Barbiturates

Barbiturates are derivatives of barbituric acid. Since their inception and implementation in practice in 1903, they have been widely used throughout the world as sleeping pills and anticonvulsants. In the practice of anesthesiology, they are used longer than all other intravenous anesthetics.

In recent years, they have given way to the dominant hypnotic means, which took several decades. Currently, the list of barbiturates used for anesthesia is limited to thiopental sodium, methohexital and hexobarbital. Thiopental sodium from 1934 to the introduction of propofol in 1989 was a hypnotic standard for the induction of anesthesia. As a means of premedication, phenobarbital can be used (see Section III), which is administered orally.

Classification of barbiturates by the duration of the action is not completely correct, since even after using LS of ultrashort action its residual plasma concentration and effects last several hours. In addition, the duration of action varies significantly with the infusion method of administration. Therefore, the division of barbiturates is only justified by the nature of the chemical substitution of carbon atoms in barbituric acid. Oxibarbiturates (hexobarbital, methohexital, phenobarbital, pentobarbital, secobarbital) retain the oxygen atom at the position of the 2-carbon atom. In thiobarbiturates (thiopental sodium, thiamylal) this atom is replaced by a sulfur atom.

The effect and activity of barbiturates largely depend on their structure. For example, the degree of branching of the chain at the positions of the 2-nd and 5-th carbon atoms in the barbituric ring determines the strength and duration of the hypnotic effect. That is why thiamylal and secobarbital are stronger than thiopental sodium and last longer. Replacement of the second carbon atom by the sulfur atom (sulfurization) increases fat solubility, and therefore makes barbiturates a strong hypnotist with a rapid onset and shorter duration of action (thiopental sodium). The methyl group at the nitrogen atom determines the short duration of action of the drug (metohexital), but causes a greater probability of excitation reactions. The presence of a phenyl group in the position of the 5-th atom gives increased anticonvulsant activity (phenobarbital).

Most barbiturates have stereoisomers due to rotation around the 5th carbon atom. With the same ability to penetrate the CNS and similar pharmacokinetics, the 1-isomers of sodium thiopental, thiamylal, pentobarbital and secobarbital are almost 2 times stronger than the d-isomers. Methohexital has 4 stereoisomers. The beta-1 isomer is 4-5 times stronger than the isomer a-1. But the beta isomer determines excessive motor activity. Therefore, all barbiturates are available in the form of racemic mixtures.

[1], [2], [3]

Barbiturates: a place in therapy

Currently, barbiturates are used mainly to induce anesthesia. Usually, hexobarbital and methohexital are administered in the form of 1% solution, and thiopental sodium - 1-2.5% solution. Loss of consciousness by clinical and EEG-signs does not reflect the depth of anesthesia and can be accompanied by hyperreflexia. Therefore, the performance of traumatic manipulations, including intubation of the trachea, should be performed with the additional use of other drugs (opioids). The advantage of methohexital is a faster recovery of consciousness after its introduction, which is important for outpatient conditions. But it more often than thiopental sodium, causes myoclonus, hiccups and other signs of arousal.

As a component to maintain anesthesia, barbiturates are now rarely used. This is determined by the presence of side effects and inappropriate pharmacokinetics. They can be used as a monoanesthetic in cardioversion and electroconvulsive therapy. With the advent of the DB, the use of barbiturates as a means of premedication was sharply limited.

In the intensive care unit (ICU), barbiturates are used to prevent and arrest seizures, to reduce ICP in neurosurgical patients and less often as sedatives. The use of barbiturates to achieve sedation is not justified in conditions of pain. In some cases, barbiturates are used to arrest psychomotor agitation.

In animal experiments, it was found that high doses of barbiturates lead to a decrease in mean BP, MK and PM02. Methohexital has a lesser effect on metabolism and vasoconstriction than thiopental sodium, and also acts more briefly. When creating an occlusion of the cerebral artery, barbiturates reduce the area of the infarction, but do not benefit from stroke or cardiac arrest.

In humans, thiopental sodium at a dose of 30-40 mg / kg body weight provided protection in cardiac valve operations under conditions of normothermic artificial circulation (IC). Thiopental sodium protects the weakly perfused areas of the brain in patients with an increase in ICP in the presence of carotid endarterectomy and aneurysm of the thoracic aorta. But such high doses of barbiturates cause pronounced systemic hypotension, require more inotropic support and are accompanied by a long period of awakening.

The ability of barbiturates to improve brain survival after general ischemia and hypoxia due to cranial trauma or circulatory arrest is not confirmed.

[4], [5], [6], [7], [8],

Mechanism of action and pharmacological effects

The mechanism of CNS drug suppression for intravenous anesthesia is not completely clear. According to modern concepts, there is no universal mechanism for all general anesthetics. The theory of ion channels and neurotransmitters replaced the lipid, protein theories. As you know, the functioning of the central nervous system occurs in a balance of systems that activate and inhibit the conduction of nerve impulses. The main inhibitory neurotransmitter in the central nervous system of mammals is GABA. The main place of its action is the GABA receptor, which is a hetero-oligomeric glycoprotein complex, consisting of at least 5 sites, united around the so-called chloride channels. Activation of the GABA receptor leads to an increased intake of chloride ions into the cell, hyperpolarization of the membrane, and a decrease in the reaction of the postsynaptic neuron to excitatory neurotransmitters. In addition to the GABA-receptor complex contains benzodiazepine, barbiturate, steroid, picrotoxin and other binding sites. In / in anesthetics can interact differently with different sites of the GABA-receptor complex.

Barbiturates, first, reduce the rate of dissociation of GABA from the activated receptor, thereby prolonging the opening of the ion channel. Secondly, in several large concentrations, they imitate GABA even in its absence, directly activate the chloride channels. Unlike the database, barbiturates are not so selective in their action, they can suppress the activity of excitatory neurotransmitters, incl. Outside the synapses. This can explain their ability to cause a surgical stage of anesthesia. They selectively inhibit impulses in the ganglia of the sympathetic nervous system, which, for example, is accompanied by a decrease in blood pressure.

The effect of barbiturates on the central nervous system

Barbiturates have a dose-dependent sedative, hypnotic, and also an anticonvulsant effect.

Depending on the dosage barbiturates cause sedation, sleep, and in cases of overdose - surgical stage of anesthesia and to whom. In various barbiturates, the severity of sedative-hypnotic and anticonvulsant effects is not the same. According to the relative power of the effect on the central nervous system and the vagus nerve system, they are arranged in the following order: metohexital> thiamylal> thiopental sodium> hexobarbital. And in equivalent doses meteohexital is about 2.5 times stronger than sodium thiopental and its effect is 2 times shorter. The effect of the remaining barbiturates is less severe.

In subanesthetic doses, barbiturates can cause an increase in sensitivity to pain - hyperalgesia, which is accompanied by lacrimation, tachypnea, tachycardia, hypertension, agitation. On this basis, barbiturates were even considered anti-analgesics, which was not confirmed in the future.

The anticonvulsant properties of barbiturates are mainly due to postsynaptic activation of GABA, changes in membrane conductivity for chlorine ions and antagonism with respect to glutaminergic and cholinergic excitations. In addition, presynaptic blocking of the entry of calcium ions into nerve endings and a decrease in the release of the transmitter are possible. Barbiturates have a different effect on convulsive activity. So, thiopental sodium and phenobarbital are able to quickly arrest seizures when other drugs are ineffective. Methohexital may cause seizures when used in high doses and prolonged infusion.

Electroencephalographic changes caused by barbiturates depend on their dose and are distinguished by their phase: from low-speed fast activity after the introduction of small doses, mixed, high-amplitude and low-frequency 5- and 9-waves with deepening of anesthesia before suppression outbreaks and flat EEG. The picture after loss of consciousness is like a physiological dream. But even with such a picture of the EEG, intense pain stimulation can cause awakening.

The effect of barbiturates on evoked potentials has features. There is a dose-dependent change in somatosensory evoked potentials (SSVP) and auditory evoked potentials (SVP) of the brain. But even when the isoelectric EEG is achieved against the background of the introduction of thiopental sodium, the SSEP components are available for registration. Thiopental sodium reduces the amplitude of motor evoked potentials (MAP) to a greater extent than metohexital. The bispectral index (BIS) is a good criterion for the hypnotic effect of barbiturates.

Barbiturates are considered drugs that provide protection for the brain. In particular, phenobarbital and thiopental sodium suppress the electrophysiological, biochemical and morphological changes resulting from ischemia, improving recovery of the pyramidal cells of the brain. Such protection may be due to a number of direct neuroprotective and mediated effects:

• reduction of cerebral metabolism in areas with high cerebral activity;
• suppression of excitation by inactivation of nitric oxide (NO), weakening of glutamate convulsive activity (in ischemia, K + is released from the neurons via glutamate cationic receptor channels, and Na + and Ca2 + enter, causing an imbalance in the neuronal membrane potential);
• vasoconstriction of healthy areas of the brain and bypassing blood in affected areas;
• decreased intracranial pressure;
• increased cerebral perfusion pressure (CPD);
• stabilization of liposomal membranes;
• a decrease in the production of free radicals.

However, it should be remembered that high doses of barbiturates, along with their negative hemodynamic effect, increase immunosuppression, which may limit their clinical effectiveness. Thiopental sodium can be useful in neurosurgical patients with elevated ICP (reduces MC and oxygen consumption by the brain - PM02), with occlusion of intracranial vessels, i.e. With focal ischemia.

The effect of barbiturates on the cardiovascular system

Cardiovascular effects of drugs are determined by the method of administration and with IV injection depend on the dose used, as well as on the initial volume of circulating blood (BCC), the state of the cardiovascular and autonomic nervous system. In normovolemic patients, after the introduction of an induction dose, there is a transient decrease in blood pressure by 10-20% with a compensatory increase in heart rate of 15-20 / min. The main cause is peripheral venodilation, which is the result of depression of the vasomotor center of the medulla oblongata and a decrease in sympathetic stimulation from the central nervous system. Dilating capacitive vessels, reducing venous return causes a reduction in cardiac output (CB) and blood pressure. Myocardial contractility is reduced to a lesser extent than with the use of inhalational anesthetics, but more than with the use of other intravenous anesthetics. Possible mechanisms are the effect on the over-membrane current of calcium and the capture of nitric oxide. The baroreflex changes insignificantly, and the heart rate increases as a result of hypotension more significantly when methohexital is used than thiopental sodium. An increase in heart rate leads to an increased consumption of oxygen by the myocardium. OPSS usually does not change. In the absence of hypoxemia and hypercarbia, rhythm disturbances are not observed. Higher doses have a direct effect on the myocardium. The sensitivity of the myocardium to catecholamines decreases. In rare cases, cardiac arrest may occur.

Barbiturates narrow the vessels of the brain, reducing MC and ICP. BP decreases less than intracranial pressure, so brain perfusion does not change significantly (CPD usually even rises). This is extremely important for patients with elevated ICP.

The degree of PM02 also depends on the dose and reflects a decrease in the neuronal, but not metabolic, requirement for oxygen. Concentrations of lactate, pyruvate, phosphocreatine, adenosine triphosphate (ATP), glucose do not change significantly. A true reduction in the metabolic needs of the brain in oxygen is achieved only by creating hypothermia.

After the introduction of barbiturates during induction, intraocular pressure decreases by about 40%. This makes their use safe for all ophthalmic interventions. Use of suxamethonium returns intraocular pressure to the baseline level or even exceeds it.

Barbiturates reduce the basal metabolism, lead to a loss of heat due to vasodilation. A decrease in body temperature and a violation of thermoregulation may be accompanied by a post-operative tremor.

Effect of barbiturates on the respiratory system

The effects of drugs depend on the dose, the rate of administration and the quality of premedication. Like other anesthetics, barbiturates cause a decrease in the sensitivity of the respiratory center to natural stimulants of its activity - CO2 and O2. As a result of this central depression, the depth and frequency of breathing (BH) decreases to apnea. The normalization of ventilation parameters occurs faster than the recovery of the respiratory center response to hypercapnia and hypoxemia. Cough, hiccough and myoclonus complicate pulmonary ventilation.

The pronounced vagotonic effect of barbiturates in a number of cases can cause hypersecretion of mucus. Laryngospasm and bronchospasm are possible. Usually, these complications occur when an airway (intubation tube, laryngeal mask) is established against a background of surface anesthesia. It should be noted that when barbiturates are induced, the laryngeal reflexes are suppressed to a lesser degree than after the administration of equivalent doses of propofol. Barbiturates suppress the protective mechanism of mucociliary cleansing of the tracheobronchial tree (TBD).

[9], [10]

Effects on the gastrointestinal tract, liver and kidneys

Induction of anesthesia with barbiturates does not have a significant effect on the function of the liver and gastrointestinal tract of healthy patients. Barbiturates, increasing the activity of the vagus nerve, increase the secretion of saliva and mucus in the digestive tract. Heckobarbital suppresses motor activity of the intestine. When used on an empty stomach, nausea and vomiting occur rarely.

As a result of lowering systemic arterial pressure, barbiturates can reduce renal blood flow, glomerular filtration and tubular secretion. Adequate infusion therapy and correction of hypotension prevent clinically significant effects of barbiturates on the kidneys.

[11], [12], [13], [14], [15]

Effect on the endocrine response

Thiopental sodium reduces the concentration of cortisol in the plasma. However, unlike etomidata, this does not prevent adrenocortical stimulation as a result of operational stress. Increased sensitivity to thiopental sodium is detected by patients with myxedema.

[16], [17], [18], [19], [20],

Effect on neuromuscular transmission

Barbiturates do not affect the neuromuscular junction and do not cause muscle relaxation. In high doses, they reduce the sensitivity of the synaptic membrane of the neuromuscular synapse to the action of acetylcholine and reduce the tone of the skeletal musculature.

[21], [22], [23], [24], [25], [26], [27]

Tolerance

Barbiturates can induce microsomal liver enzymes involved in their own metabolism. Such self-induction is a possible mechanism for the development of tolerance towards them. But acute tolerance to barbiturates outstrips in time the development of induction of enzymes. Tolerance, expressed to the maximum extent, leads to a sixfold increase in the need for drugs. Tolerance to the sedative effect of barbiturates develops faster and more pronounced than to the anticonvulsant.

Cross-tolerance to sedative-hypnotic drugs is not excluded. This should be taken into account in connection with the known urban abuses of these drugs and the prevalence of polydrug abuse.

Pharmacokinetics

As weak acids, barbiturates are absorbed very quickly in the stomach and small intestine. In this case, sodium salts are absorbed faster than free acids such as barbitol and phenobarbital.

Barbamyl, hexobarbital, methohexital and thiopental sodium can be administered intramuscularly. Barbital is also administered rectally in the form of enemas (preferably in children). Methohexital, thiopental sodium and hexobarbital can also be administered rectally in the form of a 5% solution; the action is slower.

The main way of administration of barbiturates is IV. The speed and completeness of drug penetration through the blood-brain barrier (GEB) are determined by their physico-chemical characteristics. The LS with a smaller molecule size, greater fat solubility and a lesser degree of connection with plasma proteins have a greater penetrating power.

The fat solubility of barbiturates is determined almost entirely by the fat solubility of the non-ionized (undissociated) portion of the drug. The degree of dissociation depends on their ability to form ions in the aqueous medium and on the pH of this medium. Barbiturates are weak acids with a dissociation constant (pKa) slightly higher than 7. This means that at physiological blood pH values, approximately half of the drug is in the non-ionized state. With acidosis, the ability of weak acids to dissociate decreases, which means an increase in the non-ionized form of the drug, i.e. The form in which the drug can penetrate through the BBB and provide an anesthetic effect. However, not all non-ionized drugs enter the CNS. A certain part of it binds to plasma proteins, this complex, because of its large size, loses its ability to pass through tissue barriers. Thus, a decrease in dissociation and a simultaneous increase in binding to plasma proteins are counterproductive processes.

Due to the presence of a sulfur atom, thiobarbiturates bind more strongly to proteins than oxybarbiturates. Conditions that lead to a decrease in the binding of drugs to proteins (with cirrhosis of the liver, uremia, in newborns), may cause an increased sensitivity to barbiturates.

The distribution of barbiturates is determined by their fat solubility and blood flow in the tissues. Thiobarbiturates and metohexital easily dissolve in fats, so their effect on the central nervous system begins very quickly - about one cycle of circulation of the forearm-brain. In a short period of time, the concentration of drugs in the blood and brain is balanced, after which they are further intensively redistributed into other tissues (Vdss - the volume of distribution in the equilibrium state), which determines the decrease in the concentration of drugs in the central nervous system and the rapid cessation of the effect after a single bolus. Due to the fact that in hypovolemia the blood supply to the brain does not decrease as much as muscle and adipose tissue, the concentration of barbiturates in the central chamber (blood plasma, brain) increases, which determines a greater degree of cerebral and cardiovascular depression.

Thiopental sodium and other barbiturates accumulate well in adipose tissue, but this process develops slowly because of poor perfusion of adipose tissue. With repeated injections or prolonged infusion, muscle and fatty tissues are largely saturated with drugs, and their return to the blood is delayed. The termination of the drug becomes dependent on the slow absorption of the LS of the fat tissue and its clearance. This leads to a significant increase in half-life, i.e. Time required to reduce the plasma concentration of drugs by half. The presence of large fat deposits contributes to the prolongation of the effect of barbiturates.

Due to the fact that barbiturates are weak acids, acidosis will increase their non-ionized fraction, which is more fat-soluble than ionized, and therefore more quickly penetrates into the VAT. Thus, acidosis increases, and alkalosis reduces the severity of the effect of barbiturates. But respiratory changes in blood pH, unlike metabolic ones, are not accompanied by such significant changes in the degree of ionization and the ability of drugs to penetrate the BBB.

Metabolism of oxybarbiturates occurs only in the endoplasmic reticulum of hepatocytes, and thiobarbiturates are metabolized to some extent outside the liver (probably in the kidneys, CNS). Barbiturates undergo oxidation of the side chains at the position of the 5-th carbon atom. The alcohols, acids and ketones formed are, as a rule, inactive. Oxidation proceeds much more slowly than redistribution in tissues.

By oxidizing the side chain at C5, desulfurizing position C2 and hydrolyzing the barbituric ring, thiopental sodium is metabolized to hydroxythiopental and unstable carboxylic acid derivatives. When using large doses, desulphurisation can proceed until the formation of pentobarbital. The metabolic rate of thiopental sodium after a single injection is 12-16% per hour.

Methohexital is metabolized by demethylation and oxidation. It decomposes faster than sodium thiopental because of its lower fat solubility and greater availability for metabolism. In the oxidation of the side chain, an inactive hydrometohexital is formed. The binding to proteins of both drugs is quite significant, but the clearance of thiopental sodium is less because of the lower degree of hepatic extraction. Due to the fact that T1 / 2p is directly proportional to the volume of distribution and inversely proportional to the clearance, the difference in T1 / 2/3 between thiopental sodium and metohexital is associated with the rate of their elimination. Despite a threefold difference in clearance, the main factor for the end of the induction dose effect of each of Less than 10% of these barbiturates are left in the brain 30 minutes after injection, after about 15 minutes, their concentrations in the muscles are balanced, after 30 minutes, their content in the adipose tissue continues The total recovery of the psychomotor functions is determined by the metabolic rate and occurs more rapidly after the administration of metohexital than sodium thiopental. In addition, the hepatic clearance of metohexital, in comparison with thiopental sodium, depends more on the systemic and hepatic blood flow. The pharmacokinetics of hexobarbital is close to that of sodium thiopental.

The hepatic clearance of barbiturates can be affected by violations of liver function due to diseases or age, suppression of activity of microsomal enzymes, but not hepatic blood flow. Induction of microsomal enzymes under the influence of external factors, for example, in smokers, in residents of large cities, can lead to increased needs in barbiturates.

Barbiturates (except phenobarbital) are released unchanged in small amounts (not more than 1%). Water-soluble glucuronides of metabolites are excreted mainly by the kidneys by glomerular filtration. Thus, renal dysfunction does not significantly affect the elimination of barbiturates. Despite the fact that the volume of distribution does not change with age, the rate of transition of thiopental sodium from the central sector to the peripheral in the elderly and elderly is slowed down (by about 30%) compared with younger adults. This slowing of the intersectoral clearance creates a large concentration of drugs in the plasma and brain, providing a more pronounced anesthetic effect in the elderly.

The concentration of barbiturate in plasma, necessary to turn off consciousness, does not change with age. In children, protein binding and the volume distribution of sodium thiopental do not differ from those of adults, but T1 / 2 is shorter due to faster hepatic clearance. Therefore, the restoration of consciousness in infants and children is faster. During pregnancy, T1 / 2 increases due to better binding to proteins. T1 / 2 is prolonged in obese patients due to a greater distribution to excess fat accumulation.

Contraindications

Barbiturates are contraindicated for individual intolerance, with organic diseases of the liver and kidneys, accompanied by severe insufficiency, with familial porphyria (including latent). They can not be used for shocks, collapse, severe circulatory failure.

[28], [29]

Dependence on barbiturates and withdrawal syndrome

Long-term use of any sedative-hypnotic drugs can cause physical dependence. The severity of the syndrome will depend on the dose used and the rate of elimination of a particular drug.

Physical dependence on barbiturates is closely related to tolerance to them.

The withdrawal of barbiturates resembles alcohol (anxiety, tremor, muscle twitching, nausea, vomiting, etc.). In this case, cramps are a rather late manifestation. Weaken the withdrawal symptoms can be the appointment of short-acting barbiturate, clonidine, propranolol. The severity of the withdrawal syndrome depends on the rate of elimination. Thus, barbiturates with a slow elimination will have a delayed and milder clinical picture of withdrawal syndrome. However, a sharp discontinuation of even small doses of phenobarbital in the treatment of epilepsy can lead to greater seizures.

[30], [31], [32], [33], [34], [35]

Tolerance and side effects

Barbiturates are generally well tolerated. The occurrence of side effects and toxicity of barbiturates is mainly due to their overdose and the introduction of concentrated solutions. The most common side effects of barbiturates are the dose-dependent depression of blood circulation and respiration, and the initial excitation of the CNS during induction is a paradoxical effect. Less pain is observed when injected and anaphylactic reactions occur.

The paradoxical effect of barbiturates develops when the inhibitory effects of the central nervous system are suppressed and is manifested by mild hypertension in the form of muscle hypertension, tremor or twitching, as well as cough and hiccups. The severity of these symptoms is higher in methohexital than in thiopental sodium, especially if the dose of the first exceeds 1.5 mg / kg. Excitation is removed by deepening anesthesia. In addition, the stimulatory effects are minimized by the preliminary administration of atropine or opioids and are enhanced after premedication with scopolamine or phenothiazines.

Overdose with barbiturates is manifested by the growing symptoms of depression of consciousness up to the coma and is accompanied by depression of blood circulation and respiration. Barbiturates do not have specific pharmacological antagonists for overdose treatment. Naloxone and its analogs do not eliminate their effects. As an antidote barbiturates used analeptic drugs (bemegrid, etizol), but it was later found that the probability of the unwanted effects they cause exceeds their usefulness. In particular, in addition to the "awakening" effect and stimulation of the respiratory center, the bemegrid stimulates the vasomotor center and has convulsive activity. Etimizol to a lesser degree stimulates hemodynamics, does not have convulsive activity, but lacks "awakening" activity and even enhances the effect of anesthetics.

Allergic reactions when using oxybarbiturates are rare and can be expressed in the form of itching and a rapidly passing urticaria rash on the upper part of the chest, neck and face. After induction by thiobarbiturates, allergic reactions are observed more often and manifest in the form of urticaria, edema of the face, bronchospasm and shock. In addition to anaphylactic, there are, albeit less frequently, anaphylactoid reactions. Unlike oxybarbiturates, thiopental sodium and especially thiamylal cause a dose-dependent release of histamine (within 20%), but this is rarely clinically important. In most cases, patients have an allergic history.

Severe allergic reactions to barbiturates are rare (1 per 30,000 patients), but are accompanied by high mortality. Therefore, the treatment should be vigorous and include the introduction of epinephrine (1 ml at a dilution of 1: 10 000), infusion of liquids, as well as theophylline for cupping bronchospasm.

Interestingly, about one-third of adult patients of both sexes (especially young adults) report the appearance of bulbous or garlic smell and taste when sodium thiopental is administered. The introduction of barbiturates into large veins of the forearm, as a rule, is not accompanied by pain. But with the insertion of a wrist or wrist into small veins, the frequency of pain sensation with methohexital injection is approximately twice that of thiopental sodium injection. The probability of venous thrombosis is higher when using concentrated solutions.

The question of the unintended introduction of barbiturates into the artery or under the skin is extremely important. If a 1% solution of oxybarbiturates is injected into the artery or under the skin, moderate local discomfort can occur without undesirable consequences. But if more concentrated solutions or thiobarbiturates are administered extravasally, pain, swelling and redness of the tissues at the site of injection and widespread necrosis can occur. The severity of these symptoms depends on the concentration and total amount of drugs administered. The erroneous intra-arterial administration of concentrated solutions of thiobarbiturates causes an intense arterial spasm. This is immediately accompanied by intense burning pain from the injection site to the fingers, which can persist for hours, as well as blanching. In conditions of anesthesia, spotted cyanosis and limb darkening can be observed. In the future, there may be hyperesthesia, edema, and mobility restriction. These manifestations characterize the chemical endarteritis with the depth of damage from the endothelium to the muscular layer.

In the most severe cases, thrombosis, gangrene of the limb, nerve damage develops. In order to arrest vascular spasm and dilute barbiturate, papaverine (40-80 mg in 10-20 ml of physiological solution) or 5-10 ml of 1% lidocaine solution is injected into the artery. Reduce the spasm can also sympathetic blockade (stellate ganglion or brachial plexus). The presence of a peripheral pulse does not exclude the development of thrombosis. Prophylaxis of thrombosis may be facilitated by intraarterial administration of heparin, GCS with subsequent systemic administration.

With prolonged administration of barbiturates stimulate an increase in the level of microsomal enzymes of the liver. This is clearly manifested with the appointment of maintenance doses and is most pronounced when using phenobarbital. There is also stimulation of mitochondrial enzymes. As a result of the activation of 5-aminolevulinate synthase, the formation of porphyrin and heme is accelerated, which can aggravate the course of intermittent or familial porphyria.

Barbiturates, especially in large doses, depress the function of neutrophils (chemotaxis, phagocytosis, etc.). This leads to a weakening of nonspecific cellular immunity and a protective antibacterial mechanism.

Data on the carcinogenic, mutagenic effects of barbiturates are absent. There is no adverse effect on reproductive function.

Interaction

The degree of CNS depression with barbiturates increases with the combination of the use of other depressants, such as ethanol, antihistamines, MAO inhibitors, isoniazid, etc. A joint appointment with theophylline decreases the depth and duration of the effect of sodium thiopental.

In contrast, with prolonged use, barbiturates cause induction of microsomal liver enzymes and affect the kinetics of drugs metabolized with the participation of the cytochrome P450 system. So, they accelerate the metabolism of halothane, oral anticoagulants, phenytoin, digoxin, drugs containing propylene glycol, corticosteroids, vitamin K, bile acids, but slow the biotransformation of tricyclic antidepressants.

Favorable combinations

As a rule, barbiturates are used to induce anesthesia. Any other intravenous and / or inhaled anesthetics may be used to maintain anesthesia. Barbiturates when used with a DB or opioids ensure a mutual reduction in the requirements of each drug individually. They also work well with muscle relaxants.

[36], [37], [38], [39]

Combinations that require special attention

Combined with barbiturates, the use of other anesthetics and opioids for induction increases the degree of blood circulation depression and the likelihood of apnea. This should be taken into account in weakened, depleted patients, elderly patients, with hypovolemia and concomitant cardiovascular diseases. The hemodynamic effects of barbiturates are greatly enhanced by the action of propranolol. X-ray contrast drugs and sulfonamides, displacing barbiturates from the connection with plasma proteins, increase the fraction of the free fraction of LS, enhancing their effects.

[40], [41], [42], [43]

Unwanted combinations

Sharing of barbiturates with drugs that have a similar effect on hemodynamics (for example, with propofol) is not appropriate. Thiopental sodium should not be mixed with acidic solutions of other drugs, as this may precipitate (for example, with suxamethonium, atropine, ketamine, iodides).

Caveats

Like all other anesthetics, barbiturates can not be used by specially trained individuals and without the availability of ventilator support and relief of cardiovascular changes. When working with barbiturates, the following factors should be considered:

• age of patients. Patients of elderly and senile age are more sensitive to barbiturates because of slowing of intersectoral redistribution. In addition, the elderly often have paradoxical reactions of excitation against the background of the use of barbiturates. In children, recovery from large or repeated doses of thiopental sodium may be more rapid than in adults. In infants up to one year, recovery after using methohexital is faster than after thiopental sodium;
• duration of intervention. With repeated injections or prolonged infusion, the cumulative effect of all barbiturates, including metohexital, should be considered;
• concomitant cardiovascular diseases. Barbiturates should be used with caution in patients for whom an increase in heart rate or a decrease in preload is undesirable (for example, in hypovolemia, compression pericarditis, cardiac tamponade, valve stenosis, congestive heart failure, myocardial ischemia, blockades, initial sympathicotonia). In patients with arterial hypertension, hypotension is more pronounced than in normotonics, regardless of the basal therapy. With reduced baroreflex on the background of taking beta-blockers or antihypertensive drugs of central effect, the effect will be more pronounced. Reducing the rate of administration of an induction dose does not optimize the situation. Heckobarbital stimulates the vagus nerve, so when it is used, it is advisable to prophylactic administration of M-cholinoblockers;
• concomitant diseases of the respiratory system. It is believed that thiopental sodium and methohexital are safe for patients with bronchial asthma, although, unlike ketamine, they do not cause bronchodilation. Nevertheless, barbiturates should be used with caution in patients with bronchial asthma and chronic obstructive pulmonary disease (COPD);
• concomitant liver disease. Barbiturates are metabolized mainly in the liver, so it is not recommended for use with severe dysfunction. Thiopental sodium can also reduce hepatic blood flow. Hypoproteinemia against a background of liver diseases leads to an increase in the proportion of unbound fraction and the enhanced effect of drugs. Therefore, in patients with cirrhosis of the liver, barbiturates should be administered more slowly, in doses reduced by 25-50%. In patients with hepatic failure, the duration of the effect may be longer;
• concomitant kidney disease. Hypoalbuminemia against uremia is the reason for less binding to proteins and greater sensitivity to drugs. Concomitant kidney diseases affect the elimination of hexametonium;
• anesthesia in childbirth, influence on the fetus. Thiopental sodium does not change the tone of the pregnant uterus. Barbiturates penetrate the placental barrier, and their effect on the fetus depends on the dose administered. In an induction dose of 6 mg / kg in a cesarean section, thiopental sodium does not adversely affect the fetus. But in a dose of 8 mg / kg there is a depression of the vital activity of the fetus. The limited intake of barbiturates in the fetal brain is due to their rapid distribution in the mother's body, placental circulation, hepatic clearance of the fetus, and the dilution of drugs with fetal blood. The use of thiopental sodium is considered safe for the fetus if it is recovered within 10 minutes after induction. T1 / 2 thiopental sodium in neonates after the introduction of the mother during the caesarean section varies from 11 to 43 hours. The use of sodium thiopental is accompanied by a lesser depression of the function of the neonatal CNS than induction of midazolam, but greater than with the use of ketamine; the volume of distribution of thiopental sodium changes already at the 7th-13th week of the gestational period, and despite the increase in CB, the need for barbiturate in pregnant women is reduced by about 20%. The use of barbiturates in nursing mothers requires caution;
• intracranial pathology. Barbiturates are widely used in neurosurgery and neuroanesthesiology due to their beneficial effect on MK, CPR, PMO, ICP and anticonvulsant activity. Methohexital should not be used in patients with epilepsy;
• anesthesia on an outpatient basis. After a single bolus dose of methohexital, awakening occurs more quickly than after the administration of thiopental sodium. Despite this, the recovery of psychophysiological tests and EEG pictures with methohexital is slower than with thiopental sodium. This is the basis for recommending patients to refrain from driving for 24 hours after general anesthesia.

[44], [45], [46], [47], [48], [49]