Muscle relaxants. Minimum alveolar concentration

2.2.2. Inhalational anesthetics and their properties

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

Characteristics of the distribution of anesthetics in the blood

The blood partition coefficient of anesthetics is a measure of the solubility of an inhalational anesthetic. The higher the solubility of the gas, the larger the area it spreads, and the more of this substance enters the body, the higher its partial pressure in the blood. The higher the solubility of the inhalational anesthetic, the slower the stage of induction of anesthesia; accordingly, anesthesia is well controlled and changes in its depth are insignificant. From a practical point of view, it is important that fluorothane or methoxyflurane, in contrast to isoflurane, sevoflurane or desflurane, have greater solubility in the blood. This property determines the slow introduction to sleep, since due to 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 for the anesthetic to reach the level of equilibrium between the partial pressure in the alveoli and its tension in the blood necessary for sleep. For this reason, methoxyflurane and fluorothane have a longer induction phase into anesthesia. The solubility of currently used inhalational anesthetics is in the following sequence:

Characteristics of 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 anesthetic in adipose tissue, respectively, in the brain once equilibrium in distribution has been achieved. The better the lipid solubility of the inhalational anesthetic (i.e., the higher the oil/gas partition coefficient), the lower the concentration of anesthetic required 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 inhalational anesthetic in the alveoli (at the end of expiration) at which 50% of patients do not respond to the skin incision with a motor reaction. The lower the MAC of an inhalational anesthetic, the higher the strength of its action. Regardless of the type of animal, according to the MAC value, anesthetics are usually placed in the following order:

Thus, at equilibrium distribution, more isoflurane is required to maintain anesthesia in the animal than fluorothane or methoxyflurane. The MAC value is reduced (i.e., the patient requires less inhalational anesthetic) with concomitant use of nitrous oxide, tranquilizers or sedatives, analgesics, in older animals and in those with deteriorated general condition, reduced blood volume or severe hypotension, and decreased body temperature . The MAC value increases with the use of drugs that stimulate the central nervous system, with hyperthermia, with stress or pain preceding surgery.

For modern anesthesia, easily evaporating halogen-, chlorine-, fluorine- and bromine-containing anesthetics have found wide use in veterinary medicine. The search for the “ideal” inhalational anesthetic follows the path of improving these particular drugs. Comparative characteristics of sevoflurane, isoflurane and ftorotan are presented in table. 9.

Table 9

Comparative characteristics of sevoflurane, isoflurane and ftorotan

Properties of nitrous oxide N2O (laughing gas)

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

Disadvantages include: Distribution of nitrous oxide into the airspace. In the elimination phase, diffusion hypoxia occurs, i.e., when diffusion in the alveoli, nitrous oxide displaces the rest of the air, which leads to oxygen deficiency. Upon entry, the O 2 fraction decreases.

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

– pneumothorax;

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

– the patient’s state of hypoxia (for example, with a diaphragmatic hernia);

– severe anemia in the patient;

– the patient’s failure to comply with a fasting diet.

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 rapid induction of anesthesia is achieved (double gas effect). Other inhalational anesthetics present in the mixture are “captured” by nitrous oxide and concentrated in the alveolar air.

2.2.3. Muscle relaxants

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

Peripheral muscle relaxants

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

In any case, muscle relaxants can only be used in animals 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 nicotinic-like cholinergic receptors at the motor terminal, depolarizing the postsynaptic membrane through acetylcholine and nicotine. In veterinary anesthesiology, drugs of this group are used, such as atracurium, vecuronium, and pancuronium. A comparative description of the properties of these three medications is given in table. 10.

Table 10

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

When using any peripherally acting muscle relaxant, it is necessary to realize 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 meet 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 contrary to the operation of the breathing apparatus, then the movement of the chest asynchronous to the apparatus is unpleasant for the surgeon and creates a large load on the animal’s blood circulation.

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

Intraocular operations require a central, completely resting position of the eyeball. This can only be achieved by using peripherally acting muscle relaxants.

In situations where it is necessary to be completely confident in 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 more prolonged and persistent depolarization than acetylcholine. This group of drugs includes succinylcholine (ditiline, listenone), which has a quick and short-term effect and does not have a cumulative effect.

After intravenous administration, on average, after 10–20 s, animals show consistent fibrillation of the facial muscles of the neck, limbs, torso, intercostal muscles and diaphragm. In animals with well-developed muscles, these fibrillations manifest themselves in the form of convulsive movements. After another 20 - 40 s, fibrillation stops, complete relaxation of the skeletal muscles occurs and breathing stops - apnea. Complete relaxation of the muscles lasts 3–7 minutes. Then quickly, within 60–90 s, muscle tone is restored and spontaneous breathing is restored.

Centrally acting muscle relaxants

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

Guaifenesin combined in horses and ruminants with ketamine or ultra-short-acting barbiturates, often used at the stage of induction 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 beneficial. When using guaifenesin in concentrations above 5%, there is a risk of hemolysis. The administration of guaifenesin more often leads to the development of thrombophlebitis than the use of all other sedative anesthetics.

Benzodiazepines used in old small animals with deteriorated general condition for preoperative sedation. In healthy animals, benzodiazepines can cause the opposite reaction (for example, dogs become aggressive, the horse can no longer stand) and in such cases are not used. Benzodiazepines are the treatment of choice in animals with epilepsy or other diseases associated with seizures. When seizures cannot be controlled with benzodiazepines, then barbiturates are used.

Thus, the use of muscle relaxants is permissible only against the background of sedatives and hypnotics. After administration of muscle relaxants, artificial ventilation should be started. Breathing compensation should continue until spontaneous breathing is completely restored.

2.2.4. Medicines for analgesia

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

During the preparatory period during 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 at the most traumatic moments of the operation allows for superficial anesthesia, minimizing the inhibitory effect of general anesthetics on the life-supporting systems of the body.

In the postoperative period, the use of analgesics allows animals to be mobilized earlier and thereby prevent the development of respiratory and hemodynamic complications. Observations have shown that, despite general anesthesia, sensitization of pain pathways in the central nervous system occurs. This leads to severe postoperative pain and is referred to as wind up-phenomenon.

To obtain adequate analgesia, it is necessary to take into account that the protective reaction of the animal’s body to damage (nociception) is individual in nature, depending on the location, degree, time of tissue damage, the characteristics of the nervous system, the patient’s education, his emotional state at the time of painful stimulation. The formation of pain syndrome occurs at both the peripheral and central levels of the nervous system.

In order to select an anesthesia option suitable for each specific case, it is necessary to recall the basic principles 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 through 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 transmitted impulses by a specific animal with its individual characteristics and the formation of the sensation of pain.

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

Rice. 3. Mechanism of nociception

Peripheral analgesics:

1) drugs that prevent the formation of inflammatory mediators - “minor” analgesics:

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

– prostaglandinogenesis inhibitors (ketoprofen, ketorolac, diclofenac);

– kininogenesis inhibitors (trasylol, contrical);

2) means for superficial (terminal) local anesthesia:

– lidocaine, dicaine, Hirsch’s mixture, chloroethyl;

3) means for infiltration anesthesia:

– novocaine;

4) means for regional (spinal, epidural, conduction - brainstem, plexus, ganglion) 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 - xylavet, clonidine, detomidine (domosedan), romifidine (sedivet);

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

This division of pain relief agents is quite arbitrary, but justified, since knowledge of the mechanism of action allows one to minimize the side effects of analgesics and, using their advantages, to achieve the most optimal pain relief.

“Minor” and “major” analgesics are classic parenterally administered drugs. α2-agonists and ketamine have analgesic properties. Local anesthetics are also very well suited to interrupt pain impulses, but their use is limited due to the difficulties associated with targeted action and the relatively short duration of action.

“Small” and “large” analgesics

To treat pain, “small” and “major” 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, “minor” analgesics have anti-inflammatory and antipyretic effects, which may be important for symptomatic treatment in the postoperative period.

“Large” analgesics (promedol, butorphanol, etc.) in the first stages of use can eliminate pain of almost any intensity, but with their prolonged 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 analgesia is used, i.e. the combined use of various groups of analgesics. In this way, it is possible to influence different levels of the occurrence and transmission of pain, which is most favorable for the patient.

Modern nonsteroidal anti-inflammatory drugs, classified as “minor analgesics,” are evaluated according to their ability to prevent the formation of inflammatory mediators (serotonin, cyclooxygenase, bradykinin, etc.). Based on their effect on cyclooxygenase (COX), the isoenzyme COX 1 or COX 2 is distinguished. Theoretically, selective COX 2 inhibitors have fewer side effects. However, this is not always the case clinically. For example, if an animal reacts with vomiting or gastrointestinal bleeding to any nonsteroidal anti-inflammatory drug, a trial with an alternative drug should be conducted. Often one patient tolerates a particular drug better, regardless of its COX selectivity. Undesirable side effects are a problem primarily with long-term use of non-steroidal anti-inflammatory drugs. Such side effects include irritation and ulceration in the gastrointestinal tract, bleeding with delayed blood clotting, deterioration of kidney function due to decreased renal blood flow (dangerous in the postoperative period).

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

Acetylsalicylic acid rarely used. Horses (30 – 50 mg/kg orally 2 times a day) to inhibit platelet aggregation, for example, in acute aseptic pododermatitis.

Metamizole (Novaminsulfonsäure) used intravenously or intramuscularly, primarily for horses and production animals; is prescribed in addition to a suitable strong analgesic or antipyretic component due to its good antispasmodic effect. Duration of action is about 4 hours after intravenous administration. This is an ideal remedy for initial pain relief for colic in horses (20 – 30 mg/kg intravenously or intramuscularly), and is also well suited for other species of animals; there is no danger that the pain will be “masked.” It works very well for blockage of the esophagus in cattle and horses. With repeated use, bone marrow function may be suppressed.

Phenylbutazone 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 locomotor system in all types of animals (dogs 10 mg/kg orally 3 times a day, after 3 days the dose is reduced; horses 4 mg/kg orally 2 times a day, after 2 days the dose is halved by 1 week). The analgesic effect of the drug and its therapeutic effect are enhanced when used together with bonharen (see Appendix 12). Not used in cats, as the therapeutic range is very small. Some pony breeds are hypersensitive to the drug.

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

Carprofen (Rimadyl) It is used subcutaneously, intravenously and orally in all types of animals. 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 with carprofen orally. Doses for horses: 0.7 mg/kg intravenously once a day, productive animals 1–2 mg/kg intravenously (expensive), oral administration is also possible.

Meloxicam (Metacam) applied to dogs and cats orally or intravenously, 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 suited for long-term use.

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

Vedaprofen (quadrisol) It is used orally or intravenously in horses and dogs at a dose of 0.5 – 2 mg/kg 2 times a day. Modern anti-inflammatory agent (highly selective COX 2 inhibitor).

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

Narcotic analgesics, their antagonists and synthetic substitutes

Based on their analgesic effect, narcotic analgesics, including morphine and related alkaloids (opiates) and synthetic compounds with opiate-like properties (opioids), are divided into several groups based on their selectivity and the nature of their effect on opiate receptors. Some of them (morphine, promedol, fentanyl, etc.) are “pure” (full) agonists, that is, by 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 mixed action - agonist-antagonists (pentazocine, butorphanol). The fourth group consists of partial agonists (buprenorphine). So far, 5 different opioid receptors have been identified. Their properties are presented in table. eleven.

Table 11

Classification of opioid receptors

A high density of these 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 an emetic effect, then an antiemetic; the tone of the sphincters of the urinary and gallbladder increases; stimulation of the vagus nerve: peripheral vasodilation, bradycardia; antitussive effect; often at first increased bowel movements, 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. For severe respiratory depression caused by agonist overdose, agonist-antagonists or partial agonists can be used. Thanks to this, breathing returns to normal while maintaining analgesia.

Different animal species may respond differently to the same opioid, possibly due to different receptor distributions. Before a veterinarian uses an opioid, he must become thoroughly familiar with the specific effects and side effects of the drug on a particular type of animal.

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

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 use can be replaced by motor excitement. This limits the possibility of its long-term use. Morphine stimulates the parasympathetic system, which manifests itself in the inhibition of heart contractions and increased tone of smooth muscles and sphincters. This explains the slowdown in the evacuation of food masses from the stomach and difficulty urinating. When monitoring anesthesia, it must be remembered that constriction of the pupils may depend not only on the depth of anesthesia, but also on the effect of morphine. Characteristic of morphine is depression of the respiratory center.

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

In combination with barbiturates during the administration phase of general anesthesia, serious respiratory depression is possible. During surgery, morphine can be used in small doses to deepen anesthesia, prevent shock, and potentiate the effect 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, histamine release is possible after intravenous administration, so it is used intramuscularly or subcutaneously;

– excitement is possible, 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;

– initially defecation, followed by constipation;

– passing 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 ventilation.

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

Promedol (trimeperidine) 5–6 times less active than morphine when administered via various routes. It has pharmacokinetics similar to morphine, but has a much weaker respiratory depressant effect. The absence of a spasmogenic effect reduces the possibility of urinary retention and gas in the intestines in the postoperative period. Widely used in anesthesiological practice. For premedication, 0.1–0.3 mg/kg of animal weight is administered subcutaneously or intramuscularly along with atropine (0.01 mg/kg) 30–40 minutes before surgery. For emergency premedication, drugs are injected into a vein. During surgery, the administration of fractional doses of promedol of 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 animal has restored spontaneous breathing. The drug is administered subcutaneously, intramuscularly or orally in doses of 0.2 – 0.4 mg/kg.

Promedol can be considered as a drug of choice for pain relief in obstetrics. It gives some birth-stimulating effect and has a beneficial effect on blood circulation in the uterus. To relieve labor pain, 0.5–1 ml of a 1% solution is injected subcutaneously if the condition of the fetus is satisfactory.

When working with promedol, you must have a breathing apparatus at the ready.

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

MUSCLE RELAXANTS(Greek mys, my muscle + lat. relaxare weaken, soften; syn. muscle relaxants) - drugs that reduce the tone of skeletal muscles and, therefore, cause a decrease in motor activity up to complete immobility.

There are M. of central and peripheral types of action.

K M. peripheral action include curare-like substances (see), which cause relaxation of skeletal muscles due to the blockade of neuromuscular transmission (see Synapse). In accordance with the nature of the effect on neuromuscular transmission, drugs of this group include substances of depolarizing (ditilin, etc.), non-depolarizing (tubocurarine, diplacin, qualidil, etc.) and mixed (dioxonium, etc.) types of action. In addition, peripherally acting M can include 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. Unlike curare-like drugs, such compounds inhibit the direct excitability of skeletal muscles and do not affect neuromuscular transmission. Thus, these substances can be considered as peripheral M. of direct myotropic action.

Drugs in this group include dantrolene (Dantrolene; 1 -[(5-arylfurfurylidene) amino]-hydantoin), which is used in honey. practice ch. arr. in the form of sodium salt (Dantrolene sodium; synonym Dantrium). Along with muscle relaxation, dantrolene has a certain 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 varies (the muscles of the limbs are more sensitive to its action than the respiratory muscles). The drug is satisfactorily absorbed through various routes of administration, including from the gastrointestinal tract. tract, is slowly metabolized in the liver and excreted by the kidneys mainly in the form of inactive metabolites and partly unchanged. Its half-life from the body is approx. 9 o'clock

K M. central action referred to as mianesin-like (mephenesin-like) substances, which in their properties and mechanism of muscle-relaxing action are close to miansin (mephenesin) - the first drug of this group introduced into honey. practice. According to chemistry 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 chemicals. structure - orphenadrine, etc. Mydocalm also has the properties of central action.

In the experiment, centrally acting drugs reduce the spontaneous motor activity of animals and reduce muscle tone. In very high doses they cause flaccid paralysis of skeletal muscles and apnea due to relaxation of the respiratory muscles. In subparalytic doses, M. of central action eliminates the phenomena of decerebrate rigidity and hyperreflexia in animals, and weakens convulsions caused by strychnine and electric current. In addition, most centrally acting drugs have sedatives, and some drugs (eg, benzodiazepines, meprotane) have tranquilizing properties and the ability to potentiate the effect of hypnotics and analgesics.

In contrast to peripherally acting M., central M., even in sublethal doses, have virtually no effect on neuromuscular transmission or direct excitability of skeletal muscles. The mechanism of the muscle-relaxing effect of drugs in this group is due to their inhibitory effect on the synaptic transmission of excitation in the central nervous system. n. With. A common property of central M. is the ability to suppress the activity of interneurons of polysynaptic reflex pathways of the spinal cord and certain overlying parts of c. n. With. In this regard, centrally acting drugs actively inhibit polysynaptic reflexes and do not significantly affect monosynaptic reflexes. The suppression of descending inhibitory and facilitatory influences from a number of suprasegmental structures (reticular formation, subcortical nuclei) on the motor centers of the spinal cord also has a certain significance in the mechanism of action of central muscles.

M. is used in various fields of medicine. practices to reduce the tone of skeletal muscles. In this case, the choice of drugs for a particular purpose is carried out taking into account the breadth of their myoparalytic action. Thus, the vast majority of curare-like substances of depolarizing, non-depolarizing and mixed types of action, having a small breadth of myoparalytic action, are used for the purpose of total muscle relaxation. 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 - melliktin (see) and others - 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 neurol practice, for example, they are used for spastic conditions of various origins (cerebral and spinal palsy, Little's disease, spastic torticollis, etc.). M. of central action is also used for muscle contractures of traumatic or inflammatory (for example, rheumatic diseases) origin. The use of drugs of this group for this pathology helps not only to reduce pain in the muscles of the affected area (due to decreased muscle tone), but also allows for more effective rehabilitation of patients, since elimination of contractures facilitates treatment. physical education. In anesthesiol practice, centrally acting M. and dantrolene are used relatively less frequently than curare-like substances, and are used for other indications.

The side effects of M. of central action and dantrolene are manifested by Ch. arr. weakness, drowsiness, dizziness, dyspeptic disorders. Allergic reactions may occur. These drugs should not be prescribed during work to persons whose profession requires precise and rapid mental and motor reactions (transport drivers, etc.).

The use of muscle relaxants in anesthesiology

In anesthesiology, to achieve deep muscle relaxation during surgical interventions, certain diagnostic procedures and artificial ventilation of the lungs, drugs from the group of curare-like substances are used. Depending on the expected duration of the surgical intervention or diagnostic procedure, the selection of individual curare-like drugs is made taking into account the duration of their action. Thus, for short-term (within a few minutes) muscle relaxation (during 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, ditilin (see), tubocurarine (see), anatruxonium (see), pavulon, etc.; drugs with a long duration of action are used. arr. to maintain long-term muscle relaxation during operations under anesthesia with controlled breathing, during artificial ventilation, complex and lengthy diagnostic procedures. Ditilin can be used to achieve long-term muscle relaxation only if it is administered in a fractional manner or by drip infusion. Using curare-like drugs, you can cause a total or partial block of neuromuscular transmission. Total blockade is used during long operations that require deep muscle relaxation and are usually performed under 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 skeletal muscles is carried out by administering small doses of curare-like drugs. The most convenient drugs for this purpose are non-depolarizing drugs.

Due to the preservation of spontaneous breathing, surgical interventions in this case can be performed under mask anesthesia, subject to careful monitoring of the state of gas exchange and a willingness to compensate for violations with auxiliary or artificial ventilation (see Artificial respiration). The technique of conducting total muscle relaxation during anesthesia, carried out using special masks (see Mask for anesthesia) without tracheal intubation, has not become widespread.

When using curare-like drugs in combination, it should be remembered that the administration of a usual dose of non-depolarizing substances (eg, tubocurarine) after repeated injections of ditilin causes a deeper and more prolonged neuromuscular block than under normal conditions. Repeated administration of ditilin after the use of non-depolarizing drugs in usual doses following short-term antagonism leads to a deepening of the neuromuscular block of the competitive type and a prolongation of the period of restoration of muscle tone and respiration. To assess the nature of the neuromuscular blockade caused by curare-like drugs, the electromyography method 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 facilitation of neuromuscular transmission and muscle fasciculations, a pronounced pessimum in the frequency of stimulation and the phenomenon of post-tetanic relief. Depolarizing (biphasic) neuromuscular block is characterized by transient relief of neuromuscular transmission, accompanied by muscle fasciculations, and rapid subsequent development of the neuromuscular block. In the first phase, the amplitude of a single muscle action potential is reduced, tetanus is stable, and the phenomenon of post-tetanic relief is absent. In the second phase, more or less pronounced pessimum of the frequency of stimulation and the phenomenon of post-tetanic facilitation of neuromuscular transmission are revealed. Electromyographic signs of the second phase are noted already with the first administration of ditilin 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 gravis poses a particular problem. Patients with myasthenia gravis (see) are extremely sensitive to depolarizing drugs. Administration of a standard dose of ditilin to them leads to the development of a biphasic 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 recovery of breathing and muscle tone. In the surgical treatment of myasthenia gravis, the autocurarization technique has become widespread, which consists of reducing the dose or discontinuing anticholinesterase drugs before surgery, using a minimum dose of ditilin during intubation and hyperventilation during surgery, which allows one to avoid repeated administrations of this drug or limit it to its minimum doses.

There are no absolute contraindications to the use of curare-like drugs, however, for certain diseases, certain drugs of this group may be contraindicated. Therefore, a rational and informed choice of curare-like drugs, taking into account the nature of the underlying and concomitant diseases, is of great importance. Thus, in patients with renal failure, disturbances of water-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 common reason for the unusually long action of ditilin is a decrease in the activity of pseudocholinesterase, the enzyme that hydrolyzes this drug (with genetic defects of the enzyme, liver diseases, malignant neoplasms, chronic diseases, suppurative processes, bleeding, exhaustion). It is undesirable to use ditilin during eye surgery and in patients with increased intracranial pressure due to its ability to increase intraocular and intracranial pressure. The use of ditilin is also dangerous in persons with extensive burns, paraplegia, and prolonged immobilization.

Complications when using curare-like drugs are largely determined by the irrational choice of drugs for a given patient, as well as the use of drugs without taking into account the nature of their interactions with each other and with drugs from other groups of drugs. The most common complication when using curare-like drugs in anesthesiology is prolonged apnea - an unusually long-term depression of breathing and muscle tone after using a medium dose of the drug. After the administration of competitive drugs, as well as dioxonium, prolonged apnea can develop in patients with renal failure, acidosis, water-electrolyte imbalance, hypovolemia and as a result of the potentiating effect of certain drugs (general and local anesthetics, ganglion blockers, quinidine, diphenine, beta - adrenergic blockers). Repeated injections of dithiline preceding the administration of tubocurarine may also contribute to the development of prolonged apnea. The myoparalytic effect of ditilin is clearly potentiated by anticholinesterase drugs, propanidide, aminazine, cytostatics (cyclophosphamide, sarcolysine), and trasylol. In addition, the cause of delayed recovery of breathing and muscle tone after the use of ditilin can be hypercapnia (see) and respiratory acidosis (see). For decurarization, anticholinesterase agents (prozerin, galantamine, etc.) are widely used, blocking cholinesterase and thereby promoting the accumulation of acetylcholine at neuromuscular synapses, which leads to easier neuromuscular transmission, normalization of breathing and muscle tone. It is also possible to use drugs that increase the synthesis and release of acetylcholine at neuromuscular synapses (Jermin, pimadine and less effective hydrocortisone, calcium pantothenate).

A serious, although relatively rare, complication associated with the use of curare-like substances is recurarization. Recurarization is understood as the deepening of residual muscle relaxation up to apnea or sudden 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. Such factors include respiratory and metabolic acidosis, water-electrolyte imbalance, hypovolemia, arterial hypotension, exposure to certain drugs (antibiotics from the group of aminoglycosides, quinidine, trasylol, cyclophosphamide), inadequate decurarization with anticholinesterase drugs at the end of the operation.

After the administration of ditilin and, to a lesser extent, dioxonium, noticeable amounts of potassium are released from skeletal muscles into the extracellular fluid, as a result of which transient bradycardia often develops, less often - atrioventricular block, and very rarely - asystole (the last two complications are described only after the use of ditilin).

Tubocurarine and qualidil have the ability to release histamine, resulting in transient tachycardia, which usually does not require special treatment. Rare complications associated with the use of tubocurarine and other curare-like substances with non-depolarizing action include the so-called. proserine-resistant curarization. Typically, the reason for the ineffectiveness of anticholinesterase drugs used for the purpose of decurarization is their administration against the background of a very deep block of neuromuscular transmission or against the background of metabolic acidosis. Cases of proserine-resistant curarization have been described after the use of an average dose of tubocurarine against the background of repeated prior administration of dithiline.

Treatment of complications: providing adequate artificial ventilation until restoration of normal muscle tone and eliminating the cause of the complication.

In anesthesiology, M. is also used for other indications. Thus, M. of central action, which have a pronounced tranquilizing effect, for example, diazepam, meprotane, can be used as premedication before anesthesia (see). Mydocalm is used during electroanesthesia (see). Diazepam in combination with the narcotic analgesic fentanyl is used for so-called purposes. ataralgesia (balanced anesthesia) during certain surgical interventions. In addition, centrally acting M. is sometimes used to suppress muscle tremors and reduce heat production during hyperthermic syndrome (see). Dantrolene also has the ability to relieve the manifestations of this syndrome, which sometimes occurs after the use of inhalational anesthetics (eg, fluorotane) and ditilin.

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, there are often situations when it is necessary to relax muscle fibers. For these purposes, those introduced into the body are used, neuromuscular impulses are blocked, and the striated muscles relax.

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

Mechanism of action of drugs

When severe pain occurs in the muscles, a spasm may occur, which ultimately limits movement in the joints, 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, treatment is extended indefinitely.

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

Considering the properties of muscle relaxants, we can say that they find their use at any stage of the treatment of osteochondrosis. The following procedures are more effective when using them:

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

If you often experience or suffer from osteochondrosis, then you should not prescribe muscle relaxants for yourself; 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 viewed from different points of view. If we talk about what muscle relaxants there are, there are different classifications. Analyzing the mechanism of action on the human body, we can distinguish only two types:

1. Peripheral acting drugs.
2. Central muscle relaxants.

Medicines can have effects of varying duration, depending on this they are distinguished:

• Ultra-short action.
• Short.
• Average.
• Long lasting.

Only a doctor can know exactly which drug is best for you in each specific 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, during convulsions, during paralysis during tetanus.

Muscle relaxants, peripherally acting drugs, can be divided into the following groups:

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

Centrally acting drugs

Muscle relaxants in this group can also be divided into the following types, taking into account their chemical composition:

1. Glycerol derivatives. These are Meprotan, Prenderol, Isoprotan.
2. Based on benzimidazole - "Flexin".
3. Mixed drugs, for example "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 medications not only relax, but have a broader effect, which is why they are used in the treatment of various diseases that are accompanied by increased muscle tone.

These muscle relaxants have virtually no effect on monosynaptic reflexes, so they can be used for relief without stopping natural breathing.

If you are prescribed muscle relaxants (drugs), you may come across the following names:

• "Metacarbamol".
• "Baclofen."
• "Tolperisone".
• "Tizanidine" and others.

It is better to start taking medications 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 only be used when the patient is unconscious.
2. The use of such drugs significantly facilitates artificial ventilation.
3. Removing is not the most important thing, the main task is to carry out comprehensive measures to carry out gas exchange and maintain blood circulation.
4. If muscle relaxants are used during anesthesia, this does not exclude the use of anesthetics.

When drugs from this group became firmly established in medicine, we could safely talk about the beginning of a new era in anesthesiology. Their use made it possible to simultaneously solve several problems:

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

Area of ​​application of muscle relaxants

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

1. In the treatment of neurological diseases that are accompanied by increased tone.
2. If you use muscle relaxants (drugs), the lower back pain will also subside.
3. Before surgery in the abdominal cavity.
4. During complex diagnostic procedures for certain diseases.
5. During electroconvulsive therapy.
6. When performing anesthesiology without stopping natural breathing.
7. To prevent 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 uses for 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 may occur when taking these medications. Some are possible, but there are also more serious ones, among them it is worth noting the following:

• Decreased concentration, which is most dangerous for people driving a car.
• Decreased blood pressure.
• Increased nervous excitability.
• Bed-wetting.
• Allergic manifestations.
• Problems with the gastrointestinal tract.
• Convulsive states.

Especially often, all these manifestations can be diagnosed with the wrong dosage of drugs. This is especially true for anti-depolarizing 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 normalizes, and the use of medications to eliminate symptoms is not required.

You should be careful when taking muscle relaxants (drugs) whose names are unfamiliar to you. In this case, it is better to consult a doctor.

Contraindications for use

You should start taking any medications 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 for 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. Peptic 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 cause further harm to your health and start taking them at your own peril and risk.

Requirements for muscle relaxants

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

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

As a result of taking the drug, not only muscle tension is reduced, but its vasodilating effect is also observed. This is perhaps the only medicine 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 back pain, to which we try not to react. But there comes a time when the pain can no longer be ignored.

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

Since one of the symptoms of osteochondrosis is muscle spasm, it makes sense to talk about using 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 side effects, if any, can be immediately identified and a different medicine can be prescribed.

Almost all drugs are produced not only in the form of tablets, but there are also injections. Most often, in case of severe spasm and severe pain, the second form is prescribed for emergency assistance, that is, in the form of injections. The active substance penetrates 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, necessarily in combination with physiotherapeutic procedures, therapeutic exercises, and massage.

Despite their high effectiveness, you should not take these drugs without first consulting your doctor. You cannot independently determine which medicine is suitable for your case and will bring greater effect.

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

480 rub. | 150 UAH | $7.5 ", MOUSEOFF, FGCOLOR, "#FFFFCC",BGCOLOR, "#393939");" onMouseOut="return nd();"> Dissertation - 480 RUR, delivery 10 minutes, around the clock, seven days a week and holidays

Larina Yulia Vadimovna. Pharmaco-toxicological assessment of the muscle relaxant adilinsulfame: dissertation... Candidate of Biological Sciences: 16.00.04 / Larina Yulia 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 the use of muscle relaxants 9

2.2 Classification of muscle relaxants by 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 our own research

4.1 Determination of acute toxicity of adilinsulfame and features of the manifestation of muscle relaxation in different animal species 42

4.2 Determination of the cumulative properties of adilinsulfame 47

4.3 Effect of adilinsulfame on morphological and biochemical blood parameters 49

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

4.5 Assessing the harmlessness of meat obtained from animals killed with adilin sulfame 56

4.6 Risk assessment of temporary immobilization of pregnant females 60

4.7 Determination of drug stability during storage 65

4.8 Testing the drug adilinsulfame for sterility and pyrogenicity 66

4.9 Test for allergic and irritant properties of adilinsulfame 68

4.10 Development of a method for indicating adilin sulfame in solutions, organs and tissues of animals 69

4.11 Development of the dosage form of adilinsulfame 74

4.12 Screening for potential antagonists 76

5. Discussion of results 90

References 101

Applications 120

Introduction to the work

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

In our country, the use of ditilin, obtained in 1958, which is a depolarizing muscle relaxant, has long been known to immobilize animals (Kharkevich D. A., 1989). Drugs in this group initially cause activation of H-cholinergic receptors, which results in persistent depolarization of the postsynaptic membrane, followed by relaxation of skeletal muscles.

Currently, the use of ditilin in livestock farming is difficult due to the complexity of its acquisition and production, since for this it is necessary to import the starting reagent - methyl chloride. It has some side effects when used for temporary immobilization of animals, namely: small breadth of myoparalytic action - safety factor; and, in addition, in large quantities the drug has limited solubility in water, which makes it difficult to use on large animals and at low temperatures (Sergeev P.V., 1993; Tsarev A., 2002).

In recent years, publications have appeared on new muscle relaxants - pyrocurine and amidokurine, which have a significantly greater “breadth of muscle relaxant action” compared to the previously known and used d-tubocurarine, ditilin 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 availability.

Also in veterinary practice, xylazine has become widespread, which, according to its mechanism of action, is an alpha2-adrenergic receptor agonist and, according to some data (Sagner G., Haas G., 1999), causes a sleep-like state in animals, i.e. as if allowing them to awaken. However, it is precisely the prolonged awakening, as well as the absence of antagonists, that is often indicated as a disadvantage of formulations based on both xylazine and its later analogues from among the alpha-adrenoreceptor agonists - detomidine and medetomidine (Jalanka N.N., The cited literature data indicate the need for improvement veterinary medicine intended for temporary and pre-slaughter immobilization of animals.Factors of efficiency, reliability, cost-effectiveness, and accessibility in the practice of their use are currently acquiring decisive importance.

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

The Federal State Institution "FCTRB-VNIVI" has accumulated experience in temporary immobilization and slaughter of animals using depolarizing muscle relaxants - ditilin and its structural analogue adilin.

A new muscle relaxant of the same group, adilinsulfame, was synthesized by R.D. Gareev and co-authors as a more technologically advanced, cheaper and stable analogue of dithiline and adiline.

Purpose of the study: pharmacological and toxicological assessment of adilin sulfame 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:
. determine the parameters of acute toxicity and specific muscle relaxant activity of adilin sulfame for different animal species;
. assess the safety of adilinsulfame, including oral toxicity and long-term effects (embryotoxicity, teratogenicity, postnatal development, etc.) in laboratory animals according to accepted criteria;
. study the stability of the drug during storage, its pharmacodynamics and pharmacokinetics in animals;
. Based on the research results, develop draft regulatory documentation and instructions for the use of adilinsulfame in veterinary medicine.

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

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

The experimental data obtained were used in the preparation of draft regulatory documents: laboratory regulations, technical specifications and instructions for use of the drug, which will be submitted for state registration of adilinsulfame. Main provisions submitted for defense: pharmacological and toxicological characteristics of adilinsulfame as a veterinary medicine; the use of adilinsulfame for temporary, pre-slaughter immobilization and bloodless euthanasia of animals;
. substantiation of the safety and technology of using adilinsulfame 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 “FCTRBVNIVI” 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 "Current problems of veterinary medicine", Kazan - 2007, "First Congress of Veterinary Pharmacologists of Russia", Voronezh - 2007, scientific and practical conference of young scientists and specialists "Achievements of young scientists - into production" , Kazan - 2008

Scope 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, and a 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 by mechanism of action

Based on the localization of action of muscle relaxants, they are usually divided into two groups: central and peripheral. Some tranquilizers are often classified as central: 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, ditilin, decamethonium, etc.) are divided according to their mechanism of action. Curare-like drugs are characterized by the fact that they block neuromuscular transmission, while myanesin-like drugs reduce muscle tone due to disruption of excitation in the central nervous system. These substances act like the natural transmitter of nerve impulses, acetylcholine, at the junction of nerve and muscle - the so-called end plate of the synapse. Entering with the blood flow into this place after parenteral administration, they, unlike acetylcholine, either prevent depolarization of the plate and thereby disrupt nerve conduction, 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 in the chest and in the area of ​​the abdominal muscles (Zhulenko V.N., 1967).

In surgical practice during operations of the abdominal cavity, 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: according to 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 interfere with the depolarizing effect of acetylcholine. The second - substances of the succinylcholine group cause depolarization of the postsynaptic membrane and thereby cause a 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 conduction blockade when introducing relaxants is not fundamentally different (Francois Sh., 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 the 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 to acetylcholine, which usually promotes stimulation (stimulation), and in higher doses, blockade of the neuromuscular junction, whether in skeletal muscle or smooth muscle of internal organs. A classic example of such a dual effect on cholinergic receptors, depending on the dose/concentration, is the well-known nicotine (Kharkevich D.A., 1981; Mashkovsky M.D., 1998).

With regard to ditilin and other depolarizing muscle relaxants, it should be noted that when they are administered, as muscle relaxation intensifies, the paralytic effect progresses - the muscles of the neck and limbs are consistently involved, and 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 to only 25% (Unna K.R., Pelican E.W., 1950).

Based on the sequence of involvement of skeletal muscle in relaxation, it has been postulated that depolarizing muscle relaxants, in particular decamethonium (DC), are different from d-tubocurarine, which is an antidepolarizing muscle relaxant. 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 SY causes muscle relaxation in doses that “spare” the respiratory muscles.

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

According to this classification, muscle relaxants belong to drugs that mainly affect efferent innervation, namely, the transmission of excitation in N-cholinergic synapses (Kharkevich D.A., 1981, 2001; Subbotin V.M., 2004). Motor neurons innervating striated muscles are H-cholinergic. Depending on the dose of substances, different degrees of effect can be observed - from a slight decrease in motor activity to complete relaxation (paralysis) of all muscles and cessation of breathing.

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

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 immobilizing wild and domestic animals. Immobilization of animals by pharmacological means is based on their loss of motor activity for a certain period of time, which allows them to safely work and restrain animals when providing them with any assistance, including medical assistance (Koelle G.B., 1971; Magda I.I., 1974; Kharkevich D.A., 1983).

D-tubocurarine, dimethyltubocurarine, tri-(diethylaminoethoxy)-benzyl-triethyl iodide (flaxedil), nicotine salicylate and succinylcholine chloride were used as alternative means for temporary immobilization of animals in different years and with different results (Jalanka N., 1991) . The therapeutic index when using these drugs was small, inhalation (aspiration) of stomach contents and respiratory arrest often occurred, and the mortality rate was very high. The differences in results, as assessed by different authors, were partly attributed to inaccurate dosing and imperfect administration techniques using metal or plastic darts filled with a drug, often dissolved in a glucose solution (Warner D., 1998).

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

Side effects occupy an important place when evaluating curare-like drugs. In principle, muscle relaxants should be highly selective and not cause side effects. But depolarizing muscle relaxants, including ditilin, are characterized by adverse effects due to their mechanism of action (Smith7 S.E. 1976). In addition to the selective effect on neuromuscular transmission, curare-like drugs can cause side effects associated with the release of histamine, inhibition of the autonomic ganglia, stimulation 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 the ganglion-blocking or anticholinesterase properties of the 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. back in 1961 he mentioned 1-amphetamine (phenamine) as their antagonist. For some reason these studies were not further developed or were not confirmed. It is possible that an obstacle to detailed study and implementation of this potential antidote was the fact that, along with LSD, 1-amphetamine was classified as a “drug”, as a substance that causes drug addiction.

Currently, the problem of introducing new muscle relaxants into the practice of temporary immobilization of animals remains relevant. According to experts from the State Hunting Control, the risk of accidental death of animals when using known means of immobilization, incl. ditilin, 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 administer large quantities of their solutions, as well as the difficulty of using them at low temperatures, since in this case they precipitate ( Sergeev P.V., 1993).

In recent years, publications have appeared on new muscle relaxants - pyrocurine and amidokurine, which have a significantly greater “breadth of muscle relaxant action” compared to the previously known and used d-tubocurarine, ditilin 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 availability.

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

Determination of the cumulative properties of adilinsulfame

Cumulation is usually understood as an increase in the effect of a substance upon repeated exposure. Determining the cumulative effect is necessary for the correct choice of safety factor, since cumulation processes underlie chronic poisoning (Sanotsky I.V. 1970).

When determining cumulative properties using the Kagan formula, Yu.S. and Stankevich V.V. (1964) rats were intramuscularly administered adilinsulfame, starting with its optimal muscle relaxant dose - 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 sensitivity of rats of both sexes weighing 120-180 g with repeated daily intramuscular administration of adilin sulfame (n=4)

According to the results obtained, with repeated daily administration of adilin sulfame, 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. LD5o in this experiment was calculated by probit analysis (Mukanov R.A., 2005) and it amounted to 23.1 mg/kg. Quantitative assessment of the cumulative effect, the cumulation coefficient was calculated using the formula of Kagan Yu.S. 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 exhibit functional accumulation, and secondly, it stimulates the systems that metabolize it. 4.3 Effect of adilinsulfame on morphological and biochemical blood parameters

Assessing the effect of a drug intended for use as a medicine on hematological parameters is one of the standard methods for determining its safety. This study was conducted on 10 white rats weighing 180-200g. Rats were injected intramuscularly with a single dose of adilin sulfame at a dose of LD5o- After 1; 3; 7 and 24 hours after administration, blood was taken from the heart of 6 surviving animals with a syringe for research. 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 decreases 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, by the 7th hour one can notice a tendency towards normalization of the indicators, and by 24 hours - their complete return to the original values. Consequently, the noted changes were temporary, transient in nature, and apparently they indicate a reversible adaptation process associated with the state of immobilization in animals and, perhaps, in part, with physical hypoxia.

To determine the embryotoxic effect of adilinsulfame, 36 pregnant female white rats weighing 180-220 g were used. At the first stage of the research, 2 groups of fertilized females of 12 animals each were selected. Throughout pregnancy, the rats of the first group were included in the diet with minced meat, to which the substance (powder) of adilinsulfame was added in advance at the rate of 40 mg/kg of rat weight. This dose is 10 times higher than 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 administered 12 mg/kg of adilin sulfame with food as an alternative intermediate dose, also higher than the lethal dose, but only 3 times. Rats in the control group also received the same minced meat in equal quantities throughout pregnancy, but without adding the drug. To identify the possible toxic effect of the drug, the condition and behavior of pregnant females was monitored daily and control weighing was carried out once a week.

The presented results show that pregnant rats tolerated the administration of the study drug with food well; in all groups it did not have a negative effect on the duration of pregnancy and body weight (p 0.5).

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

Next, in accordance with the accepted methodology, the number of implantation sites, resorption sites, the number of live and dead fetuses and corpora lutea in the ovaries, indicators of preimplantation and postimplantation embryo death and general embryonic mortality were calculated.

An analysis of the studies showed that the administration of adilinsulfame to pregnant animals at a calculated dose of 40 and 12 mg/kg daily for 20 days did not have a negative effect on their clinical condition, but increased the rates of preimplantation and, accordingly, 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, 6.6 and 8, respectively. 6 (p 0.05).

Next, to identify teratogenic effects, in accordance with the method described in section 3 using serial sections of the Wilson-Wilson method and skeletal development using the Dawson method under a binocular magnifying glass, we studied the internal organs of embryos obtained from pregnant female rats fed with minced meat throughout pregnancy obviously high doses of adilinsulfame 40 and 12 mg/kg. When teratogenicity was detected, an external examination of the embryos did not reveal any abnormalities in the eyes, facial skull, limbs, tail and anterior abdominal wall. As a result of comparing sections of fetuses from the control and 2 experimental groups, no significant abnormalities of internal organs. From this we can conclude that adilinsulfame powder, when included in the diet of pregnant rats with minced meat at a 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 cartilaginous anlages in the skeleton is not disturbed. The number of cervical, dorsal, and lumbar vertebrae in the control and experimental groups corresponds to the norm. In the fetuses of both groups, disturbances 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, were not established.

Testing the drug adilinsulfame for sterility and pyrogenicity

Next, the preparation was checked for sterility according to the accepted method (State Pharmacopoeia XI). Aqueous solutions of the drug substance were prepared in separate containers. From them, a solution was taken in an amount corresponding to 200 mg of the drug into a 100 ml flask with sterile water. The prepared solutions were filtered and placed in flasks with thioglycollate medium and Sabouraud medium. The crops were examined in diffuse light daily until the end of the accepted incubation period: for Sabouraud medium - 72 hours, for thioglycollate medium - 48 hours. When examining containers with nutrient media exposed to the drug at the specified concentration, the appearance of turbidity, film, sediment and other macroscopic changes indicating the growth of microorganisms was not detected. Consequently, adilinsulfame satisfies the requirements for sterility.

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

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

The purpose of this experiment was to determine the possible pyrogenic activity of the drug adilinsulfame. In accordance with the accepted methodology, the test was carried out on healthy rabbits of both sexes weighing 2-2.3 kg, not albinos, kept on a nutritious diet. The drug was administered intramuscularly at a muscle relaxant dose of 3.1 mg/kg, followed by thermometry of the animals for 3 hours. Each rabbit was kept in a separate cage in a room with a constant temperature. Experimental rabbits should not lose body weight for 3 days before testing. Each person's temperature was measured before the food was given. 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 drug was tested on 3 male rabbits. Before administering the solution, everyone's temperature was measured twice with an interval of 30 minutes. The 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 administration of adilinsulfame, the general condition of the rabbits was satisfactory without symptoms of 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 adilinsulfame, the amount of temperature increase was less than 1.4 C, which indicates the absence of pyrogenic properties of adilinsulfame.

Many medicinal substances in normal therapeutic doses and even minimal quantities cause sensitization of the body (Ado A.D., 1957; Alekseeva O.G., 1974). The allergic properties of the drug were studied in rabbits weighing 2.5-3 kg. The effect of adilinsulfame 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 nasolacrimal canal was pressed for 1 minute. Animals in the control group received 2 drops of distilled water at room temperature on the conjunctiva of the right eye. The condition of the animals was assessed 5, 30 and 60 minutes and 24 hours after application of the drug, and attention was paid to the condition of the eye shell, swelling, hyperemia, and lacrimation. The animal's behavior was calm, breathing was slightly rapid, and within 30 minutes there was redness of the eye without swelling. After 1 hour, the condition of the animals and the membranes 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 re-applied 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 did not cause an allergic reaction.

Muscle relaxants (Curare-like drugs).
Depending on the characteristics 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 eliminate 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. By inhibiting the activity of cholinesterase, they lead to the accumulation of acetylcholine in the area of ​​synapses, which, with increasing concentration, weakens the interaction of curare-like substances with H-cholinergic receptors and restores neuromuscular conduction.
Diplacinum Diplacinum.

Release form: 2% solution in ampoules of 5 ml.
It greatly reduces the tone of skeletal muscles, inhibits motor activity, and with increasing doses, muscle paralysis and complete immobility occurs (after 7 - 10 minutes and lasts 35 - 50 minutes).
By turning off the functions of the respiratory muscles, it weakens breathing and turns off voluntary breathing.
Used in surgical practice to more completely relax muscles during operations on the abdominal and thoracic cavities, to immobilize wild animals when catching and fixing them.
The antidote is prozerin.
Doses (per 1 kg of weight): intravenously - for cattle 2.5 mg; IM - dogs 2.5 - 3 mg.
Tubocurarine chloride.
White crystalline powder, easily soluble in water.
Release form: 1% solution in ampoules of 1.5 ml (15 mg per 1 ml).
Relaxes the muscles (muscles of the fingers, eyes, legs, neck, back, then the intercostal muscles and the diaphragm).
May cause respiratory arrest and decreased blood pressure. Promotes the release of histamine from tissues and can sometimes cause spasm of the bronchial muscles.
It is used mainly in anesthesiology as a muscle relaxant, causing muscle relaxation during surgery (the patient must be placed on artificial ventilation.
This group also includes: pipecuronium bromide, atracurium, qualidil, tercuronium, melliktin, etc.

B. Depolarizing drugs (leptocurare) cause muscle relaxation due to a cholinomimetic effect associated with a relatively persistent depolarization of the H-cholinergic receptors of the end plate, i.e., it acts in a similar way to how excess amounts of acetylcholine act, which also disrupts the conduction of excitation from motor nerves to skeletal nerves muscles.
An excess of acetylcholine in the neuromuscular synapse causes a stable electronegativity of the synaptic zones, which first causes fibrillar muscle twitching, and then the motor plate is paralyzed and muscle relaxation occurs - biphasic muscle relaxants.
Dithylinum 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 act for long, because in the body it is destroyed by choline sterase into choline and succinic acid.
Large doses may cause respiratory arrest.
Used for surgical interventions, reduction of dislocations, for pre-slaughter immobilization of animals, for adynamy of wild animals when 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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