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Localization of M-cholinergic receptors:

· Central nervous system: in the cortex – diffusely, in the subcortex – focally;

Postganglionic endings of parasympathetic nerves;

· cells receiving sympathetic innervation in the sweat glands, vessels of skeletal muscles and pelvic organs;

· in the heart (exception - when M2 is stimulated - inhibition, when blocked - tachycardia).

Currently, several subtypes of M-cholinergic receptors have been identified. M1 receptors are localized in the small intestine, M2 and M3 - in the atria. The presence of M1 and M2 receptors in the central nervous system has been established.

Localization of H-cholinergic receptors:

· Central nervous system (evenly in the neurohypophysis);

· sympathetic and parasympathetic ganglia;

· carotid glomeruli;

· chromaffin tissue;

· neuromuscular junctions.

In addition, there are presynaptic M- and N-cholinergic receptors that regulate the release of the transmitter.

Let us consider the mechanisms of transmission of cholinergic nerve impulses.

· A nerve impulse, passing to the presynaptic fiber, causes depolarization of the presynaptic membrane, which increases its permeability to calcium ions.

· Ca++ enters the presynaptic terminal and activates the mechanisms for the release of ACh into the synaptic cleft.

· Released ACh interacts with receptors located on the postsynaptic membrane, which leads to the opening of receptor-bound ion channels for sodium, potassium, calcium and chlorine. Where the membrane becomes permeable to Na, Ca and K, an excitatory postsynaptic potential arises, and where channels for K and Cl open, an inhibitory postsynaptic potential arises. Thus, the function of the executive body can be enhanced or reduced

· ACh is destroyed by the enzyme cholinesterase to form choline and acetic acid, which are absorbed into the presynaptic membrane and used for the synthesis of ACh.

· Due to the work of sodium/potassium ATPase, membrane repolarization occurs.

Target organ, its functions	Parasympathetic division of the ANS	Sympathetic division of the ANS
Contraction frequency Strength of contractions Conductivity	Decreasing Decreases Slows down	Rising Rising Improves
Heart, brain, lungs Skeletal muscle Skin and subcutaneous fat Abdominal organs	Expanding Expanding Not innervated Not innervated	Taper Taper Taper Taper
Smooth muscle tone Secretion of glands	Rising Rising	Decreasing Decreasing
Peristalsis Sphincter tone Secretion of gastric glands	Rising Decreasing Increases (hydrochloric acid)	Decreasing Rising Increases (mucus)
Biliary tract	Are being reduced	Relax
Bladder Sphincter	Reduced Relaxing	Relaxing Reduced
Salivary glands	Increased secretion (thin saliva)	Increased secretion (thick saliva)
Sweat glands	Not innervated	Increased secretion
Genitals		Ejaculation

Classification of drugs acting on cholinergic structures.

1. M and N-cholinomimetics:

Direct action - acetylcholine chloride, carbacholine;

Indirect action - anticholinesterase drugs:

a) reversible action - prozerin, physostigmine salicylate, galantamine hydrobromide, etc.;

c) irreversible action - armin.

2. M-cholinomimetics - pilocarpine hydrochloride, aceclidine.

3. M-anticholinergics:

Non-selective - atropine sulfate, belladonna preparations, platiphylline hydrotartrate, metacin, scopolamine hydrobromide;

Selective - ipratropium bromide (Atrovent), pirenzepine (gastrocepin).

4. N-cholinomimetics - cititon, lobeline hydrochloride.

5. N-anticholinergics:

Ganglioblockers:

a) quaternary - benzohexonium, pentamine, hygronium, arfonade;

b) non-quaternary - pyrylene.

Peripheral muscle relaxants:

a) depolarizing - ditilin;

b) anti-depolarizing - tubocurarine chloride.

6. M and N-anticholinergics - cyclodol, aprfen, arpenal.

7. Central M-anticholinergic blockers - amizil.

Acetylcholine, released from the nerve endings of postganglionic parasympathetic fibers, acts on m-cholinergic receptors; these effects can be blocked by atropine.

There are three subtypes of m-cholinergic receptors: M1, M2 and M3.

· M1-cholinergic receptors are found in brain cells and parietal cells of the stomach. These are CNS receptors.

· M 2 -cholinergic receptors are localized in the heart (they reduce heart rate, atrioventricular conduction and myocardial oxygen demand, weaken atrial contractions);

· M3-cholinergic receptors - in smooth muscles (cause constriction of the pupils, spasm of accommodation, bronchospasm, spasm of the biliary tract, ureters, contraction of the bladder, uterus, increase intestinal motility, relax sphincters); in the glands (cause lacrimation, sweating, copious secretion of liquid, protein-poor saliva, bronchorrhea, secretion of acidic gastric juice).

With the exception of pirenzepine (gastrozepin), which selectively blocks M3-cholinergic receptors, clinically used M-cholinergic receptor agonists and antagonists show either little or no selectivity for the various subtypes of these receptors.

Effects of acetylcholine

The muscarinic-like (m-cholinomimetic) effects of acetylcholine are noted when the parasympathetic nervous system is stimulated (except for sweating and vasodilation), they are generally opposite to the effects of stimulation of the sympathetic system. These effects include:

constriction of the pupil (miosis), spasm of accommodation (the eye is set to close vision),

profuse salivation,

narrowing of the bronchi,

increased secretion of bronchial glands,

arterial hypotension (caused by bradycardia and vasodilation),

increased motility and secretion of the gastrointestinal tract,

contraction of bladder smooth muscle

increased sweating.

It should be noted that the sensitivity of various effector organs receiving parasympathetic innervation to the action of m-cholinergic blockers varies significantly:

• salivary, bronchial and sweat glands are highly sensitive to the action of these drugs,
• To dilate the pupil, paralysis of accommodation and eliminate the influence of p. vagus on the heart, large doses of m-anticholinergic blockers are required
• even higher concentrations of drugs are necessary to reduce the parasympathetic effect on the tone of the smooth muscles of the intestine and bladder
• The secretion of hydrochloric acid in the stomach is most resistant to the action of m-anticholinergic blockers.

Non-selective M-anticholinergics:

ATROPINE, PLATIFYLLINE, Belladonna PREPARATIONS in doses that inhibit HCl secretion cause dry mouth, dilated pupils, paralysis of accommodation, tachycardia and therefore are rarely used for peptic ulcers at present. The only purpose of their use is to eliminate painful spasms of the smooth muscles of the stomach and intestines.

Release forms:

Atropine solution for injection 0.1% 1ml, administered subcutaneously or intramuscularly

Belladonna preparations - in the form of complex tablets Bellasthesin, becarbon, besalol

Platifillin 0.2% solution for injection 1ml. administered subcutaneously.

PIRENZEPINE (gastrocepin) selectively blocks M 3 -cholinergic receptors of enterochromaffin-like cells located in the wall of the stomach. Enterochromaffin-like cells release histamine, which stimulates the histamine receptors of parietal cells. Thus, blockade of M3 receptors of enterochromaffin-like cells leads to inhibition of hydrochloric acid secretion. Pirenzepine penetrates poorly through histagema barriers and is practically free of side effects typical of anticholinergic drugs (dry mouth is possible).

Release form: tablets 25 and 50 mg.

Usually, 1 tablet is prescribed in the morning 30 minutes before meals; if necessary, 1 tablet 3 times a day.

(M-CHOLINOBLOCKERS, ATROPINE-LIKE DRUGS)

M-CHOLINOBLOCKERS OR M-CHOLINOLYTICS, DRUGS OF THE ATROPINE GROUP - these are drugs that block M-cholinergic receptors. A typical and most well-studied representative of this group is ATROPINE - hence the group is called atropine-like drugs. M-cholinergic blockers block peripheral Mcholinergic receptors located on the membrane of effector cells at the endings of postganglionic cholinergic fibers, that is, they block PARASYMPATHIC, cholinergic innervation. By blocking the predominantly muscarinic effects of acetylcholine, the effect of atropine on the autonomic ganglia and neuromuscular synapses does not apply.

Most atropine-like drugs block M-cholinergic receptors in the central nervous system.

An M-anticholinergic blocker with high selectivity of action is ATROPINE (Atropini sulfas; tablets 0.0005; ampoules 0.1% - 1 ml; 1% eye ointment).

ATROPINE is an alkaloid found in plants of the nightshade family. Atropine and related alkaloids are found in a number of plants:

Belladonna (Atropa belladonna);

Henbane (Hyoscyamus niger);

Datura stramonium.

Atropine is currently obtained synthetically, that is, chemically. The name Atropa Belladonna is paradoxical, since the term "Atropos" means "three fates leading to an inglorious end of life", and "Belladonna" means "charming woman" (donna is a woman, Bella is a female name in Romance languages). This term is due to the fact that the extract from this plant, instilled into the eyes of the beauties of the Venetian court, gave them a “shine” - dilated the pupils.

The mechanism of action of atropine and other drugs in this group is that by blocking M-cholinergic receptors, competing with acetylcholine, they prevent the mediator from interacting with them.

The drugs do not affect the synthesis, release and hydrolysis of acetylcholine. Acetylcholine is released, but does not interact with receptors, since atropine has a greater affinity (affinity) for the receptor. Atropine, like all M-cholinergic blockers, reduces or eliminates the effects of irritation of cholinergic (parasympathetic) nerves and the effect of substances with M-cholinomimetic activity (acetylcholine and its analogues, AChE agents, M-cholinomimetics). In particular, atropine reduces the effects of irritation n. vagus The antagonism between acetylcholine and atropine is competitive, therefore, when the concentration of acetylcholine increases, the effect of atropine at the point of application of muscarine is eliminated.

MAIN PHARMACOLOGICAL EFFECTS OF ATROPINE

1. Atropine has especially pronounced antispasmodic properties. By blocking M-cholinergic receptors, atropine eliminates the stimulating effect of parasympathetic nerves on smooth muscle organs. The tone of the muscles of the gastrointestinal tract, bile ducts and gallbladder, bronchi, ureters, and bladder decreases.

2. Atropine also affects the tone of the eye muscles. Let's look at the effects of atropine on the eye:

a) when atropine is administered, especially when applied topically, due to a block of M-cholinergic receptors in the circular muscle of the iris, pupil dilation is noted - mydriasis. Mydriasis also intensifies as a result of the preservation of the sympathetic innervation of m. dilatator pupillae. Therefore, atropine acts on the eye for a long time in this regard - up to 7 days;

b) under the influence of atropine, the ciliary muscle loses its tone, it becomes flattened, which is accompanied by tension in the ligament of Zinn, which supports the lens. As a result, the lens also flattens, and the focal length of such a lens lengthens. The lens sets vision to the far point of vision, so nearby objects are not clearly perceived by the patient. Since the sphincter is in a state of paralysis, it is not able to constrict the pupil when viewing nearby objects, and photophobia (photophobia) occurs in bright light. This condition is called ACCOMMODATION PARALYSIS or CYCLOPLEGIA. Thus, atropine is both a mydriatic and a cycloplegic. Local application of a 1% atropine solution causes a maximum mydriatic effect within 30-40 minutes, and complete restoration of function occurs on average after 3-4 days (sometimes up to 7-10 days). Paralysis of accommodation occurs within 1-3 hours and lasts up to 8-12 days (approximately 7 days);

c) relaxation of the ciliary muscle and displacement of the lens into the anterior chamber of the eye is accompanied by a violation of the outflow of intraocular fluid from the anterior chamber. In this regard, atropine either does not change intraocular pressure in healthy individuals, or in individuals with a shallow anterior chamber and in patients with narrow-angle glaucoma, it may even increase, that is, lead to an exacerbation of an attack of glaucoma.

INDICATIONS FOR THE USE OF ATROPINE IN OPHTHALMOLOGY

1) In ophthalmology, atropine is used as a mydriatic to cause cycloplegia (paralysis of accommodation). Mydriasis is necessary when examining the fundus of the eye and in the treatment of patients with iritis, iridocyclitis and keratitis. In the latter case, atropine is used as an immobilization agent that promotes functional rest of the eye.

2) To determine the true refractive power of the lens when selecting glasses.

3) Atropine is the drug of choice if it is necessary to achieve maximum cycloplegia (paralysis of accommodation), for example, when correcting accommodative strabismus.

3. INFLUENCE OF ATROPINE ON ORGANS WITH SMOOTH MUSCLE. Atropine reduces the tone and motor activity (peristalsis) of all parts of the gastrointestinal tract. Atropine also reduces peristalsis of the ureters and the bottom of the bladder. In addition, atropine relaxes the smooth muscles of the bronchi and bronchioles. In relation to the biliary tract, the antispasmodic effect of atropine is weak. It should be emphasized that the antispasmodic effect of atropine is especially pronounced against the background of a previous spasm. Thus, atropine has an antispasmodic effect, that is, atropine acts in this case as an antispasmodic. And only in this sense can atropine act as a “painkiller”.

4. INFLUENCE OF ATROPINE ON THE ENDOCRECTION GLANDS. Atropine sharply weakens the secretion of all exocrine glands, with the exception of mammary glands. In this case, atropine blocks the secretion of liquid watery saliva caused by stimulation of the parasympathetic part of the autonomic nervous system, causing dry mouth. Tear production decreases. Atropine reduces the volume and overall acidity of gastric juice. In this case, suppression and weakening of the secretion of these glands can be up to their complete shutdown. Atropine reduces the secretory function of glands in the cavities of the nose, mouth, pharynx and bronchi. The secretion of the bronchial glands becomes viscous. Atropine, even in small doses, inhibits the secretion of SWEAT GLANDS.

5. INFLUENCE OF ATROPINE ON THE CARDIOVASCULAR SYSTEM. Atropine, taking the heart out of control n. vagus, causes TACHYCARDIA, that is, it increases the heart rate. In addition, atropine helps facilitate the conduction of impulses in the conduction system of the heart, in particular in the AV node and along the atrioventricular bundle as a whole. These effects are less pronounced in elderly people, since in therapeutic doses atropine does not have a significant effect on peripheral blood vessels; their tone is reduced. vagus Atropine does not have a significant effect on blood vessels in therapeutic doses.

6. INFLUENCE OF ATROPINE ON THE CNS. In therapeutic doses, atropine has no effect on the central nervous system. In toxic doses, atropine sharply excites the neurons of the cerebral cortex, causing motor and speech excitation, reaching mania, delirium and hallucinations. The so-called “atropine psychosis” occurs, leading further to a decrease in function and the development of coma. It also has a stimulating effect on the respiratory center, but with increasing doses, respiratory depression may occur.

INDICATIONS FOR USE OF ATROPINE (except ophthalmological)

1) As an ambulance for:

a) intestinal

b) renal

c) hepatic colic.

2) For bronchospasms (see adrenergic agonists).

3) In complex therapy of patients with peptic ulcer of the stomach and duodenum (reduces the tone and secretion of the glands). It is used only in a complex of therapeutic measures, since it reduces secretion only in large doses.

4) As a means of presedation in anesthesiological practice, atropine is widely used before surgery. Atropine is used as a means of drug preparation of a patient for surgery because it has the ability to suppress the secretion of the salivary, nasopharyngeal and tracheobronchial glands.

As is known, many anesthetics (ether in particular) are strong irritants of the mucous membranes. In addition, by blocking M-cholinergic receptors of the heart (the so-called vagolytic effect), atropine prevents negative reflexes on the heart, including the possibility of its reflex stop.

By using atropine and reducing the secretion of these glands, the development of inflammatory postoperative complications in the lungs is prevented. This explains the importance of the fact that resuscitation doctors attach when they talk about the full opportunity to “breathe” the patient.

5) Atropine is used in cardiology. Its M-anticholinergic effect on the heart is beneficial in some forms of cardiac arrhythmias (for example, atrioventricular block of vagal origin, that is, with bradycardia and heart block).

6) Atropine has found widespread use as an ambulance for poisoning:

a) AChE means (FOS)

b) M-cholinomimetics (muscarine).

Along with atropine, other atropine-like drugs are well known. Natural atropine-like alkaloids include SCOPOLAMINE (hyoscine) Scopolominum hydrobromidum. Available in ampoules of 1 ml - 0.05%, as well as in the form of eye drops (0.25%). Contained in the mandrake plant (Scopolia carniolica) and in the same plants that contain atropine (belladonna, henbane, datura). Structurally close to atropine. It has pronounced M-anticholinergic properties. There is one significant difference from atropine: in therapeutic doses, scopolamine causes mild sedation, central nervous system depression, sweating and sleep. It has a depressing effect on the extrapyramidal system and the transmission of excitation from the pyramidal tracts to the motor neurons of the brain. Introducing the drug into the conjunctival cavity causes less prolonged mydriasis.

Therefore, anesthesiologists use scopolomine (0.3-0.6 mg s.c.) as a premedication, but usually in combination with morphine (but not in the elderly, as it can cause confusion). It is sometimes used in psychiatric practice as a sedative, and in neurology for the correction of parkinsonism. Scopolamine has a shorter duration of action than atropine. They are also used as an antiemetic and sedative for sea and airborne illnesses (Aeron tablets are a combination of scopolamine and hyoscyamine).

PLATIFYLLINE also belongs to the group of alkaloids obtained from plant raw materials (rhombolic ragwort). (Platyphyllini hydrotartras: tablets of 0.005, as well as ampoules of 1 ml - 0.2%; eye drops - 1-2% solution). It acts in much the same way, causing similar pharmacological effects, but weaker than atropine. It has a moderate ganglion-blocking effect, as well as a direct myotropic antispasmodic effect (papaverine-like), as well as on the vasomotor centers. Has a calming effect on the central nervous system. Platiphylline is used as an antispasmodic for spasms of the gastrointestinal tract, bile ducts, gallbladder, ureters, with increased tone of the cerebral and coronary vessels, as well as for the relief of bronchial asthma. In ophthalmic practice, the drug is used to dilate the pupil (it has a shorter effect than atropine and does not affect accommodation). It is administered under the skin, but it should be remembered that solutions of 0.2% concentration (pH = 3.6) are painful.

For ophthalmic practice, HOMATROPINE (Homatropinum: 5 ml bottles - 0.25%) is proposed. It causes pupil dilation and paralysis of accommodation, that is, it acts as a mydriatic and cycloplegic. The ophthalmic effects caused by homatropine last only 15-24 hours, which is much more convenient for the patient compared to the situation when atropine is used. The risk of raising IOP is less, since atropine is weaker, but at the same time, the drug is contraindicated for glaucoma. Otherwise, it is not fundamentally different from atropine; it is used only in ophthalmic practice.

The synthetic drug METACIN is a very active M-anticholinergic blocker (Methacinum: in tablets - 0.002; in ampoules 0.1% - 1 ml. A quaternary ammonium compound that poorly penetrates the BBB. This means that all its effects are due to peripheral M - anticholinergic effect. It differs from atropine in having a more pronounced bronchodilator effect, no effect on the central nervous system. It suppresses the secretion of the salivary and bronchial glands more strongly than atropine. It is used for bronchial asthma, peptic ulcer, for the relief of renal and hepatic colic, for premedication in anesthesiology. /in - in 5-10 minutes, intramuscularly - in 30 minutes) - more convenient than atropine. The analgesic effect is superior to atropine, causes less tachycardia.

Among medicines containing atropine, belladonna (belladonna) preparations are also used, for example, belladonna extracts (thick and dry), belladonna tinctures, and combined tablets. These are weak drugs and are not used in ambulances. Used at home in the pre-hospital stage.

Finally, a few words about the first representative of selective muscarinic receptor antagonists. It turned out that in different organs of the body there are different subclasses of muscarinic receptors (M-one and M-two). Recently, the drug gastrocepin (pirenzepine) was synthesized, which is a specific inhibitor of M-one cholinergic receptors of the stomach. Clinically, this is manifested by intense inhibition of gastric juice secretion. Due to the pronounced inhibition of gastric juice secretion, gastrocepin causes persistent and rapid pain relief. Used for stomach and duodenal ulcers, gastritis, daudenitis. It has significantly fewer side effects and has virtually no effect on the heart and does not penetrate into the central nervous system.

SIDE EFFECTS OF ATROPINE AND ITS DRUGS. In most cases, side effects are a consequence of the breadth of pharmacological action of the drugs being studied and are manifested by dry mouth, difficulty swallowing, intestinal atony (constipation), blurred visual perception, and tachycardia. Topical use of atropine can cause allergic reactions (dermatitis, conjunctivitis, swelling of the eyelids). Atropine is contraindicated for glaucoma.

ACUTE POISONING WITH ATROPINE, ATROPINE-LIKE DRUGS AND PLANTS CONTAINING ATROPINE. Atropine is far from a harmless drug. Suffice it to say that even 5-10 drops can be toxic. The lethal dose for adults when taken orally begins with 100 mg, for children - with 2 mg; When administered parenterally, the drug is even more toxic. The clinical picture of poisoning with atropine and atropine-like drugs is very characteristic. There are symptoms associated with the suppression of cholinergic influences and the effect of the poison on the central nervous system. At the same time, depending on the dose of the ingested medication, MILD and SEVERE courses are distinguished.

In case of mild poisoning, the following clinical signs develop:

1) dilated pupils (mydriasis), photophobia;

2) dry skin and mucous membranes. However, due to a decrease in sweating, the skin becomes hot and red, there is an increase in body temperature, and a sharp flushing of the face (the face is “bursting with heat”);

3) dryness of mucous membranes;

4) severe tachycardia;

5) intestinal atony. In case of severe poisoning against the background of all

indicated symptoms on

the foreground is PSYCHOMOTOR EXCITATION, that is, both mental and motor excitement. Hence the well-known expression: “I’ve eaten too much henbane.” Motor coordination is impaired, speech is blurred, consciousness is confused, and hallucinations are noted. Phenomena of atropine psychosis are developing, requiring the intervention of a psychiatrist. Subsequently, depression of the vasomotor center may occur with a sharp expansion of the capillaries. Collapse, coma and respiratory paralysis develop.

HELP MEASURES FOR ATROPINE POISONING If the poison is taken

inside, then an attempt should be made to pour it in as quickly as possible (gastric lavage, laxatives, etc.); astringents - tannin, adsorbents - activated carbon, forced diuresis, hemosorption. It is important to apply specific treatment here.

1) Before washing, a small dose (0.3-0.4 ml) of sibazon (Relanium) should be administered to combat psychosis and psychomotor agitation. The dose of sibazon should not be large, as the patient may develop paralysis of vital centers.

In this situation, aminazine cannot be administered, since it has its own muscarinic-like effect.

2) It is necessary to displace atropine from its connection with cholinergic receptors; various cholinomimetics are used for these purposes. It is best to use physostigmine (iv, slowly, 1-4 mg), which is what they do abroad. We use AChE agents, most often prozerin (2-5 mg, s.c.). Medicines are administered at intervals of 1-2 hours until signs of elimination of the blockade of muscarinic receptors appear. The use of physostigmine is preferable because it penetrates well through the BBB into the central nervous system, reducing the central mechanisms of atropine psychosis. To alleviate photophobia, the patient is placed in a darkened room and rubbed with cool water. Careful care is required. Artificial respiration is often required.

N-CHOLINERGIC DRUGS

Let me remind you that H-cholinergic receptors are localized in the autonomic ganglia and end plates of skeletal muscles. In addition, H-cholinergic receptors are located in the carotid glomeruli (they are necessary to respond to changes in blood chemistry), as well as the adrenal medulla and the brain. The sensitivity of H-cholinergic receptors of different localization to chemical compounds is not the same, which makes it possible to obtain substances with a predominant effect on the autonomic ganglia, cholinergic receptors of neuromuscular synapses, and the central nervous system.

Drugs that stimulate H-cholinergic receptors are called H-cholinomimetics (nicotinomimetics), and those that block them are called H-cholinergic blockers (nicotine blockers).

It is important to emphasize the following feature: all H-cholinomimetics excite H-cholinergic receptors only in the first phase of their action, and in the second phase the excitation is replaced by an inhibitory effect. In other words, N-cholinomimetics, in particular the reference substance nicotine, have a two-phase effect on H-cholinergic receptors: in the first phase, nicotine acts as an N-cholinomimetic, in the second - as an N-cholinergic blocker.

N-CHOLINOMIMEtics OR DRUGS THAT STIMULATE NICOTINE-SENSITIVE CHOLINORESCEPTORS. This group includes alkaloids: nicotine, lobeline and cytisine (cytitone).

Since nicotine has no therapeutic value, we will focus on the last 2 N-cholinomimetics (lobeline and cytisine).

Let's analyze the drug Cytitonum (amp. 1 ml), representing a 0.15% solution of cytisine. Cytisine itself is an alkaloid from broom (Cytisus laburnum) and thermopsis (Termopsis lanceolata) plants. A special feature of the drug Cititon is that it more or less selectively excites the H-cholinergic receptors of the carotid glomeruli and the adrenal medulla, without affecting the remaining N-cholinergic receptors. The respiratory center is reflexively excited, and blood pressure levels increase.

Cititon is used to stimulate the respiratory center when it is depressed. When cititon is administered, as a drug that reflexively excites the respiratory center, after 3-5 minutes there is an excitation of breathing and an increase in blood pressure by 10-20 mm Hg. Art., for 15-20 minutes.

The drug acts reflexively, jerkily, and for a short time. It is used to excite the respiratory center with preserved reflex excitability (to the point of coma) of the respiratory center. Currently used for one indication: for carbon monoxide (CO) poisoning. Now, essentially, this is the only indication in the clinic. In experimental pharmacology it is used to determine blood flow time.

There is a similar drug - LOBELIN (Lobelini hydrochloridum: amp. 1%, 1 ml). The action is exactly the same as qi

Tithonian, but somewhat weaker than the latter.

Both drugs are used to stimulate breathing. Administer intravenously (only, since the action is reflex). In addition, both alkaloids are used as the main components of drugs that facilitate quitting tobacco smoking (cytisine in Tabex tablets, lobeline in Lobesil tablets). Weak drugs. They helped a small number of people stop smoking.

N-CHOLINOBLOCKERS OR NICOTINE SENSE BLOCKING DRUGS

BODY CHOLINORESEPTORS

Drugs with an H-anticholinergic effect include 2 groups of drugs:

1) ganglion blocking agents or ganglion blockers;

2) neuromuscular junction blockers or muscle relaxants.

In addition, there are central anticholinergic blockers. GANGLIOB

LOCATORS, that is, means that block the transmission of excitation in the autonomic ganglia. Ganglioblockers block

Sympathetic N-cholinergic receptors

and parasympathetic ganglia, as well as the adrenal medulla and carotid glomerulus. There are currently a significant number of ganglion blockers.

According to the mechanism of action, ganglion blockers used in the clinic are classified as antidepolarizing substances. They block H-cholinergic receptors, preventing the depolarizing effect of acetylcholine.

The first ganglion blocker was Benzohexonium (tables of 0.1 and 0.25; amp. 1 ml - 2.5%). Then Pentaminum appeared (amp. 1 and 2 ml - 5%). Pyrylene, hygronium, pachycarpine, etc. To the main pharmaceuticals

The ecological effects observed during the sorptive action of ganglion blockers include the following:

1) a disturbance in the transmission of impulses in the parasympathetic ganglia is manifested by inhibition of the secretion of the salivary glands, gastric glands, and inhibition of motility of the digestive tract. In this regard, ganglion blockers are used for very severe forms of peptic ulcer;

2) as a result of inhibition of the sympathetic ganglia, blood vessels (arterial and venous) dilate, arterial and venous pressure decreases. Vasodilation leads to improved blood circulation in the relevant areas, regions, and tissues. From here follows a group of indications.

Indications for the use of ganglion blockers:

1) with spasms of peripheral vessels (for example, with obliterating endarthritis); Previously - in the 60s - they were considered very valuable means;

2) in the most severe forms of hypertension (hypertensive crisis) with left ventricular failure;

3) in intensive care - with acute pulmonary and cerebral edema;

4) for controlled hypotension (hypotension). This is necessary when performing operations on the heart, on large vessels, on the thyroid gland, and during mastectomy (breast surgery). For this purpose, short-acting ganglion blockers (arfonade, hygronium) are used, the effect of which lasts 10-15 minutes. In addition, these drugs are used for acute hypertensive encephalopathy, dissecting aortic aneurysm, and retinopathy. Typically, ganglion blockers are used orally, but in emergency cases they are administered intravenously or intramuscularly.

MAIN DISADVANTAGE AND MAIN SIDE EFFECTS OF GANGLION BLOCKERS. The main disadvantage of ganglion blockers is the lack of selectivity of action. Among the side effects, it should be noted the frequent development of arthostatic collapse, that is, when, when taking a vertical position, the patient’s blood pressure sharply decreases (fainting, collapse).

To prevent the development of this condition, the patient is recommended to stay in bed for 2 hours after taking ganglion blockers.

In case of severe poisoning with ganglion blockers, a drop in blood pressure to 0 (zero) is observed, and in case of very severe poisoning, skeletal atony may even develop. This occurs when ganglion blockers lose their selectivity of action on the H-cholinergic receptors of the ganglia and then act on all H-receptors, including skeletal muscles.

Often, when taking ganglion blockers, constipation (obstipation) is observed, there may be mydriasis, urinary retention, and more. In addition, tolerance to ganglion blockers quickly develops.

ASSISTANCE MEASURES IN CASE OF POISONING WITH GANGLION BLOCKERS. Everything needs to be carried out as indicated earlier to combat the poison in the patient’s body. Give oxygen, put on artificial respiration, administer analeptics, AChE agents, proserin (ganglionic blocker antagonists). Raising blood pressure (adrenergic agonists) and from these positions the drug ephedrine looks a little better.

DRUGS BLOCKING N-CHOLINORECEPTORS OF SKELETAL MUSCLES

(CURARE-LIKE DRUGS OR PERIPHERAL MUSCLE RELOXANTS

ACTIONS)

The main effect of this group of pharmacological agents is the relaxation of skeletal muscles as a result of the blocking effect of substances on neuromuscular transmission. Since such properties were first discovered in CURARE, the substances of this group were called curare-like agents.

CURARE is an extract from plants native to South America. The natives of South America have used curare poison for a long time as an arrow poison. Since the 40s of the 20th century they began to use it in medicine. Curare contains a significant number of different alkaloids, one of the main ones being TUBOCURARINE. Now (mostly synthetics) a number of synthetic and semi-synthetic drugs have been obtained that block the transmission of excitation from motor nerves to skeletal muscles.

BY CHEMICAL STRUCTURE, all curare-like drugs belong either to quaternary (dioxonium, tubocurarine, pancuronium, ditilin) ​​ammonium compounds (they are less absorbed), or they are tertiary amines (they penetrate the BBB poorly; pachycarpine, pyrylene, melliktin, candelphin, etc.).

MECHANISM OF ACTION OF CURARE-LIKE DRUGS. Muscle relaxants inhibit neuromuscular transmission at the level of the postsynaptic membrane by interacting with cholinergic receptors in the end plates.

The neuromuscular block caused by different muscle relaxants does not have the same genesis. The classification of curare-like drugs is based on this. Based on the mechanism of action, muscle relaxants are divided into 3 groups of drugs:

1) anti-depolarizing (non-depolarizing) agents (prevent membrane depolarization): tubocurarine, anatruxonium, pancuronium, melliktin, diplacin;

2) depolarizing agents (ditilin) ​​- significantly contribute to depolarization;

3) mixed type agents - dioxin. Currently, there are many new synthetic products of mixed type.

ANTI-DEPOLARIZING DRUGS, as follows from the definition, block H-cholinergic receptors and interfere with the depolarizing effect of acetylcholine.

DEPOLARIZING DRUGS such as dithiline - excite H-cholinergic receptors and cause persistent depolarization of the postsynaptic membrane, thereby providing a persistent myoparalytic effect (if acetylcholine acts for 0.001-0.002 seconds, then dithiline - 5-7 minutes).

MIXED TYPE DRUGS (dioxonium) combine depolarizing and antidepolarizing properties. In the light of modern views, these effects are associated with ionic relaxation mechanisms. There is a blockade of ion channels and, accordingly, a blockade of ion currents. Muscle relaxants relax muscles in a specific sequence: most drugs first block the neuromuscular junctions of the face and neck, then the limbs and torso. The respiratory muscles are the most resistant to the action of muscle relaxants. Lastly, the diaphragm is paralyzed, which is accompanied by cessation of breathing. During the period when paralysis progresses, consciousness and sensitivity are not impaired. Recovery proceeds in reverse order. It has now been revised, and muscle relaxants are being created with a predominant effect on certain groups of skeletal muscles.

There are SHORT-acting muscle relaxants (5-10 minutes), these include ditilin; MEDIUM duration (20-50 minutes) - tubocurarine, pancuronium, anatruxonium and LONG-TERM action (60 minutes or more) - anatruxonium, pylecuronium, etc. in large doses.

Based on the mechanism of action, antagonists of curare-like drugs are selected. For anti-depolarizing competitive agents, active antagonists are AChE agents (proserine, galantamine, pyridostigmine, edrophonium). In addition, agents have now been developed to promote the release of acetylcholine from the endings of motor nerves (pimadine).

In case of an overdose of depolarizing agents (ditilin), AChE agents are ineffective (on the contrary, even). Therefore, the assistance measures are different. First of all, they use the introduction of fresh citrated blood containing plasma cholinesterase, which hydrolyzes dithiline (which is a double acetylcholine molecule in structure). In addition, ventilation! Route of administration: i.v. But there are drugs for per os.

INDICATIONS FOR USE. The main purpose of muscle relaxants is to relax skeletal muscles during major operations and various surgical interventions. Relaxing skeletal muscles greatly facilitates:

1) performing many operations on the organs of the abdominal and thoracic cavities, as well as on the limbs. Use long-acting drugs;

2) muscle relaxants are used for tracheal intubation, bronchoscopy, correction of dislocations and reposition of bone fragments. In this case, short-acting drugs (ditilin) ​​are used;

3) in addition, the drugs are used in the treatment of patients with tetanus, status epilepticus, and electroconvulsive therapy (d-tubocurarine is used to diagnose myasthenia gravis);

4) tertiary amines (mellictin, codelfin - larkspur alkaloids), used in some diseases of the central nervous system to reduce increased skeletal muscle tone (per os).

SIDE EFFECTS. Side effects when using curare-like drugs are not of a threatening nature. However, one should always keep in mind the instability of blood pressure.

1) Blood pressure can decrease (tubocurarine, anatruxonium) and increase (ditilin).

2) Some drugs (anatruxonium, pancuronium) have a pronounced H-anticholinergic (vagolytic) effect on the heart, which leads to tachycardia.

Depolarizing (ditylin) muscle relaxants, in the process of depolarization of the postsynaptic membrane, cause the release of potassium ions from skeletal muscles and its content in the blood plasma increases. This is facilitated by muscle microtrauma. Hyperkalemia, in turn, causes cardiac arrhythmias. By promoting the release of histamine, tubocurarine increases bronchial muscle tone (bronchospasm), and ditilin increases intraocular pressure. Ditylin > intraventricular pressure. In addition, when using depolarizing muscle relaxants (ditilin), muscle pain is typical.

Finally, when using antidepolarizing agents, one should be aware of their accumulation upon repeated administration.

M-cholinomimetic substances excite m-cholinergic receptors cells of tissues and organs. These receptors are localized in the membranes of tissue and organ cells where parasympathetic postganglionic fibers end. Excitation of parasympathetic nerves is transmitted to cells of tissues and organs through m-cholinergic receptors. Thus, the effect of m-cholinomimetic substances corresponds to the effects that are observed when parasympathetic innervation is excited (see Table 3).

Under the influence of m-cholinomimetic substances, the pupils of the eyes narrow, heart contractions slow down (bradycardia occurs), blood vessels dilate, blood pressure decreases (due to bradycardia and dilatation of blood vessels), bronchial muscle tone increases, gastrointestinal motility increases, and the secretion of glands (salivary) increases. , bronchial, glands of the gastrointestinal tract).

Of the m-cholinomimetic substances in medicine, pilocarpine and aceclidine are most often used. Due to its high toxicity, muscarine is not used in medical practice.

Pilocarpine is an alkaloid from a plant native to South America. The drug is quite toxic, and therefore is currently used only locally, in ophthalmic practice. Pilocarpine has a dual effect on the eye: it narrows the pupil and increases the curvature of the lens.

Constriction of the pupil occurs due to the fact that pilocarpine causes contraction of the circular muscle of the iris (innervated by parasympathetic fibers). When the pupil constricts, the corners of the anterior chamber of the eye open, which is located between the iris and cornea (Fig. 8, 9). Through the corners of the anterior chamber of the eye and further through the fountain spaces and the venous sinus of the sclera (Schlemm's canal), the outflow of intraocular fluid occurs; this reduces intraocular pressure.

Rice. 8. Diagram of the structure of the eye.

Rice. 9. Scheme of action of pilocarpine and atropine on the eye.

The ability of pilocarpine to reduce intraocular pressure is used in the treatment of glaucoma (a disease in which intraocular pressure sharply increases, which can lead to visual impairment and even complete blindness). For glaucoma, pilocarpine is used in the form of eye drops or eye ointment.

Pilocarpine increases the curvature of the lens (the lens becomes more convex, its refractive power increases). This is due to the fact that pilocarpine causes contraction of the ciliary muscle, to which the ciliary band (ligament of Zinn) is attached, stretching the lens. When the ciliary muscle contracts, the ciliary girdle relaxes and the lens, due to its contractility, takes on a more convex shape (see Fig. 8, 9). Due to the increase in the curvature of the lens, vision is set to the near point of vision (a person sees close objects well and distant objects poorly). This phenomenon is called a spasm of accommodation.

Aceclidine is a synthetic compound that differs from pilocarpine in less toxicity, and therefore aceclidine can not only be used in ophthalmic practice, but also administered parenterally. The M-cholinomimetic effect of aceclidine is manifested, in particular, in the fact that it increases the tone of the smooth muscles of the gastrointestinal tract and bladder. In this regard, aceclidine is administered subcutaneously for intestinal and bladder atony. Just like pilocarpine, the drug is used for glaucoma.

In case of poisoning with m-cholinomimetics (including muscarine contained in fly agarics), a decrease in heart rate, a drop in blood pressure, constriction of the pupils of the eyes, bronchospasm, severe salivation, vomiting, and diarrhea are observed. To eliminate these phenomena, substances that block m-cholinergic receptors should be prescribed - atropine, scopolamine, etc.

cholinergic receptor acetylcholine muscarinic nicotinic

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 -cholinoreceptors - 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.

Muscarinic receptors

The acetylcholine muscarinic receptor (m-cholinergic receptor) belongs to the class of serpentine receptors that transmit signals through heterotrimeric G proteins.

The muscarinic receptor family was first discovered due to its ability to bind the alkaloid muscarine. They were indirectly described at the beginning of the 20th century when studying the effects of curare. Their direct research began in the 20-30s of the same century, after the compound acetylcholine (ACh) was identified as a neurotransmitter that transmits nerve signals at neuromuscular synapses. Based on the similarity of the effects of acetylcholine and natural plant alkaloids, two general classes of acetylcholine receptors have been identified: muscarinic and nicotinic. Muscarinic receptors are activated by muscarine and blocked by atropine, while nicotinic receptors are activated by nicotine and blocked by curare; Over time, a significant number of subtypes have been discovered within both types of receptors. Only nicotinic receptors are present at neuromuscular synapses. Muscarinic receptors are found in muscle and gland cells and, together with nicotinic receptors, in nerve ganglia and neurons of the central nervous system.

Any type of muscarinic receptor consists of a single polypeptide chain 440-540 amino acid residues long, with an extracellular N-terminus and an intracellular C-terminus. Hydropathic analysis of the amino acid sequence revealed seven segments of 20-24 residues in length that form helical structures that penetrate the cell membrane of the neuron. The amino acid sequence in these stretches is highly conserved (more than 90% similar) in all five types of muscarinic receptors. Between the fifth and sixth domains, which span the membrane, there is a large intracellular loop, which is very variable in its composition and size among different types of receptors. On the third intracellular loop, as well as at the C-terminus of the receptor molecule, there are several successive segments on which phosphorylation occurs during the transmission of a nerve impulse. Cysteine ​​residues, one of which is located near the third transmembrane segment and the other in the middle of the second extracellular loop, are linked by a disulfide bridge.

Thanks to mutational analysis, regions on the receptor molecule that are involved in the process of binding the ligand and G proteins were identified. Acetylcholine binds to a site that is located in the fold formed by the coiled-coil transmembrane domains. The aspartate residue in the third transmembrane domain participates in ionic interaction with the quaternary nitrogen acetylacetylcholine, while sequences of tyrosine and threonine residues located in the transmembrane segments approximately one-third of the distance from the membrane surface form hydrogen bonds with muscarine and its derivatives. According to the results of pharmacological studies, the binding site of antagonists overlaps the site to which acetylcholine binds, but in addition attracts hydrophobic regions of the protein molecule to the receptor and the surrounding cell membrane. Muscarinic receptors, in addition, contain a site (or sites) through which the receptor response is regulated by a large number of compounds, in particular halamine, which reduces the degree of dissociation of cholinergic ligands. The halamin binding site includes a sixth transmembrane domain as well as a third extracellular loop.

A large number of regions of this receptor are involved in the interaction with transmitting G proteins. This especially applies to the structures of the second intracellular loop and the N- and C-terminal segments of the third intracellular loop. Desensitization of muscarinic receptors reliably causes phosphorylation of threonine residues at the C-terminal segment of the receptor molecule, as well as at several sites in the third intracellular loop.

Muscarinic receptors carry out a whole range of diverse physiological functions. In particular, they are present in the autonomic ganglia and postganglionic fibers that extend from these ganglia to target organs. Thus, these receptors are involved in transmitting and modulating parasympathetic effects such as smooth muscle contraction, vasodilation, decreased heart rate, and increased glandular secretion.

In the central nervous system, cholinergic fibers, which include interneurons with muscarinic synapses, are localized in the cerebral cortex, brainstem nuclei, hippocampus, striatum, and in smaller numbers in many other regions. Central muscarinic receptors influence the regulation of sleep, attention, learning and memory. Less important functional characteristics of these receptors are participation in the regulation of limb movements, analgesia and regulation of body temperature.

Receptors of the M2 and M4 types can be found on presynaptic membranes and regulate transmitter release at the synapse; but mainly muscarinic receptors of types M2 and M4 are postsynaptic.

M1 type receptors are involved in the regulation of potassium channels and in the suppression of slow, voltage-independent calcium currents. M2 type receptors take part in the formation of bradycardia, contraction of smooth muscles of the stomach, bladder and trachea. M3 type receptors affect the secretion of saliva, constriction of the pupils and contraction of the gallbladder. M4 type receptors are involved in the processes of regulating certain aspects of locomotor activity (including modulation of the effects of dopamine).

Muscarinic receptors are capable of altering the activity of the cells on which they are located through a large number of signal transduction pathways. Activation of biochemical pathways of nerve impulse transmission occurs depending on the nature and amount of the receptor subtype, effector molecules, as well as protein kinases that are expressed in a given tissue and the possibility of mutual influence between different nerve signal transmission chains. Phospholipase C releases the second messenger, diacylglycerol and inositol triphosphate, with phosphatidylinositol. Diacylglycerol activates protein kinase C, while inositol triphosphate releases Ca2+ from intracellular reservoirs. Paired numbers of receptor subtypes inhibit adenisate cyclases, involving G-proteins of the Gi subtype in this process.