7. N-cholinomimetic drugs. The use of nicotine mimetics to combat smoking.
Localization of Hn-cholinergic receptors and pharmacological effects upon their stimulation.
Localization: neuronal ganglia of the ANS, adrenal medulla, neurons of the central nervous system
Pharmacological effects when stimulated:
1) excitation of the neuronal ganglia of the ANS (sympathetic more than parasympathetic)
2) CVS: tachycardia, vasospasm, hypertension
3) Gastrointestinal tract, MPS: predominance of parasympathetic effects (vomiting, diarrhea, frequent urination)
5) CNS: psychostimulation (at low doses of agonists), vomiting, tremor, convulsions, coma (at high doses of agonists)
drugs from the group of N-cholinomimetics.
Nicotine, cytisine, anabasine hydrochloride
Classification of Hn-cholinergic blockers. Indicate the place of their action on the PNS diagram.
a) short-acting – trepirium iodide (hygronium);
b) average duration of action - hexamethonium benzosulfonate (benzohexonium), azamethonium bromide (pentamine);
c) long-acting – pempidine (pyrylene).
Place of action on the PNS diagram: ANS ganglia, adrenal medulla, central nervous system.
mechanisms of action and pharmacological effects of N-cholinomimetics.
Mechanism of action: excitation of N-Chr. The initial effect is stimulation of H-Chr, the long-term effect is a depolarization block.
Pharmacological effects of N-cholinomimetics:
1) stimulation of the autonomic ganglia (sympathetic more than parasympathetic)
2) cardiovascular system:
Tachycardia
Peripheral and coronary vasospasm
Hypertension
3) Gastrointestinal tract, urinary system: inhibition of activity
4) chemocarotid zone: stimulation of respiration
5) CNS: low doses: psychostimulation, high doses – vomiting, tremor, convulsions, coma.
side effects of N-cholinomimetics.
1) nausea, vomiting, dizziness, headache
2) diarrhea, hypersalivation
3) tachycardia, increased blood pressure, shortness of breath, turning into respiratory depression
4) mydriasis followed by miosis
5) muscle cramps
6) visual and hearing disorders
main indications and contraindications for useN-cholinomimetics.
Indications:
smoking cessation relief
reflex cessation of breathing (during operations, injuries, etc.)
shock and collaptoid states (pressor effect), respiratory and circulatory depression in patients with infectious diseases.
Contraindications:
atherosclerosis
marked increase in blood pressure
erosive and ulcerative lesions of the gastrointestinal tract in the acute phase, bleeding from large vessels
pulmonary edema
pregnancy.
LOBELIN (Lobelinum).
Lobeline racemate is obtained synthetically.
In medical practice, lobeline hydrochloride (Lobelini hydrochloridum) is used. l-1-Methyl-2-benzoylmethyl-6-(2-hydroxy-2-phenylethyl)-piperidine hydrochloride.
Synonyms: Antisol, Atmulatin, Bantron, Lobatox, Lobelinum hydrochloricum, Lobeton, Lobidan, etc.
Lobeline is a substance that has a specific stimulating effect on the ganglia of the autonomic nervous system and carotid glomeruli (see also Ganglion-blocking drugs).
This effect of lobeline is accompanied by stimulation of the respiratory and other centers of the medulla oblongata. In connection with the stimulation of breathing, lobeline was proposed as an analeptic agent for use in reflex respiratory arrests (mainly when inhaling irritants, carbon monoxide poisoning, etc.).
Due to the simultaneous stimulation of the vagus nerve, lobeline causes a slowdown in heart rate and a decrease in blood pressure. Later, blood pressure may increase slightly, which depends on the vasoconstriction caused by the stimulating effect of lobeline on the sympathetic ganglia and adrenal glands. In large doses, lobeline stimulates the vomiting center, causing deep respiratory depression, tonic-clonic convulsions, and cardiac arrest.
Recently, lobeline has been used extremely rarely as a respiratory stimulant. If breathing weakens or stops, developing as a result of progressive depletion of the respiratory center, the administration of lobeline is not indicated.
Lobeline is used as an injection intravenously, less often intramuscularly.
Lobeline is administered intravenously slowly (1 ml over 1 - 2 minutes). With rapid administration, temporary cessation of breathing (apnea) sometimes occurs and side effects from the cardiovascular system (bradycardia, conduction disturbances) develop.
Lobelin is contraindicated in acute organic diseases of the cardiovascular system.
Lobelin and others similar in action<<ганглионарные>> substances (cytisine, anabasine) have found use in recent years as smoking cessation aids. Tablets containing lobeline are available for this purpose under the name<<Лобесил>> (Tabulttae "Lobesilum").
The tablets are coated (cellulose acetylphthalyl cellulose), which ensures the passage of the drug unchanged through the stomach and its rapid release in the intestines.
Use of tablets<<Лобесил>>, as well as tablets and other medicines containing cytisine and anabasine hydrochloride, reduces the desire to smoke and alleviates the painful phenomena associated with smoking cessation for smokers.
The mechanism of action of these drugs is apparently associated with competitive relationships in the area of the same receptors and biochemical substrates with which nicotine interacts in the body, which is also<<ганглионарным>> means.
Quitting smoking requires more than just pills<<Лобесил>>, but also at the same time the smoker’s firm decision to stop smoking.
After stopping smoking, take 1 tablet 4-5 times a day for 7-10 days. Subsequently, if necessary, you can continue taking the tablets for 2 - 4 weeks with a gradual decrease in the frequency of administration. In case of relapses, the course of treatment can be repeated.
The use of tablets with lobeline, cytisine and anabasine is contraindicated in case of exacerbation of gastric and duodenal ulcers, sudden organic changes in the cardiovascular system. Treatment should be carried out under the supervision of a physician. In case of overdose, side effects are possible: weakness, irritability, dizziness, nausea, vomiting.
CITIZIN (Cytisinum).
Cytisine is an alkaloid found in the seeds of broom (Cytisus laburnum L.) and thermopsis (Thermopsis lanceolata, R. Br.), both from the legume family (Leguminosae).
Refers to substances<<ганглионарного>> actions and in connection with the stimulating effect on breathing is considered as a respiratory analeptic. For this purpose, it is available in the form of a ready-made 0.15% aqueous solution called<<Цититон>> (Cytitonum).
In recent years, cytisine has also begun to be used as a smoking cessation aid (see tablets<<Лобесил>>) .
Cytisine has an exciting effect on the ganglia of the autonomic nervous system and related formations: chromaffin tissue of the adrenal glands and carotid glomeruli.
Characteristic of the action of cytisine (as well as lobeline) is the excitation of breathing associated with reflex stimulation of the respiratory center by enhanced impulses coming from the carotid glomeruli. Simultaneous stimulation of the sympathetic nodes and adrenal glands leads to an increase in blood pressure.
The effect of cytiton (cytisine solution) on breathing is short-term<<толчкообразный>> character, however, in some cases, especially with reflex cessation of breathing, the use of cititon can lead to a permanent restoration of breathing and blood circulation.
Previously, cititone was widely used for poisoning (morphine, barbiturates, carbon monoxide, etc.). Due to the emergence of specific antagonists of opiates (naloxone, etc.) and barbiturates (bemegride) and the short duration of action, cititon and lobeline currently have limited use. Nevertheless, in case of reflex cessation of breathing (during operations, injuries, etc.), tsititon can be used as a respiratory analeptic; Due to the pressor effect (which distinguishes it from lobeline), cititone can be used in shock and collaptoid conditions, in respiratory and circulatory depression in patients with infectious diseases, etc.
Cititon is administered into a vein or intramuscularly. The most effective is intravenous administration. If indicated, the injection of cititon can be repeated after 15 - 30 minutes.
Cititon was previously also used to determine blood flow velocity. The method consists of determining the time that elapses from the moment of injection of cititon into the antecubital vein until the appearance of the first deep breath. The determination is more demonstrative than with the administration of lobeline, since the excitation of breathing is more clearly expressed and changes in breathing are easy to register. Usually 0.7 - 1 ml of tsititon is administered for this purpose (0.015 ml per 1 kg of patient body weight).
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.
Cytisine (0.0015 g = 1.5 mg) is included in the tablets<<Табекс>> (Tabex, Bulgaria), used to facilitate smoking cessation. The mechanism of action of the drug is similar to the mechanism of action of lobeline and anabasine.
Use of tablets<<Табекс>> must be carried out as directed and under the supervision of a physician. In case of an overdose, nausea, vomiting, dilated pupils, and increased heart rate are possible, which requires stopping the drug.
Films with cytisine (Membranulae cum Cytisino) are also produced. Oval-shaped polymer plates with blunted edges, white or with a yellowish tint (9 X 4.5 X 0.5 mm), contain 0.0015 g of cytisine. The film is glued to the gums or mucous membrane of the cheek area every day for the first 3 to 5 days, 4 to 8 times.
If the effect is positive, treatment is continued according to the following scheme: from the 5th to the 8th day, 1 film 3 times a day, from the 9th to 12th day, 1 film 2 times a day, from the 13th to 15th 1st day: 1 film 1 time per day. From the first day of treatment, you should stop smoking or sharply reduce the frequency of smoking.
In the first days of using the film with cytisine, unpleasant taste sensations, nausea, mild headache, dizziness, and a slight increase in blood pressure are possible. In these cases, you should stop taking the drug.
The use of films with cytisine is contraindicated in cases of bleeding, severe hypertension, and advanced stages of atherosclerosis.
ANABAZINE HYDROCHLORIDE (Anabasinum hydrochloridum).
Anabasine is an alkaloid found in the plant Anabasis aphylla L. (barnyard grass), fam. goosefoot (Chenopodiaceae).
Chemically it is 3-(piperidyl-2) pyridine.
Its pharmacological properties are similar to nicotine, cytisine and lobeline.
In small doses, anabasine hydrochloride has been proposed as a means of facilitating smoking cessation.
For this purpose, the drug is available in the form of tablets, films and chewing gum.<<Гамибазин>> .
Take tablets with anabasine hydrochloride orally or sublingually daily. From the first day of taking the pills, you must stop smoking or sharply reduce its frequency and completely stop smoking no later than 8-10 days from the start of treatment.
If the desire to smoke does not decrease within 8-10 days, stop taking the pills and make a new attempt at treatment after 2-3 months.
Tablets are contraindicated for atherosclerosis, severe increases in blood pressure, and bleeding.
In the first days of taking the pills, nausea, headache and increased blood pressure are possible. Usually these phenomena disappear when the dose is reduced. If necessary, stop taking the pills.
There are indications that the use of anabasine (in the form of tablets orally or sublingually) can cause toxicoderma.
Films with anabasine hydrochloride (Membranulae cum Anabasino hydrochloridi). Polymer oval-shaped plates of white (or with yellowish tints) color, dimensions 9 X 4.5 X 0.5 mm, containing 0.0015 g (1.5 mg) of anabasine hydrochloride. They are also intended for smoking cessation.
The film is glued to the gum of the labial part or the mucous membrane of the buccal area every day for the first 3 to 5 days, 4 to 8 times.
From the first day of treatment, it is advisable to stop smoking or sharply reduce the frequency of smoking.
In the first days of using film with anabasine hydrochloride, unpleasant taste sensations, nausea, mild headache, dizziness, and a slight increase in blood pressure are possible. In these cases, you should stop using the drug.
Gamibasin (Gamibasinum). Chewing gum (based on a special chewing mass) containing 0.003 g of anabasine hydrochloride.
A rectangular or square elastic band (22 X 22 X 8 mm, or 32 X 22 X 5 mm, or 70 X 19 X 1 mm) of light gray or light yellow color with the smell of food aromatic substances (with the addition of sugar, molasses, lemon acid, flavoring, etc.).
It is one of the dosage forms of anabasine for smoking cessation. Apply by prolonged chewing daily, initially 1 gum (0.003 g) 4 times a day for 4 - 5 days. If the effect is positive, treatment is continued according to the following scheme: from the 5th - 6th to the 8th day - 1 rubber band 3 times a day; from the 9th to the 12th day - 1 elastic band 2 times a day; further until the 20th day - 1 rubber band 1 - 2 times a day. Subsequent courses may be repeated.
N-cholinomimetics are substances that excite N-xo-linoreceptors (nicotine-sensitive receptors).
N-cholinergic receptors are directly connected to Na + channels of the cell membrane. When N-cholinergic receptors are excited, Na + channels open, and Na + entry leads to depolarization of the cell membrane and excitatory effects.
N N -cholinergic receptors are located in the neurons of the sympathetic and parasympathetic ganglia, in the chromaffin cells of the adrenal medulla, and in the carotid glomeruli. In addition, N N -cholinergic receptors are found in the central nervous system, in particular, in Ren-shaw cells, which have an inhibitory effect on motor neurons of the spinal cord.
N m -cholinergic receptors are localized in neuromuscular synapses (in the end plates of skeletal muscles); when they are stimulated, skeletal muscles contract.
Nicotine- an alkaloid from tobacco leaves. A colorless liquid that turns brown when exposed to air. Well absorbed through the mucous membrane of the mouth, respiratory tract, and skin. Easily penetrates the blood-brain barrier. Most of the nicotine (80-90%) is metabolized in the liver. Nicotine and its metabolites are excreted mainly by the kidneys. Half-elimination period (t l /2) 1-1.5 hours. Nicotine is secreted by the mammary glands.
Nicotine stimulates mainly N N -cholinergic receptors and, to a lesser extent, M m -cholinergic receptors. In the action of nicotine on synapses that have N-cholinergic receptors on the postsynaptic membrane, as the dose increases, 3 phases are distinguished: 1) excitation, 2) depolarization block (persistent depolarization of the postsynaptic membrane), 3) non-depolarizing block (associated with desensitization of N-cholinergic receptors ). When smoking, the 1st phase of the action of nicotine appears.
Nicotine stimulates neurons of the sympathetic and parasympathetic ganglia, chromaffin cells of the adrenal glands, and carotid glomeruli.
Due to the fact that nicotine simultaneously stimulates sympathetic and parasympathetic innervation at the ganglion level, some of the effects of nicotine are inconsistent. Thus, nicotine usually causes miosis and tachycardia, but the opposite effects are also possible (mydriasis, bradycardia). Nicotine usually stimulates gastrointestinal motility and the secretion of the salivary and bronchial glands.
The permanent effect of nicotine is its vasoconstrictor effect (most vessels receive only sympathetic innervation). Nicotine constricts blood vessels because: 1) it stimulates the sympathetic ganglia, 2) it increases the release of adrenaline and norepinephrine from the chromaffin cells of the adrenal glands, 3) it stimulates N-cholinergic receptors of the carotid glomeruli (the vasomotor center is reflexively activated). Due to vasoconstriction, nicotine increases blood pressure.
When nicotine acts on the central nervous system, not only excitatory but also inhibitory effects are recorded. In particular, by stimulating N N -xo-linoreceptors of Renshaw cells, nicotine can inhibit monosynaptic reflexes of the spinal cord (for example, the knee reflex). The inhibitory effect of nicotine, associated with the excitation of inhibitory cells, is also possible in the higher parts of the central nervous system.
N-cholinergic receptors in CNS synapses can be localized on both postsynaptic and presynaptic membranes. Acting on presynaptic N-cholinergic receptors, nicotine stimulates the release of CNS mediators - dopamine, norepinephrine, acetylcholine, serotonin, β-endorphin, as well as the secretion of certain hormones (ACTH, antidiuretic hormone).
In smokers, nicotine causes an increase in mood, a pleasant feeling of calm or activation (depending on the type of higher nervous activity). Increases learning ability, concentration, vigilance, reduces stress reactions, manifestations of depression. Reduces appetite and body weight.
The euphoria caused by nicotine is associated with increased release of dopamine, antidepressant effects and decreased appetite - with the release of serotonin and norepinephrine.
Smoking. A cigarette contains 6-11 mg of nicotine (the lethal dose of nicotine for humans is about 60 mg). During smoking a cigarette, 1-3 mg of nicotine enters the smoker’s body. The toxic effect of nicotine is moderated by its rapid elimination. In addition, addiction to nicotine (tolerance) quickly develops.
Smoking causes even greater harm from other substances (about 500) that are contained in tobacco smoke and have irritating and carcinogenic properties. Most smokers suffer from inflammatory diseases of the respiratory system (laryngitis, tracheitis, bronchitis). Lung cancer is much more common in smokers than in non-smokers. Smoking contributes to the development of atherosclerosis (nicotine increases the level of LDL in the blood plasma and reduces the level of HDL), the occurrence of thrombosis, and osteoporosis (especially in women over 40 years of age).
Smoking during pregnancy leads to a decrease in fetal weight, increased postpartum mortality in children, and retarded children in physical and mental development.
Mental dependence develops to nicotine; When quitting smoking, smokers experience painful sensations: worsening mood, nervousness, anxiety, tension, irritability, aggressiveness, decreased concentration, decreased cognitive abilities, depression, increased appetite and body weight. Most of these symptoms are most pronounced 24-48 hours after stopping smoking. They then decrease over about 2 weeks. Many smokers, understanding the dangers of smoking, nevertheless cannot get rid of this bad habit.
In order to reduce discomfort when quitting smoking, we recommend: 1) chewing gum containing nicotine (2 or 4 mg), 2) a transdermal therapeutic system with nicotine - a special patch that evenly releases small amounts of nicotine over 24 hours (pasted on healthy areas of the skin), 3) a mouthpiece containing a cartridge with nicotine and menthol.
These nicotine preparations are being tried as medicines for Alzheimer's disease, Parkinson's disease, ulcerative colitis, Tourette's syndrome (motor and vocal tics in children) and some other pathological conditions.
Acute nicotine poisoning manifested by symptoms such as nausea, vomiting, diarrhea, abdominal pain, headache, dizziness, sweating, visual and hearing impairment, disorientation. In severe cases, a coma develops, breathing becomes impaired, and blood pressure drops. As a therapeutic measure, gastric lavage is carried out, activated carbon is prescribed internally, and measures are taken to combat vascular collapse and breathing problems.
Cytisine(thermopsis alkaloid) and lobelia(lobelia alkaloid) are similar in structure and action to nicotine, but are less active and toxic.
Cytisine in the Tabex tablets and lobelia in the Lobesil tablets are used to facilitate smoking cessation.
Cititone (0.15% cytisine solution) and lobeline solution are sometimes administered intravenously as reflex stimulants of breathing.
Cholinomimetics are drugs that increase excitation in the area of cholinergic nerve endings.
Classification
They are divided into direct cholinomimetics, which cause stimulation of cholinergic receptors, and indirect anticholinesterase elements, which inactivate cholinesterase. The direct type is usually further divided into M- and N-cholinomimetics in pharmacology.
M-cholinomimetics are able to excite predominantly central interneuron synapses or peripheral neuro-effector areas of executive organs. They contain M-cholinergic receptors. These include Pilocarpine and Aceclidine.
H-cholinomimetics are drugs that cause stimulation of H-cholinergic receptors. They are considered innervated neurons. At the same time, their bodies are located in the central and, in addition, in the sympathetic and parasympathetic nodes. They are also found in the adrenal medulla and in the carotid glomerulus. These include the drugs “Cititon” along with “Lobeline”. M- and N-cholinomimetics that excite cholinergic receptors include Carbacholine.
We will consider the use of cholinomimetics in this article.
Operating principle
Anticholinesterase drugs block absolutely all active catalytic regions of acetylcholinesterase. Such processes lead to the accumulation of acetylcholine in the area of the synaptic cleft. As part of the classification of processes according to the mechanism of influence, they are divided into groups such as irreversible and reversible influence.
When a direct type of cholinomimetics is administered in the body, the effects associated with the excitation of parasympathetic nerves can significantly predominate. For example, this will be expressed in the form of a slowdown in heart rate, a decrease in the intensity of heart contractions.
Changes
In addition, the following changes occur:
- Intraocular pressure decreases.
- Spasms of accommodation occur.
- The pupils narrow.
- Intestinal motility increases.
- The tone of all internal organs increases, especially the condition of smooth muscles improves.
- Urination increases.
- Vessels dilate.
- There is a decrease in blood pressure along with relaxation of the sphincters.
Thus, they are agents that accelerate the mechanism of action of cholinergic nerves.
Cholinomimetics are substances that imitate the effects of acetylcholine and have an effect on the functioning of a particular organ similar to irritation of cholinergic nerves. Some cholinomimetic agents, for example nicotinomimetic substances, may act primarily on nicotine-sensitive cholinergic receptors. These include the following components: nicotine, anabasine, lobelia, cytisine and subecholine. As for muscarine-sensitive cholinergic receptors, substances such as muscarine, arecoline, pilocarpine, benzamon, aceclidine and carbacholine act on them. The effects of cholinomimetics are unique.
Their mechanism of action is identical to the mechanism of acetylcholine, which is released in the endings of cholinergic nerves. It can also be introduced externally. Like acetylcholine, these drugs have a positively charged nitrogen atom in their molecule.
Let us consider in more detail the mechanism of action of cholinomimetics for each type.
N-cholinomimetics
N-cholinomimetics are substances that excite n-cholinergic receptors. Such elements are also called nicotine-sensitive receptors. N-cholinergic receptors are associated with channels of cell membranes. When H-cholinergic receptors are excited, the channels open and membrane depolarization occurs, which causes an energetic effect. Cholinomimetics have been used in pharmacology for a long time.
H-cholinergic receptors predominate in the neurons of the parasympathetic and sympathetic ganglia, as well as in the chromaffin cells of the adrenal medulla and in the area of the carotid tangles. In addition, H-cholinergic receptors can be found in the central nervous system, especially in cells that have an inhibitory effect on motor neurons in the spinal cord.
N-cholinergic receptors are localized in neuromuscular synapses, that is, in the area of the end plates of skeletal muscles. If they are stimulated, contraction of skeletal structures may occur.
M-cholinomimetics
We will consider the drugs below. M-cholinomimetic substances can enhance the secretion of sweat, digestive, and bronchial glands. In addition, due to their effects, the following reactions of the body are observed:
It is worth noting that M-cholinomimetic drugs are used primarily for the treatment of glaucoma. The constriction of the pupils, which is caused by these components, leads to a decrease in intraocular pressure. What is the mechanism of cholinomimetics?
The effects of substances that excite M- and N-cholinergic receptors are mainly similar to the effects of M-cholinomimetic drugs. This is accomplished due to the stimulation of H-cholinergic receptors. Among the substances that belong to the M- and N-cholinomimetics, only anticholinesterase drugs are widely used.
The mechanism of action of M-cholinomimetics is of interest to many.
Drug poisoning
Poisoning with these drugs may be accompanied by the following body reactions:
- There is a sharp increase in the secretion of saliva, as well as sweat.
- Diarrhea.
- Constriction of the pupils.
- Slowing heart rate. It should be noted that in case of poisoning with anticholinesterase drugs, the pulse, on the contrary, increases.
- Fall in blood pressure.
- Asthmatic breathing.
Treatment of poisoning in this situation should be limited to administering Atropine or other anticholinergic drugs to the patient.
Application
Cholinomimetics are substances that excite cholinergic receptors. They are typically used in ophthalmic medicine as a miotic agent that can lower intraocular pressure. Within this framework, tertiary amines, which are well absorbed by the conjunctiva, are preferentially used, especially drugs such as Pilocarpine and Aceclidine.
How to explain the constriction of the pupils
Constriction of the pupils under the influence of M-cholinomimetics can be explained by contraction of the orbicularis muscles of the iris, which receives the cholinergic innervation provided to it. This orbicularis muscle contains M-cholinergic receptors. In parallel, due to the process of contraction of the ciliary muscle, which has a similar innervation, spasms of accommodation occur, that is, an adjustment to the curvature of the lens for near vision.
Decreased intraocular pressure
Along with pupil constriction, M-cholinomimetics, as part of their effect on the eye, can cause another very important clinical effect, namely, a decrease in intraocular pressure. It is this process that is used to treat glaucoma.
This effect can be explained by the fact that during the constriction of the pupil, the iris thickens, due to which the lymphatic slits located in the corner of the anterior chamber of the visual organ widen. Due to this, there is an increase in the outflow of fluid from the inner regions of the eye, which, in fact, causes a decrease in intraocular pressure. True, such a mechanism is not considered the only reason for the decrease in intraocular pressure caused by M-cholinomimetics, due to the fact that there is no strict correlation between the miotic effects they provoke and the decrease in intraocular pressure.
Miotic effect
The miotic effect of M-cholinomimetics, when alternating them with mydriatic drugs, can also be used to break adhesions that interfere with the regulation of pupil width. The resorptive effect of substances that excite M-cholinergic receptors is used for intestinal and bladder atony.
In order to avoid the wasteful process of excitation of the ganglia, it is preferable to selectively use active M-cholinomimetics, such as Mecholin or Bethanechol. They are administered subcutaneously to ensure rapid action as well as dosage accuracy. Considering that this route is not associated with absorption through the mucosa, solutions of quaternary amines, including Carbacholin, Mecholin or Bethanechol, are injected subcutaneously. The effect of cholinomimetics has not been fully studied.
Components that block cholinergic receptors and their use
Substances that block M-cholinergic receptors have wider therapeutic applications compared to M-cholinomimetics. In the clinic of diseases of the visual organs, selectively influencing M-anticholinergics are used to dilate the pupils, which causes relaxation of the circular muscles of the iris. They are also used for a temporary nature, during which the ciliary muscles relax. Most often, a solution of “Atropine” in the form of eye drops is used for such purposes. Cholinomimetic drugs are presented below.
Relaxation of the circular and ciliary muscles of the iris creates complete peace of the intraocular state, which is used for inflammatory processes, and also for eye injuries. The dilation of the pupils caused by M-anticholinergics, along with paralysis of accommodation, is also used as part of the study of refractive error. For these purposes, instead of Atropine, they prefer to use short-acting M-anticholinergics, usually they are drugs such as Amizil, Homatropin, Euphthalmin and "Metamisil." Their solutions are prescribed in the form of eye drops.
Where is Atropine used?
The main purpose for the resorptive use of selective M-anticholinergics is spasms of smooth muscle organs. Such organs are the stomach, intestines, bile ducts, and the like. For this, “Atropine” is used directly, as well as plants that contain it, for example, belladonna and others. In addition, numerous synthetic M-anticholinergics may be suitable.
An important reason for the use of M-anticholinergics is their central effect. Selective M-anticholinergics with central action include drugs such as Amizil, Benzacin, Metamizil and other amino alcohol esters, which contain tertiary nitrogen along with aromatic acids, including hydroxyl. As part of blocking central M-cholinergic receptors, they potentiate the effect of sleeping pills, as well as narcotic and analgesic drugs, preventing overexcitation of the hypothalamic centers, which manage the pituitary-adrenal system.
Conclusion
Thus, cholinomimetic drugs are substances that can excite cholinergic receptors, that is, the biochemical systems of the body. They cannot be homogeneous. They are selectively sensitive to nicotine and are located in the ganglia of the sympathetic and, in addition, parasympathetic nerves. They can also be observed in the adrenal medulla along with carotid tangles and in the endings of the motor elements of the central nervous system. Cholinergic receptors may also exhibit selective sensitivity to the alkaloid muscarine.
We reviewed the classification of 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).
Drugs of this group have a direct stimulating effect on M-cholinergic receptors located at the endings of postganglionic parasympathetic nerve fibers. As a result, they reproduce the effects of acetylcholine associated with the excitation of parasympathetic innervation: constriction of the pupil (miosis), spasm of accommodation (the eye is set to near vision), narrowing of the bronchi, profuse salivation, increased secretion of the bronchial, digestive and sweat glands, increased motility of the gastrointestinal tract , increased bladder tone, bradycardia.
Fig.7. Effect of cholinomimetics on the eye (The number of arrows indicates the intensity of the outflow of intraocular fluid)
Pilocarpine is an alkaloid of plant origin. Obtained synthetically, it is available in the form of pilocarpine hydrochloride. Its effect is a decrease in intraocular pressure, used to treat glaucoma (increased intraocular pressure up to 50-70 mm Hg). The use of pilocarpine causes constriction of the pupil due to contraction of the orbicularis muscle of the iris, and facilitates the outflow of fluid from the anterior chamber of the eye to the posterior chamber due to contraction of the ciliary muscle. At the same time, a spasm of accommodation develops (the curvature of the lens increases). (Fig. 11).
Pilocarpine is used only topically, because is quite toxic. Used for glaucoma, for optic nerve atrophy, to improve eye trophism, etc. It has a slight irritating effect. Included in the combined eye drops “Fotil” and “Pilotim”.
N - cholinomimetics
The sensitivity of H-cholinergic receptors of different locations to chemical substances is not the same due to differences in their structure.
H-cholinomimetics (cytiton, lobeline) excite H-cholinergic receptors of the sinocarotid glomeruli, which leads to reflex stimulation of the respiratory and vasomotor centers. Breathing becomes faster and deeper. Simultaneous stimulation of the synaptic nodes and adrenal glands leads to increased adrenaline release and increased blood pressure.
Cititon and Lobelina hydrochloride are reflex respiratory stimulants and can be used for reflex respiratory arrest (carbon monoxide poisoning, drowning, suffocation, electrical injuries, etc.), and for asphyxia of newborns.
These substances are more widely used to treat tobacco smoking. Tabex (cytisine) tablets are used to facilitate smoking cessation. For this purpose, small doses of nicotine are also used (Nicorette chewing gum, Nicotinell patch). These medications reduce physical dependence on nicotine.
Tobacco alkaloid - nicotine is also an N-cholinomimetic, but is not used as a drug. It enters the body when smoking tobacco and has a variety of effects. Nicotine affects both peripheral and central H-cholinergic receptors, and has a two-phase effect: the first stage - excitation - is replaced by an inhibitory effect. The constant effect of nicotine is its vasoconstrictor effect, due to the fact that nicotine stimulates H-cholinergic receptors of the sympathetic ganglia, chromaffin cells of the adrenal glands and the sinocarotid zone, stimulates the release of adrenaline and reflexively excites the vasomotor center. In this regard, nicotine increases blood pressure and contributes to the development of hypertension. Severe vascular disease of the lower extremities - obliterating endarteritis - occurs almost exclusively in smokers. Nicotine narrows the blood vessels of the heart and contributes to the development of angina, myocardial infarction, and tachycardia. Serious changes are observed in the central nervous system. Exhibits nicotine and carcinogenic effects.
M, N - cholinomimetics
These substances simultaneously stimulate M- and N-cholinergic receptors and directly or indirectly affect the executive organs. There are M, N-cholinomimetics of direct and indirect action.
Direct acting drugs include Acetylcholine and Carbacholine (carbachol). They directly stimulate postsynaptic receptors. Acetylcholine is practically not used as a medicine, because it acts for a short time (a few minutes). It is used in experimental pharmacology.
In medical practice, an acetylcholine analogue, Carbacholine, is sometimes used for glaucoma in the form of eye drops. It differs from acetylcholine in being more stable and lasting longer (up to 1-1.5 hours), because not hydrolyzed by acetylcholinesterase.
Anticholinesterase drugs (M, N - indirect-acting cholinomimetics).
These substances inhibit the activity of the acetylcholinesterase enzyme and enhance the effect of acetylcholine on M- and H-cholinergic receptors. The effects of anticholinesterase drugs are generally similar to the effects of direct M, N-cholinomimetics. The M-cholinomimetic effect is manifested in an increase in the tone and contractile activity of smooth muscles (bronchi, gastrointestinal tract, bladder, circular muscle of the iris, etc.), in increased secretion of glands (bronchial, digestive, sweat, etc.), in the occurrence of bradycardia and a drop in blood pressure. The N-cholinomimetic effect is manifested in stimulation of neuromuscular conduction. In small doses, anticholinesterase drugs stimulate the central nervous system, and in large doses they depress.
Tertiary amines (physostigmine, galantamine) penetrate biological membranes, including the BBB, and have a pronounced effect on the central nervous system. Quaternary ammonium derivatives (proserine, pyridostigmine, distigmine) are difficult to penetrate the BBB.
Inhibition of acetylcholinesterase is carried out due to the interaction of substances with the same sites of the enzyme to which acetylcholine binds. This connection can be reversible or irreversible.
Neostigmine (prozerin) is a synthetic drug, is a quaternary ammonium compound, does not penetrate the BBB and has a predominant effect in peripheral tissues. It is used for myasthenia gravis, muscular dystrophy, paralysis, motor disorders associated with neuritis, polyneuritis, residual effects after brain injury, poliomyelitis, meningitis, encephalitis, as well as intestinal and bladder atony, weak labor. Prozerin is an antagonist of M-anticholinergic drugs and curare-like drugs with an antidepolarizing type of action. Contraindicated in epilepsy, bronchial asthma, angina pectoris, atherosclerosis, pregnancy.
Galantamine (nivalin) is an alkaloid found in snowdrop tubers. Available in the form of galantamine hydrobromide. It is a tertiary amine, penetrates the BBB and has central activity. Physostigmine (physostigmine salicylate) has similar properties.
It is used for polyneuritis, cerebrovascular accidents, polio, cerebral palsy, dementia (memory impairment), myasthenia gravis, and atony of internal organs.
Distigmine bromide (ubretide), Pyridostigmine bromide (kalimin) are synthetic drugs that reversibly inhibit acetylcholinesterase. They are used for atony of the intestines and bladder, myasthenia gravis, and paralysis of the striated muscles.
Due to phosphorylation of acetylcholinesterase, its activity is irreversibly inhibited for a long time. Organophosphorus compounds (OP) have this effect, of which Phosphacol and Armin in the form of eye drops have acquired medical use in the treatment of glaucoma.
But FOS also includes a large group of insecticides used to kill insects (chlorophos, karbofos, dichlorvos, etc.), as well as fungicides, herbicides, etc. used in agriculture.
When they are used, poisoning often occurs with the following symptoms: miosis (constriction of the pupil), salivation, sweating, vomiting, bronchospasm, diarrhea. Convulsions, psychomotor agitation, coma and respiratory arrest may occur. In case of acute poisoning with FOS, first of all, it is necessary to remove the toxic substance from the injection site and rinse the skin with a 3-5% sodium bicarbonate solution. If FOS gets inside, rinse the stomach, give laxatives and adsorbents. If FOS enters the blood, then forced diuresis, hemosorption, and hemodialysis are performed.
M-anticholinergic blockers (atropine, etc.), as well as cholinesterase reactivators - dipyroxime and isonitrosine - are used as functional antagonists for FOS poisoning. They bind to FOS, destroy the phosphorus-enzyme bond and restore enzyme activity. These drugs are effective only in the first hours after poisoning.
Anticholinergic drugs
Anticholinergic or anticholinergic drugs are substances that weaken, prevent or stop the interaction of acetylcholine with cholinergic receptors. By blocking receptors, they act opposite to acetylcholine.
M - anticholinergics
Medicines in this group block M - cholinergic receptors and prevent the interaction of the mediator acetylcholine with them. In this case, the parasympathetic innervation of the organs is eliminated (blocked) and the corresponding effects occur: decreased secretion of the salivary, sweat, bronchial, and digestive glands, dilation of the bronchi, decreased tone of smooth muscles and peristalsis of internal organs, tachycardia and increased heart contractions; when applied topically, they cause dilation of the pupil (mydriasis), paralysis of accommodation (vision is set to distant vision), and increased intraocular pressure.
Non-selective M - anticholinergic blockers
They affect peripheral and central M-cholinergic receptors. Among them are herbal and synthetic medicines.
Atropine is an alkaloid of a number of plants from the nightshade family: belladonna, datura, henbane, etc. It is produced in the form of atropine sulfate. It is a racemate and is a mixture of L- and D-isomers of hyoscyamine. It is also obtained synthetically. Causes all of the above effects. Atropine has especially pronounced antispasmodic properties, effects on the eye, gland secretion, and the conduction system of the heart. In large doses, atropine stimulates the cerebral cortex and can cause motor and speech anxiety.
Atropine is used for gastric and duodenal ulcers, for spasms of the intestines and urinary tract, for bronchial asthma, for bradycardia and atrioventricular heart block, for excessive sweating, to reduce salivation in Parkinson's disease, for premedication before anesthesia due to its ability to suppress secretion salivary and bronchial glands, in case of poisoning with M-cholinomimetics and anticholinesterase drugs.
In ophthalmic practice, atropine is used to dilate the pupil for diagnostic purposes and for acute inflammatory diseases and eye injuries. Maximum pupil dilation occurs after 30-40 minutes and lasts 7-10 days. Atropine-like drugs Gomatropin (15-20 hours) and Tropicamide (2-6 hours) act less long-lasting.
Undesirable effects of atropine are associated with its M-anticholinergic effect: dry mouth, dry skin, blurred vision, tachycardia, change in voice timbre, impaired urination, constipation. Decreased sweating can lead to an increase in body temperature.
Atropine and M-anticholinergic drugs are contraindicated for glaucoma, hypersensitivity to them, fever, and during the hot season (due to the possibility of “heat stroke”).
In case of atropine poisoning, dryness of the oral mucosa, nasopharynx, impaired swallowing and speech are noted; dryness and hyperemia of the skin, increased body temperature, dilated pupils, photophobia (photophobia). Characterized by motor and speech agitation, delusions, and hallucinations.
Poisoning occurs when an overdose of drugs or when eating parts of a plant containing alkaloids. Help for acute poisoning consists of gastric lavage, the use of saline laxatives, activated charcoal, and diuretics. For severe agitation, diazepam and other central nervous system depressants are used. Functional antagonists from the group of anticholinesterase drugs - physostigmine salicylate - are also administered.
Among drugs containing atropine, belladonna (belladonna) preparations obtained from the leaves and grass of this plant are also used. Belladonna tincture, tablets “Becarbon”, “Besalol”, “Bepasal”, “Bellalgin”, “Bellasthesin” are used for spasmodic pain in the gastrointestinal tract. Belladonna extract is included in the Betiol and Anuzol suppositories, used for hemorrhoids and anal fissures. Tablets “Bellataminal”, “Bellaspon”, containing the sum of belladonna alkaloids, are used for increased irritability, neuroses, etc.
Scopolamine (hyoscine) is an atropine-like alkaloid from the same plants. It has pronounced M-anticholinergic properties, has a stronger effect on the eye and gland secretion. Unlike atropine, it depresses the central nervous system, causes sedation and drowsiness, and affects the extrapyramidal system and vestibular apparatus. Available in the form of scopolamine hydrobromide.
It is used for the same indications as atropine, as well as for sea and air sickness (part of Aeron tablets). Avia-more and Lokomotiv also have an antiemetic effect against motion sickness.
Platyphylline is a ragwort alkaloid. Used in the form of hydrogen tartrate salt. It has a more pronounced peripheral antispasmodic effect. Used mainly for spasms of the stomach, intestines, bile ducts, and ureters.
Methocinium iodide (metacin) is a synthetic M-anticholinergic blocker. It penetrates the blood-brain barrier poorly and does not affect the central nervous system. In terms of its effect on the bronchial muscles, it is more active than atropine; it suppresses the secretion of the salivary and bronchial glands more strongly. Relaxes the muscles of the esophagus, intestines, and stomach, but has a significantly less mydriatic effect than atropine.
Metacin is used for spasms of smooth muscle organs. Effective in relieving renal and hepatic colic. Undesirable side effects occur less frequently.
Selective M - anticholinergic blockers
Pirenzepine (gastrozepine, gastril) selectively blocks M1-cholinergic receptors of the stomach and suppresses the secretion of hydrochloric acid. Used for gastric and duodenal ulcers, hyperacid gastritis. Undesirable side effects are rare: dry mouth, dyspepsia, mild disturbance of accommodation. Contraindicated in glaucoma.
Ipratropium bromide (Atrovent), Tiotropium bromide (Spiriva) - block M-cholinergic receptors of the bronchi, have a bronchodilator effect, and reduce gland secretion. Used for bronchial asthma. Ipratropium is part of the combined aerosols “Berodual” and “Combivent”. Undesirable side effects: dry mouth, increased viscosity of sputum, allergic reactions.
N - anticholinergics
This group includes ganglion-blocking agents and neuromuscular synapse blockers.
Ganglioblockers
These substances block H-cholinergic receptors of the autonomic ganglia, adrenal medulla, and sinocarotid zone. In this case, the H-cholinergic receptors of the sympathetic and parasympathetic nerves are blocked simultaneously. Due to the inhibition of the sympathetic ganglia, the transmission of impulses to the blood vessels is disrupted, as a result of which the vessels dilate and arterial and venous pressure decreases. The expansion of peripheral vessels leads to improved blood circulation in them. When the parasympathetic ganglia are blocked, the secretion of glands (sweat, salivary, digestive) decreases, the muscles of the bronchi relax, and the motility of the digestive tract is inhibited.
Hexamethonium (benzohexonium) is a quaternary ammonium compound that has strong ganglion-blocking activity. More active when administered parenterally. It is used for spasms of peripheral vessels (endarteritis, Raynaud's disease, etc.), for controlled hypotension during operations, for pulmonary and cerebral edema (against the background of high blood pressure), less often - for gastric ulcers, bronchial asthma, intestinal spasms, etc., hypertension.
When hexamethonium and other ganglion blockers are administered, orthostatic collapse may develop. To prevent it, patients are recommended to remain in a lying position for 1-2 hours after injection of the ganglion blocker. In case of symptoms of collapse, α-adrenergic agonists should be administered.
When using benzohexonium, general weakness, dizziness, dry mouth, tachycardia, dilated pupils, respiratory depression, constipation, and difficulty urinating are also possible.
Drugs are contraindicated for hypotension, acute myocardial infarction, kidney and liver damage, thrombosis, and degenerative changes in the central nervous system. Caution is needed when prescribing to elderly people.
Trepirium iodide (Higronium) and Trimetaphan (Arfonad) have a short-term ganglion-blocking effect. They are used for controlled hypotension and for the relief of hypertensive crises. They are injected into a vein by drip.
Currently, ganglion blockers are rarely used.
Muscle relaxants (from Greek - mys - muscles, Lat. - relaxio - weakening) (curare-like drugs)
Drugs of this group selectively block H-cholinergic receptors at neuromuscular synapses and cause relaxation of skeletal muscles. They are called curare-like drugs after the arrow poison “curare”, which was used by the Indians during hunting to immobilize animals.
According to the mechanism of action, two groups of muscle relaxants are distinguished: non-depolarizing (antidepolarizing) and depolarizing.
Most drugs are antidepolarizing. They interact with H-cholinergic receptors of the postsynaptic membrane of neuromuscular synapses and prevent the depolarizing effect of acetylcholine. Their antagonists are anticholinesterase drugs (neostigmine, galantamine): by inhibiting the activity of cholinesterase in appropriate doses, they promote the accumulation of acetylcholine in the area of synapses, with an increase in the concentration of which the interaction of curare-like substances with H-cholinergic receptors is weakened and neuromuscular conduction is restored. These include Tubocurarine chloride, Diplacin, Pancuronium bromide (Pavulon), Pipecuronium bromide (Arduan), etc. These drugs are used to relax muscles during surgery, during tracheal intubation, during reposition of bone fragments, for convulsions, tetanus, and for the reduction of dislocations.
Curare-like drugs relax the muscles in a certain sequence: first, the muscles of the face and neck relax, then the limbs and torso, and lastly the intercostal muscles and diaphragm, which is accompanied by cessation of breathing.
Another group of drugs are depolarizing muscle relaxants. They cause persistent depolarization of the postsynaptic membrane, while repolarization occurs and subsequent impulses do not pass through. Drugs of this group are hydrolyzed relatively quickly by cholinesterase and have a short-term effect with a single administration. They have no antagonists. Such a drug is Suxamethonium chloride (dithiline, listenone). It is injected into a vein. It quickly and briefly relaxes skeletal muscles. For longer muscle relaxation, repeated administration of the drug is necessary.
When using muscle relaxants of both groups, paralysis of the respiratory muscles usually develops, so their use is permitted only if there are conditions for artificial respiration.
Undesirable side effects sometimes include a decrease in blood pressure and bronchospasm. Contraindicated in myasthenia gravis; caution should be used in cases of impaired renal and liver function, as well as in old age.
M, N - anticholinergics
These drugs have peripheral and central M-cholinergic blocking effects. The central action helps to reduce or eliminate motor disorders (tremor, rigidity) associated with damage to the extrapyramidal system. Trihexyphenidyl (cyclodol, parkopan) is widely used in the treatment of Parkinson's disease. When using drugs, side effects may occur associated with its anticholinergic properties: dry mouth, impaired accommodation, increased heart rate, dizziness. The drug is contraindicated for glaucoma, heart disease, and the elderly.
