Local anesthetics of the ester group. Local anesthetics: classification, mechanism of action, comparative characteristics

17. Local anesthetics: classification, mechanism of action, Comparative characteristics. Resorptive action local anesthetics. Application.

M local anesthesia - switching off sensitivity during direct contact of the drug with nerve conductors and receptors without turning off consciousness, reflexes and muscle tone(as opposed to drugs). Local anesthetics - these are drugs that cause a reversible inhibition of the conductivity and excitability of receptors and conductors when applied to them.

Classification by chemical structure: 1) complex esters of amino alcohols and aromatic acids cocaine (benzoic acid derivative), novocaine, dicaine, anestezin (para-aminobenzoic acid derivatives) , 2) substituted acid amides .- xicaine (lidocaine) and trimecaine (xylidine derivatives), sovcaine (cholinecarboxylic acid derivative). Drugs with an amide bond have more long-term action than anesthetics with an ether bond, which is destroyed by blood and tissue esterases.

For manifestation anesthetic effect anesthetics must pass the following transformation steps: 1) the anesthetic salt used is highly soluble in water, but poorly in lipids, therefore it droops weakly through the membranes and does not have an anesthetic effect; 2) in tissue fluid the anesthetic salt is converted into a non-ionized lipophilic base that penetrates well through membranes; 3) the base of the anesthetic acquires a cationic form, which interacts with receptors inside the sodium channels of the membranes, as a result of which the passage of sodium (and potassium) ions through the channels of the membranes is disrupted. This prevents the occurrence of the action potential and causes a block in the conduction and generation of impulses. Competitive interaction with calcium ions, which regulate the "opening-closing" of ion channels, is also important. This shows an analogy between the actions of local and general anesthetics: both block the generation of excitation in the membranes. That's why narcotic substances(ether, etc.) can cause local anesthesia, and local anesthetics when administered intravenously - general anesthesia. This is obviously related to the potentiating effect at joint application local anesthetics. narcotic, hypnotic and analgesic drugs.

Local anesthetics block the conduction of excitation in all types of nerve fibers: sensitive, motor, vegetative, but at different speeds and in different concentrations. Thin non-fleshy fibers are most sensitive to them, along which pain, tactile and temperature sensitivity is carried out, then - sympathetic fibers, which is accompanied by vasodilation, and in last turn are blocked motor fibers. Restoration of impulse conduction goes to reverse order.

Local anesthesia develops only with direct contact with the anesthetic. With resorptive action, the central nervous system is paralyzed before local sensitivity is eliminated.

Neutralization of anesthetics carried out by biotransformation. Substances with an ether bond are hydrolyzed by esterases: novocaine by plasma cholinesterase, cocaine, dicaine, anestezin by liver esterases. Biotransformation of anesthetics with an amide bond occurs in the liver by its destruction (eg, lidocaine). The decay products are excreted by the hepatic circulation. Decreased hepatic blood flow leads to a prolonged half-life and an increase in blood concentration, which can lead to intoxication. Anesthetics easily penetrate the lungs, liver, kidneys, central nervous system, through the placenta. If it enters the blood significant amount substances, occurs toxic effect: excitation, then paralysis of the centers medulla oblongata. This is manifested first by anxiety, shortness of breath, increased blood pressure, pallor of the skin, fever, and then - respiratory and circulatory depression. In case of intoxication, oxygen, artificial ventilation of the lungs, intravenous administration of barbiturates, sibazon, adrenaline, norepinephrine are used. Allergic reactions are most commonly caused by ester-linked anesthetics, especially novocaine. The most dangerous of these is anaphylactic shock.

Local anesthetics are used for the following types anesthesia:

Terminal (terminal, surface, application) - by applying an anesthetic to the mucous membranes. Apply anesthetics that are well absorbed through the mucous membranes (cocaine, dicaine, lidocaine, anestezin). They are used in otorhinolaryngology, ophthalmology, urology, dentistry, in the treatment of burns, wounds, ulcers, etc. Conductor (regional) - blockade nerve fibers. In this case, the conduction of impulses to the central nervous system is disrupted and sensitivity is lost in the area that is innervated by this nerve. Novocaine, lidocaine, trimecaine are used. One of the options for this anesthesia is spinal, which is carried out by introducing an anesthetic into the subdural space. infiltration anesthesia is carried out by layer-by-layer impregnation of tissues with anesthetic solution. This turns off the receptors and conductors. Novocaine, lidocaine and trimecaine are used. This type of anesthesia is widely used in surgery. Intraosseous anesthesia is carried out by introducing an anesthetic into the spongy substance of the bone, a tourniquet is applied above the injection site. The distribution of the anesthetic occurs in the tissues of the limb. The duration of anesthesia is determined by the allowable period of application of the tourniquet. This type of anesthesia is used in orthopedics and traumatology. Choosing the type of anesthesia depends on the nature, volume and trauma surgical intervention. For each type of anesthesia, there are drugs of choice and technique of execution. The choice of anesthetic depends on the ability to droop into the mucous membranes, on the strength and duration of action and toxicity. For diagnostic and low-traumatic interventions on superficially located areas, terminal anesthesia is used. For infiltration, conduction and intraosseous anesthesia, low-toxic and relatively safe agents are used. For spinal anesthesia usually use sovkain, which has a strong and long-lasting effect, as well as lidocaine. It is important to choose the right concentration of the solution. Weak concentrated solutions entered in in large numbers, spread widely in tissues, but diffuse poorly through membranes, while concentrated solutions in small quantities spread worse, but diffuse better. The effect does not depend on the total amount of anesthetic, but on that part of it that penetrates into nerve formations. Therefore, an increase in the amount of solution does not mean an increase in the anesthetic effect, often this only leads to an increase in toxic action.

When anesthesia is well vascularized tissues (face, oral cavity, pharynx, larynx, etc.), the anesthetic is absorbed quickly, which can lead to intoxication. To reduce this effect and prolong the effect of the drug, vasoconstrictor drugs (adrenaline, norepinephrine) are added. In this case, the concentration of adrenaline should not exceed 1:200000 (1 ml per 200 ml of anesthetic), since adrenaline itself can cause tachycardia, hypertension, headache, anxiety.

Characteristics of individual anesthetics. Cocaine - alkaloid from the leaves of Erythroxylon Coca, which grows in South America. It is well absorbed, anesthesia occurs in 3-5 minutes, the duration of the effect is 30-60 minutes. It has a pronounced sympathomimetic effect, inhibiting the reverse neuronal uptake of norepinephrine, dopamine and serotonin in synapses. This is accompanied by stimulation of the cardiovascular system and central nervous system and the development of addiction. The action on the central nervous system is manifested by euphoria, anxiety, agitation, which can progress to psychosis with hallucinations, confusion, paranoid thinking, convulsions, vomiting, cardiac arrhythmias. This is due to the dopaminergic and serotonergic effects of cocaine. Vascular spasms, increased blood pressure, tachycardia, decreased appetite are the result of an adrenomimetic effect. Symptoms of excitation during intoxication are quickly replaced by depression of the central nervous system, respiration and blood circulation. Children are especially sensitive to cocaine. Death usually comes from paralysis respiratory center. To provide emergency care thiolental sodium, diazepam, chlorpromazine are injected intravenously, artificial ventilation of the lungs is carried out. Cocainism occurs with prolonged use of cocaine and leads to intellectual and moral degradation. Abstinence (abstinence disease) is manifested by mental and vegetative disorders. Novocaine in terms of the strength of the anesthetic effect, it is 2 times inferior to cocaine, but 4 times less toxic. Used for infiltration (0.25-0.5%), conduction (1-2%) anesthesia and for various kinds blockade. Valid for about 30 minutes. In case of an overdose, it causes an increase in reflex excitability, nausea, vomiting, a drop in blood pressure, weakness, and respiratory failure. Often there is idiosyncrasy (rash, itching, swelling subcutaneous tissue, dizziness). In case of intoxication, thiopental sodium, diazepam, ephedrine, strophanthin, and artificial respiration are prescribed.

Decain it is 15 times more potent than novocaine, but 10 times more toxic than it and 2 times more toxic than cocaine. Use for surface anesthesia mucous membranes, children under 10 years of age are contraindicated. Lidocaine (Xycaine) acts stronger and longer than novocaine 2-3 times. It is used for all types of anesthesia. Well tolerated, but with rapid absorption may cause collapse. Trimecain 2.5-3 times stronger than novocaine and less toxic. Its properties are close to lidocaine. Used for infiltration and conduction anesthesia, sometimes for the terminal (2-5%). scoops 15-20 times stronger than novocaine and 6-8 times longer than its duration of action, therefore it is convenient for spinal anesthesia. However, the toxicity exceeds novocaine by 15-20 times, and therefore it is dangerous for infiltration and conduction anesthesia.

A drug	Relative power	Systemic toxicity	actions	Duration of anesthesia
Novocaine			Slow	A short
			Slow	long
Trimecain
Lidocaine
Artikain
Bupivacaine				long
Ropivacaine				long

1. Compare procaine and trimecaine in terms of chemical structure, metabolic features,

duration of action, activity, toxicity, use in various types

local anesthesia.

What are we comparing?		Trimecain
Chemical structure	Ester of aromatic acids	Aromatic amine amide
Peculiarity metabolism	Rapidly destroyed in the blood by butyrylcholinesterases (pseudocholinesterases or false esterases)	Degraded much more slowly by microsomal enzymes in the liver
Time of action	0.5 - 1 hour	2 – 3 hours
Activity
Toxicity
Application for various types of local anesthesia	1. Infiltration 0.25-0.5%% 3. Spinal – 5% 4. Terminal - 10%	1. Infiltration - 0.125- 2. Conduction and epidural 3. Spinal – 5% 4. Terminal - 2-5%%

From an anesthesiology textbook

local anesthetics. These funds, depending on the characteristics of the chemical structure, are divided into two groups: esters of aromatic acids with amino alcohols (novocaine, dicaine) and amides, mainly of the xylidine series (lidocaine, trimecaine, bupivacaine, etc.). Anesthetics of the second group have a stronger and longer-lasting effect with relatively low toxicity and the possibility long-term preservation their properties when stored in solutions. These qualities contribute to their wide application.

Novocaine is the hydrochloride of diethylaminoethyl ester of para-aminobenzoic acid. For infiltration anesthesia, 0.25 - 0.5% novocaine is used. For conduction anesthesia, novocaine is rarely used, in 1-2% solutions. The maximum allowable bolus doses of novocaine: 500 mg without adrenaline, 1000 mg with adrenaline.

Lidocaine(xicaine ) compared with novocaine, it has a more pronounced anesthetic effect, a short latent period, and a longer duration of action. Toxicity in the applied doses is small, it biotransforms more slowly than novocaine. The following solutions of xycaine are used: for infiltration anesthesia - 0.25%, conduction, epidural and spinal - 1 - 2%, terminal - 5 - 10%. Xicaine, like other local anesthetics of the amide group, has less allergenic properties than novocaine. Lidocaine is destroyed in the liver and only 17% of it is excreted unchanged in the urine and bile. The maximum allowable doses of lidocaine: 300 mg without adrenaline, 1000 mg with adrenaline.

Trimecain(mesocaine) in terms of anesthetic effect is somewhat inferior to lidocaine. According to the main properties, as well as indications for use, it is almost similar to it. The maximum allowable doses: without adrenaline 300 mg, with adrenaline -1000 mg.

Pyromecaine is also a representative of anesthetics of the amide group. It has a strong anesthetic effect on mucous membranes, is not inferior to dikain and significantly exceeds cocaine. Its toxicity is lower than that of the named anesthetics. For terminal anesthesia, it is used in the form of a 2% solution, not more than 20 ml.

Bupivacaine(marcain) also refers to anesthetics of the amide group. Compared to lidocaine and trimecaine, it has a stronger and longer-lasting effect, but is more toxic. The anesthetic is used in the form of a 0.5% solution for conduction, epidural and spinal anesthesia methods. He, like other anesthetics of this group, is biotransformed relatively slowly.

Bupivacaine is one of the anesthetics with the longest (up to 12 hours) duration of analgesic effect. By using various concentrations of bupivacaine for drug blockade of the nerve stem plexuses, it is possible to achieve different depth blockade: for example, when performing a blockade of the brachial plexus with a 0.25% solution of bupivacaine, complete “surgical” analgesia of the limb is achieved with preserved muscle tone. For anesthesia with concomitant complete muscle relaxation, bupivacaine is used at a concentration of 0.5%.

Ropivacaine(naropin) differs little in chemical structure from bupivacaine. But, unlike the latter, it has much less toxicity. The positive qualities of the drug also include the rapid cessation of the motor block with prolonged preservation of the sensory one. It is used in the form of a 0.5% solution for conduction, epidural and spinal anesthesia.

The mechanism of action of local anesthetics is currently explained from the standpoint of the membrane theory. In accordance with it, anesthetics in the zone of contact with nerve fibers violate the transmembrane permeability for sodium and potassium ions. As a result, depolarization in this section of the membrane is impossible, and, accordingly, the excitation propagating along the fiber is extinguished. In nerve fibers that conduct excitatory impulses of various modalities, when the nerve comes in contact with an anesthetic solution, the blocking effect does not appear simultaneously. The less pronounced the myelin sheath of the fiber, the faster the violation of its conduction occurs and vice versa. Thin unmyelinated fibers, which, in particular, include sympathetic ones, are blocked first. They are followed by a blockade of the fibers that carry pain sensitivity, then, sequentially, temperature and protopathic. Lastly, the conduction of impulses in the motor fibers is interrupted. The restoration of conductivity occurs in the reverse order. The time from the moment the anesthetic solution is applied to the nerve to the onset of the blocking effect varies for different anesthetics. It depends mainly on their lipoidotropy. The concentration of the solution also matters: with its increase in all anesthetics, this period decreases. The duration of the blocking effect is directly dependent on the affinity of the anesthetic for lipids and inversely on the blood supply to the tissues in the area of ​​anesthetic injection. The addition of adrenaline to the anesthetic solution prolongs its specific action due to a decrease in the blood supply to the tissues and a slowdown in the resorption of the drug from them.

The fate of the administered local anesthetics of the two considered groups in the body is significantly different. Anesthetics of the ester series undergo hydrolysis with the participation of cholinesterase. The mechanism of biotransformation in this group is well studied in relation to novocaine. As a result of its decomposition, para-aminobenzoic acid and diethylaminoethanol are formed, which has some local anesthetic effect.

Local anesthetics of the amide group are inactivated relatively slowly. The mechanism of their transformation is not well understood. It is believed that biotransformation occurs under the influence of liver enzymes. In unchanged form, only a small amount of these anesthetics is released.

With all methods of local and regional anesthesia, the anesthetic from the injection site constantly enters the bloodstream. Depending on the concentration created in it, it has a more or less pronounced general effect on the body, which manifests itself in inhibition of the function of interoreceptors, synapses, neurons and other cells. When using acceptable doses, the resorptive effect of anesthetics does not pose a danger. Moreover, a small general effect, summing up with a local one, increases the anesthetic effect. In cases where the prescribed dosage is not observed or the patient's sensitivity to the anesthetic is increased, signs of intoxication may appear to one degree or another.

These funds, depending on the characteristics of the chemical structure, are divided into two groups: one of them is esters of aromatic acids with amino alcohols (novocaine, dicaine, cocaine); the second - amides, mainly of the xylidine series (xicaine, trimecaine, pyromecaine, marcaine, etc.). Anesthetics of the second group have a stronger and longer-lasting effect with relatively low toxicity (Table 1) and the possibility of long-term preservation of their properties when stored in solutions. These qualities contribute to their wider application. But novocaine is still used for infiltration anesthesia.

Novocaine is the hydrochloride of diethylaminoethyl ester of para-aminobenzoic acid. In solution, it quickly reduces activity. In this regard, it is necessary to prepare the solution shortly before the operation. In the body, novocaine undergoes intensive hydrolysis by false cholinesterase with the formation of para-aminobenzoic acid and diethylaminoethanol. It was found that after intravenous administration two grams of novocaine, its concentration in the blood decreases by 3 times, and after an hour the anesthetic in the blood is no longer detected. For infiltration anesthesia, novocaine is used at 0.25-0.5%. For conduction anesthesia, novocaine is rarely used, in 1-2% solutions.

Decain(tetrocaine, pantocaine) in solutions also quickly reduces its activity. It has a strong local anesthetic effect. Until recently, it was widely used for conducting and spinal anesthesia(0.2-0.5% solutions). In recent years, due to the emergence of less toxic and sufficiently effective drugs amide group, it began to be used much less frequently.

Table 1. Comparative characteristics of local anesthetics

A drug	Activity during anesthesia			Toxicity
	terminal anest. (cocaine-1)	Infiltration anest. (novocain-1)	conduction anest. (novocain-1)
Novocaine	0, 1	1	1	1
Cocaine	1	3, 5	1, 9	5
Decain	10	10-15	10-15	20
Trimecain	0, 4	3	2, 3-3, 5	1, 3-1, 4
Xicaine (lidocaine)	0, 5	2-4	2-3	1,5 – 2

Xicain(lidocaine, xylocaine, lignocaine) is a crystalline powder, highly soluble in water. In solutions, it remains active for a long time. Compared with novocaine, it has a more pronounced anesthetic effect. Toxicity in the applied doses is small, it biotransforms more slowly than novocaine. The following solutions of xycaine are used: for infiltration anesthesia - 0.25%, conduction, epidural and spinal - 1-2%, terminal - 5%. Xicaine, like other local anesthetics of the amide group, has less allergenic properties than novocaine.

Trimecain(mesocaine) in terms of anesthetic effect is somewhat inferior to xicaine. According to the main properties, as well as indications for use, it is almost similar to it.

Pyromecaine is also a representative of anesthetics of the amide group. It has a strong anesthetic effect on mucous membranes, is not inferior to dikain and significantly exceeds the effect of cocaine. Its toxicity is lower than that of the named anesthetics. For terminal anesthesia, it is used in a 2% solution, not more than 20 ml.

Local, regional and combined methods of anesthesia:

M local anesthesia - switching off the sensitivity during direct contact of the drug with nerve conductors and receptors without turning off consciousness, reflexes and muscle tone (unlike anesthesia). Local anesthetics - these are drugs that cause a reversible inhibition of the conductivity and excitability of receptors and conductors when applied to them.

Classification by chemical structure : 1) complex Esthers of amino alcohols and aromatic acids cocaine (benzoic acid derivative), novocaine, dicaine, anestezin (para-aminobenzoic acid derivatives) , 2) substituted acid amides .- xicaine (lidocaine) and trimecaine (xylidine derivatives), sovcaine (cholinecarboxylic acid derivative). Drugs with an amide bond have a longer duration of action than anesthetics with an ether bond, which is destroyed by blood and tissue esterases.

For the manifestation of the anesthetic effect, anesthetics must undergo the following transformation steps: 1) the anesthetic salt used is highly soluble in water, but poorly in lipids, therefore it droops weakly through the membranes and does not have an anesthetic effect; 2) in the tissue fluid, the anesthetic salt turns into a non-ionized lipophilic base, which penetrates well through the membranes; 3) the base of the anesthetic acquires a cationic form, which interacts with receptors inside the sodium channels of the membranes, as a result of which the passage of sodium (and potassium) ions through the channels of the membranes is disrupted. This prevents the occurrence of the action potential and causes a block in the conduction and generation of impulses. Competitive interaction with calcium ions, which regulate the "opening-closing" of ion channels, is also important. This shows an analogy with the action of local and general anesthetics: both block the generation of excitation in the membranes. Therefore, narcotic substances (ether, etc.) can cause local anesthesia, and local anesthetics, when administered intravenously, can cause general anesthesia. With this, obviously, the potentiating effect is associated with the combined use of local anesthetics. narcotic, hypnotic and analgesic drugs.

Local anesthetics block the conduction of excitation in all types of nerve fibers: sensitive, motor, vegetative, but with different speed and at different concentrations. The most sensitive to them are thin non-fleshy fibers, along which pain, tactile and temperature sensitivity is carried out, then sympathetic fibers, which is accompanied by vasodilation, and lastly motor fibers are blocked. Restoration of impulse conduction proceeds in the reverse order.

Local anesthesia develops only with direct contact with the anesthetic. With resorptive action, the central nervous system is paralyzed before local sensitivity is eliminated.

Neutralization of anesthetics carried out by biotransformation. Substances with an ether bond are hydrolyzed by esterases: novocaine by plasma cholinesterase, cocaine, dicaine, anestezin by liver esterases. Biotransformation of anesthetics with an amide bond occurs in the liver by its destruction (eg, lidocaine). The decay products are excreted by the hepatic circulation. Decreased hepatic blood flow leads to a prolonged half-life and an increase in blood concentration, which can lead to intoxication. Anesthetics easily penetrate the lungs, liver, kidneys, central nervous system, through the placenta. If a significant amount of a substance enters the blood, there is toxic effect: excitation, then paralysis of the centers of the medulla oblongata. This is manifested first by anxiety, shortness of breath, increased blood pressure, pallor of the skin, fever, and then - respiratory and circulatory depression. In case of intoxication, oxygen, artificial ventilation of the lungs, intravenous administration of barbiturates, sibazon, adrenaline, norepinephrine are used. Allergic reactions are most commonly caused by ester-linked anesthetics, especially novocaine. The most dangerous of these is anaphylactic shock.

Local anesthetics are used for the following types of anesthesia:

Terminal (terminal, surface, application) - by applying an anesthetic to the mucous membranes. Apply anesthetics that are well absorbed through the mucous membranes (cocaine, dicaine, lidocaine, anestezin). They are used in otorhinolaryngology, ophthalmology, urology, dentistry, in the treatment of burns, wounds, ulcers, etc. Conductor (regional) - blockade of nerve fibers. In this case, the conduction of impulses to the central nervous system is disrupted and sensitivity is lost in the area that is innervated by this nerve. Novocaine, lidocaine, trimecaine are used. One of the options for this anesthesia is spinal, which is carried out by introducing an anesthetic into the subdural space. infiltration anesthesia is carried out by layer-by-layer impregnation of tissues with anesthetic solution. This turns off the receptors and conductors. Novocaine, lidocaine and trimecaine are used. This type of anesthesia is widely used in surgery. Intraosseous anesthesia is carried out by introducing an anesthetic into the spongy substance of the bone, a tourniquet is applied above the injection site. The distribution of the anesthetic occurs in the tissues of the limb. The duration of anesthesia is determined by the allowable period of application of the tourniquet. This type of anesthesia is used in orthopedics and traumatology. Choosing the type of anesthesia depends on the nature, volume and trauma of the surgical intervention. For each type of anesthesia, there are drugs of choice and technique of execution. The choice of anesthetic depends on the ability to droop into the mucous membranes, on the strength and duration of action and toxicity. For diagnostic and low-traumatic interventions on superficially located areas, terminal anesthesia is used. For infiltration, conduction and intraosseous anesthesia, low-toxic and relatively safe means. For spinal anesthesia, scowcaine, which has a strong and long-lasting effect, as well as lidocaine, is usually used. It is important to choose the right concentration of the solution. Weakly concentrated solutions, introduced in large quantities, spread widely in tissues, but diffuse poorly through membranes, while concentrated solutions in small quantities spread worse, but diffuse better. The effect does not depend on the total amount of anesthetic, but on that part of it that penetrates into the nerve formations. Therefore, an increase in the amount of solution does not yet mean an increase in the anesthetic effect, often this only leads to an increase in the toxic effect.

When anesthesia is well vascularized tissues (face, oral cavity, pharynx, larynx, etc.), the anesthetic is absorbed quickly, which can lead to intoxication. To reduce this effect and prolong the effect of the drug, vasoconstrictor drugs (adrenaline, norepinephrine) are added. In this case, the concentration of adrenaline should not exceed 1:200,000 (1 ml per 200 ml of anesthetic), since adrenaline itself can cause tachycardia, hypertension, headache, and anxiety.

Characteristics of individual anesthetics. Cocaine - alkaloid from the leaves of Erythroxylon Coca, native to South America. It is well absorbed, anesthesia occurs in 3-5 minutes, the duration of the effect is 30-60 minutes. It has a pronounced sympathomimetic effect, inhibiting the reverse neuronal uptake of norepinephrine, dopamine and serotonin in synapses. This is accompanied by stimulation of the cardiovascular system and central nervous system and the development of addiction. The action on the central nervous system is manifested by euphoria, anxiety, agitation, which can progress to psychosis with hallucinations, confusion, paranoid thinking, convulsions, vomiting, cardiac arrhythmias. This is due to the dopaminergic and serotonergic effects of cocaine. Vascular spasms, increased blood pressure, tachycardia, decreased appetite are the result of an adrenomimetic effect. Symptoms of excitation during intoxication are quickly replaced by depression of the central nervous system, respiration and blood circulation. Children are especially sensitive to cocaine. Death usually occurs from paralysis of the respiratory center. To provide emergency care, thiolental sodium, diazepam, chlorpromazine are administered intravenously, artificial ventilation of the lungs is carried out. Cocaine addiction occurs when long-term use cocaine and leads to intellectual and moral degradation. Abstinence (abstinence disease) is manifested by mental and autonomic disorders. Novocaine in terms of the strength of the anesthetic effect, it is 2 times inferior to cocaine, but 4 times less toxic. Used for infiltration (0.25-0.5%), conduction (1-2%) anesthesia and for various types of blockades. Valid for about 30 minutes. In case of an overdose, it causes an increase in reflex excitability, nausea, vomiting, a drop in blood pressure, weakness, and respiratory failure. Often there is idiosyncrasy (rash, itching, swelling of the subcutaneous tissue, dizziness). In case of intoxication, thiopental sodium, diazepam, ephedrine, strophanthin, and artificial respiration are prescribed.

Decain it is 15 times more potent than novocaine, but 10 times more toxic than it and 2 times more toxic than cocaine. Used for superficial anesthesia of the mucous membranes, children under 10 years of age are contraindicated. Lidocaine (Xycaine) acts stronger and longer than novocaine 2-3 times. It is used for all types of anesthesia. Well tolerated, but with rapid absorption may cause collapse. Trimecain 2.5-3 times stronger than novocaine and less toxic. Its properties are close to lidocaine. Used for infiltration and conduction anesthesia, sometimes for terminal (2-5%). scoops 15-20 times stronger than novocaine and 6-8 times longer than its duration of action, therefore it is convenient for spinal anesthesia. However, the toxicity exceeds novocaine by 15-20 times, and therefore it is dangerous for infiltration and conduction anesthesia.

M-, N-cholinomimetic drugs: classification, mechanisms of action, main effects, use, side effects. Clinic acute poisoning muscarine and M-, N-cholinomimetics are not direct action. Help measures. Anticholinesterase agents.

M -cholinergic receptors are excited by fly agaric venom muscarine and blocked by atropine. They are located in nervous system And internal organs receiving parasympathetic innervation (cause depression of the heart, contraction of smooth muscles, increase the secretory function of the exocrine glands) (Table 15 in lecture 9). M-cholinergic receptors are associated with G-proteins and have 7 segments that cross, like a serpentine, the cell membrane.

Molecular cloning made it possible to isolate five types of M-cholinergic receptors:

1. M 1 -cholinergic receptors CNS (limbic system, basal ganglia, reticular formation) and autonomic ganglia;

2. M 2 -cholinergic receptors hearts (reduce heart rate, atrioventricular conduction and myocardial oxygen demand, weaken atrial contractions);

3. M 3 -cholinergic receptors:

smooth muscles (cause constriction of the pupils, spasm of accommodation, bronchospasm, spasm of the biliary tract, ureters, contraction Bladder, uterus, increase intestinal motility, relax sphincters);

glands (cause lacrimation, sweating, copious separation of liquid, protein-poor saliva, bronchorrhea, secretion of acidic gastric juice).

· extrasynaptic M 3 -cholinergic receptors are located in the vascular endothelium and regulate the formation of a vasodilator factor - nitric oxide (NO).

4. M 4 - and M 5 -cholinergic receptors have less functional significance.

M 1 -, M 3 - and M 5 -cholinergic receptors, activating through G q /11-protein phospholipase C cell membrane, increase the synthesis of secondary messengers - diacylglycerol and inositol triphosphate. Diacylglycerol activates protein kinase C, inositol triphosphate releases calcium ions from the endoplasmic reticulum,

M 2 - and M 4 -cholinergic receptors with the participation G i - And G 0-proteins inhibit adenylate cyclase (inhibit cAMP synthesis), block calcium channels, and also increase the conductivity of the potassium channels of the sinus node.

· Additional effects M-cholinergic receptors - mobilization arachidonic acid and activation of guanylate cyclase.

· N-cholinergic receptors excited by the tobacco alkaloid nicotine in small doses, blocked by nicotine in large doses.

Biochemical identification and isolation of H-cholinergic receptors became possible due to the discovery of their selective high-molecular ligand -bungarotoxin, the venom of the Taiwan viper Bungarus multicintus and cobras Naja naja. H-cholinergic receptors are located in ion channels, within milliseconds they increase the permeability of the channels for Na +, K + and Ca 2+ (5 - 10 7 sodium ions pass through one channel of the skeletal muscle membrane in 1 s).

1. Cholinomimetic drugs: a) m-n-cholinomimetics of direct action (acetylcholine, carbachol); b) m-n-cholinomimetics indirect action, or anticholinesterase (physostigmine, prozerin, galantamine, phosphacol); b) m-choliomimetics (pilocarpine, aceclidin); c) n-cholinomimetics (lobelin, cytiton).

2. Anticholinergic drugs: a) m-anticholinergics (atropine, platifillin, scololamin, hyoscyamine, homatropine, metacin); b) n-anticholinergic ganglion blockers (benzogexonium, pentamine, pahikarpine, arfonad, hygronium, pyrilene); muscle relaxants (tubocurarine, dithylin, anatruxonium).

Cholinomimetic drugs. Mn-cholinomimetics of direct action. ACH is rapidly destroyed by cholinesterase, therefore, it acts for a short time (5-15 minutes with s / c administration), carbacholin is destroyed slowly and acts up to 4 hours. These substances produce all the effects associated with the excitation of cholinergic nerves, i.e. muscarine- and nicotine-like.

Excitation m-XR leads to an increase in the tone of smooth muscles, an increase in the secretion of the digestive, bronchial, lacrimal and salivary glands. It manifests itself following effects. There is a narrowing of the pupil (miosis) as a result of contraction of the circular muscle of the iris of the eye; decline intraocular pressure, since when the iris muscle contracts, the helmet canal and fountain spaces expand, through which the outflow of fluid from the anterior chamber of the eye increases; spasm of accommodation as a result of contraction of the ciliary muscle and relaxation of the ligament of zon, regulating the curvature of the lens, which becomes more convex and is set to the near point of vision. The secretion of the lacrimal glands increases. From the side of the bronchi there is an increase in tone smooth muscle and development of bronchospasm, increased secretion of bronchial glands. The tone increases and the peristalsis of the gastrointestinal tract increases, the secretion of the digestive glands increases, the tone of the gallbladder and biliary tract increases, the secretion of the pancreas increases. The tone of the bladder, ureters, urethra increases, secretion increases sweat glands. m-XR stimulation of cardio-vascular system accompanied by a decrease in heart rate, slow conduction, automatism and myocardial contractility, vasodilation skeletal muscle and pelvic organs, lowering blood pressure. Excitation n-XR manifested by increased and deepening of breathing as a result of stimulation of the receptors of the carotid sinus (carotid glomeruli), from where the reflex is transmitted to the respiratory center. The release of adrenaline from the adrenal medulla into the blood increases, however, its cardiotonic and vasoconstrictive action is suppressed by inhibition of the heart and hypotension as a result of m-ChR stimulation. The effects associated with increased transmission of impulses through the sympathetic ganglia (vasoconstriction, increased heart function) are also masked by the effects due to the excitation of m-ChR. If you first enter atropine, blocking m-XR, then the effect of m-n-choliomimetics on n-ChR is clearly manifested. ACH and carbacholine increase skeletal muscle tone and can cause fibrillation. This effect is associated with increased transmission of impulses from the endings motor nerves on muscles as a result of n-ChR stimulation. In high doses, they block n-ChR, which is accompanied by inhibition of ganglionic and neuromuscular conduction and decreased secretion of adrenaline from the adrenal glands. These substances do not penetrate through the BBB, since they have ionized molecules, therefore, in usual doses do not affect the CNS. Carbacholin can be used to reduce intraocular pressure in glaucoma, with bladder atony.

· M-n-cholinomimetics of indirect action (anticholinesteoase). These are substances that stimulate m- and n-ChR due to the accumulation of ACH in synapses. MD is caused by inhibition of cholinesterase, which leads to a slowdown in ACh hydrolysis and an increase in its concentration in synapses. The accumulation of ACh under their influence reproduces all the effects of ACh (with the exception of respiratory stimulation). The above effects associated with the stimulation of m- and n-ChR are characteristic of all cholinesterase inhibitors. Their action on the central nervous system depends on penetration through the BBB. Substances containing tertiary nitrogen(physostigmine, galantamine, phosphacol), penetrate well into the brain and enhance cholinergic effects, and substances with quaternary nitrogen (prozerin) penetrate poorly and act mainly on peripheral synapses.

By the nature of the action on cholinesterase they are subdivided into reversible and irreversible action. The first ones are physostigmine, galantamine and prozerin. They cause reversible inactivation of cholinesterase, as they form an unstable bond with it. The second group consists organophosphate compounds (FOS), which are used not only in the form of drugs (phosphacol), but also for the destruction of insects (chlorophos, dichlorvos, karbofos, etc.), as well as as chemical warfare nerve agents (sarin, etc.). they form a strong covalent bond with cholinesterase, which is very slowly hydrolyzed by water (about 20 days). Therefore, the inhibition of cholinesterase becomes irreversible.

Anticholinesterase drugs apply at the following diseases: 1) residual effects after poliomyelitis, skull trauma, cerebral hemorrhage (galantamine); 2) myasthenia - a disease characterized by progressive muscle weakness(prozerin, galantamine); 3) glaucoma (phosphacol, physostigmine); 4) atony of the intestines, bladder (prozerin); 5) overdose of muscle relaxants (prozerin). These substances are contraindicated in bronchial asthma and heart disease with conduction disorders. poisoning most often occur when FOS, which have an irreversible effect, enter the body. Initially, miosis develops, disturbance of accommodation of the eye, salivation and difficulty in breathing, increased blood pressure, urge to urinate. Muscle tone increases, bronchospasm increases, breathing becomes difficult, bradycardia develops, blood pressure decreases, vomiting, diarrhea, fibrillar muscle twitching, seizures occur clonic seizures. Death is usually associated with a sharp violation breathing. First aid consists in the introduction of atropine, cholinestease reactivators (diperoxime, etc.), barbiturates (to relieve convulsions), hypertensive drugs (mezaton, ephedrine), artificial ventilation lungs (preferably oxygen). M-cholinomimetics. Muscarine is not used due to its high toxicity. It is used in scientific research. Used as LS pilocarpine and aceclidine. MD of these drugs is associated with direct stimulation of m-ChR, which is accompanied by pharmacological effects due to their excitement. They are manifested by a constriction of the pupil, a decrease in intraocular pressure, a spasm of accommodation, an increase in the tone of the smooth muscles of the bronchi, gastrointestinal tract, bile and urinary tracts, an increase in the secretion of the bronchial, digestive glands, sweat glands, a decrease in automatism, excitability, conductivity and contractility of the myocardium, vasodilatation of skeletal muscles , genital organs, decreased blood pressure. Of these effects, a decrease in intraocular pressure and an increase in intestinal tone are of practical importance. Other effects are most often undesirable consequences: spasm of accommodation disrupts the adaptation of vision, depression of the heart can cause circulatory disorders and even sudden stop heart (syncope). Therefore, it is not recommended to administer these drugs intravenously. Lowering blood pressure is also undesirable. bronchospasm, hyperkinesis.

The effect of m-cholinomimetics on the eye has great importance in the treatment of glaucoma, which often gives exacerbations (crises), which are common cause blindness and therefore need emergency treatment. Instillation of solutions of cholinomimetics into the eye causes a decrease in intraocular pressure. They are also used for intestinal atony. Used for glaucoma pilocarpine, with atony aceclidine, which gives less side effects. M-cholinomimetics are contraindicated in bronchial asthma, impaired conduction in the heart, serious illnesses heart, with epilepsy, hyperkinesis, pregnancy (due to the risk of miscarriage). In case of poisoning m-cholinomimetics(most often fly agaric) first aid consists in gastric lavage and the introduction of atropine, which is an antagonist of these substances due to the blockade of m-ChR.

· N-holinominetics. Nicotine has no medicinal value. When smoked together with tobacco combustion products, it contributes to the development of many diseases. Nicotine has high toxicity. Other substances are inhaled along with smoke from smoking. poisonous products: resins, phenol, carbon monoxide, hydrocyanic acid, radioactive polonium, etc. The craving for smoking is due to the pharmacological effects of nicotine associated with the excitation of n-ChRs of the central nervous system (cortex, oblongata and spinal cord), which is accompanied by a subjective feeling of increased performance. The release of adrenaline from the adrenal glands, which increases blood circulation, is also important. Habit plays an important role in the development of attraction. psychological impact environment. Smoking contributes to the development cardiovascular disease(hypertension, angina pectoris, atherosclerosis, etc.), bronchopulmonary diseases(bronchitis, emphysema, lung cancer), gastrointestinal diseases ( peptic ulcer, gastritis). Getting rid of this bad habit depends primarily on the smoker himself. Some drugs (eg, tabex) containing cytisine or lobeline can help with this.

· lobelin And cytiton selectively stimulate n-ChR. Practical value has excitation of n-XR carotid glomeruli, which is accompanied by reflex excitation of the respiratory center. Therefore, they are used as respiratory stimulants. The effect is short-term (2-3 minutes) and is manifested only with a / in the introduction. At the same time, the work of the heart increases and blood pressure rises as a result of the release of adrenaline from the adrenal glands and the acceleration of impulse conduction through the sympathetic ganglia. These drugs are indicated for respiratory depression caused by carbon monoxide poisoning, drowning, neonatal asphyxia, brain injury, for the prevention of atelectasis and pneumonia. However medical significance their limited. More often used analeptics of direct and mixed action.

Classifications of local anesthetics

By duration of action

1. Short-range

o Novocain,

o Artikain

2. medium duration actions

o Lidocaine,

o Mepivacaine,

o Trimecain,

o Prilocaine

3. Long-acting

o Bupivacaine,

o Etidocaine

By chemical structure

1. Essential

o Novocain,

o Anestezin

2. Amide

o Lidocaine,

o Trimecain,

o Pyromecaine,

o Prilocaine,

o Artikain,

o Mepivacaine,

o Bupivacakin,

o Etidocaine

Comparative characteristics of local anesthetics for injection anesthesia (see also Table 1)

Novocaine (Procaine)- until recently, the most commonly used local anesthetic drug in Russia, but now it is gradually being squeezed out of the market and is giving way to more modern drugs. This is related to the following shortcomings novocaine:

First, among modern local anesthetics, novocaine is the least effective. According to Petrikas A. Zh. (1997), the success rate of local anesthesia using novocaine is about 50% for teeth with intact pulp, and when it is inflamed, the effect is reduced by another 20%.

Secondly, novocaine is characterized by the greatest vasodilating properties among local anesthetics. This, in turn, requires high concentrations of the vasoconstrictor. The standard concentration of adrenaline when used in conjunction with novocaine (1: 50,000), according to modern ideas, is very high and is fraught with the development of complications.

Thirdly, novocaine has the highest allergenicity (according to our data, obtained by questioning using a questionnaire to collect a general somatic history, 9.1% of patients are allergic to novocaine).

The only advantage of novocaine over other local anesthetics is its low toxicity, so this drug continues to be used in surgical dentistry and maxillofacial surgery when it is necessary to anesthetize a large volume of tissues in the area of ​​surgical intervention, which, moreover, have a much higher threshold pain sensitivity compared to dental pulp.

In therapeutic dentistry, novocaine is now used less and less.

Lidocaine (xylocaine, lignocaine)- a much more effective and reliable drug than novocaine. The success rate of anesthesia is 90-95% for infiltration anesthesia and 70-90% for conduction anesthesia. The drug is less allergic (according to our data - 1.2%), but inferior in this indicator to the most modern local anesthetics. In addition, the disadvantage inherent in lidocaine is the significant vasodilating effect of this drug, so lidocaine is used with high concentrations of adrenaline (1:50,000) and norepinephrine (1:25,000). Such concentrations of catecholamines are highly undesirable in patients with cardiovascular diseases, thyrotoxicosis, diabetes mellitus, glaucoma, concomitant drug therapy with tricyclic antidepressants, MAO inhibitors, chlorpromazine (and other drugs with a-adrenergic blocking activity), during pregnancy. When using lidocaine without a vasoconstrictor, the duration of anesthesia does not exceed 10-15 minutes.

Trimecaine (mesocaine)- a drug similar in its properties to lidocaine, comparable to lidocaine in terms of the effectiveness and duration of the local anesthetic effect, as well as the severity of the vasodilating effect. The disadvantage of the drug is often occurring local reactions(pain during and after injection, edema, infiltration, purulent-necrotic phenomena in the injection area, difficulty opening the mouth). As a result, the drug is practically not used at present.

prilocaine- this drug is approximately 30-50% less toxic compared to lidocaine, low-allergic, but also somewhat less active. It is possible to use its 4% solution without a vasoconstrictor. A 3% solution of prilocaine is used in combination with the vasoconstrictor felipressin (octapressin) at a dilution of 1:1850000, so the drug can be used if there are contraindications to the use of catecholamine vasoconstrictors. However, it should be noted that in currently local anesthetics based on prilocaine Russian market practically not represented. The disadvantage of the drug is the danger of methemoglobin formation when using the drug at a dose of more than 400 mg. In this regard, the drug is contraindicated in pregnancy, congenital or idiopathic methemoglobinemia.

mepivacaine- in terms of efficiency comparable to lidocaine, low-allergic. A feature of the drug is its minimal vasodilating effect (Anisimova E.N. et al., 1999, Stolyarenko P.Yu., Kravchenko V.V., 2000), and according to B. Bornkessel (2000) even has a vasoconstrictor effect. Therefore, it is possible to use its 3% solution without a vasoconstrictor, which makes it the drug of choice for severe forms cardiovascular disease, thyrotoxicosis, diabetes, glaucoma, that is, in cases where there are contraindications to the use of a vasoconstrictor. The duration of anesthesia in this case reaches 20-40 minutes, which is enough for small volumes of interventions.

Artikain- one of the most highly effective modern local anesthetics, has a slight vasodilating effect, therefore it is used with adrenaline in dilutions of 1:100,000 and 1:200,000. Its important quality is a short (about 20 minutes) half-life (Oertel R. et al., 1997) and a high percentage of its binding to plasma proteins (up to 90-95%), that is, this drug is the least likely to have a toxic effect when accidental intravascular injection. In addition, articaine is characterized by the maximum diffusion ability in soft tissues and bones and, accordingly, early attack anesthesia after injection. Thanks to these features, articaine received most widespread on the dental carp market and is currently the anesthetic of choice for most therapeutic, surgical and orthopedic interventions.

Bupivacaine (Marcaine) and Etidocaine (Duranest)- effective long-acting (up to 4 hours) local anesthetics. The disadvantage of these drugs is their high toxicity and prolonged paresthesia of soft tissues after dental procedures causing discomfort to the patient. 0.5% solutions with adrenaline at a dilution of 1: 200,000 and without a vasoconstrictor at a higher concentration (1.5%) are used for long-term interventions (mainly in surgical dentistry), as well as if prolonged postoperative analgesia is necessary.

Contraindications and limitations to the use of local anesthetics

All contraindications and restrictions to the use of a local anesthetic come down to three main positions (Specialites Septodont, 1995; Petrikas A.Zh.., 1997):

1) allergic reactions to local anesthetic

A history of allergic reaction is an absolute contraindication to the use of a local anesthetic. For example, according to our data obtained using a questionnaire, novocaine intolerance was noted by 9.1% of patients. However, it should be noted that intolerance to local anesthetic, indicated by many patients, is often not a true allergic reaction, but is of a stressful nature, or is associated with intravascular administration of a vasoconstrictor. This fact is indicated various authors(Baluga J. C. et al., 2002). These states should be clearly differentiated. Most often, allergic reactions to novocaine and other local anesthetics of the ester group are observed; with such an allergy, it is allowed to use anesthetics of the amide group. However, it should be noted that, in principle, it is possible allergic reaction to any local anesthetic, cross-reaction to several local anesthetics, for example, to amide group anesthetics (Bircher A . J . et al , 1996; Suhonen R ., Kanerva L ., 1997), as well as polyvalent allergy to various local anesthetics is possible and other substances.

2) insufficiency of metabolic and excretion systems

Local anesthetic drugs can have a toxic effect in case of their overdose, as well as insufficiency of their metabolism and excretion systems. Essential local anesthetics are inactivated directly in bloodstream through the enzyme pseudocholinesterase. The metabolism of amide local anesthetics occurs in the liver. In a small amount (no more than 10%), both amide and ether local anesthetics are excreted unchanged by the kidneys. Thus, relative contraindications to the use of amide local anesthetics are - liver disease, ether - deficiency of plasma pseudocholinesterase, and (for all local anesthetics) - kidney disease. In these cases, you should use a local anesthetic drug in small doses, observing all necessary measures precautions.

3) age restrictions

It should be borne in mind that for children, the minimum toxic doses of all local anesthetics are much less than for adults. To achieve guaranteed complete anesthesia and minimize the likelihood of toxic effects, the most effective and safe modern local anesthetic drugs based on articaine, mepivacaine or lidocaine, limiting the dosage of the drug used.

Lidocaine - maximum dose 1.33 mg of the drug per 1 kg of the child's weight.

(As an example: a child weighing 20 kg, which corresponds to the age of five.

1.33 mg * 20 \u003d 26.6 mg., Which corresponds to 1.3 ml. 2% lidocaine solution)

Mepivacaine - the maximum dose of 1.33 mg of the drug per 1 kg. baby mass

Articaine - the maximum dose of 7 mg of the drug per 1 kg. baby mass

Articaine is contraindicated in children under 4 years of age.

Vasoconstrictors

Adrenalin- is the most powerful catecholamine vasoconstrictor. Can cause unwanted effects due to the action on the adrenoreceptors of the heart (tachycardia), blood vessels (vasoconstriction), liver (increased blood sugar), myometrium (causes uterine muscle contractions) and other organs and tissues. It is especially dangerous due to the action on the b-adrenergic receptors of the heart, it can cause decompensation of cardiac activity when comorbidities of cardio-vascular system. It can also be very dangerous possible increase intraocular pressure under the influence of exogenous adrenaline in narrow-angle glaucoma.

Based on this, one can distinguish relative contraindications to the use of adrenaline as a vasoconstrictor in local anesthesia:

• cardiovascular diseases (hypertension (AH), coronary heart disease (CHD), heart failure)
• pregnancy
• concomitant drug therapy with glucocorticosteroids, tricyclic antidepressants, MAO inhibitors, chlorpromazine (and other drugs with a-adrenergic blocking activity)

At the same time, a relatively safe dilution of adrenaline is 1: 200,000. According to Anisimova E.N. et al. (1997) already at an adrenaline concentration of 1:100,000, after local anesthesia, there may be noticeable changes in systemic hemodynamics (raising blood pressure by 10-30 mm Hg). Some foreign authors provide data on the absence of recorded changes in systemic hemodynamics even with a dilution of adrenaline 1: 100,000 (Sack U ., Kleemann P . P ., 1992). However, according to most domestic authors, the dilution of adrenaline 1:200000 is the maximum at which its use in the above groups of patients (patients at risk) is acceptable.

Such a low concentration can only be achieved in carpulated (ready-made) preparations, Adding epinephrine ex tempore does not provide an accurate dosage and is therefore extremely dangerous! For the treatment of patients at risk who are contraindicated high concentrations adrenaline is recommended to use only karpulirovannye preparations.

Absolute contraindications to the use of adrenaline:

• diabetes
• glaucoma (narrow-angle form)
• thyrotoxicosis
• decompensated forms of cardiovascular disease Stage III, paroxysmal tachycardia, tachyarrhythmias).

Norepinephrine- similar to adrenaline, but the effect is weaker, therefore it is used in high concentrations. The effect on a-adrenergic receptors (vasoconstriction) prevails, therefore, when using norepinephrine, the risk of developing hypertensive crisis with concomitant hypertension.

The use of norepinephrine instead of adrenaline is possible with thyrotoxicosis and diabetes mellitus. However, a number of authors indicate that norepinephrine gives much more side effects due to strong peripheral vasoconstriction (Stolyarenko P.Yu., Kravchenko V.V., 2000) and its use should be refrained from.

The use of noradrenaline in glaucoma (narrow-angle form) is contraindicated.

Mezaton- catecholamine with properties similar to adrenaline and norepinephrine, but only affects?-adrenergic receptors (vasoconstriction). Vasoconstrictor action 5-10 times weaker than adrenaline. Contraindicated in hypertension and hyperthyroidism. Used in dilution 1:2500 (0.3-0.5 ml of 1% solution per 10 ml of anesthetic solution).

Felipressin(Octapressin) is not a catecholamine, it does not act on adrenoreceptors, therefore it is devoid of all the above disadvantages. It is an analogue of the hormone of the posterior pituitary gland - vasopressin. It causes only venuloconstriction, so the hemostatic effect is not pronounced, as a result of which it is little used. Contraindicated in pregnancy, as it can cause contractions of the myometrium, it also has an antidiuretic effect, so patients with ischemic disease heart failure and heart failure, no more than one cartridge of the drug containing felipressin should be administered.

Please note that the use of all of the above vasoconstrictors is contraindicated in children under 5 years of age (Kononenko Yu. G. et al., 2002)