Barbiturates

Barbiturates are derivatives of barbituric acid. Since their creation and introduction into practice in 1903, they have been widely used throughout the world as hypnotics and anticonvulsants. In the practice of anesthesiology, they have been used longer than other intravenous anesthetics.

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

Classification of barbiturates by duration of action is not entirely correct, since even after the use of ultra-short-acting drugs, their residual plasma concentration and effects last for several hours. In addition, the duration of action changes significantly with infusion administration. Therefore, it is justified to classify barbiturates only by the nature of chemical substitution of carbon atoms in barbituric acid. Oxybarbiturates (hexobarbital, methohexital, phenobarbital, pentobarbital, secobarbital) retain an oxygen atom in the position of the 2nd carbon atom. In thiobarbiturates (sodium thiopental, 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 chain branching in positions 2 and 5 of carbon atoms in the barbiturate ring determines the strength and duration of the hypnotic effect. That is why thiamylal and secobarbital are stronger than sodium thiopental and act longer. Replacing the 2nd carbon atom with a sulfur atom (sulfurization) increases fat solubility, and therefore makes barbiturates a strong hypnotic with a rapid onset and shorter duration of action (sodium thiopental). The methyl group at the nitrogen atom determines the short duration of action of the drug (methohexital), but causes a higher probability of excitatory reactions. The presence of a phenyl group in position 5 of the 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 central nervous system and similar pharmacokinetics, 1-isomers of sodium thiopental, thiamylal, pentobarbital and secobarbital are almost 2 times stronger than d-isomers. Methohexital has 4 stereoisomers. The beta-1 isomer is 4-5 times stronger than the a-1 isomer. But the beta isomer determines excessive motor activity. Therefore, all barbiturates are produced as racemic mixtures.

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Barbiturates: place in therapy

Currently, barbiturates are used mainly to induce anesthesia. Hexobarbital and methohexital are usually administered as a 1% solution, and sodium thiopental is administered as a 1-2.5% solution. Loss of consciousness based on clinical and EEG signs does not reflect the depth of anesthesia and may be accompanied by hyperreflexia. Therefore, traumatic manipulations, including tracheal intubation, should be performed with the additional use of other drugs (opioids). The advantage of methohexital is a faster recovery of consciousness after its administration, which is important for outpatient settings. But it causes myoclonus, hiccups and other signs of excitement more often than sodium thiopental.

Barbiturates are now rarely used as a component for maintaining anesthesia. This is determined by the presence of side effects and unsuitable pharmacokinetics. They can be used as a monoanesthetic in cardioversion and electroconvulsive therapy. With the advent of BD, the use of barbiturates as premedication agents has been sharply limited.

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

Animal experiments have shown that high doses of barbiturates lead to a decrease in mean arterial pressure, MC, and PM02. Methohexital has a lesser effect on metabolism and vasoconstriction than sodium thiopental, and also acts more briefly. When creating cerebral artery occlusion, barbiturates reduce the infarction zone, but are of no benefit in stroke or cardiac arrest.

In humans, sodium thiopental at a dose of 30-40 mg/kg body weight provided protection during heart valve surgery under normothermic artificial circulation (AC). Sodium thiopental protects poorly perfused areas of the brain in patients with increased ICP due to carotid endarterectomy and thoracic aortic aneurysm. However, such high doses of barbiturates cause severe systemic hypotension, require greater inotropic support, and are accompanied by a prolonged period of awakening.

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

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Mechanism of action and pharmacological effects

The mechanism of CNS depression by intravenous anesthetic drugs is not completely clear. According to modern concepts, there is no universal mechanism for all general anesthetics. The lipid and protein theories have been replaced by the theory of ion channels and neurotransmitters. As is known, the functioning of the central nervous system occurs under conditions of a balance of systems that activate and inhibit the conduction of nerve impulses. GABA is considered to be the main inhibitory neurotransmitter in the central nervous system of mammals. Its main site of action is the GABA receptor, which is a heterooligomeric glycoprotein complex consisting of at least 5 sites combined around the so-called chloride channels. Activation of the GABA receptor leads to increased influx of chloride ions into the cell, membrane hyperpolarization, and a decrease in the response of the postsynaptic neuron to excitatory neurotransmitters. In addition to the GABA receptor, the complex contains benzodiazepine, barbiturate, steroid, picrotoxin, and other binding sites. IV anesthetics may interact differently with different sites of the GABAA receptor complex.

Barbiturates, firstly, reduce the rate of GABA dissociation from the activated receptor, thereby prolonging the opening of the ion channel. Secondly, in somewhat higher concentrations, they, imitating GABA even in its absence, directly activate chloride channels. Unlike BD, barbiturates are not so selective in their action, they can suppress the activity of excitatory neurotransmitters, including outside the synapses. This may explain their ability to cause the surgical stage of anesthesia. They selectively suppress the conduction of impulses in the ganglia of the sympathetic nervous system, which, for example, is accompanied by a decrease in blood pressure.

Effects of barbiturates on the central nervous system

Barbiturates have dose-dependent sedative, hypnotic, and anticonvulsant effects.

Depending on the dosage, barbiturates cause sedation, sleep, and in cases of overdose, the surgical stage of anesthesia and coma. The intensity of sedative-hypnotic and anticonvulsant effects varies among different barbiturates. According to the relative strength of the effect on the central nervous system and the vagus nerve system, they are arranged in the following order: methohexital > thiamylal > sodium thiopental > hexobarbital. Moreover, in equivalent doses, methohexital is approximately 2.5 times stronger than sodium thiopental and its effect is 2 times shorter. The effect of other barbiturates is less strong.

In subanesthetic doses, barbiturates can cause increased sensitivity to pain - hyperalgesia, which is accompanied by lacrimation, tachypnea, tachycardia, hypertension, and agitation. On this basis, barbiturates were even considered antianalgesics, which was not confirmed later.

The anticonvulsant properties of barbiturates are explained mainly by postsynaptic activation of GABA, changes in membrane conductivity for chloride ions, and antagonism of glutaminergic and cholinergic excitations. In addition, presynaptic blocking of calcium ion entry into nerve endings and a decrease in transmitter release are possible. Barbiturates have different effects on convulsive activity. Thus, sodium thiopental and phenobarbital are able to quickly stop convulsions when other drugs are ineffective. Methohexital can cause convulsions when used in high doses and prolonged infusion.

Electroencephalographic changes caused by barbiturates depend on their dose and differ in phase: from low-voltage rapid activity after the introduction of small doses, mixed, high-amplitude and low-frequency 5- and 9-waves during deepening anesthesia to bursts of suppression and flat EEG. The picture after loss of consciousness is similar to physiological sleep. But even with such an EEG picture, intense pain stimulation can cause awakening.

The effect of barbiturates on evoked potentials has its own peculiarities. Dose-dependent changes in somatosensory evoked potentials (SSEP) and auditory evoked potentials (AEP) of the brain are observed. But even when an isoelectric EEG is achieved against the background of sodium thiopental administration, the components of SSEP are available for recording. Sodium thiopental reduces the amplitude of motor evoked potentials (MEP) to a greater extent than methohexital. The bispectral index (BIS) is a good criterion for the hypnotic effect of barbiturates.

Barbiturates are considered to be brain-protective drugs. In particular, phenobarbital and sodium thiopental suppress the electrophysiological, biochemical, and morphological changes that occur as a result of ischemia, improving the recovery of pyramidal cells in the brain. This protection may be due to a number of direct neuroprotective and indirect effects:

• decreased cerebral metabolism in areas of high brain activity;
• suppression of excitation by inactivating nitric oxide (NO), weakening of glutamate convulsive activity (during ischemia, K+ leaves neurons through glutamate cation receptor channels, and Na+ and Ca2+ enter, causing an imbalance in neuronal membrane potential);
• vasoconstriction of healthy areas of the brain and shunting of blood to the affected areas;
• reduction of intracranial pressure;
• increased cerebral perfusion pressure (CPP);
• stabilization of liposomal membranes;
• reducing the production of free radicals.

However, it should be remembered that high doses of barbiturates, along with their negative hemodynamic effect, enhance immunosuppression, which may limit their clinical effectiveness. Sodium thiopental may be useful in neurosurgical patients with increased ICP (reduces MBF and oxygen consumption by the brain - PM02), with occlusion of intracranial vessels, i.e. focal ischemia.

The effect of barbiturates on the cardiovascular system

The cardiovascular effects of drugs are determined by the route of administration and, with intravenous injection, depend on the dose used, as well as on the initial circulating blood volume (CBV), the state of the cardiovascular and autonomic nervous system. In normovolemic patients, after the administration of an induction dose, there is a transient decrease in blood pressure by 10-20% with a compensatory increase in heart rate by 15-20/min. The main cause is peripheral venodilation, which is a result of depression of the vasomotor center of the medulla oblongata and a decrease in sympathetic stimulation from the central nervous system. Dilation of capacitance vessels and a decrease in venous return cause a decrease in cardiac output (CO) and blood pressure. Myocardial contractility decreases to a lesser extent than with the use of inhalation anesthetics, but more than with the use of other intravenous anesthetics. Possible mechanisms include the effect on the transmembrane calcium current and nitric oxide uptake. The baroreflex changes slightly, and the heart rate increases as a result of hypotension more significantly with methohexital than with sodium thiopental. The increase in heart rate leads to increased myocardial oxygen consumption. OPSS is usually unchanged. In the absence of hypoxemia and hypercarbia, rhythm disturbances are not observed. Higher doses have a direct effect on the myocardium. Myocardial sensitivity to catecholamines decreases. In rare cases, cardiac arrest may occur.

Barbiturates constrict the cerebral vessels, reducing CBF and ICP. BP decreases to a lesser extent than intracranial pressure, so cerebral perfusion does not change significantly (CPP usually even increases). This is extremely important for patients with increased ICP.

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

After the introduction of barbiturates during induction, the intraocular pressure decreases by approximately 40%. This makes their use safe in all ophthalmological interventions. The use of suxamethonium returns the intraocular pressure to the initial level or even exceeds it.

Barbiturates reduce the basal metabolic rate, causing heat loss due to vasodilation. A decrease in body temperature and a disturbance in thermoregulation may be accompanied by postoperative shivering.

Effects of barbiturates on the respiratory system

The effects of drugs depend on the dose, rate of administration and 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 (RR) decrease up to apnea. Normalization of ventilation parameters occurs faster than the restoration of the reaction of the respiratory center to hypercapnia and hypoxemia. Cough, hiccups and myoclonus complicate pulmonary ventilation.

The pronounced vagotonic effect of barbiturates in some cases may be the cause of mucus hypersecretion. Laryngospasm and bronchospasm are possible. These complications usually occur when installing an airway (intubation tube, laryngeal mask) against the background of superficial anesthesia. It should be noted that when inducing with barbiturates, laryngeal reflexes are suppressed to a lesser extent than after the introduction of equivalent doses of propofol. Barbiturates suppress the protective mechanism of mucociliary clearance of the tracheobronchial tree (TBT).

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Effects on the gastrointestinal tract, liver and kidneys

Induction of anesthesia with barbiturates does not significantly affect 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 gastrointestinal tract. Hexobarbital suppresses intestinal motor activity. When used on an empty stomach, nausea and vomiting are rare.

By decreasing systemic blood pressure, barbiturates may 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.

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Effect on endocrine response

Sodium thiopental reduces plasma cortisol concentrations. However, unlike etomidate, it does not prevent adrenocortical stimulation as a result of surgical stress. Patients with myxedema show increased sensitivity to sodium thiopental.

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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 post-synaptic membrane of the neuromuscular synapse to the action of acetylcholine and reduce the tone of skeletal muscles.

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Tolerance

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

Cross-tolerance to sedative-hypnotic drugs cannot be ruled out. This should be taken into account in connection with the known urban abuse of these drugs and the prevalence of polydrug addiction.

Pharmacokinetics

As weak acids, barbiturates are very rapidly absorbed in the stomach and small intestine. The sodium salts are absorbed faster than free acids such as barbital and phenobarbital.

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

The main route of administration of barbiturates is intravenous. The speed and completeness of drug penetration through the blood-brain barrier (BBB) are determined by their physicochemical characteristics. Drugs with a smaller molecule size, greater lipid solubility and a lower degree of binding to plasma proteins have greater penetrating ability.

The lipid solubility of barbiturates is determined almost entirely by the lipid solubility of the non-ionized (non-dissociated) portion of the drug. The degree of dissociation depends on their ability to form ions in an 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 a non-ionized state. In acidosis, the ability of weak acids to dissociate decreases, which means that the non-ionized form of the drug increases, i.e., the form in which the drug is able to penetrate the BBB and exert an anesthetic effect. However, not all of the non-ionized drug penetrates the CNS. A certain portion of it binds to plasma proteins; this complex, due to its large size, loses the ability to pass through tissue barriers. Thus, a decrease in dissociation and a simultaneous increase in binding to plasma proteins are counteracting processes.

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

Distribution of barbiturates is determined by their fat solubility and blood flow in tissues. Thiobarbiturates and methohexital are easily soluble in fats, so their effect on the central nervous system begins very quickly - approximately in one forearm-brain circulation cycle. In a short period of time, the concentration of drugs in the blood and brain is balanced, after which their further intensive redistribution to other tissues occurs (Vdss - distribution volume in the equilibrium state), which determines a decrease in the concentration of drugs in the central nervous system and a rapid cessation of the effect after a single bolus. Due to the fact that with hypovolemia, the blood supply to the brain is reduced not as much as to muscles 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 due to poor perfusion of adipose tissue. With repeated administration or prolonged infusion, muscle and adipose tissues are largely saturated with the drug, and their return to the blood is delayed. The end of the drug's effect becomes dependent on the slow process of drug absorption by adipose tissue and on its clearance. This leads to a significant increase in the half-life, i.e. the time required to reduce the plasma concentration of the drug by half. The presence of large fat deposits helps to prolong the effect of barbiturates.

Since barbiturates are weak acids, acidosis will increase their non-ionized fraction, which is more lipid-soluble than the ionized fraction, and therefore penetrates the blood-brain barrier more quickly. Thus, acidosis increases, and alkalosis decreases, the effect of barbiturates. However, respiratory changes in blood pH, unlike metabolic changes, are not accompanied by such significant changes in the degree of ionization and the ability of drugs to penetrate the blood-brain barrier.

Oxybarbiturates are metabolized only in the endoplasmic reticulum of hepatocytes, while thiobarbiturates are metabolized to some extent outside the liver (probably in the kidneys and CNS). Barbiturates undergo oxidation of the side chains at the 5th carbon atom. The resulting alcohols, acids, and ketones are usually inactive. Oxidation occurs much more slowly than tissue redistribution.

By oxidation of the side chain at C5, desulfurization of the C2 position, and hydrolytic opening of the barbiturate ring, sodium thiopental is metabolized to hydroxythiopental and unstable carboxylic acid derivatives. At high doses, desulfurization may occur to form pentobarbital. The rate of metabolism of sodium thiopental after a single administration is 12-16% per hour.

Methohexital is metabolized by demethylation and oxidation. It is degraded faster than sodium thiopental due to its lower lipid solubility and greater availability for metabolism. Oxidation of the side chain produces inactive hydromethohexital. Protein binding of both drugs is quite significant, but the clearance of sodium thiopental is lower due to a lower degree of hepatic extraction. Since T1/2p is directly proportional to the volume of distribution and inversely proportional to clearance, the difference in T1/2(3 between sodium thiopental and methohexital is associated with the rate of their elimination. Despite the three-fold difference in clearance, the main factor in the termination of the effect of the induction dose of each of the drugs is the redistribution process. Less than 10% of these barbiturates remain in the brain 30 minutes after administration. Approximately 15 minutes later, their concentrations in the muscles are equilibrated, and after 30 minutes, their content in adipose tissue continues to increase, reaching a maximum after 2.5 hours. Complete recovery of psychomotor functions is determined by the metabolic rate and occurs faster after the administration of methohexital than sodium thiopental. In addition, the hepatic clearance of methohexital, compared with sodium thiopental, depends more on systemic and hepatic blood flow. The pharmacokinetics of hexobarbital are close to such as sodium thiopental.

Liver clearance of barbiturates may be affected by liver dysfunction due to disease or age, inhibition of microsomal enzyme activity, but not by hepatic blood flow. Induction of microsomal enzymes by external factors, such as smokers and city dwellers, may result in increased requirements for barbiturates.

Barbiturates (except phenobarbital) are excreted unchanged in small quantities (no more than 1%). Water-soluble glucuronides of metabolites are excreted mainly by the kidneys through 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, in the elderly and old people the rate of transition of sodium thiopental from the central to the peripheral sector is slower (by about 30%) compared to younger adults. This slowdown in intersectoral clearance creates a higher concentration of the drug in the plasma and brain, providing a more pronounced anesthetic effect in elderly people.

The plasma concentration of barbiturate required to induce unconsciousness does not change with age. In children, protein binding and volume of distribution of sodium thiopental do not differ from those in adults, but T1/2 is shorter due to faster hepatic clearance. Therefore, recovery of consciousness in infants and children occurs faster. During pregnancy, T1/2 increases due to better protein binding. T1/2 is prolonged in obese patients due to greater distribution into excess fat deposits.

Contraindications

Barbiturates are contraindicated in cases of individual intolerance, organic liver and kidney diseases accompanied by severe insufficiency, and familial porphyria (including latent porphyria). They cannot be used in cases of shock, collapse, or severe circulatory failure.

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Barbiturate Dependence 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 the specific drug.

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

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

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Tolerability and side effects

Barbiturates are generally well tolerated. The occurrence of side effects and toxicity of barbiturates is associated mainly with their overdose and the administration of concentrated solutions. The most common side effects of barbiturates are dose-dependent depression of blood circulation and respiration, as well as initial excitation of the central nervous system during induction - a paradoxical effect. Less common are pain upon administration and anaphylactic reactions.

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

An overdose of barbiturates is manifested by increasing symptoms of depression of consciousness up to coma and is accompanied by depression of blood circulation and respiration. Barbiturates do not have specific pharmacological antagonists for the treatment of overdose. Naloxone and its analogues do not eliminate their effects. Analeptic drugs (bemegride, etimizole) were used as an antidote to barbiturates, but it was subsequently established that the probability of the undesirable effects they cause exceeds their usefulness. In particular, in addition to the "awakening" effect and stimulation of the respiratory center, bemegride stimulates the vasomotor center and has convulsive activity. Etimizole stimulates hemodynamics to a lesser extent, does not have convulsive activity, but is devoid of "awakening" activity and even enhances the effect of anesthetics.

Allergic reactions to oxybarbiturates are rare and may include itching and a transient urticarial rash on the upper chest, neck, and face. After induction with thiobarbiturates, allergic reactions are more common and include urticaria, facial edema, bronchospasm, and shock. In addition to anaphylactic reactions, anaphylactoid reactions occur, although less frequently. Unlike oxybarbiturates, sodium thiopental and especially thiamylal cause a dose-dependent release of histamine (up to 20%), but this is rarely of clinical significance. In most cases, patients have a history of allergies.

Severe allergic reactions to barbiturates are rare (1 in 30,000 patients), but are associated with high mortality. Therefore, treatment should be vigorous and include epinephrine (1 ml at a dilution of 1:10,000), fluid infusion, and theophylline to relieve bronchospasm.

Interestingly, about one-third of adult patients of both sexes (especially younger ones) report an onion- or garlic-like odor and taste when injecting sodium thiopental. Barbiturates are generally painless when injected into large veins of the forearm. However, when injected into small veins of the back of the hand or wrist, the incidence of pain with methohexital is approximately twice that with sodium thiopental. The risk of venous thrombosis is higher with concentrated solutions.

Of extreme importance is the issue of unintentional intraarterial or subcutaneous injection of barbiturates. If a 1% solution of oxybarbiturates is injected intraarterially or subcutaneously, moderate local discomfort without undesirable consequences may be observed. However, if more concentrated solutions or thiobarbiturates are injected extravasally, pain, swelling, and redness of the tissues at the injection site and widespread necrosis may occur. The severity of these symptoms depends on the concentration and the total amount of the drug injected. Erroneous intraarterial injection of concentrated thiobarbiturate solutions causes intense arterial spasm. This is immediately accompanied by intense burning pain from the injection site to the fingers, which may persist for hours, as well as blanching. Under anesthesia, spotted cyanosis and darkening of the limb may be observed. Hyperesthesia, swelling, and limited mobility may be observed later. The above manifestations characterize chemical endarteritis with damage depth from the endothelium to the muscular layer.

In the most severe cases, thrombosis, gangrene of the limb, and nerve damage develop. In order to stop vascular spasm and dilute the 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. Sympathetic blockade (of the stellate ganglion or brachial plexus) can also reduce spasm. The presence of a peripheral pulse does not exclude the development of thrombosis. Intra-arterial administration of heparin and GCS followed by their systemic administration can help prevent thrombosis.

With prolonged administration, barbiturates stimulate an increase in the level of liver microsomal enzymes. This is clearly evident when prescribing maintenance doses and is most pronounced when using phenobarbital. Mitochondrial enzymes are also stimulated. As a result of activation of 5-aminolevulinate synthetase, the formation of porphyrin and heme is accelerated, which can exacerbate the course of intermittent or familial porphyria.

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

There is no data on carcinogenic or mutagenic effects of barbiturates. No adverse effects on reproductive function have been established.

Interaction

The degree of CNS depression when using barbiturates increases with the combined use of other depressants, such as ethanol, antihistamines, MAO inhibitors, isoniazid, etc. Co-administration with theophylline reduces the depth and duration of the effect of sodium thiopental.

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

Favorable combinations

Barbiturates are generally used to induce anesthesia. Any other intravenous and/or inhalation anesthetics can be used to maintain anesthesia. Barbiturates, when used with BD or opioids, provide a mutual reduction in the need for each drug separately. They also combine well with muscle relaxants.

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Combinations that require special attention

The combined use of other anesthetics and opioids with barbiturates for induction increases the degree of circulatory depression and the likelihood of apnea. This should be taken into account in weakened, exhausted patients, elderly patients, with hypovolemia and concomitant cardiovascular diseases. The hemodynamic effects of barbiturates are significantly enhanced by the action of propranolol. Radiocontrast drugs and sulfonamides, displacing barbiturates from their bond with plasma proteins, increase the proportion of the free fraction of drugs, enhancing their effects.

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Undesirable combinations

The combined use of barbiturates with drugs that have a similar effect on hemodynamics (e.g., propofol) is inappropriate. Sodium thiopental should not be mixed with acidic solutions of other drugs, as this may result in precipitation (e.g., with suxamethonium, atropine, ketamine, iodides).

Cautions

Like all other anesthetics, barbiturates should not be used by untrained individuals and without the ability to provide ventilation support and manage cardiovascular changes. When working with barbiturates, the following factors must be taken into account:

• age of patients. Elderly and senile patients are more sensitive to barbiturates due to slower intersectoral redistribution. In addition, paradoxical excitatory reactions against the background of barbiturate use occur more often in the elderly. In children, recovery from large or repeated doses of sodium thiopental may be faster than in adults. In infants under one year of age, recovery from the use of methohexital is faster than after sodium thiopental;
• duration of intervention. With repeated administrations or prolonged infusion, the cumulative effect of all barbiturates, including methohexital, should be taken into account;
• 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, constrictive pericarditis, cardiac tamponade, valve stenosis, congestive heart failure, myocardial ischemia, blockades, initial sympathicotonia). In patients with arterial hypertension, hypotension is more pronounced than in normotensive patients, regardless of the basic therapy. With a reduced baroreflex against the background of taking beta-blockers or centrally acting antihypertensive drugs, the effect will be more pronounced. Reducing the rate of administration of the induction dose does not optimize the situation. Hexobarbital stimulates the vagus nerve, therefore, when using it, prophylactic administration of M-anticholinergics is advisable;
• concomitant respiratory diseases. Sodium thiopental and methohexital are considered safe for patients with bronchial asthma, although, unlike ketamine, they do not cause bronchodilation. However, barbiturates should be used with caution in patients with bronchial asthma and chronic obstructive pulmonary diseases (COPD);
• concomitant liver diseases. Barbiturates are metabolized mainly in the liver, so they are not recommended for use in cases of severe liver dysfunction. Sodium thiopental may also reduce hepatic blood flow. Hypoproteinemia against the background of liver diseases leads to an increase in the proportion of unbound fraction and an increased effect of the drug. Therefore, in patients with liver cirrhosis, barbiturates should be administered more slowly, in doses reduced by 25-50%. In patients with liver failure, the duration of the effect may be longer;
• concomitant kidney diseases. Hypoalbuminemia against the background of uremia is the cause of lower protein binding and greater sensitivity to drugs. Concomitant kidney diseases affect the elimination of hexamethonium;
• pain relief during labor, effect on the fetus. Sodium thiopental 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 during cesarean section, sodium thiopental does not have a harmful effect on the fetus. But at a dose of 8 mg / kg, fetal activity is suppressed. Limited entry of barbiturates into the fetal brain is explained by their rapid distribution in the mother's body, placental circulation, hepatic clearance of the fetus, as well as dilution of drugs in fetal blood. The use of sodium thiopental is considered safe for the fetus if it is removed within 10 minutes after induction. T1/2 of sodium thiopental in neonates after administration to the mother during cesarean section ranges from 11 to 43 hours. The use of sodium thiopental is accompanied by less depression of the central nervous system function of neonates than the induction of midazolam, but more than with the use of ketamine; the volume of distribution of sodium thiopental changes already at the 7-13th week of the gestation period, and despite the increase in SV, the need for barbiturate in pregnant women decreases by approximately 20%. The use of barbiturates in nursing mothers requires caution;
• intracranial pathology. Barbiturates are widely used in neurosurgery and neuroanesthesiology due to their beneficial effects on MC, CPP, PMOa, ICP and anticonvulsant activity. Methohexital should not be used in patients with epilepsy;
• outpatient anesthesia. After a single bolus dose of methohexital, awakening occurs more quickly than after the administration of sodium thiopental. Despite this, the recovery of psychophysiological tests and the EEG pattern with methohexital is slower than with sodium thiopental. This is the basis for recommending that patients refrain from driving a vehicle for 24 hours after general anesthesia.

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