Gastroesophageal reflux disease: a new approach to causes and treatment

Surprisingly, the same drugs can help with different diseases. Let's take gastroesophageal reflux disease (GERD) and the so-called lazy bowel as an example. In the first case, the main manifestation is heartburn, in the second - constipation. Both of them use prokinetics - drugs that regulate the motility of the gastrointestinal tract. Simply put, the intensity and frequency of its contractions.

With GERD, increased activity of the gastrointestinal tract helps get rid of heartburn: food moves faster through the digestive tract and does not provoke the reflux of acid into the esophagus. In addition, the functioning of the lower esophageal sphincter, the valve between the stomach and esophagus, improves. And prokinetics simply make the “lazy intestines” move. But, unfortunately, not all drugs in this group have such a universal effect. Let's figure out which prokinetic agent is optimal in terms of effectiveness and side effects.

Pathophysiology

The content of the article

Under normal conditions (in a healthy person), the contents of the gastric juice with high acidity periodically enter the esophagus, but internal protective mechanisms either reduce the amount of acid secreted to a minimum or remove the acid, which is quickly removed by “cleansing” the esophagus. Therefore, symptoms of acid irritation of the esophagus are not felt or are minimal.

Mechanisms that protect the esophagus from stomach acid include the lower esophageal sphincter (sphincter) and normal esophageal motility (motility). When these mechanisms are disrupted, reflux occurs and symptoms of GERD occur.

Gastroesophageal reflux

Types of prokinetics and names of drugs

There are several pharmacological groups of prokinetics.

Dopaminergic D2 receptor blockers

They are the most studied and widely used group of prokinetics. Drugs in this group, by blocking dopamine D2 receptors, regulate the motor activity of the digestive tract by increasing the tone of smooth muscle cells in the intestines and stomach. They have antiemetic and antihiccup effects.

• Metoclopramide (Gastrosil, Cerucal, Reglan). The peculiarity of this drug is its effect on dopamine D2 receptors and serotonin H3 receptors simultaneously. Stimulates the work of the upper digestive tract (stomach, esophagus, sphincter between these organs). Reduces the excitability of the vomiting center in the central nervous system, therefore it has proven itself well as an antiemetic agent. It has virtually no effect on intestinal motility. Use is limited by the appearance of specific adverse reactions (extrapyramidal disorders, hormonal disorders, dizziness), which is associated with penetration through the blood-brain barrier and effects on the central structures of the brain, as well as effects on the cardiovascular system (causes arrhythmias).
• Domperidone (Domperon, Motilak, Motilium). The drug belongs to the 1st generation of selective blockers of dopamine D2 receptors, which does not penetrate the blood-brain barrier and has no side effects from the central nervous system. The main effect is on the motility of the stomach and duodenum, since the largest number of peripheral D2 receptors are located there. Does not affect the intestines. The antiemetic effect is moderate. Domperidone is one of the main prokinetic drugs used in medical practice. Adverse reactions from the cardiovascular system are less common than with metoclopramide.

Serotonin 5-HT4 receptor agonists

Drugs of this group, acting on serotonin H4 receptors in the submucosal layer of the digestive tract, stimulate the release of acetylcholine. Acetylcholine increases the motor activity of the stomach and intestines. Studies have revealed the ability of these drugs to reduce abdominal discomfort and normalize stool in irritable bowel syndrome. At this stage, active trials of drugs from this group are underway as a promising direction in treatment.

• Tegaserod. The first synthesized agonist of serotonin H4 receptors, which showed high effectiveness in the treatment of intestinal neurosis with constipation. The disadvantages of the drug included a high percentage of side effects from the cardiovascular system. Now prohibited for use.
• Cisapride (Coordinax, Peristil). It affects the entire gastrointestinal tract, stimulating motility. Improves the passage of food through the intestines, affects the functioning of the esophageal sphincter. During the use of Cisapride, serious adverse reactions from the cardiovascular system were identified, so the drug was banned from production.
• Mosapride. Has similar properties to Cisapride. Approved for use in a number of countries (Belarus, Kazakhstan). Not registered in Russia. The disadvantages of the drug include interaction with other drugs, so it is used with caution with non-steroidal anti-inflammatory drugs, cholinergic drugs, etc.
• Prucalopride (Rezolor). It has the highest affinity for serotonin receptors, therefore it has a pronounced effect on intestinal motility. It is used in the treatment of chronic constipation, when the main groups of laxatives do not have an effect. When used, the most common side effects were headache, nausea, and abdominal pain. Registered in Russia.

Serotonin H3 receptor antagonists

The research of this pharmaceutical group began after the discovery of the properties of Metoclopramide to inhibit the functioning of serotonin H3 receptors and the advancement of the theory that part of its prokinetic properties are associated specifically with serotonin and its receptors. The synthesis of drugs that would selectively act only on H3 receptors began.

• (Latran, Zofran). The drug accelerates the movement of food from the stomach into the duodenum and normalizes the tone of the large intestine. Used in the treatment of nausea and vomiting caused by chemotherapy in cancer patients or anesthesia. It has not found widespread use in the treatment of gastroesophageal reflux disease and irritable bowel syndrome.
• Tropindole (Tropisetron, Navobane). The first drug from this group, which can normalize the functioning of the lower esophageal sphincter for a long time, preventing the reflux of gastric contents. Has a pronounced antiemetic effect. Used in cancer patients after chemotherapy.

New generation prokinetics with dual action

• Itopride (Ganaton, Itomed). The drug simultaneously affects dopamine D2 receptors and anticholinesterase receptors, which expands the scope of its application. It has a positive effect on the tone of the lower esophageal sphincter, preventing the reflux of gastric contents into the esophagus. At the same time, it stimulates peristalsis of all parts of the intestine, improving bowel movements during constipation. Has a moderate antiemetic effect. Does not affect the secretory activity of the stomach. Does not affect the structures of the central nervous system. In the treatment of gastroesophageal reflux disease it has proven to be better than Domperidone. The advantages of Itopride include the absence of interaction with other drugs.

The choice of prokinetic agent is based on clinical effectiveness in the treatment of different parts of the digestive tract, safety and contraindications.

Of all the listed drugs, only 2 drugs meet the effectiveness/safety conditions - Itopride and Domperidone. In the treatment of motor activity disorders of the upper gastrointestinal tract (esophagus, stomach), the drug of choice is Itopride.

Etiology: a new approach

The prevailing theory (since 1935) is that GERD occurs when acidic stomach acid spills from the stomach into the esophagus, chemically and mechanically damaging the lining of the esophagus, causing burns, irritation, erosions, and ultimately more serious consequences. However, this traditional theory of chemical and mechanical irritation of the esophageal mucosa cannot fully explain many things associated with the onset, symptoms and course of GERD.

There are now reports that GERD may be an immune-mediated inflammatory disease caused by immune reactions rather than direct chemical damage to the lining of the esophagus by gastric juices. The hypothesis about the etiology of immune GERD is confirmed by one of the clinical studies conducted in the USA. The study results were published in the Journal of the American Medical Association.

Preliminary data from this study showed that T-cell esophagitis, basal cell hyperplasia, and spleen cell hyperplasia were observed in patients with severe GERD treated effectively with proton pump inhibitors (PPIs) after PPI discontinuation, but with resistant superficial cells.

According to study leader at the Dallas Veterans Medical Center, Dr. Kerry Dunbar, This finding suggests that the pathogenesis of reflux disease may be related more to inflammatory mediators and cytokines than to chemical damage to the esophageal mucosa.

The inflammatory immune theory of GEB could more easily and better explain not only the onset and course of the typical symptoms of this disease, but also the pathophysiology of the complications of this pathology - metaplasia of the esophagus and Barrett's mucosa.

Barrett's esophagus

Recent experimental studies in rats also suggest that GERD is more related to immune rather than chemical acid damage to the esophageal mucosa. Reflux and chemical acid irritation are thought to only initiate immune inflammatory responses in the esophageal mucosa and therefore play a less important role.

If the immuno-inflammatory theory of the etiopathogenesis of GERD turns out to be correct, it may be necessary to reconsider the existing regimen for the treatment and prevention of relapses of GERD. It is possible that the location and role of antisecretory drugs (PPIs, H2 blockers) may change.

It is assumed that the immune theory of reflux disease can explain in more detail the causes and essence of not only typical, but also recently described atypical forms (so-called subtypes) of GERD.

Researchers suggest that PPIs and H2 blockers may remain the most important drugs for treating GERD, but treatment regimens for this disease should also include drugs that affect the immune-inflammatory response cascade, especially for more severe and refractory forms of GERD.

Treatment of gastroesophageal reflux disease

According to current guidelines, GERD is treated in stages. Goal of treatment: control the symptoms of the disease, treat esophagitis, prevent relapses of esophagitis and complications of the disease.

Treatment of GERD consists of the following steps:

• Lifestyle changes and control of gastric juice secretion (antacids, PSI, H2B).
• If necessary, surgical treatment is used, and corrective antireflux surgery is performed.

Non-pharmacological measures include the following:

• Reducing excess weight;
• Refusal of certain drinks and foods (alcohol, chocolate, citrus fruits, tomatoes), mint, coffee, onions, garlic;
• Frequent meals at regular intervals;
• Sleep at least 3 hours after eating, with your head raised (~ 20 cm);
• Limiting squats, bending, etc.

Eating frequently at regular intervals

Antacids

Until the 1980s, antacids were the standard treatment for mild forms of GERD. They are still used to reduce symptoms of mild reflux. Antacids are taken after each meal and before bed.

Taking antacids before bed

Antacids are also useful for side effects: they relieve constipation (aluminum antacids: ALternaGEL, Amphojel), they can increase loose stools (magnesium antacids: Phillips Milk of Magnesia). Aluminum hydroxide increases the pH of the stomach contents to >4 and inhibits the proteolytic activity of pepsin, reducing the symptoms of indigestion. Antacids do not reduce the frequency of reflux, but they do reduce the acidity of the fluid.

Magnesium hydroxide suppresses the symptoms of acidosis and improves digestion. Magnesium hydroxide antacids osmotically retain fluids in the intestine, which distends the intestinal wall, stimulates intestinal motility, and softens stools (laxative effect). When interacting with hydrochloric acid of gastric juice, magnesium hydroxide is converted into magnesium chloride.

Top 10 drugs from the pharmacy

Prokinetics for reflux esophagitis or other intestinal problems accompanied by pain, heaviness, nausea or bloating will help normalize the functioning of the entire gastrointestinal tract.

Prokinetics for reflux esophagitis

If peristalsis disturbances are not corrected in time, stagnation will appear in one or another part of the intestine. And in some cases, diarrhea may persist for a long time. Medicines for stagnation are aimed at stimulating peristalsis, but with frequent bowel movements, on the contrary, they reduce motility.

In one case or another, medications are prescribed depending on the cause that provoked the disorder.

Only a specialist should select a drug, and there are a huge number of them, after a thorough examination. Otherwise, incorrect selection can only aggravate the condition.

Cerucal

This is an antiemetic that belongs to the group of dopamine receptor blockers. Available in tablet form. The main component is metoclopravid hydrochloride, and additional components: starch, gelatin, lactose, magnesium stearate, silicon dioxide.

Thanks to this composition, the tablets help reduce nausea and hiccups and stimulate peristalsis. The medicine helps speed up bowel movements by stopping the body of the stomach from relaxing and increasing the activity of the antrum and upper part of the small intestine.

Cerucal is prescribed to be taken for vomiting, severe nausea, hiccups, as well as the following pathologies:

• dyskinesia;
• reflux esophagitis;
• hypotension and atony of the stomach;
• flatulence.

The drug is taken by children from 6 years old, 5 mg up to 3 times a day, and up to 6 years, 0.5 mg per kg of body weight 1-3 times a day. Adults take 5-10 mg up to 4 times. The daily dose should not exceed 60 mg.

Failure to follow the recommendations leads to the development of undesirable symptoms: constipation, diarrhea, dry mouth, drowsiness, headache, muscle spasms, menstrual irregularities, skin rash, galactorrhea.

Cerucal should not be prescribed for:

• bleeding in the digestive tract;
• perforation of the digestive organs;
• pregnancy and breastfeeding;
• pheochromocytoma;
• epilepsy;
• special sensitivity to the main component.

The cost of packaging the drug varies within 700 rubles.

Raglan

This is an antiemetic drug that is available in tablet form, injection solution and oral liquid. The medicine activates the production of prolactin, helps speed up the processing of food in the stomach, reduces the motor activity of the stomach, and normalizes peristalsis. Does not provoke the development of diarrhea.

The medicine is recommended to be taken in the following cases:

• with vomiting and feeling of nausea;
• in preparation for examination of the digestive organs;
• hiccups of various origins;
• after undergoing radiation and chemotherapy;
• in the period after surgery for hypotension of the digestive organs;
• worsened peptic ulcer disease;
• reflux esophalitis;
• dyspepsia.

It is recommended to take the medicine only after a doctor’s prescription; self-medication can provoke the development of complications. The medicine should be taken 1 tablet or 1 tbsp. l. solution orally up to 3 times a day. In severe forms of the disease, the drug is administered as intramuscular or intravenous injections.

The drug should not be prescribed to people with the following problems:

• intolerance to components of the composition;
• bleeding in the digestive organs;
• perforation of the intestine or stomach;
• vomiting from taking antipsychotics
• pheochromocytoma;
• muscular dyskinesia;
• pregnancy and breastfeeding;
• stenosis.

If the recommendations are not followed, undesirable symptoms may appear: insomnia, dizziness, diarrhea, amenorrhea, constipation.

The price of the drug varies within 200 rubles.

Metoclopramide

Prokinetics for reflux esophagitis Metoclopramide is available in tablet form and the main component is a substance with the same composition. The medicine acts in two directions, eliminates vomiting and speeds up the processing of food in the stomach. In addition, peristalsis increases.

Medicines are prescribed not only for reflux esophagitis, but also for other problems with the digestive system:

• gagging;
• preparatory stage before examination of the digestive organs;
• dyskinesia of bile excretion pathways;
• flatulence.

It is recommended to take the drug 10 mg three times a day. For children, the dose is calculated according to body weight: 0.15 mg per 1 kg of body weight. The course is individual.

It is prohibited to prescribe the drug to people who have intolerance to the components of the composition, as well as with the following problems:

• intestinal obstruction;
• perforation of the digestive organs;
• bleeding in the stomach and intestines;
• kidney failure;
• liver failure.

It is important to strictly adhere to the dose, otherwise undesirable manifestations may occur: headache, increased thirst, urticaria, muscle spasm of the digestive organs, hyperprolactinemia.

The price of a package of the drug varies within 50 rubles.

Tegaserod

This is the first synthesized substance that has properties such as suppressing serotonin receptors, having an agonistic effect on them.

Thanks to this effect on the body, the drug has a positive effect on the clinical picture of problems with the digestive system:

• enhances intestinal secretion;
• stimulates peristalsis;
• stabilizes motility along the entire length of the intestine;
• normalizes stool.

The medicine is produced in tablet form, and the active component is a substance of the same name.

The drug should be taken 2-12 mg per day, divided into 3 doses. The course ranges from 2 to 6 weeks.

The prokinetic agent Tegaserod, recommended for reflux esophagitis and other problems with the digestive system, cannot be prescribed for:

• intolerance to components of the composition;
• severe form of liver failure;
• pregnancy and breastfeeding.

Also, the drug is prohibited in children.

Failure to comply with doctor's instructions can lead to serious consequences and the development of unwanted symptoms:

• diarrhea;
• flatulence;
• dizziness;
• pain in the peritoneum and back.

The average price of a medicine is 100 rubles.

Zelmak

The prokinetic agent Zelmak, available in tablet form, helps regulate the motor function of the digestive organs, all thanks to its active effect on serotonin receptors. The medicine also helps to strengthen peristalsis and increase basal motor activity.

The active component is the substance tegaserod. And this component helps reduce the severity of symptoms of irritable bowel syndrome.

The medicine should be taken 6 mg twice a day. The course is selected individually.

The drug should not be prescribed for the following health problems:

• liver failure;
• carrying a baby;
• breast-feeding;
• intolerance to the active component.

The drug is contraindicated for children.

If you violate the doctor's prescription and increase the prescribed dosage, undesirable symptoms may appear: abdominal discomfort, flatulence, headache, diarrhea, nausea.

The average price varies within 400 rubles.

Fractal

This is a drug from the group of prokinetics, which is prescribed for the treatment of functional disorders, and has an antiemetic effect.

Functional ailments of the digestive organs are associated with dysfunctions of the digestive tract and are not accompanied by organic changes: inflammatory processes, neoplasms and others.

Fractal is a drug, available in tablet form, that is prescribed for irritable bowel disease, which manifests itself in the form of constipation. The main component is the substance tegaserod.

The medicine should be taken 1 tablet in the morning and evening, the course of administration is from 2 to 6 weeks.

The drug is contraindicated for oral administration if there is a history of the following ailments:

• kidney failure;
• obstruction in the intestines;
• gallbladder;
• adhesive disease;
• sphincter dysfunction;
• breastfeeding period;
• age under 18 years;
• intolerance to the components of the drug.

If dosages are not observed, undesirable symptoms may develop: flatulence, nausea, diarrhea, increased appetite, exacerbation of cholecystitis.

The price for a package of tablets is on average 250 rubles.

Ondansetron

This antiemetic, available in the form of an oral solution, contains a substance of the same name. It is thanks to him that the medicine effectively prevents and also eliminates the feeling of nausea and vomiting.

The mechanism of action of the drug is due to the unique ability to suppress serotonin receptors. In the most severe cases, the patient may be prescribed the drug in the form of an injection solution for therapy by intravenous or intramuscular administration.

Medicine is prescribed to eliminate nausea and vomiting after chemotherapy and radiation therapy, as well as for preventive purposes after surgery.

The solution should be taken orally, 1 scoop (5 ml). Children over 4 years of age can also be prescribed the drug, but only with the permission of the doctor. The dose is selected individually depending on the course of the disease.

You cannot prescribe a medicine if the patient has the following health problems:

• intolerance to components of the composition;
• carrying a baby or breastfeeding;
• children under 4 years of age;
• fructose intolerance;
• impaired absorption of glucose-galactose.

If you do not follow the doctor's instructions, the following symptoms may appear: allergies, visual disturbances, headache, bradycardia, hypotension, hypertension, tachycardia.

The average price of the drug is from 150 rubles.

Domet

This is an antiemetic medicine that soothes hiccups and relieves the unpleasant feeling of nausea. The effect of the drug is due to the fact that the active substance, domperidone, blocks central dopamine receptors.

Such properties of the drug inhibit the effect of dopamine on the motor function of the digestive organs and increase their motor activity. The drug is available in tablet form.

The remedy is prescribed for the following problems:

• feeling of nausea and vomiting;
• postoperative hypotension;
• flatulence;
• reflux esophagitis;
• cholecystitis;
• cholangitis.

Take the drug 1 tablet three times a day. The course is individual.

You should not take pills if you have the following problems:

• pregnancy and breastfeeding;
• bleeding in the digestive organs;
• children under 12 years of age;
• sensitivity to the main component;
• perforation of the digestive organs.

Failure to follow the recommendations may cause the following undesirable symptoms:

• cramps in the stomach;
• allergy;
• dry mouth;
• gynecomastia;
• headache;
• children's age up to one year.

The average price of the drug is within 100 rubles.

Motilium

Often, due to the consumption of fast foods or congenital developmental anomalies, young children experience problems with the stomach and intestines. Children should take the drug with extreme caution. The dose of prokinetics is selected according to the child’s weight. Most children are prescribed Motilium, as it is easily tolerated and has a positive effect on the child’s body.

Available in the form of a suspension or tablets. Children under 5 years of age are prescribed a suspension - 2.5 ml per 10 kg. The dose can be increased if necessary, but only for children over one year of age.

Medicine is prescribed for:

• vomiting and nausea;
• slow digestion;
• frequent regurgitation;
• dyspepsia disorders;
• deterioration of the functions of the digestive organs.

Prokinetics for reflux esophagitis Motilium should not be prescribed for:

• intolerance to components;
• bleeding in the digestive organs;
• dysfunction of the liver and kidneys;
• children weighing less than 35 kg;
• phenylketonuria.

Failure to comply with the prescription may cause unwanted symptoms:

• dry mouth;
• strong thirst;
• stool disorder;
• menstruation disorders in women.

Pregnant women, breastfeeding women and children under 5 years of age should take the drug with extreme caution.

The price for a package of the drug varies within 150 rubles.

Domperidone

This is a drug with antiemetic effect. Helps calm hiccups and also eliminate nausea. This feature of the drug is caused by blocking central dopamine receptors.

The thing is that the medicine removes the inhibitory effect of dopamine on the motor function of the digestive organs and helps increase the motor activity of the stomach. Available in tablet form with the active ingredient of the same name.

Prokinetics are prescribed for reflux esophagitis or for other problems:

• nausea;
• vomit;
• postoperative hypotension;
• atony of the digestive organs;
• dyspepsia;
• dyskinesia of bile excretion pathways.

The drug is taken orally, the dosage and course are selected individually depending on the disease and the complexity of its course.

The drug is not prescribed for the following problems:

• bleeding from the digestive organs;
• carrying a baby;
• lactation;
• intolerance to the main component;
• perforation of the digestive organs;
• children weighing up to 35 kg.

Violation of the doctor's instructions can provoke the development of the following symptoms: headache, allergies, dry mouth, thirst, stool disorders. The price varies within 100 rubles.

Prokinetics are drugs that help not only relieve discomfort in the digestive organs, but also in the treatment of dyskinesia, reflux esophagitis, and gastritis.

Many drugs have a number of contraindications for use, so they should be selected by a specialist so as not to further aggravate the patient’s condition. Failure to follow recommendations may provoke the development of unwanted symptoms.

New antacids and antirefluxants

Alginic acid salts have been used clinically to relieve symptoms of heartburn and esophagitis for over 30 years. Alginic acid salts have a unique mechanism of action: when interacting with gastric acid, alginates precipitate and form a gel that covers the esophageal mucosa with a protective layer and promotes its restoration.

In vitro and in vivo studies have shown that alginates combine carbon dioxide and some antacid components. Recent kinetic studies have shown that alginates bypass acidic contents and reach the esophagus before the esophageal contents, protecting the organ mucosa from mechanical and chemical irritation from hydrochloric acid. According to clinical studies, alginates also act as a physical barrier, thereby more effectively suppressing reflux.

Alginate products contain antacids, which are acid neutralizing agents that reduce heartburn, but studies have not shown that the effectiveness of these combination drugs depends on their neutralizing properties.

The clinical effectiveness of alginate preparations depends on many factors: the amount and penetration of carbon dioxide released, the characteristics of the molecule, additional ingredients (aluminum, calcium) that have a positive potentiating effect.

Alginate preparations remain in the stomach for several hours, so they last significantly longer and are more effective in suppressing the symptoms of GERD than traditional antacids, they begin to work quickly and last a long time. Alginate preparations are completely safe and are therefore used to reduce the symptoms of reflux in infants, children and pregnant women.

For example, one of these magnesium alginate preparations, Refluxaid, is used in European countries to reduce the symptoms of reflux and acidosis in GERD, peptic ulcers, esophagitis, functional dyspepsia, and other functional and inflammatory diseases of the gastrointestinal tract, manifested by heartburn, reflux, and epigastric discomfort.

Refluxaid drug

The magnesium alginate in Rexluxaid is a natural substance extracted from seaweed. The drug has a high viscosity, which increases anti-reflux effectiveness and duration of action. It has emulsion and swelling properties.

Studies have shown that the highly viscous compound Refluxaid, when ingested into the stomach, creates a physical barrier that binds and neutralizes gastric juice, thereby protecting the esophagus from symptoms of reflux: heartburn, burning behind the sternum, chest pain, epigastric discomfort, etc. Taking these The medication reduces heartburn, acid regurgitation, dysphagia and odynophagia (difficulty swallowing and pain) are reduced, and extrazophaginic symptoms of GERD are also suppressed - cough, hoarseness.

Refluxaid is a prescription medication. It is used for episodic relief of symptoms of acidosis, reflux and esophagitis, on demand or in combination with anti-reflux medications (antisecretory PPIs, H2 blockers, prokinetics).

It has been found that when a person sleeps, magnesium alginate can remain in the stomach for up to 8 hours without breaking down—enough time for the patient to get a good night's sleep. Taking reflux before bed may improve the quality of sleep in a patient with GERD because the symptoms caused by nocturnal reflux will be suppressed.

Prokinetics: present and future

The search for means that normalize the motor-evacuation activity of the digestive tract has attracted the attention of medical researchers for several centuries. Probably one of the first representatives of this group is ginger, which has been used since ancient times in traditional Chinese medicine [1] as a remedy that eliminates heaviness in the abdomen and nausea, and has weak antagonistic activity against 5-HT3 receptors [2]. To date, agents that affect the motor activity of the digestive tract and prevent antiperistaltic contractions of smooth muscles have been combined into the group of prokinetics [3].

First of all, it is necessary to outline the range of indications for which evidence has been obtained of the effectiveness of the use of prokinetics.

Firstly, diseases of the digestive tract, in the development of which disturbances in the motor activity of the digestive tract play a significant role (gastroesophageal reflux disease, postprandial distress syndrome as a variant of functional dyspepsia, peptic ulcer with impaired antroduodenal coordination, idiopathic gastroparesis, functional nausea, functional constipation, and also irritable bowel syndrome - a variant with constipation).

Secondly, the use of prokinetics as antiemetics (for example, for nausea and vomiting associated with the use of cytostatics) [4].

Third, diabetic gastroparesis, in which delayed gastric emptying affects variability in glucose absorption, causing difficulty in glycemic control and can lead to chronic gastroparesis symptoms and poor glycemic control. This should also include the prescription of prokinetics for gastroparesis of other etiologies [5].

What drugs have prokinetic activity?

Domperidone , in its chemical structure, also belongs to benzimidazole derivatives, is a highly selective blocker of peripheral dopamine receptors (D) type 2 and, unlike metoclopramide, is devoid of many side effects due to the lack of penetration of the drug through the blood-brain barrier [6]. By suppressing the influence of dopamine, domperidone increases the spontaneous activity of the stomach, increases the pressure of the lower esophageal sphincter and activates peristalsis of the esophagus and antrum of the stomach. The drug also increases the frequency, amplitude and duration of contractions of the duodenum and reduces the time of passage of food masses through the small intestine.

Metoclopramide . Metoclopramide, in its chemical structure, belongs to the benzamide subtype with several prokinetic mechanisms (

.): agonism of 5-hydroxytryptamine (HT) 4 receptors, antagonism towards central and peripheral dopamine (D) type 2 receptors, as well as direct stimulation of contractions of the smooth muscles of the digestive tube [7].

The prokinetic effect of metoclopramide is limited to the upper parts of the digestive tract; it increases the tone of the lower esophageal sphincter, enhances gastric and small intestinal motility, accelerates gastric emptying, and improves antroduodenal coordination. However, along with proven effectiveness, the use of metoclopramide is limited by the development of side effects [8] (about 30%), namely extrapyramidal disorders, headache, dizziness, drowsiness, depression and hormonal disorders: hyperprolactinemia with galactorrhea, gynecomastia, menstrual irregularities.

Metoclopramide and domperidone have an antiemetic effect, which is due to the suppression of the activity of chemoreceptor trigger zones located at the bottom of the fourth ventricle outside the blood-brain barrier. However, the ability to act on the adenohypophysis, which also lacks a blood-brain barrier, contributes to an increase in the level of prolactin in the blood serum in some patients during long-term use of domperidone, leading to the development of gynecomastia, galactorrhea and amenorrhea. It should be emphasized that this adverse effect becomes clinically significant only with long-term use of the drug (for example, if domperidone is prescribed to patients with Parkinson's disease). Thus, when using domperidone at a daily dose of 80 mg (for 12 years), the frequency of adverse events does not differ from placebo, and the drug is better tolerated than metoclopramide at a dose of 40 mg/day [9]. Domperidone is widely used in clinical practice as an effective and safe prokinetic agent. Even in countries with strict OTC regulations, this drug is usually sold without a prescription, for example in Germany it is available as long as the total dose of domperidone per package does not exceed 200 mg.

Itopride hydrochloride is both a dopamine receptor antagonist and an acetylcholinesterase blocker. The drug activates the release of acetylcholine and prevents its degradation, and has minimal ability to penetrate the blood-brain barrier into the central nervous system, including the brain and spinal cord. Metabolism of the drug allows you to avoid unwanted drug interactions when taking medications metabolized by enzymes of the cytochrome P450 system. As experimental and clinical studies have shown [10, 11], itopride hydrochloride enhances propulsive motility of the stomach and accelerates its emptying. In addition, the drug has an antiemetic effect, which is realized through interaction with D2-dopamine chemoreceptors of the trigger zone.

Cisapride , a 5-HT4 receptor agonist with little 5-HT3 receptor antagonist activity, was withdrawn from the US market in 2000 due to numerous reports of sudden death (QT prolongation, dangerous ventricular arrhythmias) [12]. Subsequently, drugs with a similar prokinetic mechanism were created. Thus, another 5-HT4 receptor agonist, mosapride, has demonstrated an effect on accelerating gastric emptying in studies involving healthy volunteers, as well as in cases of diabetic gastroparesis. Unlike cisapride, mosapride has little effect on potassium channel activity [13], and therefore has a significantly lower risk of cardiac arrhythmias. The prokinetic activity of another drug in this subgroup, renzapride, is due to two mechanisms: agonism with 5-HT4 receptors and antagonism with respect to 5-HT3 receptors. To date, the level of evidence on the effectiveness and safety of mosapride and renzapride has not been determined due to insufficient data. Tegaserod is an agonist of 5-HT4 presynaptic receptors [14] with preferential stimulation of peristaltic activity of the colon. Tegaserod improves stool consistency and promotes the urge to defecate in patients with chronic constipation. However, according to 29 randomized, controlled studies with short follow-up periods (1-3 months), conducted in 2007 at the initiative of the FDA, tegaserod increases the risk of cardiovascular events (including angina), as a result of which this drug was completely withdrawn from the American pharmaceutical market in April 2008. Currently, among the drugs in this subgroup, alosetron and ramosetron (5-HT3 receptor antagonists) are also used with a better safety profile. Nevertheless, it is still too early to talk definitively about the high safety profile of this subgroup of drugs.

Bethanechol , a muscarinic receptor agonist, increases the pressure of the lower esophageal sphincter, coordinates contractions of the fundus and antrum, accelerating gastric emptying [15]. However, the use of bethanechol is limited only to cases of gastroparesis refractory to standard therapy due to the high frequency of side effects: abdominal pain, bronchospasm, dysuria, increased blood pressure, etc.

Motilin receptor agonists . The polypeptide hormone motilin is produced in the distal stomach and duodenum, increases the pressure of the lower esophageal sphincter and increases the amplitude of peristaltic contractions of the antrum, stimulating gastric emptying. The macrolide antibiotic erythromycin has prokinetic activity as a motilin receptor agonist. Interestingly, erythromycin promotes gastric emptying after vagotomy, as well as after antrectomy [16]. However, as a prokinetic agent, erythromycin is unlikely to find its therapeutic niche, and this is not only due to the antibacterial effect of the drug. Long-term use of erythromycin (a month or more) doubles the risk of mortality associated with cardiac conduction disorders [17]. A similar, although less pronounced effect on motilin receptors was later described for other macrolides - azithromycin and clarithromycin. However, like erythromycin, these antibacterial agents are unlikely to ever find use in medical practice as independent prokinetics. At the same time, these drugs gave impetus to the synthesis of new molecules with agonistic activity towards motilin receptors. One of the most promising drugs in this subgroup, atilmotin [18], has demonstrated an effect on accelerating the emptying of both liquid and solid foods in studies involving healthy volunteers, as well as in individuals with diabetic gastroparesis. The study of the effectiveness and safety of long-term use of atilmotin, as well as research on the creation of new motilin agonists, continues. Thus, the effects of ghrelin [19], a neurohumoral neurotransmitter secreted by the gastric mucosa, are being studied as one of the promising agents of this subgroup of prokinetics. Ghrelin is a physiological stimulant of gastrointestinal motility and is structurally related to motilin; it has a prokinetic effect with normalization of gastric emptying in patients with both diabetic and idiopathic gastroparesis.

Researchers continue to actively study new drugs with targeted selective prokinetic activity [20], including physostigmine and neostigmine, muscarinic receptor agonists that stimulate intestinal activity and only slightly improve gastric emptying; the cholecystokinin receptor antagonists loxiglumide and dexloxiglumide, which accelerate gastric transit, as well as the phosphodiesterase-5 inhibitor sildenafil; alpha-2 agonist (adrenomodulator) clonidine, normalizing the evacuation of gastric contents in functional dyspepsia (postprandial distress syndrome), slowing down intestinal transit with a decrease in visceral hypersensitivity of the colon.

A wide range of indications for which the administration of prokinetics is effective, as well as the characteristics of each subgroup of prokinetics (various mechanisms of prokinetic influence, safety profile, preferential activity in relation to the upper or lower level of the digestive tract) allow the doctor to choose the most effective and safe prokinetic in each clinical case.

For questions regarding literature, please contact the editor.

M. A. Livzan , Doctor of Medical Sciences, Professor

GOU VPO "Omsk State Medical Academy of Roszdrav ", Omsk

Rice.

Antisecretory drugs, H2 receptor blockers

This is the first-line treatment for mild to moderate GERD and grade I-II esophagitis. Four H2 blockers are commonly used in clinical practice: ranitidine, famotidine, cimetidine, and nizatidine. They are more effective in suppressing unstimulated secretion of gastric juice with food and are therefore recommended on an empty stomach or at night.

H2 blockers are effective in the treatment of mild esophagitis (70-80% of patients recover), as well as in antirecessive treatment and prevention of relapses. The effectiveness of H2 blockers decreases with long-term use, leading to tachyphylaxis. An H2 blocker is recommended for patients suffering from nocturnal reflux symptoms, especially in Barrett's temple.

Proton pump inhibitors (PPIs)

These are powerful drugs that suppress gastric secretion. Clinical studies have shown that they are most effective in treating GERD. PPIs are generally well tolerated and cause relatively few side effects. However, PPIs can disrupt calcium homeostasis, exacerbating existing cardiac conduction abnormalities. PPIs increase the risk of hip fractures in postmenopausal women.

Multiple clinical trials have concluded that PPIs are more effective than H2 blockers in controlling GERD symptoms over 4 weeks. And are more effective in treating esophagitis within 8 weeks. It also reports that no one PSI drug was found to be more effective than others in controlling GERD symptoms over 8 weeks.

Although PPIs are the most effective antisecretory drugs, their use, especially over a long period of time, is associated with many side effects. Firstly, PPIs have restrictions on their use: they cannot be used in children under 1 year of age, pregnant or lactating women. PPI use during pregnancy has been shown to increase the risk of birth defects (heart defects).

Restrictions on the use of PPIs

Research conducted in the United States shows that overuse of PPIs has dangerous consequences. Therefore, the US FDA warns doctors and patients that there should be no more than three 14-day courses of treatment per year. Long-term or frequent use of PPIs is associated with an increased risk of bone fractures, hypovitaminosis B12, electrolyte imbalances (primarily hypomagnesemia), muscle spasms, and even seizures.

Excessive suppression of gastric acid secretion when taking PPIs can cause epigastric discomfort, indigestion, increased intestinal infections (C. difficile, etc.), and the risk of aspiration pneumonia. The risk of infectious complications is even higher when PPIs are used with H2 blockers.

Proposals from manufacturers and suppliers, descriptions from the “Encyclopedia of Medicines” for the drugs mentioned in the article:
- metoclopramide - domperidone - cisapride - erythromycin Widespread introduction into clinical practice of modern methods for studying the motor function of the gastrointestinal tract has opened up new perspectives in the understanding and rational treatment of a number of diseases associated with dyskinesias of the gastrointestinal tract, such as gastroesophageal reflux disease (GERD), functional dyspepsia, irritable bowel syndrome, etc.

In recent years, a new group of medications has emerged—prokinetics—that can correct motility disorders of the digestive tract. These include a group of pharmacological drugs that, at different levels and using different mechanisms, enhance the motor, especially propulsive, activity of the gastrointestinal tract.

The endpoints of the mechanisms of action of drugs acting on the motility of the gastrointestinal tract are the blockade of ion transport, or the effect on the metabolism of acetylcholine at the synapses of nerve fibers. Clinical effects are achieved through:

• stimulation of the formation of acetylcholine molecules in the nerve terminal (increasing the release of acetylcholine into the synaptic space);
• stimulation of cholinesterase activity (reducing the number of acetylcholine molecules in the synaptic space);
• reducing the production of acetylcholine molecules in the nerve terminal.

The main classes of receptors involved in the regulation of motor-evacuation function of the gastrointestinal tract are cholinergic, adrenergic, dopaminergic, serotonin, motilin, cholecystokinin.

Prokinetics include drugs with different mechanisms of action (Table 1). The pharmacological effect of betanekol, an acetylcholine analogue, metoclopramide (Cerucal, Reglan) is due to direct interaction with muscarinic cell receptors. Another mechanism of action shared by metoclopramide, clebopride, levosulpiride and domperidone is antagonism of dopamine (D-2) cell receptors. Metoclopramide and cisapride (Coordinax) have a direct stimulating effect on the release of acetylcholine. Coordinax also interacts with serotonin receptors of the cell - it has antagonism to 5-HT-3 and agonism to 5-HT-4 receptors.

Table 1. Mechanisms of action of prokinetic agents (not shown in the online version)

If we compare the pharmacological activity of betanekol, Metoclopramide and Coordinax, several features are revealed that are important for the clinician. Coordinax more energetically ensures the evacuation of a food bolus from the stomach, stimulates intestinal peristalsis to a greater extent and, unlike betanekol, stimulates antroduodenal coordination, i.e. synchronization of the motility of the stomach and duodenum, necessary in order to move from the phase of gastric digestion to the phase digestion in the duodenum. Moreover, the concentration of Coordinax at which these effects occur is lower than the concentration of bethanecol or metoclopramide.

Table 2. Comparative assessment of some pharmacological features of prokinetics (not shown in the online version)

Comparing the clinical effects of various prokinetics (Table 2), it should be noted that levosulpiridine, Cerucal and Motilium have an antiemetic effect. When assessing the effect of drugs on intestinal motility, it should be taken into account that activity in the proximal part of the intestine is inherent in all drugs. While Coordinax, Erythromycin and loxiglumide have prokinetic activity throughout the intestine.

Metoclopramide penetrates the blood-brain barrier, which causes various side effects, such as headache, fatigue, impotence, gynecomastia, extrapyramidal disorders, etc. When using Coordinax, Erythromycin and loxiglumide, adverse effects are rarely observed. However, when prescribing Coordinax, it must be remembered that the drug is prescribed with caution to elderly patients and persons with cardiac arrhythmias and intraventricular conduction disorders.

The physiological effects of prokinetics are:

• increased tone of the lower esophageal sphincter;
• increasing the evacuation function of the stomach;
• normalization of the phase relationship of the migrating motor complex;
• increased antroduodenal coordination;
• increasing productive intestinal motility;
• increased contractility of the gallbladder.

It is important to consider that from the heterogeneous group of prokinetic drugs, only domperidone (Motilium), cisapride (Coordinax, Peristil) and metoclopramide (Cerucal) are currently available and used in clinical practice in Russia. The most widely used are Motilium and Coordinax. The drug metoclopramide is prescribed much less frequently due to its side effects and lower effectiveness compared to Motilium.

Indications for the use of prokinetic drugs are diseases of the upper digestive tract with a primary impairment of motor function - this is, first of all, widespread gastroesophageal reflux disease. Prokinetics are considered drugs for the pathogenetic treatment of GERD. This is due to the fact that they eliminate the immediate cause of gastroesophageal reflux - esophageal dysmotility, and increase the tone of the lower esophageal sphincter.

Many years of experience in using Motilium in clinical practice have shown its high effectiveness in the treatment of endoscopically negative gastroesophageal reflux disease and mild reflux esophagitis. Moreover, the drug is effective in 83% of cases when used as monotherapy and in 100% of cases when combined with antisecretory drugs. It is prescribed 10 mg 3 times a day 30 minutes before meals and 1 time at night.

The most effective prokinetic agent in the treatment of GERD is the gastrointestinal prokinetic agent Coordinax. Its effect is based on binding to 5-hydroxytryptamine receptors. It blocks 5-HT-3 receptors and stimulates 5-HT-4 receptors in presynaptic nerve endings, thereby having an indirect cholinergic effect on the neuromuscular apparatus of the entire gastrointestinal tract. It is also prescribed 1 tablet (10 mg) 3 times a day 30 minutes before meals and 1 time at night.

Coordinax is used as monotherapy both for the treatment of reflux esophagitis grades A-C according to the Los Angeles classification (1997), and in combination with antisecretory drugs for the treatment of severe degrees of the disease.

Motilium has proven itself in the treatment of functional (non-ulcer) dyspepsia. The use of Motilium for 2-4 weeks led to a significant improvement in the general condition, a decrease in pain in the epigastric region and dyspeptic disorders in 65-90% of patients.

Of course, one of the main reasons for prescribing this group of drugs is chronic gastritis, including its atrophic forms, which occur with symptoms of delayed gastric emptying. Prokinetics are also used in patients with idiopathic and diabetic gastroparesis, with gastroparesis that developed after vagotomy and gastrectomy, in patients with reflux gastritis, duodenogastric reflux after cholecystectomy. They are prescribed for gastrointestinal manifestations of systemic diseases such as scleroderma and amyloidosis.

Prokinetics are used for irritable bowel syndrome with constipation. Coordinax and Peristil are used, which enhance the propulsive activity of all parts of the digestive tube, including its distal parts. The use of Coordinax in a daily dose of 30 mg in patients with irritable bowel syndrome with a predominance of constipation contributed to an increase in the average frequency of stool from 1.5-2 times a week to 3.5-5 times a week and made it possible to reduce the use of laxatives by patients. The stimulating effect of Coordinax on colonic peristalsis, when prescribed in a dosage of 10 to 40 mg per day, is quite pronounced even in some cases of colonic atony.

Among other intestinal diseases, indications for the use of prokinetics include chronic intestinal pseudo-obstruction syndrome and postoperative intestinal obstruction.

An important indication for the use of prokinetics is vomiting during pregnancy or vomiting associated with chemotherapy for malignant diseases.

In diagnostic studies, prokinetics are widely used, in particular during enterography.

Among the drugs that will take their place among prokinetics in the near future, cholecystokinin receptor antagonists deserve attention first of all. Currently, the drug loxiglumide, a selective antagonist of CCK receptors, has been synthesized. When it is used in the esophagus, there is an increase in the motility index (propulsion), an increase in the rate of peristalsis, in the stomach - an increase in the rate of food evacuation, in the intestine - an increase in the motility index.

The action of another class of new prokinetics, motilin receptor agonists, is based on the effect of motilin on the motor activity of the digestive tract. The antibiotic Erythromycin mimics the effects of motilin, increasing pressure in the lower esophageal sphincter and increasing the rate of gastric emptying. Erythromycin and other (14-membered) macrolides competitively inhibit the binding of motilin to its receptors on GI smooth muscle and may act as motilin agonists. It has been established that high-density motilin receptors are present on the smooth muscles of the stomach, small and large intestine. Erythromycin increases the rate of gastric emptying in a number of pathological conditions, in particular gastroparesis in diabetics and patients with progressive systemic scleroderma, and reduces the transit time of intestinal contents in the proximal colon.

The next group of drugs are drugs that interact with 5-hydroxytryptamine (5-HT) receptors. The biological effects of 5-hydroxytryptamine are due to its interaction with specific receptors: 5-HT-1, 5-HT-2, 5-HT-3, 5-HT-4. One of the serotonin receptor modulators was the drug tropisetron. The drug lasts for a long period and significantly increases the pressure in the lower esophageal sphincter, accelerating the evacuation from the stomach. In the colon, it increases the duration of oral-cecal and colonic transit, reduces the tonic component of the gastrocolic response to food and normalizes the tone of the colon. Clinically, 5-HT3 receptor antagonists are effective in the treatment of patients with irritable bowel syndrome with dominant diarrhea.

Thus, currently, practicing doctors have a sufficient arsenal of modern prokinetic drugs for the rational treatment of dyskinesias of various parts of the gastrointestinal tract.

Literature

Ivashkin V.T., Trukhmanov A.S. Diseases of the esophagus. Pathological physiology, clinic, diagnosis, treatment. - M., 2000. - 184 p.

Prokinetics

Prokinetics are only effective in treating mild forms of GERD. If GERD is more severe, in addition to prokinetics, drugs that inhibit the secretion of gastric juice are usually prescribed.

Of the prokinetic agents, metoclopramide (10 mg/day orally) is prescribed in European clinics - this is the most commonly prescribed regimen in adults with GERD. Long-term treatment with prokinetic drugs can be dangerous, with serious, even fatal, complications.

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