Muscle relaxants

Muscle relaxants (MP) are drugs that relax the striated muscle (arbitrary) and are used to create an artificial myoplegia in anesthesiology-resuscitation. At the beginning of its use, muscle relaxants were called curare-like drugs. This is due to the fact that the first muscle relaxant - tubocurarine chloride is the main alkaloid tubular curare. The first information about curar penetrated into Europe more than 400 years ago after the return of the Columbus expedition from America, where the American Indians used curare to lubricate the arrowheads during archery. In 1935, King isolated from curare its main natural alkaloid - tubocurarine. For the first time tubocurarine chloride was used in the clinic on January 23, 1942 in the Montreal homeopathic hospital by Dr. Harold Griffith and his resident Enid Johnson during an appendectomy operation to a 20-year-old plumber. This moment was revolutionary for anesthesiology. It was with the advent of the medical devices of muscle relaxants in the arsenal that the surgeons developed rapidly, which allowed it to reach today's heights and conduct surgical interventions on all organs in patients of all ages, beginning with the period of newborn. It was the use of muscle relaxants that made it possible to create the concept of multicomponent anesthesia, which made it possible to maintain a high level of patient safety during surgery and anesthesia. It is commonly believed that it was from this moment on that anesthesiology began to exist as an independent specialty.

There are many differences among muscle relaxants, but in principle they can be grouped according to the mechanism of action, the speed of the onset of the effect, the duration of the action.

Most often, muscle relaxants are divided depending on the mechanism of their action on two large groups: depolarizing and not depolarizing, or competitive.

By origin and chemical structure, nondepolarizing relaxants can be divided into 4 categories:

• natural origin (tubocurarine chloride, metokurin, Alcoronium - currently not used in Russia);
• steroids (pancuronium bromide, vecuronium bromide, pipecuronium bromide, rocuronium bromide);
• benzylisoquinolines (atracurium bezylate, cisatracurium bezylate, miwakuria chloride, doxakuria chloride);
• others (gallamine - currently not applicable).

More than 20 years ago, John Savarese divided the muscle relaxants, depending on the duration of their action on long-acting drugs (the onset of action 4-6 min after injection, the beginning of recovery of the neuromuscular block (NIB) through 40-60 min), the average duration of action (onset of action - 2-3 minutes, the onset of recovery is 20-30 min), short-acting (the onset of action is 1-2 min, recovery after 8-10 min) and ultrashort action (the onset of action is 40-50 sec, recovery in 4-6 min) .

Classification of muscle relaxants according to the mechanism and duration of action:

• depolarizing relaxants:
• ultrashort action (suxamethonium chloride);
• non-depolarizing relaxants:
• short-acting (myvacuria chloride);
• average duration of action (atracurium bezylate, vecuronium bromide, rocuronium bromide, cisatracurium bezylate);
• long-acting (pipecuronium bromide, pancuronium bromide, tubocurarine chloride).

[1], [2], [3], [4], [5],

Muscle relaxants: a place in therapy

At present, it is possible to identify the main indications for the use of MP in anesthesiology (we are not talking about indications for their use in intensive care):

• relief of intubation of the trachea;
• prevention of reflex activity of voluntary muscles during surgery and anesthesia;
• facilitating the implementation of ventilation;
• the possibility of adequate performance of surgical operations (upper abdominal and thoracic), endoscopic procedures (bronchoscopy, laparoscopy, etc.), manipulation of bones and ligaments;
• creation of complete immobilization in microsurgical operations; prevention of trembling with artificial hypothermia;
• reduction in the need for anesthetic agents. The choice of MP largely depends on the period of general anesthesia: induction, maintenance and recovery.

Induction

The rate of onset of the effect and the resulting conditions for intubation are mainly used to determine the choice of MP during induction. It is also necessary to take into account the duration of the procedure and the required depth of myoplegia, as well as the patient's status - anatomical features, the state of the circulation.

Muscle relaxants for induction should have a rapid onset. Suxamethonium chloride in this respect remains unsurpassed, but its use is limited by numerous side effects. In many respects it was replaced by rocuronium bromide - with its use, intubation of the trachea can be carried out at the end of the first minute. Other non-depolarizing muscle relaxants (mitakuriya chloride, vecuronium bromide, atrakury bezilat and cisatrakuria besylate) allow intubating the trachea within 2-3 min, which, with the appropriate induction technique, also provides optimal conditions for safe intubation. The long-acting muscle relaxants (pancuronium bromide and pipecuronium bromide) are not rationally used for intubation.

Maintaining anesthesia

When choosing MP to maintain the block, factors such as the expected duration of the operation and the NMB, its predictability, the technique used for relaxation are important.

The last two factors largely determine the manageability of SGB during anesthesia. The effect of MP does not depend on the mode of administration (infusion or boluses), but with an infusion of medium-duration MP provide smooth myoplegia and predictability of the effect.

The short duration of the action of mitakuriya chloride is used in surgical procedures that require the deactivation of spontaneous breathing for a short period of time (for example, endoscopic operations), especially in outpatient and one-day hospital settings, or in operations where the end of the operation is difficult to predict.

The use of medium-duration MP (vecuronium bromide, rocuronium bromide, atrakury bezylate and cisatracurium bezylate) allows effective myoplegia, especially with their constant infusion in operations of the most varied duration. The use of long-acting MP (tubocurarine chloride, pancuronium bromide and pipecuronium bromide) is justified in long-term operations, and in cases of a known early transition in the postoperative period to prolonged mechanical ventilation.

In patients with impaired liver and kidney function, it is more rational to use muscle relaxants with organ-independent metabolism (atracuria bezilate and cisatracurium bezylate).

Recovery

The recovery period is most dangerous due to the development of complications due to the introduction of MP (residual curarization and recurrence). Most often they occur after using long-acting MP. Thus, the incidence of postoperative pulmonary complications in the same groups of patients with long-acting MP was 16.9% compared with a mean duration of 5.4% of MP. Therefore, the use of the latter is usually accompanied by a more smooth recovery period.

The recurrence associated with carrying out decurarization with neostigmine is also most often required when using long MP. In addition, it should be noted that the use of neostigmine itself can lead to the development of serious side effects.

At the time of using the MP, it is also necessary to take into account the cost of drugs. Without going into the details of the analysis of the pharmacoeconomics of MP and knowing well that not only and not so much the price determines the true costs in the treatment of patients, it should be noted that the price of the ultra-short LS of suxamethonium chloride and MP of long-acting is significantly lower than that of short- and medium-duration muscle relaxants.

In conclusion, we present the recommendations of one of the leading experts in the field of MP research of Dr. J. Viby-Mogensen at the choice of MP:

• intubation of the trachea:
  • suxamethonium chloride;
  • rocuronium bromide;
• procedures of unknown duration:
  •  miwakuria chloride;
• very short procedures (less than 30 min)
  • operations where the use of anticholinesterase drugs should be avoided:
  • miwakuria chloride;
• operations of medium duration (30-60 min):
  • any MP of medium duration;
• long-term operations (more than 60 min):
  • cisatracurium bezylate;
  • one of the MP of average duration of action;
• patients with cardiovascular diseases:
  • vecuronium bromide or cisatracurium bezylate;
• patients with liver and / or kidney disease:
  • cisatracurium bezylate;
  • atracurium bezylate;
• in cases where it is necessary to avoid the release of histamine (for example, with allergies or bronchial asthma):
  • cisatracurium bezylate;
  • vecuronium bromide;
  • rocuronium bromide.

Mechanism of action and pharmacological effects

In order to present the mechanism of action of muscle relaxants, it is necessary to consider the mechanism of neuromuscular conduction (NLM), which was described in detail by Bowman.

A typical motor neuron includes the body of the cell with an easily distinguishable nucleus, many dendrites and a single myelinated axon. Each branch of the axon ends on one muscle fiber, forming a neuromuscular synapse. It is a membrane of the nerve end and muscle fiber (presynaptic membrane and motor end plate with nicotine-sensitive cholinergic receptors), separated by a synaptic gap filled with intercellular fluid, which is close in composition to the blood plasma. The presynaptic terminal membrane is a neurosecretory apparatus, in which the sarcoplasmic vacuoles with a diameter of about 50 nm contain the mediator acetylcholine (AX). In turn, nicotine-sensitive cholinergic receptors of the postsynaptic membrane have a high affinity for ACh.

Choline and acetate are necessary for the synthesis of ACh. They enter the vacuole from the wasting extracellular fluid and are then stored in the mitochondria in the form of acetylcoenzyme-A. Other molecules used for the synthesis and storage of AX are synthesized in the body of the cell and transported to the end of the nerve. The main enzyme that catalyzes the synthesis of AX in the end of the nerve is choline-O-acetyltransferase. Vacuoles are located in triangular arrays, the top of which includes a thickened part of the membrane, known as the active zone. Vacuum discharge points are located on either side of these active zones, aligned exactly along opposite shoulders - curvatures on the postsynaptic membrane. Post-synaptic receptors are concentrated just on these shoulders.

Modern understanding of the physiology of NRM confirms the quantum theory. In response to the incoming nerve impulse, the calcium channels reacting to tension open, and calcium ions quickly enter the nerve end, connecting with calmodulin. The complex of calcium and calmodulin causes the interaction of vesicles with the nerve end-membrane, which in turn leads to the release of AX into the synaptic cleft.

Rapid change of stimulation requires that the nerve increase the amount of ACh (a process known as mobilization). Mobilization includes transportation of choline, synthesis of acetylcoenzyme-A and movement of vacuoles to the place of release. Under normal conditions, nerves are able to mobilize the mediator (in this case - AC) quickly enough to replace the one that was realized as a result of the previous transfer.

The liberated AX crosses the synapse and binds to the holinoretseptors of the postsynaptic membrane. These receptors consist of 5 subunits, 2 of which (a-subunits) are able to bind AX molecules and contain places for its binding. The formation of the AX complex and the receptor leads to conformational changes in the associated specific protein, as a result of which cation channels are opened. Through them ions of sodium and calcium move inside the cell, and the ions of potassium from the cell, there is an electrical potential that is transmitted to the neighboring muscle cell. If this potential exceeds the necessary threshold for the adjacent muscle, an action potential arises that passes through the membrane of the muscle fiber and initiates the contraction process. In this case, the synaptic depolarization occurs.

The action potential of the motor plate extends along the muscle cell membrane and the so-called T-tube system, which opens the sodium channels and releases calcium from the sarcoplasmic reticulum. This liberated calcium causes the interaction of contractile proteins of actin and myosin, and muscle fiber contraction occurs.

The amount of muscle contraction does not depend on the excitation of the nerve and the magnitude of the action potential (being a process known as "all or nothing"), but depends on the number of muscle fibers involved in the contraction process. Under normal conditions, the amount of AX released and postsynaptic receptors significantly exceeds the threshold required for muscle contraction.

AX within a few milliseconds ceases to be due to the destruction of its acetylcholinesterase (it is called a specific, or true, cholinesterase) on choline and acetic acid. Acetylcholinesterase is located in the synaptic cleft in the folds of the postsynaptic membrane and is constantly present in the synapse. After the destruction of the receptor complex with AX and biodegradation of the latter under the influence of acetylcholinesterase, the ion channels are closed, the postsynaptic membrane repolarses and its ability to respond to the next bolus of acetylcholine is restored. In the muscle fiber with the termination of the potential action, the sodium channels in the muscle fiber are closed, the calcium enters back into the sarcoplasmic network, and the muscle relaxes.

The mechanism of action of nondepolarizing muscle relaxants is that they have an affinity for acetylcholine receptors and compete for them with AX (which is why they are also called competitive), preventing its access to receptors. As a result of this action, the motor end plate temporarily loses the ability to depolarize, and the muscle fiber to contraction (therefore these muscle relaxants are called nondepolarizing). So, in the presence of tubocurarine chloride, the mobilization of the transmitter is slow, the release of ACh is not able to provide the pace of incoming commands (stimuli) - as a result, the muscle response falls or stops.

The cessation of HMB caused by nondepolarizing muscle relaxants can be accelerated by the use of anticholinesterase drugs (neostigmine methyl sulphate), which, by blocking cholinesterase, lead to accumulation of AX.

The myoparalytic effect of depolarizing muscle relaxants is due to the fact that they act on the synapse like AX due to structural similarity with it, causing a depolarization of the synapse. Therefore, they are called depolarizing. However, since depolarizing muscle relaxants are not removed from the receptor immediately and are not hydrolyzed by acetylcholinesterase, they block the access of AX to the receptors and thereby reduce the sensitivity of the terminal plate to AX. This relatively stable depolarization is accompanied by a relaxation of the muscle fiber. In this case, repolarization of the end plate is not possible until the depolarizing muscle relaxant is associated with the holinoretseptors of the synapse. The use of anticholinesterase agents with such a block is ineffective, because Accumulating AH will only enhance depolarization. Depolarizing muscle relaxants quickly split by pseudocholinesterase of blood serum, so they do not have antidotes other than fresh blood or freshly frozen plasma.

Such a SLE, based on the depolarization of the synapse, is called the first phase of the depolarizing block. However, in all cases of even single administration of depolarizing muscle relaxants, not to mention the introduction of repeated doses, such changes are caused on the end plate caused by the initial depolarizing blockade, which then lead to the development of a blockade of the non-depolarizing type. This is the so-called second phase of the action (according to old terminology - the "double block") of depolarizing muscle relaxants. The mechanism of the second phase of action remains one of the mysteries of pharmacology. The second phase of action can be eliminated by anticholinesterase drugs and aggravated with nondepolarizing muscle relaxants.

In order to characterize NMP with the use of muscle relaxants, indicators such as the onset of action (time from the end of the injection to the onset of the complete block), the duration of action (duration of the complete block), and the recovery period (time to recovery of 95% neuromuscular conduction) are used. An accurate assessment of these characteristics is carried out on the basis of myographic studies with electrical stimulation and is largely dependent on the dose of muscle relaxant.

Clinically, the onset of action is the time through which intubation of the trachea can be performed in comfortable conditions; duration of the block is the time through which the next dose of the muscle relaxant is required to prolong the effective myoplegia; the recovery period is the time when the trachea can be extubated and the patient will be able to adequately self-ventilate.

To judge the potency of the muscle relaxant, the "effective dose" value, ED95, is introduced. The dose of MP required for 95% suppression of the contractile response of the tapping muscle of the thumb in response to irritation of the ulnar nerve. To intubate the trachea, 2 or even 3 ED95 is usually used.

Pharmacological Effects of Depolarizing Muscle Relaxants

The only representative of the group of depolarizing muscle relaxants is suxamethonium chloride. It is also the only JIC of ultrashort action.

Effective doses of muscle relaxants

Medicine	EDg5, mg / kg (adults)	Recommended doses for intubation, mg / kg
Pancuronium bromide	0.067	0.06-0.08
Tubocurarine chloride	0.48	0.5
Vecuronium bromide	0.043	0.1
Atracuria bezylate	0.21	0.4-0.6
Miwakuria chloride	0.05	0.07
Cisatracurium bezylate	0.305	0.2
Rokuronium bromide	0.29	0,15
Suxamethonium chloride	1-2	0.6

Relaxation of skeletal muscles is the main pharmacological effect of this drug. The miorelaksiruyuschee effect, caused by suxamethonium chloride, characterized by the following: and complete NMB occurs within 30-40 seconds. The duration of the blockade is rather short, usually 4-6 minutes;

• The first phase of the depolarizing block is accompanied by convulsive twitchings and contractions of the muscles, which start from the moment of their introduction and subside after about 40 seconds. Probably, this phenomenon is associated with the simultaneous depolarization of most neuromuscular synapses. Muscle fibrillation can cause a number of negative consequences for the patient, and therefore for their prevention are used (with greater or less success) different methods of prevention. Most often this is the previous introduction of small doses of nondepolarizing relaxants (the so-called precurarization). The main negative effects of muscle fibrillation are the following two characteristics of drugs of this group:
  • appearance of postoperative muscle pain in patients;
  • after the administration of depolarizing muscle relaxants, a release of potassium occurs, which, with initial hyperkalemia, can lead to serious complications, up to cardiac arrest;
  • the development of the second phase of the action (the development of a non-depolarizing unit) can be manifested by an unpredictable lengthening of the block;
  • excessive lengthening of the block is also observed with qualitative or quantitative deficiency of pseudocholinesterase, an enzyme that destroys suxamethonium chloride in the body. Such pathology is found in 1 out of 3,000 patients. The concentration of pseudocholinesterase may decrease in pregnancy, liver diseases and under the influence of certain drugs (neostigmine methyl sulfate, cyclophosphamide, mechlorethamine, trimetaphane). In addition to influencing the contractility of the skeletal muscles of suxamethonium, chloride causes other pharmacological effects.

Depolarizing relaxants can increase intraocular pressure. Therefore, they should be used with caution in patients with glaucoma, and in patients with penetrating wounds, their eyes should be avoided whenever possible.

The introduction of suxamethonium chloride can provoke the onset of malignant hyperthermia, an acute hypermetabolic syndrome, first described in 1960. It is believed that it develops as a result of excessive release of calcium ions from the sarcoplasmic reticulum, which is accompanied by rigidity of muscles and increased heat production. The basis for the development of malignant hyperthermia are genetic defects of calcium-releasing channels, which are autosomal dominant. As direct stimulating the pathological process of stimuli, depolarizing muscle relaxants such as suxamethonium chloride and some inhalational anesthetics can act.

Suxamethonium chloride stimulates not only the N-cholinergic receptors of the neuromuscular synapse, but also the cholinergic receptors of other organs and tissues. This is especially evident in its effect on CAS in the form of an increase or decrease in blood pressure and heart rate. Metabolite suxamethonium chloride, succinylmonocholine, stimulates the M-holinoretseptory sinoatrial node, which causes bradycardia. Sometimes suxamethonium chloride causes nodular bradycardia and ventricular ectopic rhythms.

Suxamethonium chloride more often than other muscle relaxants is mentioned in the literature in connection with the occurrence of cases of anaphylaxis. It is believed that it can act as a true allergen and cause in the human body the formation of antigens. In particular, the presence of IgE antibodies (IgE-immunoglobulins of class E) to quaternary ammonium groups of the suxamethonium chloride molecule has already been proved.

Pharmacological Effects of Nondepolarizing Muscle Relaxants

Non-depolarizing include short, medium and long-acting muscle relaxants. Currently, most often in clinical practice, drugs of steroid and benzylisoquinoline series are used. The muscle relaxant effect of nondepolarizing muscle relaxants is characterized by the following:

• the slower in comparison with suxamethonium chloride, the onset of HMB: within 1-5 min, depending on the type of drug and its dose;
• a considerable duration of the NMB, which exceeds the duration of the depolarizing drugs. The duration of action is from 12 to 60 minutes and depends largely on the type of drugs;
• in contrast to depolarizing blockers, the administration of LS of the non-depolarizing series is not accompanied by muscle fibrillation and, as a result, postoperative muscle pain and the release of potassium;
• the end of HMB with its complete recovery can be accelerated by the administration of anticholinesterase drugs (neostigmine methyl sulfate). This process is called decurarization - restoration of neuromuscular function by the administration of cholinesterase inhibitors;
• one of the drawbacks of most nondepolarizing muscle relaxants is the greater or lesser cumulation of all drugs of this group, which results in a poorly predicted increase in block duration;
• Another significant drawback of these drugs is the dependence of the characteristics of the induced HMB on liver and / or kidney function in connection with the mechanisms of their elimination. In patients with impaired functions of these organs, the duration of the block and especially the recovery of NRM can significantly increase;
• The use of non-depolarizing muscle relaxants can be accompanied by the phenomena of residual curarization, i.e. Extension of the SSC after the restoration of the NRM. This phenomenon, which significantly complicates the course of anesthesia, is associated with the following mechanism.

With the restoration of NRM, the number of postsynaptic cholinergic receptors far exceeds their number required to restore muscle activity. So, even with normal respiratory rate, vital capacity of the lungs, head lift test for 5 seconds and other classic tests indicating complete cessation of HMB, up to 70-80% of the receptors can still be occupied by nondepolarizing muscle relaxants, so that the possibility of re-development of SML . Thus, the clinical and molecular recovery of NRM is not the same. Clinically, it can be 100%, but up to 70% of the postsynaptic membrane receptors are occupied by MP molecules, and although clinically the restoration is complete, it is not yet at the molecular level. At the same time, muscle relaxants of medium duration release the receptors at a molecular level much faster, in comparison with long-acting drugs. The development of tolerance for MP is noted only when they are used in intensive care with their long-term (for several days) constant administration.

Nondepolarizing muscle relaxants also have other pharmacological effects in the body.

Just like suxamethonium chloride, they can stimulate the release of histamine. This effect can be associated with two basic mechanisms. The first, rather rare, is due to the development of an immunological reaction (anaphylactic). In this case, the antigen-MP binds to specific immunoglobulins (Ig), usually IgE, which is fixed on the surface of mast cells, and stimulates the release of endogenous vasoactive substances. The complementary cascade is not involved at the same time. In addition to the histamine, endogenous vasoactive substances include proteases, oxidative enzymes, adenosine, tryptase, and heparin. As an extreme manifestation, anaphylactic shock develops in response to this. At the same time caused by these agents myocardial depression, peripheral vasodilation, a sharp increase in the permeability of the capillaries and spasm of the coronary artery are the cause of profound hypotension and even cardiac arrest. Immunological reaction is usually observed if earlier this muscle relaxant was administered to a patient and, consequently, the production of antibodies is already stimulated.

Histamine release during the administration of non-depolarizing MP is mainly associated with a second mechanism - the direct chemical effect of drugs on mast cells without involvement in the interaction of surface Ig (anaphylactoid reaction). For this, no preliminary sensitization is required.

Among all the causes of allergic reactions in general anesthesia MP are on the 1st place: 70% of all allergic reactions in anesthesiology are associated with MP. A large multicenter analysis of severe allergic reactions in anesthesia in France showed that life-threatening reactions occur at a frequency of approximately 1: 3,500 to 1: 10,000 anesthesia (usually 1: 3,500), half of which were caused by immunological reactions and half of the chemical.

At the same time, 72% of immunological reactions were observed in women and 28% in men, and 70% of these reactions were associated with the introduction of MP. Most often (in 43% of cases), the cause of immunological reactions was suxamethonium chloride, 37% of cases were associated with the introduction of vecuronium bromide, 6.8% with atra- curium bezylate and 0.13% pancuronium bromide.

Virtually all muscle relaxants can have more or less influence on the circulatory system. Hemodynamic disorders in the use of various MP can have the following reasons:

• ganglionic block - depression of pulse propagation in sympathetic ganglia and vasodilation of arterioles with arterial hypertension and heart rate reduction (tubocurarine chloride);
• muscarinic receptor block - vagolytic action with a decrease in heart rate (pancuronium bromide, rocuronium bromide);
• vagomimetichesky effect - increased heart rate and arrhythmia (suksametoniya chloride);
• blockade of norepinephrine resynthesis in sympathetic synapses and myocardium with increased heart rate (pancuronium bromide, vecuronium bromide);
• histamine release (suxamethonium chloride, tubocurarine chloride, myvacuria chloride, atracurium bezylate).

Pharmacokinetics

All quaternary ammonium derivatives, which include nondepolarizing muscle relaxants, are poorly absorbed in the digestive tract, but well enough from muscle tissue. A rapid effect is achieved with the / in the route of administration, which is the main one in anesthesia practice. Very rarely is the administration of suxamethonium chloride in / m or under the tongue. In this case, the beginning of its action is extended by 3-4 times in comparison with IV. From the systemic circulation, muscle relaxants must pass through extracellular spaces to their place of action. This is associated with a certain delay in the rate of development of their myoparalytic effect, which is a definite restriction of quaternary ammonium derivatives in the case of emergency intubation.

Miorelaxants are quickly distributed to organs and tissues of the body. Since muscle relaxants exert their effect mainly in the area of neuromuscular synapses, the calculation of their dose is primarily based on muscle mass, not the total body weight. Therefore, in obese patients, overdose is more often dangerous, and in lean patients - an inadequate dose.

Suxamethonium chloride is characterized by the fastest onset of action (1 to 1.5 minutes), which is explained by its low fat solubility. Among non-depolarizing MPs, rocuronium bromide (1-2 min) has the highest rate of development of the effect. This is due to the rapid achievement of an equilibrium between the concentration of drugs in the plasma and postsynaptic receptors, which ensures the rapid development of HMB.

In the organism suxamethonium chloride is rapidly hydrolyzed by pseudocholinesterase of blood serum into choline and succinic acid, which is associated with an extremely short duration of action of this drug (6-8 min). Metabolism is disturbed by hypothermia and pseudocholinesterase deficiency. The cause of this defect may be hereditary factors: in 2% of patients, one of the two alleles of the pseudocholinesterase gene can be pathological, which prolongs the duration of the effect to 20-30 min, and one in 3000 has a violation of both alleles, as a result of which the HMB can last up to 6 -8 hours In addition, a decrease in the activity of pseudocholinesterase can be observed in liver diseases, pregnancy, hypothyroidism, kidney diseases and artificial circulation. In these cases, the duration of the drug also increases.

The metabolic rate of myvacuria chloride, as well as suxamethonium chloride, mainly depends on the activity of plasma cholinesterase. This is what allows us to assume that the muscle relaxants are not cumulated in the body. As a result of the metabolism, quaternary monoester, quaternary alcohol and dicarboxylic acid are formed. Only a small amount of active drugs is excreted unchanged in urine and bile. Mivakuriya chloride consists of three stereoisomers: trans-trans and cis-trans, accounting for about 94% of its potency, and cis-cis isomer. The pharmacokinetics of the two main isomers (trans-trans and cis-trans) of myvacuria chloride consist in the fact that they have a very high clearance (53 and 92 ml / min / kg) and a low distribution volume (0.1 and 0.3 l / kg), so that T1 / 2 of these two isomers is about 2 minutes. The cis-cis isomer having less than 0.1 of the potency of the other two isomers has a low volume of distribution (0.3 l / kg) and low clearance (only 4.2 ml / min / kg), so that its T1 / 2 is 55 minutes, but, as a rule, does not violate the characteristics of the unit.

Vecuronium bromide is largely metabolized in the liver with the formation of an active metabolite - 5-hydroxy-rouxvicuronium. However, even with repeated administration, the accumulation of drugs was not observed. Vecuronium bromide refers to a medium-duration MP.

The pharmacokinetics of atracurium bezilate is unique in connection with the peculiarities of its metabolism: under physiological conditions (normal body temperature and pH) in the body, the atracurium besylate molecule undergoes spontaneous biodegradation by the mechanism of self-destruction without any involvement of enzymes, so that T1 / 2 is about 20 minutes. This mechanism of spontaneous biodegradation of drugs is known as the elimination of Hofmann. The chemical structure of atracurium besylate includes an ester group, so about 6% of the LS is subjected to ester hydrolysis. Since the elimination of atracurium bezilate is mainly an organ-independent process, its pharmacokinetic parameters differ little in healthy patients and in patients with hepatic or renal insufficiency. Thus, T1 / 2 in healthy patients and patients in the terminal stage of hepatic or renal failure is 19.9, 22.3 and 20.1 minutes, respectively.

It should be noted that atracurium bezylate should be stored at a temperature of 2 to 8 ° C. At room temperature, every month storage reduces the power of drugs in connection with the elimination of Hofmann by 5-10%.

None of the metabolites formed has a blocking neuromuscular action. At the same time, one of them, laudanosine, when administered in very high doses to rats and dogs, has convulsive activity. However, in humans, the concentration of laudanosine, even with many months of infusions, was 3 times lower than the threshold for the development of convulsions. Convulsive effects of laudanosine may be of clinical significance when using excessively high doses or in patients with hepatic insufficiency, it is metabolized in the liver.

Cisatracurium bezylate is one of the 10 isomers of atracurium (11-cis-11'-cis-isomer). Therefore, in the organism of cisatracurium bezylate is also subjected to Hoffmann's organon-independent elimination. Pharmacokinetic parameters are basically similar to those of atracurium bezylate. Because this is a more powerful muscle relaxant than atracurium bezylate, it is administered in smaller doses, and therefore laudanosine is produced in lesser amounts.

About 10% of pancuronium bromide and pi-procouronium bromide are metabolized in the liver. One of the metabolites of pancuronium bromide and pipecuronium bromide (3-hydroxypancuronium and 3-hydroxypipecuronium) has approximately half the activity of the original drug. This may be one of the reasons for the cumulative effect of these drugs and their prolonged myoparalytic effect.

The processes of elimination (metabolism and excretion) of many MP are associated with the functional state of the liver and kidneys. Severe liver damage can delay the elimination of such drugs as vecuronium bromide and rocuronium bromide, increasing their T1 / 2. Kidneys are the main way of excretion of pancuronium bromide and pipecuronium bromide. The existing diseases of the liver and kidneys should also be taken into account when using suxamethonium chloride. The agents of choice for these diseases are atracurium bezylate and cisatracurium bezylate due to characteristic organ-independent elimination.

Contraindications and cautions

Absolute contraindications to the use of MP when used during anesthesia manual ventilation, in addition to known hypersensitivity to drugs, no. Relative contraindications for the use of suxamethonium chloride have been noted. You can not:

• patients with eye injuries;
• with diseases that cause an increase in intracranial pressure;
• with a deficiency of plasma cholinesterase;
• with severe burns;
• with traumatic paraplegia or spinal cord injuries;
• at conditions associated with the risk of malignant hyperthermia (congenital and dystrophic myotonia, Duchenne muscular dystrophy);
• patients with high plasma potassium levels and risk of cardiac arrhythmias and cardiac arrest;
• children.

Many factors can influence the characteristics of the BMS. In addition, with many diseases, especially the nervous system and muscles, the reaction to MP administration can also vary considerably.

MP administration to children has certain differences, related both to the developmental neuromuscular synapse in children of the first months of life, and to the peculiarities of the pharmacokinetics of MP (increased volume of distribution and slowing of drug elimination).

In pregnancy suksametoniya chloride should be used with caution, because repeated injections of drugs, as well as the possible presence of atypical pseudocholinesterase in fetal plasma can cause severe inhibition of NRM.

The use of suxamethonium chloride in elderly patients has no significant differences from other age categories of adults.

[6], [7], [8]

Tolerance and side effects

In general, the tolerance of MP depends on such properties of drugs as the presence of cardiovascular effects, the ability to release histamine or cause anaphylaxis, the ability to cumulate, the possibility of interrupting the block.

Histaminoliberation and anaphylaxis. It is believed that on average, an anesthesiologist can meet with a severe histamine response once a year, but less serious chemically caused by the release of histamine reactions occur very often.

As a rule, the reaction to the release of histamine after the administration of MP is limited to a skin reaction, although these manifestations can be much more severe. Usually, these reactions manifest reddening of the skin of the face and breast, less often a urticaria rash. Such formidable complications as the appearance of severe arterial hypotension, the development of laryngo- and bronchospasm, are rare. Most often they are described when using suxamethonium chloride and tubocurarine chloride.

According to the frequency of histamine effect, neuromuscular blockers can be arranged according to the following ranking: suxamethonium chloride> tubocurarine chloride> miwakuria chloride> atrakury bezilat. Next are the approximately equal ability for histaminoliberation of vecuronium bromide, pancuronium bromide, pipecuronium bromide, cisatracurium bezylate and rocuronium bromide. To this we must add that in the main it concerns anaphylactoid reactions. As for true anaphylactic reactions, they are fixed quite rarely and the most dangerous are suxamethonium chloride and vecuronium bromide.

Perhaps the most important for an anesthesiologist is the question of how to avoid or weaken the histamine effect when using MP. In patients with an allergic anamnesis, muscle relaxants should be used that do not cause a significant release of histamine (vecuronium bromide, rocuronium bromide, cisatracurium bezylate, pancuronium bromide and pipecuronium bromide). For the prevention of histamine-effect the following measures are recommended:

• inclusion in premedication of H1 and H2 antagonists, and if necessary, corticosteroids;
• the introduction of MP as possible into the central vein;
• the rapid introduction of drugs;
• breeding of drugs;
• washing the system with an isotonic solution after each MP injection;
• Prevention of mixing MP in one syringe with other pharmacological drugs.

The use of these simple techniques for any anesthesia can dramatically reduce the number of cases of histamine reactions in the clinic, even in patients with an allergic anamnesis.

Very rare, less predictable and life-threatening complication of suxamethonium chloride is malignant hyperthermia. It is almost 7 times more common in children than in adults. The syndrome is characterized by a rapid rise in body temperature, a significant increase in oxygen consumption and the production of carbon dioxide. With the development of malignant hyperthermia, it is recommended to quickly cool the body, inhale 100% oxygen and control acidosis. Dantrolene has a decisive role in treating the syndrome of malignant hyperthermia. The drug blocks the release of calcium ions from the sarcoplasmic reticulum, reduces muscle tone and heat production. Abroad, in the last two decades, there has been a significant reduction in the incidence of deaths in the development of malignant hyperthermia, which is associated with the use of dantrolene.

In addition to allergic and hyperthermic reactions, suxamethonium chloride has a number of other side effects that limit its use. These are muscle pains, hyperkalemia, increased intraocular pressure, increased ICP, cardiovascular effects. In this regard, there are contra-indications for its use.

To a large extent, the safety of using MP during anesthesia can be provided by monitoring NRM.

Interaction

MP is always used in the form of various combinations with other pharmacological agents and is never used in its pure form. They provide the only component of general anesthesia - myoplegia.

Favorable combinations

All inhalation anesthetics to some extent potentiate the degree of HMB caused by both depolarizing and non-depolarizing agents. This effect is less pronounced in the oxide dinitrogen. Halothane causes the block to lengthen by 20%, and enflurane and isoflurane - by 30%. In this regard, when using inhalation anesthetics as an anesthetic component of the anesthetic, it is necessary to accordingly reduce the MP dosage as for intubation of the trachea (if the inhalation anesthetic was used for induction), while maintaining boluses or calculating the rate of permanent infusion MP. When inhalation anesthetics are used, MP doses are generally reduced by 20-40%.

It is believed that the use of ketamine for anesthesia also causes potentiation of the effects of nondepolarizing MP.

Thus, such combinations can reduce the dosages of the MPs used and, therefore, reduce the risk of possible side effects and the expense of these agents.

[9], [10], [11], [12], [13]

Combinations that require special attention

Cholinesterase inhibitors (neostigmine methyl sulfate) are used for decararization using non-depolarizing MPs, but they significantly extend the first phase of the depolarizing block. Therefore, their use is justified only in the second phase of the depolarizing block. It should be noted that doing this is recommended in exceptional cases because of the danger of recurring. Rekurarizatsiya - repeated paralysis of skeletal muscles, deepening the residual effect of MP under the influence of adverse factors after the restoration of adequate independent breathing and tone of skeletal muscles. The most common reason for the recurrence is the use of anticholinesterase drugs.

It should be noted that with the use of methyl isosulfate neostigmine for decurization, in addition to the risk of developing a recurrence, a number of serious side effects can also occur, such as:

• bradycardia;
• increased secretion;
• stimulation of smooth muscles:
  • intestinal peristalsis;
  • bronchospasm;
• nausea and vomiting;
• central effects.

Many antibiotics can disrupt the mechanism of NMP and potentiate HMB when using MP. The strongest action has polymyxin, which blocks the ion channels of acetylcholine receptors. Aminoglycosides reduce the sensitivity of the postsynaptic membrane to AX. Tobramycin can have a direct effect on the muscles. Similar action is also possessed by such antibiotics as lincomycin and clindamycin. In this regard, whenever possible, the prescription of the above antibiotics should be avoided immediately before or during surgery, using other drugs of this group instead.

It should be borne in mind that the HMB potentiates the following drugs:

• antiarrhythmics (calcium antagonists, quinidine, procainamide, propranolol, lidocaine);
• cardiovascular drugs (nitroglycerin - only affects the effects of pancuronium bromide);
• diuretics (furosemide and, possibly, thiazide diuretics and mannitol);
• local anesthetics;
• magnesium sulfate and lithium carbonate.

In contrast, in the case of prolonged prior use of anticonvulsant drugs, pheny- ton or carbamazepine, the effect of nondepolarizing MPs is weakened.

[14], [15], [16], [17]

Unwanted combinations

Since the muscle relaxants are weak acids, chemical interactions can occur between them when mixed with alkaline solutions. Such interaction occurs when a muscle syringe and hypnotics are injected into one syringe of thiopental sodium, which often causes severe blood circulation depression.

In this regard, do not mix muscle relaxants with any other drugs, except for the recommended solvents. Moreover, before and after the administration of the muscle relaxant, it is necessary to wash the needle or cannula with neutral solutions.