Prokinetic Agents

prokinetic agents

Prokinetics help with the movement of the gut, also known as gastrointestinal motility.

In people with digestive disorders such as IBS, SIBO, gastroparesis, or any other digestive issue where there is an alteration of the way the gut functions, prokinetic drugs can be an effective solution to help restore this movement in order to prevent these digestive issues from happening.

In this article, we will walk you through the basics of GI motility, what the migrating motor complex is and why it’s important, the different pharmaceutical and natural prokinetic agents, and how this relates to SIBO and IBS.

This topic is one of the most important topics for people dealing with SIBO or IBS but it doesn’t get as much attention as it should. It is super important because altered motility can be one of the main underlying causes, and proper gut motility is vital for prevention.

Why is Gastrointestinal Motility Important?

GI motility is defined as the movements of the muscles of the organs of the digestive system including the esophagus, stomach, small and large intestines that allow for the contents within these organs to move through each stage of digestion 1.

When the nerves and/or muscles of these organs do not function properly, people can suffer from common symptoms associated with impaired GI motility 1.

These symptoms include:

  • Severe constipation
  • Acid reflux disease
  • Recurrent vomiting
  • Recurrent obstructions
  • Bloating

Below are the GI disorders that are associated with motility issues occurring in the specified organs 2.

 Area of Intestine  Issues That Occur
Esophagus
  • Gastroesophageal Reflux Disease (GERD)
  • Dysphagia
  • Achalasia
  • Functional Chest Pain
Stomach
  • Gastroparesis
  • Dumping Syndrome (Rapid Gastric Emptying)
  • Functional Dyspepsia
  • Cyclic Vomiting Syndrome
Small Intestine
  • Intestinal Dysmotility
  • Intestinal Pseudo-Obstruction
  • Small Bowel Bacterial Overgrowth (SIBO)
Large Intestine
  • Constipation
  • Diarrhea
  • Hirschsprung’s Disease
  • Irritable Bowel Syndrome (IBS)
 Rectum and Pelvic Floor
  • Fecal Incontinence
  • Hirschsprung’s Disease
  • Outlet Obstruction Type Constipation (Pelvic Floor Dyssynergia)

Migrating Motor Complex: A Critical Motility Promoter

phases of mmc

The migrating motor complex (MMC) is a cyclic and recurring pattern of motility that occurs in the stomach and small intestine during periods of fasting and is interrupted following food consumption 3. The GI systems of numerous species, aside from human beings, have the MMC, which can be further subdivided into four main phases that repeats itself every 1.5 to 2 hours in normal and healthy individuals.

Phases of MMC

  1. 45-60 minute period of smooth muscle inactivity in the GI system. Muscle contraction during this state of motility is rare.
  2. 30 minute period in which peristalsis, or muscle contractions of the GI system beginning in the stomach and continuing through the small intestine, occur and progressively increase in their frequency.
  3. 5-15 minute period in which rapid and evenly spaced peristaltic contractions occur. During this phase, the pylorus of the stomach remains open to allow for any indigestible materials to continue through the small intestine.
  4. Short transition period between the contractions of phase 3 into the inactivity of phase 13.

Control of the MMC is believed to be a role of the central nervous system, which includes the brain and spinal cord, as well as, in part, due to the secretion of the enteric hormone known as motilin.

Motilin is produced by endocrine cells in the small intestine and plays an important role in the regulation of MMC, as the concentrations of this hormone are directly related to the different phases of MMC 4.

GI contraction can therefore be measured by analyzing the concentration of motilin within the blood plasma, as these levels will increase every 90-120 minutes during the fasting period, and will practically disappear once you eat a meal.

MMC and SIBO

mmc and sibo

SIBO, which is defined as the presence of excessive bacterial growth within the small intestine that exceeds 105 colony forming units per milliliter (ml) of content in this organ, is often determined through a glucose or lactulose breath test, or also by cultures of cells obtained from the small intestine 3.

Since some of the most common symptoms of SIBO include bloating, diarrhea and abdominal pain, intestinal dysmotility plays a crucial role in contributing to the severity of these symptoms.

To further investigate the causes of SIBO, researchers have shown through a number of animal studies that any disruption or disappearance in the MMC significantly contributes to animals being more susceptible to bacterial overgrowth.

Therefore, MMC, in addition to controlling motility, also proves to be an important mechanism by which bacterial flora of the small intestine is controlled 3. In fact, it has been hypothesized that since the MMC promotes contraction of the small intestine, or motility, it allows for the migration of bacteria to move towards the lower intestine, rather than remaining in the small intestine to cause many of the symptoms associated with SIBO.

What are Prokinetic Agents?

When you break down the word ‘prokinetic,’ ‘pro’ indicates a promotion or giving rise to something, whereas ‘kinetics’ indicates the movement or activation of something.

Prokinetic agents, therefore, are a class of drugs that are used to promote motility within the gastrointestinal (GI) tract for the management of clinical disorders that show the following symptoms:

  • Impaired motility
  • Gastro-esophageal reflux (acid reflux, occasionally)
  • Gastroparesis (muscles in the stomach prevent proper emptying or motility)
  • Intestinal pseudo-obstruction
  • Colonic inertia (motility disorder of the large intestine) 5

Pharmaceutical Prokinetic Drugs

prokinetic drugs

Advertised Drug Name Generic Name How it Works Other Information
Motilium ® Domperidone
  • Stimulates contraction
  • Assists in stomach/intestine emptying
  • Reduces small intestine transit time
  • Prevents vomiting (antiemetic) 6
  • Blocks the action of dopamine
Reglan ®, Maxeran ® Metoclopramide
  • Reduces relaxation of muscles in the GI tract – leads to more contraction
  • Assists in stomach/intestine emptying
  • Reduces small intestine transit time 7
  • Blocks the action of dopamine
  • Listed as one of the top 100 most prescribed medications in the U.S.
Levobren ®, Levopraid ®, Levosulpiride
  • Assists in stomach/intestine emptying
  • Reduces small intestine transit time 8
  • Dopamine antagonist (acts opposite to dopamine)
  • Can also be used for psychological disorders including schizophrenia, anxiety and other panic disorders
Zithromax ®, Zmax ® Erythromycin
  • Antibiotic
  • Helps motilin initiate phase 3 of MMC 9
Zelnorm ®, Zelmac ® Tegaserod
  • Helps motilin initiate phase 3 of MMC 10
  • Increase muscle contraction in the stomach
Gasmotin ® Mosapride Citrate
  • Stimulates the release of acetylcholine – a chemical of the nervous system that, when released, increases GI motility 11
n/a Renzapride
  • Helps motilin initiate phase 3 of MMC 12
  • Does not cause some of the side effects that similar drugs (e.g., ciaspride) cause, such as cardiac arrhythmias
Resolor ® Prucalopride
  • Stimulates the release of serotonin – a chemical of the nervous system that, when released, helps promote intestinal and colonic motility 13
  • Involved mainly with movement in the large intestine, not emptying of the stomach but does stimulate MMC

Pros and Cons of Pharmaceutical Prokinetic Drugs

People who suffer from altered motility or chronic constipation that occurs from either a known GI disorder or no reason at all, often suffer from a number of other symptoms including bloating, vomiting, nausea, feeling full too early during your meals or upper abdominal pain.

Unfortunately, there are not many medications available for patients with chronic constipation, the use of prokinetic agents can provide patients with some relief.

Overall, the use of prokinetic drugs can help improve the body to absorb nutrient better, especially following extended periods of dysmotility that may have affected our body’s natural ability to absorb important nutrients.

Since many of these drugs act on chemicals that play important roles in the brain to regulate memory, mood, and behavior, it is important for you to have all the information in front of you to make the most informed decision possible before deciding to take a pharmaceutical prokinetic drug.

Below is a table listing both the benefits and possible side effects of taking the specified pharmaceutical prokinetic drugs.

Drug Name Benefits Adverse Effects
Domperidone Improves nausea, vomiting, bloating the feeling
  • Headache
  • Dizziness
  • Dry mouth
  • Nervousness
  • Flushing
  • Irritability
  • Trouble Sleeping
  • Chest pain
  • Irregular heart beat
  • Stomach cramps
Metoclopramide Treats nausea, loss of appetite, heartburn and feeling full too quickly
  • Low energy; tiredness
  • Diarrhea
  • Dizziness
  • Drowsiness
  • Headache
  • Vomiting
  • Restlessness
  • Trouble sleeping
  • Can cause serious side effects to the brain (e.g., depression) and heart – not indicated to be taken for longer than 12 week duration
Levosulpiride Improves movement and food within the body
  • Drowsiness; low energy, tiredness
  • Irregular periods (women)
  • Abdominal pain and cramps
  • Weight gain
  • Trouble sleeping
  • Increased saliva production
  • Decrease libido (sexual desire)
Erythromycin Anti-inflammatory effects are beneficial for reducing bacterial overgrowth in cases like SIBO
  • Vomiting
  • Diarrhea
  • Abdominal pain
  • Loss of appetite
  • Nausea
  • Antibiotic Resistance**
Tegaserod Useful for the treatment of IBS symptoms including constipation, abdominal pain and bloating
  • Associated with a higher risk of causing heart attack, stroke and unstable heart pain in patients
  • Further studies still need to be performed to fully assess its risk/benefit analysis
  • Only used in Europe and Canada, as well as in the United States only in emergency situations
Mosapride Citrate Anti-inflammatory effects may be helpful for GI motility

Helps in stomach motility by accelerating stomach emptying

  • Dry Mouth
  • Abdominal Pain
  • Dizziness
  • Headache
  • Trouble sleeping
  • Nausea
  • Diarrhea
  • Overall, safer than other prokinetic agents in regards to cardiovascular effects
Renzapride Can be used to treat gastroparesis, GERD and functional dyspepsia

Shown to provide a full relief of IBS-C symptoms

  • Overall a well-tolerated drug
  • Does not show any signs of causing cardiovascular problems that other prokinetic drugs cause
Prucalopride Helpful in relieving the cardinal symptoms of chronic constipation

Especially beneficial for patients who have tried conventional laxatives that do not work to resolve their symptoms

  • Diarrhea
  • Abdominal pain
  • Headache
  • Nausea
  • Flatulence
  • Vomiting
  • Abnormal abdominal sounds
  • Not interested in eating
  • Feeling overly tired
  • Dizziness

Natural Prokinetic Agents

natural prokinetics

As you can see from the various possible side effects associated with the use of pharmaceutical drugs, it is not surprising that many individuals suffering from motility issues will look towards more natural remedies.

While a number of herbal remedies have been shown to promote GI motility, there is a lack of sufficient scientific studies that are currently available to fully determine whether these drugs are in fact useful for the treatment of constipation and motility disorders.

Below is a table listing some of the natural prokinetic drugs and how they work to reduce constipation and improve motility disorders.

Natural Remedy How it Works
Ginger
  • Can be used to treat dyspepsia, flatulence, nausea and abdominal pain
  • Has been shown to increase contractions in the GI muscles
  • Accelerate stomach emptying processes
  • Exact mechanism by which ginger promotes these effects are not well understood 14
Iberogast
  • Contains 9 natural plant extracts that provide fast-acting relief for multiple digestive symptoms
  • Diarrhea
  • Abdominal Cramps
  • Heartburn
  • Stomach pain
  • Bloating
  • Gas
  • Fullness
  • Nausea
  • Constipation
  • 9 natural plant extracts include:
  • Bitter candytuft
  • Angelica
  • Caraway
  • Chamomile
  • St. Mary’s thistle
  • Lemon Balm
  • Greater Celandine
  • Peppermint
  • Licorice
  • Particularly useful for medically diagnosed IBS
  • Activates GI muscles
  • Anti-inflammatory and anti-oxidative effects15
Motilpro
  • Active ingredients include:
  • Ginger extracted from Zingiber officinale root
  • Griffonia simplicifolia seed
  • Ascorbyl palmitate (made from corn and palm oil)
  • Supports the chemicals in the brain that support smooth muscle contraction in the GI tract 16
Triphala
  • Lowers cholesterol
  • Normalizes blood pressure
  • Anti-oxidant activity
  • Made up of three different types of herbal fruits (Harada, Amla & Bihara)
  • Free of side effects
  • More useful alternative than some prokinetic drugs; has been shown to increase stomach emptying by 86% as compared to metoclopramide (76% increase in stomach emptying) 17
Daikenchuto
  • Consists of a powder extracted from dried Sichuan pepper, processed ginger, ginseng and maltose
  • Widely used in Japan as a prophylactic after colon operations; currently a candidate for FDA approval
  • Prokinetic effects on intestinal motility, specifically of the major components of the small intestine 18
Rikkunshito
  • Often prescribed in Japan to treat anorexia and upper GI disorders (nausea and vomiting)
  • Prepared from 8 herbs including:
  • Lancea Rhizome
  • Ginseng
  • Rinellia Tuber
  • Poria Sclerotium
  • Jujube
  • Citrus Unshiu Peel
  • Glycyrrhiza
  • Ginger 19
Si Mo Tang
  • Widely used in China to treat functional dyspepsia (FD)
  • Can be taken either as an oral liquid alone or in combination with pharmaceutical drugs
  • Has been shown to promote gastric emptying, reduce relapse rates of FD and show safer effects as compared to more traditional prokinetic drugs 20
  • Active ingredients:
  • Radix Aulkandiae (dried root)
  • Fructus Aurantii (derived from dried and unripe fruit of Citrus aurantium L.)
  • Areca catechu Linn (a type of palm found in Asia and Africa)
  • Lindera aggregate (commonly known as Japanese evergreen spicebush; root)

Pros and Cons of Natural Prokinetic Drugs

One of the biggest benefits associated with the use of natural prokinetic drugs is the fact that these drugs often exhibit much less adverse effects as compared to pharmaceutical prokinetic agents. Since most pharmaceutical prokinetics function directly at either promoting or antagonizing the action of chemicals involved in important processes in the brain, they are not always able to specifically target these chemicals within the GI tract.

Therefore, there is an increased ability of these drugs to be nonspecific and cause several different types of effects outside of the GI tract.

It is important to realize that most natural and herbal medications are not regulated by the FDA, therefore the benefits posted on their labels may not always be completely accurate so it is important to be equipped with all the necessary information before deciding to try a natural remedy.

Also, keep in mind that to get the medicinal benefits it is important to buy quality herbal products made with organic or wildcrafted herbs.

Herbal formulas are very safe, you just have to make sure you are using the correct dosage and buying quality herbs.

When Should Prokinetics be Used?

Since many individuals with GI disorders, such as IBS and SIBO, have a very slow movement of food throughout their body, which can result from nerve damage within the GI tract or overgrowth of bacteria, they subsequently will often suffer from constipation and a plethora of other symptoms that come with it.

Once an individual has completed their rounds of primary treatment for their disorder, it is suggested to follow up their treatments with prokinetics to stimulate the MMC to aid in prevention.

It is also recommended to take prokinetic agents immediately before going to sleep, since, while we sleep, our body is going through several detoxifying and repairing processes and this is also the time period where we experience the most MMC waves.

Prokinetics for SIBO


A number of different types of pharmaceutical prokinetics are indicated for the treatment of SIBO. These, along with their rationale for SIBO treatment, include:

  • 50 mg/day Erythromycin: Not harmful at this dose
  • 2-6 mg/day Tegaserod: Can only be used outside of the U.S., useful for gastroparesis
  • 0.5-1 mg/day Prucalopride: Can only be used outside of the U.S., strong prokinetic agent which stimulates MMC
  • Low-dose Naltrexone (LDN): This drug balances the immune system and, at low doses, can act as a prokinetic as a result of its ability to reduce both inflammation and pain

As far as natural remedies are concerned, triphala, ginger, and Iberogast are safe prokinetics that can be used for extended periods of time without causing any harmful effects that are associated with the use of common pharmaceutical drugs.

Additionally, the various different types of herbs that make up the Iberogast drug can be used to treat both diarrhea and constipation. Approximately 80% of IBS patients using 20 drops of Iberogast 3 times/day have demonstrated positive results with this treatment protocol.