Causes of intestinal dyskinesia
Dyskinesia can develop independently or against the background of other diseases of the gastrointestinal tract. Depending on this parameter, the disease is classified into primary and secondary.
Secondary dyskinesias may be associated with the following diseases:
- cholecystitis;
- peptic ulcer of the stomach, duodenum;
- bacterial and viral intestinal infections;
- endocrine diseases (diabetes mellitus, hypothyroidism, etc.).
If the digestive system is healthy, other factors may be the cause of dyskinesia: taking certain medications (antibiotics, psychotropic drugs, contraceptives, etc.), improper (unbalanced) nutrition, allergic reactions, inflammatory diseases of other organs and systems, excess weight.
Pathophysiological basis of gastrointestinal motility disorders. Recovery Mechanisms
Lecture transcript
XXV All-Russian Educational Internet Session for doctors
Total duration: 22:43
00:00
Oksana Mikhailovna Drapkina, Secretary of the Interdepartmental Scientific Council on Therapy of the Russian Academy of Medical Sciences, Doctor of Medical Sciences, Professor:
— Now we will discuss the very interesting topic of functional gastrointestinal disorders, the pathophysiological basis of motility disorders. It is with great satisfaction, with great joy, that I give the floor to the next lecturer - Professor Marina Fedorovna Osipenko from Novosibirsk, our great friend, member of the Organizing Committee of the Internet Session.
Marina Fedorovna, I think the whole of Novosibirsk has fallen to the screens and is now looking at you!
Marina Fedorovna Osipenko, professor:
— Good afternoon, dear colleagues! The topic of my message: “The pathophysiological basis of gastrointestinal motility disorders. Mechanisms of their recovery."
Of course, the question is very difficult and occupies a significant place when we talk about gastrointestinal diseases. In a number of situations, movement disorders play a leading role in the development of diseases such as gastroesophageal reflux disease, achalasia of the esophagus, and a number of functional diseases.
In some cases, motor disorders accompany organic diseases. In this case, in addition to correcting the diseases themselves, in a number of situations we are forced to correct those motor disorders that accompany this pathology.
In a number of situations, we are faced with diseases other than the gastrointestinal tract, but with them various motor and movement disorders arise. You and I know very well that we are talking about a number of endocrine diseases (diabetes mellitus, thyroid diseases). In addition, these are neurological diseases (parkinsonism, amyloidosis and some others).
If we talk about the mechanisms by which very complex, more or less coordinated (ideally, coordinated) activity of the gastrointestinal tract is carried out, then we cannot help but talk about the enteric nervous system. It is localized in the wall of the digestive tube from the esophagus to the anal canal. Consists of at least ten billion neurons, represented by the Auerbach and Meissner plexuses.
02:20
Regulation of the enteric nervous system is carried out at the central, segmental level and directly at the local level (related to the digestive tube itself).
The enteric nervous system, in addition to the fact that it includes at least 30 varieties of a wide variety of neurons, in addition to motor function, also takes part in endocrine regulation, regulation of gastrointestinal microcirculation, immune and inflammatory processes.
It is clear that the final place of application of the enteric nervous system and the implementation of motor activity is the smooth muscle cell. It has a colossal, very diverse receptor apparatus. It interacts or is influenced by a huge number of different neurons and neurotransmitters, some of which act directly on the smooth muscle cell itself, while others mediate their influence through the nervous system.
Here are the main mediators of the enteric nervous system. These are acetylcholine, norepinephrine, serotonin, dopamine, nitric oxide, enkephalins. These are only the most famous and well-studied.
Today it is clear that the ENS mediators are at least 25 different types of neurotransmitters.
As for the stimulating factors, in addition to the ENS, that influence the motility of the gastrointestinal tract, they include the food itself and the products of their metabolism. In addition, a large number of a wide variety of hormonal substances, including those substances that are produced directly by the gastrointestinal tract itself.
A large number of different reflex relationships between different parts of the gastrointestinal tract are involved here. Of course, parasympathetic innervation. This is one of the most studied and long understood mechanisms that provide a stimulating effect on gastrointestinal motility.
With regard to inhibition, these are again biologically active components, a hormonal component, reflex relationships between organs, sympathetic innervation.
04:42
Very briefly, a few words regarding problems associated with hormonal components and gastrointestinal hormones. Here you need to keep in mind that a number of them have a stimulating effect on one organ or part of the gastrointestinal tract, while on another it may have the opposite effect. The relationship between them is quite complex.
The next section or the next mechanism that takes part in the formation of motor or motor activity of the gastrointestinal tract is the interstitial cells of Cajal. They were described quite a long time ago - in 1891. Below is a drawing of Cajal after he was able to verify, detect and describe them.
The mechanism of their action and their functions are still being actively studied. Today it is clear that, most likely, they are the drivers of the stable rhythm of various parts of the gastrointestinal tract. An interesting fact is the following. For example, if part of the stomach is resected, the interstitial cells of Cajal, which are located in other, preserved sections, take on the functions of pacemakers.
In addition to the fact that they themselves directly generate slow waves in smooth muscles, they probably act as intermediates of neuromuscular transmission (transmission of impulses from nervous tissue to smooth muscle cells).
The combination of all the above points, and quite possibly those that we may not know well enough today, ensures gastric motility. When there are waves of different types, one of them ensures the mixing of food with gastric juice, is peristaltic in nature, and determines the tone of the stomach. Other waves provide a propulsive character and concern mainly or are related to the pyloric part of the stomach.
In addition, contractions of the stomach, on the one hand, provide phase activity. On the other hand, the tonic activity of the stomach.
07:08
If we talk about the intestines, then it would not be entirely correct not to talk about the migrating and electrical complex. It, of course, also plays an important role, but to a greater extent having to do with more distal parts of the gastrointestinal tract than the stomach.
For the first time, the migrating complex, or rather, not even it, but cyclic motor interdigestive activity, was described by the Russian physiologist Vasily Nikolaevich Boldyrev in 1911. Then in 1969, experiments described the propagation of the electromyographic signal in the distal direction. The term “migrating myoelectric complex” has appeared, which is currently being actively studied.
It is absolutely clear that today it is understood as high-amplitude potentials that arise in the duodenum and spread distally throughout the large and small intestine. Moreover, when one complex reaches the ileum, the other at this time is again excited or arises in the duodenum.
The functional significance of the phases of the motor migrating complex lies in the fact that the secretory and motor activity of the corresponding part of the gastrointestinal tract changes. Moreover, at least three phases are described. In the first phase there is no activity. This corresponds to a state of secretory and motor rest. In the second phase, active mixing of chyme with digestive juices occurs. Irregular activity, segmenting and pendulum-like movements occur.
The third phase is the phase of regular activity, which is represented by propulsive peristalsis, during which active evacuation of intestinal contents occurs.
In addition to the above, the importance of this complex may be in maintaining cellular metabolism, providing endogenous nutrition, cleansing the epithelium, and maintaining microflora.
Of course, this complex is closely interconnected and most likely represents part of the existing enteric nervous system, which, in addition to regulating motility, also takes an active part in the formation of visceral sensitivity of the gastrointestinal tract.
In general, if we talk about gastrointestinal motility disorders, the main causes are damage to neurons and ganglia due to either a decrease in their number, or due to degenerative changes, or due to functional failure. Another cause may be damage to smooth muscle. Further, this may be damage to the interstitial cells of Cajal.
10:08
Motor skills disorders come in a variety of forms and can be described by a wide variety of terms. Among the actively studied idiopathic neuropathies, we should remember about achalasia, the probable etiological factors of which are immune-mediated inflammation, genetic factors, or neurotropic viruses. They cause a defect in inhibitory innervation.
This is gastroparesis, which can also be primary or secondary. Secondary due to diabetes mellitus, paraneoplastic manifestations, degenerative neuropathy.
Congenital hypertrophic pyloric stenosis, which mainly occurs in childhood and is associated with selective neuronal damage.
It may be chronic idiopathic intestinal pseudo-obstruction due to degenerative and inflammatory neuropathy. Constipation, well known to us, is due to slow transit, which is based on deterioration of neurotransmission.
Perhaps the most well-studied pathological situation is Hirschsprung's disease, which is or is a congenital defect of neurons. It arises as a result of a number of genetic factors, some of which have now been quite well verified.
As I have already said, the regulation of motor function and the levels of symptom occurrence are very diverse. Despite the fact that we seem to understand the pathophysiological mechanisms quite well today, it is not yet possible to influence them with such precision.
If we talk about drugs that are used in the treatment of motor disorders, then these are drugs that regulate central mechanisms, regulatory mechanisms (antidepressants and anxiolytics).
Further, this is a large group of drugs that directly affect either smooth muscle, thereby most often causing its relaxation, or have a more complex effect on motor mechanisms (the group of prokinetics). Here is a large class of receptor drugs, through or by influencing which prokinetics exert their influence on gastrointestinal motility.
Some of them also have a functional ability for visceral analgesia. In addition, a whole range of very diverse drugs, ranging from prebiotics to laxatives of various classes, essentially also interfere with issues of motor function.
12:49
Here are the most studied groups of drugs that we use to regulate the motor function of the gastrointestinal tract. These are acetylcholinesterase blockers, which, through activation of the cholinergic link, enhance motor skills. These are agonists of motilin (a gastrointestinal peptide that also has a stimulating effect on the gastrointestinal tract). These are serotonin type 4 receptor agonists.
There are quite a lot of drugs. Some of them have already left the market. Some, we hope, will appear on our domestic market - also having a stimulating effect on motor skills.
Perhaps the largest class of drugs that are on the market in Russia are dopaminergic receptor blockers. They enhance motor skills by removing the inhibitory effect of dopamine.
We practically do not use selective β-adrenergic receptor blockers. There are few drugs that have a blocking effect on the synthesis of nitric oxide. Non-selective opiate receptor agonists, of which until recently we mainly used loperamide. Now trimebutine has appeared on the market, which has a modeling effect on motor skills.
14:12
The slide shows different receptor apparatus, located both at the level of the nerve plexus and at the level of smooth muscles of the gastrointestinal tract. By influencing it, we can influence the motility of the gastrointestinal tract. Of course, we should not forget about the group of antispasmodic drugs, which, by directly affecting smooth muscle, relieving spasms, affect a number of motor disorders.
One of the latest reviews from 2010 lists those drugs that are just appearing on the market or that are still undergoing various phases of clinical trials. You see that their mechanism of action is extremely diverse. Starting from an antagonistic effect on some hormonal hormones (in particular cholecystokinin), ending with drugs that affect chloride channels.
If we look at another classification of those prokinetics that we most widely use in practice, we see that these are mainly dopaminergic receptors, type 4 serotonergic receptors, motilin.
Basically, most of the drugs that are currently on the market and are widely used are drugs that mostly affect the upper gastrointestinal tract.
But, looking again at the slide that we looked at a few moments ago, it is noteworthy that most of the drugs that are used have a very clear effect on motor skills, mainly having an enhancing or stimulating effect, less often a weakening one.
It is perhaps impossible not to notice that a special place among them is occupied by drugs belonging to the group of non-selective opiate receptor agonists. The only one, essentially, is trimebutine. It has a modulating effect on motor skills.
It must be said that when we talk about opiate receptors, we must remember that opiate receptors are at least represented by three options. These are µ, delta and kappa. They represent the enkephalinergic system - one of the components of the enteric nervous system, closely interacting with it. Opiate receptors are located throughout the gastrointestinal tract, both on smooth muscle and on various types of neurons of the enteric nervous system.
16:49
They work in different directions. Some of them slow down motor skills and cause relaxation of smooth muscles. Others stimulate it and cause contraction of smooth muscle cells. In addition, the enkephalinergic system (today this is clear) plays a significant role in the formation of pain sensitivity.
By influencing opiate receptors and thereby interfering with the enkephalinergic system, you and I can influence visceral sensitivity throughout the gastrointestinal tract.
The only drug currently on the market is trimebutine. It was synthesized in 1969. The drug is quickly absorbed from the gastrointestinal tract when used orally. Penetrates to a small extent through the placental barrier.
Its active metabolite is nortrimebutine. This is very important to understand, because a large number of experimental studies have been conducted with this active metabolite of trimebutine.
The mechanism of action of the drug, despite the fact that it has been on the market for 50 years, has been actively studied and continues to be studied. The effect of the drug is associated with its antispasmodic effect, effect on opioid receptors and thereby on the enkephalinergic system, direct effect on the migratory motor complex and on visceral afferent innervation.
All this ensures, which has been very well demonstrated in experiments, pain relief, normalization of motility in various parts of the gastrointestinal tract, reduction of visceral sensitivity, and reduction of mucus formation processes.
The antispasmodic effect of the drug was one of the first to be described experimentally. It is associated with blocking sodium channels, resulting in blocking calcium mobilization. This is a direct antispasmodic effect. In addition, experiments have shown that through its effect on the dorsal ganglia it reduces visceral sensitivity.
An experiment on rats demonstrated a direct effect on the receptors of the Meissner and Auerbach plexus (on the enteric nervous system). Various experiments have demonstrated the effect or reduction of visceral hypersensitivity.
19:16
Trimebutine has a stimulating effect on the third phase of the migratory motor complex, affecting primarily opioid receptors that have or act in different directions. This leads to an improvement in the propulsive peristalsis of the gastrointestinal tract.
Interesting experimental work has been carried out relatively recently. The effect of trimebutine on smooth muscle contractility was demonstrated in a model of post-infectious IBS. Muscle hyperreactivity was relieved.
Its effect on MNDA pain receptors has been shown, which is associated with the effect of local anesthesia when used. Either through the enteric nervous system or otherwise, gastrointestinal hormone levels were significantly altered by its use.
Along with other drugs that affect opioid receptors (along with them), trimebutine inhibits stress-induced diarrhea. In experiments where massive resection of the small intestine was performed, its use reduced the severity of diarrhea and malabsorption.
Another very important interesting point was that the use of the drug in experimental dysfunction of the sphincter of Oddi along with other drugs demonstrated its multidirectional effect on the sphincter of Oddi. In some doses it stimulated contraction, in others it inhibited it.
A number of other drugs studied in this work either showed no effect on the sphincter of Oddi (for example, tegaserod) or demonstrated a unidirectional effect (relaxation or spasm, contraction).
This very interesting work done on dogs (cholecystectomy performed) demonstrated an increase in the incidence of duodenogastric reflux. The only drug that was able to stop duodenogastric reflux in dogs after cholecystectomy was also trimebutine.
Based on a fairly large list of experimental studies that were carried out earlier and actively carried out in the last 10 years, it was shown that trimebutine is a universal regulator of the motility of visceral hypersensitivity. It had an antispasmodic, prokinetic effect, realizing it through its effect on opioid receptors (enteric nervous system). Directly blocked sodium and calcium channels. Affected the third phase of the motor migratory complex. It was an antagonist of pain receptors.
An important point of this drug is that it acts throughout the gastrointestinal tract, including the biliary system.
There is a large experimental base demonstrating the possibilities of using this drug and the rationale for its use in various clinical situations, which will be reported in future reports from my colleagues.
Thank you for your attention.
Oksana Drapkina: Thank you very much, Marina Fedorovna, for the most interesting speech. Now we are waiting for questions.
Symptoms and manifestations
Manifestations of intestinal dyskinesia depend on the form of the disease: spastic is characterized by colic and diarrhea, atonic is characterized by impaired peristalsis and constipation (including the discharge of large amounts of mucus). Common symptoms include the following:
- bloating, especially in the evening;
- pain (dull or aching, cutting, spasmodic), heaviness in the abdomen, discomfort;
- belching;
- nausea.
Typically, unpleasant symptoms intensify after eating and subside immediately after bowel movement.
The consequences of the disease also depend on its form. As a result of prolonged bowel dysfunction, dehydration or intoxication, anal fissures, and exacerbation of hemorrhoids may occur. With prolonged intoxication with feces, general health worsens, appetite decreases, dizziness and skin rashes appear.
