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, central nervous system stimulation is possible: 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 intestine or bladder.
Rice. 12. Structure of the eye.
LECTURE 14
DRUGS AFFECTING CHOLINERGIC SYNAPSES. CHOLINOMIMETICS
FUNCTION OF CHOLINERGIC SYNAPSES
Cholinergic synapses are localized in the central nervous system (acetylcholine reg. ulits motor skills, awakening, memory, learning), as well as in the vegetative state ive ganglia, adrenal medulla, carotid glomerulus X, skeletal muscles and internal organs receiving postganglionic parasympathetic fibers.
In skeletal muscles, synapses occupy a small part of the membrane and are isolated from each other. In the superior cervical ganglion, about 100,000 neurons are packed in a volume of 2-3 mm 3.
Acetylcholine is synthesized in the axoplasm of cholinergic endings from acetyl coenzyme A(mitochondrial origin) and the essential amino alcohol choline with the participation of the enzyme choline acetyltransferase (choline acetylase). The immunocytochemical method for determining this enzyme makes it possible to establish the localization of cholinergic neurons.
Acetylcholine is deposited in synaptic vesicles (vesicles) in association with ATP and neuropeptides (vasoactive intestinal peptide, neuropeptide Y). It is released in quanta during depolarization of the presynaptic membrane and excites cholinergic receptors. At the end of the motor nerve there are about 300,000 synaptic vesicles, each of them contains from 1000 to 50,000 acetylcholine molecules.
All acetylcholine located in the synaptic cleft is subjected to tsya hydrolysis by the enzyme acetylcholinesterase (true cholinesterase) to form choline and acetic acid. One molecule of mediator is inactivated within 1 millisecond. Acetylcholinesterase is localized in axons, dendrites, perikaryon, presynaptic and postsynaptic membranes.
Choline is 1000-10,000 times less active than acetylcholine; 50% of its molecules undergo neuronal uptake and again participate in the synthesis of acetylcholine. Acetic acid is oxidized in the tricarboxylic acid cycle.
Pseudocholinesterase (butyrylcholinesterase) in the blood, liver, and neuroglia catalyzes the hydrolysis of esters of plant origin and drugs.
Cholinergic receptors
Cholinergic receptors are glycoproteins consisting of several subunits. Most cholinergic receptors are reserve. On the postsynaptic membrane in the neuromuscular synapse there are hundreds of millions of cholinergic receptors, of which 40-99% do not function. In the cholinergic synapse on smooth muscle there are about 1.8 million cholinergic receptors, 90-99% are reserve.
In 1914, Henry Dale found that choline esters can have both muscarinic-like and nicotinone-like effects. According to chemical sensitivity, cholinergic receptors are classified into muscarine-sensitive (M) and nicotine-sensitive (N). Acetylcholine has a flexible molecule capable of exciting M- and H-cholinergic receptors in various stereoconformations.
Table. Cholinergic receptors.
|
Localization |
Mechanism |
||
|
Autonomic ganglia |
Depolarization (late postsynaptic potential) |
Activation of phospholipase C by G protein |
|
|
Control of mental and motor functions, awakening and learning reactions |
|||
|
Heart: sinus node |
Slowing of spontaneous depolarization, hyperpolarization |
Inhibition of adenylate cyclase by G i protein, activation of K channels |
|
|
Atria |
Shortened action potential, decreased contractility |
||
|
Atriventricular node |
Decreased conductivity |
||
|
Ventricles |
Slight decrease in contractility |
||
|
Smooth muscle |
reduction | ||
|
Increased secretory function |
|||
|
Skeletal muscles |
Depolarization of the end plate, contraction |
Opening of channels for Na, K, Ca |
|
|
Autonomic ganglia |
Depolarization and excitation of postganglionic neurons |
||
|
Adrenal medulla |
Secretion of adenaline and norepinephrine |
||
|
Carotid glomerulus |
Reflex excitation of the respiratory center |
||
|
Control of mental and motor functions, awakening reactions and learning |
M-cholinergic receptors stimulated by the fly agaric poison muscarine and blocked by atropine. They are localized in the nervous system and internal organs that receive parasympathetic innervation (they cause cardiac depression, contraction of smooth muscles, and increase the secretory function of the exocrine glands). M-cholinergic receptors are associated with G-proteins and have 7 segments that cross the cell membrane like a serpentine.
Molecular cloning made it possible to identify 5 types of M-cholinergic receptors:
M 1 -cholinergic receptors Central nervous system (limbic system, basal ganglia, reticular formation) and autonomic ganglia;
M 2 -cholinergic receptors heart (cause bradycardia, weaken atrial contractions, reduce atrioventricular conduction and myocardial oxygen demand);
M 3 - cholinergic receptors:
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);
Glands (cause lacrimation, sweating, copious secretion of liquid, protein-poor saliva, bronchorrhea, secretion of acidic gastric juice).
Extrasynaptic M 3 -cholinergic receptors are located in the vascular endothelium and regulate the formation of the vasodilator factor nitric oxide (NO}.
M 4 - them 5 -cholinorsceptors have less functional significance.
M 1 -, M3 - and M 5 -cholinergic receptors, activating phospholipase through G protein WITH cell membrane, increase the synthesis of secondary messengers - diacylglycerol and inositol triphosphate. Diacylglycerol activates protein kinase C, inositol triphosphate releases calcium ions from the endoplasmic reticulum,
M 2 - and M 4 -cholinergic receptors with the participation of G i - and G o -proteins inhibit adenylate cyclase (inhibit cAMP synthesis), block calcium channels, and also increase the conductivity of potassium channels in the sinus node.
Additional effects of M-cholinergic receptors are the mobilization of arachidonic acid and activation of guanylate cyclase.
H-cholinergic receptors stimulated by the tobacco alkaloid nicotine in small doses, blocked by nicotine in large doses.
Biochemical identification and isolation of H-cholinergic receptors became possible thanks to the discovery of their selective high-molecular ligand α-bungarotoxin, the venom of the Taiwanese viper. Burn rus multicintus and cobras Naja naja.
N-cholinergic receptors are widely present in the body. They are classified into H-cholinergic receptors of neuronal (H) and muscular (M) types,
Neuronal H-cholinergic receptors are pentamers and consist of subunits 2 - 9 and 2 - 4 (4 transmembrane loops). The localization of neuronal N-cholinergic receptors is as follows;
Cerebral cortex, medulla oblongata, Renshaw cells of the spinal cord, neurohypophysis (increase the secretion of vasopressin)
Autonomic ganglia (participate in conducting impulses from preganglionic fibers to postganglionic fibers);
Adrenal medulla (increases the secretion of adrenaline, norepinephrine);
Carotid glomeruli (participate in reflex excitation of the respiratory center).
Muscle H-cholinergic receptors cause contraction of skeletal muscles. They are a mixture of monomer and dimer. The monomer consists of 5 subunits ( 1 - 2, , , , ) surrounding ion channels. To open ion channels, the binding of acetylcholine by two α-subunits is necessary. Within milliseconds, permeability to Na\ TO" And Ca 2 ^ (5-10 7 sodium ions pass through one channel of the membrane of the muscle skeleton in 1 second).
Presynaptic M-cholinergic receptors inhibit, presynaptic N-cholinergic receptors stimulate the release of acetylcholine
CLASSIFICATION OF DRUGS AFFECTING CHOLINERGIC SYNAPSES
MAIN DRUGS INDICATED
|
^ Cholinomimetics |
||
|
M, N-cholinomimetics M-cholinomimetics N-cholinomimetics (gangliostimulants) |
acetylcholine chloride, carbacholine pilocarpine, aceclidine cytisine, lobeline |
|
|
Drugs that increase the release of acetylcholine |
||
|
cisapride |
||
|
Anticholinesterase drugs |
||
|
Reversible blockers Irreversible blockers |
physostigmine, galantamine, amiridine, proserine |
|
|
Anticholinergics |
||
|
M-anticholinergics N-cholinergic blockers (ganglion blockers) |
atropine, scopolamine, platyphylline, metacin, pirenzepine, ipratropium benzohexonium bromide, pentamin, hygronium arfonade, pachycarpine, pyrylene |
|
|
Muscle relaxants |
||
|
Antidepolarizing Depolarizing |
Tubocurarine chloride, pipecuronium bromide, atracurium besilate, melliktin |
|
|
Myooelaxants |
||
M,N-CHOLINOMIMETICS
ACETYLCHOLINE CHLORIDE, synthesized in 1867 by A. Beyer, has a strong cholinomimetic effect. The effect of acetylcho-1in is short-term due to rapid hydrolysis by enzymes of the cholinesterase group.
The effects of acetylcholine chloride depend on the dose:
In doses of 0.1-0.5 mcg/kg, it affects M-cholinergic receptors and causes the effects of excitation of the parasympathetic system;
In doses of 2-5 mcg/kg it affects M- and N-cholinergic receptors, while the N-cholinomimetic effect corresponds to the effects of the sympathetic system.
Selective stimulation of H-cholinergic receptors is possible only after blockade of M-cholinergic receptors.
Acegylcholine, when administered into a vein, has a significant effect on the cardiovascular system: "
Causes generalized vasodilation and arterial hypotension (releases NO from the endothelium);
Suppresses spontaneous diastolic depolarization and lengthens the refractory period in the sinus node, which is accompanied by bradycardia:
Weakens the contractions of the atria, shortens the action potential and refractory period in them (danger of flutter and flicker);
Extends the refractory period and disrupts conduction in the atrioventricular node (danger of blockade);
Reduces the automaticity of Purkinje fibers, moderately weakens ventricular contractions.
Acetylcholine chloride is used primarily in experimental pharmacology. Sometimes it is injected under the skin for intestinal and bladder atony and paralytic intestinal obstruction, and is also infused into the arteries to dilate them in obliterating diseases. Infusion of acetylcholine into a vein is unacceptable due to the risk of cardiac arrest and collapse. |
CARBACHOLIN- the ester of choline and carbamic acid is not hydrolyzed by cholinesterase and has a weak and long-lasting effect. This drug is used in eye drops for glaucoma, injected under the skin or into muscles for atony of the intestines and bladder (mainly stimulates the smooth muscles of the intestines and urinary system).
M-CHOLINOMIMETICS
M-cholinomimetics selectively excite M-cholinergic receptors of the central nervous system and internal organs. For affinity to M-cholinergic receptors, the distance between the active centers of the cationic head and the ester bond is of greatest importance. It should be 2 carbon atoms (0.3 im). Most compounds have a branch at the carbon closest to the ethereal oxygen. In a typical drug of this group, pilocarpine, the distance between the nitrogen of the imidazole heterocycle and the oxygen of the lactone ring is 5 carbon atoms, however, when the molecule rotates around the methylene bridge, the functional groups come closer to a distance of 0.3 nm.D.. Another drug, aceclidine, is an ester of acetic acid and amino alcohol of quinuclidine structure. In aceclidine, the distance between the active centers is equal to two carbon atoms.
PILOCARPINE - an alkaloid from the leaves of the South American shrub Lilocarpus pinnate (Haoorandi), isolated in 187, used to treat glaucoma.
Pilocarpine has a local and resorbent effect. Its local effect on the eye is due to the stimulation of M-cholinergic receptors, which is accompanied by contraction of the circular and ciliary (accommodative) muscles. The effects of pilocarpine are as follows:
Constriction of the pupils (miosis; Greek. moiosis- decrease) - the result of contraction of the circular muscle of the iris.
2. Reduced intraocular pressure - when the pupils constrict, the iris becomes thin, its root frees up the angle of the anterior chamber, this facilitates the outflow of intraocular fluid into the drainage system of the eye - fountain spaces, Schlemm's canal and veins of the eyeball.
3. Accommodation spasm (artificial myopia) - with contraction of the ciliary muscle, the tension of the zonule and lens capsule decreases; The lens, acquiring a convex shape due to its elasticity, creates a clear image on the retina from nearby objects.
4. Macropsia - objects seem enlarged and are not clearly visible.
Indications for the use of pilocarpine are course treatment of glaucoma before surgery (iridectomy) and relief of glaucomatous crisis. For course treatment, use 1-2% solutions of pilocarpine hydrochloride in eye drops 3-4 times a day (with increasing concentration, the hypotensive effect does not increase, but side effects appear). The action of pilocarpine is prolonged by adding methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Eye films are also used. During the year, it is necessary to discontinue pilocarpine for 1-3 months (beta-blockers timolol or proxodolol are used instead). Combination preparations of pilocarpine are produced - PILAREN eye films (with adrenaline hydrochloride), FOPIL eye drops (with timolol) and PROXOPHELINE (with proxodolol).
During a glaucomatous crisis, 1-2% solutions are instilled into the eye: in the first hour - every 15 minutes, in the second hour - 2 times, then - 1 time every 4 hours. Timolol eye drops are used 2 times a day, carbonic anhydrase inhibitors (diacarb, dorzolamide) are prescribed orally.
In patients with glaucoma who have been using pilocarpine for a long time, fibrous degeneration of the intraocular muscles, irreversible miosis, posterior synechiae (fusion of the iris with the lens), increased capillary permeability (edema, hemorrhage), changes in the composition of the intraocular fluid, dark adaptation due to displacement of the vitreous body ( difficult to work in poor lighting)
The resorptive effect of pilocarpine is directed by M 2 -cholinergic receptors of the heart and M 3 -cholinergic receptors of smooth muscles and exocrine glands.
Pilocarpine was used to treat stomatitis and uremia, because. when 10-15 mg of the drug is administered under the skin, 1 liter of lysozyme-rich saliva and 2-3 liters of sweat containing a large amount of nitrogenous waste are released in 2-3 hours.
ACECLIDINE is similar in pharmacological properties to pilocarpine. It is injected under the skin for atony, paralytic intestinal obstruction, atony of the bladder, decreased tone and subinvolution of the uterus, uterine bleeding in the postpartum period, and is also used in eye drops for glaucoma.
With long-term use of aceclidine in eye drops, irritation of the conjunctiva, injection of eye vessels, and pain in the eye are possible.
The poison MUSCARINE is found in fly agaric in a very low concentration, is a quaternary amine and does not penetrate the central nervous system. Muscarine causes bradycardia, atrioventricular block, arterial hypotension, bronchospasm, bronchorrhea, cyanosis, vomiting, increased painful intestinal motility, diarrhea, sweating, hypersalivation, miosis, accommodation spasm.
Fly agaric also contains tertiary amines - isoxazole derivatives - ibotenic acid and its metabolite muscimol. Muscimol, by disrupting the function of GABAergic synapses of the central nervous system, causes euphoria, hallucinations, sleep with vivid dreams, ataxia, and muscle fibrillation. In severe poisoning, hypothermia, myoclonus, convulsions develop, and coma occurs from paralysis of the respiratory center.
It is known that the great playwright of Ancient Greece, Euripides (480-406 BC), with his wife and three children, died of fly agaric poisoning.
Emergency measures include gastric lavage with activated charcoal, enterosorption, oxygen inhalation, infusion therapy. A competitive antagonist of muscarine, the M-anticholinergic blocker atropine, is injected into the muscles. Calcium channel blockers are used to reduce the toxic effects of muscimol. For two | weeks after the elimination of symptoms of acute poisoning, limit the consumption of tyramine-containing foods.
AREKOLIN - betel nut alkaloid (fruit of the areca catechu palm, native to Southeast Asia). Betel chewing (betel nut with lime and pepper added) Piper bette) widespread in India and other countries in this region, since arecoline, by stimulating the M1-cholinergic receptors of the central nervous system, causes euphoria. M, N-cholinomimetics and M-cholinomimetics in eye drops and films are contraindicated for iritis and iridocyclitis. They are not used for resorptive action in bradycardia, angina pectoris, organic heart diseases, atherosclerosis, bronchial asthma, bleeding from the stomach and intestines, inflammatory diseases of the abdominal cavity before surgery, mechanical intestinal obstruction, epilepsy, other convulsive diseases, pregnancy.
N-CHOLINOMIMETICS (GANGLIOSTIMULANTS)
Neuronal agonists have an N-cholinomimetic effect x H H -cholinergic receptors of the carotid glomeruli, sympathetic and pasympathetic ganglia and the adrenal medulla. Drugs in this group do not affect NM-cholinergic receptors of skeletal muscles.
The excitation of H-cholinergic receptors of the carotid glomeruli is of therapeutic importance.
As is known, in the carotid glomeruli, acetylcholine plays the role of a mediator, acting not on efferent impulses, as usual, but on afferent impulses. The cells of the carotid glomeruli are rich in mitochondria and synaptic vesicles containing deposited acetylcholine. The endings of the carotid branch of the glossopharyngeal nerve approach these cells. The tissue of the carotid glomeruli is characterized by a rich blood supply and significant oxygen consumption. Meanwhile, the carotid glomeruli do not produce mechanical contractile work and do not incur energy costs for chemical synthesis. Energy is spent on the functioning of the Na/K pump, since sodium ions enter through the membrane of the cells of the carotid glomeruli even at resting potential (the membrane is easily depolarized). Stopping the pump during hypoxia is accompanied by depolarization and release of acetylcholine. The mediator, stimulating N-cholinergic receptors at the endings of the carotid nerve, creates a flow of impulses for reflex stimulation of the respiratory center.
N-cholinomimetics, which reflexively tonic the respiratory center, are of plant origin:
CITIZINE - alkaloid of broom and thermopsis lanceolatum, pyrimidine derivative, strong H-cholinomimetic (used in a 0.15% solution called cititone).
LOBELIN- alkaloid of lobelia, growing in tropical countries, a derivative of piperidine.
Both remedies act for a short time - within 2-5 minutes. They are injected into a vein (without glucose solution) when respiratory depression occurs.
Center in patients with preserved reflex excitability, for example, in case of poisoning with narcotic analgesics, carbon monoxide.
Lobelin, stimulating the vagal center in the medulla oblongata, causes bradycardia and arterial hypotension. Later, blood pressure rises due to stimulation of the sympathetic ganglia and adrenal medulla. Cytisine has only a pressor effect.
When introducing N-cholinol mimetics under the skin and into the muscles to tone the respiratory center, it is necessary to use doses 10-20 times higher than intravenous infusion. In this case, cytisine and lobeline, as tertiary amines, penetrate the central nervous system and, by affecting the H-cholinergic receptors of the brain, cause vomiting, tonic-clonic convulsions, bradycardia and cardiac arrest.
It should be noted that in case of breathing problems, artificial ventilation of the lungs is always more reliable and more effective than any respiratory analeptics. The latter is resorted to only when artificial respiration is not possible.
N-cholinomimetics are contraindicated in cases of arterial hypertension, atherosclerosis, bleeding from large vessels, and pulmonary edema.
Cytisine, lobeline and ANABAZINE have found use as smoking cessation agents. Taking tablets TABEX (cytisine), LOBESIL (lobeline), sticking films with cytisine and anabasine in the oral cavity and using chewing gum GAMIBAZINE (anabasine) reduce the craving for nicotine and alleviate the painful phenomena associated with quitting smoking. The action of these drugs is associated with the stimulation of central H-cholinergic receptors (a strong drug is replaced with a weaker one). The success of such therapy is possible with a firm decision to quit smoking.
The use of tablets with lobeline, cytisine, and anabasine is contraindicated for peptic ulcer disease and organic pathology of the cardiovascular system. In case of an overdose of drugs, weakness, irritability, dizziness, tachycardia, arterial hypertension, dilated pupils, nausea, and vomiting develop.
MEDICINES THAT INCREASE THE RELEASE OF ACETYLCHOLINE
CISAPRIDE(COORDINAX, PERISTIL), stimulating the smooth muscles of the digestive tract; acts as a prokinetic. It is an agonist of presynaptic 5HT 4 serotonin receptors, which facilitate the release of acetylcholine, and therefore increases the release of acetylcholine from the endings of postganglionic parasympathetic fibers of the mesenteric plexus. Cisapride tones the lower sphincter of the esophagus, prevents the reflux of stomach contents into the esophagus, and accelerates peristalsis of the stomach, small and large intestines.
Cisapride is prescribed orally in tablets and suspensions for reflux esophagitis, gastric paresis, and chronic constipation. In pediatrics, this drug is indicated for persistent regurgitation and vomiting in infants. Side effects of cisapride include abdominal pain, diarrhea, headache, dizziness, allergic reactions, and in rare cases, extrapyramidal disorders and arrhythmia occur. Cisapride is contraindicated in case of bleeding from the digestive tract, its perforation, suspected obstructive intestinal obstruction, pain, allergies. During treatment with cisapride, breastfeeding is interrupted. The drug is prescribed with caution to patients with cardiovascular diseases, reduced concentrations of potassium and magnesium in the blood, and elderly patients.
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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 |
Increasing Increasing 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 |
Increasing Increasing |
Decreasing Decreasing |
|
Peristalsis Sphincter tone Secretion of gastric glands |
Increasing Decreasing Increases (hydrochloric acid) |
Decreasing Increasing 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, platyphylline 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.
Cholinergic synapses are localized in internal organs that receive postganglionic parasympathetic fibers, in the autonomic ganglia, adrenal medulla, carotid glomeruli, and skeletal muscles. The transmission of excitation in cholinergic synapses occurs with the help of acetylcholine.
Acetylcholine is synthesized in the cytoplasm of the endings of cholinergic nerves from acetyl-Co A and choline with the participation of the enzyme choline acetyltransferase (choline acetylase) and deposited in synaptic vesicles (vesicles). Under the influence of nerve impulses, acetylcholine is released from the vesicles into the synaptic cleft. This happens as follows. An impulse that reaches the presynaptic membrane causes its depolarization, as a result of which voltage-gated calcium channels open, through which calcium ions penetrate into the nerve ending. The concentration of Ca 2+ in the cytoplasm of the nerve ending increases, which promotes the fusion of the vesicle membrane with the presynaptic membrane and exocytosis of the vesicles (Fig. 8.1). The process of fusion of the vesicular and presynaptic membranes, and, consequently, the exocytosis of vesicles and the release of acetylcholine is blocked by botulinum toxin. The release of acetylcholine is also blocked by substances that reduce the entry of Ca 2+ into the cytoplasm of nerve endings, for example, aminoglycoside antibiotics.
After release into the synaptic cleft, acetylcholine stimulates cholinergic receptors located on both the postsynaptic and presynaptic membranes of cholinergic synapses.
In the synaptic cleft, acetylcholine is very quickly hydrolyzed by the enzyme acetylcholinesterase to form choline and acetic acid. Choline is captured by nerve endings (subject to reverse neuronal uptake) and is again included in the synthesis of acetylcholine. An enzyme is present in the blood plasma, liver and other organs - butyrylcholinesterase (pseudocholinesterase, false cholinesterase), which can also inactivate acetylcholine.
The transmission of excitation in cholinergic synapses can be affected by substances that affect the following processes: the synthesis of acetylcholine and its deposition in vesicles; release of acetylcholine; interaction of acetylcholine with cholinergic receptors; hydrolysis of acetylcholine in the synaptic cleft; reverse neuronal uptake of choline by presynaptic terminals. The deposition of acetylcholine in vesicles is reduced by vesamicol, which blocks the transport of acetylcholine from the cytoplasm into the vesicles. The release of acetylcholine into the synaptic cleft is stimulated by 4-aminopyridine (pimadine). Botulinum toxin (Botox) blocks the release of acetylcholine. Neuronal reuptake of choline is inhibited by hemicholinium, which is used in experimental studies.
In medical practice, substances that directly interact with cholinergic receptors are mainly used: cholinomimetics (substances that stimulate cholinergic receptors) or cholinergic blockers (substances that block cholinergic receptors and thus prevent the action of acetylcholine on them). Substances that inhibit the hydrolysis of acetylcholine are used - acetylcholinesterase inhibitors (anticholinesterase drugs).
DRUGS THAT STIMULATE CHOLINERGIC SYNAPSES
This group includes cholinomimetics - substances that, like acetylcholine, directly stimulate cholinergic receptors, and anticholinesterase drugs, which, by inhibiting acetylcholinesterase, increase the concentration of acetylcholine in the synaptic cleft and thus enhance and prolong the action of acetylcholine.
Cholinomimetics
Cholinergic receptors of different cholinergic synapses have unequal sensitivity to the same substances. Cholinergic receptors, localized in the postsynaptic membrane of effector organ cells at the endings of postganglionic parasympathetic fibers, exhibit increased sensitivity to muscarine (an alkaloid isolated from some types of fly agarics). Such receptors are called muscarine-sensitive, or M-cholinergic receptors.
Cholinergic receptors, located in the postsynaptic membrane of neurons of the sympathetic and parasympathetic ganglia, chromaffin cells of the adrenal medulla, in the carotid glomeruli (which are located at the site of division of the common carotid arteries) and on the end plate of skeletal muscles, are most sensitive to nicotine and are therefore called nicotine-sensitive receptors or N-cholinergic receptors. These receptors are divided into N-cholinergic receptors of the neuronal type (N n) and N-cholinergic receptors of the muscular type (N m), differing in localization (see Table 8.1) and in sensitivity to pharmacological substances.
Substances that selectively block H n -cholinergic receptors of the ganglia, adrenal medulla and carotid glomeruli are called ganglion blockers, and substances that predominantly block H n -cholinergic receptors of skeletal muscles are called curare-like drugs.
Among cholinomimetics, there are substances that predominantly stimulate M-cholinergic receptors (M-cholinomimetics), N-cholinergic receptors (H-cholinomimetics) or both subtypes of cholinergic receptors simultaneously (M-, N-cholinomimetics).
Classification of cholinomimetics
M-cholinomimetics: muscarine, pilocarpine, aceclidine.
N-cholinomimetics: nicotine, cititon, lobelia.
M,N-cholinomimetics: acetylcholine, carbacholine.
M-cholinomimetics
M-cholinomimetics stimulate M-cholinergic receptors located in the membrane of cells of effector organs and tissues that receive parasympathetic innervation. M-cholinergic receptors are divided into several subtypes, which exhibit unequal sensitivity to different pharmacological substances. 5 subtypes of M-cholinergic receptors have been discovered (M, -, M 2 -, M 3 -, M 4 -, M 5 -). The most well studied are M, -, M 2 - and M 3 - cholinergic receptors (see Table 8.1). All M-cholinergic receptors belong to membrane receptors that interact with G-proteins, and through them with certain enzymes or ion channels (see chapter “Pharmacodynamics”). Thus, M 2 -cholinergic receptors of the membranes of the cardio-
Table 8.1. Subtypes of cholinergic receptors and effects caused by their stimulation
M-cholinergic receptors
| m, | CNS Enterochromaffin-like cells of the stomach | Release of histamine, which stimulates the secretion of hydrochloric acid by the parietal cells of the stomach |
| m 2 | Heart Presynaptic membrane of the endings of postganglionic parasympathetic fibers | Decreased heart rate. Depression of atrioventricular conduction. Decreased atrial contractility Decreased release of acetylcholine |
| m 3 (innervated) | Circular muscle of the iris Ciliary (ciliary) muscle of the eye Smooth muscles of the bronchi, stomach, intestines, gallbladder and bile ducts, bladder, uterus Exocrine glands (bronchial glands, glands of the stomach, intestines, salivary, lacrimal, nasopharyngeal and sweat glands) | Contraction, constriction of the pupils Contraction, spasm of accommodation (the eye is set to the closest point of vision) Increased tone (except for the sphincters) and increased motility of the stomach, intestines and bladder Increased secretion |
| m 3 (non-innervated) | Endothelial cells of blood vessels | Release of endothelial relaxing factor (N0), which causes relaxation of vascular smooth muscle |
H-cholinergic receptors
myocytes interact with Gj proteins that inhibit adenylate cyclase. When they are stimulated in cells, the synthesis of cAMP decreases and, as a consequence, the activity of cAMP-dependent protein kinase, which phosphorylates proteins. In cardiomyocytes, phosphorylation of calcium channels is disrupted - as a result, less Ca 2+ enters the cells of the sinoatrial node in phase 4 of the action potential. This leads to a decrease in the automaticity of the sinoatrial node and, consequently,
to a decrease in heart rate. Other indicators of heart function also decrease (see Table 8.1).
M 3 -cholinergic receptors of smooth muscle cells and cells of exocrine glands interact with Gq proteins, which activate phospholipase C. With the participation of this enzyme, inositol 1,4,5-triphosphate (1P 3) is formed from phospholipids of cell membranes, which promotes the release of Ca 2+ from the sarcoplasmic reticulum (intracellular calcium depot). As a result, when M 3 -cholinergic receptors are stimulated, the concentration of Ca 2+ in the cytoplasm of cells increases, which causes an increase in the tone of the smooth muscles of internal organs and an increase in the secretion of exocrine glands. In addition, non-innervated (extra-naptic) M3-cholinergic receptors are located in the membrane of vascular endothelial cells. When they are stimulated, the release of endothelial relaxing factor (NO) from endothelial cells increases, which causes relaxation of vascular smooth muscle cells. This leads to a decrease in vascular tone and a decrease in blood pressure.
M-cholinergic receptors are coupled to Gq proteins. Stimulation of M,-cholinergic receptors of enterochromaffin-like cells of the stomach leads to an increase in the concentration of cytoplasmic Ca 2+ and an increase in the secretion of histamine by these cells. Histamine, in turn, acting on the parietal cells of the stomach, stimulates the secretion of hydrochloric acid. Subtypes of M-cholinergic receptors and the effects caused by their stimulation are presented in table. 8.1.
The prototype of M-cholinomimetics is the alkaloid muscarine, found in fly agaric mushrooms. Muscarine causes effects associated with stimulation of all subtypes of M-cholinergic receptors given in table. 8.1. Muscarine does not penetrate the blood-brain barrier and therefore does not have a significant effect on the central nervous system. Muscarine is not used as a medicine. When poisoning with fly agaric mushrooms containing muscarine, its toxic effect is manifested, associated with the stimulation of M-cholinergic receptors. In this case, constriction of the pupils, spasm of accommodation, profuse salivation and sweating, increased tone of the bronchi and secretion of the bronchial glands (which is manifested by a feeling of suffocation), bradycardia and decreased blood pressure, cramping abdominal pain, diarrhea, nausea and vomiting are noted. In case of fly agaric poisoning, the stomach is washed and saline laxatives are given. To eliminate the effect of muscarine, the M-anticholinergic blocker atropine is used.
Pilocarpine is an alkaloid from the leaves of the Pilocarpus pinna-tifolius Jaborandi shrub, native to South America. Pilocarpine, used in medical practice, is obtained synthetically. Pilocarpine has a direct stimulating effect on M-cholinergic receptors and causes all the effects characteristic of drugs in this group (see Table 8.1). Pilocarpine especially strongly increases the secretion of glands, so it is sometimes prescribed orally for xerostomia (dryness of the oral mucosa). But since pilocarpine has quite high toxicity, it is mainly used topically in the form of ophthalmic dosage forms to reduce intraocular pressure.
The amount of intraocular pressure mainly depends on two processes: the formation and outflow of intraocular fluid (aqueous humor of the eye), which is produced by the ciliary body and flows mainly through the drainage system of the angle of the anterior chamber of the eye (between the iris and cornea). This drainage system includes the trabecular meshwork (pectineal ligament) and the scleral venous sinus (Schlemm's canal). Through the slit-like spaces between the trabeculae (fountain spaces) of the trabecular network, the fluid is filtered into Schlemm’s canal, and from there it flows through the collector vessels into the superficial veins of the sclera (Fig. 8.2).
Intraocular pressure can be reduced by reducing the production of intraocular fluid and/or increasing its outflow. The outflow of intraocular fluid largely depends on the size of the pupil, which is regulated by two muscles of the iris: the circular muscle (m. sphincter pupillae) and the radial muscle (m. dilatator pupillae). The circular muscle of the pupil is innervated by parasympathetic fibers (n. oculomotorius), and the radial muscle is innervated by sympathetic fibers (n. sympaticus). When the orbicularis muscle contracts, the pupil narrows, and when the radial muscle contracts, the pupil dilates.
Pilocarpine, like all M-cholinomimetics, causes contraction of the orbicularis muscle of the iris and constriction of the pupils (miosis). At the same time, the iris becomes thinner, which helps to open the angle of the anterior chamber of the eye and the outflow of intraocular fluid through the fountain spaces into Schlemm's canal. This leads to a decrease in intraocular pressure.
The ability of pilocarpine to reduce intraocular pressure is used in the treatment of glaucoma, a disease characterized by a constant or periodic increase in intraocular pressure, which can lead to optic nerve atrophy and vision loss. Glaucoma can be open-angle or closed-angle. The open-angle form of glaucoma is associated with a violation of the drainage system of the angle of the anterior chamber of the eye, through which the outflow of intraocular fluid occurs; the corner itself is open. The angle-closure form develops when access to the angle of the anterior chamber of the eye is impaired, most often when it is partially or completely covered by the root of the iris. In this case, intraocular pressure can increase to 60-80 mm Hg. (normal intraocular pressure ranges from 16 to 26 mm Hg).
Due to the ability to constrict the pupils (miotic effect), pilocarpine is highly effective in the treatment of angle-closure glaucoma and in this case is used primarily (it is the drug of choice). Pilocarpine is also prescribed for open-angle glaucoma. Pilocarpine is used in the form of 1-2% aqueous solutions (duration of action - 4-8 hours), solutions with the addition of polymer compounds that have a prolonged effect (8-12 hours), ointments and special eye films made of polymer material (eye films with pilocarpine are placed for the lower eyelid 1-2 times a day).
Pilocarpine causes contraction of the ciliary muscle, which leads to relaxation of the zonular ligament, which stretches the lens. The curvature of the lens increases, it takes on a more convex shape. As the curvature of the lens increases, its refractive power increases - the eye is set to the near point of vision (objects that are nearby are better visible). This phenomenon, called spasm of accommodation, is a side effect of pilocarpine. When instilled into the conjunctival sac, pilocarpine is practically not absorbed into the blood and does not have a noticeable resorptive effect.
Aceclidine is a synthetic compound with a direct stimulating effect on M-cholinergic receptors and causes all the effects associated with the stimulation of these receptors (see Table 8.1).
Aceclidine can be used topically (installed into the conjunctival sac) to lower intraocular pressure in glaucoma. After a single installation, the decrease in intraocular pressure continues for up to 6 hours. However, aceclidine solutions have a locally irritating effect and can cause irritation of the conjunctiva.
Due to its lower toxicity compared to pilocarpine, aceclidine is used for resorptive action in intestinal and bladder atony. Side effects: drooling, diarrhea, smooth muscle spasms. Due to the fact that aceclidine increases the tone of bronchial smooth muscles, it is contraindicated in bronchial asthma.
In case of overdose of M-cholinomimetics, their antagonists are used - M-cholinoblockers (atropine and atropine-like drugs).
N-cholinomimetics
This group includes alkaloids nicotine, lobelia, cytisine, which act primarily on neuronal-type H-cholinergic receptors localized on neurons of the sympathetic and parasympathetic ganglia, chromaffin cells of the adrenal medulla, in the carotid glomeruli and in the central nervous system. These substances act on the H-cholinergic receptors of skeletal muscles in much larger doses.
N-cholinergic receptors are membrane receptors directly associated with ion channels. Structurally, they are glycoproteins and consist of several subunits. Thus, the H-cholinergic receptor of neuromuscular synapses includes 5 protein subunits (a, a, (3, y, 6), which surround the ion (sodium) channel. When two acetylcholine molecules bind to the α-subunits, the Na + channel opens Na+ ions enter the cell, which leads to depolarization of the postsynaptic membrane of the skeletal muscle end plate and muscle contraction.
Nicotine is an alkaloid found in tobacco leaves (Nicotiana tabacum, Nicotiana rustica). Basically, nicotine enters the human body during smoking tobacco, approximately 3 mg during smoking one cigarette (a lethal dose of nicotine is 60 mg). It is quickly absorbed from the mucous membranes of the respiratory tract (it also penetrates well through intact skin).
Nicotine stimulates H-cholinergic receptors of the sympathetic and parasympathetic ganglia, chromaffin cells of the adrenal medulla (increases the release of adrenaline and norepinephrine) and carotid glomeruli (stimulates the respiratory and vasomotor centers). Stimulation of the sympathetic ganglia, adrenal medulla and carotid glomeruli leads to the most characteristic cardiovascular effects of nicotine: an increase in heart rate, vasoconstriction and an increase in blood pressure. Stimulation of the parasympathetic ganglia causes an increase in intestinal tone and motility and an increase in the secretion of exocrine glands (large doses of nicotine have an inhibitory effect on these processes). Stimulation of H-cholinergic receptors in the parasympathetic ganglia is also the cause of bradycardia, which can be observed at the onset of nicotine action.
Since nicotine is highly lipophilic (it is a tertiary amine), it quickly penetrates the blood-brain barrier into brain tissue. In the central nervous system, nicotine causes the release of dopamine, some other biogenic
amines and stimulating amino acids, which are associated with the subjective pleasant sensations that occur in smokers. In small doses, nicotine stimulates the respiratory center, and in large doses it causes depression, leading to respiratory arrest (paralysis of the respiratory center). In large doses, nicotine causes tremors and convulsions. By acting on the trigger zone of the vomiting center, nicotine can cause nausea and vomiting.
Nicotine is mainly metabolized in the liver and excreted by the kidneys unchanged and in the form of metabolites. Thus, it is quickly eliminated from the body (t ]/2 - 1.5-2 hours). Tolerance (addiction) quickly develops to the effects of nicotine.
Acute nicotine poisoning can occur when nicotine solutions come into contact with the skin or mucous membranes. In this case, hypersalivation, nausea, vomiting, diarrhea, bradycardia, and then tachycardia, increased blood pressure, first shortness of breath, and then respiratory depression are observed, and convulsions are possible. Death occurs from paralysis of the respiratory center. The main measure of assistance is artificial respiration.
When smoking tobacco, chronic poisoning is possible with nicotine, as well as other toxic substances that are contained in tobacco smoke and can have an irritating and carcinogenic effect. For most smokers, inflammatory diseases of the respiratory tract, for example, chronic bronchitis, are typical; Lung cancer is more common. The risk of cardiovascular diseases increases.
Mental dependence develops on nicotine, therefore, when smoking stops, smokers experience withdrawal syndrome, which is associated with the occurrence of painful sensations and decreased performance. To reduce withdrawal symptoms, it is recommended to use chewing gum containing nicotine (2 or 4 mg) or a transdermal therapeutic system (a special skin patch that evenly releases small amounts of nicotine over 24 hours) during the period of quitting smoking.
In medical practice, N-cholinomimetics lobelia and cytisine are sometimes used.
Lobelia - The alkaloid of the plant Lobelia inflata is a tertiary amine. By stimulating the H-cholinergic receptors of the carotid glomeruli, lobelia reflexively excites the respiratory and vasomotor centers.
Cytisine is an alkaloid found in broom (Cytisus laburnum) and thermopsis (Thermopsis lanceolata) plants; its structure is a secondary amine. The action is similar to lobeline, but stimulates the respiratory center somewhat more strongly.
Cytisine and lobelia are included in the tablets “Tabex” and “Lobesil”, which are used to facilitate smoking cessation. The drug cititon (0.15% cytisine solution) and lobeline solution are sometimes administered intravenously for reflex stimulation of breathing. However, these drugs are effective only if the reflex excitability of the respiratory center is preserved. Therefore, they are not used in case of poisoning with substances that reduce the excitability of the respiratory center (hypnotics, narcotic analgesics).
M, N-cholinomimetics
Acetylcholine is a mediator at all cholinergic synapses and stimulates both M- and N-cholinergic receptors. Acetylcholine is produced in the form of a lyophilized preparation of acetylcholine chloride. When introducing acetylcho-
lina into the body, its effects associated with the stimulation of M-cholinergic receptors predominate: bradycardia, vasodilation and lowering blood pressure, increased tone and increased peristalsis of the gastrointestinal tract, increased tone of smooth muscles of the bronchi, gall and bladder, uterus, increased secretion of the bronchial and digestive glands. The stimulating effect of acetylcholine on peripheral N-cholinergic receptors (nicotine-like effect) is manifested by blockade of M-cholinergic receptors (for example, with atropine). As a result, against the background of atropine, acetylcholine causes tachycardia, vasoconstriction and, as a consequence, an increase in blood pressure. This occurs due to stimulation of the sympathetic ganglia, increased release of adrenaline by chromaffin cells of the adrenal medulla and stimulation of the carotid glomeruli.
In very large doses, acetylcholine can cause persistent depolarization of the postsynaptic membrane and blockade of excitation transmission at cholinergic synapses.
According to its chemical structure, acetylcholine is a quaternary ammonium compound and therefore poorly penetrates the blood-brain barrier and does not have a significant effect on the central nervous system.
In the body, acetylcholine is quickly destroyed by acetylcholinesterase and therefore has a short-term effect (a few minutes). For this reason, acetylcholine is almost never used as a medicine. Acetylcholine is mainly used in experiments.
Carbachol (carbacholin) is an analogue of acetylcholine, but unlike
it is practically not destroyed by acetylcholinesterase and therefore acts more effectively
longer (for 1-1.5 hours). Causes the same pharmacological
some effects. Carbachol solution in the form of eye drops is occasionally used for
glaucoma.
M 1,2,3 - cholinergic receptors (postsynaptic)
· Smooth muscles of the intestine, bladder, ureter, bile duct, uterus, bronchi.
· Digestive, bronchial, lacrimal, sweat glands.
· Iris and ciliary muscles of the eye.
· Heart.
H-cholinergic receptors (postsynaptic)
· Skeletal muscles.
· Autonomic ganglia of the sympathetic and parasympathetic nervous system, carotid glomerulus, adrenal medulla.
Classification of drugs acting in the field of cholinoreactive systems
I. Cholinomimetics– drugs that stimulate M- and N-cholinergic receptors, sensitive to the mediator acetylcholine.
Classification of cholinomimetics:
All cholinomimetics are divided into straight And indirect.
Direct cholinomimetics:
1. M-, N-cholinomimetics: acetylcholine, carbacholin (practically not used in medicine).
2. M-cholimimetics: pilocarpine hydrochloride, aceclidine.
3. N-cholinomimetics: nicotine, cititone, lobeline hydrochloride.
Indirect cholinomimetics (anticholinesterase agents):
Preparations: physostigmine salicylate, galantamine hydrobromide, proserine, armin.
M-HM – cause local (when applied topically) or general effects of M-ChR stimulation.
Pilocarpine - an alkaloid found in the leaves of jaborandi (Folia Pilocarpus Jaborandi). In its pure form it is a thick, honey-like consistency, colorless, non-volatile liquid, bitter taste, difficult to dissolve in water and easily soluble in alcohol, ether and chloroform.
The mechanism of action is due to the stimulation of peripheral M-ChRs, which causes contraction of the circular muscle of the iris and ciliary muscle, accompanied by constriction of the pupil and opening of the angle of the anterior chamber of the eye, improving the outflow of intraocular fluid. Which generally causes a decrease in intraocular pressure and improves trophic processes in the tissues of the eye.
Aceclidine– white crystalline powder. Easily soluble in water. Aqueous solutions (pH 4.5 - 5.5) are sterilized at +1OO◦C for 30 minutes. It is a tertiary base, which allows it to penetrate histohematic barriers, including the blood-brain barrier.
Mechanism of action: has a direct stimulating effect on M-ChR and causes all the effects associated with the stimulation of these receptors. The effect on the eye is the same as that of pilocarpine (lowering intraocular pressure, constriction of the pupil - miosis, spasm of accommodation, vision is set to a close point).
N-HM – a feature of the agents that excite N-ChR is the presence of cationic nitrogen (quaternary, secondary or tertiary) and an electric dipole. As a rule, the highest dipole moment values directly correlate with CM activity. In this case, the orientation of the dipole is optimal if it is similar to the relative position of the carbonyl carbon and the nitrogen atom in the ACh molecule. A typical ganglion drug that stimulates H-ChR in small doses is nicotine. Large doses of nicotine inhibit H-ChR. Nicotine is not used in practical medicine; it serves as a standard in the study of new compounds that activate H-ChRs.
Nicotine– from among the liquid alkaloids contained in tobacco leaves with an immediate effect on the central nervous system (within 7 seconds from inhalation). Nicotine has a two-phase effect on the H-ChR of the ganglia and the central nervous system, first stimulating (due to a direct cholinomimetic effect), and with increasing doses, paralyzing them (as a result of antagonism with ACh). In small doses, nicotine causes excitation of the DC and, consequently, an increase in the frequency and depth of breathing, stimulates the release of adrenaline by the adrenal glands, facilitates neuromuscular transmission, excites the central nervous system, reduces the heart rate, increases blood pressure, and stimulates gastrointestinal motility. In large doses, the effects of nicotine are opposite: it can cause nausea, vomiting, convulsions, arrhythmias, and collapse.
Death from nicotine poisoning occurs as a result of inhibition of DC. With repeated use of nicotine, addiction and addiction quickly arises, which is due to stimulation of presynaptic H-ChRs and stimulation of the release of dopamine in the central nervous system.
Mechanism of action: ion channels open, resulting in Na + /Ca 2+ diffusion into the cell, which causes depolarization of nerve or muscle cells.
Due to the widespread use of tobacco smoking, nicotine is only of toxicological importance, which is used in transdermal patches and chewing gum for smoking cessation and for the treatment of nicotine addiction (Nicorette, Nicotinel). These remedies help avoid the development of withdrawal syndrome in people who quit smoking. At the same time, the concentration of nicotine in the blood increases more slowly than during smoking and has lower values. It is easily absorbed from mucous membranes; half-life is about 2 hours. In the body (mainly in the liver), it is quickly converted into cotinine, which is slowly excreted in the urine throughout the day.
In medical practice, preparations of lobeline and cytiton (0.15% cytisine solution) are used to stimulate H-ChR. They stimulate the H-ChR of the sinocarotid glomeruli and reflexively increase the tone of the respiratory and vasomotor centers.
Lobelin– an alkaloid found in the plant Lobelia inflata, family bellflowers (Campanulacea). In medical practice, lobeline hydrochloride (Lobelini hydrochloridum) is used. Mechanism of action: lobeline is a substance that has a specific stimulating effect on the ganglia of the autonomic nervous system and carotid glomeruli. This action of lobeline is accompanied by stimulation of the respiratory and vasomotor centers. If breathing weakens or stops, developing as a result of progressive depletion of the DC, the administration of lobeline is not indicated. Previously used for reflex cessation of breathing (mainly due to inhalation of carbon monoxide and asphyxia, etc.).
Fig. 4. Consequences of smoking
Cititon– refers to substances with “ganglionic” action due to its stimulating effect on breathing, and is considered as a respiratory analeptic. For this purpose, it is produced in the form of a ready-made 0.15% aqueous solution of cytisine called “Cititon”. In recent years, cytisine has also begun to be used as a means of quitting smoking (in the form of the drugs Lobesil, Tabex and Cypercuten TTS).
Cititon has a stimulating effect on the ganglia of the autonomic nervous system and related formations: chromaffin tissue of the adrenal glands and carotid glomeruli.
Indications for the use of direct cholinomimetics:
1. Glaucoma, vitreous hemorrhage, optic nerve atrophy, central retinal vein thrombosis (aceclidine, pilocarpine).
2. Atony of the intestines, bladder, decreased tone of the uterus and its subinvolution, postpartum hemorrhage (aceclidine, proserin).
3. Rarely during collapse (the release of adrenaline and norepinephrine increases and blood pressure rises) - tsititon, lobeline.
4. Carbon monoxide poisoning without suppressing the reflex excitability of the respiratory center (lobeline, cititon).
5. Nicotine addiction (Lobesil, Tabex).
Side effects:
1. Bradycardia.
2. Decrease in blood pressure.
3. Excessive sweating, drooling.
4. Abdominal pain, nausea, vomiting, diarrhea.
6. Bronchospasm, visual impairment.
Contraindications:
1. Bronchial asthma.
2. Angina.
3. Myocardial damage.
4. Intraatrial and atrioventricular blockade.
5. Gastrointestinal bleeding.
6. Peritonitis (before surgery).
7. Epilepsy.
8. Pregnancy.
9. Severe atherosclerosis.
10. Hypertension.
11. Pulmonary edema.
Children's features: M-CMs are rarely used in pediatrics, which is associated with high toxicity for young children. For infants, M-XM is used to treat gastrointestinal reflux. The use of N-CMs is also limited, since they can inhibit DC, leading to short-term or long-term respiratory arrest. Dangerous for newborns born in hypoxic conditions.
Poisoning with M-cholinomimetics and fly agaric
· Symptoms:
1. Salivation and sweating.
2. Dyspeptic disorders (nausea, vomiting, diarrhea).
3. Miosis, visual impairment.
4. Bradycardia.
5. Decrease in blood pressure.
· Treatment:
Administration of antidotes: atropine sulfate subcutaneously, 1 ml until the pupil dilates (30-60 minutes) and bronchospasm is eliminated. Gastric lavage, symptomatic therapy if necessary.
Anticholinesterase
Mechanism of action: inhibition of cholinesterase, and, consequently, protection from the destruction and inactivation of released ACh, the effect of which becomes longer and stronger. Depending on how AChE bind to the esterase center of cholinesterase, they are divided into reversible (physostigmine, galantamine, proserine) and irreversible types of action (armin).
Indications for use:
1. Open-angle form of glaucoma.
2. Motor disorders associated with previous meningitis or encephalitis, polio.
3. Facial nerve paralysis.
4. Injuries to the nervous system (during the recovery period after meningitis, encephalitis).
5. Amyotrophic lateral sclerosis.
6. Atony of the intestines and bladder.
7. Myasthenia gravis.
Side effects:
1. From the digestive system: nausea, vomiting, diarrhea, abdominal pain.
2. From the cardiovascular system: decreased blood pressure, bradycardia.
3. Dermatological reactions: skin rash.
4. Other: hypersecretion of bronchial glands, salivation, lacrimation, sweating, frequent urination, blurred vision, convulsions, muscle fasciculations, muscle weakness.
Contraindications:
2. Bronchial asthma.
3. Collapse, heart failure.
4. Hypermotility of the intestines and bladder.
5. Peptic ulcer of the stomach and duodenum, enteritis.
6. Epilepsy, Parkinson's disease
7. Normal pregnancy, childbirth and threat of miscarriage.
Poisoning with FOS
The symptoms are similar to those observed with M-XM poisoning, but there are differences - increased blood pressure, myofibrillar twitching, convulsions.
Treatment: atropine sulfate, cholinesterase reactivators (dipyroxime, isonitrosine).
II. Anticholinergics– substances that block the interaction of acetylcholine with cholinergic receptors remove the effects of excitation of the parasympathetic nervous system and sympathetic influences begin to predominate.
Classification of anticholinergics:
 |
1. Non-selective M-anticholinergics
Blocks all M-ChRs, which leads to pupil dilation, decreased tone of smooth muscles of the gastrointestinal tract, ureters, bladder, uterus, bronchi; reduces the secretion of exocrine glands (salivary, bronchial, digestive and others); in the heart causes an increase in automaticity and conductivity. Drugs: atropine, scopolamine, homatropine, metacin, midriacil.
2. Non-systemic M-anticholinergics
More active against bronchial M-ChR; It is used by inhalation and practically does not enter the general bloodstream. Medicines: atrovent (ipratropium), troventol (truven), oxithromium.
3. Selective M-anticholinergics
Inhibits the formation and release of hydrochloric acid in the stomach. Drugs: pirenzepine (gastrocepin, gastrin).
Indications for use of M-CL:
1. Heart block, arrhythmias (atropine).
2. Bronchial asthma (Atrovent).
3. Peptic ulcer of the stomach and duodenum - relieves spasm and secretion (gastrozepine).
4. Colic of hepatic, renal, intestinal origin (platifillin, metacin, atropine).
5. Parkinsonism (scopolamine).
6. Examination of the fundus, selection of glasses (scopolamine, atropine, midriacil), diagnostics in ophthalmology.
7. Iritis (inflammation of the iris), iridocyclitis (homatropine, scopolamine).
8. Premedication (methacin, atropine).
9. Air sickness (“Aeron”).
10. Poisoning with FOS
Children's features: atropine in children has a longer effect due to the immaturity of enzymatic systems. For bronchial asthma, use is limited, since the bronchial glands produce thicker secretions. Atropine is ineffective in children with pyloric spasm, since in early childhood the contraction of the pylorus depends not on the stimulation of M-ChR, but on the stimulation of α-AR. Cannot be used during hyperthermia, as the secretion of the glands is reduced. Children in the first 3 months of life are especially sensitive to atropine (respiratory depression from one drop). In children, due to the fact that they are sympathotonic, atropine poisoning occurs from a higher dose than in adults.
Side effects:
1. Excitation of the central nervous system.
2. Dry mouth.
3. Tachycardia.
4. Visual impairment.
5. Photophobia.
6. Intestinal atony.
7. Dizziness.
Contraindications:
1. Glaucoma.
2. Kidney diseases.
3. Heart diseases.
4. Prostate hypertrophy.
Atropine poisoning
Poisoning occurs in two phases:
1. Excitement phase: anxiety, increased motor and speech activity, convulsions, hallucinations, mydriasis, no reaction of the pupil to light, macroscopy, photophobia, tachycardia, dysphagia, dysarthria, shortness of breath, aphonia, dry and hot skin, small scarlet-like rash.
2. Oppression phase: depression of all vital centers, while mydriasis persists and changes in skin condition - small scarlet-like rash, loss of consciousness up to coma, muscle hypotonia, decreased or absent tendon reflexes, death from paralysis of the respiratory center.
Help: resuscitation measures, gastric lavage, anticholinesterase drugs (galantamine, proserine), which are competitive inhibitors of atropine. Physiological antagonists: morphine and morphine-like drugs.