M cholinomimetics characteristics and development history. M- and N-cholinomimetics of direct and indirect action. Pharmacodynamics. Drugs. Use in medicine. Indications for the use of M-cholinomimetics

Representatives of this series of drugs:

1. acetylcholine (ampoules of 5 ml with 0.2 g of dry matter)

2. carbacholine (0.5-1% solutions for eye drops)

Pharmacodynamics is based on the fact that M- and N-cholinergic receptors of internal organs are simultaneously stimulated:

n N-cholinoreceptors of the parasympathetic ganglion and M-cholinoreceptors of internal organs are excited - the parasympathetic nervous system is activated

n the sympathetic ganglion is excited and the sympathetic nervous system is slightly activated

n in therapeutic doses they do not affect the myoneural synapse.

n As a result, a general pattern of excitation of the parasympathetic nervous system is observed. Effects:

SNS (m. dilatator pupillae)

PNS (m. sphincter pupillae) pupil (pupilla)

1. miosis (constriction of the pupil)

2. spasm of accommodation - the ciliary muscle contracts and moves towards the lens, the ligaments of Zinn relax, the lens becomes more convex (that is, it is set to near vision)

3. decrease in intraocular pressure - when the pupil narrows, access of intraocular fluid in the fountain space to Schlemm's canal improves (these are lymphatic elements at the base of the cornea and iris, that is, in the corner of the anterior chamber of the eye. The outflow of intraocular fluid improves.

2) BRONCHI – bronchospasm and increased secretion of the bronchial glands.

3) CARDIOVASCULAR SYSTEM receives the following effects, firstly on the HEART:

1. slightly, but the strength of heart contractions is weakened, which has no practical significance

2. bradycardia (decreased heart rate)

3. decreased excitability (minor)

4. decreased conductivity (slight)

on VESSELS – mainly on resistive vessels. There is no parasympathetic nervous system, but there are M-cholinergic receptors that cause vasodilation. The result is that blood pressure decreases.

Resistive vessel

(vasodilation)

4) GASTROINTESTINAL TRACT:

1. increase in gastrointestinal tone

2. increased peristalsis

3. increased secretion of gastrointestinal glands

4. relaxation of smooth muscle sphincters.

5) URINARY AND GALL BLADDER (urinary and bile ducts) – strengthening muscle tone and relaxing sphincter tone.

6) UTERUS – increased tone and increased strength of uterine contractions.

APPLICATION:

CARBACHOLINE - only in eye drops, duration of action is 30-40 minutes. Indication: glaucoma. Side effect is visual impairment (spasm of accommodation), has an irritating effect.

CARBACHOL is a long-acting drug (effect up to 4-5 hours).

LECTURE No. 7. ANTICHOLINESTERASE DRUGS.

ATROPINE POISONING. CHOLINOBLOCKERS.

Anticholinesterase drugs are substances that inhibit the AChE enzyme. According to their pharmacological effect, they are indirect cholinomimetics; they have a predominant stimulation of the parasympathetic nervous system.

inhibitors

AChE

AChE ACh acetate

postsynaptic membrane

Cholinergic receptors

In denervated organs, the properties of these drugs do not appear, since they combine with ACh into a strong complex that is inaccessible to AChE. Therefore, there are 2 groups of anticholinesterase drugs according to the DEGREE of AChE inhibition:

1) reversible AChE inhibitors

n physostigmine

n proserin

n galantamine

n deoxypeganine

2) irreversible AChE inhibitors

n phosphacol (eye drops)

n FOS (organophosphorus compounds)

Pharmacodynamics - due to the fact that ACh accumulates in the cholinergic synapses of internal organs and they are excited, that is:

1. myoneural synapse is excited (especially under pathological conditions)

2. the sympathetic ganglion is excited (sympathetic influences are slightly enhanced)

3. the parasympathetic ganglion is excited, and accordingly the synapses in the organs receiving parasympathetic innervation; this is manifested by increased activity of parasympathetic influences.

1) EYE – miosis, spasm of accommodation, decreased intraocular pressure.

2) BRONCHI – increased secretion of the bronchial glands, narrowing of the bronchi.

3) CARDIOVASCULAR SYSTEM – effects on heart:

Bradycardia

Slight decrease in heart rate

Weak conduction inhibition

Slight decrease in excitability.

Effects on vessels: - in therapeutic doses - no effect, in toxic doses - hypotension (drop in blood pressure).

Resistive vessel

(vasodilation)

4) GASTROINTESTINAL TRACT:

1. increased smooth muscle tone

2. increased peristalsis

3. increase in gland secretion

5) URINARY AND GALL BLADDER – increased tone and contractility.

6) UTERUS - slight increase in tone, do not act for up to 3 months, stimulate contractility in pregnant women.

In general, the most pronounced changes are observed in the eyes and gastrointestinal tract.

APPLICATION.

1) glaucoma, angle-closure form (phosphakol, physostigmine). Side effects in this case are a burning sensation, “specks” in the eye, spasm of accommodation.

2) Atony of the intestines and bladder (proserin - maximum long-term effect up to 5 hours)

3) Birth weakness (prozerin)

4) Myasthenia gravis – weakness of skeletal muscles (prozerin).

5) Paralysis and paresis

6) tachyarrhythmias

7) overdose of muscle relaxants

8) atropine poisoning.

SIDE EFFECTS:

Spasm of accommodation

Bronchospasm (contraindicated in bronchial asthma)

Activation of the gastrointestinal tract - exacerbation of gastrointestinal diseases (peptic ulcer, gastritis)

Increased tone of the urinary and biliary tract, which increases the tendency to renal and hepatic colic

Increased uterine tone (increased pain during menstruation).

POISONING BY FOS (organophosphorus compounds).

FOS are anticholinesterase agents: phosphacol, insecticides, poisons for seed dressing.

K L I N I K A.

Caused by severe stimulation of the parasympathetic nervous system: miosis, difficulty breathing, severe bradycardia, hypotension, dyspeptic disorders (nausea, vomiting, abdominal pain, diarrhea), central nervous system stimulation (tremor of the fingers, clonic convulsions), increased sweating, increased salivation.

TREATMENT.

1. remove the person from the affected area; gastric lavage with a weak solution of potassium permanganate or tannin in cold water

2. prescription of functional antagonists or antidotes (antidotes):

n M-anticholinergics (atropine subcutaneously until dry mouth appears, until the pupil dilates)

n Prescription of AChE reactivators (dipyroxime, isonitrosine)

3. symptomatic therapy (for hypotension - norepinephrine intravenously, for paralysis of the respiratory muscles - respiratory analeptics).

4. Forced diuresis (furosemide, Lasix) with fluid replacement (5% glucose, saline solution, polyglucin, rheopolyglucin, hemodez).

M-CHOLINOMIMETICS

1. pilocarpine (chemical structure – alkaloid)

2. aceclidine (synthetic drug).

In their pharmacological effect, they imitate the effect of acetylcholine on M-cholinergic receptors, showing the influence of the parasympathetic system in them.

M-ChRs of internal organs are irritated, which allows them to be affected by their parasympathetic dysfunction.

MECHANISM OF ACTION (see diagram)

aceclidine

AChE ACh acetate

+ + + + + + + + -- -- -- -- -- -- -- + + + + + + + + + + + +

postsynaptic membrane

-- -- -- -- -- -- -- -- -- + + + + + + + -- -- -- -- -- -- -- -- -- -- -- -- -- --

Cholinergic receptors

Pharmacodynamics - they excite M-cholinergic receptors of internal organs and reproduce the effects of the parasympathetic nervous system there (see effects above).

APPLICATION.

The action develops after 30-40 minutes and lasts 3-4 hours.

1) glaucoma

2) atony of the intestines and bladder (aceclidine) in the postoperative period

3) birth weakness.

MUSCARINA POISONING is an alkaloid of the fly agaric mushroom.

Clinic – it is based on excessive excitation of the parasympathetic nervous system (see above FOS poisoning)

1. preventing the absorption of poison from the gastrointestinal tract (induce vomiting, lavage the stomach with a 0.02% solution of potassium permanganate, which oxidizes and neutralizes alkaloids, 0.25-0.5% tannin, which adsorbs toxins, to clean wash water).

2. Prescription of functional antagonists or antidotes (M-cholinergic blockers - atropine until dry mouth appears)

3. Accelerated introduction of absorbed poison from the body - forced diuresis (furosemide intravenous or intravenous) + intravenous blood substitutes.

4. Symptomatic therapy.

M-CHOLINOBLOCKERS.

THERE IS a rule of one-sided antagonism: “blockers are always stronger than mimetics.” That is, there are no functional antidotes for atropine poisoning. So, M-anticholinergics are:

1) ALKALOIDS

1. atropine (henbane, belladonna, datura)

2. platiphylline (for colic)

3. scopolamine (for the treatment of parkinsonism only)

2) SYNTHETIC

1. homatropine (eye drops only)

2. metacin (bronchial asthma).

MECHANISM OF ACTION (see diagram)

atropine

AChE ACh acetate

+ + + + + + + + -- -- -- -- -- -- -- + + + + + + + + + + + +

postsynaptic membrane

-- -- -- -- -- -- -- -- -- + + + + + + + -- -- -- -- -- -- -- -- -- -- -- -- -- --

Cholinergic receptors

Atropine is a dipole whose active part blocks receptors,

and the other end keeping other substances out, the so-called “dog in the manger.”

Pharmacodynamics.

M-cholinergic receptors of internal organs are blocked and the influence of the parasympathetic nervous system on these organs is reduced.

1) EYE – such a triad:

n mydriasis – dilation of the pupil

n paralysis of accommodation

n increase in intraocular pressure due to compression of the lymphatic

cracks and worsening outflow.

SNS (m. dilatator pupillae)

PNS (m. sphincter pupillae) pupil (pupilla)

atropine

2) BRONCHI – dilation of the bronchi and decreased secretion of the bronchial glands.

3) CARDIOVASCULAR SYSTEM

On the heart: - severe tachycardia

Weak inotropic effect

Weak conduction enhancement

Weak increase in excitability.

On the vessels - there is no significant change in vascular tone, but there is an increase in systolic blood pressure due to tachycardia.

4) GASTROINTESTINAL TRACT – decreased tone, peristalsis, secretion.

5) URINARY AND GALL BLADDER – decreased tone – antispasmodic effect.

6) UTERUS – loss of tone and contractility in pregnant women.

APPLICATION.

1. to create long-term mydriasis (atropine up to 12 hours) - in the treatment of strabismus, eye injuries, inflammation of the iris (iritis, iridocyclitis) - functional rest is created for the muscles of the eye.

2. Short-term mydriasis (platiphylline, homatropine 2-4 hours) – for examination of the fundus

3. Bronchial asthma and bronchospastic diseases (metacin)

4. To prevent reflex cardiac arrest during operations

5. Peptic ulcer of the stomach and duodenum with high acidity - eliminates pain, reduces the secretion of HCl.

6. Renal and hepatic colic - to eliminate spasm of the outflow tract.

SIDE EFFECTS:

n dry mouth

n palpitations, pain in the heart area

n visual impairment.

ACUTE ATROPINE POISONING

The alkaloid atropine is found in the poison of henbane, datura, and belladonna; poisoning is more common in children.

It is based on blockade of M-cholinergic receptors and elimination of parasympathetic effects.

The first symptoms appear after 2-3 hours: mydriasis, blurred vision, dry mouth, thirst, difficulty swallowing, and possibly loss of voice. This is followed by redness of the skin and rash, mental and motor agitation, then depression of the central nervous system occurs: depression, weakness of skeletal muscles, drowsiness, coma, death from paralysis of the respiratory center.

If the patient has not died within 36-48 hours, then he can still be saved.

TREATMENT.

1. preventing the absorption of poison in the gastrointestinal tract (gastric lavage to clean lavage water with a slightly pink 0.02% solution of potassium permanganate, 0.25% tannin)

2. prescribing functional antagonists or antidotes - in this case there are none. They use anticholinesterase drugs (physostigmine and galantamine), but their effectiveness is practically zero, but suddenly! – not all receptors are blocked.

3. Removal of absorbed poison from the body - forced diuresis (furosemide + intravenous blood substitutes)

4. Symptomatic therapy - stimulation of the respiratory center when it stops (respiratory analeptics).

N-CHOLINOMIMETICS

1. cititon

2. lobeline

3. nicotine, which has no practical significance.

Mechanism of action (see diagram).

cititon

AChE ACh acetate

+ + + + + + + + -- -- -- -- -- -- -- + + + + + + + + + + + +

postsynaptic membrane

-- -- -- -- -- -- -- -- -- + + + + + + + -- -- -- -- -- -- -- -- -- -- -- -- -- --

Cholinergic receptors

Pharmacodynamics.

It is caused by stimulation of H-cholinergic receptors of internal organs (parasympathetic and sympathetic ganglia, adrenal medulla - release of catecholamines); in therapeutic doses, H-cholinergic receptors of the myoneural synapse are not excited. As a result, both the sympathetic and parasympathetic systems are simultaneously excited. In those organs where there is predominantly parasympathetic innervation (GIT) or sympathetic innervation (vessels), corresponding autonomic effects are observed.

PARASYMPATHETIC effects:

1) Gastrointestinal tract - increased tone, peristalsis and secretion of the stomach and intestines

2) The heart – at first – bradycardia, which is then replaced by tachycardia.

SYMPATHETIC effects:

1) heart - an increase in strength with an increase in myocardial oxygen demand (cardiotonic effect), a slight increase in excitability and conductivity.

2) Vessels – narrowing and increasing blood pressure (hypertensive reaction, see diagram)

cititon

Hering's nerve

carotid sinus

ka" spasm of arteries and

hypertension

3) myoneural synapse - they do not act in therapeutic doses.

Application:

They are administered exclusively intravenously and are used as respiratory analeptics. The action develops within 1-2 minutes and lasts no more than 5-6 minutes. Disadvantages - weak effect, since the action is based on a reflex, the effect is possible with preserved excitability (integrity) of the spinal cord, for example, in hanged people, drug overdose, does not work in drowning, barbiturate poisoning.

N-CHOLINOBLOCKERS.

These are drugs that block H-cholinergic receptors. These include ganglion blockers and muscle relaxants.

According to the CHEMICAL structure, these are bis-quaternary ammonium compounds (polymethylene-bis-trimethylammonium).

H3C-N+ -- (CH2)n -- N+ --CH3

If n=5 or 6, then these substances block H-cholinergic receptors in the autonomic ganglia, that is, they are ganglion blockers And:

1. pentamine

2. benzohexonium.

When n > 6, myoneural synapses are blocked, and these substances are called muscle relaxants.

For example, n=10, then this is decamethonium.. (o – receptors)

o o o o o o o o o o o

o o o o o o o o o o o

o o o o o o o o o o o

7 Angstrom (n=5-6) 15 Angstrom (n more than 6)

autonomic ganglion myoneural synapse

They are poorly absorbed from the gastrointestinal tract, so they are prescribed intravenously. They penetrate the blood-brain barrier poorly, so they act predominantly peripherally.

GANGLION BLOCKERS

According to the duration of action, they are distinguished:

1) short-acting (lasts up to 4 hours)

n benzohexonium

n pentamine

n hygronium (ultra-short-acting up to 10-15 minutes), used for controlled hypotension, for example, during brain surgery

2) g.b long-acting (effect up to 6-12 hours)

n pachycarpine (used for labor stimulation)

n he is a non-competitive antagonist.

Mechanism of action (see diagram)

benzohexonium

AChE ACh acetate

+ + + + + + + + -- -- -- -- -- -- -- + + + + + + + + + + + +

postsynaptic membrane

-- -- -- -- -- -- -- -- -- + + + + + + + -- -- -- -- -- -- -- -- -- -- -- -- -- --

H-cholinergic receptors

Pharmacodynamics.

The autonomic ganglia are blocked and sympathetic and parasympathetic influences are eliminated, that is, pharmacological denervation of the internal organs occurs. The final effects depend on the predominance of sympathetic or parasympathetic in a particular organ.

THE CARDIOVASCULAR SYSTEM.

Weak tachycardia

Hypotensive reaction (blockade of sympathetic ganglia and decreased sympathetic influences, blockade of H-cholinergic receptors in the adrenal medulla and decreased production of adrenaline)

A decrease in venous return to the heart and a drop in MOC (minute blood volume), simultaneously with the arterioles, the venules of the lower half of the body expand

Orthostatic hypotension (undesirable effect).

GASTROINTESTINAL TRACT

Decreased tone, peristalsis, secretion of the stomach and intestines.

SIDE effects - orthostatic collapse - first aid: lie the patient down, elevate the legs, inject adrenaline.

APPLICATION

1. obliterating endarteritis (Raynaud's disease)

in men – more often the lower extremities (intermittent claudication)

in women - mainly the upper limbs.

(used in the early stages)

2. cerebral edema and pulmonary edema

3. treatment of hypertensive crisis

4. controlled hypotension (hygrony)

5. labor weakness (pachycarpine).

MUSCLE RELAXANTS

These are agents that relax striated muscles.

Mechanism of action (see diagram):

muscle relaxant muscle relaxant

Antidepolarizing - depolarizing

AChE ACh acetate

+ + + + + + + + -- -- -- -- -- -- -- + + + + + + + + + + + +

postsynaptic membrane

-- -- -- -- -- -- -- -- -- + + + + + + + -- -- -- -- -- -- -- -- -- -- -- -- -- --

H-cholinergic receptors

Muscle relaxation sequence:

1. external muscles of the eyeball, tongue, neck

2. muscles of the lower limb

3. muscles of the trunk and upper limbs

4. respiratory muscles (there is a danger of death from paralysis - mechanical ventilation is required).

There are two large groups of muscle relaxants:

I. ANTI-DEPOLARIZING muscle relaxants

1. tubocurarine

2. melliktin

They cause mild muscle paralysis because they simply block the H-ChR of the myoneural synapse; their functional antagonists are anticholinesterase drugs (prozerin, etc.)

II. DEPOLARIZING muscle relaxants

2. ditilin.

They cause prolonged depolarization of the membrane, it becomes unresponsive; here anticholinesterase drugs are functional agonists!

APPLICATION – based on the duration of action of muscle relaxants (classification according to duration of action):

1) short-acting muscle relaxants – ditilin– only intravenously, acts in 40-60 seconds, lasts 5-7 minutes. Used for intubation, reduction of dislocations, skeletal traction for repositioning fragments

2) muscle relaxants of medium duration of action – tubocurarine, decamethonium- only intravenously, in doses that do not depress the respiratory center. Starts in 3-5 minutes, lasts 30 minutes-1.5 hours. Used during surgical operations to relax skeletal muscles (abdominal cavity, pelvis, lower extremities).

3) long-acting muscle relaxants – melliktin– acts for 3-4 hours – trivalent nitrogen does not contain a charge; it is given orally in tablets. Used for the treatment of convulsive diseases as an adjuvant (parkinsonism, epilepsy).

M-cholinergic receptors

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 Ca2+ 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).
M3-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 (1P3) is formed from phospholipids of cell membranes, which promotes the release of Ca2+ from sarcoplasmic reticulum (intracellular calcium depot). As a result, when M3 cholinergic receptors are stimulated, the concentration of Ca2+ 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 (extrasynaptic) 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 Ca2+ 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. In case of poisoning with fly agaric mushrooms containing muscarine, its toxic effect is manifested, associated with the stimulation of M-cholinoreceptors. 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.

N
Aceclidine

C2H5- CH- CH - CH2~ C N - CH3
* ° i i * i i °


Pilocarpine hydrochloride
Acetylcholine

Pilocarpine is an alkaloid from the leaves of the Pilocarpus pinnatifolius 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.
facilities
Radial muscle


Reduced outflow of intraocular fluid
NORM
Lens
Ligament of Zinn M-cholinergic receptor Ciliary muscle
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).
Spasm of accommodation NORMAL Paralysis of accommodation
Rice. 8.2. The effect on the eye of substances that affect cholinergic innervation (the thickness of the arrow shows the intensity of the outflow of intraocular fluid).

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 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 its 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 instillation, 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-cholinergic blockers (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 a-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.
CH
"-"Pz
Lobeline hydrochloride
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 biogens
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).

Cholinomimetics

Cholinomimetics- see Cholinomimetic drugs.

M-cholinomimetics- see M-cholinomimetic drugs.

N-cholinomimetics- see N-cholinomimetic drugs.

Cholinomimetic agents

Cholinomimetic agents - I

drugs that reproduce the effects of stimulation of cholinergic receptors by their natural ligand - acetylcholine. The cholinergic effect can be enhanced both by direct interaction of Ch. with a certain type of cholinergic receptor (direct-acting cholinergic), and the preservation of excess acetylcholine in the synapse by inhibiting cholinesterase that destroys it (indirect-acting cholinergic). In the second case, excitation of all types of cholinergic receptors is initiated, incl. localized in the central nervous system and at neuromuscular junctions of skeletal muscles. H. s. indirect action form an independent group of anticholinesterase drugs (Anticholinesterase drugs).

H. s. direct action in accordance with the classification of cholinergic receptors (see Receptors) are divided into m-, n- and n+m-cholinomimetics.

m-cholinomimetics- aceclidine and pilocarpine - cause local (when applied topically) or general effects of stimulation of m-cholinergic receptors: miosis, accommodation spasm, decrease in intraocular pressure; bradycardia, slowing of atrioventricular conduction; bronchospasm, increased tone and motility of the gastrointestinal tract, bladder, uterus; secretion of liquid saliva, increased secretion of bronchial, gastric and other exocrine glands. All these effects are prevented or eliminated by the use of atropine and other m-cholinergic drugs (see Anticholinergic drugs), which are always used in cases of overdose of m-cholinomimetics, poisoning with substances with a similar or anticholinesterase effect.

Indications for the use of m-cholinomimetics: glaucoma, thrombosis of the central retinal vein; atony of the stomach, intestines, bladder, uterus, postpartum uterine bleeding. General contraindications to their use are bronchial asthma, angina pectoris, myocardial damage, intra-atrial and atrioventricular blockade, gastrointestinal bleeding, peritonitis (before surgery), hyperkinesis, epilepsy, normal pregnancy.

Aceclidine- powder (for the preparation of eye drops in the form of 2%, 3% and 5% aqueous solutions) and 0.2% solution in ampoules of 1 and 2 ml for subcutaneous injections. For glaucoma, instillation into the eye is carried out from 2 to 6 times a day. In case of acute atony of the bladder, 1-2 ml of 0.2% solution is injected subcutaneously; in the absence of the expected result, the injections are repeated 2-3 times with an interval of half an hour, unless undesirable effects are expressed (hypersalivation, bronchospasm, bradycardia, etc.).

Pilocarpine hydrochloride used mainly in ophthalmological practice. Its main forms of release: 1% and 2% solutions in bottles of 5 and 10 ml; 1% solution in dropper tubes; 1% solution with methylcellulose in bottles of 5 and 10 ml; eye films (2.7 mg of pilocarpine hydrochloride each); 1% and 2% eye ointment. Most often, 1% and 2% solutions are used, instilling them into the eye 2 to 4 times a day.

n-cholinomimetics- alkaloids lobeline and cytisine - excite postsynaptic cholinergic receptors in the ganglia of the sympathetic and parasympathetic nervous system, in the carotid glomeruli and in the chromaffin tissue of the adrenal glands (increased adrenaline secretion). As a result, both adrenergic and cholinergic influences on the executive organs are activated. At the same time, the action of cytisine (the drug Cititon) is dominated by adrenergic peripheral effects (increased blood pressure, increased heart contractions), while the action of lobeline is dominated by cholinergic effects (bradycardia, decreased blood pressure are possible). Both alkaloids reflexively (from the receptors of the carotid reflex zone) excite the respiratory center and are used mainly as respiratory analeptics in cases of acute respiratory arrest (against the background of long-term depression of the respiratory center, the effect is unstable). Their nicotine-like effect became a prerequisite for the use of lobeline (Lobesil tablets) and cytisine (Tabex films and tablets) to facilitate smoking cessation. Their use for this purpose is contraindicated in case of organic diseases of the cardiovascular system, persistent arterial hypertension, angina pectoris, gastric and duodenal ulcers, bleeding.

Lobeline hydrochloride- 1% solution in ampoules of 1 ml; tablets 2 mg (drug "Lobesil"). In case of acute respiratory arrest in adults, 0.3-0.5 ml (for children 0.1-0.3 ml depending on age) is administered intramuscularly or intravenously slowly (over 1-2 minutes), because rapid administration threatens collapse and cardiac arrest. In case of overdose, vomiting, convulsions, severe bradycardia, and profound respiratory depression are also possible. During the period of quitting smoking, Lobesil is prescribed in the first week, 1 tablet up to 5 times a day, then the frequency of doses is reduced until withdrawal (20-30 days). In case of poor tolerability (dizziness, weakness, nausea), the drug is discontinued.

Cititon- 0.15% cytisine solution in ampoules of 1 ml; Tabex tablets and films for cheek (or gum) application, 1.5 mg each. Due to its pressor effect, it is used more often than lobeline, because acute respiratory depression often occurs against the background of collapse or shock. Adults are administered intravenously or intramuscularly 0.5-1 ml (children under 1 year - 0.1 ml). For those who quit smoking, the general scheme for using Tabex tablets is the same as Lobesil tablets; The films are changed 4-8 times in the first three days, then 3 times a day, from the 13th to the 15th day 1 film is used, then discarded.

n+m-cholinomimetics are represented by acetylcholine (a drug), which is practically not used in medical practice, and carbacholine, which is similar in chemical structure.

Carbacholine is not destroyed by cholinesterase and has a longer lasting and more pronounced cholinergic effect than acetylcholine. The overall effect is dominated by the effects of excitation of m-cholinergic receptors, and only against the background of their blockade do n-cholinergic effects clearly appear. At the same time, carbocholine has no advantages over drugs from the m-cholinomimetics group, therefore, of the previously known forms of its release, only eye drops (in the form of 0.75%, 1.5%, 2.25% and 3% p -carbacholine) for the treatment of glaucoma. During eye surgeries, sometimes 0.5 ml of 0.01% carbacholine solution is injected into the anterior chamber of the eye to narrow the pupil.

cholinergic drugs with different mechanisms of action, causing effects characteristic of excitation of cholinergic receptors.

M-cholinomimetic drugs(syn.: M-cholinomimetics, M-cholinergic drugs) - X. s., stimulating or promoting the excitation of M-cholinergic receptors (pilocarpine, aceclidine, etc.)

N-cholinomimetic drugs(syn.: H-cholinomimetics, H-cholinergic drugs) - X. s., stimulating or promoting the excitation of H-cholinergic receptors (lobeline, cytisine, etc.).

Encyclopedic Dictionary of Medical Terms M. SE-1982-84, PMP: BRE-94, MME: ME.91-96.

Effects of M-cholinomimetics (=excitation of M-cholinergic receptors):

Effect on the eyes. Excitation of M-cholinergic receptors of the circular muscle of the iris leads to its contraction, and the pupil narrows (miosis). Constriction of the pupil and flattening of the iris helps to open the angles of the anterior chamber of the eye and improve the outflow of intraocular fluid, which reduces intraocular pressure. M-cholinomimetics increase the curvature of the lens, causing a spasm of accommodation. The eye is set to near vision (myopia). Side effect “Disturbance of accommodation”

Effect on the exocrine glands. The secretion of saliva increases, as well as lacrimation and sweating

Effect on the bronchi: stimulate contraction of the circulatory muscles of the bronchi (tone increases to bronchospasm), mucus secretion in the bronchi increases.

Effect on the heart: slow down the heart rate (bradycardia), inhibit the conduction of impulses along

conduction system of the heart.

Effect on the gastrointestinal tract: increase the secretion of the glands of the gastrointestinal tract, increase peristalsis, and the tone of the sphincters of the digestive tract (and bladder), on the contrary, decreases.

Effect on the bladder: increased tone bladder, possible urinary incontinence

Indications for the use of M-cholinomimetics:

1) glaucoma, to reduce intraocular pressure (symptomatic therapy).

2) When atony of the intestines and bladder: drugs increase tone while simultaneously relaxing the sphincters, increasing contraction (peristalsis) of these smooth muscle organs, facilitating their emptying.

Clinical picture of poisoning M-cholinomimetics, as well as fly agaric mushroom(contains muscarine)

severe bradycardia, bronchospasm, painful increased peristalsis (diarrhea), sudden sweating, salivation, constriction of the pupils and spasm of accommodation occur, and convulsions are possible. All these symptoms are eliminated

M-cholinergic blockers (atropine and others are antidotes).

Pilocarpine(Pilocarpinum). Synonyms: Pilocarpinum hydrochloridum

Pharmaceutical group: M-cholinomimetic

Mechanism of action: Pilocarpine excites peripheral m-cholinergic receptors, causes constriction of the pupil, reduces intraocular pressure and improves trophism of eye tissue. When instilled into the conjunctival sac of the eye, it is poorly absorbed in normal concentrations and does not have a pronounced systemic effect. When taken orally, pilocarpine is quickly absorbed, but it does not exist per os. are prescribed.

Indications for use: - glaucoma!!!

To improve the trophism of the eye in case of thrombosis of the central retinal vein, acute obstruction of the retinal artery, with atrophy of the optic nerve, with hemorrhages into the vitreous body.

To stop the mydriatic effect after using atropine, homatropine, scopolamine or other anticholinergic substances to dilate the pupil during ophthalmological examinations.

Side effects:

Headache (in the temporal or periorbital areas), pain in the eye area; myopia; decreased vision, especially in the dark, due to the development of persistent miosis and spasm of accommodation; lacrimation, rhinorrhea, superficial keratitis; allergic reactions. With prolonged use, the development of conjunctivitis and eyelid dermatitis is possible; when using systems with prolonged release of the drug - the development of tolerance

Contraindications:

Hypersensitivity, iritis, cyclitis, iridocyclitis, keratitis, condition after ophthalmological operations and other eye diseases in which constriction of the pupil is undesirable. Caution in patients with a history of retinal detachment and in young patients with high myopia.

Release forms: 1% solutions in bottles of 5 and 10 ml; 1% solution in dropper tubes of 1.5 ml; Now there is no -1% and 2% eye ointment; eye films

Drugs that stimulate H-cholinergic receptors (H-cholinomimetics)

Effects:

1) reflex excitation of the respiratory center of the medulla oblongata through activation of cholinergic receptors of the sinocarotid zone

2) increase blood pressure due to stimulation of cells of the adrenal medulla and sympathetic ganglia (the release of adrenaline and norepinephrine increases).

3) facilitate the conduction of impulses to skeletal muscles (in case of overdose - convulsions)

N-cholinomimetics penetrate well into the central nervous system, especially lobeline, and can cause bradycardia and a decrease in blood pressure (activation of the vagal center), vomiting (excitation of the vomiting center), convulsions (excitation of cells of the anterior central gyrus and anterior horns of the spinal cord).

Indications for use of AChE agents:

1) in case of respiratory arrest associated with carbon monoxide poisoning, drowning, brain injury, electrical injury, or inhalation of irritating substances. They are effective only if the reflex excitability of the respiratory center is maintained.

2) to facilitate smoking cessation.

Cytisine (Cytisinum) is an alkaloid found in the seeds of the Russian broom and Thermopsis lanceolifolia plants, both from the legume family. As a respiratory analeptic, it is available in the form of a 0.15% solution called “Cytitonum” in 1 ml ampoules. As a means of quitting smoking - in the form of Tabex tablets.

Cititon. Mechanism of action: excites H-cholinergic receptors in the carotid zone, which reflexively leads to excitation of the respiratory center. Simultaneous stimulation of the sympathetic nodes and adrenal glands leads to an increase in blood pressure.

The effect of cititon (cytisine solution) on breathing is of a short-term “push-like” nature, but in some cases, especially with reflex stops of breathing, the use of cititon can lead to a permanent restoration of breathing and blood circulation.

It is used for reflex cessation of breathing (during operations, injuries, etc.) It has a pressor effect (which distinguishes it from lobeline). Therefore, cititon can be used in shock and collaptoid conditions, in respiratory and circulatory depression in patients with infectious diseases, etc. Cititon is administered intravenously or intramuscularly.

Cititon is contraindicated (due to its ability to increase blood pressure) in cases of severe atherosclerosis and hypertension, bleeding from large vessels, and pulmonary edema.

"Tabex"- tablets to ease smoking cessation. Mechanism of action: excites the same H-cholinergic receptors as nicotine. Reduces the need for the number of cigarettes smoked, facilitates temporary abstinence from smoking, and alleviates withdrawal symptoms that occur when quitting smoking completely.

Drugs that stimulate M and H cholinergic receptors

Classification of cholinomimetics:

1. Direct-acting cholinomimetics – they themselves directly act on cholinergic receptors

· M, N – cholinomimetics (acetylcholine, carbocholine)

M-cholinomimetics (pilocarpine, acyclidine)

N-cholinomimetics (cytiton, lobeline, anazine, Tabex, Lobesil

2. Indirect-acting cholinomimetics – they do not act directly on receptors.

Stimulators of presynaptic release of acetylcholine (cisapride, cerulitide)

ACH enzyme inhibitors

ü Reversible action: proserine, aminostigmine, pyridostigmine, axosyl. pimadine

ü Irreversible action: armin

M, N – cholinomimetics.

These drugs are not distinguished by their selective action - they stimulate all types of cholinergic receptors, but when they are used, the M-cholinomimetic effect primarily develops because they are more sensitive. They are used extremely rarely, especially in pediatrics.

Acetylcholine: It is not used in medical practice, but only in experiments as a pharmacological analyzer. The short-term effect is quickly destroyed, the action is not selective.

Carbachol: synthetic is more stable – it lasts 105 hours and is not hydrolyzed by acetylcholine esterase. It is used in medical practice to a limited extent only in ophthalmology in the form of drops and films in adults - it causes constriction of the pupil, spasm of accommodation, reduces intraocular pressure. Not selective, toxic.

Side effects are common: bronchospasm, decreased heart function, increased secretion of all glands, increased blood pressure.

M-cholinomimetics.

Selectively stimulates only MHR. Activating the receptors is similar to increasing the effects of the parasympathetic nervous system.

Increased smooth muscle tone

· Affect cardiac activity: slower excitability, conductivity, especially in the AV node, decreased automaticity, bradycardia.

· Effect on the secretion of glands: stimulate the secretion of bronchial, salivary, sweat and other glands.

Effect on the organ of vision:

ü constriction of the pupil - the orbicularis iris muscle contracts,

ü decrease in intraocular pressure - expansion of the helmet canal and fountain spaces → fluid outflow increases,

ü spasm of accommodation → the lens takes on a more convex shape - the ciliary muscle narrows

Pilocarpine: a herbal preparation used in the form of a hydrochloride salt, Aceclidine– are used limitedly in ophthalmology with the aim of reducing intraocular pressure; they are not used in pediatrics. But they can be used in dentistry to increase saliva secretion.

Side effects: sweating, salivation, increased bronchial tone, bradycardia - antagonist M-anticholinergic atropine.

Contraindications: bronchial asthma, heart disease, angina pectoris. Stomach and intestinal bleeding, epilepsy, pregnancy.

N-cholinomimetics.

They are distinguished by their two-phase action. In the first phase it stimulates receptors, and then inhibition occurs. NHMs are used to a limited extent. Previously, they were used as respiratory analeptics - “breathing stimulants,” they stimulated the NChR of the carotid glomeruli in the vessels → reflexively increased the tone of the respiratory center. Used for carbon monoxide poisoning, drowning, and injuries. Today they are used as a smoking cessation aid.

Side effects: excitation of the vagus nerve nuclei → bradycardia, decreased blood pressure, vomiting, convulsions.

Stimulators of presynaptic acetylcholine release.

They modulate the release of ACh into the synaptic cleft→the concentration increases→the rate of excitation transmission increases→the duration increases.

· treatment of postoperative intestinal atony, paralytic intestinal obstruction – increasing the tone of smooth muscles of the gastrointestinal tract

treatment of gastric paresis

· treatment of gastroesophageal reflux – normalizes sphincter motility

Treatment of neonatal regurgitation

X-ray studies

Side effects: explained by non-selectivity and an increased concentration of ACh leads to an increase in the tone of other systems: gastrointestinal disorders (pain, dyspepsia), dizziness, decreased blood pressure.

Anticholinesterase drugs.

They block acetylcholinesterase and increase the concentration of ACh in the synapse. The most widely used of all cholinomimetics.

AChES is reversible: it does not block the enzyme forever, after which they are destroyed, and the enzyme continues to work. Irreversible drugs are destroyed along with the enzyme.

Arnin– used only in ophthalmology as drops to reduce intraocular pressure.

Effects due to MX-ergic action:

Increases smooth muscle tone

· disrupt excitability, conduction in the heart → bradycardia

Constriction of the pupil, spasm of accommodation, decreased intraocular pressure

· increased secretion of glands

Effects caused by HX-ergic action:

Improvement of neuromuscular conduction

Improvement of impulse transmission in the area of ​​the autonomic ganglia

· capable of penetrating the central nervous system (only drugs with a tertiary structure) - in small doses they stimulate, in large doses they depress.

Application:

· ophthalmology – treatment of glaucoma (irritates the conjunctiva)

· for intestinal atony – postoperative, post-infectious

· for the treatment of myasthenia gravis – increasing conductivity

· Cerebral palsy, consequences of poliomelitis - symptomatic treatment

in case of overdose of non-depolarizing muscle relaxants

for tachyarrhythmias

Side effects:

• increased salivation
• bronchospasm
• heart rate slowdown
• heart rhythm disorder
• spasm of the intestinal and bladder muscles
• nausea, diarrhea, frequent urination
• constriction of the pupils
• skeletal muscle twitching

Contraindication.