Muscle relaxants. Minimum alveolar concentration

2.2.2. Inhalation anesthetics and their properties

An ideal inhalation anesthetic should have the following properties: fast inflow and outflow, good controllability, sufficient analgesia and muscle relaxation without toxic side effects. Unfortunately, currently known inhalation anesthetics do not meet all of these requirements. With any inhalation anesthesia in the conditions of surgical intervention, cardiopulmonary complications of varying severity may occur. The higher the applied dose of inhalation anesthetic, the more pronounced these complications. Let us consider in general terms the main properties of inhalation anesthetics used in veterinary medicine and give their comparative characteristics.

Characteristics of the distribution of anesthetics in the blood

The distribution coefficient of anesthetics in the blood is a measure of the solubility of an inhalation anesthetic. The higher the solubility of the gas, the larger the area it spreads, and the more this substance entered the body, the higher its partial pressure in the blood. The higher the solubility of the inhalation anesthetic, the slower the stage of introduction into anesthesia, respectively, anesthesia is well controlled and changes in its depth are insignificant. From a practical point of view, it is important that halothane or methoxyflurane, in contrast to isoflurane, sevoflurane or desflurane, have a greater solubility in the blood. This property determines the slow introduction to sleep, because due to the rapid solubility in the blood, the partial pressure of the anesthetic in the alveoli remains at a low level for a long time. It takes more time to reach the level of equilibrium of the anesthetic between the partial pressure in the alveoli and its tension in the blood, necessary for sleep. For this reason, for methoxyflurane and halothane, the stage of introduction into anesthesia is longer. The solubility of currently used inhalation anesthetics is in the following sequence:

Characterization of the distribution of anesthetics in tissues

Odds oil/gas and oil/blood are a measure of the solubility of the anesthetic in fats. With their help, it is possible to determine the concentration of the anesthetic in adipose tissue, respectively, and in the brain after reaching an equilibrium in distribution. The better the fat solubility of the inhalation anesthetic (i.e., the higher the oil/gas partition coefficient), the lower the concentration of anesthetic needed to maintain anesthesia.

Minimum alveolar concentration

Meaning minimum alveolar concentration(MAS) is an experimental value that must be determined anew for each animal. It reflects the concentration of inhalation anesthetic in the alveoli (at the end of exhalation), at which 50% of patients do not respond to a skin incision with a motor reaction. The lower the MAC of an inhalation anesthetic, the higher its potency. Regardless of the type of animal, according to the MAC value, anesthetics are usually arranged in the following order:

Thus, in an equilibrium distribution, more isoflurane is required to maintain anesthesia in an animal than either halothane or methoxyflurane. MAC decreases (i.e., the patient requires less inhalation anesthetic) with concomitant use of nitrous oxide, tranquilizers or sedatives, analgesics, in older animals and with a worsened general condition, reduced blood volume or with severe hypotension, as well as with reduced body temperature . The MAS value increases with the use of drugs that stimulate the central nervous system, with hyperthermia, with stress or pain prior to surgery.

Easily evaporating halogen-, chlorine-, fluorine- and bromine-containing anesthetics have found wide application in modern anesthesia in veterinary medicine. The search for the “ideal” inhalation anesthetic is on the path of improving these particular drugs. Comparative characteristics of sevoflurane, isoflurane and halothane are presented in table. 9.

Table 9

Comparative characteristics of sevoflurane, isoflurane and halothane

Properties of nitrous oxide N 2 O (laughing gas)

As an inhalation anesthetic, nitrous oxide has a number of advantages. Through its analgesic action, it reduces the MAC value of the inhalation anesthetic (i.e., less anesthetic consumption is required); has low blood solubility. There are practically no side effects on the cardiovascular system. Accelerates the introduction to anesthesia through a dual gas and ventilation effect (explained below). There is no inhibitory effect on the motility of the gastrointestinal tract.

The disadvantages include: the spread of nitrous oxide into the airspace. In the elimination phase, diffusion hypoxia occurs, i.e., during diffusion in the alveoli, nitrous oxide displaces the rest of the air, which leads to oxygen deficiency. At the entrance, the fraction O 2 decreases.

The use of nitrous oxide is contraindicated in the following cases:

- pneumothorax;

- expansion / volvulus of the stomach, suspicion of intestinal obstruction;

- the state of hypoxia in the patient (for example, with a diaphragmatic hernia);

- severe anemia in the patient;

- non-compliance with a starvation diet by the patient.

Nitrous oxide is used in concentrations up to 60%. At the beginning of anesthesia, there is a large difference in the concentration of N 2 O in the blood and alveolar air. Due to the low solubility of nitrous oxide in the blood, its partial pressure in the alveoli increases and a rapid induction into anesthesia is achieved (double gas effect). Other inhalation anesthetics present in the mixture are "captured" by nitrous oxide and concentrated in the alveolar air.

2.2.3. Muscle relaxers

For muscle relaxation, which ensures the immobilization of animals during surgical interventions, drugs have been used for a long time, the main pharmacological action of which was hypnotic (ether, barbiturates, halothane), analgesic (ketamine, butorphanol) or neuroplegic (sedative, benzodiazepine derivatives) effects. Good muscle relaxation is achieved by the introduction of large doses of these drugs, which leads to uncontrollability of the components of general anesthesia (respiratory depression, salivation, other side effects) and complications in the postoperative period.

Peripherally acting muscle relaxants

Classical muscle relaxation is provided by muscle relaxants of peripheral action. They provide control over only one component - muscle relaxation. Peripherally acting muscle relaxants interfere with neuromuscular transmission in skeletal muscle. The use of muscle relaxants of peripheral action is accompanied by paralysis of the diaphragm and auxiliary respiratory muscles, therefore, artificial ventilation of the lungs is always necessary. Blockade after the introduction of non-depolarizing muscle relaxants of peripheral action is achieved by stopping the production of anticholinesterase. Anticholinergics should always be given before anticholinesterase drugs are used. This will avoid the muscarinic side effects of neostigmine such as bradycardia, hypotension, or salivation.

In any case, muscle relaxants can be used in animals only when consciousness is turned off.

According to the mechanism of action, two groups of peripheral muscle relaxants are distinguished:

Antidepolarizing(non-depolarizing, competitive) muscle relaxants act by blocking nicotine-like cholinergic receptors at the motor ending, depolarizing the postsynaptic membrane by acetylcholine and nicotine. In veterinary anesthesiology, such drugs of this group as atracurium, vecuronium, pancuronium are used. Comparative characteristics of the properties of these three medicines are given in table. ten.

Table 10

Comparative characteristics of the properties of non-depolarizing muscle relaxants of peripheral action

When using any peripherally acting muscle relaxant, one must be aware that the relaxed animal must be under mechanical ventilation and it is not easy to assess the actual depth of anesthesia in the animal. To be able to assess the depth of anesthesia, it is necessary to regularly measure heart rate and blood pressure. We must not forget that muscle relaxants do not cause either analgesia or loss of consciousness. When using muscle relaxants without anesthetics, animals are fully conscious and sensitive to pain, but cannot move. To fulfill the conditions that guarantee an adequate depth of anesthesia, the use of muscle relaxants in an animal is advisable in the following situations.

If the nature of the operation (for example, a diaphragmatic hernia) requires mechanical ventilation and the animal breathes despite the operation of the respiratory apparatus, then the movement of the chest asynchronous to the apparatus is unpleasant for the surgeon and creates a large load on the blood circulation of the animal.

In fractures in which reposition is difficult due to muscle contracture, the use of muscle relaxants provides complete muscle relaxation of all muscles and facilitates reposition.

Intraocular operations require a central, completely calm position of the eyeball. This is achieved only by the use of muscle relaxants of peripheral action.

In situations where it is necessary to be completely sure of the patient's relaxation, in vascular surgery and microsurgery, when the patient's protective movement during the operation can have fatal consequences.

Depolarizing relaxants cause a longer and more persistent depolarization than acetylcholine. This group of drugs includes succinylcholine (ditilin, listenone), which has a quick and short-term effect, does not have a cumulative effect.

After intravenous administration, after an average of 10–20 s, animals show consistent fibrillation of the mimic muscles of the neck, limbs, trunk, intercostal muscles and diaphragm. In well-muscled animals, these fibrillations appear as convulsive movements. After another 20 - 40 s, fibrillation stops, complete relaxation of the skeletal muscles occurs and breathing is turned off - apnea. Complete relaxation (relaxation) of the muscles lasts 3-7 minutes. Then, quickly within 60-90 seconds, muscle tone is restored and spontaneous breathing is restored.

Muscle relaxants of central action

Muscle relaxants of the central action lead to relaxation of the skeletal muscles. They differ from peripherally acting muscle relaxants in that they act on receptors in the CNS rather than on motor endings. The place of influence of drugs of this group are the centers responsible for the regulation of muscle tone. A characteristic of centrally acting muscle relaxants is that they primarily suppress polysynaptic reflexes. In addition, they lead to dose-dependent sedation. Breathing is not oppressed (or oppressed to a very small extent) and, as a rule, you can do without mechanical ventilation. Centrally acting muscle relaxants commonly used in veterinary medicine are guaifenesin and benzodiazepines.

Guaifenesin combined in horses and ruminants with ketamine or ultra-short-acting barbiturates, often used during the induction phase of general anesthesia. This reduces the need for anesthetics without significant side effects on the cardiovascular and respiratory systems. The combination of ketamine and guaifenesin is very favorable. When using guaifenesin in concentrations above 5%, there is a risk of hemolysis. The introduction of guaifenesin leads to the development of thrombophlebitis more often than the use of all other sedative anesthetics.

Benzodiazepines are used in old small animals with a worsened general condition for preoperative sedation. In healthy animals, benzodiazepines may cause the opposite reaction (eg, dogs become aggressive, horses can no longer stand) and are not used in such cases. Benzodiazepines are the drug of choice in animals with epilepsy or other seizure disorders. When convulsions cannot be controlled with benzodiazepines, then barbiturates are used.

Thus, the use of muscle relaxants is permissible only against the background of sedative and hypnotic drugs. After the introduction of muscle relaxants, artificial ventilation of the lungs should be started. Breathing compensation should continue until spontaneous breathing is fully restored.

2.2.4. Medicines for analgesia

Analgesia is a key component in the provision of anesthetic support at all stages of surgery.

In the preparatory period for drug preparation (premedication), the administration of analgesics reduces the threshold of pain sensitivity, and, consequently, reduces the amount of anesthetics and their possible negative effects on animals.

During surgical interventions, the use of analgesics in the most traumatic moments of the operation allows for surface anesthesia, minimizing the inhibitory effect of general anesthetics on the life-supporting systems of the body.

In the postoperative period, the use of analgesics makes it possible to activate animals earlier and thereby prevent the development of respiratory and hemodynamic complications. Observations have shown that, despite general anesthesia, there is a sensitization of pain pathways in the CNS. This leads to severe postoperative pain and is referred to as wind up-phenomenon.

To obtain adequate analgesia, it must be taken into account that the protective reaction of the animal's body to damage (nociception) is individual in nature, depending on the place, degree, time of tissue damage, the characteristics of the nervous system, the patient's upbringing, his emotional state at the time of pain irritation. The formation of pain syndrome occurs both at the peripheral and central levels of the nervous system.

In order to choose the option of anesthesia suitable for each specific case, it is necessary to recall the main provisions of the theory of the occurrence and spread of pain, the mechanisms of nociception and antinociception.

Nociception includes 4 main physiological processes (Fig. 3):

- transduction - the damaging effect is transformed in the form of electrical activity at the endings of sensory nerves;

- transmission - conduction of impulses along the system of sensory nerves through the spinal cord to the thalamocortical zone;

- modulation - modification of nociceptive impulses in the structures of the spinal cord;

- perception - the final process of perception of the transmitted impulses by a specific animal with its individual characteristics and the formation of a sensation of pain.

Antinociception can be undertaken at any stage of the propagation and perception of damaging impulses. Adequate pain protection is achieved by the simultaneous administration of peripheral and central analgesics.

Rice. 3. Mechanism of nociception

Peripheral analgesics:

1) drugs that prevent the formation of inflammatory mediators - "small" analgesics:

- non-narcotic analgesics and non-steroidal anti-inflammatory drugs (analgin, amidopyrine, aspirin, ortofen);

- inhibitors of prostaglandinogenesis (ketoprofen, ketorolac, diclofenac);

- inhibitors of kininogenesis (trasylol, contrykal);

2) means for surface (terminal) local anesthesia:

- lidocaine, dicaine, Hirsch mixture, chloroethyl;

3) means for infiltration anesthesia:

- novocaine;

4) funds for regional (spinal, epidural, conduction - stem, plexus, ganglionic) anesthesia:

- novocaine, lidocaine, trimecaine.

Centrally acting analgesics:

1) narcotic opioid analgesics and their synthetic substitutes - "large" analgesics (morphine, omnopon, promedol, ceptazocine, buprenorphine, butorphanol);

2) stimulants (agonists) of central α 2 -adrenergic receptors - xilavet, clonidine, detomidine (domosedan), romifidine (sedivet);

3) NMDA receptor antagonists (ketamine, tiletamine, phencyclidine).

Such a division of analgesic drugs is rather arbitrary, but justified, since knowledge of the mechanism of action allows minimizing the side effects of analgesic drugs and, using their advantages, to achieve the most optimal pain relief.

"Small" and "large" analgesics are classic parenteral drugs. Analgesic properties have α 2 -agonists and ketamine. Local anesthetics are also very well suited to interrupt pain impulses, but their use is limited due to the difficulty of targeting and relatively short duration of action.

"Small" and "large" analgesics

For the treatment of pain, "small" and "large" analgesics are used. "Small" analgesics (analgin, ortofen, etc.) do not eliminate pain of moderate and severe intensity. When used in its pure form, but in various combinations, it can bring some relief to the animal. In addition, "small" analgesics have anti-inflammatory and antipyretic effects, which may be important in symptomatic treatment in the postoperative period.

"Large" analgesics (promedol, butorphanol, etc.) at the first stages of use can eliminate pain of almost any intensity, but with their long-term use, tolerance and addiction gradually develop. "Large" analgesics, along with analgesic properties, also have hypnotic and sedative effects, which gives them certain advantages over other drugs and explains their use in clinical practice.

To achieve ideal analgesia, multimodal anesthesia is used, i.e. the combined use of various groups of analgesics. Thus, it is possible to influence different levels of occurrence and transmission of pain, which is most favorable for the patient.

Modern non-steroidal anti-inflammatory drugs, related to "small analgesics", are evaluated according to their ability to prevent the formation of inflammatory mediators (serotonin, cyclooxygenase, bradykinin, etc.). According to the action on cyclooxygenase (COX), the isoenzyme COX 1 or COX 2 is isolated. Theoretically, selective COX 2 inhibitors have fewer side effects. Clinically, however, this is not always the case. For example, if an animal responds with vomiting or gastrointestinal bleeding to any non-steroidal anti-inflammatory drug, an alternative drug should be tested. Often one patient tolerates a particular drug better, regardless of its COX selectivity. Undesirable side effects are a problem especially with long-term use of non-steroidal anti-inflammatory drugs. These side effects include irritation and ulceration in the gastrointestinal tract, bleeding with delayed blood clotting, deterioration of kidney function due to a decrease in renal blood flow (dangerous in the postoperative period).

Some non-steroidal anti-inflammatory drugs with their specific properties for a certain animal species are described below. In combination with opioids, they can be used before surgery, which will help to successfully deal with severe pain. The first 4 drugs have been on the market for a very long time. Following them, carprofen belongs to a new generation of non-steroidal anti-inflammatory drugs.

Acetylsalicylic acid rarely used. Horses (30–50 mg/kg po bid) to inhibit platelet aggregation, eg in acute aseptic pododermatitis.

Metamizole (Novaminsulfonsäure) applied intravenously or intramuscularly, primarily for horses and productive animals; is prescribed in addition to a suitable strong analgesic or antipyretic component due to a good antispasmodic effect. The duration of action is about 4 hours after intravenous administration. It is an ideal initial pain reliever for colic in horses (20-30mg/kg IV or IM) and is well suited to other animal species as there is no danger of "masking" the pain. It works very well for blockage of the esophagus in cattle (cattle) and horses. With repeated use, inhibition of bone marrow function is possible.

Phenylbutazone is used intravenously or intramuscularly primarily for horses and productive animals. Causes prolonged irreversible inhibition of cyclooxygenase in the inflammatory exudate and thus has a very good antipyretic effect. Ideal for acute inflammatory diseases of the musculoskeletal system in all animal species (dogs 10 mg/kg po 3 times a day, dose reduced after 3 days; horses 4 mg/kg po bid, after 2 days the dose is halved by 1 weeks). The analgesic effect of the drug and its therapeutic effect are enhanced when used together with bonharen (see Appendix 12). Not applicable to cats, as it has a very small therapeutic latitude. Some pony breeds are hypersensitive to the drug.

Flunixin (Flunixin) used intravenously in all animal species. It is a very strong analgesic, effective for about 8 hours for pain associated with colic, especially in horses (at a dose of 1.1 mg / kg - intravenously). Symptoms can be masked, therefore, it is prescribed only in cases where the cause of colic is known.

Carprofen (Rimadyl) applied subcutaneously, intravenously and orally to all animal species. This is a new anti-inflammatory, very strong long-acting analgesic (18-24 hours, comparable in strength to opioids); primarily used for dogs and cats (4 mg/kg - subcutaneously, intravenously once a day) with acute somatic pain (fractures, etc.), postoperative pain is relieved by carprofen orally. Doses for horses - 0.7 mg/kg IV once a day, productive animals 1 - 2 mg/kg IV (expensive), oral administration is also possible.

Meloxicam (Metacam) used in dogs and cats orally or intravenously at first 0.2 mg/kg, then 0.1 mg/kg every 24 hours. It is a modern anti-inflammatory agent (highly selective COX 2 inhibitor); very strong, long-acting analgesic. Very well adapted for long-term use.

Tolfenamide (Tolfedine) is used for dogs and cats intramuscularly, subcutaneously, orally at a dose of 4 mg / kg (not before surgery), acts for 24 hours, but the course is only up to three days, since the drug is relatively toxic. Ideal in cases of exacerbation of a chronic inflammatory process. Modern anti-inflammatory drug, long-acting analgesic.

Vedaprofen (quadrisol) is administered to horses and dogs orally or intravenously at a dose of 0.5 - 2 mg / kg 2 times a day. A modern anti-inflammatory agent (highly selective COX 2 inhibitor).

Ketoprofen (Romefen) is used in dogs, cats, horses, cows, pigs, camels, rats orally at a dose of 1.1-2.2 mg/kg, primarily for chronic pain and as an antipyretic. In operations, subcutaneously in dogs and cats, intravenously in horses or intramuscularly in ruminants and pigs.

Narcotic analgesics, their antagonists and synthetic substitutes

According to the analgesic effect, narcotic analgesics, including morphine and alkaloids close to it (opiates) and synthetic compounds with opiate-like properties (opioids), are divided into several groups according to the selectivity and nature of the effect on opiate receptors. Some of them (morphine, promedol, fentanyl, etc.) are "pure" (full) agonists, that is, acting on receptors, they have an analgesic effect. Others (naloxone) block the binding of agonists or displace them from opiate receptors. The third group includes drugs of a mixed type of action - agonist-antagonists (pentazocine, butorphanol). The fourth group consists of partial (partial) agonists (buprenorphine). So far, 5 different opioid receptors have been isolated. Their properties are presented in table. eleven.

Table 11

Classification of opioid receptors

A high density of such receptors is found in the limbic system, spinal cord, thalamus, hypothalamus, striatum, and midbrain. They are also found in the gastrointestinal tract, urinary tract and other smooth muscle organs and joints.

Opioids may also have the following actions: first emetic, then antiemetic; the tone of the sphincters of the urinary and gallbladder increases; vagus nerve stimulation: peripheral vasodilation, bradycardia; antitussive action; often at first increased defecation, then constipation.

The action of any opioid is determined by binding to various receptors. It is important that opioid agonist-antagonists and partial agonists have not only the least side effects, but also less pronounced analgesia than pure agonists. Therefore, for very painful interventions (thoracotomy, spinal surgery), it is advisable to use pure agonists, for routine interventions, agonist-antagonists or partial agonists are sufficient. With severe respiratory depression caused by an overdose of agonists, agonist-antagonists or partial agonists can be used. Thanks to this, breathing returns to normal with continued analgesia.

Different animal species may respond differently to the same opioid, possibly due to different distribution of receptors. Before a veterinarian will use an opioid, he must be familiar with the specific action and side effects of the drug on a particular type of animal.

Most opioids are metabolized in the liver. In animals with hepatic insufficiency, these drugs should be used in minimal doses. Opioids cross the placental barrier and are excreted in milk. They should only be used in childbirth if naloxone (a pure opioid antagonist) is administered to the newborn, otherwise life-threatening respiratory depression ensues.

Opioid agonists

Morphine (Vendal) - classic reference analgesic. Being a "pure" agonist, it binds to opiate receptors and has a pronounced analgesic effect. At the same time, it has a sedative effect, which is not always constant and, with repeated applications, can be replaced by motor excitation. This limits the possibility of its long-term use. Morphine stimulates the parasympathetic system, which is manifested in the inhibition of heart contractions, in an increase in the tone of smooth muscles and sphincters. This explains the slowdown in the evacuation of food masses from the stomach, difficulty urinating. When monitoring anesthesia, it must be remembered that pupillary constriction may depend not only on the depth of anesthesia, but also on the action of morphine. Characteristic of morphine is the depression of the respiratory center.

Morphine is rapidly absorbed both when administered orally and subcutaneously. In the body, it is mainly oxidized in the liver (about 90%), the remaining 10% are excreted from the body through the kidneys and the gastrointestinal tract unchanged. Revealed a significant increase in free morphine in debilitated, young and old animals. This explains their high sensitivity to the drug.

In combination with barbiturates during the administration phase under general anesthesia, severe respiratory depression is possible. During surgery, morphine can be used in small doses to deepen anesthesia, prevent shock, and potentiate the action of local anesthetics. To prevent respiratory failure, even during endotracheal anesthesia with controlled ventilation, it is not recommended to administer morphine later than 40-60 minutes before the end of the operation.

Side effects:

- relatively severe respiratory depression;

- in all animal species, the release of histamine after intravenous administration is possible, therefore it is used intramuscularly or subcutaneously;

- possible excitation, the effect of the drug is relatively short (about 2 - 4 hours);

- vomiting in cats and dogs;

- hypothermia in dogs, hyperthermia in other animals;

- itching in dogs;

- first defecation, followed by constipation;

- transient slight decrease in blood pressure;

- sometimes spasms of the gastrointestinal tract.

To reduce side effects, premedication must include atropine, metacin, or other anticholinergics. To prevent respiratory disorders, it is necessary to have equipment for artificial lung ventilation.

Omnopon (pantopon) contains 48 - 50% morphine and 29.9 - 34.2% other alkaloids. The composition of omnopon determines half the analgesic activity, but due to other alkaloids, the drug has an antispasmodic and sedative effect. Therefore, omnopon causes less side effects characteristic of morphine.

Promedol (trimeperidine) 5 - 6 times less active than morphine with various methods of administration. It has similar pharmacokinetics to morphine, but is much less depressing of respiration. The absence of a spasmodic effect reduces the possibility of urinary retention and gases in the intestines in the postoperative period. Widely used in anesthesia practice. For premedication, 0.1-0.3 mg/kg of animal weight is injected under the skin or intramuscularly together with atropine (0.01 mg/kg) 30-40 minutes before surgery. For emergency premedication, drugs are injected into a vein. During the operation, the introduction of fractional doses of Promedol 3-5 mg enhances analgesia, allows for more superficial anesthesia, reducing the consumption of general anesthetics for the purpose of analgesia and muscle relaxants. In the postoperative period, promedol should be administered only after the restoration of spontaneous breathing in the animal. The drug is administered subcutaneously, intramuscularly or orally in doses of 0.2-0.4 mg/kg.

Promedol can be considered as the drug of choice for anesthesia in obstetrics. It gives some kind of labor-stimulating effect, favorably affects blood circulation in the uterus. To anesthetize childbirth, 0.5 - 1 ml of a 1% solution is injected subcutaneously with a satisfactory condition of the fetus.

When working with promedol, it is necessary to have an apparatus for assisted breathing at the ready.

Fentanyl (Durogesic) has a very high analgesic activity, 50-100 times greater than morphine. With a single injection, the analgesic effect develops quickly (after 3-10 minutes with intramuscular injection) and briefly (15-30 minutes), after which fentanyl is destroyed (mainly by the liver) and excreted in the urine. A strong rapidly developing, but short-term effect of the drug served as the basis for neuroleptanalgesia. For neuroleptanalgesia, fentanyl is used in combination with neuroleptics - the drug thalamonal (droperidol).

MIORELAXANTS(Greek mys, my muscle + Latin relaxare to weaken, soften; syn. muscle relaxers) - drugs that reduce the tone of skeletal muscles and, in connection with this, cause a decrease in motor activity up to complete immobility.

Distinguish M. of the central and peripheral types of action.

K M. peripheral action carry curariform substances (see), to-rye cause a relaxation of skeletal muscles due to blockade of neuromuscular transmission (see. Synapse). In accordance with the nature of the effect on neuromuscular transmission, among the drugs of this group, substances of depolarizing (ditilin, etc.), non-depolarizing (tubocurarine diplacin, qualidil, etc.) and mixed (dioxonium, etc.) types of action are distinguished. In addition, pharmacologically active compounds that have a direct inhibitory effect on the tone and contractility of skeletal muscles by reducing the release of Ca 2+ ions from the sarcoplasmic reticulum of muscle tissue can be attributed to M. of peripheral action. Unlike curare-like agents, such compounds inhibit direct excitability of skeletal muscles and do not affect neuromuscular transmission. Thus, these substances can be considered as peripheral M. of direct myotropic action.

This group includes dantrolene (Dantrolene; 1-[(5-arylfurfurylidene) amino]-hydantoin), which is used in honey. practice ch. arr. in the form of sodium salt (Dantrolene sodium; syn. Dantrium). Along with muscle relaxation, dantrolene has a nek-swarm depressing effect on c. n. With. However, unlike M. of the central type of action, it does not affect the central mechanisms of regulation of muscle tone (see). The sensitivity of different groups of skeletal muscles to dantrolene is not the same (the muscles of the limbs are more sensitive to its action than the respiratory muscles). The drug is satisfactorily absorbed by various routes of administration, including from went. - kish. a path, is slowly metabolized in a liver and is allocated by kidneys mainly in the form of inactive metabolites and partially in not changed form. Its half-life from the body is approx. 9 o'clock

K M. central action are referred to as mianezin-like (mefenesin-like) substances, to-rye, in their properties and mechanism of muscle-relaxing action, are close to mianesin (mefenesin), the first drug of this group introduced into honey. practice. According to chem. M.'s structure of central action can be divided into the following groups: 1) propanediol derivatives - mianesin, meprotan (see), isoprotan (see), etc.; 2) oxazolidine derivatives - metaxolone, chlorzoaxazone; 3) benzodiazepines - diazepam (see), chlordiazepoxide (see), etc.; 4) preparations of various chem. structures - orphenadrin, etc. M.'s properties of the central action are also possessed by midokalm.

In the experiment, M. of central action reduce the spontaneous motor activity of animals and reduce muscle tone. At very high doses, they cause flaccid paralysis of the skeletal muscles and apnea due to the relaxation of the respiratory muscles. In subparalytic doses, M. of central action eliminates the phenomena of decerebrate rigidity and hyperreflexia in animals, weakens convulsions caused by strychnine and electric current. Besides, the majority of M. of the central action possesses sedative, and nek-ry preparations (eg, benzodiazepines, meprotan) tranquilizing properties and ability to potentiate action of sleeping pills and analgesics.

Unlike M. of peripheral action, central M., even in sublethal doses, have practically no effect on neuromuscular transmission or direct excitability of skeletal muscles. The mechanism of the muscle-relaxing action of drugs in this group is due to their inhibitory effect on the synaptic transmission of excitation in the c. n. With. The general property of central M. is ability to suppress activity of intercalary neurons of polysynaptic reflex ways of a spinal cord and nek-ry overlying departments of c. n. With. In this regard, M. of the central action actively inhibit polysynaptic reflexes and do not significantly affect monosynaptic reflexes. The inhibition of descending inhibitory and facilitating influences from a number of suprasegmental structures (the reticular formation, subcortical nuclei) on the motor centers of the spinal cord also has a certain significance in the mechanism of action of the central M..

M. is used in various areas of honey. practices to reduce skeletal muscle tone. At the same time, the choice of drugs for a particular purpose is carried out taking into account the breadth of their myoparalytic action. So, the vast majority of curare-like substances of depolarizing, non-depolarizing and mixed types of action, which have a small breadth of myoparalytic action, are used for total muscle relaxation of ch. arr. in anesthesiology, as well as in the treatment of tetanus and for the prevention of traumatic complications during electroconvulsive therapy.

Central M., dantrolene and curare-like drugs from among tertiary amines - mellictin (see), etc. - have a wide range of myoparalytic action, which allows them to be used to reduce muscle tone without inhibiting or turning off spontaneous respiration. Such drugs are used for diseases accompanied by patol, increased skeletal muscle tone. In nevrol, practice, for example, they are used in spastic conditions of various origins (cerebral and spinal paralysis, Little's disease, spastic torticollis, etc.). M. central action is also used for muscle contractures of traumatic or inflammatory (eg, rheumatic diseases) origin. The use of drugs of this group with this pathology contributes not only to a decrease in pain in the muscles of the affected area (due to a decrease in muscle tone), but also allows for more efficient rehabilitation of patients, since the elimination of contractures facilitates the treatment. physical education. In anesthesiology, M.'s practice of central action and dantrolene are used relatively less frequently than curare-like substances, and are used for other indications.

Side influence of M. of the central action and dantrolene is shown by hl. arr. weakness, drowsiness, dizziness, dyspeptic disorders. Possible allergic reactions. The specified preparations should not be appointed during work to persons, a profession to-rykh demands exact and fast mental and motive reactions (drivers of transport, etc.).

The use of muscle relaxants in anesthesiology

In anesthesiology, to achieve deep muscle relaxation during surgical interventions, certain diagnostic procedures and mechanical ventilation, drugs from the group of curariform substances are used. Depending on the expected duration of surgery or diagnostic procedure, the choice of individual curare-like drugs is made taking into account the duration of their action. So, for short-term (within a few minutes) muscle relaxation (with tracheal intubation, reduction of dislocations, reposition of bone fragments, short-term operations and diagnostic procedures), it is advisable to use short-acting curare-like drugs, for example, dithylin (see), tubocurarine (see), anatruksoniy (see), pavulon, etc.; preparations with a long duration of action apply hl. arr. to maintain long-term muscle relaxation during operations under anesthesia with controlled breathing, with artificial lung ventilation, complex and lengthy diagnostic procedures. Ditilin to achieve long-term muscle relaxation can only be used if it is administered by a fractional method or by drip infusion. With the help of curare-like drugs, it is possible to cause a total or partial blockade of neuromuscular transmission. Total blockade is resorted to during long-term operations that require deep muscle relaxation and are performed, as a rule, under conditions of endotracheal general anesthesia (see Inhalation anesthesia).

In cases where total muscle relaxation is not required. but during the operation, it may be necessary to relax the muscles of a certain part of the body (abdomen, limbs), a partial blockade of the skeletal muscles is carried out by introducing small doses of curare-like drugs. The most convenient for this purpose are drugs of a non-depolarizing type of action.

In connection with the preservation of spontaneous respiration, surgical interventions in this case can be performed under mask anesthesia, subject to careful monitoring of the state of gas exchange and readiness to compensate for violations of auxiliary or artificial ventilation of the lungs (see Artificial respiration). The technique of carrying out total muscle relaxation during anesthesia, carried out with the help of special masks (see Mask for anesthesia) without tracheal intubation, has not received wide distribution.

With the combined use of curare-like drugs, it should be remembered that the introduction of the usual dose of non-depolarizing substances (eg, tubocurarine) after repeated injections of dithylin causes a deeper and more prolonged neuromuscular block than under normal conditions. Repeated administration of dithylin after the use of non-depolarizing drugs in normal doses, following short-term antagonism, leads to a deepening of the neuromuscular block of the competitive type and a delay in the recovery period of muscle tone and respiration. To assess the nature of the neuromuscular blockade caused by curare-like drugs, the method of electromyography can be used (see). Electromyographically, a non-depolarizing neuromuscular block is characterized by a gradual decrease in the amplitude of the muscle action potential without previous relief of neuromuscular transmission and muscle fasciculations, a pronounced pessimum in the frequency of irritation, and the phenomenon of post-tetanic relief. Depolarizing (biphasic) neuromuscular block is characterized by a transient relief of neuromuscular transmission, accompanied by muscle fasciculations, and a rapid subsequent development of neuromuscular block. In the first phase, the amplitude of a single muscle action potential is reduced, the tetanus is stable, and the phenomenon of post-tetanic relief is absent. In the second phase, a more or less pronounced pessimum in the frequency of irritation and the phenomenon of post-tetanic facilitation of neuromuscular transmission are revealed. Electromyographic signs of the second phase are noted already at the first injection of dithylin and dioxonium, and with an increase in the number of injections, the severity and stability of these signs increase.

The use of curare-like drugs in myasthenia is a particular problem. Patients with myasthenia gravis (see) are extremely sensitive to drugs of the depolarizing type. The introduction of a standard dose of dithylin leads to the development of a two-phase neuromuscular block with pronounced signs of the second phase, and therefore repeated injections of the drug can lead to excessively prolonged and deep muscle relaxation, impaired respiratory recovery and muscle tone. In the surgical treatment of myasthenia gravis, the autocurarization technique has become widespread, which consists in reducing the dose or canceling anticholinesterase drugs before surgery, using the minimum dose of dithylin during intubation and hyperventilating during surgery, which avoids repeated injections of this drug or limits it to its minimum doses.

There are no absolute contraindications to the use of curare-like drugs, however, with certain diseases, individual drugs of this group may be contraindicated. Therefore, a rational and reasonable choice of curare-like drugs is of great importance, taking into account the nature of the underlying and concomitant diseases. So, in patients with renal insufficiency, impaired water and electrolyte balance, acidosis, hypoproteinemia, there is an increased sensitivity to M. from the group of curare-like substances of a non-depolarizing type of action (tubocurarine, etc.), as well as to curare-like drugs of a mixed type of action (dioxonia, etc. ) due to impaired distribution and elimination of these drugs. A frequent reason for the unusually long action of dithylin is a decrease in the activity of pseudocholinesterase, an enzyme that hydrolyzes this drug (with genetic defects in the enzyme, liver diseases, malignant neoplasms, hron, suppurative processes, bleeding, exhaustion). It is undesirable to use dithylin during eye operations and in patients with increased intracranial pressure due to its ability to increase intraocular and intracranial pressure. The use of dithylin is also dangerous in people with extensive burns, paraplegia, and prolonged immobilization.

Complications in the use of curare-like drugs are largely due to the irrational choice of drugs for a given patient, as well as the use of drugs without taking into account the nature of their interaction with each other and with drugs from other groups of drugs. The most common complication in the use of curare-like drugs in anesthesiology is prolonged apnea - an unusually prolonged respiratory depression and muscle tone after using an average dose of the drug. After the introduction of drugs of a competitive type, as well as dioxonia, prolonged apnea may develop in patients with renal failure, acidosis, water and electrolyte imbalance, hypovolemia, and as a result of the potentiating effect of certain drugs (general and local anesthetics, ganglionic blockers, quinidine, diphenine, beta - adrenoblockers). Repeated injections of dithylin prior to the introduction of tubocurarine may also contribute to the development of prolonged sleep apnea. The myoparalytic effect of dithylin is clearly potentiated by anticholinesterase agents, propanidide, chlorpromazine, cytostatics (cyclophosphamide, sarcolysine), and trasylol. In addition, hypercapnia (see) and respiratory acidosis (see) can be the cause of delayed recovery of breathing and muscle tone after the use of ditilin. For decurarization, anticholinesterase agents (prozerin, galanthamine, etc.) are widely used, blocking cholinesterase and thereby contributing to the accumulation of acetylcholine in neuromuscular synapses, which leads to facilitation of neuromuscular transmission, normalization of respiration and muscle tone. It is also possible to use agents that increase the synthesis and release of acetylcholine in neuromuscular synapses (jermine, pimadin and less effective hydrocortisone, calcium pantothenate).

Terrible, although relatively rare complication associated with the use of curare-like substances, is recurarization. Recurarization is understood as a deepening of residual muscle relaxation up to apnea or severe respiratory depression, which develops, as a rule, in the first two hours after surgery under the influence of a number of factors that disrupt the distribution, metabolism and elimination of drugs. These factors include respiratory and metabolic acidosis, disturbances in water and electrolyte balance, hypovolemia, arterial hypotension, exposure to certain drugs (antibiotics from the group of aminoglycosides, quinidine, trasilol, cyclophosphamide), inadequate decurarization with anticholinesterase agents at the end of the operation.

After the administration of dithylin and, to a lesser extent, dioxonia, noticeable amounts of potassium are released from skeletal muscles into the extracellular fluid, resulting in often transient bradycardia, less often atrioventricular block, and very rarely asystole (the last two complications are described only after the use of dithylin).

Tubocurarine and qualidil have the ability to release histamine, and therefore there is a transient tachycardia that usually does not require special treatment. Rare complications associated with the use of tubocurarine and other curare-like substances of non-depolarizing action include the so-called. proserin-resistant curarization. Usually, the reason for the ineffectiveness of anticholinesterase agents used for the purpose of decurarization is their administration against the background of a very deep blockade of neuromuscular transmission or against the background of metabolic acidosis. Cases of proserin-resistant curarization after the use of an average dose of tubocurarine against the background of repeated preliminary administration of dithylin are described.

Treatment of complications: ensuring adequate artificial ventilation of the lungs up to the restoration of normal muscle tone and elimination of the cause of the complication.

In anesthesiology, M. is also used for other indications. So, M. of central action, which have a pronounced tranquilizing effect, for example, diazepam, meprotan, can be used as a means for premedication before anesthesia (see). Mydocalm is used during electroanesthesia (see). Diazepam in combination with the narcotic analgesic fentanyl is used for the purposes of the so-called. ataralgesia (balanced anesthesia) during certain surgical interventions. Besides, M. of the central action is sometimes used for suppression of a muscular trembling and decrease in heat production at a hyperthermic syndrome (see). Dantrolene also has the ability to stop the manifestations of this syndrome, which sometimes occurs after the use of inhalation anesthetics (eg, halothane) and dithyline.

Bibliography: Kharkevich D. A. Pharmacology of curare-like drugs, M., 1969; The pharmacological basis of therapeutics, ed. by L. S. Goodman a. A. Gilman, p. 239, N. Y. a. o., 1975; Physiological pharmacology, ed. by W. S. Root a. F. G. Hoffmann, v. 2, p. 2, N. Y.-L., 1965; PinderR.M. a. o. Dantrolene sodium, a review of its pharmacological properties and therapeutic efficacy in spasticity, Drugs, v. 13, p. 3, 1977.

V. K. Muratov; V. Yu. Sloventantor, Ya. M. Khmelevsky (anest).

In medicine, quite often there are situations when it is necessary to relax muscle fibers. For these purposes, they are introduced into the body, they block neuromuscular impulses, and the striated muscles relax.

Medicines of this group are often used in surgery, to relieve convulsions, before repositioning a dislocated joint, and even during exacerbations of osteochondrosis.

The mechanism of action of drugs

With severe pain in the muscles, a spasm may occur, as a result, movement in the joints is limited, which can lead to complete immobility. This issue is especially acute in osteochondrosis. Constant spasm interferes with the proper functioning of muscle fibers, and, accordingly, the treatment is stretched indefinitely.

To bring the patient's general well-being back to normal, muscle relaxants are prescribed. Preparations for osteochondrosis are quite capable of relaxing muscles and reducing the inflammatory process.

Given the properties of muscle relaxants, we can say that they find their application at any stage of the treatment of osteochondrosis. The following procedures are more effective in their application:

• Massage. Relaxed muscles respond best to exposure.
• Manual therapy. It's no secret that the effect of a doctor is the more effective and safer, the more relaxed the muscles.
• Physiotherapy procedures.
• The effect of painkillers is enhanced.

If you often experience or suffer from osteochondrosis, then you should not prescribe muscle relaxants on your own, drugs in this group should only be prescribed by a doctor. The fact is that they have a fairly extensive list of contraindications and side effects, so only a doctor can choose a medicine for you.

Classification of muscle relaxants

The division of drugs in this group into different categories can be considered from different points of view. If we talk about what muscle relaxants are, there are different classifications. Analyzing the mechanism of action on the human body, only two types can be distinguished:

1. Peripheral drugs.
2. Central muscle relaxants.

Medicines can have a different effect in duration, depending on this, they distinguish:

• Ultra short action.
• short.
• Medium.
• Long.

Only a doctor can know exactly which drug is best for you in each case, so do not self-medicate.

Peripheral muscle relaxants

Able to block nerve impulses that pass to muscle fibers. They are widely used: during anesthesia, with convulsions, with paralysis during tetanus.

Muscle relaxants, drugs of peripheral action, can be divided into the following groups:

All of these drugs affect cholinergic receptors in skeletal muscles, and therefore are effective for muscle spasms and pain. They act quite gently, which allows them to be used in various surgical interventions.

Central acting drugs

Muscle relaxants of this group can also be divided into the following types, given their chemical composition:

1. Derivatives of glycerin. These are Meprotan, Prenderol, Isoprotan.
2. Based on benzimidazole - "Flexin".
3. Mixed drugs, such as Mydocalm, Baclofen.

Central muscle relaxants are able to block reflexes that have many synapses in muscle tissue. They do this by reducing the activity of interneurons in the spinal cord. These drugs not only relax, but have a wider effect, which is why they are used in the treatment of various diseases that are accompanied by increased muscle tone.

These muscle relaxants have practically no effect on monosynaptic reflexes, so they can be used to remove and not turn off natural breathing.

If you are prescribed muscle relaxants (drugs), you can find the following names:

• "Metacarbamol".
• "Baclofen".
• "Tolperizon".
• "Tizanidin" and others.

It is better to start taking drugs under the supervision of a doctor.

The principle of using muscle relaxants

If we talk about the use of these drugs in anesthesiology, we can note the following principles:

1. Muscle relaxants should be used only when the patient is unconscious.
2. The use of such drugs greatly facilitates artificial ventilation of the lungs.
3. It is not the most important thing to remove, the main task is to carry out comprehensive measures for the implementation of gas exchange and maintaining blood circulation.
4. If muscle relaxants are used during anesthesia, then this does not preclude the use of anesthetics.

When drugs of this group firmly entered medicine, one could safely talk about the beginning of a new era in anesthesiology. Their use allowed us to simultaneously solve several problems:

After the introduction of such drugs into practice, anesthesiology was able to become an independent industry.

Scope of muscle relaxants

Considering that substances from this group of drugs have an extensive effect on the body, they are widely used in medical practice. The following directions can be listed:

1. In the treatment of neurological diseases that are accompanied by increased tone.
2. If you use muscle relaxants (drugs), lower back pain will also recede.
3. Before surgery in the abdominal cavity.
4. During complex diagnostic procedures for certain diseases.
5. During electroconvulsive therapy.
6. When conducting anesthesiology without turning off natural breathing.
7. For the prevention of complications after injuries.
8. Muscle relaxants (drugs) for osteochondrosis are often prescribed to patients.
9. To facilitate the recovery process after
10. The presence of an intervertebral hernia is also an indication for taking muscle relaxants.

Despite such an extensive list of the use of these drugs, you should not prescribe them yourself, without consulting a doctor.

Side effects after taking

If you have been prescribed muscle relaxants (drugs), lower back pain should definitely leave you alone, only side effects can occur when taking these drugs. On some it is possible, but there are more serious ones, among them it is worth noting the following:

• Reduced concentration, which is most dangerous for people sitting behind the wheel of a car.
• Lowering blood pressure.
• Increased nervous excitability.
• Bed-wetting.
• allergic manifestations.
• Problems from the gastrointestinal tract.
• Convulsive conditions.

Especially often, all these manifestations can be diagnosed with the wrong dosage of drugs. This is especially true for antidepolarizing drugs. It is urgent to stop taking them and consult a doctor. Neostigmine solution is usually prescribed intravenously.

Depolarizing muscle relaxants are more harmless in this regard. When they are canceled, the patient's condition is normalized, and the use of medications to eliminate symptoms is not required.

You should be careful to take those muscle relaxants (drugs), the names of which are unfamiliar to you. In this case, it is better to consult a doctor.

Contraindications for use

Taking any medications should be started only after consulting a doctor, and these medications even more so. They have a whole list of contraindications, among them are:

1. They should not be taken by people who have kidney problems.
2. Contraindicated in pregnant women and nursing mothers.
3. Psychological disorders.
4. Alcoholism.
5. Epilepsy.
6. Parkinson's disease.
7. Liver failure.
8. Children's age up to 1 year.
9. Ulcer disease.
10. Myasthenia.
11. Allergic reactions to the drug and its components.

As you can see, muscle relaxants (drugs) have many contraindications, so you should not harm your health even more and start taking them at your own peril and risk.

Requirements for muscle relaxants

Modern drugs should not only be effective in relieving muscle spasm, but also meet certain requirements:

One of these drugs, which practically meets all the requirements, is Mydocalm. This is probably why it has been used in medical practice for more than 40 years, not only in our country, but also in many others.

Among the central muscle relaxants, it differs significantly from others for the better. This drug acts on several levels at once: it removes increased impulses, suppresses the formation in pain receptors, and slows down the conduction of hyperactive reflexes.

As a result of taking the drug, not only muscle tension decreases, but also its vasodilating effect is observed. This is perhaps the only drug that relieves spasm of muscle fibers, but does not cause muscle weakness, and also does not interact with alcohol.

Osteochondrosis and muscle relaxants

This disease is quite common in the modern world. Our lifestyle gradually leads to the fact that back pain appears, to which we try not to react. But there comes a point when the pain can no longer be ignored.

We turn to the doctor for help, but precious time is often lost. The question arises: "Is it possible to use muscle relaxants in diseases of the musculoskeletal system?"

Since one of the symptoms of osteochondrosis is muscle spasm, it makes sense to talk about the use of drugs to relax spasmodic muscles. During therapy, the following drugs from the group of muscle relaxants are most often used.

In therapy, it is usually not customary to take several drugs at the same time. This is provided so that you can immediately identify side effects, if any, and prescribe another medicine.

Almost all drugs are available not only in the form of tablets, but there are also injections. Most often, with severe spasm and severe pain syndrome, the second form is prescribed for emergency care, that is, in the form of injections. The active substance penetrates into the blood faster and begins its therapeutic effect.

Tablets are usually not taken on an empty stomach, so as not to harm the mucous membrane. You need to drink water. Both injections and tablets are prescribed to be taken twice a day, unless there are special recommendations.

The use of muscle relaxants will only bring the desired effect if they are used in complex therapy, a combination with physiotherapy, therapeutic exercises, and massage is mandatory.

Despite their high effectiveness, you should not take these drugs without first consulting with your doctor. You cannot decide for yourself which medicine is right for you and will have the best effect.

Do not forget that there are a lot of contraindications and side effects that should not be discounted either. Only competent treatment will allow you to forget about pain and spasmodic muscles forever.

480 rub. | 150 UAH | $7.5 ", MOUSEOFF, FGCOLOR, "#FFFFCC",BGCOLOR, "#393939");" onMouseOut="return nd();"> Thesis - 480 rubles, shipping 10 minutes 24 hours a day, seven days a week and holidays

Larina Julia Vadimovna Pharmaco-toxicological assessment of the muscle relaxant adilinsulfam: dissertation... candidate of biological sciences: 16.00.04 / Larina Yuliya Vadimovna; [Place of protection: Federal State Institution "Federal Center for Toxicological and Radiation Safety of Animals"].- Kazan, 2009.- 117 p.: ill.

Introduction

2. Literature review

2.1 History of use of muscle relaxants 9

2.2 Classification of muscle relaxants according to the mechanism of action 12

2.3 New muscle relaxants and problems of their use in veterinary medicine 29

3. Material and research methods 3 5

4. Results of own research

4.1 Determination of acute toxicity of adilinsulfam and features of the manifestation of myorelaxation in different animal species 42

4.2 Determination of the cumulative properties of adilinsulfam 47

4.3 Influence of adilinsulfam on morphological and biochemical parameters of blood 49

4.4 Study of embryotoxic, teratogenic and mutagenic properties of adilinsulfam 50

4.5 Assessment of the safety of meat from animals slaughtered with adilinsulfam 56

4.6 Hazard assessment of temporary immobilization of pregnant females 60

4.7 Determination of drug storage stability 65

4.8 Sterility and pyrogenicity testing of adilinsulfam preparation 66

4.9 Allergic and irritant test for adilinsulfam 68

4.10 Development of a method for the indication of adilinsulfam in solutions, organs and tissues of animals 69

4.11 Development of the dosage form of adilinsulfam 74

4.12 Screening for potential antagonists 76

5. Discussion of results 90

List of references 101

Applications 120

Introduction to work

Relevance of the topic. The use of means for temporary immobilization of animals - muscle relaxants is one of the urgent problems when working with "domestic and" wild animals in the provision of medical care, trapping, marking or transportation (Stove K.M., 1971; Chizhov M.M., 1992 ; Jalanka N.N., 1992). They are also used in large doses as a means of mass bloodless slaughter of animals that are ill or suspicious of a disease, in the practice of preventing and eliminating epizootics when pathogens are especially dangerous infections (foot-and-mouth disease, anthrax, etc.). The bloodless method of slaughter is indispensable in fur farming in order to obtain a full-fledged high-quality fur (Ilyina E.D., 1990). In addition, the problem of the possibility of using the meat of productive agricultural and hunting animals that were killed or accidentally died with the use of depolarizing muscle relaxants still remains unexplored (Makarov V.A., 1991).

In our country, the use of dithylin obtained in 1958, which belongs to depolarizing muscle relaxants, has long been known to immobilize animals (Kharkevich D. A., 1989). The drugs of this group initially cause the activation of H-cholinergic receptors, which results in a persistent depolarization of the postsynaptic membrane, after which relaxation of the skeletal muscles occurs.

At present, the use of dithylin in animal husbandry practice is difficult due to the complexity of its acquisition and production, since for this it is necessary to import the initial reagent - methyl chloride. It has some side effects when used for temporary immobilization of animals, namely: a small breadth of myoparalytic action - a safety factor; and, in addition, in large quantities, the drug is limitedly soluble in water, which makes it difficult to use it on large animals and at low temperatures (Sergeev P.V., 1993; Tsarev A., 2002).

In recent years, there have been publications about new muscle relaxants - pyrocurine and amidocurine, which have a significantly greater "breadth of muscle relaxant action" in comparison with the known and used earlier and now d-tubocurarine, dithiline and their analogues (Kharkevich D.A., 1989; Chizhov M .M., 1992). However, so far information about them is scarce and insufficient to judge their prospects and accessibility.

Also in veterinary practice, xylazine is widely used, which, according to the mechanism of action, belongs to alpha2-adrenoreceptor agonists and, according to some reports (Sagner G., Haas G., 1999), causes a sleep-like state in animals, i.e. as if to wake them up. However, it is the prolonged awakening, as well as the absence of antagonists, that are often indicated as shortcomings of formulations based on both xylazine and its later analogues from among alpha-adrenergic receptor agonists - detomidine and medetomidine (Jalanka N.N., The cited literature data indicate the need to improve means of veterinary medicine intended for temporary and pre-slaughter immobilization of animals.Factors of efficiency, reliability, cost-effectiveness, availability in practice of their use are now becoming decisive.

In this regard, the search for new effective and safe drugs is an urgent task of theoretical and practical veterinary medicine.

FGU "FTsTRB-VNIVI" has accumulated experience in temporary immobilization and slaughter of animals with the help of depolarizing muscle relaxants - dithylin and its structural analogue adiline.

A new muscle relaxant of the same group, adilinsulfam, was synthesized by R.D. Gareev et al. as a more technologically advanced, cheap, and stable analogue of dithyline and adiline.

The purpose of the study: "" pharmaco-toxicological evaluation of adilinsulfam and experimental substantiation of the possibility of using it in veterinary medicine as a potential veterinary medicine for temporary, pre-slaughter immobilization and bloodless slaughter of animals.

Research objectives. To achieve the goal, the following tasks were set:
. to determine the parameters of acute toxicity and specific muscle relaxant activity of adilinsulfam for different animal species;
. evaluate the safety of adilinsulfam use, including oral toxicity and long-term effects (embryotoxicity, teratogenicity, postnatal development, etc.) in laboratory animals according to accepted criteria;
. to study the stability of the drug during storage, its pharmacodynamics and pharmacokinetics in animals;
. based on the results of the research, develop a draft regulatory documentation and instructions for the use of adilinsulfam in veterinary medicine.

Scientific novelty. For the first time on laboratory, domestic and some types of productive animals, the toxicity and specific efficacy and safety of using adilinsulfam for temporary, pre-slaughter immobilization and bloodless slaughter of animals were studied. A thin-layer chromatography method has been developed for the determination of the drug in organs and tissues of animals, with the help of which the pharmacokinetics of adilinsulfam in the body of animals has been studied and a high rate of its metabolism has been established. When screening potential antidotes and correctors, for the first time 4 compounds were identified - antagonists that prevent the death of animals after the introduction of lethal doses of adilinsulfam.

practical value. Based on the research results, a new drug is proposed for veterinary practice - adilinsulfam for bloodless slaughter and immobilization of animals.

The experimental data obtained were used in the drafting of regulatory documents: laboratory regulations, specifications and Instructions for the use of the drug, which will be submitted for state registration of adilinsulfam. the use of adilinsulfam for temporary, pre-slaughter immobilization and bloodless euthanasia of animals;
. substantiation of the safety and technology of using adilinsulfam in veterinary medicine.

Approbation of work. The results of research on the topic of the dissertation were reported, discussed and approved at the scientific sessions of the Federal State Institution "FTsTRBVNIVI" based on the results of research for 2005-2008; at the international scientific conference "Animal toxicoses and current problems of diseases of young animals", Kazan - 2006; scientific and practical conference of young scientists and specialists "Actual problems of veterinary medicine", Kazan - 2007, "The First Congress of Veterinary Pharmacologists of Russia", Voronezh - 2007, scientific and practical conference of young scientists and specialists "Achievements of young scientists - in production" , Kazan - 2008

The volume and structure of the dissertation. The dissertation is presented on 119 pages of computer text and consists of an introduction, literature review, research material and methods, own results, discussion, conclusions, practical suggestions, list of references. The work contains 26 tables and 2 figures. The list of used literature includes 204 sources, including 69 foreign ones.

Classification of muscle relaxants according to the mechanism of action

Based on the localization of the action of muscle relaxants, they are usually divided into two groups: central and peripheral. Some tranquilizers are often referred to as central ones: meprobamate (meprotan) and tetrazepam; mianesin, zoxazolamine, as well as central anticholinergics: cyclodol, amizil and others (Mashkovsky M.D., 1998). Peripheral or curare-like drugs (d-tubocurarine chloride, paramion, diplacin, dithylin, decamethonium, etc.) are divided according to their mechanism of action. Curare-like agents are characterized in that they block neuromuscular transmission, while myanesin-like drugs reduce muscle tone due to impaired conduction of excitation in the central nervous system. These substances act like the natural transmitter of nerve impulses acetylcholine at the junction of the nerve and muscle - the so-called end plate of the synapse. Acting with the blood flow to this place after parenteral administration, they, unlike acetylcholine, either prevent the depolarization of the plate and thereby disrupt conduction along the nerve, or cause its persistent depolarization with a similar effect. As a result of this, the muscles relax, although small contractions (fasciculations) of individual muscles are observed, especially noticeable on the chest and in the abdominal muscles (Zhulenko V.N., 1967).

In surgical practice during operations of the abdominal cavity, small pelvis and chest, muscle relaxation is an integral component of general anesthesia along with sedation, analgesia and areflexia (Gologorsky V.A., 1965).

Classification options have been proposed: by chemical structure, mechanism of action and duration of action. Currently, it is generally accepted to divide muscle relaxants according to the mechanism of action: according to the genesis of the neuromuscular block they cause. The first substances of the d-tubocurarine group prevent the depolarizing action of acetylcholine. The second - substances of the succinylcholine group cause depolarization of the postsynaptic membrane and thereby cause blockade, which is quite justified for the first phase of action from the action as depolarizing muscle relaxants (Thesleff S., 1952; Briskin A.I., 1961; Rereg K., 1974). According to Danilov A.F. (1953) and Bunatyan A.A., (1994), the 2nd phase is based on the mechanisms of progressive desensitization and developing tachyphylaxis.

A study of the physiology of neuromuscular conduction and the pharmacology of neuromuscular blockers showed that the nature of the blockade of conduction with the introduction of relaxants does not differ significantly (Francois Ch., 1984), but its mechanism is different for deolarizing and antidepolarizing drugs (Dillon J.B, 1957; Wastila W.B. , 1996). Depolarizing agents form, as it were, an “island” of persistent depolarization on the end plate in the middle of a normally depolarized muscle fiber membrane (BuckM.L., 1991; Kharkevich D.A., 1981).

Depolarizing muscle relaxants are widely used to immobilize animals, both in our country (ditilin) ​​and abroad (myorelaxin, succinylcholine iodide or chloride, anectin).

The term "cholinomimetic" refers to the effects of drugs similar in action to acetylcholine, which usually promotes excitation (stimulation), and at higher doses, blockade of the neuromuscular junction, whether in skeletal muscles or smooth muscles of internal organs. The well-known nicotine can serve as a classic example of such a dual effect on cholinergic receptors depending on the dose / concentration (Kharkevich D.A., 1981; Mashkovsky M.D., 1998).

With regard to dithylin and other depolarizing muscle relaxants, it should be noted that when they are administered, as muscle relaxation increases, the paralytic effect progresses, the muscles of the neck and limbs are consistently involved, the tone of the muscles of the head decreases: masticatory, facial, lingual and larynx. At this stage, a significant weakening of the respiratory muscles is not yet observed, and the vital capacity of the lungs decreases only to 25% (Unna K.R., Pelican E.W., 1950).

Based on the sequence of involvement in the process of skeletal muscle relaxation, it was postulated that depolarizing muscle relaxants, in particular, decamethonium (SC), differs from d-tubocurarine, which belongs to antidepolarizing muscle relaxants. According to a number of authors (Unna K.K., Pelican E.W., 1950; Foldes F.F., 1966; Grob D., 1967), their most important difference is that SU causes muscle relaxation at doses that “spare” the respiratory muscles.

Below we will consider some of the theoretical aspects that are essential for our - - research related to the general pharmacological classification and practice of using curare-like substances.

According to this classification, muscle relaxants are classified as agents that mainly affect efferent innervation, namely, the transmission of excitation in H-cholinergic synapses (Kharkevich D.A., 1981, 2001; Subbotin V.M., 2004). The motor neurons that innervate the striated muscles are H-cholinergic. Depending on the dose of substances, various degrees of effect can be observed - from a slight decrease in motor activity to complete relaxation (paralysis) of all muscles and respiratory arrest.

To date, a large number of curare-like substances belonging to different classes of chemical compounds have been obtained from plant sources and synthetically.

When classifying curare-like drugs, they usually proceed from the following principles (Kharkevich D.A., 1969, 1981, 1989, 1983; Foldes F., 1958; Cheymol J., 1972; Zaimis E., 1976; Bowman W., 1980): the structure and mechanism of the neuromuscular block, the duration of the effect, the breadth of the myoparalytic action, the sequence of relaxation of different muscle groups, the effectiveness with different routes of administration, side effects, the presence of antagonists, etc. According to the chemical structure, they are divided into: - bis-Quaternary ammonium compounds ( d-tubocurarine chloride, diplacin, paramion, dithylin, decamethonium, etc.); - tertiary amines (erythrina alkaloids - b-erythroidine, dihydro-b-erythroidine; larkspur alkaloids - condelfin, mellictin).

New muscle relaxants and problems of their use in veterinary medicine

The use of muscle relaxants in combination with narcotic substances and local anesthetic properties is of great importance in the immobilization of wild and domestic animals. The immobilization of animals with pharmacological agents is based on the loss of their motor activity for a certain period of time, which allows them to work safely and fix animals when providing them with any assistance, including medical one (Koelle G.B., 1971; Magda I.I., 1974; Kharkevich D.A., 1983).

D-tubocurarine, dimethyltubocurarine, tri-(diethylaminoethoxy)-benzyl-triethyl iodide (fluxedil), nicotine salicylate and succinylcholine chloride were used as alternative means for temporary immobilization of animals in different years and with different results (Jalanka H., 1991) . The therapeutic index with the use of these drugs was small, inhalation (aspiration) of the contents of the stomach and respiratory arrest often occurred, and the mortality rate was very high. The difference in the results, according to the estimates of different authors, was partly attributed to inaccurate dosing and imperfection of the injection technique using metal or plastic darts equipped with a drug, more often dissolved in a glucose solution (Vorner D., 1998).

Subsequently, antagonists of antidepolarizing muscle relaxants were found, incl. reversible cholinesterase inhibitors: prozerin (neostigmine), galantamine and tensilone, They allowed to slightly reduce the risk of overdose of drugs of this group. However, according to Butaev B.M. (1964) non-depolarizing muscle relaxants have a high ability to accumulate, which manifests itself when they are repeated. Therefore, one of the important requirements for a new generation of muscle relaxants is the absence of cumulative properties.

An important place in the evaluation of curare-like drugs is occupied by side effects. In principle, muscle relaxants should have a high selectivity of action and not cause side effects. But depolarizing muscle relaxants, including dithylin, are just characterized by adverse effects due to the mechanism of their action (Smith7 S.E. 1976). In addition to a selective effect on neuromuscular transmission, curare-like drugs can cause side effects associated with the release of histamine, inhibition of the autonomic ganglia, excitation or blocking of M-cholinergic receptors.

In some cases, especially in conditions of shock from fright when using muscle relaxants (Makushkin A.K. et al., 1982), this becomes vital and is accompanied by a decrease in body temperature and blood pressure caused by ganglioblocking or anticholinesterase properties of drugs; acute bronchospasm; increased secretion of gastric juice; increased intestinal motility; the appearance of swelling and itching of the skin; an increase in lymph flow (Kharkevich D.A., 1969; Colonhoun D., 1986). Ultimately, shock can be fatal after the muscle relaxant wears off.

According to the generally accepted opinion, antagonists of depolarizing muscle relaxants have not yet been found, although Thomas W.D. as early as 1961 he mentioned 1-amphetamine (phenamine) as their antagonist. For some reason, these studies have not received further development or have not been confirmed. It is possible that an obstacle to the detailed study and implementation of this potential antidote in practice was that, along with LSD, 1-amphetamine was classified as a "drug", as an addictive substance.

At present, the problem of introducing new muscle relaxants into the practice of temporary immobilization of animals remains relevant. According to the Gosohotkontrolya specialists, the risk of accidental death of animals when using known means of immobilization, incl. dithylin, sometimes reaches 70% (Tsarev S.A., 2002). This indicates the need to increase the breadth of therapeutic (muscle relaxant) action and develop reliable antagonists. One of the disadvantages of drugs used in the practice of temporary immobilization is their relatively low solubility and the associated need, when working with large animals, to introduce large amounts of their solutions, as well as the difficulty of using them at low temperatures, since they precipitate ( Sergeev P.V., 1993).

In recent years, publications have appeared about new muscle relaxants - pyrocurine and amidocurine, which have a significantly greater "breadth of muscle relaxant action" in comparison with the known and previously used and now d-tubocurarine, dithyline and their analogues (Kharkevich D.A., 1989; Chizhov M .M., 1992). However, so far information about them is scarce and insufficient to judge their prospects and accessibility.

At the same time, along with muscle relaxants, in recent years, some psychotropic drugs have successfully shown themselves in the veterinary practice of temporary immobilization of animals. As anesthetics, opioids (diethylthiambutene, fentanyl and etorphine), cyclohexamines, phenothiazines and xylazine, in combination with muscle relaxants or without them, were included in a number of formulations widely known in our country and abroad for temporary immobilization and anesthesia of animals (Jalanka N.N. ., 1991).

Determination of the cumulative properties of adilinsulfam

Under cumulation, it is customary to understand the strengthening of the action of a substance during its repeated exposure. The determination of the cumulative effect is necessary for the correct choice of the safety factor, since the processes of cumulation underlie chronic poisoning (Sanotsky IV 1970).

When determining the cumulative properties according to the Kagan formula, Yu.S. and Stankevich V.V. (1964) adilinsulfam was administered intramuscularly to rats, starting from its optimal muscle relaxant dose of 3.25 mg/kg with a gradual increase by 7% in each subsequent group of animals with an interval of 1 day. The results of the experiments are presented in table 5. Table 5 - Change in the sensitivity of rats of both sexes weighing 120-180 g with repeated daily intramuscular administration of adilinsulfam (n=4)

According to the results obtained, with repeated daily administration of adilinsulfam, no increase in toxicity was observed, moreover, signs of tolerance were clearly visible. At the end of the experiment, the animals died from increased lethal doses of the drug. LD50 in this experiment was calculated by probit analysis (Mukanov R.A., 2005) and it amounted to 23.1 mg/kg. and Stankevich V.V. (1964).

According to the research results, the cumulation coefficient was 6.6. This indicates that the drug, firstly, is rapidly metabolized and does not show functional accumulation, and secondly, it stimulates the systems that metabolize it. 4.3 Effect of adilinsulfam on morphological and biochemical parameters of blood

Evaluation of the effect of a drug intended for use as a drug on hematological parameters is one of the standard methods for determining its safety. This study was carried out on 10 white rats weighing 180-200g. The rats were injected intramuscularly once with adilinsulfam at a dose of LD5o- After 1; 3; 7 and 24 hours after administration, 6 surviving animals were bled from the heart with a syringe for analysis. The results obtained are shown in table 6.

According to the data obtained, the most significant deviations in the blood picture are observed by the 3rd hour. The amount of hemoglobin is reduced by 12.3%, total protein by 4% and γ-globulins by 13.2% with a simultaneous increase in the amount of α-globulins by 15.9%. However, already by 7 o'clock one can note a tendency to normalize the indicators, and by 24 o'clock - their complete return to their original values. Consequently, the noted changes were of a temporary, transient nature, and apparently they indicate a reversible process of adaptation associated with the state of immobilization in animals and, perhaps, in part, with fusacional hypoxia.

To determine the embryotoxic effect of adilinsulfam, 36 pregnant female white rats weighing 180-220 g were used. At the first stage of the research, 2 groups of fertilized females, 12 heads each, were selected. The rats of the first group during the entire pregnancy were included in the diet of minced meat, in which the substance (powder) of adilinsulfam was added in advance at the rate of 40 mg/kg of the rat's weight. This dose exceeds 10 times the lethal dose of the drug, equal to 4 mg / kg when administered intramuscularly. This excess was made to determine the safety margin factor. For comparison, the second group of experimental rats was given adilinsulfam 12 mg/kg with food as an alternative intermediate dose, also exceeding the lethal dose, but only 3 times. During the entire period of pregnancy, rats of the control group also received the same minced meat in equal amounts, but without the addition of the drug, throughout the entire pregnancy.

These results show that pregnant rats tolerated the introduction of the study drug with food, in all groups it did not adversely affect the duration of pregnancy and body weight (p 0.5).

To take into account the consequences of the introduction of the muscle relaxant and its effect on the embryos, on the 21st day of pregnancy, the rats were decapitated under light ether anesthesia, the abdominal cavity was opened, and the embryos were removed for further studies.

Further, in accordance with the accepted methodology, the number of implantation sites, resorption sites, the number of live and dead fetuses and corpus luteum in the ovaries, indicators of pre-implantation, post-implantation embryo death and total embryonic mortality were counted.

The analysis of the conducted studies showed that the administration of adilinsulfam to pregnant animals at a calculated dose of 40 and 12 mg/kg daily for 20 days did not adversely affect their clinical condition, but increased the pre-implantation and, accordingly, the overall mortality of embryos, although not statistically significant ( p 0.05). Significant individual fluctuations in indicators allow us to speak only of a pronounced trend. In addition, in the 1st group of animals - at the level of the calculated dose of 40 mg / kg when fed daily with food to pregnant female rats, signs of embryotoxicity were revealed in the form of a decrease in the number of live fetuses compared to the control group, respectively, 6.6 and 8, 6 (p 0.05).

Further, in order to detect teratogenic effects in accordance with the method described in Section 3 using the Wilson-method and the development of the skeleton according to the Dawson method under a binocular magnifier, we studied the internal organs of embryos obtained from pregnant female rats treated with minced meat during the entire period of pregnancy deliberately high doses of adilinsulfam 40 and 12 mg/kg.When teratogenicity was detected, an external examination of the embryos did not reveal anomalies in the eyes, facial skull, limbs, tail and anterior abdominal wall.As a result of comparing the sections of the fetuses of the control and 2 experimental groups, no significant From this we can conclude that adilinsulfam powder, when included in the diet of pregnant rats with minced meat at the rate of 40 and 12 mg/kg, did not cause a teratogenic effect.

As a result of the study of embryos, it was found that the topography of bone and cartilage anlages in the skeleton is not disturbed. The number of cervical, dorsal, and lumbar vertebrae in the control and experimental groups is normal. In the fetuses of both groups, there were no abnormalities in the ossification of the bones of the skull, shoulder, pelvic girdle and limbs, as well as quantitative deviations in the structure of the skeleton.

Sterility and pyrogenicity test of adilinsulfam preparation

Next, the preparations were checked for sterility according to the accepted method (State Pharmacopoeia XI). In separate containers, aqueous solutions were prepared from the drug substance. A solution was taken from them, in an amount corresponding to 200 mg of the drug in a flask with 100 ml of sterile water. The prepared solutions were filtered and placed into flasks with thioglycol medium and Sabouraud's medium. The crops were examined in scattered light daily until the end of the accepted incubation period: for Sabouraud medium - 72 hours, for thioglycol medium - 48 hours. When examining containers with nutrient media exposed to the drug at the indicated concentration, no appearance of turbidity, film, sediment, or other macroscopic changes indicating the growth of microorganisms was found. Therefore, adilinsulfam satisfies the requirements for sterility.

When evaluating the quality of medicines, an important role is given to the results of pyrogenicity testing - one of the main indicators of drug safety. All medicinal products for parenteral use with a single dose volume of 10 ml or more are subject to a pyrogenicity test. The use of depolarizing muscle relaxants is usually significantly lower than the indicated volume, as a rule, no more than 2-3 ml, even for large animals. This is due to the high efficiency and good solubility of drugs.

The introduction of pyrogenic solutions is especially dangerous, since the pyrogenic reaction depends on the amount of the drug that has entered the body. It is known that sterilization frees the solution from the presence of viable organisms. However, dead cells and their decay products remain in the solutions, which have pyrogenic properties due to lipopolysaccharides present in the bacterial cell wall.

The purpose of this experiment was to determine the possible pyrogenic activity of the drug adilinsulfam. In accordance with the accepted methodology, the test was carried out on healthy rabbits of both sexes weighing 2-2.3 kg, not albinos, contained on a complete diet. The drug was administered intramuscularly at a muscle relaxant dose of 3.1 mg/kg, followed by animal thermometry for 3 hours. Each rabbit was kept in a separate cage in a room with a constant temperature. Experimental rabbits should not lose in body weight for 3 days before testing. Each was measured temperature before giving food. The thermometer was inserted into the rectum to a depth of 7 cm. The initial temperature of the experimental rabbits should be in the range of 38.5-39.5C.

The test preparation was tested on 3 male rabbits. Before the introduction of the solution, each temperature was measured twice with an interval of 30 minutes. Differences in readings did not exceed 0.2C. The muscle relaxant solution was administered 15 minutes after the last temperature measurement.

The drug is considered non-pyrogenic if the sum of temperature increases in 3 rabbits was less than or equal to 1.4C. After the administration of adilinsulfam, the general condition of the rabbits was satisfactory without toxicosis. After 10 minutes, the animals assumed a lateral position, in which they remained for 20 minutes. The results of thermometry showed that with intramuscular administration of adilinsulfam, the sum of the temperature increase was less than 1.4C, which indicates the absence of pyrogenic properties in adilinsulfam.

Many medicinal substances in the usual therapeutic doses and even minimal amounts cause sensitization of the body (Ado A.D., 1957; Alekseeva O.G., 1974). Allergic properties of the drug were studied on rabbits weighing 2.5-3 kg. The effect of adilinsulfam on the mucous membrane of the eyes was determined by a single application of 2 drops of a 50% solution to the conjunctiva of the eyes of rabbits. When applying the solution, the inner corner of the conjunctival sac was pulled back, then the lacrimal canal was pressed for 1 minute. Animals of the control group were instilled with 2 drops of distilled water at room temperature on the conjunctiva of the right eye. The state of the animals was assessed after 5, 30 and 60 minutes and 24 hours after application of the drug, while paying attention to the condition of the eye membrane, swelling, hyperemia, tearing. The behavior of the animal was calm, breathing was slightly quickened, redness of the eye without edema was observed within 30 minutes. After 1 hour, the condition of the animals and the shell of their eyes returned to normal. After 24 hours, there were no signs of irritation or inflammation. After 2 days, a solution of the drug of the same 50% concentration was reapplied to the conjunctiva of the eyes of the same rabbits. The observed effect after 1 hour and the next day was identical to that observed during the initial application, and therefore it was concluded that the drug does not cause an allergic reaction.

Muscle relaxants (Curare-like drugs).
Depending on the peculiarities of their mechanism of action, curare-like muscle relaxants are divided into two main groups:
A. Non-depolarizing (antidepolarizing) muscle relaxants (pa-hicurare). They paralyze neuromuscular transmission due to a decrease in the sensitivity of H-cholinergic receptors to acetylcholine and thereby exclude the possibility of depolarization of the end plate and excitation of the muscle fiber. As a result, muscle tone decreases and paralysis of all skeletal muscles occurs.
The ancestor of this group is tubocurarine.
Pharmacological antagonists of this group are anticholinesterase substances. Inhibiting the activity of cholinesterase, they lead to the accumulation of acetylcholine in the synapse area, which, with increasing concentration, weakens the interaction of curare-like substances with H-cholinergic receptors and restores neuromuscular conduction.
Diplacin Diplacinum.

Release form: 2% solution in 5 ml ampoules.
It greatly lowers the tone of skeletal muscles, inhibits motor activity, and with increasing doses, muscle paralysis and complete immobilization occur (after 7-10 minutes and lasts 35-50 minutes).
Turning off the functions of the respiratory muscles, weakens breathing and turns off voluntary breathing.
It is used in surgical practice for a more complete relaxation of the muscles during operations on the organs of the abdominal and thoracic cavities, for immobilizing wild animals during catching and fixing them.
The antidote is prozerin.
Doses (per 1 kg of weight): IV - cattle 2.5 mg; i / m - to dogs 2.5 - 3 mg.
Tubocurarine chloride Tubocurarine chloride.
White crystalline powder, easily soluble in water.
Release form: 1% solution in ampoules of 1.5 ml (15 mg in 1 ml).
Relaxes the muscles (muscles of the fingers eyes feet neck back, then intercostal muscles and diaphragm).
May cause respiratory arrest, lowering blood pressure. It promotes the release of histamine from tissues and can sometimes cause spasm of the muscles of the bronchi.
It is mainly used in anesthesiology as a muscle relaxant that causes muscle relaxation during surgery (the patient must be transferred to mechanical ventilation.
This group also includes: pipecuronium bromide, atracurium, qualidil, tercuronium, mellictin, etc.

B. Depolarizing drugs (leptocurare) cause muscle relaxation due to the cholinomimetic action associated with the relatively stable depolarization of the H-cholinergic receptors of the end plate, i.e., it acts in the same way as excess amounts of acetylcholine act, which also disrupts the conduction of excitation from the motor nerves to the skeletal muscles.
An excess of acetylcholine in the neuromuscular synapse causes a stable electronegativity of synaptic zones, which first causes fibrillar muscle twitching, and then the motor plate is paralyzed and muscle relaxation occurs - muscle relaxants of a biphasic action.
Dithylin Dithylinum.
White crystalline powder, highly soluble in water. Synthetic drug.
Release form: 2% solution in ampoules of 5 or 10 ml. List A.
The immobilization effect occurs after intravenous administration in 1-2 minutes and lasts 10-30 minutes.
It does not last long, because in the body it is destroyed by choline sterase into choline and succinic acid.
Large doses may cause respiratory arrest.
They are used for surgical interventions, reduction of dislocations, for pre-slaughter immobilization of animals, for adynamia of wild animals during catching and fixing, when working with zoo animals.
Doses IM (per 1 kg of animal weight): cattle 0.1 mg; horses 1 mg; pigs 0.8 mg; sheep 0.6 mg; dogs 0.25 mg; fur seals 1 - 1.2 mg; bears 0.3 - 0.4 mg; wolves 0.1 mg; jackals, foxes 0.075 mg.
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