Benzodiazepines

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

[1], [2], [3], [4], [5],

Benzodiazepines: a place in therapy

In clinical anesthesiology and intensive care, benzodiazepines are used for premedication, induction of anesthesia, its maintenance, with a view to sedation when performing interventions in conditions of regional and local anesthesia, during various diagnostic manipulations (for example, endoscopy, endovascular surgeons), sedation in the ICU.

As a component of benzodiazepine premedication, barbiturates and antipsychotics were virtually eliminated because of the fewer undesirable effects. For this purpose, the medication is given orally. Midazolam distinguishes possibility of its or his purpose or appointment rectally (advantage at children); In addition, not only its tablet form, but also the injection solution, can be administered internally. Anxiolytic and sedative effects are most pronounced and occur more quickly with the use of midazolam. In lorazepam, the development of effects occurs more slowly. It should be borne in mind that 10 mg of diazepam is equivalent to 1 to 2 mg of lorazepam or 3-5 mg of midazolam.

A wide use of benzodiazepines was found to provide sedation with preservation of consciousness during regional and local anesthesia. At the same time, their desirable properties are anxiolysis, amnesia and an increase in the convulsive threshold for local anesthetics. Benzodiazepines should be administered by titration until adequate sedation or dysarthria is achieved. This is achieved by introducing a loading dose followed by repeated bolus injections or continuous infusion. Not always there is a correspondence between the level of sedation and amnesia (visibility of wakefulness and lack of memories of it), caused by all benzodiazepines. But the duration of amnesia is especially unpredictable when using lorazepam.

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

In the ICU, benzodiazepines are used to obtain sedation with preserved consciousness, as well as for deep sedation, to synchronize the patient's respiration with the respirator in an ICU. In addition, benzodiazepines are used to prevent and arrest convulsive and delirious states.

Rapid development of the effect, absence of venous complications make midazolam preferable to other benzodiazepines for induction of general anesthesia. However, because of the speed of the onset of sleep, midazolam is inferior to hypnotics from other groups, for example thiopental sodium and propofol. The speed of action of benzodiazepines is affected by the dose used, the rate of administration, the quality of the premedication, the age and overall physical status, and the combination with other drugs. Typically, the induction dose is reduced by 20% or more in patients over 55 years of age and in patients at high risk for complications (grade III ASA (American Association of Anaesthesiologists) and above). A rational combination of two or more anesthetics (co-induction) achieves a reduction in the amount of each drug administered. In the case of short-term interventions, the administration of induction doses of benzodiazepines is not entirely justified. This lengthens the awakening time.

Benzodiazepines are able in a number of cases to protect the brain from hypoxia and are used in critical conditions. The greatest effectiveness in this case demonstrates midazolam, although it is inferior to that of barbiturates.

The antagonist of benzodiazenine receptors flumazenil is used in the practice of anesthesiology for therapeutic purposes - to eliminate the effects of benzodiazepine receptor agonists after surgical interventions and diagnostic procedures. At the same time, it actively removes sleep, sedation and respiratory depression, rather than amnesia. The medication should be administered iv in the titration method until the desired effect is obtained. It is important to note that higher doses are required for stronger benzodiazepines. In addition, because of the likelihood of recurrence for long-acting benzodiazepines, repeated doses or infusion administration of flumazenil may be required. The use of flumazenil to neutralize the effects of the DB does not give grounds for allowing patients to drive the vehicle.

Another application of flumazenil is diagnostic. It is introduced for differential diagnosis of possible benzodiazepine poisoning. In this case, if the reduction in the degree of sedation does not occur, the most likely other causes of CNS depression.

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

[6], [7], [8], [9]

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 sedation, anxiolytic (anxiety reduction), hypnotic, anticonvulsant, myorelaxing and amnestic (anterograde amnesia) are fundamentally important.

All of their pharmacological effects of benzodiazepines are manifested by facilitating the action of GABA, the main inhibitory neurotransmitter in the central nervous system, which balances the effect of activating neurotransmitters. The discovery in the 1970s of the benzodiazepine receptor largely explained the mechanism of action of benzodiazepines on the central nervous system. One of the two GABA receptors, the GABA-receptor pentametric complex, is a large macromolecule and contains protein units (alpha, beta and gamma), which include various ligand binding sites for GABA, benzodiazepines, barbiturates, and alcohol. Several different subunits of the same type (six different a, four beta and three gamma) with different ability to form a chloride channel were found. The structure of receptors in different parts of the CNS may be different (for example, alpha1, beta and gamma2 or alpha3, beta1 and gamma2), which also determines the different pharmacological properties. For affinity to the DB, the receptor should have a y2 subunit. There is a definite structural correspondence between the GABAA receptor and the nicotinic acetylcholine receptor.

By binding to specific sites of the GABA-receptor complex located on the subsynaptic membrane of the effector neuron, benzodiazepines strengthen the receptor binding to GABA, which enhances the opening of channels for chloride ions. The increased penetration of chloride ions into the cell leads to hyperpolarization of the postsynaptic membrane and the stability of the neurons to excitation. Unlike barbiturates, which increase the duration of the opening of ion channels, benzodiazepines increase the frequency of their opening.

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

It is also not excluded that anxiolytic, anticonvulsant and myorelaxing effects are realized through the GABAA receptor, and hypnotic action is mediated by changing the flow of calcium ions through potential-dependent channels. Sleep is close to the physiological with the characteristic EEG-phases.

The highest density of benzodiazepine receptors is present in the cerebral cortex, hypothalamus, cerebellum, hippocampus, olfactory bulb, black substance and lower tubercle; a lower density was found in the striatum, the lower part of the brainstem, and the spinal cord. The degree of modulation of the GABA receptor is limited (the so-called "limiting effect" of benzodiazepines for CNS depression), which determines the rather high safety of DB application. The predominant localization of GABA receptors in the central nervous system determines the minimal effects of drugs beyond its limits (minimal circulatory effects).

There are 3 types of ligands acting on the benzodiazepine receptor: agonists, antagonists and inverse agonists. The action of the agonists (eg, diazepam) is described above. Agonists and antagonists bind the same (or overlapping) regions of the receptor, forming various reversible links with it. Antagonists (eg, flumazenil) occupy the receptor, but do not have intrinsic activity and therefore block the action of both the agonists and the inverse agonists. Inverse agonists (eg, beta-carbolines) reduce the inhibitory effect of GABA, which leads to anxiety and seizures. There are also endogenous agonists with benzodiazepine-like properties.

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

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

As a competitive antagonist, flumazenil does not displace the agonist from the receptor, but occupies the receptor when the agonist is separated from it. Since the ligand binding to the receptor lasts for a few seconds, the receptor binds dynamically to an agonist or antagonist. The receptor occupies that ligand, which has a greater affinity for the receptor and whose concentration is higher. The affinity of flumazenil to 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 at which it is eliminated.

Effects on cerebral blood flow

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

[10], [11], [12], [13], [14], [15], [16], [17], [18], [19]

Electroencephalographic picture

An electroencephalographic picture of benzodiazepine anesthesia is characterized by the appearance of rhythmic beta activity. Tolerance to the effects of benzodiazepines on the EEG is not noted. Unlike barbiturates and propofol, midazolam does not cause an isoelectric EEG.

When the DB is introduced, the amplitude of the cortical SSVP decreases, the latency of the early potential is shortened and the peak latency is lengthened. Midazolam also reduces the peak amplitude of mid-latent SVPs in the brain. Other criteria for the depth of benzodiazepine anesthesia include the registration of BIS and the AAI ™ ARX index (an improved version of SVP treatment).

In rare cases, benzodiazepines provoke nausea and vomiting. Attributed to them by some authors, the antiemetic effect is small and is more likely due to the sedation effect.

[20], [21], [22], [23], [24], [25], [26], [27]

Influence on the cardiovascular system

With the isolated use of benzodiazepines have a moderate effect on the cardiovascular system. And in healthy subjects, and in patients with heart disease, the predominant changes in hemodynamics are a slight decrease in blood pressure due to a decrease in OPSS. Heart rate, heart rate and ventricular filling pressure vary to a lesser extent.

In addition, after reaching the equilibrium concentration of the drug in the plasma, further decrease in blood pressure does not occur. 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 in midazolam. But even in high doses and in cardiosurgical patients, hypotension is not excessive. Reducing pre- and afterload in patients with congestive heart failure benzodiazepine may even increase CB.

The situation changes with the combination of benzodiazepines 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 not ruled out that such synergy is caused by a decrease in the tone of the sympathetic nervous system. More significant oppression of hemodynamics is observed in patients with hypovolemia.

Benzodiazepines have minor analgesic properties and do not prevent reactions to traumatic manipulations, in particular, intubation of the trachea. The most appropriate in these stages is the additional use of opioids.

Influence on the respiratory system

Benzodiazepines have a central effect on respiration and, like most intravenous anesthetics, increase the threshold level of carbon dioxide to stimulate the respiratory center. The result is a decrease in the respiratory volume (DO) and minute volume of respiration (MOD). The rate of development of respiratory depression and the degree of its expression are higher in midazolam. In addition, faster administration of the drug leads to a more rapid development of respiratory depression. Depression of breathing is more pronounced and lasts longer in patients with COPD. Lorazepam, to a lesser degree than midazolam and diazepam, depresses breathing, but in combination with opioids, all benzodiazepines exert a synergistic inhibitory effect on the respiratory system. Benzodiazepines suppress the swallowing reflex and 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 increases with debilitating diseases and in senile 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 adversely affect the gastrointestinal tract, incl. When administered orally and with rectal administration (midazolam). They do not induce the induction of liver enzymes.

There is evidence of a decrease in the night secretion of gastric juice and a decrease in intestinal motility against the background of diazepam and midazolam, but these manifestations are likely with prolonged medication. In rare cases, when taking benzodiazepine inside, nausea, vomiting, hiccough, dry mouth can be observed.

[28], [29], [30], [31], [32]

Effect on the endocrine response

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

[33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43]

Effect on neuromuscular transmission

Benzodiazepines have no direct effect on neuromuscular transmission. Their miorelaxing effect is performed at the level of intercalary neurons of the spinal cord, and not at the periphery. However, the severity of benzodiazepine-induced miorelaxation is not sufficient to perform surgical interventions. Benzodiazepines do not determine the mode of administration of relaxants, although they can, to some extent, potentiate their action. In animal experiments, high doses of benzodiazepine suppressed impulses in the neuromuscular junction.

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

Other effects

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

Tolerance

Long-term administration of benzodiazepines causes a decrease in their effectiveness. The mechanism for the development of tolerance is not fully understood, but it is assumed that prolonged exposure to benzodiazepines is the cause of a decrease in binding to the GABAA receptor. This explains the need for higher doses of benzodiazepines for anesthetizing patients who took them for a long time.

The expressed tolerance to benzodiazepines is typical for drug addicts. It can be expected to appear in patients with burns, which often undergo anesthesia. In general, tolerance to benzodiazepines is less likely than to barbiturates.

Pharmacokinetics

In accordance with the duration of elimination from the body, benzodiazepines are divided into 3 groups. For drugs with prolonged T1 / 2 (> 24 h) include chlordiazepoxide, diazepam, medazepam, nitrazepam, phenazepam, flurazepam, alprazolam. The average duration of elimination (T1 / 2 (3 from 5 to 24 hours) is oxazepam, lorazepam, flunitrazepam .The shortest T1 / 2 (<5 h) have midazolam, triazolam and temazepam.

Benzodiazepines can be administered orally, rectally, IM or IV.

All benzodiazepines are fat soluble compounds. When administered tablet form they are well and completely absorbed, mainly in the duodenum. Their bioavailability is 70-90%. Midazolam in the form of an injection is well absorbed from the digestive tract when ingested, which is important in children's practice. Midazolam is rapidly absorbed and rectally administered and reaches a maximum plasma concentration within 30 minutes. Its bioavailability in this route of administration approaches 50%.

With the exception of lorazepam and midazolam, the absorption of benzodiazepines from muscle tissue is incomplete and uneven, and because of the need to use a solvent, it is associated with the development of local reactions with an im injection.

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

Similar to the onset of action, the duration of the effect is also related to fat-solubility and drug concentration in the plasma. The binding of benzodiazepine to plasma proteins in parallel to their solubility in fats, i.e. High fat solubility increases binding to proteins. A high degree of binding to proteins limits the effectiveness of hemodialysis in overdose of diazepam.

Long-term T1 / 2 in the phase of elimination of diazepam is due to its large volume of distribution and slow extraction in the liver. A shorter compared with diazepam T1 / 2 beta lorazepam due to its lower fat solubility and a smaller volume of distribution. Despite the high fat solubility and large volume of distribution, midazolam has the shortest T1 / 2 beta since it is extracted with a liver more than other benzodiazepines.

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

At the beginning of the IR, the concentration of benzodiazepine in the plasma decreases, and after the end - increases. Such changes are related to the redistribution of the composition of the liquid from the apparatus to the tissue, the change in the fraction of the non-protein-bound fraction of the drug. As a result, T1 / 2 benzodiazepine after the procedure, the IR is extended.

Elimination of benzodiazepines largely depends on the speed of biotransformation, which occurs in the liver. Benzodiazepines are metabolized by two main routes: microsomal oxidation (N-dealkylation, or aliphatic hydroxylation) or binding (conjugation) to form more water-soluble glucuronides. The predominance of one of the ways of biotransformation is clinically important, since oxidative processes can change under the influence of external factors (for example, age, liver diseases, the action of other drugs), and conjugation from these factors is less dependent.

Due to the presence of an imidazole ring, midazolam oxidizes faster than others and has a more significant hepatic clearance compared to diazepam. Age reduces, and smoking increases the hepatic clearance of diazepam. For midazolam, these factors are not significant, but its clearance increases with alcohol abuse. Oppression of the function of oxidative enzymes (eg, cimetidine) decreases the clearance of diazepam, but does not affect the conversion of lorazepam. The hepatic clearance of midazolam is 5 times higher than that of lorazepam, and 10 times higher than diazepam. The hepatic clearance of midazolam is inhibited by fentanyl; its metabolism is also associated with the participation of cytochrome P450 isoenzymes. It should be borne in mind that many factors influence the activity of enzymes, including. Hypoxia, mediators of inflammation, so the elimination of midazolam in patients in the ICU becomes poorly predictable. There are also data on genetic racial features of the metabolism of benzodiazepine, in particular, a decrease in the hepatic clearance of diazepam in Asians.

Metabolites of benzodiazepines have different pharmacological activity and can cause a long-term effect with prolonged use. Lorazepam forms five metabolites, of which only the principal binds to glucuronide, is not metabolically active, 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 only slightly inferior to the power of diazepam. His T1 / 2 is 80-100 hours, so it determines the total duration of diazepam. When ingesting up to 90% of diazepam is excreted by the kidneys in the form of glucuronides, up to 10% - with feces and only about 2% is excreted in urine unchanged. Flunitrazepam is oxidized to three active metabolites, the main one being demethylflunitrazepam. The main metabolite of midazolam alpha-hydroxymethyl-imidazolam (alpha-hydroxymidazolam) has a 20-30% activity of the precursor. It is quickly conjugated and 60-80% is excreted in the urine within 24 hours. Two other metabolites are found in small amounts. In patients with normal renal and hepatic function, the importance of midazolam metabolites is small.

Since the change in the concentration of benzodiazepine in the blood does not correspond to the kinetics of the first order, the infusion method of their administration should be guided by context-sensitive T1 / 2. From the figure it is clear that the cumulation of diazepam is such that after a short infusion of T1 / 2 multiply increases. The time of cessation of the effect can be approximately predicted only with the infusion of midazolam.

Recently, the possibilities of clinical use of two benzodiazepine receptor agonists - RO 48-6791 and RO 48-8684, which have a large volume of distribution and clearance in comparison with midazolam have recently been studied. Therefore, recovery after anesthesia occurs faster (approximately 2-fold). The appearance of such drugs will bring benzodiazepines closer to propofol by the rate of development and termination of action. In the more distant future - the creation of benzodiazepines, rapidly metabolized by esterases of blood.

The specific antagonist of benzodiazepine receptors flumazenil is able to dissolve in both fats and water, which allows it to be released as an aqueous solution. Perhaps a relatively low association with plasma proteins promotes the rapid onset of flumazenil. Flumazenil has the shortest T1 / 2 and the highest clearance. This feature of pharmacokinetics explains the possibility of relapse at a relatively high dose of the injected agonist with a large T1 / 2-T1 / 2 more variable in children older than 1 year (20 to 75 min), but generally shorter than in adults.

Flumazenil is almost completely metabolized in the liver. The details of metabolism have not been sufficiently studied. It is believed that flumazenil metabolites (N-desmethylflumazenil, N-desmethoflumazenilic acid and flumazenilic acid) form the corresponding glucuronides that are excreted in the urine. There are also data on the final metabolism of flumazenil to pharmacologically neutral carbonic acid. The total clearance of flumazenil approaches the rate of hepatic blood flow. His metabolism and elimination are slowed down in patients with impaired liver function. The agonists and antagonists of benzodiazepine receptors do not affect the pharmacokinetics of each other.

Dependence on benzodiazepines and withdrawal syndrome

Benzodiazepines, even in therapeutic doses, can cause dependence, as evidenced by the appearance of physical and psychological symptoms after a dose reduction or drug withdrawal. Symptoms of dependence can be formed after 6 months or more of the usually prescribed weak benzodiazepines. The severity of dependence and withdrawal symptoms is significantly inferior to that of other psychotropic drugs (eg, opioids and barbiturates).

Symptoms of withdrawal are usually manifested by irritability, insomnia, tremor, loss of appetite, sweating, confusion. The duration of the withdrawal syndrome corresponds to the duration of T1 / 2 of the drug. Usually withdrawal symptoms appear within 1-2 days for short-acting and for 2-5 days (sometimes up to several weeks) for long-acting medicines. In patients with epilepsy, abrupt withdrawal of benzodiazepine can lead to seizures.

[56], [57], [58], [59]

Pharmacological effects of flumazenil

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

Flumazenil does not cause respiratory depression, does not affect blood circulation, even in high doses and in patients with ischemic heart disease. It is extremely important that it does not cause hyperdynamics (such as naloxone) and does not increase the level of catecholamines. Its effect on the 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 gravis, severe hepatic-renal failure, I trimester of pregnancy, breast-feeding, angle-closure glaucoma.

Contraindication to the appointment of an antagonist of benzodiazenine receptors is increased sensitivity to flumazenil. Although there is no conclusive evidence of withdrawal reactions when administered, flumazenil is not recommended in situations where benzodiazepines are used in potentially life-threatening conditions (eg, epilepsy, intracranial hypertension, traumatic brain injury). Carefully it should be used in cases of mixed drug overdose, when benzodiazepines "cover up" the toxic effect of other agents (eg, cyclic antidepressants).

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

[50], [51], [52], [53], [54], [55]

Tolerance 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 depends on the purpose, duration of use and modes of administration. With constant reception, drowsiness and fatigue are typical. When using benzodiazepines for sedation, induction or maintenance of anesthesia, they can cause respiratory depression, marked and prolonged postoperative amnesia, sedation. These residual effects can be eliminated by flumazenil. Depression of respiration is eliminated by respiratory support and / or administration of flumazenil. Depression of the circulation rarely requires specific measures.

Significant side effects of diazepam and lorazepam are venous irritation and delayed thrombophlebitis, which is associated with poor water solubility of the drug and the use of solvents. For the same reason, benzodiazepines insoluble in water should not be introduced into the artery. The severity of the local irritant effect of benzodiazepines is arranged in the following order:

Diazepam> lorazepam> flunitrazepam> midazolam. To reduce the severity of this side effect can be by sufficient dilution of the drug, the introduction of the drug into large veins or a decrease in the rate of administration of the drug. The introduction of diazepam as a fat emulsion in the formulation also reduces its irritant effect. Accidental intraarterial administration (in particular, flunitrazepam) can lead to necrosis.

An important advantage of using benzodiazepines (especially midazolam) is a low probability of allergic reactions.

In rare cases, with the use of benzodiazepines, paradoxical reactions are possible (excitation, excessive activity, aggressiveness, convulsive alertness, hallucinations, insomnia).

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

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

Interaction

Benzodiazepines interact with different groups of drugs, which are used both for the operation and for the treatment of underlying and associated diseases.

Favorable combinations

The joint use of benzodiazepines and other drugs for anesthesia is beneficial in many respects, their synergy allows you to reduce the amount of each drug individually, and therefore reduce their side effects. In addition, significant savings of 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 medicines. The quality of premedication in many ways determines the number of injected induction agents, and hence the likelihood of developing side effects.

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

[60], [61]

Combinations that require special attention

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

Elimination of most benzodiazepines and their active metabolites extends some inhibitors of liver enzymes (erythromycin, cimetidine, omeprazole, verapamil, diltiazem, itraconazole, ketoconazole, fluconazole). In this case, cimetidine does not change the metabolism of midazolam, and other drugs from these groups (for example, ranitidine, nitrendipine) or cyclosporin do not inhibit the activity of cytochrome P450 isoenzymes. Valproate sodium displaces midazolam from the connection with plasma proteins and thus can enhance its effects. Analeptics, psychostimulants and rifampicin can reduce the activity of diazepam, speeding up its metabolism. Scopolamine increases sedation and provokes hallucinations when combined with lorazepam.

[62], [63], [64], [65]

Unwanted combinations

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

Caveats

In spite of the broad margin of safety of benzodiazepines, certain precautions must be taken in connection with the following factors:

• age. The sensitivity of elderly patients to benzodiazepines, as well as to most other drugs, is higher than that of young patients. This is due to the greater sensitivity of the CNS receptors, the age-related changes in the pharmacokinetics of benzodiazepines (change in binding to proteins, decreased hepatic blood flow, metabolism and excretion). Doses of benzodiazepines for premedication and anesthesia should therefore be significantly reduced. Age changes have less effect on glucuronization than on the oxidative pathway of benzodiazepine metabolism. Therefore, in the elderly, it is preferable to use midazolam and lorazepam exposed in the liver to glucuronization, rather than diazepam, metabolized by oxidation. In appointing premedication, it is important to consider that midazolam in the elderly can quickly cause respiratory depression;
• duration of intervention. The different duration of action of benzodiazepines presupposes a differentiated approach to their choice for short-term interventions (choice in favor of midazolam, especially in diagnostic procedures) and obviously long-term operations (any benzodiazepines), including. With the proposed extended artificial ventilation (IVL);
• concomitant diseases of the respiratory system. Respiratory depression in prescribing benzodiazepines to patients with COPD is more pronounced in degree and duration, especially when combined with opioids. Caution is given to the appointment of benzodiazepines as part of premedication in patients with nighttime apnea syndrome;
• concomitant liver disease. Due to the fact that benzodiazepines are almost completely biotransformed in the liver, a pronounced impairment of the function of microsomal enzyme systems and a decrease in hepatic blood flow (for example, in cirrhosis) slows the metabolism of the drug (oxidation, but not glucuronization). In addition, the proportion of the free fraction of benzodiazepines in the plasma increases the volume of drug distribution. T1 / 2 diazepam can increase 5 times. The sedative effect of benzodiazepines is increased and prolonged. It should also be taken into account that if a single bolus injection of benzodiazepines is not accompanied by significant changes in pharmacokinetics, then with repeated injections or prolonged infusion these pharmacokinetic changes may manifest clinically. In patients who abuse alcohol and drugs, it is possible to develop tolerance to benzodiazepines and the emergence of paradoxical reactions of excitation. On the contrary, in persons who are intoxicated, the effect of the drug is most likely to increase;
• kidney diseases accompanied by hyperproteinuria increase the free fraction of benzodiazepines and thus can enhance their effect. This is the basis for titrating the dose of the drug to the desired effect. In renal failure, prolonged use of benzodiazepines generally leads to cumulation 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. At T1 / 2, the volume of distribution and renal clearance of midazolam, renal failure is not affected;
• anesthesia in childbirth, influence on the fetus. Midazolam and flunitrazepam penetrate the placenta, and in small quantities are found in breast milk. Therefore, their use in the first trimester of pregnancy and use in high doses during labor and during breastfeeding is not recommended;
• intracranial pathology. Inhibition of respiration under the action of benzodiazepines with the development of hypercapnia leads to an expansion of the cerebral vessels and an increase in ICP, which is not recommended in patients with intracranial volume formations;
• anesthesia on an outpatient basis.

When using benzodiazepines for anesthesia in a clinic, the criteria for safe discharge should be carefully assessed and patients should be advised not to drive the vehicle.

[66], [67], [68],