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Last up-date: April 13, 2010
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Last up-date: April 13, 2010
GPDA's web site has been
Thank you WEGO Health
Treatments for Gastroparesis, Functional Dyspepsia with Delayed Gastric Emptying, and Related Dysmotilities
Prokinetic drugs (Motility Rx)
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. Here is a list of the more common prokinetics in use for treating gastroparesis and related dysmotilities:
Cisapride (still available under compassionate-release programs)
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)
A historical perspective on cisapride
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. 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:
- 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.
Dopamine receptor drugs:
DOMPERIDONE (MOTILIUM®), METOCLOPROMIDE (REGLAN®/MAXERAN®), LEVOSULPIRIDE (LEVOBREN®, LEVOPRAID®), ITOPRIDE HYDROCHLORIDE (GANATON®)
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 (Reglan® US, Maxeran® Canada, Maxolon® GB)
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.
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.
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.
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®)
Cisapride has already been mentioned. It 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.
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.
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 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.
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.
The motilitde 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.
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.