Functions of cholinergic synapses. Cholinergic and adrenergic transmission: structure of synapses, synthesis and release of mediators. Effects of stimulation of sympathetic and parasympathetic nerves Classification of drugs affecting cholinergic

Biochemistry

Acetylcholine is synthesized in the cytoplasm of the endings of cholinergic neurons. It is formed from choline and acetyl coenzyme A (mitochondrial origin) with the participation of the cytoplasmic enzyme choline acetylase (choline acetyltransferase). Acetylcholine is deposited in synaptic vesicles (vesicles). Each of them contains several thousand acetylcholine molecules. Nerve impulses cause the release of acetylcholine into the synaptic cleft, after which it interacts with cholinergic receptors.

According to available data, the cholinergic receptor of the neuromuscular synapse includes 5 protein subunits (α, α, β, γ, δ) surrounding the ion (sodium) channel and passing through the entire thickness of the lipid membrane. Two molecules of acetylcholine interact with two α-subunits, which leads to the opening of the ion channel and depolarization of the postsynaptic membrane.

Types of cholinergic receptors

Cholinergic receptors of different locations have unequal sensitivity to pharmacological substances. This is the basis for the identification of the so-called

muscarine-sensitive cholinergic receptors - m-cholinergic receptors (muscarine is an alkaloid from a number of poisonous mushrooms, such as fly agarics) and
nicotine-sensitive cholinergic receptors - n-cholinergic receptors (nicotine is an alkaloid from tobacco leaves).

M-cholinergic receptors are located in the postsynaptic membrane of cells of effector organs at the endings of postganglionic cholinergic (parasympathetic) fibers. In addition, they are present on neurons of the autonomic ganglia and in the central nervous system - in the cerebral cortex, reticular formation). The heterogeneity of m-cholinergic receptors of different localization has been established, which is manifested in their unequal sensitivity to pharmacological substances.

The following types of m-cholinergic receptors are distinguished:

m 1 -cholinergic receptors in the central nervous system and in the autonomic ganglia (however, the latter are localized outside the synapses);
m 2 -cholinergic receptors - the main subtype of m-cholinergic receptors in the heart; some presynaptic m 2 -cholinergic receptors reduce the release of acetylcholine;
m 3 -cholinergic receptors - in smooth muscles, in most exocrine glands;

The main effects of substances affecting m-cholinergic receptors are associated with their interaction with postsynaptic m2- and m3-cholinergic receptors

Effect on cholinergic receptors

The main effects of known pharmacological substances affecting m-cholinergic receptors are associated with their interaction with postsynaptic m 2 - and m 3 -cholinergic receptors.

N-cholinergic receptors are located in the postsynaptic membrane of ganglion neurons at the endings of all preganglionic fibers (in the sympathetic and parasympathetic ganglia), the adrenal medulla, the sinocarotid zone, the end plates of skeletal muscles and the central nervous system (in the neurohypophysis, Renshaw cells, etc.). The sensitivity to substances of different n-cholinergic receptors is not the same. Thus, n-cholinergic receptors of the autonomic ganglia (neural-type n-cholinergic receptors) differ significantly from the n-cholinergic receptors of skeletal muscles (muscular-type n-cholinergic receptors). This explains the possibility of selective block of ganglia (ganglion blocking drugs) or neuromuscular transmission (curare-like drugs)

Presynaptic cholinergic and adrenergic receptors take part in the regulation of acetylcholine release at neuroeffector synapses. Their excitement inhibits the release of acetylcholine.

By interacting with n-cholinergic receptors and changing their conformation, acetylcholine increases the permeability of the postsynaptic membrane. With the excitatory effect of acetylcholine, sodium ions penetrate into the cell, which leads to depolarization of the postsynaptic membrane. Initially, this is manifested by a local synaptic potential, which, having reached a certain value, generates an action potential. Then local excitation, limited to the synaptic region, spreads throughout the cell membrane. When stimulating m-cholinergic receptors, G-proteins and secondary messengers (cyclic adenosine monophosphate - cAMP; 1,2-diacylglycerol; inositol (1,4,5) triphosphate) play an important role in signal transmission.

The action of acetylcholine is very short-lived, since it is quickly hydrolyzed by the enzyme acetylcholinesterase (for example, at neuromuscular synapses or, as in the autonomic ganglia, diffuses from the synaptic cleft). Choline, formed during the hydrolysis of acetylcholine, is captured in a significant amount (50%) by presynaptic endings and transported into the cytoplasm, where it is again used for the biosynthesis of acetylcholine.

Substances that act on cholinergic synapses

Chemical (including pharmacological) substances can affect various processes related to synaptic transmission:

acetylcholine synthesis;
release of the mediator (for example, carbacholin enhances the release of acetylcholine at the level of presynaptic terminals, as well as botulinum toxin, which prevents the release of the mediator);
interaction of acetylcholine with cholinergic receptors;
enzymatic hydrolysis of acetylcholine;
capture by presynaptic endings of choline formed during the hydrolysis of acetylcholine (for example, hemicholinium, which inhibits neuronal uptake - the transport of choline across the presynaptic membrane).

Substances that affect cholinergic receptors can have a stimulating (cholinomimetic) or inhibitory (cholinergic) effect. The basis for the classification of such drugs is the focus of their action on certain cholinergic receptors. Based on this principle, drugs that affect cholinergic synapses can be systematized as follows:

Drugs affecting m- and n-cholinergic receptors
- M,n-cholinomimetics
- M,n-anticholinergics
Anticholinesterase drugs
- physostigmine salicylate
- galantamine hydrobromide
Drugs affecting m-cholinergic receptors
- M-cholinomimetics (muscarinomimetic agents)
  - pilocarpine hydrochloride
  - bethanechol
- M-cholinergic blockers (anticholinergic, atropine-like drugs)
  - atropine sulfate
  - metacin

And acetyl coenzyme A (mitochondrial origin) with the participation of the cytoplasmic enzyme choline acetylase (choline acetyltransferase). Acetylcholine is deposited in synaptic vesicles (vesicles). Each of them contains several thousand acetylcholine molecules. Nerve impulses cause the release of acetylcholine into the synaptic cleft, after which it interacts with cholinergic receptors.

Types of cholinergic receptors

Cholinergic receptors of different locations have unequal sensitivity to pharmacological substances. This is the basis for the identification of the so-called

muscarine-sensitive cholinergic receptors - m-cholinergic receptors (muscarine is an alkaloid from a number of poisonous mushrooms, such as fly agarics) and
nicotine-sensitive cholinergic receptors - n-cholinergic receptors (nicotine is an alkaloid from tobacco leaves).

The following types of m-cholinergic receptors are distinguished:

m 1 -cholinergic receptors in the central nervous system and in the autonomic ganglia (however, the latter are localized outside the synapses);
m 2 -cholinergic receptors - the main subtype of m-cholinergic receptors in the heart; some presynaptic m 2 -cholinergic receptors reduce the release of acetylcholine;
m 3 -cholinergic receptors - in smooth muscles, in most exocrine glands;
m 4 -cholinergic receptors - in the heart, the wall of the pulmonary alveoli, the central nervous system;
m 5 -cholinergic receptors - in the central nervous system, in the salivary glands, iris, in mononuclear blood cells.

Effect on cholinergic receptors

The main effects of known pharmacological substances affecting m-cholinergic receptors are associated with their interaction with postsynaptic m 2 - and m 3 -cholinergic receptors.

Presynaptic cholinergic and adrenergic receptors take part in the regulation of acetylcholine release at neuroeffector synapses. Their excitement inhibits the release of acetylcholine.

Substances that act on cholinergic synapses

Chemical (including pharmacological) substances can affect various processes related to synaptic transmission:

acetylcholine synthesis;
release of the mediator (for example, carbacholin enhances the release of acetylcholine at the level of presynaptic terminals, as well as botulinum toxin, which prevents the release of the mediator);
interaction of acetylcholine with cholinergic receptors;
enzymatic hydrolysis of acetylcholine;
capture by presynaptic endings of choline formed during the hydrolysis of acetylcholine (for example, hemicholinium, which inhibits neuronal uptake - the transport of choline across the presynaptic membrane).

Drugs affecting m- and n-cholinergic receptors
- M,n-cholinomimetics
- M,n-anticholinergics
Anticholinesterase drugs
- physostigmine salicylate
- galantamine hydrobromide
Drugs affecting m-cholinergic receptors
- M-cholinomimetics (muscarinomimetic agents)
  - pilocarpine hydrochloride
  - bethanechol
- M-cholinergic blockers (anticholinergic, atropine-like drugs)
  - atropine sulfate
  - platyphylline hydrotartrate
  - ipratropium bromide
  - scopolamine hydrobromide
  - tropicamide
  - homatropine
  - dicycloverine
  - darifenacin
  - pirenzepine (gastrozepine)
  - prifinium bromide
Drugs affecting n-cholinergic receptors
- N-cholinomimetics (nicotinomimetics)
  - lobeline hydrochloride
  - nicotine
  - Anabasine hydrochloride
  - gamibazin
- Blockers of n-cholinergic receptors or related ion channels
  - Ganglion blocking agents
    - Trepirium iodide
    - pachycarpine
  - Curare-like drugs (peripheral muscle relaxants)
    - tubocurarine chloride
    - pancuronium bromide
    - pipecuronium bromide

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Literature

Kharkevich D.A. Pharmacology. M.: GEOTAR-MED, 2004

An excerpt characterizing cholinergic synapses

– You forgot that language is not important to me, Sever. “I feel and see him,” I smiled.
- Forgive me, I know... I forgot who you are. Do you want to see what is given only to those who know, Isidora? You won't have another opportunity, you won't come back here again.
I just nodded, trying to hold back the angry, bitter tears that were ready to pour down my cheeks. The hope of being with them, of receiving their strong, friendly support was dying before I even had time to properly wake up. I was left alone. Without learning something very important to me... And almost defenseless, against a strong and terrible man, with a formidable name - Caraffa...
But the decision was made, and I was not going to back down. Otherwise, what was our Life worth if we had to live betraying ourselves? Suddenly, I completely calmed down - everything finally fell into place, there was nothing more to hope for. I could only rely on myself. And this is exactly what we should have started from. And what the end will be - I forced myself not to think about it anymore.
We moved along a high stone corridor, which, ever expanding, went deeper. The cave was just as light and pleasant, and only the smell of spring herbs became much stronger the further we went. Suddenly, a luminous golden “wall” shone right in front of us, on which a single large rune sparkled... I immediately realized that this was protection from the “uninitiated”. It looked like a dense shimmering curtain, created from some kind of material, unprecedented to me, shining with gold, through which I most likely would not have been able to pass without outside help. Stretching out his hand, North lightly touched it with his palm, and the golden “wall” immediately disappeared, opening a passage into an amazing room... I immediately had a bright feeling of something “alien”, as if something was telling me what it was It was not quite the familiar world in which I had always lived... But after a moment the strange “foreignness” disappeared somewhere, and again everything became familiar and good. The probing sensation of someone invisible watching us intensified. But, again, it was not hostile, but rather similar to the warm touch of a good old friend, once long lost and now suddenly found again... In the far corner of the room a small natural fountain sparkled with iridescent splashes. The water in it was so clear that it was visible only by the rainbow reflections of light shining on the trembling mirror drops. Looking at this miracle spring, I suddenly felt a burning thirst. And before she had time to ask Sever if I could have a drink, she immediately received an answer:
– Of course, Isidora, try it! This is the water of Life, we all drink it when we lack strength, when the burden becomes too heavy to bear. Try!
I bent down to scoop up the miraculous water with my palms, and felt incredible relief, even before I even had time to touch it!.. It seemed that all my troubles, all the bitterness suddenly receded somewhere, I felt unusually calm and happy... It was incredible – I didn’t even have time to try!.. Confusedly, I turned to the North – he was smiling. Apparently, everyone who touched this miracle for the first time experienced the same sensations. I scooped up the water with my palms - it sparkled with small diamonds, like morning dew on sunlit grass... Carefully, trying not to spill precious drops, I took a tiny sip - a unique lightness spread throughout my body!.. As if someone had waved a magic wand, taking pity on me, he gave me fifteen years off! I felt light, like a bird soaring high in the sky... My head became clean and clear, as if I had just been born.
- What is this?!. – I whispered in surprise.
“I told you,” Sever smiled. – Living Water... It helps to absorb knowledge, relieves fatigue, and returns light. Everyone who is here drinks it. She has always been here, as far as I remember.
He pushed me further. And then I suddenly realized what seemed so strange to me... The room did not end!.. In appearance it seemed small, but continued to “lengthen” as we moved through it!.. It was incredible! I looked at Sever again, but he just nodded, as if saying: “Don’t be surprised by anything, everything is fine.” And I stopped being surprised... A man “came out” right from the wall of the room... Startled in surprise, I immediately tried to pull myself together so as not to show surprise, since for everyone else living here, this was apparently completely familiar. The man came straight up to us and said in a low, sonorous voice:
- Hello, Isidora! I am the Magus Isten. I know it’s hard for you... But you yourself chose the path. Come with me - I'll show you what you've lost.
We moved on. I followed a wonderful man from whom incredible power emanated, and sadly thought how easy and simple everything would be if he wanted to help! But, unfortunately, he didn’t want to either... I walked, deep in thought, completely not noticing how I found myself in an amazing space, completely filled with narrow shelves, on which rested an incredible number of unusual gold plates and very old “packages” similar to ancient manuscripts kept in my father’s house, with the only difference being that those stored here were made on some very thin unfamiliar material, which I had never seen anywhere before. The plates and scrolls were different - small and very large, short and long, as tall as a man. And in this strange room there were a great many of them...
– This is KNOWLEDGE, Isidora. Or rather, a very small part of it. You can absorb it if you wish. It will not harm, and may even help you in your quest. Try it, honey...
Isten smiled affectionately, and it suddenly seemed to me that I had always known him. A wonderful warmth and peace emanated from him, which I so missed all these terrible days fighting Caraffa. He apparently felt all this very well, because he looked at me with deep sadness, as if he knew what an evil fate awaited me outside the walls of Meteora. And he mourned me in advance... I approached one of the endless shelves, “filled to the top” with semicircular gold plates, to see how Isten suggested... But before I even had time to bring my hand closer, a flurry of stunning things literally fell on me. wonderful visions!!! Stunning pictures, unlike anything I had ever seen, flashed through my exhausted brain, replacing each other with incredible speed... Some of them for some reason remained, and some disappeared, immediately bringing with them new ones that I I also almost didn’t have time to look at it. What was that?!.. The life of some long-dead people? Our Great Ancestors? The visions changed, rushing by at crazy speed. The stream did not end, taking me to some amazing countries and worlds, not allowing me to wake up. Suddenly one of them flashed brighter than the others, and a stunning city was revealed to me... it was airy and transparent, as if created from White Light.

1. Cholinergic synapse, its structure. Classification of agents influencing the transmission of excitation in cholinergic synapses. Examples of drugs.

2. Antihypertensive drugs acting on the renin-angiotensin system (angiotensin converting enzyme inhibitors, angiotensin II receptor blockers).

3. Write out a prescription: 10 tablets of Dexamethasone, 0.0015 g each.

4.Name a remedy for the treatment of psychomotor agitation in a patient with schizophrenia.

5. Provide advice to a client who comes to you with a complaint of severe pain in the stomach that arose as a result of taking indomethacin tablets. During the conversation, it turned out that the client has a stomach ulcer, and he began taking indomethacin on his own due to joint pain. What is the complication? What is the mechanism of its development?

1 A synapse is the point of contact between two neurons or between a neuron and a signal-receiving effector cell. A synapse consists of a pre- and postsynaptic membrane, a synaptic cleft. A nerve impulse is transmitted using a mediator (transmitter substance) through the interaction of the mediator and receptors on the postsynaptic membrane.

In the parasympathetic nervous system, the mediator is Acetylcholine, and the receptors are two types of cholinergic receptors: M (muscarine) and N (nicotine). Direct-acting M-cholinomimetics stimulate receptors on the postsynaptic membrane. Preparations Pilocarpine for glaucoma and Acecledine for intestinal and bladder atony. Indirect cholinomimetics block the enzyme acetylcholinesterase, which destroys acetylcholine and returns it to the presynaptic membrane. Having blocked the enzyme, there is no one to destroy acetylcholine in the synaptic cleft and therefore there is a lot of it - a cholinomimetic effect appears. Preparations Prozerin, Galantamine, Aminostigmine for the treatment of myasthenia gravis, paralysis, paresis.

M-cholinergic blockers are drugs that block m-cholinergic receptors on the postsynaptic membrane. Drugs: Atropine is used to examine the fundus, treat bradyarrhythmias, and AV block. Atrovent or Ipratropium bromide is used to treat bronchial asthma and is part of the combination drug Berodual. Gastrocepin or Pirenzepine for the treatment of ulcerative gastrointestinal tract, Metacin for relieving uterine tone and spasms of internal organs. Platyfillin, Spasmolitin, Aeron - for the treatment of seasickness.

N-cholinomimetics stimulate receptors on the postsynaptic membrane. Drugs of a central type - Cititon and Lobelin stimulate the respiratory center of the medulla oblongata and are used as respiratory analeptics during respiratory arrest. Peripheral-acting drugs are Tabex and Lobesil for smoking cessation.

N-anticholinergic drugs are divided into 2 groups: ganglion blockers and muscle relaxants. This is due to the presence of 2 subtypes of n-cholinergic receptors. Type 1 is in the muscles and the drugs are called muscle relaxants, type 2 is in the ganglia - nerve ganglia and drugs are ganglion blockers. Gangloblockers block the conduction of nerve impulses in the ganglia of both the sympathetic and parasympathetic nervous systems. The drugs Pahicarpin, Pentamin, Gigroniy are used to treat hypertension and relieve hypertensive crises. The main complication is orthostatic collapse.

Muscle relaxants - disrupt the conduction of impulses in skeletal muscles, relax muscles. Used for tracheal intubation, reduction of dislocations, bone fragments. Preparations Ditilin, Tubocurarine.

2 Angiotensinogen____Renin (enzyme)_______=AngiotensinI ____Angiotensin-converting enzyme (ACE)__ __________=AngiotensinII

Angiotensin II is a pressor factor in the body, causing vasospasm and increased blood pressure. Its effect is manifested when interacting with Angiotensin receptors. To treat arterial hypertension, it is necessary to block this system. There are 2 groups of drugs: 1 ACE enzyme inhibitors drugs: Captopril, Enalapril, Lisinopril.

2 Angiotensin II receptor blockers drugs: Losartan and Valsartan.

The main indication for this group of drugs is hypertension.

4 Neuroleptic haloperidol or droperidol.

5 Stomach pain occurred as a result of the damaging effect of indomethacin on the mucous membrane. This is due to the ability of the drug to inhibit the synthesis of prostaglandins in the gastric mucosa, which leads to the development of erosive and ulcerative lesions of the gastrointestinal tract. A direct contraindication for taking NSAIDs is gastric ulcer. Changes in the dosage form of the drug or the method of its administration do not significantly reduce the risk of gastrointestinal lesions. The patient should stop taking the drug and consult a doctor. General rules for taking NSAIDs: take during or after meals, wash down with milk.

Figure 10 shows a diagram of a synapse in which excitation is transmitted using acetylcholine. Acetylcholine is synthesized in the cytoplasm of cholinergic nerve endings from acetylcoenzyme A and choline; by active transport penetrates into vesicles and is deposited in vesicles.

When nerve impulses arrive, the membrane of the nerve ending is depolarized, voltage-dependent calcium channels open, Ca 2+ ions enter the cytoplasm of the nerve ending and promote the interaction of vesicle membrane proteins with presynaptic membrane proteins. As a result, the vesicles are embedded in the presynaptic membrane, open towards the synaptic cleft and release acetylcholine.

Rice. 10. Cholinergic synapse.

CHAT - choline acetyltransferase; AcCoA - acetyl coenzyme A; Acch - acetylcholine;

AChE - acetylcholinesterase.

Acetylcholine excites receptors on the postsynaptic membrane (cholinergic receptors) and is broken down by the enzyme acetylcholine esterase into choline and acetic acid. Choline is reuptaken by nerve endings (reverse neuronal uptake) and again participates in the synthesis of acetylcholine.

Substances are known that act on different stages of cholinergic transmission.

Vesamicol blocks the entry of acetylcholine into vesicles.

Mg 2+ ions and aminoglycosides prevent Ca 2+ from entering the nerve ending through voltage-gated calcium channels (aminoglycosides can interfere with neuromuscular transmission).

Botulinum toxin causes proteolysis of synaptobrevin (a vesicle membrane protein that interacts with presynaptic membrane proteins) and therefore prevents the incorporation of vesicles into the presynaptic membrane. This reduces the release of acetylcholine from the cholinergic ending. With botulism, neuromuscular transmission is disrupted; in severe cases, paralysis of the respiratory muscles is possible.

4-Aminopyridine blocks K + channels of the presynaptic membrane. This promotes membrane depolarization and the release of acetylcholine. 4-Aminopyridine facilitates neuromuscular transmission.

Anticholinesterase substances inhibit acetylcholinesterase and thus prevent the breakdown of acetylcholine; Cholinergic transmission is activated.

Substances that stimulate cholinergic receptors are called cholinergic mimetics (from the Greek mimesis - imitation; these substances “imitate” acetylcholine in their action).

Substances that block cholinergic receptors are called cholinergic blockers.

Hemicholinium prevents the neuronal reuptake of acetylcholine.

A. Drugs that stimulate cholinergic synapses

Among the drugs that stimulate cholinergic synapses, substances that stimulate cholinergic receptors - cholinomimetics, as well as anticholinesterase drugs (block acetylcholinesterase) are used in medical practice.

Cholinomimetics

Cholinergic receptors of different synapses exhibit unequal sensitivity to pharmacological substances. Cholinergic receptors of organ and tissue cells in the area of the endings of parasympathetic nerve fibers show increased sensitivity to the stimulating effect of muscarine (an alkaloid of fly agaric mushrooms). These cholinergic receptors are referred to as M-cholinergic receptors(muscarinic-sensitive cholinergic receptors).

The remaining cholinergic receptors of efferent innervation show high sensitivity to the stimulating effect of nicotine (Nicotine; tobacco alkaloid), which is why they are called N-cholinergic receptors(nicotine-sensitive cholinergic receptors). There are 2 types of N-cholinoreceptors: N N -cholinoreceptors and N m -cholinoreceptors (Fig. 11).

Rice. 11. Localization of chopinoreceptors.

Adr - adrenaline; NA - norepinephrine; M - M-cholinergic receptors; N N - N-cholinoreceptor-

neuronal type tori; N M - N-cholinergic receptors of skeletal muscles.

N N -cholinergic receptors include ganglionic N-cholinoreceptors (N-cholinergic receptors of neurons of the sympathetic and parasympathetic ganglia), as well as N-cholinergic receptors of chromaffin cells of the adrenal medulla, which secrete adrenaline and norepinephrine. The same receptors are located in the carotid glomeruli (located at the division sites of the common carotid arteries); when they are stimulated, the respiratory and vasomotor centers of the medulla oblongata are reflexively excited.

N M -cholinergic receptors include N-cholinergic receptors of skeletal muscles.

Both M-cholinergic receptors and N-cholinergic receptors are also present in the central nervous system.

In accordance with the division of cholinergic receptors into M- and N-cholinergic receptors, cholinomimetics are divided into M-cholinomimetics, N-cholinomimetics and M, N-cholinomimetics (stimulate both M- and N-cholinomimetics).

M-cholinomimetics

There are subtypes of M-cholinergic receptors - M 1 -, M 2 - and M 3 -cholinergic receptors.

In the central nervous system, M1-cholinergic receptors are localized in enterochromaffin-like cells of the stomach; in the heart - M 2 -cholinergic receptors, in the smooth muscles of internal organs, glands and in the vascular endothelium - M 3 -cholinergic receptors (Table 1).

When M, -cholinergic receptors and M 3 -cholinoreceptors are excited, phospholipase C is activated through G proteins; inositol 1,4,5-triphosphate is formed, which promotes the release of Ca 2+

Table 1. Localization of M-cholinergic receptor subtypes

1 When M 3 -cholinergic receptors of the endothelium of blood vessels are stimulated, endothelial relaxing factor - NO is released, which dilates blood vessels.

from the sarcoplasmic (endoplasmic) reticulum. The level of intracellular Ca 2+ increases, and excitatory effects develop.

When stimulating M 2 -cholinergic receptors of the heart through G proteins, adenylate cyclase is inhibited, the level of cAMP, protein kinase activity and the level of intracellular Ca 2+ are reduced. In addition, when M 2 -cholinergic receptors are excited through G o -proteins, K + channels are activated, and hyperpolarization of the cell membrane develops. All this leads to the development of inhibitory effects.

M2-cholinergic receptors are present at the endings of postganglionic parasympathetic fibers (on the presynaptic membrane); when they are excited, the release of acetylcholine decreases.

Muscarine stimulates all subtypes of M-cholinergic receptors.

Muscarine does not penetrate the blood-brain barrier and therefore does not have a significant effect on the central nervous system.

Due to the stimulation of M1-cholinergic receptors of enterochromaffin-like cells of the stomach, muscarine increases the release of histamine, which stimulates the secretion of hydrochloric acid by parietal cells.

Due to the stimulation of M2-cholinergic receptors, muscarine reduces heart contractions (causes bradycardia) and impedes atrioventricular conduction.

Due to the stimulation of M3-cholinergic receptors, muscarine:

1) constricts the pupils (causes contraction of the orbicularis muscle of the iris);

2) causes a spasm of accommodation (contraction of the ciliary muscle leads to relaxation of the ligament of cinnamon; the lens becomes more convex, the eye is set to the near point of vision);

3) increases the tone of smooth muscles of internal organs (bronchi, gastrointestinal tract and bladder), with the exception of sphincters;

4) increases the secretion of bronchial, digestive and sweat glands;

5) reduces the tone of blood vessels (most vessels do not receive parasympathetic innervation, but contain non-innervated M 3 -cholinergic receptors; stimulation of M 3 -cholinergic receptors of the vascular endothelium leads to the release of NO, which relaxes vascular smooth muscles).

Muscarine is not used in medical practice. The pharmacological effect of muscarine can occur in case of fly agaric poisoning. Constriction of the pupils of the eyes, severe salivation and sweating, a feeling of suffocation (increased secretion of the bronchial glands and increased bronchial tone), bradycardia, decreased blood pressure, cramping abdominal pain, vomiting, and diarrhea are noted.

Due to the action of other fly agaric alkaloids, which have M-anticholinergic properties, the central nervous system may be excited: anxiety, delirium, hallucinations, convulsions.

When treating fly agaric poisoning, the stomach is washed and a saline laxative is given. To weaken the effect of muscarine, the M-anticholinergic blocker atropine is administered. If symptoms of central nervous system excitation predominate, atropine is not used. To reduce central nervous system excitation, benzodiazepine drugs (diazepam, etc.) are used.

Of the M-cholinomimetics, pilocarpine, aceclidine and bethanechol are used in practical medicine.

Pilocarpine- an alkaloid of a plant native to South America. The drug is used mainly topically in ophthalmic practice. Pilocarpine constricts the pupils and causes a spasm of accommodation (increases the curvature of the lens).

Constriction of the pupils (miosis) occurs due to the fact that pilocarpine causes contraction of the circular muscle of the iris (innervated by parasympathetic fibers).

Pilocarpine increases the curvature of the lens. This is due to the fact that pilocarpine causes contraction of the ciliary muscle, to which the ligament of Zinn is attached, which stretches the lens. When the ciliary muscle contracts, the ligament of Zinn relaxes and the lens takes on a more convex shape. Due to the increase in the curvature of the lens, its refractive power increases, the eye is set to the near point of vision (a person sees close objects well and far objects poorly). This phenomenon is called a spasm of accommodation. In this case, macropsia occurs (seeing objects in an enlarged size).

In ophthalmology, pilocarpine in the form of eye drops, eye ointment, and eye films is used for glaucoma, a disease that is manifested by increased intraocular pressure and can lead to visual impairment.

At closed-angle shape glaucoma, pilocarpine reduces intraocular pressure by constricting the pupils and improving access of intraocular fluid to the angle of the anterior chamber of the eye (between the iris and cornea), in which the pectineal ligament is located (Fig. 12). Through the crypts between the trabeculae of the pectineal ligament (fountain spaces), there is an outflow of intraocular fluid, which then enters the venous sinus of the sclera - Schlemm's canal (trabeculo-canalicular outflow); increased intraocular pressure decreases. Miosis caused by pilocarpine lasts 4-8 hours. Pilocarpine in the form of eye drops is used 1-3 times a day.

At open-angle shape glaucoma, pilocarpine can also improve the outflow of intraocular fluid due to the fact that when the ciliary muscle contracts, tension is transferred to the trabeculae of the pectineal ligament; in this case, the trabecular network is stretched, the fountain spaces increase and the outflow of intraocular fluid improves.

Sometimes pilocarpine in small doses (5-10 mg) is prescribed orally to stimulate the secretion of the salivary glands for xerostomia (dry mouth) caused by radiation therapy for tumors of the head or neck.

Aceclidine- a synthetic compound, less toxic than pilocarpine. Aceclidine is administered subcutaneously for postoperative atony of the intestines or bladder.

Bethanechol- a synthetic M-cholinomimetic, which is used for postoperative atony of the intestines or bladder.

Rice. 12. Structure of the eye.

N-cholinomimetics

N-cholinomimetics are substances that excite N-xo-linoreceptors (nicotine-sensitive receptors).

N-cholinergic receptors are directly connected to Na + channels of the cell membrane. When N-cholinergic receptors are excited, Na + channels open, and Na + entry leads to depolarization of the cell membrane and excitatory effects.

N N -cholinergic receptors are located in the neurons of the sympathetic and parasympathetic ganglia, in the chromaffin cells of the adrenal medulla, and in the carotid glomeruli. In addition, N N -cholinergic receptors are found in the central nervous system, in particular, in Ren-shaw cells, which have an inhibitory effect on motor neurons of the spinal cord.

N m -cholinergic receptors are localized in neuromuscular synapses (in the end plates of skeletal muscles); when they are stimulated, skeletal muscles contract.

Nicotine- an alkaloid from tobacco leaves. A colorless liquid that turns brown when exposed to air. Well absorbed through the mucous membrane of the mouth, respiratory tract, and skin. Easily penetrates the blood-brain barrier. Most of the nicotine (80-90%) is metabolized in the liver. Nicotine and its metabolites are excreted mainly by the kidneys. Half-elimination period (t l /2) 1-1.5 hours. Nicotine is secreted by the mammary glands.

Nicotine stimulates mainly N N -cholinergic receptors and, to a lesser extent, M m -cholinergic receptors. In the action of nicotine on synapses that have N-cholinergic receptors on the postsynaptic membrane, as the dose increases, 3 phases are distinguished: 1) excitation, 2) depolarization block (persistent depolarization of the postsynaptic membrane), 3) non-depolarizing block (associated with desensitization of N-cholinergic receptors ). When smoking, the 1st phase of the action of nicotine appears.

Nicotine stimulates neurons of the sympathetic and parasympathetic ganglia, chromaffin cells of the adrenal glands, and carotid glomeruli.

Due to the fact that nicotine simultaneously stimulates sympathetic and parasympathetic innervation at the ganglion level, some of the effects of nicotine are inconsistent. Thus, nicotine usually causes miosis and tachycardia, but the opposite effects are also possible (mydriasis, bradycardia). Nicotine usually stimulates gastrointestinal motility and the secretion of the salivary and bronchial glands.

The permanent effect of nicotine is its vasoconstrictor effect (most vessels receive only sympathetic innervation). Nicotine constricts blood vessels because: 1) it stimulates the sympathetic ganglia, 2) it increases the release of adrenaline and norepinephrine from the chromaffin cells of the adrenal glands, 3) it stimulates N-cholinergic receptors of the carotid glomeruli (the vasomotor center is reflexively activated). Due to vasoconstriction, nicotine increases blood pressure.

When nicotine acts on the central nervous system, not only excitatory but also inhibitory effects are recorded. In particular, by stimulating N N -xo-linoreceptors of Renshaw cells, nicotine can inhibit monosynaptic reflexes of the spinal cord (for example, the knee reflex). The inhibitory effect of nicotine, associated with the excitation of inhibitory cells, is also possible in the higher parts of the central nervous system.

N-cholinergic receptors in CNS synapses can be localized on both postsynaptic and presynaptic membranes. Acting on presynaptic N-cholinergic receptors, nicotine stimulates the release of CNS mediators - dopamine, norepinephrine, acetylcholine, serotonin, β-endorphin, as well as the secretion of certain hormones (ACTH, antidiuretic hormone).

In smokers, nicotine causes an increase in mood, a pleasant feeling of calm or activation (depending on the type of higher nervous activity). Increases learning ability, concentration, vigilance, reduces stress reactions, manifestations of depression. Reduces appetite and body weight.

The euphoria caused by nicotine is associated with increased release of dopamine, antidepressant effects and decreased appetite - with the release of serotonin and norepinephrine.

Smoking. A cigarette contains 6-11 mg of nicotine (the lethal dose of nicotine for humans is about 60 mg). During smoking a cigarette, 1-3 mg of nicotine enters the smoker’s body. The toxic effect of nicotine is moderated by its rapid elimination. In addition, addiction to nicotine (tolerance) quickly develops.

Smoking causes even greater harm from other substances (about 500) that are contained in tobacco smoke and have irritating and carcinogenic properties. Most smokers suffer from inflammatory diseases of the respiratory system (laryngitis, tracheitis, bronchitis). Lung cancer is much more common in smokers than in non-smokers. Smoking contributes to the development of atherosclerosis (nicotine increases the level of LDL in the blood plasma and reduces the level of HDL), the occurrence of thrombosis, and osteoporosis (especially in women over 40 years of age).

Smoking during pregnancy leads to a decrease in fetal weight, increased postpartum mortality in children, and retarded children in physical and mental development.

Mental dependence develops to nicotine; When quitting smoking, smokers experience painful sensations: worsening mood, nervousness, anxiety, tension, irritability, aggressiveness, decreased concentration, decreased cognitive abilities, depression, increased appetite and body weight. Most of these symptoms are most pronounced 24-48 hours after stopping smoking. They then decrease over about 2 weeks. Many smokers, understanding the dangers of smoking, nevertheless cannot get rid of this bad habit.

In order to reduce discomfort when quitting smoking, we recommend: 1) chewing gum containing nicotine (2 or 4 mg), 2) a transdermal therapeutic system with nicotine - a special patch that evenly releases small amounts of nicotine over 24 hours (pasted on healthy areas of the skin), 3) a mouthpiece containing a cartridge with nicotine and menthol.

These nicotine preparations are being tried as medicines for Alzheimer's disease, Parkinson's disease, ulcerative colitis, Tourette's syndrome (motor and vocal tics in children) and some other pathological conditions.

Acute nicotine poisoning manifested by symptoms such as nausea, vomiting, diarrhea, abdominal pain, headache, dizziness, sweating, visual and hearing impairment, disorientation. In severe cases, a coma develops, breathing becomes impaired, and blood pressure drops. As a therapeutic measure, gastric lavage is carried out, activated carbon is prescribed internally, and measures are taken to combat vascular collapse and breathing problems.

Cytisine(thermopsis alkaloid) and lobelia(lobelia alkaloid) are similar in structure and action to nicotine, but are less active and toxic.

Cytisine in the Tabex tablets and lobelia in the Lobesil tablets are used to facilitate smoking cessation.

Cititone (0.15% cytisine solution) and lobeline solution are sometimes administered intravenously as reflex stimulants of breathing.

M.N-cholinomimetics

M,N-cholinomimetics include primarily acetylcholine- a mediator through which excitation is transmitted in all cholinergic synapses. The drug acetylcholine is produced. The drug is rarely used in the clinic due to its short duration of action (several minutes; the drug is quickly inactivated by plasma cholinesterase and acetylcholinesterase). At the same time, acetylcholine is a favorite drug for experimental work; the short duration of action allows the drug to be administered multiple times during the study.

Acetylcholine simultaneously excites M- and N-cholinoreceptors. The effect of acetylcholine on M-cholinergic receptors predominates. Therefore, the “muscarinic-like” effects of acetylcholine are usually observed. Acetylcholine has a pronounced effect on the cardiovascular system:

1) reduces heart contractions (negative chronotropic effect);

2) weakens the contractions of the atria and, to a lesser extent, the ventricles (negative inotropic effect);

3) makes it difficult to conduct impulses in the atrioventricular node (negative dromotropic effect);

4) dilates blood vessels.

Most blood vessels do not receive parasympathetic innervation, but contain non-innervated M3-cholinergic receptors in the endothelium and smooth muscles. When acetylcholine excites endothelial M3-cholinergic receptors, endothelial relaxing factor NO is released from endothelial cells, which causes dilation of blood vessels (when the endothelium is removed, acetylcholine constricts blood vessels - stimulation of M3-cholinergic receptors of vascular smooth muscles). In addition, acetylcholine reduces the vasoconstrictor effect of sympathetic innervation (stimulates M2-cholinergic receptors at the ends of sympathetic adrenergic fibers and thereby reduces the release of norepinephrine).

In connection with bradycardia and dilatation of the arteries, acetylcholine in the experiment, when administered intravenously, reduces blood pressure. But if M-cholinergic receptors are blocked with atropine, large doses of acetylcholine cause not a decrease, but an increase in blood pressure (Fig. 13). Against the background of blockade of M-cholinergic receptors, the “nicotine-like” effect of acetylcholine appears: stimulation of the sympathetic ganglia and chromaffin cells of the adrenal glands (release of adrenaline and norepinephrine, which constrict blood vessels).

Acetylcholine increases bronchial tone, stimulates intestinal motility, increases bladder detrusor tone, increases the secretion of bronchial, digestive and sweat glands.

By slightly changing the structure of acetylcholine, it was synthesized carbacholine, which is not destroyed by acetylcholinesterase and acts longer. Carbacholine solutions are sometimes used as eye drops for glaucoma.

Cholinergic synapses are the point at which contact occurs between two neurons or a neuron and an effector cell receiving a signal. The synapse consists of two membranes - presynaptic and postsynaptic, as well as the synaptic cleft. Transmission is carried out through a mediator, that is, a transmitter substance. This occurs as a result of the interaction of the receptor and the transmitter on the postsynaptic membrane. This is the main function of the cholinergic synapse.

Mediator and receptors

In the parasympathetic nervous system, the mediator is acetylcholine, the receptors are two types of cholinergic receptors: H (nicotine) and M (muscarine). M-cholinomimetics, which have a direct type of action, can stimulate receptors on the postsynaptic type membrane.

Acetylcholine synthesis occurs in the cytoplasm of neuronal cholinergic endings. It is formed from choline, as well as acetyl coenzyme-A, which is of mitochondrial origin. Synthesis occurs under the action of the cytoplasmic enzyme choline acetylase. Acetylcholine is deposited in synaptic vesicles. Each of these vesicles can contain up to several thousand acetylcholine molecules. A nerve impulse provokes the release of acetylcholine molecules into the synaptic cleft. After this, it interacts with cholinergic receptors. The structure of the cholinergic synapse is unique.

Structure

According to the data available to biochemists, the cholinergic receptor of the neuromuscular synapse may include 5 protein subunits that surround the ion channel and pass through the entire thickness of the membrane consisting of lipids. A pair of acetylcholine molecules interacts with a pair of α-subunits. This causes the ion channel to open and the postsynaptic membrane to depolarize.

Types of cholinergic synapses

Cholinergic receptors are localized differently and are also differently sensitive to the effects of pharmacological substances. In accordance with this, they distinguish:

Mascarin-sensitive cholinergic receptors are the so-called M-cholinergic receptors. Muscarine is an alkaloid found in a number of poisonous mushrooms, such as fly agarics.
Nicotine-sensitive cholinergic receptors are the so-called H-cholinergic receptors. Nicotine is an alkaloid found in tobacco leaves.

Their location

The former are located in the postsynaptic membrane of cells as part of effector organs. They are located at the endings of postganglionic parasympathetic fibers. In addition, they are also found in neuronal cells of the autonomic ganglia and in the cerebral cortex. It has been established that M-cholinergic receptors of different localization are heterogeneous, which causes different sensitivity of cholinergic synapses to substances of a pharmacological nature.

Types depending on location

Biochemists distinguish several types of M-cholinergic receptors:

Located in the autonomic ganglia and in the central nervous system. The peculiarity of the former is that they are localized outside the synapses - M1-cholinergic receptors.
Located in the heart. Some of them help reduce the release of acetylcholine - M2-cholinergic receptors.
Located in smooth muscles and in most of the endocrine glands - M3 cholinergic receptors.
Located in the heart, in the walls of the pulmonary alveoli, in the central nervous system - M4 cholinergic receptors.
Located in the central nervous system, in the iris of the eye, in the salivary glands, in mononuclear blood cells - M5 cholinergic receptors.

Effect on cholinergic receptors

Most of the effects exerted by known pharmacological substances affecting M-cholinergic receptors are associated with the interaction of these substances and postsynaptic M2 and M3 cholinergic receptors.

Let's consider the classification of drugs that stimulate cholinergic synapses below.

N-cholinergic receptors are located in the postsynaptic membrane of ganglion neurons at the endings of each of the preganglionic fibers (in the parasympathetic and sympathetic ganglia), in the sinocarotid zone, in the adrenal medulla, in the neurohypophysis, in Renshaw cells, in skeletal muscles. The sensitivity of various H-cholinergic receptors to substances is not the same. For example, H-cholinergic receptors in structure (neutral type receptors) have significant differences from H-cholinergic receptors in skeletal muscles (muscle type receptors). It is precisely this feature that allows them to selectively block the ganglia with special substances. For example, curarepod substances can block neuromuscular transmission.

Presynaptic cholinergic receptors and adrenergic receptors are involved in regulating the process of acetylcholine release at neuroeffector synapses. Stimulation of these receptors will inhibit the release of acetylcholine.

Acetylcholine interacts with H-cholinergic receptors and changes their conformation, increasing the level of permeability of the postsynaptic membrane. Acetylcholine has an exciting effect on sodium ions, which then penetrate into the cell, and this leads to the fact that the postsynaptic membrane is depolarized. Initially, a local synaptic potential arises, which reaches a certain value and begins the process of generating an action potential. After this, local excitation, which is limited to the synaptic region, begins to spread throughout the cell membrane. If the M-cholinergic receptor is stimulated, then secondary messengers and G-proteins play a significant role in signal transmission.

Acetylcholine acts for a very short time. This is due to the fact that it is rapidly hydrolyzed by the enzyme acetylcholinesterase. Choline, which is formed during the hydrolysis of acetylcholine, will be captured in half the volume by presynaptic endings and transported into the cell cytoplasm for subsequent biosynthesis of acetylcholine.

Substances that act on cholinergic synapses

Pharmacological and various chemical substances can affect many processes that are associated with synaptic transmission:

The process of acetylcholine synthesis.
The process of releasing a mediator. For example, carbacholin can enhance the process of acetylcholine release, or can interfere with the process of release of the mediator.
The process of interaction between acetylcholine and the cholinergic receptor.
Hydrolysis of acetylcholine of enzymatic nature.
The process of uptake of choline, formed as a result of the hydrolysis of acetylcholine, by presynaptic endings. For example, hemicholinium is capable of inhibiting the neuronal uptake and transport of choline into the cell cytoplasm.

Classification

Drugs that stimulate cholinergic synapses can have not only this effect, but also an anticholinergic (depressant) effect. As a basis for classifying such substances, biochemists use the direction of action of these substances on various cholinergic receptors. If we adhere to this principle, then substances that affect cholinergic receptors can be classified as follows: