Local anesthetics

Local anesthetics are selective drugs that specifically provide reversible interruption of primarily pain impulses in the conductors of the peripheral nervous system.

The possibility of selectively changing pain sensitivity and achieving local tissue anesthesia was first noted by V.K. Anrep (1878), who described the local anesthetic effect of cocaine, isolated almost 20 years earlier by the German chemist Niemann (1860) from the leaves of Erythroxylum coca. And soon Karl Koller (K. Roller, 1984) successfully used a cocaine solution to anesthetize manipulations on the cornea of the eye. The next two decades became an impressive demonstration of the wide possibilities of the clinical use of cocaine for local anesthesia of various areas. Such prospects were constantly fueled by the unflagging interest of clinicians in finding an alternative to the early realized dangers of mask anesthesia.

The appearance of procaine (Einhorn, 1904), and later the synthesis of other, less toxic drugs with local anesthetic activity (tetracaine - 1934, lidocaine - 1946, bupivacaine - 1964, ropivaquine - 1994, etc.), along with the development and improvement of various technical methods that ensure the achievement of blockade of pain conductors for various regions of the body, made this approach to the evolution of local anesthesia quite justified at this stage of the development of anesthesiology.

Currently, local anesthesia is a separate area of anesthesiology, covering both the various techniques of administering local anesthetics and the operational pathophysiology for which the pharmacological effects of these drugs are responsible, and is used as the main or special component of anesthesia. From the standpoint of applying the effects of local anesthetics, it is customary to distinguish:

• application anesthesia;
• infiltration anesthesia;
• intravenous regional injection under a tourniquet according to A. Bir;
• conduction blocks of peripheral nerves;
• conduction blocks of nerve plexuses;
• epidural anesthesia;
• subarachnoid anesthesia.

The availability and accessibility of highly effective local anesthetics, but differing in the spectrum of the main action, made the choice of drugs for local anesthesia a truly independent problem. This diversity of clinical manifestations of the main pharmacological action is rightly associated with both the histomorphological and physiological characteristics of the nerve structures and the physicochemical properties of the drug itself, which determines the uniqueness of the pharmacodynamics and pharmacokinetics of each drug and various options for local anesthesia. Therefore, the choice of a local anesthetic should be considered as the first step to achieving rational and safe local anesthesia.

Chemical compounds with local anesthetic activity have certain common structural features. Lufgren was the first to note that almost all local anesthetics consist of a hydrophilic and a hydrophobic (lipophilic) component separated by an intermediate chain. The hydrophilic group is usually a secondary or tertiary amine, and the hydrophobic group is usually an aromatic residue. The classification of local anesthetics is based on the differences in the structure of the compound with the aromatic group. Local anesthetics with an ester connection between the aromatic residue and the intermediate chain are known as aminoesters. Examples of local anesthetics of this group are cocaine, procaine, and tetracaine. Local anesthetics with an amide connection between the aromatic group and the intermediate chain are known as aminoamides and are represented by such anesthetics as lidocaine, trimecaine, bupivacaine, and other well-known drugs. The type of compound with an aromatic group determines the metabolic pathways of local anesthetics; ester compounds are readily hydrolyzed in plasma by pseudocholinesterase, while amide local anesthetics are more slowly metabolized by liver enzymes.

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Local anesthetics: place in therapy

The ability of local anesthetics to cause total conduction block and regional anesthesia or selectively switch off sympathetic or sensory innervation is widely used today in anesthesiology practice both to provide various surgical interventions and for therapeutic and diagnostic purposes. In this case, conduction block is implemented either as the main or as a special component of anesthesia.

It is advisable to distinguish between the variants of peripheral and central, or segmental, anesthesia. The term "anesthesia" implies achieving a blockade of all types of sensitivity, while analgesia characterizes the shutdown of predominantly sensory sensitivity. The concept of block also carries a similar terminological load, while the term "blockade" should be used to designate the technique of some, in particular conduction, variants of local anesthesia. In domestic literature, the term "regional anesthesia" covers exclusively the technique of conduction blockades. However, as emphasized in all modern manuals, it is true for all variants of local anesthesia. The term "prolonged conduction anesthesia" implies the use of the technique of catheterization of paraneural structures in order to maintain the block by repeated injections or infusion of local anesthetic solutions both in the intra- and postoperative periods:

• Application anesthesia is achieved by applying (spraying) highly effective local anesthetics (e.g. 2-10% lidocaine solution) to the skin or mucous membranes (e.g. Bonica intratracheal anesthesia). This type of anesthesia includes the introduction of a local anesthetic into cavities covered with a serous membrane rich in receptor apparatus (e.g. interpleural anesthesia);
• infiltration anesthesia involves the sequential introduction of a local anesthetic solution into the soft tissues in the area of the proposed operation. The most effective version of such anesthesia is considered to be anesthesia using the creeping infiltrate method according to A.V. Vishnevsky;
• Conduction anesthesia of peripheral nerves includes precise verification of anatomical structures for the purpose of precise creation of a compact depot of local anesthetic. Blockades of large nerve trunks of the extremities are of the greatest practical importance;
• i/v regional anesthesia according to Biru is used for operations lasting up to 100 min on the upper and lower extremities below the peripheral tourniquet. Local anesthetics (0.5% lidocaine or prilocaine solutions without the addition of epinephrine) are injected into a peripheral vein after the application of a double-lumen pneumatic tourniquet in a volume of up to 50 ml for the upper extremity or up to 100 ml for the lower extremity. This anesthesia is preferable for operations on soft tissues. Operations on bones and nerves under these conditions can be painful. A variety of i/v regional anesthesia is intraosseous anesthesia with 0.5% lidocaine solution at a dose of up to 6 mg/kg, when local anesthetics are injected into tubular bones in places where there is a thin cortical layer;
• conduction block of nerve plexuses is based on the creation of a compact depot of local anesthetic within the anatomical case containing nerve trunks. Taking into account the anatomical features of the structure of various nerve plexuses, several levels are distinguished to achieve an effective block (for example, axillary, subclavian, supraclavicular and interscalene approaches to the brachial plexus);
• epidural anesthesia is achieved by introducing anesthetic solutions into the epidural space, causing a blockade of the spinal roots or spinal nerves passing through it;
• spinal (subarachnoid) anesthesia occurs as a result of the introduction of a local anesthetic solution into the cerebrospinal fluid of the spinal subarachnoid space;
• Combined spinal-epidural anesthesia is a combination of spinal and epidural blockade, when a needle for puncture of the epidural space (a Tuohy-type needle) serves as a guide for the introduction of a thin (26G) needle for the purpose of subarachnoid injection of local anesthetic and subsequent catheterization of the epidural space.

The fundamental differences in the indications for the use of a particular local anesthetic with respect to a specific technique of its administration are the correspondence of the pharmacological properties of the drug to the nature of the surgical intervention. Short surgeries, often performed on an outpatient basis, require the use of local anesthetics with a short duration of action, such as novocaine and lidocaine. This choice of drug ensures a short recovery period for the patient and reduces the length of his stay in the medical institution. Conversely, for surgeries lasting more than 2 hours, the use of bupivacaine and ropivacaine is indicated. The urgency of the clinical situation forces one to choose not only local anesthetics with a short latent period, but also a technique that has such an advantage, for example, subarachnoid anesthesia with 0.5% bupivacaine or 0.5% tetracaine for emergency cesarean section.

In addition, the peculiarities of obstetric practice force the anesthesiologist to choose a local anesthetic with minimal systemic toxicity. Recently, such a drug has become ropivacaine for pain relief of both vaginal births and cesarean sections.

Achieving special effects of regional blockades (regional sympathetic block, postoperative pain relief, treatment of chronic pain) is ensured by using low concentrations of local anesthetic solutions. The most popular drugs for these purposes are 0.125-0.25% bupivacaine solutions and 0.2% ropivacaine solution.

Mechanism of action and pharmacological effects

The object of interest of local anesthetics is the peripheral nervous system. It includes the roots, branches and trunks of both cranial and spinal nerves, as well as components of the autonomic nervous system. The peripheral and central nervous systems can be divided into gross anatomical and histological components in accordance with the two stages of local anesthesia development. The gross anatomical structure of a nerve formation determines the latent period of blockade of the drug applied to a given site. In contrast, the histological structure, in addition to accompanying neurophysiological factors (pain, inflammation) that influence the action of the drug, determines the penetrating ability of the drug through the sheaths of the nerve fiber before its function is interrupted.

A nerve fiber is the functional unit of a peripheral nerve. The term refers exclusively to the axon originating from a centrally located neuron, but is often used as a broader definition, referring in addition to the neuron and the sheath of Schwann cells that surrounds it. This sheath provides structural and supportive functions, but its most significant function is to participate in impulse transmission.

There are two types of nerve fiber arrangement. In the first type, a protrusion from a single Schwann cell surrounds several axons, which are described as unmyelinated. At junctions, the Schwann cells, which have a maximum length of 500 microns, simply partially overlap each subsequent one. The other type of arrangement consists of a protrusion from each Schwann cell that repeatedly wraps around a single axon. Such an axon is surrounded by a "tube" formed by multiple double layers of phospholipid cell membrane - the myelin sheath. Each Schwann cell extends 1 mm or more, and at the junctions (nodes of Ranvier) myelin is absent. At the same time, significant gaps between the processes of individual cells are overlapped by protrusions, so that the axonal membranes have an additional sheath. The axoplasm contains the usual organelles, such as mitochondria and vesicles, which are necessary for normal cellular metabolism. There is a possibility that some chemical "transmitters" pass into the axoplasm.

Differences in the histomorphological structure of the fibers that make up the nerve make it possible to achieve differentiated blockade of fibers that carry a specific functional load. This becomes possible when the nerve is exposed to different local anesthetics in different concentrations, which is often necessary in the clinical practice of regional blockades.

The most important structure for the transmission of nerve impulses is the axonal membrane. Its basic structure is a double phospholipid sheet oriented so that the polar hydrophilic phosphate groups are in contact with the interstitial and intracellular fluid. The hydrophobic lipid groups are directed, on the contrary, to the center of the membrane. Large protein molecules are included in the membrane. Some of them have a structural function, others are active and function as enzymes, receptors for hormones and drugs, or as channels for the movement of ions in and out of the cell.

Most important for the effects of local anesthetics are these protein ion channels. Each has a pore through which ions move. There are several different types of filters that make the channel specific for a particular ion. This specificity may be based on the diameter of the pore, or on the electrostatic properties of the channel, or both. Many channels also have gates that regulate the movement of ions through them. This is due to a sensory mechanism that causes structural changes in the protein to open or close the gate. Local anesthetics cause a decrease in the permeability of the cell membrane to sodium ions so that although the resting and threshold potentials are maintained, there is a marked depression of the rate of membrane depolarization, making it insufficient to reach the threshold potential. Therefore, propagation of the action potential does not occur, and conduction block develops.

It has been established that the increase in permeability for sodium is associated with depolarization of the cell membrane and is ensured by the opening of gates or pores (sodium channel) in it. The exit of sodium from the cell through the pores is prevented by excess calcium ions. The opening of the sodium channel is explained by the movement of calcium into the extracellular fluid during depolarization. At rest, calcium ions contribute to the channel remaining closed. These ideas are the basis for the hypothesis that local anesthetics compete with calcium ions for placement in the sodium channel, i.e. they compete with calcium for the receptor that controls the permeability of the membrane for sodium ions.

The exact mechanism of action of local anesthetics is still a matter of debate. Three main mechanisms of nerve conduction blockade caused by these drugs are discussed:

• receptor theory, according to which local anesthetics interact with receptors of the sodium channels of the nerve membrane, blocking conduction along the nerve;
• The membrane expansion theory suggests that local anesthetics cause expansion of the nerve membrane, compressing sodium channels, thereby blocking nerve conduction;
• The surface charge theory is based on the fact that the lipophilic portion of the local anesthetic binds to the hydrophilic link of the nerve membrane end. This ensures that the positive charge is exceeded, so that the transmembrane potential increases. An approaching impulse is able to reduce the potential to threshold levels, and a conduction block occurs.

Many biotoxins (e.g. tetrodotoxin, saxitoxin), phenothiazines, beta-blockers and some opioids are capable of blocking sodium channels under the conditions of their application in vitro. However, only local anesthetics are used in clinical practice for nerve conduction blockade, since they are capable of penetrating the nerve sheath and are relatively free of local and systemic toxicity. The basis of the mechanism of action of these drugs is their chemical behavior in solution. All clinically used local anesthetics have common structural elements: an aromatic ring and an amine group connected by an intermediate chain. In addition to blocking the conduction of pain impulses, local anesthetics have clinically significant concomitant effects on the central nervous system, cardiovascular system and neuromuscular transmission.

Effect on the central nervous system

Local anesthetics easily penetrate the BBB, causing CNS stimulation, and with excess doses - its depression. The severity of the response effects of the CNS correlates with the concentration of the drug in the blood. At so-called therapeutic concentrations of the anesthetic in the plasma, minimal effects are observed. Minor symptoms of toxicity are manifested in the form of numbness of the tongue and skin around the mouth, which can be accompanied by ringing in the ears, nystagmus and dizziness. Continuous growth of the concentration of the anesthetic in the plasma causes excitation of the CNS in the form of anxiety and tremor. These symptoms indicate that the concentration of the drug is close to the toxic level, which is manifested by convulsions, coma and cessation of blood circulation and breathing.

Effect on the cardiovascular system

Local anesthetics cause peripheral arteriolar dilation and myocardial depression. Plasma lidocaine concentrations of 2 to 5 μg/mL produce little or no peripheral vasodilation and little or no change in contractility, diastolic volume, or CO. Lidocaine concentrations of 5 to 10 μg/mL progressively worsen myocardial contractility, increase diastolic volume, and decrease CO. Concentrations above 10 μg/mL cause depression of total peripheral vascular resistance and a marked decrease in myocardial contractility, leading to profound hypotension. The cardiovascular effects of local anesthetics are usually not evident with most regional anesthetics unless inadvertent intravascular injection occurs, creating high blood concentrations. This situation is common with epidural anesthetics as a result of absolute or relative overdose.

Some local anesthetics have an antiarrhythmic effect on the heart. Procaine increases the refractory period, increases the excitability threshold, and increases conduction time. Although procaine is not used as an antiarrhythmic drug, procainamide remains popular in the treatment of cardiac arrhythmias.

Effect on neuromuscular conduction

Local anesthetics may affect neuromuscular conduction and in certain situations potentiate the effects of depolarizing and non-depolarizing muscle relaxants. In addition, there are isolated reports linking the development of malignant hyperthermia with the use of bupivacaine.

Pharmacokinetics

Physicochemical properties

Structural changes in the molecule significantly affect the physicochemical properties of the drug, which control the potency and toxicity of the local anesthetic. Fat solubility is an important determinant of anesthetic potency. Changes in either the aromatic or amine moiety of the local anesthetic can alter lipid solubility and, therefore, anesthetic potency. In addition, lengthening the intermediate link increases the anesthetic potency until it reaches a critical length, after which potency usually decreases. Increasing the degree of protein binding increases the duration of local anesthetic activity. Thus, adding a butyl group to the aromatic residue of the ether local anesthetic procaine increases lipid solubility and protein binding capacity. Tetracaine, which is highly active and has a long duration of action, was obtained in this way.

Thus, the severity of the main pharmacological action of local anesthetics depends on their lipid solubility, ability to bind to plasma proteins, and pKa.

Fat solubility

Highly lipid-soluble drugs easily penetrate the cell membrane. In general, the most lipid-soluble local anesthetics are more powerful and have a longer duration of action.

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Protein binding

The increased duration of anesthetic action correlates with a high ability to remain in plasma. Although protein binding reduces the amount of free drug that is capable of diffusion, it provides drug deposition to maintain local anesthesia. In addition, binding of a larger mass of active drug to plasma proteins reduces the likelihood of systemic toxicity of the local anesthetic.

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Dissociation constant

The degree of ionization plays a major role in the distribution of a drug and largely determines the severity of its main pharmacological action, since only its non-ionized forms easily pass through cell membranes. The degree of ionization of a substance depends on the nature of the substance (acid or base), pKa and pH of the environment in which it is located. The pKa of a drug is the pH value at which 50% of the drug is in the ionized form. A weak base is ionized to a greater extent in an acidic solution, so a decrease in pH will increase the ionization of the base. Local anesthetics are weak bases with pKa values from 7.6 to 8.9. Local anesthetics with a pKa value close to the physiological pH (7.4) are represented in the solution by a higher concentration of the non-ionized form of molecules (which more easily diffuses through the nerve sheaths and membranes to the site of their action) than local anesthetics with a higher pKa. Drugs with a high pKa will dissociate more at physiological pH, and therefore there is less unionized drug available to penetrate the nerve sheath and membrane. This is why local anesthetics with pKa values close to physiological pH tend to have a faster onset of action (lidocaine - 7.8; mepivacaine - 7.7).

In light of the above, the reasons for the low efficiency of amino esters - procaine and tetracaine - become clearer. As can be seen in Table 6.2, procaine is characterized by low lipid solubility, weak ability to bind to proteins and a very high pKa value. On the other hand, tetracaine, at first glance, at least in two respects, approaches the ideal local anesthetic. This is confirmed by a fact well known to clinicians - its high potency. One could reconcile oneself to the long latent period of tetracaine, which is determined by the high pKa, but insufficiently high binding of the drug to proteins is responsible for the high concentration of the active substance in the blood. If procaine is characterized by simply a weak local anesthetic effect, then tetracaine should be considered an extremely toxic local anesthetic. As a result, today the use of tetracaine is permissible only for application and subarachnoid anesthesia.

On the contrary, modern local anesthetics, the aminoamides available today (lidocaine, ultracaine and bupivacaine), differ favorably from procaine and tetracaine in their physicochemical properties, which predetermines their high efficiency and sufficient safety. The rational combination of physicochemical properties inherent in each of these drugs predetermines a wide range of clinical possibilities when using them.

The emergence of highly effective local anesthetics (articaine and ropivacaine) expands the possibilities of choosing a local anesthetic for various conduction blocks. Articaine is a new local anesthetic with unusual physicochemical properties: pKa = 8.1; lipid solubility - 17; protein binding - 94%. This explains its minimal toxicity and the features of clinical pharmacology - a short latent period and a relatively long duration of action.

Knowledge of the pharmacokinetic laws of local anesthetic behavior in the body is of vital importance when administering local anesthesia (Table 6.3), since the systemic toxicity and severity of the therapeutic effect of these drugs depend on the balance between the processes of their absorption and systemic distribution. From the injection site, the local anesthetic penetrates into the blood through the walls of blood vessels and enters the systemic circulation. Active blood supply to the central nervous system and cardiovascular system, as well as high lipid solubility of local anesthetics predispose to rapid distribution and growth of concentrations to potentially toxic levels in these systems. This is counteracted by the processes of ionization (cations do not cross the membrane), protein binding (bound drugs are also unable to cross the membrane), biotransformation and renal excretion. Further redistribution of drugs to other organs and tissues occurs depending on regional blood flows, concentration gradients and solubility coefficients.

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Absorption

The pharmacokinetics of local anesthetics can be divided into two main processes - the kinetics of absorption and the kinetics of systemic distribution and elimination.

Most pharmacokinetic studies of local anesthetics in humans have involved measuring their blood concentrations at various time points after drug administration. Plasma drug concentrations depend on absorption from the injection site, interstitial distribution, and elimination (metabolism and excretion). Factors determining the extent of systemic absorption include the physicochemical properties of the local anesthetic, dose, route of administration, addition of a vasoconstrictor to the solution, vasoactive properties of the local anesthetic, and pathophysiological changes caused by underlying medical conditions.

Thus, systemic absorption after epidural injection can be represented as a two-phase process - the formation of a local anesthetic depot and the absorption itself. For example, absorption from the epidural space of a long-acting, well-fat-soluble anesthetic with a high ability to bind to proteins will occur more slowly. This is probably explained by a greater delay of the drug in the fat and other tissues of the epidural space. It is clear that the vasoconstrictor effect of epinephrine will have an insignificant effect on the absorption and duration of action of a long-acting drug. At the same time, slow absorption of a long-acting drug causes less systemic toxicity.

The injection site also influences the systemic absorption of the drug, since blood flow and the presence of tissue proteins capable of binding local anesthetics are important elements determining the activity of drug absorption from the injection site. The highest blood concentrations were found after intercostal block, and they decreased in the following order: caudal block, epidural block, brachial plexus block, femoral and sciatic nerve blocks, and subcutaneous infiltration of local anesthetic solution.

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Distribution and excretion

After absorption of local anesthetics from the injection site and entry into the systemic circulation, local anesthetics are primarily transferred from the blood into the interstitial and intracellular fluids and then eliminated primarily by metabolism and in small amounts through renal excretion.

The distribution of a drug is influenced by its physicochemical properties such as lipid solubility, plasma protein binding, and ionization degree, as well as physiological conditions (regional blood flow). Long-acting amide local anesthetics are bound to plasma protein to a greater extent than short-acting amide and ester local anesthetics. In addition, these local anesthetics also bind to erythrocytes, and the blood/plasma concentration ratio is inversely proportional to plasma binding. The main binding protein for most major amide local anesthetics is α-glycoprotein acid, and the decrease in mepivacaine binding in neonates is explained, in particular, by the low amount of α1-glycoprotein acid in them.

Amide-type anesthetics are metabolized primarily in the liver, so their clearance is reduced in disease states such as heart failure, liver cirrhosis, and decreased liver blood flow.

Ester anesthetics are broken down both in plasma and in the liver, undergoing rapid hydrolysis by plasma cholinesterase. The rate of metabolism varies considerably for different drugs. Chloroprocaine has the highest hydrolysis rate (4.7 μmol/ml x h), procaine - 1.1 μmol/ml x h and tetracaine - 0.3 μmol/ml x h. This explains their difference in toxicity; chloroprocaine is the least toxic drug of the ester group, and tetracaine is the most toxic anesthetic. Excretion of local anesthetics is carried out by the kidneys and liver mainly in the form of metabolites and to a lesser extent in an unchanged state.

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Contraindications

Contraindications for the use of local anesthetics are:

• indications of allergic reactions to local anesthetics;
• the presence of infection in the area of their intended administration.

Relative contraindications include all conditions associated with hypoproteinemia, anemia, metabolic acidosis and hypercapnia.

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Tolerability and side effects

Allergic reactions

Allergy to local anesthetics is quite rare and may manifest as local edema, urticaria, bronchospasm, and anaphylaxis. Dermatitis may occur after skin applications or as contact dermatitis in dentistry. Derivatives of ester anesthetics - derivatives of para-aminobenzoic acid cause the majority of hypersensitivity reactions, and hypersensitivity to amide local anesthetics is extremely rare, although isolated observations of hypersensitivity to lidocaine have been described.

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Local toxicity

An example of local toxicity is the development of the "horse tail" syndrome in the practice of subarachnoid anesthesia when using lidocaine. The main reason for the damaging effect of this widely used drug is the weak diffusion barriers between the anesthetic and the subarachnoid nerve structures. The use of more concentrated solutions than recommended for each technique can lead to the development of neurological deficit, which is a manifestation of local toxicity of local anesthetics in relation to the corresponding options of local anesthesia.

Systemic toxicity

Excessive absorption of local anesthetics into the blood is the cause of systemic toxic reactions. Most often, this is an accidental intravascular injection and/or absolute or relative, due to the presence of concomitant pathological changes, drug overdose. The severity of local anesthetic toxicity closely correlates with the drug concentration in arterial blood plasma. Factors that determine the drug concentration in blood plasma, and therefore the toxicity of the anesthetic, include the injection site and rate of injection, the concentration of the administered solution and the total dose of the drug, the use of a vasoconstrictor, the rate of redistribution in various tissues, the degree of ionization, the degree of binding to plasma and tissue proteins, as well as the rate of metabolism and excretion.

Clinical picture of toxic reactions

Toxic effects of local anesthetics are manifested by changes in the cardiovascular system (CVS) and the central nervous system (CNS). There are 4 phases of manifestations of a toxic reaction to a local anesthetic from both the CNS and the CVS.

Pregnant women are especially sensitive to the toxic effect of bupivacaine on the cardiovascular system. The cardiovascular system is more resistant to the toxic effect of local anesthetics than the central nervous system, but powerful local anesthetics, in particular bupivacaine, can cause severe impairment of its function. Cases of ventricular arrhythmia have been described.

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Treatment of toxic reaction

Early, timely diagnosis of toxic reactions and immediate initiation of treatment are the key to patient safety during regional anesthesia. Availability and readiness to use of all equipment and medications for the treatment of toxic reactions is mandatory. There are two basic rules:

• always use oxygen, and if necessary, artificial ventilation through a mask;
• stop convulsions if they last more than 15-20 seconds by intravenous administration of 100-150 mg thiopental or 5-20 mg diazepam.

Some experts prefer to administer 50-100 mg of suxamethonium, which quickly stops the seizures but requires tracheal intubation and mechanical ventilation. The manifestations of the toxic reaction may disappear as quickly as they appeared, but at this time a decision must be made: either postpone the operation and repeat the conduction block using a different technique (for example, spinal anesthesia instead of epidural), or switch to general anesthesia.

If signs of hypotension or myocardial depression occur, it is necessary to use a vasopressor with alpha- and beta-adrenergic activity, in particular ephedrine at a dose of 15-30 mg intravenously. It should be remembered that the use of local anesthetic solutions containing epinephrine completely excludes the inhalation of fluorothane during anesthesia, since this causes sensitization of the myocardium to catecholamines with the subsequent development of severe arrhythmia.

Cardiac arrest caused by overdose of local anesthetics requires long and intensive resuscitation measures, often unsuccessful. This dictates the need to observe precautions and not neglect all measures to prevent intoxication. Intensive therapy should be started at the earliest stages of its development.

Interaction

In the context of local anesthesia performed with lidocaine, there is always a risk of absolute or relative drug overdose in the case of attempts to use lidocaine to treat ventricular extrasystoles, which can lead to the development of systemic toxicity.

A reconsideration of the need to discontinue beta-blockers dictates the need for careful use of local anesthetics for regional blockades due to the risk of developing threatening bradycardia, which can be masked by the effects of regional sympathetic blockade. Similarly, the risk of bradycardia and hypotension is present when using drugs with alpha-adrenolytic activity (droperidol) in regional blockades.

Vasoconstrictors

The use of vasopressors in regional blockades has at least two independent aspects. It is generally recognized that vasoconstrictors can enhance the effects and increase the safety of regional blockade by slowing the absorption of local anesthetics in the injection zone. This applies to both central (segmental) and peripheral nerve blockades. Recently, great importance has been attached to the mechanism of direct adrenomimetic action of epinephrine on the adrenergic antinociceptive system of the gelatinous substance of the spinal cord. Due to this direct action, the main pharmacological effect of the local anesthetic is potentiated. This mechanism is more important in spinal than in epidural anesthesia. At the same time, due to the peculiarities of the blood supply to the spinal cord, one should not forget about the danger of its ischemic damage with serious neurological consequences as a result of the local action of excess concentrations of epinephrine on the arteries of the spinal cord. A reasonable solution in this situation seems to be either the use of officinal solutions containing a fixed dose of epinephrine (5 mcg/ml) or the refusal to add it to the local anesthetic ex tempore. The latter conclusion is determined by the fact that in clinical practice, rough dosing of epinephrine in drops is often allowed, which is mentioned in domestic articles, manuals, and sometimes in the annotations to the local anesthetic. Safe practice for preparing such a solution involves diluting epinephrine to a concentration of at least 1: 200,000, which corresponds to adding 0.1 ml of a 0.1% epinephrine solution to 20 ml of a local anesthetic solution. Apparently, the use of such a combination is justified with a one-stage epidural block technique, whereas with prolonged infusion of anesthetic, a technique quite popular in obstetrics, the likelihood of neurological complications increases many times over. When performing peripheral blockades, it is permissible, in particular in dental practice, to use epinephrine in a dilution of 1:100,000.

Local anesthetics of the ester group are hydrolyzed, forming para-aminobenzoic acid, which is an antagonist of the pharmacological action of sulfonamides. Amino esters can prolong the effect of suxamethonium, since they are metabolized by the same enzyme. Anticholinesterase drugs increase the toxicity of normal doses of procaine, inhibiting its hydrolysis. Novocaine metabolism is also reduced in patients with congenital pathology of plasma cholinesterase.

Cautions

Toxic reactions can be avoided in most cases by following a number of rules:

• Do not initiate anesthesia without providing oxygen inhalation using a mask;
• Always use only recommended doses;
• Always perform aspiration tests before injecting local anesthetic through a needle or catheter;
• use a test dose of a solution containing epinephrine. If the needle or catheter is located in the lumen of a vein, the test dose will cause a rapid increase in heart rate 30-45 seconds after the injection. Tachycardia quickly goes away, but in this situation constant ECG monitoring is necessary;
• if there is a need to use large volumes of drugs or administer them intravenously (for example, intravenous regional anesthesia), drugs with minimal toxicity should be used and slow distribution of the drug in the body should be ensured;
• Always administer slowly (not faster than 10 ml/min) and maintain verbal contact with the patient, who can immediately report minimal manifestations of a toxic reaction.

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