Understanding GP

Treatments for Gastroparesis, Functional Dyspepsia with Delayed Gastric Emptying, and Related Dysmotilities

Intro / Digestion / Who gets GP / What happens / Symptoms / Dx / Mild forms / Tx

Introduction / Motility Rx / Antidepressants / Other drugs / Novel Rx / Misc.

This page was completely updated for you in April 2010. Here you will find the most comprehensive compilation—taken from the published literature—of old, new, and scheduled-to-be-launched medical treatments for gastroparesis, functional (motility-like) dyspepsia and related dysmotilities.

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(Listing of references used for treatment section)
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Medical Therapies for Gastroparesis

It is most discouraging when your doctor tells you nothing more can be done to help quell your overwhelming digestive symptoms. Fortunately, that may not be the case.

GPDA will take you through a short lesson on pharmacology. A better understanding of your options helps to further discussions with your physician. This medical compendium and guide covers most existing medical treatments and those currently working their way through pre-marketing clinical trials. Have we missed anything? You can let us know via e-mail.

Right now, all drugs for the treatment of gastroparesis (except for metoclopramide, Reglan^®, Maxeran^® ) remain off-label. Therefore, insurance plans will not cover their costs.

Please note: While we cover and highlight particularly troublesome drug side effects in our drug discussion guide below, this is not to be taken as a comprehensive, in-depth tour though all the medication risks.

It is essential that you obtain drug monographs (manufacturer’s detailed product guides to their medications), that you talk to your pharmacist and finally, that you never take any medication without the knowledge of your treating physician. All medications possess the threat of serious and potentially fatal side effects.

General drug information:

In the past, researchers had searched for drugs to influence the emptying power of the stomach believing normalizing emptying would resolve digestive symptoms. This view was found to be overly simplistic and not necessarily helpful.

Further observations were made. For example, some individuals with delayed emptying of the stomach may regain normal emptying over time while persistent, intractable symptoms would remain. These individuals are labelled as dyspeptic.

Over the years, evidence has been sought to find newer paradigms to explain chronic and persistent upper digestive symptoms. Much work has been done studying the electrical physiology of the stomach with a focus on drugs that help to normalize the electrical generation and rhythm of the stomach and mid-gut. Such an approach, too, has proven elusive for nailing down effective symptom-management therapies.

Other therapeutic approaches have sought medical measures to relax the upper portion of the stomach (fundus), which would, thereby, enhance the ability to fill with food during a meal. The goal of such measures would be to achieve a more pleasurable meal experience through a reduction of feelings of fullness, heaviness, discomfort and pain often experienced by many who have dyspepsia/gastroparesis.

Other medical approaches have sought to find drugs that might relax sphincter muscles (circular muscles). A key sphincter muscle, called the pylorus, which lies at the base of the stomach, can spasm in some cases of gastroparesis. The spasm impedes food slurry from easily passing through the pylorus sphincter to the small intestine.

Finally, for more global symptom relief, the search now is focused towards neurotransmitting agents, bio-chemical catalysts (enzymes), ion channel mediators, and small proteins (called peptide hormones), all of which play their primary roles upon nerve functions within the gut (enteric nervous system), autonomic nervous system, or the central nervous system.

Quick pharmacy course

In general, drugs are biologically active chemicals, which work by either blocking the action of certain families of cell receptors or, by binding to receptors and triggering their cellular activity directly or indirectly. Examples of receptor families are the serotonin receptors and dopamine receptors. There are thousands upon thousands of different receptors in our bodies. Other methods used to manipulate the on/off triggering of a receptor include interfering with the action of a bio-chemical catalyst (enzymes). Enzymes are responsible for aiding in the construction or deconstruction of an active chemical, chemicals, which in this case, act upon cell receptors.

Cell receptors are biologically dynamic systems. When receptors are artificially interfered with by medications, they will change structure or attempt to build more receptor sites. It is their dynamic nature that poses problems with long-term medication use. Some drugs rapidly lose effectiveness due to the changing nature of the receptors. Doctors call this phenomenon tachyphylaxis. As an example, low dosages of erythromycin are used to treat gastroparesis. However, usually after six months, erythromycin no longer works as well for managing digestive symptoms of gastroparesis and the medical regimen must be changed.

No drug is site-specific for receptor action since the same family of receptors may be found in many different organs; also, the drug may act upon more than one receptor type. Older drugs tend to have a broader reactivity upon numerous receptor groups; think of the adage of using a cannon to kill a fly. Older drugs, then, tend to have numerous side effects.

So, if you take a drug for its beneficial action upon your gut, it may also be binding to receptors on your heart or brain, leading to unwanted effects.

With people suffering from more severe symptoms of gastroparesis, maximum drug dosages may be required for symptom management. Higher drug dosages may also increase side effects of the drug.

Drugs are usually categorized into families based upon the receptor types of their primary action. As an example metoclopramide (Reglan^®), a commonly used drug to treat gastroparesis) shares the same pharmacological family as domperidone (Motilum^®). Both act to block the action of dopamine in the gut (the D₂ receptors). Though the two drugs may share the same family as dopamine antagonists (blockers), they are subtly different in their affinity for the target receptors and the receptor’s sub-classes as well as in their ability to penetrate dopamine receptors within the brain.

While one drug in a pharmacological family may bind to 10% of the target receptors, another drug in the same family may bind to 100% of the receptors, making for a more robust drug response with differing effectiveness profile. Clearance of each drug from the body is also handled differently, making each drug’s safety profile within a pharmacological family very different too.

Doctors use the knowledge of drug receptor families when selecting combinations of medications to maximize effectiveness in symptom management. Combining drugs from different pharmacological families for symptom management leads to what is termed polypharmacy. Close medical supervision is essential since risk of more serious side effects may increase in polypharmacy.

In gastrointestinal medicine, concerns with polypharmacy often relate to cardiac toxicity. Many drugs hold the risk of side effects affecting heart-rhythm stability (cardiac toxicity). Combining two or more differing chemical families of drugs that possess varying degrees of cardiac toxicity may mean multiplying the risk of heart-rhythm disturbances. In the worst case, the result can be sudden death. The good news is that this dangerous risk can be mitigated by routine ECGs (electrocardiograms).

Key chemical receptor families, which have been utilized in the search to lessen various types of gastrointestinal symptoms, including gut pain, and/or improved gut transit, are:

~ serotonin receptors ~ acetylcholine receptors

~ nitric oxide receptors ~ cholecystokinin-A receptors

~ dopamine receptors ~ kappa-opioid receptors

~ sympathetic receptor types ~ motilide receptors ~ ghrelin receptors

The above list is not comprehensive, but the vast majority of GI motility drugs come from these pharmacological classes of agents.