Treatment of mental disorders (cholinesterase inhibitors)

There are many drugs that work with various pathologies of the nervous system. So, there is a separate category - cholinesterase inhibitors. What is it?

Cholinesterase inhibitors are drugs that act on peripheral neurotransmitter processes.

Cholinesterases are a group of enzymes with different biological roles in the body. Some enzymes (acetylcholinesterase) play an important role in the process of nerve fiber excitation. When this option is inhibited, the transmission of nerve impulses is blocked, resulting in disorganization of body processes. Serum cholinesterase protects the body from the effects of quite heavy substances, such as heavy poisonous gases. Drugs based on it are prescribed for drug overdoses.

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Cholinesterase inhibition may vary in nature. Some substances for this purpose can cause temporary and reversible inhibition of enzyme activity; they act for a short time, and after their interaction with the enzyme, the activity of the latter is restored. Other groups of inhibitor drugs lead to loss of enzyme activity, which is not restored; the effect of such drugs is persistent and irreversible.

Cholinesterase inhibitors can be used both locally and systemically. In the first case, they talk about the use of drugs in ophthalmology. In this case, they help to establish the outflow of intraocular fluid, reduce pressure in the eye and spasms. But when using them, pain in the eye, hyperemia of the sclera and conjunctiva may occur; long-term treatment may even cause the development of cataracts.

Detailed description of the study

Cholinesterase (ChE) is a group of enzymes that play an important role in the functioning of the nervous system. ChE is produced in the liver, from where the enzyme enters the bloodstream, accumulating in organs and tissues.

There are two forms of cholinesterase:

1. Acetylcholinesterase (cholinesterase I, AChE, acetylcholine hydrolase);
2. Pseudocholinesterase (butyrylcholinesterase, BuChE, cholinesterase II, propionylcholinesterase PChE).

Acetylcholinesterase is found in the brain, nerve endings, skeletal muscles, heart, lungs, intestines, spleen and red blood cells, where it breaks down acetylcholine, a substance that binds to a receptor on the surface of a neuron, activating it. Thanks to the action of acetylcholine, the neuron transmits impulses through the endings of nerve cells. This ensures muscle contraction. To prevent constant uncontrolled activation of neurons, acetylcholine molecules must be broken down in a timely manner. Acetylcholinesterase is a substance that prevents excessive activation of nerve cells.

Pseudocholinesterase is a very similar enzyme present in the heart, liver, muscle, pancreas, intestines, placenta, brain and spinal cord. This substance is involved in the breakdown of many chemical compounds. It destroys acetylcholine and substances similar in structure. These include a number of poisons (organophosphorus compounds) and some drugs, such as succinylcholine, used in anesthesia.

ChE has also been identified in amyloid plaques in people with Alzheimer's disease. A connection was found between ChE activity and the severity of obesity and lipid metabolism disorders in the body.

Preoperative analysis of ChE activity makes it possible to assess the possibility of using the muscle relaxant succinylcholine for anesthesia, which can cause breathing problems in people with reduced enzyme activity. This study is especially important for those who have had complications among close relatives (prolonged muscle paralysis or suffocation) due to anesthesia.

In some cases, there is a genetically determined deficiency of ChE in the body. This is due to a mutation in the gene encoding the formation of this enzyme. Assessment of the level of ChE in the blood can be used in a comprehensive diagnosis of the described condition.

However, more often the determination of ChE activity is carried out to detect and monitor poisoning by a number of toxic compounds. The analysis may be required by employees of fertilizer and organophosphate production plants.

Normal levels of ChE in the blood can vary within certain limits among individuals. It is an individual indicator, but in the absence of damage to the cholinergic system it is stable throughout life. Moderate changes in ChE levels accompany a wide range of inflammatory diseases. In view of this, the results of the analysis should only be assessed by a specialist. The greatest diagnostic value is monitoring the concentration of ChE in the body over time.

How do they behave when they get into the blood?

Cholinesterase inhibitors, when absorbed into the blood, show the following effects - improvement of memory and learning, activation of motor skills, but at the same time inhibition of cardiac activity, lowering blood pressure, contraction of smooth muscles, and increased secretory function of the glands. A person may experience reflex shortness of breath, a release of adrenaline and norepinephrine, and an increase in skeletal muscle tone. Inhibitors individually affect the state of the body. If we talk about average symptoms, then most often they give a decrease in heart rate and pressure. However, sometimes they can cause the opposite - tachycardia and increased blood pressure.

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References

1. Kamyshnikov, V.S. Handbook of clinical and biochemical laboratory diagnostics. Minsk, 2000. -T. 2. - P. 258¬260.
2. Starostina, V.K., Degteva, S.A. Cholinesterase: methods of analysis and diagnostic value. Information and methodological manual. Novosibirsk, 2008.
3. Bajgar, J., Bartosova, L., Kuca, K. et al. Changes of cholinesterase activities in the rat blood and brain after sarin intoxication pretreated with butyrylcholinesterase. Drug Chem. Toxicol., 2007. - Vol. 30. - No. 4. - R. 351-359.
4. Ghebremedhin, E., Thal, D., Schultz, C. et al. Homozygosity for the K variant of BCHE gene increases the risk for development of neurofibrillary pathology but not amyloid deposits at young ages. ActaNeurophatol., 2007. - Vol. 114. - No. 4. - P. 359–363.
5. Giacobini, E. Cholinesterases: new roles in brain function and in Alzheimer's disease. Neurochem. Res., 2003. - Vol. 28. - No. 3–4. — P. 515–522.
6. Girard, E., Bernard, V., Minic, J. et al. Butyrylcholinesterase and the control of synaptic responses in acetylcholinesterase knockout mice. Life Sci, 2007. - Vol. 80. - No. 24–25. — P. 2380–2385.

When to use

Cholinesterase inhibitor drugs are prescribed in some cases. Thus, they are used to treat diseases of the nervous system, which can be either inflammatory or degenerative, paralysis accompanying diseases such as polio, encephalitis, meningitis, etc. Some drugs are prescribed for mild to moderate dementia and are also used to treat Alzheimer's disease.

In addition, the indication for prescribing such drugs is increased fatigue and weakness of skeletal muscles, called myasthenia, which occurs against the background of disruptions in the process of neuromuscular transmission. They are also used for atony of smooth muscles due to the fact that they enhance the motility of the esophagus, stomach and intestines.

Cholinesterase inhibitors cannot be used for heart rhythm disorders, for example, bradycardia, angina pectoris, recent myocardial infarction, organic heart pathologies, bronchial asthma, pathologies of the stomach and duodenum, peritonitis, epilepsy, Parkinson's disease, etc.

Binding affinity[edit]

Acetylcholinesterase inhibitors[edit]

Donepezil, Phenserine, huperzine and BW284c51 are selective AChE inhibitors. [14] [12]

Butyrylcholinesterase inhibitor[edit]

Tetra(monoisopropyl) pyrophosphoramide (Iso-OMPA) and ethopropazine are selective BuChE inhibitors. [14]

AChE and BChE inhibitor[edit]

Paraoxon and rivastigmine are acetylcholinesterase inhibitors and butyrylcholinesterase inhibitors. [14] [12] [7]

In 2015, the US Food and Drug Administration's Adverse Event Reporting System database compared rivastigmine with other CEI drugs donepezil and galantamine and found that rivastigmine was associated with a higher incidence of death as an adverse event. [15]

Acetylcholinesterase inhibitors and nicotinic receptor modulator[edit]

See also: allosteric modulator and nicotinic receptor

Galantamine may be less well tolerated than donepezil and rivastigmine. [12]

Cholinesterase is an enzyme necessary for the normal functioning of the nervous system. It comes in two types: acetylcholinesterase, which plays a role in the transmission of nerve impulses, and pseudocholinesterase, which is found in the serum and cells of some internal organs and is involved in the processing and decomposition of chemicals that enter the body.

Synonyms Russian

Butyrylcholinesterase, pseudocholinesterase, BCHE, acetylcholinesterase.

English synonyms

CHS, AChE, RBC cholinesterase, red cell cholinesterase, BChE, plasma cholinesterase, pseudocholinesterase, PCHE, erythrocyte acetylcholinesterase, butyrylcholinesterase.

Research method

Kinetic colorimetric method.

Units

U/L (unit per liter).

What biomaterial can be used for research??

Venous blood.

How to properly prepare for research?

• Do not eat for 8 hours before the test; you can drink clean still water.
• Avoid physical and emotional stress and do not smoke for 30 minutes before the test.

General information about the study

Cholinesterase is an enzyme necessary for the functioning of the nervous system.

There are two types of cholinesterase in the body: acetylcholinesterase, present in red blood cells, as well as in the lungs, spleen, nerve endings and gray matter of the brain, and pseudocholinesterase (butyrylcholinesterase), found in the blood serum, liver, muscle, pancreas, heart and white matter of the brain. . Acetylcholinesterase is involved in the transmission of nerve impulses by breaking down acetylcholine, a chemical that transmits signals through the endings of nerve cells. Decreased acetylcholinesterase activity leads to the accumulation of acetylcholine in nerve endings. This, in turn, leads to over-irritation of nerve cells.

Pseudocholinesterase is necessary for the breakdown and metabolization of toxins and drugs.

What is the research used for?

• To test a patient who has been exposed to pesticides containing organophosphates - they may inhibit cholinesterase and pseudocholinesterase activity. Symptoms appear abruptly in cases of acute poisoning or may occur gradually over chronic exposure to these substances. Insecticides can enter the body through inhalation, ingestion, or skin contact.
• To identify hereditary pseudocholinesterase deficiency. Sometimes enzyme deficiency can be inherited due to genetic variations in the enzyme. Pseudocholinesterase is necessary for the body to inactivate succinylcholine, a muscle relaxant commonly used during surgery. In patients with low activity or a defective form of pseudocholinesterase after anesthesia, the effect of medications may be delayed, threatening prolonged muscle paralysis and suffocation.

When is the study scheduled?

• Periodically for patients using organophosphorus substances in agriculture or the chemical industry.
• When assessing acute poisoning from harmful substances that may cause neuromuscular damage. Symptoms of poisoning vary depending on the substance, its quantity and method of entry into the body: headache, dizziness, nausea, increased tearing and salivation, sweating. In very severe poisoning, additional symptoms appear: vomiting, diarrhea, darkening or blurred vision due to constriction of the pupils, muscle weakness, convulsive twitching, poor coordination of movements, slow breathing leading to respiratory failure and the need for artificial ventilation.
• Before surgery, if close relatives of the patient have ever had prolonged paralysis and suffocation after using succinylcholine.

What do the results mean?

Reference values

When pesticide poisoning is detected

After poisoning with organophosphorus substances, the activity of acetylcholinesterase and pseudocholinesterase can become 80% less than normal, and when the drop is more than 40%, symptoms become severe.

A significant decrease in cholinesterase activity usually indicates excessive absorption of organophosphates by the body.

When testing for sensitivity to succinylcholine

In 3% of people, pseudocholinesterase activity is reduced due to heredity, and if administered the muscle relaxant succinylcholine, they will experience its effects for a longer period of time than necessary. In such patients, low pseudocholinesterase activity indicates an increased risk of prolonged muscle relaxant action.

In addition, cholinesterase activity may be decreased in chronic liver disease and malnutrition, pregnancy, kidney failure, shock, and some types of cancer.

Medical use[edit]

Further information: Donepezil § Medical uses

While 4 ChEIs are approved in the US, only three are commercially available. [6] The three available drugs are rivastigmine, donepezil and galantamine, but tacrine is not. [6] They are commonly used to treat Alzheimer's disease and dementia. [6] If improvement occurs, it is usually within the second or third month after onset. [6]

It is difficult to determine which ChEI has superior efficacy due to design flaws in direct comparison studies. [12]