Benzodiazepines

The term "benzodiazepines" reflects the chemical affiliation with drugs with a 5-aryl-1,4-benzodiazepine structure, which appeared as a result of the combination of a benzene ring into a seven-membered diazepine. Various benzodiazepines have found wide application in medicine. Three drugs have been well studied and are most widely used for the needs of anesthesiology in all countries: midazolam, diazepam and lorazepam.

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Benzodiazepines: place in therapy

In clinical anesthesiology and intensive care, benzodiazepines are used for premedication, induction of anesthesia, its maintenance, for the purpose of sedation during interventions under regional and local anesthesia, during various diagnostic procedures (for example, endoscopy, endovascular surgery), and sedation in intensive care units.

As a component of premedication, benzodiazepines have practically replaced barbiturates and neuroleptics due to fewer adverse effects. For this purpose, the medication is prescribed orally or intramuscularly. Midazolam is distinguished by the possibility of its administration rectally (advantage in children); in addition, not only its tablet form, but also an injection solution can be administered orally. The anxiolytic and sedative effects are most pronounced and occur more quickly when using midazolam. With lorazepam, the development of effects occurs more slowly. It should be taken into account that 10 mg of diazepam is equivalent to 1-2 mg of lorazepam or 3-5 mg of midazolam.

Benzodiazepines are widely used to provide conscious sedation during regional and local anesthesia. Particularly desirable properties include anxiolysis, amnesia, and an increase in the seizure threshold for local anesthetics. Benzodiazepines should be titrated to achieve adequate sedation or dysarthria. This is achieved by administering a loading dose followed by repeated bolus injections or continuous infusion. There is not always a correspondence between the level of sedation and amnesia (appearance of wakefulness and lack of memory of it) caused by all benzodiazepines. But the duration of amnesia is especially unpredictable with lorazepam.

Overall, among other sedative-hypnotic drugs, benzodiazepines provide the best degree of sedation and amnesia.

In the ICU, benzodiazepines are used to achieve conscious sedation and deep sedation to synchronize the patient's breathing with the ventilator in the ICU. Benzodiazepines are also used to prevent and treat seizures and delirium.

Rapid onset of effect and absence of venous complications make midazolam preferable to other benzodiazepines for induction of general anesthesia. However, in terms of the speed of sleep onset, midazolam is inferior to hypnotics from other groups, such as sodium thiopental and propofol. The speed of action of benzodiazepines is affected by the dose used, the rate of administration, the quality of premedication, age and general physical status, as well as the combination with other drugs. Usually, the induction dose is reduced by 20% or more in patients over 55 years of age and in patients with a high risk of complications (ASA (American Association of Anesthesiologists) class III and higher). A rational combination of two or more anesthetics (coinduction) reduces the amount of each drug administered. In short-term interventions, the administration of induction doses of benzodiazepines is not entirely justified, since this prolongs the awakening time.

Benzodiazepines are capable in some cases of protecting the brain from hypoxia and are used in critical conditions. Midazolam demonstrates the greatest effectiveness in this case, although it is inferior to that of barbiturates.

The benzodiazepine receptor antagonist flumazenil is used in anesthesiology for therapeutic purposes - to eliminate the effects of benzodiazepine receptor agonists after surgical interventions and diagnostic procedures. In this case, it eliminates sleep, sedation and respiratory depression more actively than amnesia. The drug should be administered intravenously by titration until the desired effect is achieved. It is important to consider that stronger benzodiazepines will require larger doses. In addition, due to the likelihood of re-sedation, long-acting benzodiazepines may require repeated doses or infusion of flumazenil. The use of flumazenil to neutralize the effects of BD does not provide grounds for allowing patients to drive a vehicle.

Another use of flumazenil is diagnostic. It is administered for differential diagnosis of possible benzodiazepine poisoning. In this case, if the degree of sedation does not decrease, other causes of CNS depression are most likely.

When performing prolonged sedation with benzodiazepines, flumazenil can be used to create a "diagnostic window".

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Mechanism of action and pharmacological effects

Benzodiazepines have many properties that are desirable for anesthesiologists. At the level of the central nervous system, they have various pharmacological effects, of which the most important are sedative, anxiolytic (reducing anxiety), hypnotic, anticonvulsant, muscle relaxant, and amnestic (anterograde amnesia).

Benzodiazepines exert all their pharmacological effects by facilitating the action of GABA, the main inhibitory neurotransmitter in the CNS, which counterbalances the effect of activating neurotransmitters. The discovery of the benzodiazepine receptor in the 1970s largely explained the mechanism of action of benzodiazepines on the CNS. One of the two GABA receptors, the GABA receptor pentametric complex, is a large macromolecule and contains protein subdivisions (alpha, beta, and gamma) that include various ligand binding sites for GABA, benzodiazepines, barbiturates, and alcohol. Several different subunits of the same type have been discovered (six different a, four beta, and three gamma) with different abilities to form a chloride channel. The structure of receptors in different parts of the CNS may be different (e.g., alpha1, beta, and gamma2 or alpha3, beta1, and gamma2), which determines different pharmacological properties. For affinity to BD, the receptor must have a γ2 subunit. There is a certain structural correspondence between the GABAA receptor and the nicotinic acetylcholine receptor.

By binding to specific sites of the GABAA receptor complex located on the subsynaptic membrane of the effector neuron, benzodiazepines strengthen the receptor's connection with GABA, which increases the opening of channels for chloride ions. Increased penetration of chloride ions into the cell leads to hyperpolarization of the postsynaptic membrane and the resistance of neurons to excitation. Unlike barbiturates, which increase the duration of ion channel opening, benzodiazepines increase the frequency of their opening.

The effect of benzodiazepines depends largely on the dose of the drug used. The order of appearance of the central effects is as follows: anticonvulsant effect, anxiolytic effect, mild sedation, decreased concentration, intellectual inhibition, amnesia, deep sedation, relaxation, sleep. It is assumed that binding of the benzodiazepine receptor by 20% provides anxiolysis, the capture of 30-50% of the receptor is accompanied by sedation, and stimulation of > 60% of the receptor is required to turn off consciousness. It is possible that the difference in the effects of benzodiazepines on the CNS is associated with the effect on different receptor subtypes and / or on different numbers of occupied receptors.

It is also possible that the anxiolytic, anticonvulsant and muscle relaxant effects are realized through the GABAA receptor, and the hypnotic effect is mediated by changing the flow of calcium ions through potential-dependent channels. Sleep is close to physiological with its characteristic EEG phases.

The highest density of benzodiazepine receptors is found in the cerebral cortex, hypothalamus, cerebellum, hippocampus, olfactory bulb, substantia nigra, and inferior colliculus; lower density is found in the striatum, lower part of the brainstem, and spinal cord. The degree of GABA receptor modulation is limited (the so-called "marginal effect" of benzodiazepines in relation to CNS depression), which determines the fairly high safety of BD use. The predominant localization of GABA receptors in the CNS determines the minimal effects of drugs outside it (minimal circulatory effects).

There are three types of ligands that act on the benzodiazepine receptor: agonists, antagonists, and inverse agonists. The action of agonists (e.g., diazepam) is described above. Agonists and antagonists bind the same (or overlapping) sites on the receptor, forming various reversible bonds with it. Antagonists (e.g., flumazenil) occupy the receptor but have no activity of their own and therefore block the action of both agonists and inverse agonists. Inverse agonists (e.g., beta-carbolines) reduce the inhibitory effect of GABA, which leads to anxiety and seizures. There are also endogenous agonists with benzodiazepine-like properties.

Benzodiazepines vary in potency for each pharmacological action, depending on the affinity, stereospecificity, and intensity of binding to the receptor. The potency of the ligand is determined by its affinity for the benzodiazepine receptor, and the duration of the effect is determined by the rate of drug removal from the receptor. The order of potency of the hypnotic action of benzodiazepines is lorazepam > midazolam > flunitrazepam > diazepam.

Most benzodiazepines, unlike all other sedative-hypnotic agents, have a specific receptor antagonist - flumazenil. It belongs to the group of imidobenzodiazepines. With structural similarity to the main benzodiazepines, the phenyl group in flumazenil is replaced by a carbonyl group.

As a competitive antagonist, flumazenil does not displace the agonist from the receptor, but occupies the receptor at the moment of separation of the agonist from it. Since the period of ligand-receptor binding lasts up to several seconds, a dynamic renewal of the receptor binding with the agonist or antagonist occurs. The receptor is occupied by the ligand that has a higher affinity for the receptor and whose concentration is higher. The affinity of flumazenil for the benzodiazepine receptor is extremely high and exceeds that of agonists, especially diazepam. The concentration of the drug in the receptor zone is determined by the dose used and the rate of its elimination.

Effect on cerebral blood flow

The degree of reduction of MC, metabolic PMOa and reduction of intracranial pressure depend on the dose of benzodiazepine and are inferior to that of barbiturates. Despite a slight increase in PaCO2, benzodiazepines in induction doses cause a decrease in MC, but the ratio of MC and PMO2 does not change.

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Electroencephalographic picture

The electroencephalographic pattern during benzodiazepine anesthesia is characterized by the appearance of rhythmic beta activity. No tolerance to the effects of benzodiazepines on the EEG is observed. Unlike barbiturates and propofol, midazolam does not cause an isoelectric EEG.

When BD is administered, the amplitude of cortical SSEPs decreases, the latency of the early potential is shortened, and the peak latency is lengthened. Midazolam also decreases the amplitude of the peaks of mid-latency SEPs of the brain. Other criteria for the depth of benzodiazepine anesthesia can be the registration of BIS and the AAI™ ARX index (an improved version of SEP processing).

Benzodiazepines rarely cause nausea and vomiting. The antiemetic effect attributed to them by some authors is small and is more likely due to the sedative effect.

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Effect on the cardiovascular system

When used alone, benzodiazepines have a moderate effect on the cardiovascular system. In both healthy subjects and patients with heart disease, the predominant hemodynamic change is a slight decrease in blood pressure due to a decrease in total peripheral vascular resistance. Heart rate, cardiac output, and ventricular filling pressure are altered to a lesser extent.

In addition, once the drug reaches equilibrium in plasma, there is no further reduction in blood pressure. It is assumed that such a relatively mild effect on hemodynamics is associated with the preservation of protective reflex mechanisms, although the baroreflex changes. The effect on blood pressure depends on the dose of the drug and is most pronounced with midazolam. However, even in high doses and in cardiac surgery patients, hypotension is not excessive. By reducing pre- and afterload in patients with congestive heart failure, benzodiazepines can even increase cardiac output.

The situation changes when benzodiazepines are combined with opioids. In this case, the decrease in blood pressure is more significant than for each drug, due to the pronounced additive effect. It is possible that such synergism is due to a decrease in the tone of the sympathetic nervous system. More significant hemodynamic depression is observed in patients with hypovolemia.

Benzodiazepines have minor analgesic properties and do not prevent the reaction to traumatic manipulations, in particular to tracheal intubation. The additional use of opioids is most justified at such stages.

Effect on the respiratory system

Benzodiazepines have a central effect on respiration and, like most intravenous anesthetics, increase the threshold level of carbon dioxide for stimulation of the respiratory center. The result is a decrease in tidal volume (TV) and minute respiratory volume (MV). The rate of development of respiratory depression and the degree of its severity are higher with midazolam. In addition, a more rapid administration of the drug leads to a more rapid development of respiratory depression. Respiratory depression is more pronounced and lasts longer in patients with COPD. Lorazepam depresses respiration to a lesser extent than midazolam and diazepam, but in combination with opioids, all benzodiazepines have a synergistic depressive effect on the respiratory system. Benzodiazepines suppress the swallowing reflex and the reflex activity of the upper respiratory tract. Like other hypnotics, benzodiazepines can cause respiratory arrest. The likelihood of apnea depends on the dose of benzodiazepine used and the combination with other drugs (opioids). In addition, the frequency and severity of respiratory depression increase in debilitating diseases and in elderly patients. There is evidence of a slight synergistic effect on respiration of midazolam and local anesthetics administered subarachnoidally.

Effect on the gastrointestinal tract

Benzodiazepines do not have an adverse effect on the gastrointestinal tract, including when taken orally and when administered rectally (midazolam). They do not cause induction of liver enzymes.

There is evidence of decreased nocturnal secretion of gastric juice and slower intestinal motility when taking diazepam and midazolam, but these manifestations are likely with prolonged use of the drug. In rare cases, nausea, vomiting, hiccups, and dry mouth may occur when taking benzodiazepine orally.

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Effect on endocrine response

There is evidence that benzodiazepines reduce catecholamine (cortisol) levels. This property is not the same for all benzodiazepines. It is believed that alprazolam's increased ability to suppress adrenocorticotropic hormone (ACTH) and cortisol secretion contributes to its pronounced effectiveness in the treatment of depressive syndromes.

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Effect on neuromuscular transmission

Benzodiazepines do not have a direct effect on neuromuscular transmission. Their muscle relaxant effect occurs at the level of interneurons of the spinal cord, not at the periphery. However, the severity of muscle relaxation caused by benzodiazepines is insufficient for performing surgical interventions. Benzodiazepines do not determine the mode of administration of relaxants, although they can potentiate their effect to some extent. In animal experiments, high doses of benzodiazepine suppressed the conduction of impulses along the neuromuscular junction.

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Other effects

Benzodiazepines increase the primary seizure threshold (important when using local anesthetics) and are able to some extent to protect the brain from hypoxia.

Tolerance

Long-term administration of benzodiazepines causes a decrease in their effectiveness. The mechanism of tolerance development is not fully understood, but it is suggested that prolonged exposure to benzodiazepines causes decreased binding to the GABAA receptor. This explains the need to use higher doses of benzodiazepines for anesthesia in patients who have been taking them for a long time.

Marked tolerance to benzodiazepines is typical of drug addicts. It can be expected to occur in burn patients who undergo frequent dressing changes under anesthesia. In general, tolerance to benzodiazepines is less likely than to barbiturates.

Pharmacokinetics

According to the duration of elimination from the body, benzodiazepines are divided into 3 groups. Drugs with a long T1/2 (> 24 h) include chlordiazepoxide, diazepam, medazepam, nitrazepam, phenazepam, flurazepam, alprazolam. Oxazepam, lorazepam, flunitrazepam have an average duration of elimination (T1/2 (3 from 5 to 24 h). Midazolam, triazolam and temazepam have the shortest T1/2 (< 5 h).

Benzodiazepines can be administered orally, rectally, intramuscularly, or intravenously.

All benzodiazepines are fat-soluble compounds. When taken orally in tablet form, they are well and completely absorbed, mainly in the duodenum. Their bioavailability is 70-90%. Midazolam in the form of an injection solution is well absorbed from the gastrointestinal tract when taken orally, which is important in pediatric practice. Midazolam is quickly absorbed when administered rectally and reaches maximum plasma concentration within 30 minutes. Its bioavailability with this route of administration approaches 50%.

With the exception of lorazepam and midazolam, absorption of benzodiazepines from muscle tissue is incomplete and uneven and, due to the need to use a solvent, is associated with the development of local reactions when administered intramuscularly.

In the practice of anesthesiology and intensive care, the intravenous route of administration of benzodiazepine is preferable. Diazepam and lorazepam are insoluble in water. Propylene glycol is used as a solvent, which is responsible for local reactions when administering the drug. The imidazole ring of midazolam gives it stability in solution, rapid metabolism, the highest lipid solubility, and solubility in water at low pH. Midazolam is specially prepared in an acidic buffer with a pH of 3.5, since the opening of the imidazole ring depends on pH: at pH < 4, the ring is open and the drug is water-soluble, at pH > 4 (physiological values), the ring closes and the drug becomes lipid-soluble. The water solubility of midazolam does not require the use of an organic solvent, which causes pain when administered intravenously and prevents absorption when administered intramuscularly. In the systemic circulation, benzodiazepines, with the exception of flumazenil, are strongly bound to plasma proteins (80-99%). Benzodiazepine molecules are relatively small and highly lipid soluble at physiological pH. This explains their relatively high distribution volume and rapid effect on the central nervous system. Maximum drug concentrations (Cmax) in the systemic circulation are reached after 1-2 hours. Due to their greater solubility in fats, midazolam and diazepam have a faster onset of action than lorazepam when administered intravenously. However, the rate of establishment of the equilibrium concentration of midazolam in the effector zone of the brain is significantly inferior to that of sodium thiopental and propofol. The onset and duration of action of a single bolus dose of benzodiazepine depend on their solubility in fats.

Like the onset of action, the duration of effect is also related to the lipid solubility and plasma drug concentration. The binding of benzodiazepines to plasma proteins parallels their lipid solubility, i.e. high lipid solubility increases protein binding. High protein binding limits the effectiveness of hemodialysis in diazepam overdose.

The long T1/2 in the elimination phase of diazepam is explained by its large volume of distribution and slow extraction in the liver. The shorter T1/2 beta of lorazepam compared to diazepam is explained by its lower lipid solubility and smaller volume of distribution. Despite its high lipid solubility and large volume of distribution, midazolam has the shortest T1/2 beta because it is extracted by the liver at a higher rate than other benzodiazepines.

T1/2 of benzodiazepine in children (except infants) is somewhat shorter. In elderly patients and patients with impaired liver function (including congestive nature), T1/2 may increase significantly. The increase in T1/2 is especially significant (up to 6 times even for midazolam) at high equilibrium concentrations of benzodiazepine created during continuous infusion for sedation. The volume of distribution is increased in obese patients.

At the beginning of IR, the concentration of benzodiazepine in plasma decreases, and after its completion, it increases. Such changes are associated with the redistribution of the fluid composition from the apparatus to the tissues, a change in the proportion of the drug fraction not bound to protein. As a result, T1/2 of benzodiazepine after the IR procedure is extended.

The elimination of benzodiazepines depends largely on the rate of biotransformation that occurs in the liver. Benzodiazepines are metabolized by two main pathways: microsomal oxidation (N-dealkylation, or aliphatic hydroxylation) or conjugation to form more water-soluble glucuronides. The predominance of one of the biotransformation pathways is clinically important, since oxidative processes can be altered by external factors (e.g., age, liver disease, the action of other drugs), while conjugation is less dependent on these factors.

Due to the presence of the imidazole ring, midazolam is oxidized faster than others and has a greater hepatic clearance compared to diazepam. Age decreases, and smoking increases the hepatic clearance of diazepam. For midazolam, these factors are not significant, but its clearance increases with alcohol abuse. Inhibition of the function of oxidative enzymes (for example, cimetidine) reduces the clearance of diazepam, but does not affect the conversion of lorazepam. The hepatic clearance of midazolam is 5 times higher than lorazepam, and 10 times higher than diazepam. The hepatic clearance of midazolam is inhibited by fentanyl, since its metabolism is also associated with the participation of cytochrome P450 isoenzymes. It should be borne in mind that many factors affect the activity of enzymes, including hypoxia, inflammatory mediators, so the elimination of midazolam in patients in the intensive care unit becomes poorly predictable. There is also evidence of genetic racial characteristics of benzodiazepine metabolism, in particular, a decrease in the hepatic clearance of diazepam in Asians.

Benzodiazepine metabolites have different pharmacological activities and can cause a prolonged effect with long-term use. Lorazepam forms five metabolites, of which only the main one binds to glucuronide, is metabolically inactive and is rapidly excreted in the urine. Diazepam has three active metabolites: desmethyldiazepam, oxazepam and temazepam. Desmethyldiazepam is metabolized significantly longer than oxazepam and temazepam and is only slightly inferior in potency to diazepam. Its T1/2 is 80-100 hours, due to which it determines the overall duration of action of diazepam. When taken orally, up to 90% of diazepam is excreted by the kidneys as glucuronides, up to 10% - with feces and only about 2% is excreted in the urine unchanged. Flunitrazepam is oxidized to three active metabolites, the major one being demethylflunitrazepam. The major metabolite of midazolam, alpha-hydroxymethylmidazolam (alpha-hydroxymidazolam), has 20-30% of the activity of its precursor. It is rapidly conjugated and 60-80% is excreted in urine within 24 hours. The other two metabolites are found in minor amounts. In patients with normal renal and hepatic function, the significance of midazolam metabolites is low.

Since the change in benzodiazepine concentration in the blood does not correspond to first-order kinetics, the context-sensitive T1/2 should be used as a guide when administering them by infusion. It is clear from the figure that the accumulation of diazepam is such that after a short infusion T1/2 increases several-fold. The time of termination of the effect can be approximately predicted only with midazolam infusion.

Recently, the possibilities of clinical application of two benzodiazepine receptor agonists - RO 48-6791 and RO 48-8684, which have a larger distribution volume and clearance compared to midazolam, have been studied. Therefore, recovery from anesthesia occurs faster (approximately 2 times). The appearance of such drugs will bring benzodiazepines closer to propofol in the speed of development and end of action. In the more distant future - the creation of benzodiazepines that are quickly metabolized by blood esterases.

The specific benzodiazepine receptor antagonist flumazenil is soluble in both fats and water, allowing it to be released as an aqueous solution. Possibly, the relatively low binding to plasma proteins contributes to the rapid onset of action of flumazenil. Flumazenil has the shortest T1/2 and the highest clearance. This pharmacokinetic feature explains the possibility of resedation with a relatively high dose of the administered agonist with a long T1/2 - T1/2 is more variable in children over 1 year of age (from 20 to 75 min), but is generally shorter than in adults.

Flumazenil is almost entirely metabolized in the liver. The details of metabolism are not yet fully understood. It is believed that the metabolites of flumazenil (N-desmethylflumazenil, N-desmethylflumazenilic acid, and flumazenilic acid) form the corresponding glucuronides, which are excreted in the urine. There is also evidence of the final metabolism of flumazenil to pharmacologically neutral carbonic acid. The total clearance of flumazenil approaches the rate of hepatic blood flow. Its metabolism and elimination are slower in patients with impaired liver function. Benzodiazepine receptor agonists and antagonists do not affect each other's pharmacokinetics.

Benzodiazepine dependence and withdrawal syndrome

Benzodiazepines, even in therapeutic doses, can cause dependence, as evidenced by the appearance of physical and psychological symptoms after dose reduction or drug withdrawal. Dependence symptoms can develop after 6 months or more of use of commonly prescribed weak benzodiazepines. The severity of the manifestations of dependence and withdrawal syndrome are significantly inferior to those of other psychotropic drugs (for example, opioids and barbiturates).

Withdrawal symptoms usually include irritability, insomnia, tremor, loss of appetite, sweating, and confusion. The timing of withdrawal syndrome development corresponds to the duration of the T1/2 of the drug. Withdrawal symptoms usually appear within 1-2 days for short-acting drugs and within 2-5 days (sometimes up to several weeks) for long-acting drugs. In patients with epilepsy, abrupt withdrawal of benzodiazepine may lead to seizures.

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Pharmacological effects of flumazenil

Flumazenil has weak pharmacological effects on the central nervous system. It does not affect the EEG and brain metabolism. The order of elimination of the effects of benzodiazepine is the reverse of the order of their onset. The hypnotic and sedative effect of benzodiazepine after intravenous administration is eliminated quickly (within 1-2 minutes).

Flumazenil does not cause respiratory depression, does not affect blood circulation even in high doses and in patients with coronary heart disease. It is extremely important that it does not cause hyperdynamia (like naloxone) and does not increase the level of catecholamines. Its effect on benzodiazepine receptors is selective, so it does not eliminate analgesia and respiratory depression caused by opioids, does not change the MAC of volatile anesthetics, does not affect the effects of barbiturates and ethanol.

Contraindications to the use of benzodiazepines

Contraindications to the use of benzodiazepines are individual intolerance or hypersensitivity to the components of the dosage form, in particular to propylene glycol. In anesthesiology, most contraindications are relative. They are myasthenia, severe hepatic and renal failure, the first trimester of pregnancy, breastfeeding, and closed-angle glaucoma.

Contraindication to the use of benzodiazepine receptor antagonists is hypersensitivity to flumazenil. Although there is no convincing evidence of withdrawal reactions when it is administered, flumazenil is not recommended in situations where benzodiazepines are used in potentially life-threatening conditions (e.g., epilepsy, intracranial hypertension, traumatic brain injury). It should be used with caution in cases of mixed drug overdose, when benzodiazepines "cover up" the toxic effects of other drugs (e.g., cyclic antidepressants).

A factor that significantly limits the use of flumazenil is its high cost. The availability of the drug may increase the frequency of benzodiazepine use, although it will not affect their safety.

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Tolerability and side effects

In general, benzodiazepines are relatively safe drugs, for example, compared to barbiturates. Midazolam is the best tolerated.

The spectrum and severity of side effects of benzodiazepines depend on the purpose, duration of use and route of administration. With continuous use, drowsiness and fatigue are typical. When benzodiazepines are used for sedation, induction or maintenance of anesthesia, they can cause respiratory depression, severe and prolonged postoperative amnesia, sedation. These residual effects can be eliminated by flumazenil. Respiratory depression is eliminated by respiratory support and/or administration of flumazenil. Circulatory depression rarely requires specific measures.

Significant side effects of diazepam and lorazepam include venous irritation and delayed thrombophlebitis, which is due to the poor water solubility of the drug and the use of solvents. For the same reason, water-insoluble benzodiazepines should not be injected into an artery. According to the severity of the local irritant effect, benzodiazepines are arranged in the following order:

Diazepam > lorazepam > flunitrazepam > midazolam. This side effect can be reduced by sufficiently diluting the drug, administering the drug into large veins, or reducing the rate of administration of the drug. Incorporating diazepam into the dosage form as a solvent for the fat emulsion also reduces its irritant effect. Accidental intra-arterial injection (in particular, flunitrazepam) can lead to necrosis.

An important advantage of using benzodiazepines (especially midazolam) is the low risk of allergic reactions.

In rare cases, paradoxical reactions (excitement, excessive activity, aggressiveness, convulsive readiness, hallucinations, insomnia) are possible when using benzodiazepines.

Benzodiazepines do not have embryotoxic, teratogenic or mutagenic effects. All other toxic effects are associated with overdose.

The safety of flumazenil exceeds that of LS-agonists. It is well tolerated by all age groups of patients, does not have a local irritant effect. In doses 10 times higher than those recommended for clinical use, it does not cause an agonist effect. Flumazenil does not cause toxic reactions in animals, although the effect on the human fetus has not been established.

Interaction

Benzodiazepines interact with various groups of drugs that are used both to provide surgery and to treat the underlying and concomitant diseases.

Favorable combinations

The combined use of benzodiazepines and other anesthetic drugs is largely beneficial, as their synergism allows for a reduction in the amount of each drug separately, and therefore, a reduction in their side effects. In addition, significant savings on expensive drugs are possible without deteriorating the quality of anesthesia.

Often, the use of diazepam for premedication does not provide the desired effect. Therefore, it is advisable to combine it with other drugs. The quality of premedication largely determines the number of induction agents administered, and therefore the likelihood of side effects.

Benzodiazepines reduce the need for opioids, barbiturates, propofol. They neutralize the adverse effects of ketamine (psychomimetic), gamma-hydroxybutyric acid (GHB) and etomidate (myoclonus). All this serves as a basis for using rational combinations of these drugs to conduct conduction. At the stage of maintaining anesthesia, such combinations provide greater stability of anesthesia and also reduce the awakening time. Midazolam reduces the MAC of volatile anesthetics (in particular, halothane by 30%).

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Combinations that require special attention

The sedative-hypnotic effect of benzodiazepines is enhanced by the combined use of drugs that cause CNS depression (other sleeping pills, sedatives, anticonvulsants, neuroleptics, antidepressants). Narcotic analgesics and alcohol, in addition, increase depression of respiration and blood circulation (more pronounced decrease in OPSS and BP).

Elimination of most benzodiazepines and their active metabolites is prolonged by some liver enzyme inhibitors (erythromycin, cimetidine, omeprazole, verapamil, diltiazem, itraconazole, ketoconazole, fluconazole). Cimetidine does not change the metabolism of midazolam, and other drugs from the indicated groups (e.g., ranitidine, nitrendipine) or cyclosporine do not inhibit the activity of cytochrome P450 isoenzymes. Sodium valproate displaces midazolam from its binding to plasma proteins and can thereby enhance its effects. Analeptics, psychostimulants, and rifampicin can reduce the activity of diazepam by accelerating its metabolism. Scopolamine enhances sedation and provokes hallucinations when combined with lorazepam.

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Undesirable combinations

Diazepam should not be mixed in a syringe with other drugs (it forms a precipitate). For the same reason, midazolam is incompatible with alkaline solutions.

Cautions

Despite the wide safety margins of benzodiazepines, certain precautions must be taken regarding the following factors:

• Age. The sensitivity of elderly patients to benzodiazepines, as to most other drugs, is higher than that of young patients. This is explained by the higher sensitivity of CNS receptors, age-related changes in the pharmacokinetics of benzodiazepines (changes in protein binding, decreased hepatic blood flow, metabolism and excretion). Therefore, the doses of benzodiazepines for premedication and anesthesia should be significantly reduced. Age-related changes have less effect on glucuronidation than on the oxidative pathway of benzodiazepine metabolism. Therefore, in the elderly, it is preferable to use midazolam and lorazepam, which undergo glucuronidation in the liver, rather than diazepam, which is metabolized by oxidation. When prescribing premedication, it is important to take into account that midazolam in the elderly can quickly cause respiratory depression;
• duration of the intervention. The different duration of action of benzodiazepines suggests a differentiated approach to their choice for short-term interventions (choice in favor of midazolam, especially for diagnostic procedures) and obviously long operations (any benzodiazepines), including with expected prolonged artificial ventilation of the lungs (ALV);
• concomitant respiratory diseases. Respiratory depression when prescribing benzodiazepines to patients with COPD is more pronounced in degree and duration, especially when used in combination with opioids. Caution is required when prescribing benzodiazepines as part of premedication in patients with sleep apnea syndrome;
• concomitant liver diseases. Due to the fact that benzodiazepines are almost completely biotransformed in the liver, severe impairment of the microsomal enzyme systems and decreased hepatic blood flow (e.g., in cirrhosis) slows down the metabolism of the drug (oxidation, but not glucuronidation). In addition, the proportion of the free fraction of benzodiazepines in plasma and the volume of distribution of the drug increase. T1/2 of diazepam can increase 5-fold. The sedative effect of benzodiazepines is mainly enhanced and prolonged. It should also be taken into account that if a single bolus administration of benzodiazepines is not accompanied by significant changes in pharmacokinetics, then with repeated administrations or prolonged infusion, these pharmacokinetic changes may manifest clinically. In patients who abuse alcohol and drugs, tolerance to benzodiazepines and paradoxical excitation reactions may develop. On the contrary, in people who are intoxicated, the drug's effect is most likely to be enhanced;
• renal diseases accompanied by hyperproteinuria increase the free fraction of benzodiazepines and thus may enhance their effect. This is the basis for titrating the drug dose to the desired effect. In renal failure, long-term use of benzodiazepines usually leads to accumulation of the drug and their active metabolites. Therefore, with an increase in the duration of sedation, the total administered dose should be reduced and the dosing regimen should be changed. Renal failure does not affect the T1/2, distribution volume and renal clearance of midazolam;
• pain relief during childbirth, effects on the fetus. Midazolam and flunitrazepam cross the placenta and are also found in small amounts in breast milk. Therefore, their use in the first trimester of pregnancy and use in high doses during childbirth and during breastfeeding are not recommended;
• intracranial pathology. Respiratory depression under the influence of benzodiazepines with the development of hypercapnia leads to dilation of cerebral vessels and an increase in ICP, which is not recommended for patients with intracranial space-occupying lesions;
• outpatient anesthesia.

When using benzodiazepines for anaesthesia in an outpatient setting, safe discharge criteria should be carefully assessed and patients should be advised to refrain from driving.

[ 66 ], [ 67 ], [ 68 ]