Prokinetic Agents

prokinetic agents

A prokinetic is anything that improves the movement in your gut, which is called gastrointestinal motility.

In people with digestive disorders such as IBS, SIBO, gastroparesis, or any other digestive issue where gut function is altered, prokinetic drugs can be an effective solution to help restore normal movement in order to prevent further digestive issues.

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

This is one of the most important topics for people dealing with SIBO or IBS, but it rarely gets the attention it should. It is very important because altered motility can be one of the main underlying causes of SIBO, 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 digestive organs, which include the esophagus, stomach, small and large intestines. GI motility allows the content of the digestive tract 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 such as:

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

Below are the GI disorders that are associated with motility issues by specific 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.

Many species, including humans, have the MMC, which is further subdivided into four main phases that repeat 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.

The MMC appears to be controlled by the nervous system, which includes the brain, spinal cord and its nerve extensions, as well as by the secretion of the enteric hormone, motilin.

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

GI contraction can be measured by analyzing the concentration of motilin in the blood plasma, as these levels will fluctuate every 90-120 minutes as we fast (reaching a peak during phase 3 of the MMC), and will almost disappear once you eat.

MMC and SIBO

mmc and sibo

SIBO, which is defined as an excessive bacterial growth greater than 105 colony forming units per milliliter (ml) in the small intestine, is often diagnosed by a glucose or lactulose breath test, or by cultures obtained from the small intestine 3.

Intestinal dysmotility plays a crucial role in the severity of the most common symptoms of SIBO such as bloating, diarrhea and abdominal pain. Researchers have shown through a number of animal studies that any disruption to the MMC significantly increases the risk of bacterial overgrowth.

Therefore, MMC, in addition to controlling motility, is also an important mechanism for controlling the bacterial flora of the small intestine and is known as the “intestinal housekeeper”3. This is because the MMC promotes motility of the small intestine, allowing the bacteria to migrate towards the large intestine, effectively stopping accumulation of bacteria in the small intestine and the associated symptoms of SIBO.

What are Prokinetic Agents?

When you break down the word ‘prokinetic,’ ‘pro’ means to promote or give rise to something, whereas ‘kinetics’ means movement or activation of something.

Prokinetic agents, therefore, are a class of drugs that promote motility within the gastrointestinal (GI) tract and manage the following symptoms:

  • Impaired motility
  • Gastro-esophageal reflux (acid reflux, occasionally)
  • Gastroparesis (paralysis of the stomach muscles so that food is stuck)
  • 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, whether due to a known GI disorder or no known reason at all, often suffer from a plethora of symptoms including bloating, vomiting, nausea, and early feeling of fullness or upper abdominal pain after eating.

The use of prokinetic agents can provide patients with chronic constipation with some relief.

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

However, these drugs affect other parts of the body apart from the gut, leading to many side effects. For example, many of the drugs act on chemicals that are important for regulating memory, mood, and behavior. It is important for you to have all the information to make the most informed decision possible before taking a pharmaceutical prokinetic drug.

Below is a table listing the benefits and possible side effects of specific 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 heartbeat
  • 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 numerous side effects associated with pharmaceutical drugs, many individuals suffering from motility issues look towards more natural remedies.

While several herbal remedies have been used for a long time to promote GI motility, there is a lack of sufficient scientific studies currently available to investigate whether these drugs are truly useful for treating 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 with using natural prokinetic drugs is that they often have less adverse effects compared to pharmaceutical prokinetic agents. Since most pharmaceutical prokinetics either directly promote or antagonize chemicals involved in important brain processes, they are often nonspecific and cause several 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 (and purity of ingredients) posted on the labels may not be completely accurate. IT is crucial to equip yourself with all the available information before trying 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.

While herbal formulas are generally safe, you should make sure you are using the correct dosage and buying quality herbs. Also, if you take prescribed medications, know that herbal supplements (especially in large doses) sometimes interact with your prescriptions causing other side effects.

When Should Prokinetics be Used?

Individuals with GI disorders, such as IBS and SIBO, often have nerve damage or bacterial overgrowth, which causes a very slow transit of food through the gut. Subsequently, they will often suffer from constipation and a plethora of associated symptoms.

Once an individual has completed primary treatment for the disorder, it is helpful to follow up with prokinetics to stimulate the MMC and to prevent relapse.

It is also helpful to take the prokinetic agents immediately before going to sleep, since we go through many detoxifying and repairing processes during sleep and also have the most number of MMCs as we are fasting.

Prokinetics for SIBO

Pharmaceutical Remedies:

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: Low rate of side effects 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 may help to decrease overactivity of the immune system and, at low doses, can act as a prokinetic since it reduces inflammation and pain. (Note: this is an off-label use of the medicine)

Remember that it may be best to take these medications at night before bed.

Natural Remedies:

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 medicine can be used to treat both diarrhea and constipation. 

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