Myorelaxants

Muscle relaxants (MR) are drugs that relax striated (voluntary) muscles and are used to create artificial myoplegia in anesthesiology and resuscitation. At the beginning of their 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 of tubular curare. The first information about curare penetrated into Europe more than 400 years ago after the return of Columbus's expedition from America, where American Indians used curare to lubricate arrowheads when shooting from a bow. In 1935, King isolated from curare its main natural alkaloid - tubocurarine. Tubocurarine chloride was first used in a clinic on January 23, 1942, at the Montreal Homeopathic Hospital by Dr. Harold Griffith and his resident Enid Johnson during an appendectomy on a 20-year-old plumber. This was a revolutionary moment for anesthesiology. It was with the advent of muscle relaxants in the arsenal of medical means that surgery experienced rapid development, which allowed it to reach today's heights and perform surgical interventions on all organs in patients of all ages, starting from the neonatal period. 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 generally accepted that it was from this moment that anesthesiology began to exist as an independent specialty.

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

Most often, muscle relaxants are divided into two large groups depending on their mechanism of action: depolarizing and non-depolarizing, or competitive.

Based on their origin and chemical structure, non-depolarizing relaxants can be divided into 4 categories:

• natural origin (tubocurarine chloride, metocurine, alcuronium - currently not used in Russia);
• steroids (pancuronium bromide, vecuronium bromide, pipecuronium bromide, rocuronium bromide);
• benzylisoquinolines (atracurium besylate, cisatracurium besylate, mivacurium chloride, doxacurium chloride);
• others (gallamin - currently not used).

More than 20 years ago, John Savarese divided muscle relaxants depending on the duration of their action into long-acting drugs (onset of action 4-6 minutes after administration, onset of recovery of neuromuscular block (NMB) after 40-60 minutes), medium-acting (onset of action - 2-3 minutes, onset of recovery - 20-30 minutes), short-acting (onset of action - 1-2 minutes, recovery after 8-10 minutes) and ultra-short-acting (onset of action - 40-50 seconds, recovery after 4-6 minutes).

Classification of muscle relaxants by mechanism and duration of action:

• depolarizing relaxants:
• ultra-short-acting (suxamethonium chloride);
• non-depolarizing muscle relaxants:
• short-acting (mivacurium chloride);
• medium duration of action (atracurium besylate, vecuronium bromide, rocuronium bromide, cisatracurium besylate);
• long-acting (pipecuronium bromide, pancuronium bromide, tubocurarine chloride).

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

Muscle relaxants: place in therapy

At present, the main indications for the use of MP in anesthesiology can be identified (we are not talking about indications for their use in intensive care):

• facilitating tracheal intubation;
• prevention of reflex activity of voluntary muscles during surgery and anesthesia;
• facilitating the implementation of artificial ventilation;
• the ability to adequately perform surgical operations (upper abdominal and thoracic), endoscopic procedures (bronchoscopy, laparoscopy, etc.), manipulations on bones and ligaments;
• creation of complete immobilization during microsurgical operations; prevention of shivering during artificial hypothermia;
• reducing the need for anesthetic agents. The choice of MP largely depends on the period of general anesthesia: induction, maintenance and recovery.

Induction

The speed 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, circulatory status.

Muscle relaxants for induction must have a rapid onset. Suxamethonium chloride remains unrivaled in this regard, but its use is limited by numerous side effects. In many ways, it has been replaced by rocuronium bromide - when used, tracheal intubation can be performed at the end of the first minute. Other non-depolarizing muscle relaxants (mivacurium chloride, vecuronium bromide, atracurium besylate and cisatracurium besylate) allow tracheal intubation within 2-3 minutes, which, with appropriate induction technique, also provides optimal conditions for safe intubation. Long-acting muscle relaxants (pancuronium bromide and pipecuronium bromide) are not rationally used for intubation.

Maintenance of anesthesia

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

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

The short duration of action of mivacurium chloride is used in surgical procedures requiring the cessation of spontaneous respiration for a short period of time (e.g., endoscopic surgeries), especially in outpatient and day hospital settings, or in surgeries where the end date of the operation is difficult to predict.

The use of medium-acting MP (vecuronium bromide, rocuronium bromide, atracurium besylate, and cisatracurium besylate) allows for effective myoplegia, especially with their continuous infusion during operations of varying duration. The use of long-acting MP (tubocurarine chloride, pancuronium bromide, and pipecuronium bromide) is justified during long operations, as well as in cases of a known transition to prolonged mechanical ventilation in the early postoperative period.

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

Recovery

The recovery period is most dangerous due to complications associated with the introduction of MP (residual curarization and recurarization). They are most common after the use of long-acting MP. Thus, the frequency of postoperative pulmonary complications in the same groups of patients when using long-acting MP was 16.9% compared to MP of average duration of action - 5.4%. Therefore, the use of the latter is usually accompanied by a smoother recovery period.

Recurarization associated with decurarization with neostigmine is also most often necessary when using long-term MP. In addition, it should be noted that the use of neostigmine itself can lead to the development of serious side effects.

When using MP at present, one also has to take into account the cost of the drug. Without going into detail about the pharmacoeconomics of MP and fully understanding that it is not only and not even so much the price that determines the true costs of treating patients, it should be noted that the price of the ultra-short-acting drug suxamethonium chloride and long-acting MP is significantly lower than short- and medium-acting muscle relaxants.

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

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

Mechanism of action and pharmacological effects

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

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

Choline and acetate are required for the synthesis of ACh. They are released into the vacuoles from the extracellular bathing fluid and then stored in the mitochondria as acetyl coenzyme A. Other molecules used for the synthesis and storage of ACh are synthesized in the cell body and transported to the nerve terminal. The major enzyme catalyzing the synthesis of ACh at the nerve terminal is choline O-acetyltransferase. The vacuoles are arranged in triangular arrays, the apex of which includes a thickened portion of the membrane known as the active zone. The unloading sites of the vacuoles are on either side of these active zones, aligned precisely with opposite arms, curvatures in the postsynaptic membrane. The postsynaptic receptors are concentrated precisely on these arms.

Current understanding of NMP physiology supports the quantum theory. In response to an incoming nerve impulse, voltage-sensitive calcium channels open and calcium ions rapidly enter the nerve terminal, combining with calmodulin. The calcium-calmodulin complex causes vesicles to interact with the nerve terminal membrane, which in turn causes ACh to be released into the synaptic cleft.

Rapid changes in excitation require the nerve to increase the amount of ACh (a process known as mobilization). Mobilization involves the transport of choline, the synthesis of acetyl coenzyme-A, and the movement of vacuoles to the site of release. Under normal conditions, nerves are able to mobilize the messenger (in this case, ACh) quickly enough to replace that released by the previous transmission.

The released ACh crosses the synapse and binds to the cholinergic receptors of the postsynaptic membrane. These receptors consist of 5 subunits, 2 of which (a-subunits) are capable of binding ACh molecules and contain sites for its binding. The formation of the ACh-receptor complex leads to conformational changes in the associated specific protein, resulting in the opening of cation channels. Through them, sodium and calcium ions move into the cell, and potassium ions out of the cell, an electrical potential arises that is transmitted to the neighboring muscle cell. If this potential exceeds the threshold required for the adjacent muscle, an action potential arises that passes through the muscle fiber membrane and initiates the contraction process. In this case, depolarization of the synapse occurs.

The action potential of the motor plate spreads along the muscle cell membrane and the so-called T-tubule system, causing sodium channels to open and calcium to be released from the sarcoplasmic reticulum. This released calcium causes the contractile proteins actin and myosin to interact, causing the muscle fiber to contract.

The magnitude of muscle contraction does not depend on nerve excitation and the magnitude of the action potential (an all-or-none process), but depends on the number of muscle fibers involved in the contraction. Under normal conditions, the amount of ACh released and postsynaptic receptors greatly exceeds the threshold required for muscle contraction.

ACh ceases to act within a few milliseconds due to its destruction by acetylcholinesterase (called specific or true cholinesterase) into 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 receptor complex with ACh is destroyed and the latter is biodegraded under the influence of acetylcholinesterase, the ion channels close, the postsynaptic membrane is repolarized and its ability to respond to the next bolus of acetylcholine is restored. In the muscle fiber, with the cessation of the propagation of the action potential, the sodium channels in the muscle fiber close, calcium flows back into the sarcoplasmic reticulum, and the muscle relaxes.

The mechanism of action of non-depolarizing muscle relaxants is that they have an affinity for acetylcholine receptors and compete for them with ACh (that is why they are also called competitive), preventing its access to receptors. As a result of such an effect, the motor end plate temporarily loses the ability to depolarize, and the muscle fiber to contract (that is why these muscle relaxants are called non-depolarizing). Thus, in the presence of tubocurarine chloride, the mobilization of the transmitter is slowed down, the release of ACh is unable to ensure the rate of incoming commands (stimuli) - as a result, the muscle response decreases or stops.

The cessation of NMB caused by non-depolarizing muscle relaxants can be accelerated by the use of anticholinesterase agents (neostigmine methyl sulfate), which, by blocking cholinesterase, lead to the accumulation of ACh.

The myoparalytic effect of depolarizing muscle relaxants is due to the fact that they act on the synapse like ACh due to their structural similarity to it, causing depolarization of the synapse. That is why they are called depolarizing. However, since depolarizing muscle relaxants are not removed from the receptor immediately and are not hydrolyzed by acetycholinesterase, they block the access of ACh to the receptors and thereby reduce the sensitivity of the end plate to ACh. This relatively stable depolarization is accompanied by relaxation of the muscle fiber. In this case, repolarization of the end plate is impossible as long as the depolarizing muscle relaxant is bound to the cholinergic receptors of the synapse. The use of anticholinesterase agents for such a block is ineffective, since the accumulating ACh will only increase depolarization. Depolarizing muscle relaxants are broken down fairly rapidly by serum pseudocholinesterase, so they have no antidotes other than fresh blood or fresh frozen plasma.

Such NMB, based on synapse depolarization, is called the first phase of the depolarizing block. However, in all cases of even a single administration of depolarizing muscle relaxants, not to mention the administration of repeated doses, such changes are found on the end plate caused by the initial depolarizing block, which then lead to the development of a non-depolarizing block. This is the so-called second phase of action (in the old terminology - "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 by non-depolarizing muscle relaxants.

To characterize NMB when using muscle relaxants, such parameters as the onset of action (time from the end of administration to the onset of a complete block), duration of action (duration of a complete block) and recovery period (time to recovery of 95% of neuromuscular conductivity) are used. An accurate assessment of the above characteristics is carried out on the basis of a myographic study with electrical stimulation and largely depends on the dose of the muscle relaxant.

Clinically, the onset of action is the time at which tracheal intubation can be performed comfortably; the duration of block is the time at which the next dose of muscle relaxant is required to prolong effective myoplegia; and the recovery period is the time at which tracheal extubation can be performed and the patient is capable of adequate spontaneous ventilation.

To judge the potency of a muscle relaxant, the value of "effective dose" - ED95, i.e. the dose of MP required for 95% suppression of the contractile reaction of the abductor muscle of the thumb in response to irritation of the ulnar nerve, is introduced. For tracheal intubation, 2 or even 3 ED95 are 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 ultra-short-acting JIC.

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 besilate	0.21	0.4-0.6
Mivacurium chloride	0.05	0.07
Cisatracurium besilate	0.305	0.2
Rocuronium bromide	0.29	0.15
Suxamethonium chloride	1-2	0.6

Relaxation of skeletal muscles is the main pharmacological effect of this drug. The muscle relaxant effect caused by suxamethonium chloride is characterized by the following: and complete NMB occurs within 30-40 sec. The duration of the block is quite short, usually 4-6 min;

• the first phase of the depolarizing block is accompanied by convulsive twitching and muscle contractions that begin at the moment of their introduction and subside after approximately 40 seconds. This phenomenon is probably associated with the simultaneous depolarization of most of the neuromuscular synapses. Muscle fibrillations can cause a number of negative consequences for the patient, and therefore various methods of prevention are used (with greater or lesser success) to prevent them. Most often, this is the previous introduction of small doses of non-depolarizing relaxants (the so-called precurarization). The main negative consequences of muscle fibrillations are the following two features of drugs in this group:
  • the appearance of postoperative muscle pain in patients;
  • after the introduction of depolarizing muscle relaxants, potassium is released, which, in the case of initial hyperkalemia, can lead to serious complications, including cardiac arrest;
  • the development of the second phase of action (development of non-depolarizing block) may be manifested by an unpredictable prolongation of the block;
  • Excessive prolongation of the block is also observed with qualitative or quantitative deficiency of pseudocholinesterase, an enzyme that destroys suxamethonium chloride in the body. This pathology occurs in 1 out of 3,000 patients. The concentration of pseudocholinesterase can decrease during pregnancy, liver disease, and under the influence of certain drugs (neostigmine methyl sulfate, cyclophosphamide, mechlorethamine, trimethaphan). In addition to the effect on skeletal muscle contractility, suxamethonium chloride also causes other pharmacological effects.

Depolarizing relaxants may increase intraocular pressure. Therefore, they should be used with caution in patients with glaucoma and, if possible, avoided in patients with penetrating eye injuries.

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 muscle rigidity and increased heat production. The basis for the development of malignant hyperthermia are genetic defects of calcium-releasing channels, which have an autosomal dominant nature. Depolarizing muscle relaxants such as suxamethonium chloride and some inhalation anesthetics can act as direct stimuli provoking the pathological process.

Suxamethonium chloride stimulates not only the H-cholinergic receptors of the neuromuscular synapse, but also the cholinergic receptors of other organs and tissues. This is especially evident in its effect on the cardiovascular system in the form of an increase or decrease in blood pressure and heart rate. The metabolite of suxamethonium chloride, succinylmonocholine, stimulates the M-cholinergic receptors of the sinoatrial node, causing bradycardia. Sometimes suxamethonium chloride causes nodal bradycardia and ventricular ectopic rhythms.

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

Pharmacological effects of non-depolarizing muscle relaxants

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

• slower onset of NMB compared to suxamethonium chloride: within 1-5 minutes depending on the type of drug and its dose;
• significant duration of NMB, exceeding the duration of action of depolarizing drugs. The duration of action is from 12 to 60 minutes and depends largely on the type of drug;
• Unlike depolarizing blockers, the administration of non-depolarizing drugs is not accompanied by muscle fibrillations and, as a result, postoperative muscle pain and potassium release;
• the end of NMB with its complete restoration can be accelerated by the introduction of anticholinesterase drugs (neostigmine methylsulfate). This process is called decurarization - restoration of neuromuscular function by the introduction of cholinesterase inhibitors;
• one of the disadvantages of most non-depolarizing muscle relaxants is the greater or lesser cumulation of all drugs in this group, which entails a poorly predictable increase in the duration of the block;
• Another significant disadvantage of these drugs is the dependence of the characteristics of the induced NMB on the function of the liver and/or kidneys due to the mechanisms of their elimination. In patients with dysfunction of these organs, the duration of the block and especially the restoration of NMB can increase significantly;
• The use of non-depolarizing muscle relaxants may be accompanied by residual curarization phenomena, i.e. prolongation of NMB after restoration of NMP. This phenomenon, which significantly complicates the course of anesthesia, is associated with the following mechanism.

During the restoration of NMP, the number of postsynaptic cholinergic receptors greatly exceeds their number required for the restoration of muscle activity. Thus, even with normal indices of respiratory force, vital capacity of the lungs, 5-second head lift test and other classical tests indicating the complete cessation of NMP, up to 70-80% of receptors may still be occupied by non-depolarizing muscle relaxants, as a result of which the possibility of repeated development of NMP remains. Thus, clinical and molecular restoration of NMP are not the same. Clinically, it may be 100%, but up to 70% of the receptors of the postsynaptic membrane are occupied by MP molecules, and although clinically the restoration is complete, it is not yet at the molecular level. At the same time, medium-duration muscle relaxants release receptors at the molecular level much faster, compared to long-acting drugs. The development of tolerance to the action of MP is observed only when they are used in intensive care conditions with their long-term (over several days) continuous administration.

Non-depolarizing muscle relaxants also have other pharmacological effects in the body.

Like suxamethonium chloride, they are capable of stimulating the release of histamine. This effect may be associated with two main mechanisms. The first, quite 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 complement cascade is not involved. In addition to histamine, endogenous vasoactive substances include proteases, oxidative enzymes, adenosine, tryptase and heparin. As an extreme manifestation in response to this, anaphylactic shock develops. In this case, myocardial depression, peripheral vasodilation, a sharp increase in capillary permeability and spasm of the coronary artery caused by these agents cause profound hypotension and even cardiac arrest. An immunological reaction is usually observed if the muscle relaxant has previously been administered to the patient and, therefore, antibody production has already been stimulated.

The release of histamine upon administration of non-depolarizing MPs is mainly associated with the second mechanism - the direct chemical effect of the drug on mast cells without the involvement of surface Ig in the interaction (anaphylactoid reaction). This does not require preliminary sensitization.

Among all causes of allergic reactions during general anesthesia, MPs are in first place: 70% of all allergic reactions in anesthesiology are associated with MPs. A large multicenter analysis of severe allergic reactions in anesthesiology in France showed that life-threatening reactions occur with a frequency of approximately 1:3500 to 1:10,000 anesthesias (more often 1:3500), with half of them caused by immunological reactions and half by chemical reactions.

In this case, 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 the introduction of atracurium besylate and 0.13% with pancuronium bromide.

Almost all muscle relaxants can have a greater or lesser effect on the circulatory system. Hemodynamic disturbances when using various MPs can have the following causes:

• ganglionic block - depression of impulse propagation in the sympathetic ganglia and vasodilation of arterioles with a decrease in blood pressure and heart rate (tubocurarine chloride);
• muscarinic receptor blocker - vagolytic effect with a decrease in heart rate (pancuronium bromide, rocuronium bromide);
• vago-mimetic effect - increased heart rate and arrhythmia (suxamethonium chloride);
• blockade of norepinephrine resynthesis in sympathetic synapses and myocardium with an increase in heart rate (pancuronium bromide, vecuronium bromide);
• histamine release (suxamethonium chloride, tubocurarine chloride, mivacurium chloride, atracurium besylate).

Pharmacokinetics

All quaternary ammonium derivatives, which include non-depolarizing muscle relaxants, are poorly absorbed from the gastrointestinal tract, but are absorbed quite well from muscle tissue. A rapid effect is achieved with the intravenous route of administration, which is the main one in anesthesiology practice. Very rarely, suxamethonium chloride is administered intramuscularly or sublingually. In this case, the onset of its action is prolonged by 3-4 times compared to intravenous. Muscle relaxants must pass from the systemic bloodstream through extracellular spaces to their site of action. This is associated with a certain delay in the rate of development of their myoparalytic effect, which is a certain limitation of quaternary ammonium derivatives in the case of emergency intubation.

Muscle relaxants are quickly distributed throughout the body's organs and tissues. Since muscle relaxants exert their effect primarily in the area of neuromuscular synapses, muscle mass, rather than total body weight, is of primary importance when calculating their dose. Therefore, overdosing is more often dangerous in obese patients, while underdosing is more dangerous in thin patients.

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

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

The rate of metabolism of mivacurium chloride, as well as suxamethonium chloride, mainly depends on the activity of plasma cholinesterase. This is what allows us to assume that muscle relaxants do not accumulate in the body. As a result of metabolization, a quaternary monoester, a quaternary alcohol and a dicarboxylic acid are formed. Only a small amount of the active drug is excreted unchanged in urine and bile. Mivacurium chloride consists of three stereoisomers: trans-trans and cis-trans, which make up about 94% of its potency, and a cis-cis isomer. The pharmacokinetic features of the two main isomers (trans-trans and cis-trans) of mivacurium chloride are 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), due to which T1 / 2 of these two isomers is about 2 min. The cis-cis isomer, which has 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), and therefore its T1/2 is 55 min, but, as a rule, does not interfere with the blocking characteristics.

Vecuronium bromide is largely metabolized in the liver to form an active metabolite, 5-hydroxyvecuronium. However, even with repeated administration, accumulation of the drug was not observed. Vecuronium bromide is a medium-acting MP.

The pharmacokinetics of atracurium besylate is unique due to 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 self-destruction mechanism without any participation of enzymes, so that T1/2 is about 20 min. This mechanism of spontaneous biodegradation of the drug is known as the Hofmann elimination. The chemical structure of atracurium besylate includes an ester group, so about 6% of the drug undergoes ester hydrolysis. Since the elimination of atracurium besylate is mainly an organ-independent process, its pharmacokinetic parameters differ little in healthy patients and in patients with liver or kidney failure. Thus, T1/2 in healthy patients and patients with terminal liver or kidney failure is 19.9, 22.3 and 20.1 min, respectively.

It should be noted that atracurium besylate should be stored at a temperature of 2 to 8° C, since at room temperature each month of storage reduces the potency of the drug due to Hofmann elimination by 5-10%.

None of the resulting metabolites have a neuromuscular blocking effect. However, one of them, laudanosine, has convulsive activity when administered in very high doses to rats and dogs. However, in humans, the concentration of laudanosine, even with multi-month infusions, was 3 times lower than the threshold for the development of convulsions. The convulsive effects of laudanosine may be clinically significant when using excessively high doses or in patients with liver failure, since it is metabolized in the liver.

Cisatracurium besylate is one of 10 isomers of atracurium (11-cis-11'-cis isomer). Therefore, in the body, cisatracurium besylate also undergoes organ-independent Hofmann elimination. The pharmacokinetic parameters are basically similar to those of atracurium besylate. Since it is a more potent muscle relaxant than atracurium besylate, it is administered in lower doses and, therefore, laudanosine is produced in smaller amounts.

About 10% of pancuronium bromide and pipecuronium 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 action.

The processes of elimination (metabolism and excretion) of many MPs 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. The kidneys are the main route of excretion of pancuronium bromide and pipecuronium bromide. Existing liver and kidney diseases should also be taken into account when using suxamethonium chloride. The drugs of choice for these diseases are atracurium besylate and cisatracurium besylate due to their characteristic organ-independent elimination.

Contraindications and warnings

There are no absolute contraindications to the use of MP when using artificial ventilation during anesthesia, except for known hypersensitivity to drugs. Relative contraindications for the use of suxamethonium chloride have been noted. It is prohibited:

• patients with eye injuries;
• for diseases that cause increased intracranial pressure;
• in case of plasma cholinesterase deficiency;
• for severe burns;
• in case of traumatic paraplegia or spinal cord injury;
• in 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 NMB. In addition, in many diseases, especially of the nervous system and muscles, the response to the introduction of MP can also change significantly.

The use of MP in children has certain differences associated with both the developmental characteristics of the neuromuscular synapse in children in the first months of life and the pharmacokinetics of MP (increased distribution volume and slower drug elimination).

During pregnancy, suxamethonium chloride should be used with caution, since repeated administration of the drug, as well as the possible presence of atypical pseudocholinesterase in the fetal plasma, can cause severe suppression of the LUT.

The use of suxamethonium chloride in elderly patients does not differ significantly from other age categories of adults.

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Tolerability and side effects

In general, the tolerability of MP depends on such properties of the drug as the presence of cardiovascular effects, the ability to release histamine or cause anaphylaxis, the ability to accumulate, and the possibility of interrupting the block.

Histamine release and anaphylaxis. It is estimated that the average anesthesiologist will encounter a serious histamine reaction once a year, but less serious chemically mediated histamine release reactions occur very frequently.

As a rule, the reaction to the release of histamine after the introduction of MP is limited to a skin reaction, although these manifestations can be much more severe. Usually, these reactions are manifested by reddening of the skin of the face and chest, less often by urticarial rash. Such serious complications as the occurrence of severe arterial hypotension, the development of laryngo- and bronchospasm, develop rarely. Most often, they are described when using suxamethonium chloride and tubocurarine chloride.

According to the frequency of occurrence of the histamine effect, neuromuscular blockers can be arranged in the following order: suxamethonium chloride > tubocurarine chloride > mivacurium chloride > atracurium besylate. Next come vecuronium bromide, pancuronium bromide, pipecuronium bromide, cisatracurium besylate and rocuronium bromide, which have approximately equal ability to histamine liberation. It should be added that this mainly concerns anaphylactoid reactions. As for true anaphylactic reactions, they are recorded quite rarely and the most dangerous are suxamethonium chloride and vecuronium bromide.

Perhaps the most important question for the anesthesiologist is how to avoid or reduce the histamine effect when using MP. In patients with a history of allergies, muscle relaxants should be used that do not cause a significant release of histamine (vecuronium bromide, rocuronium bromide, cisatracurium besylate, pancuronium bromide, and pipecuronium bromide). The following measures are recommended to prevent the histamine effect:

• inclusion of H1- and H2-antagonists in premedication, and, if necessary, corticosteroids;
• introduction of MP into the central vein if possible;
• slow administration of drugs;
• dilution of drugs;
• flushing the system with isotonic solution after each MP administration;
• avoiding mixing MP in one syringe with other pharmacological drugs.

The use of these simple techniques under any anesthesia can dramatically reduce the incidence of histamine reactions in the clinic, even in patients with a history of allergies.

A very rare, unpredictable 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 increase in body temperature, a significant increase in oxygen consumption and carbon dioxide production. In the development of malignant hyperthermia, it is recommended to quickly cool the body, inhale 100% oxygen and control acidosis. The use of dantrolene is of decisive importance for the treatment of malignant hyperthermia syndrome. The drug blocks the release of calcium ions from the sarcoplasmic reticulum, reduces muscle tone and heat production. Abroad, in the last two decades, a significant decrease in the frequency of fatal outcomes in the development of malignant hyperthermia has been noted, 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 pain, hyperkalemia, increased intraocular pressure, increased intracranial pressure, and cardiovascular effects. In this regard, contraindications for its use are highlighted.

To a large extent, the safety of the use of MP during anesthesia can be ensured by monitoring the NMP.

Interaction

MPs are always used in various combinations with other pharmacological agents and are never used in pure form, since they provide the only component of general anesthesia - myoplegia.

Favorable combinations

All inhalation anesthetics to some extent potentiate the degree of NMB caused by both depolarizing and non-depolarizing agents. This effect is least pronounced in dinitrogen oxide. Halothane causes a 20% prolongation of the block, and enflurane and isoflurane - by 30%. In this regard, when using inhalation anesthetics as a component of anesthesia, it is necessary to correspondingly reduce the MP dosage both during tracheal intubation (if the inhalation anesthetic was used for induction) and when administering maintenance boluses or calculating the rate of continuous MP infusion. When using inhalation anesthetics, MP doses are usually reduced by 20-40%.

The use of ketamine for anesthesia is also believed to potentiate the action of non-depolarizing MPs.

Thus, such combinations allow to reduce the dosages of MPs used and, consequently, to reduce the risk of possible side effects and the consumption of these funds.

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

Combinations that require special attention

Cholinesterase inhibitors (neostigmine methylsulfate) are used for decurarization when using non-depolarizing MP, but they significantly prolong 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 this is recommended in exceptional cases due to the risk of recurarization. Recurarization is a repeated paralysis of skeletal muscles, deepening of the residual effect of MP under the influence of unfavorable factors after the restoration of adequate spontaneous breathing and skeletal muscle tone. The most common cause of recurarization is the use of anticholinesterase agents.

It should be noted that when using neostigmine methylsulfate for decurarization, in addition to the risk of developing recurarization, a number of serious side effects may also be observed, such as:

• bradycardia;
• increased secretion;
• Smooth muscle stimulation:
  • intestinal peristalsis;
  • bronchospasm;
• nausea and vomiting;
• central effects.

Many antibiotics can disrupt the mechanism of NMP and potentiate NMB when using MP. The strongest effect is exerted by polymyxin, which blocks ion channels of acetylcholine receptors. Aminoglycosides reduce the sensitivity of the postsynaptic membrane to ACh. Tobramycin can have a direct effect on muscles. Such antibiotics as lincomycin and clindamycin also have a similar effect. In this regard, it is necessary to avoid prescribing the above antibiotics immediately before or during surgery, using other drugs of this group instead.

It should be taken into account that NMB is potentiated by the following drugs:

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

On the contrary, in case of long-term previous use of anticonvulsant drugs phenythion or carbamazepine, the effect of non-depolarizing MPs is weakened.

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

Undesirable combinations

Since muscle relaxants are weak acids, chemical interactions may occur between them when mixed with alkaline solutions. Such interactions occur when a muscle relaxant and the hypnotic sodium thiopental are injected in the same syringe, which often causes severe depression of blood circulation.

Therefore, muscle relaxants should not be mixed with any other medications, except for the recommended solvents. Moreover, the needle or cannula should be flushed with neutral solutions before and after the muscle relaxant is administered.