Reducing the tone of skeletal muscles with a decrease motor activity up to complete immobilization.
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Basic pharmacology of peripherally acting muscle relaxants
Muscle relaxants | Trigger point blockade | Trigger Point Injection
Anticholinergics. M and N-anticholinergics.
Mechanism of action - blockade of H-cholinergic receptors at synapses stops the supply of nerve impulses to skeletal muscles, and the muscles stop contracting. Relaxation comes from bottom to top, from the tips of the toes to the facial muscles. The last thing to relax is the diaphragm. Conductivity restoration proceeds in the reverse order. The first subjective sign of the end of muscle relaxation is the patient’s attempts to breathe on his own. Signs of complete decurarization: the patient can raise and hold his head for 5 seconds, squeeze his hand tightly and breathe independently for 10-15 minutes without signs of hypoxia.
Objectively, the degree of effect of muscle relaxants is determined using the following methods: electromyography, accelomyography, peripheral neurostimulation, mechanomyography.
The duration of action of muscle relaxants is prolonged in the presence of such factors: hypotension, hypoxia, hypercapnia, metabolic acidosis, hypovolemia, microcirculation disorders, hypokalemia, deep anesthesia, hypothermia, old age patient.
2. Providing muscle relaxation during surgical interventions to create optimal working conditions for the surgical team without excessive doses of drugs for general anesthesia, as well as the need for muscle relaxation during certain diagnostic procedures performed under general anesthesia (for example, bronchoscopy).
3. Suppression spontaneous breathing for the purpose of performing mechanical ventilation.
4. Elimination convulsive syndrome when anticonvulsants are ineffective.
5. Blockade defensive reactions in the cold as muscle tremors and muscle hypertonicity during artificial hypothermia.
6. Myorelaxation during reposition of bone fragments and reduction of dislocations in joints where there are powerful muscle masses.
4. Increased pressure inside hollow organs and body cavities.
5. The release of potassium into the blood can lead to hyperkalemia, which in turn leads to bradycardia and cardiac arrest.
Contraindications:
1. Patients with baseline hyperkalemia ( renal failure, extensive burns and muscle injuries).
2. Patients with cardiac arrhythmias.
3. Patients at risk of complications due to increased ICP, increased pressure in the hollow organs of the gastrointestinal tract. Patients with glaucoma.
Preparations:
Currently due to possible complications in the clinic only listenone is used, but it is also gradually being replaced by short-acting non-depolarizing muscle relaxants.
Non-depolarizing muscle relaxants- block receptors and membrane channels without opening them, without causing depolarization. The duration of action and properties depend on the drug.
Anticholinesterase drugs block cholinesterase, the amount of acetylcholine increases and it competitively displaces the non-depolarizing muscle relaxant. Prozerin is used at a dose of 0.03-0.05 mg/kg body weight. 2-3 minutes before use for leveling side effects proserina, atropine 0.1% 0.5 ml is administered. intravenously. Decurarization is contraindicated in cases of deep muscle block and any disturbance of water and electrolyte balance. If the effect of proserin ends earlier than the effect of the muscle relaxant, then recurarization- resumption of muscle relaxation due to activation of cholinesterase and a decrease in the amount of acetylcholine in the synaptic cleft.
Muscle relaxants- drugs intended to relax striated muscles. An important property of muscle relaxants is their ability to prevent reflex activity of all voluntary muscles. This property has great value in surgery and anesthesiology, since muscle tone often interferes with creating optimal conditions for surgery and intubation.
All muscle relaxants can be divided into depolarizing and non-depolarizing. In addition, from a clinical point of view, it is advisable to subdivide muscle relaxants into ultra-short-acting drugs (acting for 5-7 minutes), short-acting (duration of action less than 20 minutes), average duration(less than 40 min) and muscle relaxants long acting(more than 40 minutes).
To depolarizing muscle relaxants include suxamethonium drugs - listenone, dithiline, succinylcholine. They are also ultra-short-acting muscle relaxants and differ from each other only in the salt they contain.
To non-depolarizing muscle relaxants short-acting drugs include mivacurium. Non-depolarizing muscle relaxants of intermediate duration are atracurium, vecuronium, rocuronium, cisatracurium. Representatives of long-acting non-depolarizing muscle relaxants are pipecuronium, pancuronium, and tubocurarine.
The structure of depolarizing muscle relaxants is similar to the acetylcholine molecule. When interacting with H-cholinergic receptors, suxamethonium drugs cause an action potential in the muscle cell. Thus, like acetylcholine, depolarizing muscle relaxants cause depolarization and stimulation of the muscle fiber. However, acetylcholinesterase does not act on suxamethonium drugs, as a result of which their concentration in the synaptic cleft increases. This leads to prolonged depolarization of the end plate and muscle relaxation.
The destruction of depolarizing muscle relaxants occurs by plasma cholinesterase.
When suxamethonium is administered, complete neuromuscular blockade occurs within 30-40 seconds, which allows them to be used for tracheal intubation. The duration of the neuromuscular block is from 4 to 6 minutes. This time may increase with quantitative or qualitative deficiency of plasma cholinesterase. The incidence of failure is 1:3000.
Sometimes depolarizing relaxants can cause a second phase of the block - non-depolarizing block. Then the effect of suxamethonium drugs acquires an unpredictable effect and duration.
When using suxamethonium drugs, one should keep in mind their high histamine effect.
Side effects of depolarizing muscle relaxants on the cardiovascular system is expressed in rhythm disturbances, fluctuations blood pressure and heart rate. Moreover, suxamethonium drugs more often cause bradycardia.
Another side effect inherent in all depolarizing muscle relaxants is fasciculations, the presence of which is used to judge the onset of action of the drug. If the appearance of fasciculations is undesirable, then precuration should be performed before administering suxamethonium. This is the name of the method of administering a non-depolarizing muscle relaxant (for example, 1 mg of arcuron) 5 minutes before the administration of suxamethonium to prevent the side effects of the latter.
A serious side effect when using suxamethonium drugs is hyperkalemia. If your baseline potassium level is normal, this side effect will not occur. clinical significance. In conditions accompanied by an increase in the level of potassium in the blood (burns, extensive injuries, myopathy, tetanus, acute intestinal obstruction) the use of depolarizing muscle relaxants can be life-threatening.
A common side effect of suxamethonium drugs is muscle pain in the postoperative period.
The increase in gastric pressure caused by muscle relaxants from the group of depolarizing drugs does not increase the risk of gastric reflux and pulmonary aspiration.
Succinylcholine increases intraocular pressure, which may limit its use in ophthalmic operations in the absence of precurarization.
Ultrashort muscle relaxants increase cerebral blood flow and intracranial pressure, which can also be prevented by precurarization.
Depolarizing muscle relaxants can cause malignant hyperthermia.
The administration of suxamethonium for myotonia is dangerous - it can provoke generalized contractions (myoclonus).
A typical representative of the muscle relaxants most widely used in the CIS countries is ditilin.
Ditilin is available in ampoules of 2 ml in the form of a 2% solution. When administered intravenously, the effect develops after 60 seconds and lasts 5-10 minutes; when administered intramuscularly, muscle relaxation develops after 2-4 minutes and lasts 5-10 minutes.
Ditilin is successfully used for tracheal intubation, during broncho- and esophagoscopy, and for short-term operations.
Molecules of non-depolarizing muscle relaxants compete with the acetylcholine molecule for the right to bind to the receptor. When a muscle relaxant binds to the receptor, the latter loses sensitivity to acetylcholine, the postsynaptic membrane is in a state of polarization and depolarization does not occur. Thus, non-depolarizing muscle relaxants in relation to choline receptors can be called competitive antagonists.
Non-depolarizing muscle relaxants are not destroyed by either acetylcholinesterase or blood cholinesterase.
Mivacurium- muscle relaxant, effective for up to 20 minutes. Its use is limited due to the relatively common side effect of histamine release. In addition, the dependence of its metabolism on pseudocholinesterase does not allow complete decurarization with anticholinesterase drugs.
Having appeared on the market, mivacurium did not live up to the expectations of manufacturers, although its use still has to be resorted to under certain conditions.
Atracurium (tracrium)- muscle relaxant of medium duration of action. Available in ampoules of 2.5 and 5 ml. 1 ml contains 10 mg of active substance.
Tracrium is used as a component of general anesthesia for tracheal intubation. Its action is especially useful when surgical interventions and to facilitate mechanical ventilation.
In adults, Tracrium is used at a rate of 0.3-0.6 mg/kg. If additional administration of a muscle relaxant is necessary, the dose should be calculated in the amount of 0.1-0.2 mg/kg.
For children over the age of two years, atracurium is prescribed in the same dosages as adults. In children under two years of age, a muscle relaxant is used at a rate of 0.3-0.4 mg/kg under halothane anesthesia.
Restoration of conduction after neuromuscular blockade caused by atracurium occurs after approximately 35 minutes.
Side effects of using Tracrium can be:
Verocuronium- non-depolarizing muscle relaxant of steroid structure. Verocuronium has little effect on histamine release and is cardiac stable.
Cisatracurium (nimbex), which is a stereoisomer of atracurium, is three times stronger than it, although the time of onset of the effect and its duration is approximately the same as that of atracurium.
Cisatracurium is available in the form of 2.5 and 5 ml ampoules of 2 and 5 mg.
As with all muscle relaxants, indications for the use of cisatracurium include tracheal intubation, maintaining muscle relaxation, and performing mechanical ventilation.
Nimbex is used for tracheal intubation at a dose of 0.15 mg/kg, a maintenance dose of 0.1 mg/kg.
Rocuronium (esmeron)- non-depolarizing muscle relaxant of medium duration of action, positive feature which is the speed of onset of the effect. In addition, minimal histamine release and negligible cardiovascular effects have made rocuronium a very popular drug in anesthesiology.
Esmeron is available in bottles of 5 ml, 10 ml and 25 ml. 1 ml contains 10 mg of rocuronium bromide.
The dose of rocuronium for tracheal intubation is 0.3-0.6 mg/kg, the maintenance dose is 0.15 mg/kg.
Pipecuronium (arduan, arcuron) refers to long-acting non-depolarizing muscle relaxants.
Arduan is available in ampoules of 2 ml (1 ml contains 4 mg of pipecuronium bromide).
In adults, pipecuronium is used at the rate of 0.07-0.08 mg/kg, in children - 0.08-0.09 mg/kg. The effect of the drug lasts for 50-70 minutes.
From side effects pipecuronium, bradycardia, hypotension, and rarely anaphylactic reactions should be noted.
Pankurina (pavulon)- available in ampoules for intravenous administration of 2 ml (1 ml contains 2 mg of pancuronium bromide).
In adults and children from four weeks of age, pancuronium is used at a dose of 0.08-0.1 mg/kg. The drug causes good muscle relaxation for tracheal intubation in 90-120 seconds.
Side effects from cardiovascular system caused by pancuronium - slight increase Heart rate and blood pressure.
Tubocurarine Available in the form of a 1% solution in ampoules of 1.5 ml.
Currently, tubocurarine is practically not used due to the arterial hypotension and tachycardia it causes, which is a consequence of increased histamine release.
Muscle relaxants are antispasmodics medicines, the action of which is intended to relieve spasms in muscle tissue and elimination of increased muscle tone. This eliminates symptoms such as pain and numbness. Some drugs tend to completely inhibit muscle activity.
Indications for the use of these drugs are the following pathologies accompanied by spasm of muscle tissue:
Antispasmodics are also used during operations, massage, and some procedures to inhibit conductivity. Very often such means are used in rehabilitation period after surgery and trauma.
The use of muscle relaxants is prohibited in the presence of the following indications:
Antispasmodics are divided into 4 types, depending on the duration of the relaxing effect:
Depending on how muscle relaxants interact with receptors, there are 2 types of drugs:
According to the nature of the effect, muscle relaxants are:
The most effective muscle relaxants are drugs such as:
In order for the effect of using antispasmodics to be maximum, they must be used in accordance with the rules:
If the drugs are used incorrectly, side effects may occur such as weakness, headaches, nausea, decreased attention, insomnia, increased drowsiness, increased excitability, rapid pulse, liver and stomach problems.
MILITARY MEDICAL ACADEMY
DEPARTMENT OF ANESTHESIOLOGY AND RESUSCITATION
“MUSLELAXANTS, THEIR APPLICATION IN ANESTHESIOLOGY AND RESUSCITATION”
Introduction
Back in the 16th century. It became known that South American Indians use poisoned arrows for hunting and war, the poison of which - curare - causes death due to paralysis of the respiratory muscles.
After Harold Griffith published the results of the use of purified curare extract during anesthesia in 1942, muscle relaxants quickly gained their rightful place in the arsenal of anesthesiologists and resuscitators.
The discovery of the active principle of curare, tubocurarine, had a huge impact on the development of anesthesiology and surgery and made it possible to study the mechanism of neuromuscular transmission.
Muscle relaxants are drugs that block neuromuscular transmission. They are used for controlled mechanical ventilation of the lungs, creating conditions for the work of the surgical team, especially during operations on the chest and abdomen, to reduce intracranial hypertension, reducing oxygen consumption, eliminating tremors, ensuring immobility during certain diagnostic procedures, relieving convulsive syndrome and in a number of other cases.
All neuromuscular transmission blockers are similar in chemical structure to acetylcholine. For example, succinylcholine actually consists of 2 molecules of acetylcholine (slide). Non-depolarizing relaxants hide their acetylcholine-like structure in the form of ring systems of 2 types - isoquinoline and steroid (slide). The presence of one or two quaternary nitrogen atoms in all neuromuscular transmission blockers makes these drugs poorly lipid soluble, which prevents them from entering the central nervous system.
All neuromuscular transmission blockers are highly polar and inactive when taken orally. They are administered only intravenously.
Elimination of the drug is carried out due to its destruction by pseudocholinesterase (butyrylcholinesterase) of the blood plasma into choline and succinyl monocholine, followed by further hydrolysis of the latter into succinic acid and choline.
The metabolism of the drug is impaired by hypothermia (slow hydrolysis) and by low concentrations or a hereditary defect of pseudocholinesterase. Non-depolarizing relaxants exhibit an antagonistic effect on succinylcholine. So even precurarization (as mentioned above) forces you to increase the dose of succinylcholine by 50-100%. The exception here is pancuronium. It enhances the effect of succinylcholine by inhibiting the activity of pseudocholinesterase.
From a fairly large list of non-depolarizing relaxants, we will consider only the most frequently used. And we'll start with an idea of the ideal muscle relaxant.
Properties of the “ideal” muscle relaxant (slide):
High activity;
Competitive mechanism of action;
Selectivity of action on n-cholinergic receptors of skeletal muscles;
Fast onset of action;
Short-term block of neuromuscular transmission (with a single injection no more than 15 minutes);
No potentiation or accumulation upon repeated administration;
No side effects;
Low toxicity;
Lack of physiological and toxic activity of metabolites and their rapid elimination from the body;
Availability of effective antagonists;
Storage stability;
Profitability for industrial production.
Table 4
Modern muscle relaxants (1)
| Name | Histamine release | Vagus | Ganglion stimulation | Release form | Dosage | Block development time | Duration actions |
Price |
| Succinylcholine | Steam | Steam | 20 mg/ml | 1 mg/kg | 30 s | 5-10 min | $0.36/200 mg | |
| d-tubocurarine | - | Block. | 3 mg/ml | 0.5 mg/kg | 3 min | 60-100 min | $4.51/60 mg | |
| Metokurin | - | - | Block. | 2 mg/ml | 0.3 mg/kg | 3 min | 60-120 min | $20.27/40 mg |
| Pancuronium | - | Block. | - | 1 mg/ml | 0.1 mg/kg | 3 min | 60-120 min | $1.31/10 mg |
| Doxacurium | - | - | - | 1 mg/ml | 0.06 mg/kg | 4 min | 90-150 min | $13.49/5 mg |
| Vecuronium | - | - | - | 10 mg | 0.1 mg/kg | 2 min | 45-90 min | $18.11/10 mg |
| Cisatracurium | - | - | - | 10 mg/ml | 0.5 mg/kg | 2 min | 30-45 min | $39.47/100 mg |
| Rocuronium | - | Block. | - | 10 mg/ml | 1 mg/kg | 1 min | 45-75 min | $14.62/50 mg |
| Miwakuri | - | - | 20 mg/ml | 0.2 mg/kg | 1 min | 15-20 min | $8.05/100 mg |
Table 5
Modern muscle relaxants (2)
| Muscle relaxant | Metabolism | Main route of elimination | Start of action | Duration of action | Histamine release | Vagus nerve block | Relative power | Relative cost |
| Tubocurarine | Minor | Kidneys | ++ | +++ | +++ | 0 | 1 | Low |
| Metokurin | Minor | Kidneys | ++ | +++ | ++ | 0 | 2 | Average |
| Atracurium | +++ | Minor | ++ | ++ | + | 0 | 1 | High |
| Miwakuri | +++ | Minor | ++ | + | + | 0 | 2,5 | Average |
| Doxacurium | Minor | Kidneys | + | +++ | 0 | 0 | 12 | High |
| Pancuronium | + | Kidneys | ++ | +++ | 0 | ++ | 5 | Low |
| Pipecuronium | + | Kidneys | ++ | +++ | 0 | 0 | 6 | High |
| Vecuronium | + | Bile | ++ | ++ | 0 | 0 | 5 | High |
| Rocuronium | Minor | Bile | +++ | ++ | 0 | + | 1 | High |
According to the literature, the most used non-depolarizing muscle relaxants in the world today are atracurium and cisatracurium, doxacurium, mivacurium, vecuronium, and the rapidly gaining popularity of rocuronium. Pancuronium (Pavulon) and pipecuronium (Arduan) are still widely used in our country. In this regard, we will dwell in more detail on the main and side effects of these particular representatives of the class of non-depolarizing relaxants.
Atracurium
The undoubted advantage of the drug is its ability to undergo spontaneous destruction in the body due to two processes - hydrolysis of the ester bond (catalyzed by nonspecific esterases without the participation of acetylcholine and pseudocholinesterase), and Hoffman elimination (spontaneous non-enzymatic destruction with physiological values pH and body temperature). No more than 10% of the drug is excreted in urine and bile.
For tracheal intubation, a dose of 0.5 mg/kg is required. An effective block develops after 2.3±1.1 minutes (Mellinghoffetal., 1996) or even after 1.2 minutes (Debaene B. etal., 1995). The duration of the block is 20-30 minutes (SharpeM.D., 1992). The loading dose for intraoperative muscle relaxation is 0.25 mg/kg, maintenance dose is 0.1 mg/kg every 10-20 minutes, an infusion of 5-9 mcg/kg/min can be used. BeattieW.S. et al. (1992) reported the effectiveness of an infusion dose of 7.6 ± 1.1 μg/kg/min.
Moreover, even after a long-term infusion of the drug during intensive care rapid spontaneous restoration of neuromuscular conduction is noted. SharpeM.D. (1992) provides the results of a study in which, after a 90-hour infusion of the drug, the termination of the block occurred on average after 39 minutes, which is associated with the absence of cumulation against the background of the destruction of atracurium due to Hoffman elimination.
Side effects of the drug (SharpeM.D., 1992; MorganG.E., MikhailM.S., 1996):
Hypotension and tachycardia associated with histamine release occur rarely, especially with slow administration and avoiding overdose. Observed mainly in elderly patients and patients with hypovolemia;
Bronchospasm can occur even without a history of bronchial asthma;
Excitation of the central nervous system and convulsions associated with the action of the atracurium metabolite, laudanosine, can be observed with an absolute or relative (liver failure) overdose of the drug.
Kumar A. A. et al. (1993) described severe anaphylactic shock after administration of atracurium, requiring large doses of adrenaline and prolonged cardiopulmonary resuscitation.
It must be remembered that hypothermia and acidosis, complicating Hoffman's elimination, prolong the effect of the drug (MorganG.E., MikhailM.S., 1996).
Cisatracurium
This drug is an isomer of atracurium. It is also subject to Hoffman elimination, however, unlike atracurium, it is not destroyed by nonspecific esterases. Hepatic and renal failure do not affect the metabolism of cisatracurium (PrielippR.C. etal., 1995; DeWolfA.M. etal., 1996; MorganG.E., MikhailM.S., 1996).
The dose for intubation is 0.1 – 0.15 mg/kg. Moreover, when administered, respectively, 0.1; 0.15 and 0.2 mg/kg, the effective block develops after 4.6; 3.4 and 2.8 minutes, and its duration is 45; 55 and 61 min. Intubation can be performed respectively 2 minutes after administration of 0.1 mg/kg and 1.5 minutes after administration of a larger dose (Bluestein L.S. etal., 1996). According to Bunyanat A.A. et al. (1999) and Mizikova V.M. et al. (1999) after administration of 0.15 mg/kg of the drug good conditions for tracheal intubation occur within 3 minutes.
To maintain relaxation, infusion is used at a rate of 1-2 mcg/kg/min (MorganG.E., MikhailM.S., 1996) or repeated bolus doses of 0.03 mg/kg (Bunyatyan A.A. et al., 1999; Mizikov V.M. et al., 1999). Repeated bolus doses provide clinically effective myoplegia within 18-26 minutes, and the duration of the 95% block after the initial dose of 0.15 mg/kg averaged 54±10 minutes (Bunyatyan A.A. et al., 1999 ).
Mellinghoff H. et al. (1996) used 0.1 mg/kg cisatracurium as an initial dose. The effect developed after 3.1±1.0 minutes. To maintain a 95% block, an infusion of the drug at a rate of 1.5 ± 0.4 μg/kg/min was required. After stopping the infusion, the spontaneous recovery time from 25% to 75% TOF was 18±11 minutes, and during decurarization it was 5±2 minutes.
Unlike atracurium, the drug does not cause an increase in plasma histamine levels and, accordingly, does not affect heart rate, blood pressure and the autonomic nervous system. No allergic skin reactions or bronchospasm were also noted (Lepage J.-Y. et al., 1996; Bunyatyan A.A. et al., 1999; Mizikov V.M. et al., 1999).
The toxicity of laudanosine, formed during Hoffman elimination, and sensitivity to temperature and pH are similar to those of atracurium (DeWolfA.M. etal., 1996; MorganG.E., MikhailM.S., 1996).
The advantage of cisatracurium over vecuronium and rocuronium is its dose-independent rate of block termination. The advantage compared to atracurium comes down to almost only a clearly lower histamine liberation and a threefold advantage in potency (PrielippR.C. etal., 1995; BluesteinL.S. etal., 1996; DeWolfA.M. etal., 1996). Recovery after a long-term infusion of cisatracurium occurs faster than after a similar administration of vecuronium (Prielipp R.C. et al., 1995).
Thus, as noted by most researchers, cisatracurium is a strong non-depolarizing muscle relaxant with an average duration of action, characterized by no effect on blood circulation and does not cause histamine release, which allows its use in patients with high surgical and anesthetic risk.
Miwakuri
Distinctive feature this drug is its hydrolysis, like succinylcholine, using pseudocholinesterase. Although, in the presence of even minimally restored muscle tone, anticholinesterase drugs are effective in terms of decurarization. In case of hepatic and renal (?) failure, the concentration of cholinesterase decreases, thereby increasing the duration of action of mivacrone.
To carry out tracheal intubation, a dose of 0.15-0.2 mg/kg is required. In the future, it is recommended to maintain muscle relaxation with an infusion at a rate of 4-10 mcg/kg/min or fractional administration of 0.1-0.15 mg/kg. A complete muscle block after administration of an intubation dose develops in 1.5-2.2 minutes, the duration of the block is 10-12 minutes (Bashev N.N. et al., 1998). According to other data, the onset of action of the drug is 2-3 minutes, and the duration of the block is about 20 minutes (SharpeM.D., 1992; MorganG.E., MikhailM.S., 1996; Grinenko, T.F. et al., 1998).
Mivacurium can cause histamine liberation, which can manifest as arterial hypotension and tachycardia. Therefore, it is recommended to include in premedication antihistamines(Bashev N.N. et al., 1998). Although according to Rovina A.K. et al. (1998), pronounced changes hemodynamics and histaminogenic complications were absent when using mivacurium. SharpeM.D. (1992) indicates that hypotension develops more often when a dose is administered higher than 0.15 mg/kg, or when the drug is administered rapidly as a bolus (faster than 60 s).
Mivacurium reduces intraocular pressure, therefore it is recommended for intraocular operations (Maloyaroslavtsev V.D. et al., 1998).
In general, mivacron is considered the drug of choice for short operations, especially in a one-day hospital (Grinenko T.F. et al., 1998).
Doxacurium
Partially hydrolyzed by pseudocholinesterase. The main route of elimination is excretion by the kidneys (up to 40%) and bile (Sharpe M.D., 1992; Morgan G.E., Mikhail M.S., 1996). Therefore, its effect is prolonged in case of liver and/or kidney failure.
For intubation, a dose of 0.05 mg/kg is required. In this case, acceptable conditions are created after 5 (MorganG.E., MikhailM.S., 1996) or 6 minutes (SharpeM.D., 1992), while the average duration of the block is 83 minutes (60-90 minutes) - the longest among all muscle relaxants. The loading dose for intraoperative muscle relaxation is 0.02 mg/kg; for maintenance it is sufficient to administer the drug in fractional doses of 0.005 mg/kg.
Doxacurium does not release histamine and therefore does not affect circulation.
Due to its mild side effects and long duration of action, it is considered the most convenient for long-term relaxation during intensive therapy (SharpeM.D., 1992).
Pancuronium (pavulon)
To a certain extent, it undergoes deacetylation in the liver, in addition, the main part of the drug is excreted by the kidneys. Therefore, hepatic and renal failure affect the pharmacokinetics of the drug.
For tracheal intubation, a dose of 0.08-0.12 mg/kg is required. Satisfactory conditions for intubation occur within 2-3 minutes. The loading dose for muscle relaxation is 0.04 mg/kg, the maintenance dose is 0.01 mg/kg every 20-40 minutes (MorganG.E., MikhailM.S., 1996). By SharpeM.D. (1992), after administration of 0.1 mg/kg of the drug, satisfactory conditions for tracheal intubation arise after 90-120 s. The block lasts up to 60 minutes. For prolonged myoplegia, it is recommended to use an infusion of 0.02-0.04 mg/kg/h.
Renal and liver failure, liver cirrhosis, and impaired bile outflow prolong the effect of the drug (up to twofold). Therefore, it should be used with caution in intensive care, where significant prolongation of neuromuscular block is possible (Sharpe M.D., 1992). For prolonged myoplegia in intensive care Khuenl-Brady K.S. et al. (1994) recommends an average dose of 3 mg/hour.
A distinctive feature of the drug is its ability to block the influence of the vagus and release catecholamines from adrenergic nerve endings, and also inhibit norepinephrine retake. In this regard, the side effects of the drug are tachycardia, moderate hypertension, arrhythmias, increased myocardial oxygen demand (SharpeM.D., 1992; MorganG.E., MikhailM.S., 1996).
In general, the drug has quite unpleasant side effects; in case of hepatic-renal failure, its effect can be significantly prolonged, but among all non-depolarizing relaxants of medium and long action, it is the cheapest drug.
Vecuronium
It is very close in chemical structure to pancuronium, and therefore side effects are much less pronounced.
Metabolized to a small extent in the liver, excreted in bile and kidneys. Vecuronium is equally effective as pancuronium and is administered in similar doses. When 0.1 mg/kg was administered after 90-120 s, ideal conditions for intubation were created. The duration of action of the drug ranged from 20-25 minutes (Nalapko Yu.I., 1998) to 45 minutes (SharpeM.D., 1992).
Its use at an initial dose of 0.4 mg/kg reduced the time until the development of block to 78 s without the manifestation of any hemodynamic effects. The use of a dose of 0.5 mg/kg caused the development of a block similar in speed to succinylcholine. Therefore SharpeM.D. (1992) concludes that in patients for whom succinylcholine is contraindicated, vecuronium at a dose of 0.4-0.5 mg/kg is an alternative for tracheal intubation. However, the average block duration is 115 minutes.
HuemerG. et al. (1995) recommends that to accelerate the development of the block, first administer 0.01 mg/kg, then after 4 minutes 0.05 mg/kg. In this case, 1-2 minutes after the administration of the second dose, good conditions arise for tracheal intubation. The duration of the block is short, which is important for outpatient anesthesiology.
An incremental bolus dose is 0.03 mg/kg, its duration of action is 25-30 minutes (Babaeva N.P., 1998). Possible infusion at a dose of 1-2 mcg/kg/min (MorganG.E., MikhailM.S., 1996) or 0.1-0.2 mg/kg/h (SharpeM.D., 1992). However, the latter applies mainly to operations, since during intensive therapy either large doses may be required, or (in the presence of renal or liver failure, cholestasis) the block can be significantly prolonged (Sharpe M.D., 1992). In any case, there is no consensus in the literature regarding the advisability of using vecuronium for myoplegia in intensive care, although in this sense it is practically attractive complete absence it has side effects.
BeattieW.S. et al. (1992) notes that with the required block duration of up to 30 minutes, the drug should be infused at a rate of 1.01±0.16 mcg/kg/min, with a block of up to 60 minutes - 0.89±0.12 mcg/kg/min , and with a block of 90 minutes or more – 0.85±0.17 mcg/kg/min (on average, 0.94±0.23 mcg/kg/min). A similar decrease in the infusion rate to maintain sufficient relaxation (which indicates cumulation) was also noted by Martineau R.J. et al. (1992). In his study, it was possible to reduce the infusion rate to 0.47 ± 0.13 μg/kg/min.
The duration of action of the drug is generally somewhat shorter than that of pancuronium due to faster elimination. It has no effect on blood circulation, since it does not have a ganglion-blocking effect and does not release histamine. Therefore, it is recommended for use in patients with high anesthetic risk (Babaeva N.P., 1998), as well as in military field anesthesiology and disaster medicine (Bakeev R.F., 1998). In the latter case, the short duration of action, rapid restoration of muscle tone and spontaneous breathing, and the absence of accumulation upon repeated administration are of particular importance, which allows increasing the throughput of the medical evacuation stage and ensuring, if necessary, immediate evacuation of the wounded.
Due to fast recovery muscle tone, which does not require the use of anticholinesterase drugs, is recommended for use during thoracic operations (Kuznetsova O.Yu. et al., 1998), during laparoscopic cholecystectomies (Nalapko Yu.I., 1998).
The drug is considered optimal from the standpoint of the cost/effectiveness criterion with an average duration and long operations(Grinenko T.F. et al., 1998).
Pipecuronium (Arduan)
Also very similar in structure to pancuronium. Metabolism is negligible. Elimination is determined by excretion through the kidneys (70%) and bile (20%). The drug is slightly more powerful than pancuronium. The dose for intubation is 0.06-0.1 mg/kg. Maintenance doses are 20% less than pancuronium. The drug does not cause the release of histamine and does not affect blood circulation (MorganG.E., MikhailM.S., 1996). With the introduction of 0.07 mg/kg, optimal conditions for intubation occur after 3 minutes, and a clinically effective block lasts 70 minutes (Sharpe M.D., 1992).
As with pancuronium, an average dose of 3 mg/h is recommended for prolonged myoplegia in intensive care (Khuenl-Brady K.S. etal., 1994).
Rocuronium
It is not metabolized and is eliminated mainly through bile, less through the kidneys. Moreover, according to Suslov V.V. et al (1998), the pharmacodynamic characteristics of the drug do not depend on the degree of renal failure. The potency of the drug is significantly lower than that of other relaxants, in particular, the ratio of its potency compared to atracurium and vecuronium looks like 1: 1.2: 8.5 (Bartkowski R.R. etal., 1993). To carry out intubation, it is necessary to administer 0.45-0.6 mg/kg of the drug. After administration of 0.6 mg/kg, good or excellent conditions for intubation (MarenovicT., MarkovichM., 1998). And PuuhringerF.K. et al. (1992) noted acceptable conditions for tracheal intubation within 60 s after administration of the specified dose of the drug. For maintenance, rocuronium is administered at 0.15 mg/kg.
Rocuronium at a dose of 0.9-1.2 mg/kg begins to act almost as quickly as succinylcholine. Therefore, it is convenient for tracheal intubation. The duration of action and recovery time after an intubation dose are similar to those of vecuronium and atracurium, no accumulation was observed over 7 consecutive administrations, does not affect hemodynamics and does not release histamine, and gives a fairly pronounced vagolytic effect. Therefore, the drug comes close to the “ideal” relaxant (Marenovic T., Markovich M., 1998; Suslov V.V. et al., 1998), and it is considered the most preferable for operations in elderly and old age(Suslov V.V. et al., 1998), patients with high anesthetic risk (McCoy E.P. et al., 1993).
Comparative assessment drugs
J. Viby-Mogensen (1998) believes that it is more economically profitable to use more expensive relaxants of medium and short duration of action (vecuronium, atracurium) compared to cheap but long-acting ones active drugs(pancuronium, tubocurarine), since this significantly (4 times) reduces the incidence of residual curarization and postoperative pulmonary complications.
BeattieW.S. et al. (1992), comparing atracurium and vecuronium, note that predicting the end time of the block in the first case is influenced only by age, while in the case of vecuronium, in addition to age, the duration of the maintenance infusion should also be taken into account. The same work indicates that 19% of anesthetic mortality occurs in acute respiratory failure in the post-anesthesia period, caused by the residual effect of relaxants. Up to 42% of patients are admitted to the recovery room with signs of incomplete restoration of neuromuscular conduction. The use of drugs such as atracurium and vecuronium (as opposed to, for example, pancuronium) can reduce the incidence of complications, since the time for restoration of neuromuscular conduction to 85% level (against the background of decurarization with neostigmine) when used as an infusion is for the majority patients less than 20 min.
The influence of some homeostasis parameters on the pharmacology of muscle relaxants. Hypothermia prolongs the block by inhibiting metabolism and slowing excretion. Respiratory acidosis, hypocalcemia, hypokalemia, hypermagnesemia potentiate the effect of non-depolarizing muscle relaxants. Hepatic and renal failure increase the volume of extracellular fluid and, accordingly, the volume of distribution and, thereby, reduce the concentration of drugs in plasma. At the same time, due to the slow elimination of drugs, their duration of action increases. Therefore, it is recommended to use a larger loading dose, but smaller maintenance doses.
Table 6
Interaction of muscle relaxants with other drugs (potentiation “+” and inhibition of “–” neuromuscular block)
For the most successful application muscle relaxants, it is advisable to use monitoring of neuromuscular conduction.
It can be in the form of mechanomyography, electromyography (most suitable for scientific purposes), acceleromyography (most convenient in clinical practice).
The following stimulation patterns are possible (slide):
Stimulation with one pulse (0.1-1 Hz);
Stimulation with a series of 4 pulses (2 Hz with an interval of 15 s);
Tetanic stimulation (30,50 or 100Hz);
Post-tetanic stimulation (50 Hz for 5 s, pause 3 s, then pulses at a frequency of 1 Hz with counting muscle responses);
Stimulation "2 flashes" (2 "bursts" of tetanic stimulation 50 Hz).
The most commonly used nerve for stimulation is the ulnar nerve (the abductor muscle). thumb) or facial nerve (orbicularis muscle eyes).
Neuromuscular monitoring makes it possible to assess the time of tracheal intubation (approximately), the development of maximum block, control its depth during anesthesia (during intensive care), and determine the possibility of extubation (along with clinical signs).
There is often a need to accelerate the restoration of neuromuscular conduction after the end of general anesthesia. Artificially stopping the action of non-depolarizing muscle relaxants is called decurarization.
It is recommended to carry out it if there is at least minimally restored muscle tone. In the presence of a neuromuscular conduction monitor, this corresponds to 10% or more of its baseline. Otherwise, the risk of recurarization (that is, the resumption of the action of the muscle relaxant is high) is extremely high.
For decurarization, acetylcholinesterase inhibitors are used, leading to the accumulation of acetylcholine in the synapse, its competition with the non-depolarizing relaxant and facilitating neuromuscular conduction. In addition, neostigmine and its analogues help facilitate the release of acetylcholine by nerve endings.
The mechanism of action of acetylcholinesterase inhibitors is as follows. The drug binds to the active center of the enzyme, blocks it, preventing it from reacting with acetylcholine. Moreover, the anticholinesterase drug itself undergoes hydrolysis, similar to what occurs with acetylcholine. Only if, when acetylcholine itself interacts with the enzyme, hydrolysis is completed in a period of about 150 μs, then the reaction with edrophonium lasts from 2 to 10 minutes, and neostigmine and analogues (due to the two-stage process) are in covalent bond with the enzyme from 30 minutes to 6 hours.
Considering the pronounced m-cholinomimetic effect that develops when administering anticholinesterase drugs (bradycardia, salivation, bronchorrhea, laryngospasm), it is necessary to precede their administration with an injection of atropine (about 0.01 mg/kg).
Neostigmine and its analogues (prozerin) are administered at a dose of 40-80 mcg/kg (but not more than 5 mg) under heart rate control. If necessary, repeat the atropine injection. If the effect is insufficient, it is allowed reintroduction anicholinesterase drugs (the total dose of neostigmine, however, should not exceed 5 mg, i.e. 10 ml of 0.05% solution). The effect develops 5-10 minutes after injection.
Edrophonium is administered at a dose of 0.5-1 mg/kg. At the same time, its effect develops faster - after 1-2 minutes, but also lasts much less than that of neostigmine.
As with any other drug, various complications are possible when using muscle relaxants. Most of them are related to the main and side effects relaxants themselves, so their frequency is low if used correctly.
Naturally possible allergic reactions up to anaphylactic. Their diagnosis and treatment is carried out according to generally accepted rules, so let us not dwell on them.
The most common muscle pain occurs after the use of succinylcholine (it was previously said that they are noted by up to 90% of patients). Prevention consists of precurarization, i.e. administering approximately ¼ of the calculated dose of a non-depolarizing muscle relaxant a few minutes before the injection of succinylcholine, although this measure is not always effective. An alternative to precursorization is intravenous administration also a few minutes before succinylcholine, 60-120 mg of lidocaine.
Effects associated with the release of histamine and ganglion blockade in the form of cardiac arrhythmias and arterial hypotension. Hyperkalemia in response to the administration of depolarizing muscle relaxants in severe trauma, burns, and in other situations mentioned above can lead to severe bradycardia and even cardiac arrest.
Long-term residual effects of muscle relaxants due to hypovolemia, circulatory disorders, electrolyte disturbances and acidosis can lead to prolonged apnea. If decurarization was used, then when the action of anticholinesterase drugs is stopped, a fairly pronounced neuromuscular block may resume, called recurarization. Prevention of this complication is facilitated by careful monitoring of the patient, the use of decurarization only after the appearance of clear signs of restoration of muscle tone (it is advisable to use neuromuscular monitoring). If recurarization does develop, it is necessary to either perform repeated decurarization or reintubate the trachea and transfer the patient to assisted or artificial ventilation.
As mentioned earlier, when using muscle relaxants, especially in patients with a “full” stomach, regurgitation and aspiration of gastric contents into the tracheobronchial tree are possible. For the purpose of prevention, it is recommended to empty the stomach using a tube, perform the Sellick maneuver, and ensure an elevated position of the head and torso. In addition, it is recommended to use drugs that reduce gastric secretion(for example, H2-histamine receptor blockers).
However, I would like to dwell in more detail on the syndrome of malignant hyperthermia, a rare but extremely dangerous complication with high mortality.
Malignant hyperthermia is the most dangerous complication, encountered with the use of succinylcholine. It manifests itself as a hypermetabolic response to the triggering effects of certain medicines or stress.
Fatal pyrogenic reactions during anesthesia were not explained until M. Denborough described the syndrome of malignant hyperthermia in Australia in 1963. This complication is quite rare (according to various sources, about 1:100,000 anesthesia cases). However, in some areas (for example, Canada) it occurs much more often (up to 1:1500) due to the familial nature of the condition. It is most common in people aged 3 to 30 years. It is more common in men, given their size muscle mass. Mortality exceeds 70%, but can be significantly reduced with timely diagnosis. Specific treatment dantrolene since 1979 has increased survival to 90%.
The syndrome can develop both during induction of anesthesia and several hours after its completion. The most common triggers are succinylcholine and halothane, although they can also be other drugs (calypsol, lidocaine, etc.). Malignant hyperthermia can be enhanced by adrenaline, cardiac glycosides, calcium salts, and theophylline derivatives. It can occur without the use of any medications, in response to an emotional reaction (the participation of endogenous norepinephrine is assumed).
Malignant hyperthermia – functional disorders calcium metabolism during pathological abnormalities in muscle physiology, although other structures associated with calcium (myocardium, nerves, platelets, lymphocytes, etc.) are also damaged.
Clinical signs of malignant hyperthermia during general anesthesia (slide):
Clinical:
Tachycardia;
Tachypnea;
Blood pressure instability;
Heart rhythm disturbances;
Skin moisture;
Fever (increase in tº by 2º per hour or tº>42.2ºС);
Fasciculations;
Generalized rigidity;
Spasm of the chewing muscles;
Change in urine color;
Dark blood in the wound.
Pathophysiological:
Central venous desaturation;
Central venous hypercapnia;
Arterial hypercapnia;
Metabolic acidosis;
Respiratory acidosis;
Hyperkalemia;
Myoglobinemia;
Myoglobinuria;
Increased CPK.
Differential diagnosis should be made (in addition to inadequate anesthesia) with hyperthyroidism and pheochromocytoma.
To identify a “risk group”, an anamnesis is taken, and a study of CPK levels, identification of anomalies in the structure of myofibrils (especially variations in their diameter), muscle biopsy with an in vitro test for halothane and caffeine (the most accurate method) are also proposed.
Treatment of malignant hyperthermia (slide)
1. Stop surgery and anesthesia.
2. Stop administering gaseous anesthetics.
3. Hyperventilation with 100% oxygen.
4. Dantrolene 2.5 mg/kg IV followed by infusion to a total dose of 10 mg/kg.
5. Monitoring of ECG, body temperature, urine, blood pressure, central venous pressure, end-expired CO 2, SatO 2.
6. Cool the patient (iv ice crystalloid solution 15 ml/kg, 3 times; ice on the body surface, lavage of the stomach and cavities with ice solutions; extracorporeal blood circulation) - stop at a temperature of less than 38.3ºC.
7. Stop rhythm disturbances (procainamide, IV 15 mg/kg over 10 minutes).
8. Correction of acidosis (sodium bicarbonate 1-2 mmol/l initially, then under the control of blood tests).
9. Maintain diuresis above 2 ml/kg/h (mannitol 0.125 g/kg, Lasix 1 mg/kg, repeat up to 4 times if necessary).
10. Relief of hyperkalemia (glucose with insulin).
11. In the postoperative period:
Dantrolene orally or intravenously for 1-3 days,
Continue monitoring for 48 hours,
Conduct family research.
The most promising drugs for use in military field conditions are those that do not cause serious side effects and have a controlled, preferably, medium-duration effect. These muscle relaxants include vecuronium (Norcuron) and rocuronium (Esmeron). The latter is especially preferred due to its uniquely rapid onset of action, not much inferior to succinylcholine. Naturally, it will be impossible to refuse the use of succinylcholine itself in situations requiring the fastest possible provision of reliable patency of the upper respiratory tract.
Unfortunately, it should be noted that none of these drugs are produced in Russia, which makes their use in large-scale combat situations difficult.
Standard drugs are currently
Ditilin,
Diplacin.
Conclusion: today, anesthesiology and resuscitation is unthinkable without the use of muscle relaxants. It is the duty of each specialist in our field to know modern muscle relaxants and be able to use them in everyday practical work.
1. Katzung B.G. Basic and clinical pharmacology: Trans. from English - M.; St. Petersburg, 1998.- T.1.- 611 p.
2. Morgan D.E., Mikhail M.S. Clinical anesthesiology: Trans. from English - M.; St. Petersburg, 1998.- 430 p.
3. Levshankov A.I., Somov S.V. Comparative assessment of modern muscle relaxants: Scientific research report. work No. 4.99.276p.12.- St. Petersburg: VMedA, 2000 (in print).
4. Pharmacology of muscle relaxants. - M.: Medicine, 1989. - 288 p.
5. Bevan D.R., Bevan J.C., Donati F. Muscle relaxants in clinical anesthesia. - Chicago; London, 1988.- 443 p.
Griffith performed the first anesthesia with relaxation on a 20-year-old plumber undergoing surgery for acute appendicitis.
The indications for the use of ditilin must include the low qualifications of the anesthesiologist (in terms of tracheal intubation).
Muscle relaxants - drugs that are used in anesthesiology to relax skeletal muscles by interrupting the transmission of excitation from nerve to muscle. This transmission is carried out under the influence of acetylcholine, which is released when the nerve is excited. Complex bioelectric processes occur, which are called polarization, depolarization, repolarization. Since muscle relaxants influence these processes according to their mechanism of action, they are conventionally divided into non-depolarizing and depolarizing.
Non-depolarizing (antidepolarizing) muscle relaxants - drugs that paralyze neuromuscular transmission, as they reduce the sensitivity of cholinergic receptors to acetylcholine and prevent depolarization of the end plate. All non-depolarizing relaxants should be administered after tracheal intubation. And.
Tubocurarine chloride (tubarin) - quaternary ammonium compound. It is used intravenously, the initial dose is 0.3-0.5 mg/kg. The action occurs within 3-5 minutes without muscle fibrillation. Muscle relaxation begins with the face - eyes, eyelids, masticatory muscles, then the pharynx, larynx, chest, abdomen and limbs; The last one to turn off is the diaphragm. Recovery is underway in reverse order. Tubocurarine has a ganglion-blocking and histamine-like effect, so its use may result in a decrease in blood pressure and allergic reactions. It is excreted in the urine and is very slowly inactivated. The duration of the first dose is 20-40 minutes, a repeat dose (1/2 of the initial dose) gives a longer lasting effect.
The drug is used during the period of maintaining anesthesia, after tracheal intubation. It is used with caution in the elderly, with damage to the kidneys and liver. Tubocurarine is contraindicated in myasthenia gravis.
Pancuronium bromide (pavulon) - a synthetic steroid muscle relaxant, but hormonally inactive. Causes a non-depolarizing block. Initial dose - 0.08-0.09 mg/kg body weight, duration of action - 60-80 minutes; repeat dose - 0.02-0.03 mg/kg. The drug does not cause changes in hemodynamics and histamine effect.
Close to it ardouane (pipecurium bromide) - steroid, synthetic muscle relaxant without side effects on hemodynamics. It is widely used both during operations and in the postoperative period for artificial ventilation lungs in children, adults and the elderly. The average dose is 0.07-0.08 mg/kg, duration of action is 60-90 minutes; The repeat dose is 1/2-1/3 of the initial dose.
Arduan is used for tracheal intubation at a dose of 0.07 mg/kg, when the administration of ditilin is contraindicated. The drug is contraindicated in myasthenia gravis and early stages pregnancy. Pavulon and Arduan are indicated in patients with increased surgical risk.
Anatruxonium - antidepolarizing relaxant. The initial dose is 0.07 mg/kg, causing relaxation of the abdominal muscles, breathing is maintained, but becomes inadequate, which requires artificial ventilation. At a dose of 0.15-0.2 mg/kg body weight, total muscle relaxation develops for 60-120 minutes. Usually repeated doses should be reduced by 3 times. The drug was not found wide application due to prolonged action, tachycardia during surgery and ganglion-blocking effect.
Diplacin - synthetic drug domestically produced, administered at a dose of 3-4 mg/kg body weight after tracheal intubation. The duration of action is 30-40 minutes, repeated doses are 1/2-1/4 of the initial dose and cause prolonged apnea, which has significantly limited its use.
The antidotes of all non-depolarizing relaxants are proserine and galantamine, which are used for decurarization.
