lack a marked effect on esophageal acid clearance. Domperidone improves gastric emptying of liquids and solids by an inhibition of adaptive fundic relaxation, an increase in antral contractility and an improved antroduodenal coordination. Metoclopramide has more convincing effects on gastric emptying but this is probably due to the fact that this drug not only has antidopaminergic properties but also possesses a 5-hydroxy-tryptamine₄ (5-HT₄ receptor agonist activity, as will be discussed below.

            3. Substituted benzamides (metoclopramide, cisapride, renzapride, zacopride) act in the gastrointestinal tract as agonists of the 5-HT₄ receptor. The enhanced cholinergic transmission which is induced by stimulation of this 5-HT₄ receptor is proposed to be responsible for the prokinetic effects of cisapride and other related benzamides. On circular muscular strips of the esophagus of the cat, contractile responses can be induced by electrical stimulation of cholinergic enteric neurons. These responses are enhanced by benzamides such as cisapride and metoclopramide and are mediated by 5-HT₄ receptors. Cisapride increases the LESP. Intravenous cisapride increases the amplitude of primary peristaltic contractions. Long-term effects of cisapride on esophageal peristalsis and LESP in patients with gastroesophageal reflux disease have not yet been published. Cisapride decreases the total time of esophageal acid exposure as measured by prolonged intraesophageal pH monitoring. Cisapride (and somewhat less noticeably metoclopramide) enhance antroduodenal coordination and gastric emptying of solid and liquid meals.

            4. Experimental molecules (macrolides, CCK antagonists, mixed µ/K opioid agonists) are currently under investigation. Although macrolides (erythromycin) primarily bind to motilin receptors located in the gastric antrum and proximal duodenum, preliminary studies indicate that erythromycin increases the LESP. It has no or only a small effect on esophageal peristalsis and it increases gastric emptying. Further studies, with modern gastrointestinal ambulatory motility techniques, are needed to assess the mode of action of macrolides in patients with gastroesophageal reflux disease with and without delayed gastric emptying. The CCK antagonist loxiglumide has no effect on basal LESP but it is able to counteract a high-fat-meal-induced decreased sphincter pressure. Furthermore, loxiglumide can only accelerate gastric emptying of a meal that releases endogenous CCK. This indicates that loxiglumide has no intrinsic effect on gastric emptying. More studies are needed to judge the possible role for CCK antagonists as esophagoprokinetics. Fedotozine, a new synthetic ligand with peripheral selective affinity for K opioid receptors, has no effect on basal LESP but it decreases the percentage and duration of LES relaxations and increases the duration, amplitude and velocity of peristaltic contractions.

Types of Prokinetics

Cholinergic agonists                           bethanechol                                     

Macrolides                                          erythromycin, erythromycin derivatives

Antidopaminergics                             metoclopramide, clebopride, domperidone

CCK antagonists                                  loxiglumide, devazepine        

Substituted benzamides                    metoclopramide, rensapride, zacopride, cisapride Mixed µ/K opiate agonists                       trimebutine, fedotozine

Here is a list of the more common prokinetics in use for treating gastroparesis and related dysmotilities:

• Cisapride (still available under compassionate-release programs)

• Domperidone (Motilium^®)
• Metoclopromide (Reglan^®, Maxeran^®)
• Levosulpiride (Levobren^®, Levopraid^®, available in Italy/Korea)
• Erythromycin (low dosages, not antibiotic dosing levels)
• Tegaserod (Zelnorm^®, Zelmac^®, now only available under special FDA protocols)
• Mosapride Citrate (Gasmotin^®, available in Asia, SE Asia, South America, and Japan)
• Itopride hydrochloride (Ganaton^®, available in Asia, SE Asia, and Japan)
• Renzapride (2008, a Phase III trial in USA has been completed)
• Pruclopride (Resolor^®, available in the UK and EU countries)

Dopamine receptor drugs

DOMPERIDONE (MOTILIUM^®), METOCLOPROMIDE (REGLAN^®/MAXERAN^®), LEVOSULPIRIDE (LEVOBREN^®, LEVOPRAID^®), ITOPRIDE HYDROCHLORIDE (GANATON^®)

General Information:

            These drugs, all in the same pharmacological family, currently provide the mainstay for the medical management of upper gut dysmotilities and are offshoots from psychiatric or psychotropic drugs (drugs used in the treatment of psychiatric disorders). They belong to a pharmacological class of drugs called the substitute benzamides, which hail from the phenothiazine psychotropic drug family.

            This broad category of drugs has been around for a long time. The phenothiazine drugs were brought into use for psychiatry in the late 1940s and early 1950s. The medical management of psychiatric patients really started to blossom in this era. Psychiatry finally had some medical tools to help these patients. It was soon realized that this category of drugs also had a wide application.

            They were very good anti-nauseants, probably due to their ability to suppress dopamine receptors in the brain. Some examples are promethazine (Phenergren^®) and prochlorperazine (Compazine^®). They also had some antihistamine and sedative action. Dopamine receptors are found in the brain as well as throughout the GI tract. Scientists believe that the patient feels the pro-motility action of these drugs, in part because of their ability to block dopamine receptors (D2) in the gut. Blocking dopamine can also have an effect on increased prolactin secretions.

            Contrary to popular belief, domperidone does cross the blood-brain barrier and is commonly used for its side effect of increasing prolactin levels in the breast-feeding mother to boost milk supplies for her baby. In non-breast-feeding women, galactorrhea, or milk leakage, may be a problem.

            The ability for domperidone, metoclopromide, itopride and levosulpiride to penetrate the brain varies but this variation illustrates why, for some individuals, very bothersome central nervous system side effects—depression, an overall feeling of restlessness, restless legs (akathisia), tremors and rigidity (Parkinsonism), insomnia and galactorrhea— may result.

            The problem of an acute onset of muscle twitchiness or a sense of restlessness is often reversible with a decrease in dosage or discontinuation of the medication, or it may be countered with the use of Benadryl. In more severe cases of nausea and vomiting, one may have to put up with these side effects for better symptom management and avoidance of constant hospitalizations from uncontrolled vomiting.

            However, one very serious side effect from the dopamine receptor blocking drugs is a central nervous system side effect called tardive dyskinesia (tardive meaning late onset, and dyskinesia meaning abnormal muscle movements). This more serious, potentially non-reversible side effect shows up after months or years of treatment. While theoretically all the dopamine receptor blocking drugs possess this risk, remember that each one is chemically different enough to change its affinity to domperidone receptor groups. In addition, the way they are processed in the body and their ability to penetrate brain tissue varies.

 Metoclopromide

            Metoclopromide was used in the early 1960s in Europe to help prevent vomiting in pregnancy¹². It was found to have a wide action of promotility on the entire gut, having the effect of coordinating gastric, plyoric, and small bowel motor functions¹².

            Approximately 60% of patients have minimal side effects and can tolerate this drug. Others have to discontinue this medication due to bothersome side effects such as fatigue or a feeling of agitation, and in rare cases, as already mentioned, abnormal muscle movements, or what is called tardive dyskinesia. Milder forms of movement problems can also occur. These can be moderated with the additional use of an antihistamine such as Benadryl^®. Metoclopromide can also be given subcutaneously (by injection), thus allowing for administration and good absorption helping to abort episodes of vomiting.

            Metoclopramide is a central dopaminergic antagonist and peripheral 5-HT3 receptor antagonist and 5-HT4 receptor agonist with GI and CNS effects. In the upper GI tract, metoclopramide increases both acetylcholine release from neurons and cholinergic receptor sensitivity to acetylcholine. Metoclopramide stimulates and coordinates esophageal, gastric, pyloric, and duodenal motor activity. It increases lower esophageal sphincter tone and stimulates gastric contractions, while relaxing the pylorus and duodenum. Inadequate cholinergic activity is incriminated in many GI motility disorders; therefore, metoclopramide should be most effective in diseases in which normal motility is diminished or impaired. Metoclopramide speeds gastric emptying of liquids but may slow the emptying of solids. It is effective in treating postoperative ileus in dogs, which is characterized by decreased GI myoelectric activity and motility. Metoclopramide has little or no effect on colonic motility.

            Metoclopramide is primarily indicated for relief of vomiting associated with chemotherapy in dogs, as an antiemetic for dogs with parvoviral enteritis, and for treatment of gastroesophageal reflux and postoperative ileus. GI obstruction, such as intussusception in puppies with parvoviral enteritis, must be excluded before initiating metoclopramide therapy. Its prokinetic action is negated by narcotic analgesics and anticholinergic drugs, such as atropine. Drugs that dissolve or are absorbed in the stomach, such as digoxin, may have reduced absorption. Bioavailability may be increased for drugs absorbed in the small intestine. Because of accelerated food absorption, metoclopramide therapy may increase the insulin dose required in diabetic patients.

            Metoclopramide readily crosses the blood-brain barrier, where dopamine antagonism at the CRTZ produces an antiemetic effect. However, dopamine antagonism in the striatum causes adverse effects known collectively as extrapyramidal signs, which include involuntary muscle spasms, motor restlessness, and inappropriate aggression. Concurrent use of phenothiazine and butyrophenone tranquilizers should be avoided, because they also have central antidopaminergic activity, which increases the potential for extrapyramidal reactions. If recognized in time, the extrapyramidal signs can be reversed by restoring an appropriate dopamine:acetylcholine balance with the anticholinergic action of an antihistamine, such as diphenhydramine hydrochloride given IV at a dosage of 1 mg/kg.

            Metoclopramide (brand name: Reglan) is a prokinetic agent that has been used to treat GERD by improving muscle action in the gastrointestinal tract. It’s available in both tablet and liquid forms. Like other prokinetics, metoclopramide's efficacy is hindered by serious side effects.

            Side effects may include an increased risk of neurological conditions, such as tardive dyskinesia in patients who remain on the drug for more than three months. People taking metoclopramide also should be extremely cautious while driving or operating heavy machinery or equipment.  

Alerts:
            Metoclopramide possesses the greatest risk for tardive dyskinesia (TD), a central nervous system side effect resulting in possibly irreversible involuntary muscle movement of the face, arms, legs, trunk or hands. It can cause ambulatory disability.

            Cases of metoclopramide-induced TD have been reported to the FDA. Children, too, can be affected. Those at greatest risk for TD are women, people over 65 years of age, those who have used the offending drug long term, and/or those who have taken high dosages of the drug.

            Metoclopramide-induced neuroleptic malignant syndrome, a syndrome trigged by an imbalance to the autonomic nervous system, which causes blood pressure instability, fever and a stuporous-like state, has been reported to the FDA. A mortality rate of 10% occurs with this syndrome. Immediate discontinuation of the medication can resolve the symptoms.

            Also note that many of the older anti-nauseant drugs from this same phenothiazine drug family—promethazine (Phenergren^®), prochlorperazine (Compazine^®), trifluoperazine HCL (Stelazine^®), chlorpromazine (Thoarzine^®) and others—also hold a risk for TD as well as cardiac toxicity with documented cases of sudden death. The safest drug from this group is promethazine while the worst offenders are Stelazine^® and Thorazine^®. Furthermore, if used in combination with a drug such as erythromycin, the risk of cardiac toxicity and sudden death is extremely high.

            Anyone taking dopamine receptor blocking medications needs close medical supervision.

            Anyone taking pheothiazine anti-nauseant medications should consider switching to a different pharmacological family of medications for nausea management.

Domperidone
            The prokinetic agent domperidone (brand names: Costi, Motilium, Motillium, and Motinorm), like cisapride, was developed by Janssen Pharmaceutica. Also like cisapride, it is unavailable in the United States. However, it’s still used in several other countries as treatment for acid reflux and GERD—especially in newborns and infants. With cisapride off the market, domperidone has become very popular with gastroenterologists (motility specialists) and patients. It has a much better safety profile than metoclopramide (Reglan^®) with no reported cases of TD or neuroleptic malignant syndrome. It has excellent anti-nauseant properties with only modest promotility action.

            Domperidone is a peripheral dopamine receptor antagonist that has been marketed outside the USA since 1978. It is available in Canada as a 10-mg tablet. Currently, it is available in the USA only as an investigational new drug (1% oral domperidone gel) to treat agalactia in mares due to fescue toxicosis. Domperidone regulates the motility of gastric and small-intestinal smooth muscle and has some effect on esophageal motility. It appears to have very little physiologic effect in the colon. It has antiemetic activity from dopaminergic blockade in the CRTZ. But because very little domperidone crosses the blood-brain barrier, reports of extrapyramidal reactions are rare; however, if a reaction occurs, the treatment is the same as for reactions to metoclopramide. Domperidone failed to enhance gastric emptying in healthy dogs in one study. In other studies, however, domperidone was superior to metoclopramide in stimulating antral contractions in dogs but not cats, and it improved antroduodenal coordination in dogs. Because of its favorable safety profile, domperidone appears to be an attractive alternative to metoclopramide.

            A 2009 study published in the Journal of Perinatology found that domperidone had "little effect on the central nervous system" of newborns. This makes it safer to use in children than other prokinetics. However, researchers concluded that, because of the adverse effects of other drugs, the effectiveness of domperidone in this age group is doubtful.

Levosulpiride
            Similar to Reglan^® in its medical profile, levosulpiride is not available in North America but is used in Italy and Korea, and is possibly available elsewhere in Europe and Asia. Research has been conducted on the comparison of levosulpiride vs. cisapride. In a double-blind crossover comparison of these two drugs, Mansi et al concluded: "The effectiveness of levosulpiride and cisapride in reducing gastric emptying times with no relevant side effects is similar. The impact of symptoms on patients' everyday activities and the improvement of some symptoms such as nausea, vomiting and early satiety (feeling of fullness after a few bites of food) was more evident with levosulpiride than [with] cisapride¹³." (Note: Levosulpiride, like cisapride, is not approved by Health Canada nor by the USA’s FDA). Another study showed that levosulpiride also improved the symptoms of gastroparesis in patients with diabetes¹⁴. Levosulpiride demonstrates an antiemetic/antinauseant effect too.

Itopride Hydrochloride (HCL).

            Developed by Hokuriku Seiyaku Co. and marketed in Japan in 1995, itopride HCL is an effective anti-nauseant and promotility drug. Attempts were made to bring itopride to the North American market by Axcan Pharma but failed to progress beyond a Phase III trial. The drug is marketed throughout Asia. It is very similar to domperidone and seems to be devoid of any cardiac toxic effects or unwanted central nervous system side effects.

            Itopride performs a similar action to cisapride by increasing acetylcholine (AChE) at nerve junctions. Acetylcholine is a critical chemical for nerve cell communications.

            Itopride has been studied for the symptom management of esophageal reflux symptoms, chronic gastritis, diabetic gastroparesis and functional dyspepsia. Its effectiveness is comparable to domperidone and considered to have an even better safety profile.

Gut peripheral serotonin receptors active medications:

TEGASEROD (ZELNORM^®, ZELMAC^®), PRUCALOPRIDE (RESOLOR^®), RENZAPRIDE (^®) MOSAPRIDE CITRATE (GASMOTIN^®)

A historical perspective on cisapride

            Cisapride (brand names: Prepulsid and Propulsid) was discovered by Janssen Pharmaceutica in 1980. Cisapride acts on serotonin receptors in the stomach and was primarily used to improve muscle tone in the LES. Prior to being pulled from the worldwide market, cisapride was the most prescribed promotility agent used for GERD, chronic intestinal pseudo-obstruction, slow-transit constipation and gastroparesis. Cisapride was once considered as effective in treating GERD as H2 receptor blockers such as famotidine (Pepcid, Pepcid AC) and ranitidine (Zantac). However, due to side effects such as irregular heartbeat, it has been removed from the market in several countries, including the United States. Cisapride is still often used in veterinary medicine. Volumes of published evidence helped to establish it as a first-line treatment choice for these disorders. The good news: it is still readily available in many countries through special-access programs.

            Cisapride was brought to the market by Janssen Pharmaceutica originally to treat severe nocturnal gastroesophageal reflux disease (GERD). When it was released in the 1980s, it was quickly recognized to have a broad range of pro-motility effects on various segments of the GI tract. This was welcome news for people suffering with severe gut dysmotilities.

Published research studies showed that cisapride:

• is a serotonin-active agent
• enhanced antroduodenal coordination and gastric emptying
• stimulated propulsive motility patterns in the human jejunum.
• accelerated intestinal transit.
• increased lower esophageal sphincter pressure.

            Many studies showed that it was a good drug if used with appropriate patient selection, keeping in mind risk factors. Cisapride soon became a first-line medical treatment option for patients with upper motility disorders.

            In June 1998, Janssen announced the relabelling of cisapride to reflect increased warnings regarding the association between use of the drug and adverse cardiac events.

            In response to this relabelling, the NASPGAN (professional society for pediatric gastroenterologists) came out with the position statement, "Use of Cisapride in Children."

            The NASPGAN group put together a committee of experts to review the literature on the safety and effectiveness of cisapride. They concluded that cisapride still had a role with a select group of GI pediatric patients, with illnesses such as:
 - gastroparesis

 - pseudo-obstruction

 - reflux disease with failure to thrive (children who are not growing),
and other GI problems outlined in their report. Their recommendations (to the pediatric doctors) to decrease adverse cardiac risks were:

• to perform electrocardiograms on selected patients
• the temporary discontinuation of cisapride during acute illnesses such as vomiting and/or diarrhea that might result in electrolyte imbalances (potassium, magnesium, calcium)
• to recognize that abnormalities in serum potassium, magnesium, and calcium can increase the risk of abnormal heart rhythms—presumably more so in the presence of cisapride
• to screen for liver and renal functions when appropriate
• to educate families, doctors and pharmacists, as to which drugs cisapride should not be used with
• to limit dosage range to 0.8 mg per kilogram of child's weight per day divided into three to four doses in 24 hours.

            Some of the medications cisapride should NOT be taken with are erythromycin, clarithromycin and the azole antifungal drugs and grapefruit juice. (Note: this is not a comprehensive list).

            Cisapride was voluntarily pulled from the market by Janssen Pharmaceutica in July 2000 (in the United States) due to the risk of rare but serious cardiac events, which in some cases led to deaths. A significant proportion of these reported cases had other known risk factors. In less than one percent of the cases, the events occurred in the absence of risk factors.

            Cisapride remains available under restricted access programs. It is very easily obtained by Canadians and remains an excellent option in more severe forms of gastrointestinal dysmotilities.           

            Cisapride is chemically related to metoclopramide, but unlike metoclopramide, it does not cross the blood-brain barrier or have antidopaminergic effects. Therefore, it does not have antiemetic action or cause extrapyramidal effects (extreme CNS stimulation). Cisapride is a serotonin 5-HT4 agonist with some 5-HT3 antagonist activity, so it enhances the release of acetylcholine from postganglionic nerve endings of the myenteric plexus and antagonizes the inhibitory action of serotonin (5-HT3) on the myenteric plexus, resulting in increased GI motility and increased heart rate. Cisapride is more potent and has broader prokinetic activity than metoclopramide, increasing the motility of the colon, as well as that of the esophagus, stomach, and small intestine. Cisapride is especially useful in animals that experience neurologic effects from metoclopramide. Cisapride is very useful in managing gastric stasis, idiopathic constipation, and postoperative ileus in dogs and cats. Cisapride may be especially useful in managing chronic constipation in cats with megacolon; in many cases, it alleviates or delays the need for subtotal colectomy. Cisapride is also useful in managing cats with hairball problems and in dogs with idiopathic megaesophagus that continue to regurgitate frequently despite a carefully managed, elevated feeding program. In comparative studies of GI motility in people and animals, cisapride is clearly superior to other treatments.

            Initially, the only adverse effects reported in people were increased defecation, headache, abdominal pain, and cramping and flatulence; cisapride appeared to be well tolerated in animals. As cisapride became widely used in management of gastroesophageal reflux in people, cases of heart rhythm disorders and deaths were reported to the FDA. These cardiac problems in people were highly associated with concurrent drug therapy or specific underlying conditions. In veterinary medicine, adverse reactions to clinical use of cisapride have not been reported. Cisapride for animals can only be obtained through compounding veterinary pharmacies.

            Cisapride was a novel chemical when originally developed and help to stimulate the search for more and safer formulations. The serotonin receptor family produces diverse, wide-ranging effects on: gut-motor action, secretion and sensation making for a tantalizing array of chemical targets. The gut and the brain are richly embedded with serotonin receptors. Each of the drugs listed here have different actions and different subsets of serotonin receptors, which they act upon. Many are used for treating the colon as in irritable bowel syndrome or constipation but many also act favorably upon upper gut function, sensation and motility.

Mosapride Citrate (Gasmotin^®),

            In October 1998, Dainippon Pharmaceutical Co. Ltd. launched mosapride citrate for the treatment of dyspeptic symptoms associated with chronic gastritis.

            Mosapride binds to the same class of serotonin receptors as cisapride. However, it differs chemically enough from cisapride as to show no statistically significant impact upon cardiac function when studied. It is however, broken down by the same enzymatic pathway as cisapride (cytochrome P450 Enzyme pathway), therefore avoidance of other medications and foods (grapefruit juice/red wine) which may bind or inhibit this pathway (a partial list was provided above under cisapride) needs to be avoided.).

            In 2006, a large Japanese multi-centre clinical trial using mosapride in the treatment of functional dyspepsia was published. Mosapride demonstrated effectiveness, substantially reducing the feelings of abdominal discomfort and fullness.

            Other studies have shown that mosapride does accelerate gastric emptying while also improving small bowel and colon transit. Mosapride has been studied in the treatment of constipation in people with Parkinson’s disease. Like cisapride, mosapride shows promotility action throughout the whole GI tract.

            Mosapride has an excellent safety profile when compared to all current and past serotonin- active promotility drugs.

Prucalopride (Resolor^®)

            Resolor in now available and on the market in the UK and EU countires for the treatment of chronic constipation. It is doubtful it will come to the North American market due to reports of carcinogenic problems, which have shown up in the obligatory chronic (long-term) studies conducted in animals. These animal studies are part of the data that must be prepared for regulatory pre-market submissions.

            Prucalopride binds to similar receptors as cisapride, but not as strongly; therefore, it may not be expected to have a strong upper-gut motility-enhancing action. However, it shows excellent promise for relieving slow-transit constipation.

Renzapride

            Renzapride is a novel new prokinetic agent currently progressing through clinical trials in Europe and the United States. The first Phase IIB trial has been completed with a second Phase III trial to begin enrolling in early 2008. As of early 2010, this Phase III trial has concluded. Renzapride is developed for the treatment of constipated-predominate IBS and mixed IBS (constipation alternating with diarrhea).

            A published report using renzapride in the symptomatic relief of diabetic gastroparesis showed very promising results. Furthermore, renzapride may also have an anti-nauseant effect due to its ability to block 5HT₃ serotonin receptors. This is a drug to watch.

Tegaserod (Zelnorm^®, Zelmac^®)

            In July, 2002, Novartis received approval to market tegaserod to women with irritable bowel syndrome.

            Further studies of tegaserod showed it accelerated stomach emptying and transit through the small bowel. It also decreased gut sensitivity helping to diminish abdominal discomfort. Gastroenterologists then began using tegaserod for the treatment of gastroparesis and chronic intestinal pseudo-obstruction. As well, Novartis was able to demonstrate effective treatment of slow-transit constipation with tegaserod and subsequently received marketing approval for the new application.

            In April 2004, the FDA issued a warning related to reports of severe side effects associated with tegaserod. These side effects included severe diarrhea needing IV fluid replacement, low blood pressure with episodes of passing out, and ischemic colitis (restricted blood flow to the large bowel, which in severe cases, requires surgical removal of the bowel).

            By March 2007, the FDA asked Novartis to stop marketing tegaserod. The results of an FDA re-analysis of clinical trial data on tegaserod showed a slight, but definite, increased risk of angina, heart attacks, and strokes.

            In the United States, tegasarod has been brought back to the market under a restricted-release program. Currently, there is no access for Canadians.

            For some patients, tegaserod was highly effective in the treatment of slow-transit constipation. Without tegaserod, unmanageable constipation would require surgical removal of the colon for some patients.

The motilide receptor drugs, ERYTHROMYCIN

            First developed in the 1950s, erythromycin was not used in gastroenterology until some decades later¹⁶. Numerous studies have proven that this antibiotic is highly effective at producing peristaltic contractions in the stomach antrum¹⁷. This effect is gained at very low doses (lower doses than those needed for an antibiotic effect)¹⁷. In reality, it produces a dumping syndrome in the stomach (emptying too rapidly). This might explain why individuals that need to use this drug for its antibiotic effect have a good number of side effects such as nausea and abdominal cramping. This particular prokinetic is frequently used in pre-term infants who have delayed gastric emptying.

 Alert:

            Erythromycin, when used at antibiotic dosage levels, has numerous documented cases of sudden death due to cardiac toxicity. The risk of this occurrence is greatly increased when erythromycin is taken with other drugs that also have a propensity for cardiac toxicity. Risk is also dose-related. Fortunately, when used for treating gastroparesis, erythromycin dosages are very small. However, many of the anti-nauseant drugs used by gastroparetic patients have a similar risk profile for cardiac toxicity as erythromycin. If you are advised to take erythromycin, insist upon a baseline ECG and follow-up ECGs at 3 months, then at 6-month intervals, even if you have to pay for your own ECG—they are not that expensive.

            Macrolide antibiotics, including erythromycin and clarithromycin, are motilin receptor agonists. They also appear to stimulate cholinergic and noncholinergic neuronal pathways to stimulate motility. At microbially ineffective doses, some macrolide antibiotics stimulate migrating motility complexes and antegrade peristalsis in the proximal GI tract. Erythromycin has been effective in the treatment of gastroparesis in human patients in whom metoclopramide or domperidone was ineffective. Erythromycin increases the gastric emptying rate in healthy dogs, but large food chunks may enter the small intestine and be inadequately digested. Erythromycin induces contractions from the stomach to the terminal ileum and proximal colon, but the colon contractions do not appear to result in propulsive motility. Therefore, erythromycin is unlikely to benefit patients with colonic motility disorders.

Human pharmacokinetic studies indicate that erythromycin suspension is the ideal dosage form for administration of erythromycin as a prokinetic agent. Other macrolide antibiotics have prokinetic activity with fewer adverse effects than erythromycin and may be suitable for use in small animals. Both erythromycin and clarithromycin are metabolized by the hepatic cytochrome P450 enzyme system and inhibit the hepatic metabolism of other drugs, including theophylline, cyclosporine, and cisapride. Nonantibiotic derivatives of erythromycin are being developed as prokinetic agents.

            Ranitidine and nizatidine are histamine H₂-receptor antagonists that are prokinetics in addition to inhibiting gastric acid secretion in dogs and rats. Their prokinetic activity is due to acetylcholinesterase inhibition, with the greatest activity in the proximal GI tract. Cimetidine and famotidine are not acetylcholinesterase inhibitors and do not have prokinetic effects. Ranitidine and nizatidine stimulate GI motility by increasing the amount of acetylcholinesterase available to bind smooth muscle muscarinic cholinergic receptors. They also stimulate colonic smooth muscle contraction in cats through a cholinergic mechanism.

            Ranitidine causes less interference with cytochrome P450 metabolism of other drugs than does cimetidine, and nizatidine does not affect hepatic microsomal enzyme activity, so both drugs have a wide margin of safety.

            IV lidocaine is used in the treatment of postoperative ileus in people and has been shown to be useful in treating ileus and proximal duodenitis-jejunitis in horses. It is thought to suppress firing of primary afferent neurons, as well as to have anti-inflammatory properties and direct stimulatory effects on smooth muscle. It is also thought to suppress the primary afferent neurons from firing, as well as have anti-inflammatory properties and direct stimulatory effects on smooth muscle. Most horses respond within 12 hr of starting an infusion.

Bethanechol

            Bethanechol (brand name: Urecholine) is a parasympathomimetic choline carbamate available in tablet form. It helps to strengthen the LES and make the stomach empty faster. It also helps prevent nausea and vomiting.

            However, its usefulness may be outweighed by frequent side effects. Side effects can include anxiety, depression, drowsiness, fatigue, and physical problems such as involuntary movements and muscle spasms.  

Prokinetic Drugs
Drug	Dosage
Metoclopramide	Dogs and cats: 0.2–0.5 mg/kg, PO or SC, tid; 0.01–0.02 mg/kg/hr, IV infusion
	Horses: 0.125–0.25 mg/kg, diluted in 500 mL of polyionic solution and administered IV over 60 min
Domperidone	0.1–0.5 mg/kg, IM; 0.5–1 mg/kg, PO
Cisapride	Dogs: 0.1 mg/kg, PO, tid
	Cats: 2.5 mg/cat, tid for cats <5 kg, and 5 mg/cat for cats >5 kg
Erythromycin	0.5–1 mg/kg, PO, bid-tid
Ranitidine	1–2 mg/kg, PO, bid
Nitazidine	2.5–5 mg/kg, PO, bid
Lidocaine	Horses: 1.3 mg/kg, IV, as a bolus followed by a continuous infusion of 0.05 mg/kg/min

Research

            Animal research has found that supplementation with the probiotics lactobacillus rhamnosus and bifidobacterium lactis enhances the speed and strength of phase III of the migrating motor complex in the small intestine resulting in reduced small intestinal bacterial overgrowth and bacterial translocation.

            Research in rats has found that supplementation with lactobacillus acidophilus and bifidobacterium bifidum increases small intestinal motility with a measurable decrease in the duration of migrating motor complex cycles. A further study found that in rats supplemented with a diet of lactobacillus rhamnosus and bifidobacterium lactis, the number and velocity of phase iii of the migrating motor complex increased. These effects make the small intestine more effective at propelling food, bacteria and luminal secretions into the colon.^[10] Bifidobacterium bifidum in combination with lactobacillus acidophilus accelerated small intestine transit in rats.

            Research into the prokinetic effects of probiotics on the gastrointestinal tract has also been conducted in humans. Lactobacillus reuteri in infants and lactobacillus casei and bifidobacterium breve in children have been found to be effective in the treatment of constipation. Lactobacillus plantarum, in adults has been found to increase defecation frequency.

            Possible future prokinetics compounds aimed to interfere with nonadrenergic noncholinergic (NANC)-mediated LES-relaxations and esophageal peristalsis.

            Of all the drugs mentioned above, it is clear that cisapride has the most convincing prokinetic effects on esophageal motility and gastric emptying. However, no data are available yet on the effect of these drugs on TLESRs. These studies are urgently

needed because abnormally frequent TLESRs are probably the most important mechanism of gastroesophageal reflux.

            An interesting new area for future research concerning the sensible or sensitized gut is opened with the development of fedotozine. Fedotozine increases the threshold of discomfort to gastric distention. It has been suggested that the peripheral opioid system is involved in the initiation and/or the afferent pathway of gastric visceral sensitivity. It would be very interesting to study fedotozine in the sensitized or "irritable" esophagus. The discovery of nitric oxide (NO) as an important neurotransmitter of nonadrenergic-noncholinergic (NANC) nerves in the enteric nervous system has opened doors to a new area of research.

            Pharmacological stimulation or inhibition of NANC-excitation or inhibition, or interference with afferent sensory nerves or mechanisms of sensitization will hopefully lead to new therapeutic possibilities in gastroesophageal reflux disease.

Conclusions

            Prokinetic drugs which may have beneficial effects in gastroesophageal reflux disease can be divided into four groups:

1) Direct cholinergic agents (bethanechol). Various unwanted effects, such as stimulation of uncoordinated gastroduodenal motility and stimulation of gastric acid secretion, limit their use in clinical practice;

2) Antidopaminergics (metoclopramide, domperidone). These drugs only moderately increase lower esophageal sphincter pressure and enhance gastric emptying;

3) Substituted benzamides (metoclopramide, cisapride) increase motility through an indirect potentiation of cholinergic neurotransmission by excitation of presynaptic 5HT₄ receptors. They increase lower esophageal sphincter pressure, stimulate the amplitude of peristaltic contractions and enhance gastric emptying rate. Furthermore, cisapride is effective in reducing the duration of esophageal acid exposure in 24-h pH monitoring. Cisapride has fewer side effects than metoclopramide.

4) Experimental molecules (macrolides, CCK antagonists and mixed u- and K-opioid agonists) are currently under investigation. These drugs directly increase the lower esophageal sphincter pressure (erythromycin and fedotozine) or counteract meal-induced decreased sphincter pressures (CCK antagonists). Gastric emptying is enhanced directly by macrolides. CCK antagonists only increase emptying of a meal that stimulates sufficiently CCK plasma levels.

Examples

• Benzamide
• Cisapride
• Domperidone
• Erythromycin
• Itopride
• Mosapride
• Metoclopramide
• Mirtazapine
• Prucalopride
• Renzapride
• Tegaserod
• Mitemcinal
• levosulpiride
• Cinitapride