Calming medications (Tranquilizers)

Benzodiazepines with anti-anxiety effects

The most powerful representatives of the benzodiazepine group are those with an anti-anxiety effect - Diazepam, Phenazepam, Chlordiazepoxide, Lorazepam, Oxazepam, Clozepam, Medazepam, Grandaxin.
They are prescribed in short regimens of up to 2 weeks, which is associated with a high risk of developing withdrawal syndrome and dependence. Also, the group of benzodiazepines with a predominantly anti-anxiety effect includes drugs with a moderate anxiolytic effect (Medazepam, Chlordiazepoxide, Oxazepam). They have a moderate sedative and muscle relaxant effect, and therefore belong to the category of daytime tranquilizers. The main target of this group is anxiety in psychosomatic disorders (depression, post-traumatic shock, social phobias, etc.).

Benzodiazepines with hypnotic effects

Benzodiazepines prescribed as sleep aids are in turn classified into short-acting and long-acting drugs. These include Nitrazepam, Flunitrazepam, Temazepam, Triazolam, Midazolam, Estazolam. Preference is given to drugs with a rapid half-life from the body, for example, Temazepam, which makes it possible to prevent daytime sleepiness. Long-acting drugs, for example, Nitrazepam, are prescribed to patients if there is a clinical need for a tranquilizing effect during the day and relief of insomnia at night.

Benzodiazepines with a hypnotic effect are usually used in short courses - no more than 2-4 weeks. Long-term use of drugs is dangerous due to the formation of addiction. Also, the use of this group of drugs is justified in single doses in cases of insomnia.

Benzodiazepines with anticonvulsant effects

The anticonvulsant effect of benzodiazepines is due to the suppression of epileptogenic activity in the central nervous system due to increased inhibition of GABA receptors. Drugs in this group are prescribed for the treatment of epilepsy and parkinsonism as part of complex therapy. Representatives of benzodiazepines with anticonvulsant action are Sibazon and Clonazepam.

In addition to the anticonvulsant effect, both drugs have a sedative, hypnotic and muscle relaxant effect. They have virtually no negative effect on the cardiovascular system and respiration, therefore they are used in combination with “balanced anesthesia” with powerful analgesics and antipsychotics. The main complication of this group of drugs is considered to be retrograde amnesia.

Classification Features

The classification of anxiolytics was carried out by a number of specialists, including such mastodons of domestic pharmacology as M. D. Mashkovsky and D. A. Kharkevich. And at present, drugs in this group are divided according to various characteristics: chemical structure, severity of sedative effect, mechanism of action, predominant effect, etc. One of the most complete at the moment is the classification developed at the Research Institute of Pharmacology of the Russian Academy of Medical Sciences by T. A. Voronina and S. B. Seredinin [1].

Mechanism of action

A kind of “target” for benzodiazepines is specific GABAergic receptors, which selectively interact with γ-aminobutyric acid, the main “inhibitory” transmitter of the central nervous system. Roughly speaking, it is GABA that protects our brain from emotional overload, regulates higher nervous activity, and indirectly participates in the hormonal regulation of vascular tone, rhythm and heart rate.

The pathogenetic rationale for prescribing benzodiazepines is that at the biochemical level, when they are used, the sensitivity of GABA receptors increases. This allows the use of such medications to relieve alcohol and drug withdrawal, accompanied by:

• severe sleep disturbances;
• generalized convulsive seizures;
• phobic, anxiety and panic disorders.

Classification of anxiolytics according to T. A. Voronina and S. B. Seredinin [2]

I. Traditional anxiolytics

1. Direct agonists of the GABAA-benzodiazepine receptor complex (benzodiazepine derivatives).
2. Preparations of different chemical structures (benactizine, tetramethyltetraazabicyclooctanedione, oxylidine and others).

II. New anxiolytics

1. Partial agonists of benzodiazepine receptors - zolpidem, gidazepam and others.
2. Endogenous regulators of the GABAA-benzodiazepine receptor complex (endosepines, derivatives of β-carboline, nicotinamide and others).
3. Agonists of the GABAB receptor complex.
4. Membrane modulators of the GABAA-benzodiazepine receptor complex (ethylmethylhydroxypyridine succinate, fabomotizol and others).
5. Glutamatergic anxiolytics.
6. Serotonergic anxiolytics (buspirone, ondansetron and others).
7. β-blockers - propranolol and others.
8. Metabolites of nucleic acids.
9. Substances that affect the energy status of the brain.
10. Hormonal substances.
11. Anxiolytics based on neuropeptides.
12. Various substances.

In clinical practice, traditional and some representatives of new anxiolytics are most often used. We will dwell on them in detail.

Overdose

The use of high doses of benzodiazepine derivatives leads to overdose or intoxication of the body. The condition is life-threatening. Against the background of an increased concentration of metabolites of psychoactive substances in the blood, a person develops a soporotic state (loss of consciousness with preservation of unconditioned defensive reflexes) followed by a transition to a coma.

Progressive intoxication leads to depression of the respiratory center and disorders of external respiration, damage to the renal system, abnormalities of the heart and blood vessels. Symptoms such as cerebral spasms and mydriasis (dilation of the pupil) are also recorded. Increasing intoxication is dangerous due to cardiac arrest.

Basic treatment:

• detoxification of the body - gastric lavage, enema, adsorbents
• introduction of an antidote - Aminophylline or Flumazenil
• symptomatic and supportive therapy

The incidence of death due to overdose of benzodiazepine derivatives is 3.8%, but this figure increases significantly if tranquilizers and sleeping pills were used in combination with ethanol or psychotropic substances. After relief of intoxication, the patient needs to be monitored by a psychiatrist.

Traditional anxiolytics

Benzodiazepine derivatives have been used in medicine for 60 years - their first representatives, diazepam and chlordiazepoxide, began to be used in the 60s of the last century. It turned out that radicals in the benzodiazepine molecule are easily replaced, and thanks to this, more than 3,000 compounds were synthesized over several decades. More than 40 of them are used as anxiolytics (2).

Main properties of benzodiazepines:

• anxiolytic (tranquilizing);
• sedative;
• hypnotic;
• anticonvulsant;
• muscle relaxant;
• amnesiac.

In addition, drugs of this subgroup exhibit antiphobic, activating, antidepressant, antihypoxic, hypotensive, antiarrhythmic, analgesic and some other effects [3].

The action of benzodiazepines is aimed at the most important parts of the limbic system, in which neurons are activated by external impulses: the hypothalamus and cerebral cortex. The activity of the drugs is primarily associated with the ability to facilitate the postsynaptic action of gamma-aminobutyric acid (GABA) due to binding to receptors located on the synaptic membrane of GABAergic neurons [2, 3]. Let us remind you: GABA is the main inhibitory transmitter of the central nervous system, which is released in approximately 1/3 of all synapses.

Despite low toxicity and good tolerability, long-term use of benzodiazepines, especially in high doses, can lead to withdrawal syndrome, as well as psychological and physical dependence. Therefore, benzodiazepines are discontinued gradually. [2, 3].

An atypical drug occupies a special place in the group of benzodiazepine anxiolytics

tofisopam. It differs from traditional benzodiazepines in the location of the nitro group, which determines its unique properties. Tofizopam does not have a muscle relaxant or anticonvulsant effect, does not affect cognitive functions and can be prescribed in situations requiring concentration and important decision-making. In addition, unlike other benzodiazepines, the use of tofisopam is much less likely to develop mental or physical dependence, as well as withdrawal symptoms. At the same time, tofisopam exhibits anxiolytic effects characteristic of benzodipazepines [4].

Among drugs of other chemical structure

It is worth mentioning tetramethyltetraazabicycloocanedione. Its molecule consists of two urea fragments in a bicyclic structure, due to which the drug is structurally close to the body’s natural metabolites [5].

Like all benzodiazepines, tetramethyltetraazabicycloocandione acts on structures included in the limbic-reticular complex. It also affects all 4 major neurotransmitter systems - GABA, choline, serotonin and adrenergic. Due to this, the drug has an anti-anxiety, calming effect, without reducing mental and motor activity. Therefore, it can be used during the working day. The drugs do not exhibit a hypnotic effect, but enhance the effect of sleeping pills. It should be noted the ability of this drug to improve cognitive functions, attention and mental performance. In addition, unlike benzodiazepines, it does not cause dependence or withdrawal symptoms [5].

When dispensing tetramethyltetraazabicyclootcanedione, it should be noted that the drug can cause a decrease in blood pressure, weakness, and also negatively affect the ability to drive a car, so drivers should be especially careful [5].

Side effects

Long-term use of benzodiazepine derivatives causes the development of complications and undesirable effects. First of all, we are talking about addiction and physical dependence on medications. The condition is characterized by the following manifestations:

• The drug ceases to have a therapeutic effect at the previous dosage. Increased chemical tolerance and an increase in the dose of the drug provoke the development of side effects.
• Withdrawal of the medication leads to physical and psychological discomfort. Those clinical signs for which tranquilizers or sleeping pills were prescribed return and become doubly intensified, signaling the “rebound” syndrome.

Also, the occurrence of side effects during treatment with benzodiazepine derivatives is associated with their half-life:

• Short-acting benzodiazepines are partially eliminated from the body within 1-12 hours. They provoke sleep disturbances, anxiety and fears. Examples: Triazolam, Midazolam.
• Benzodiazepines with a moderate duration of action are eliminated from the body within 12-40 hours. A residual complication is insomnia. Examples: Clonazepam, Lorazepam.
• Long-acting benzodiazepines have a half-life of 40-250 hours. Undesirable reactions associated with their use are due to the retention of metabolites in the body, which most likely leads to rebound and withdrawal syndrome, and the formation of addiction. Examples: Diazepam, Flurazepam.

Also, the side effects of benzodiazepine derivatives are associated with their sedative and muscle relaxant effects. These include:

• increased drowsiness, weakness
• deterioration of attention, memory
• incoordination of movements
• deterioration in the speed of psychomotor reactions
• decreased libido, sexual dysfunction
• depression, apathy
• respiratory depression, pulmonary hypoventilation
• euphoria, confusion
• sleep disorders, nightmares

Among the listed adverse reactions, the most common in terms of frequency of occurrence are drowsiness, weakness and changes in psychomotor reactions - according to statistics, they occur in at least 10% of patients. Other undesirable effects are recorded almost 5 times less often. These statistics do not apply to older people - due to the deterioration of metabolic processes and the slowness of all physiological reactions, medications remain in their bodies longer, causing an increase in side effects.

New anxiolytics

In the subgroup of partial benzodiazepine receptor agonists

an original drug is released - the selective anxiolytic gidazepam. The indications for its use are the same diseases as for benzodiazepine drugs. However, unlike the latter, gidazepam does not have a muscle relaxant, sedative or amnesic effect. Therefore, it can be prescribed in the daytime, including to weakened patients, the elderly and children [3]. However, it should be noted that gidazepam is not currently registered in the Russian Federation [5].

But membrane modulators of the GABA-benzodiazepine receptor complex

- fabomotizol and ethylmethylhydroxypyridine succinate are widely used. Fabomotizol was developed at the Research Institute of Pharmacology of the Russian Academy of Medical Sciences. An innovative component of its mechanism of action was the absence of benzodiazepine receptor agonism. The drug prevents the development of membrane-dependent changes in the GABA-benzodiazepine receptor complex, which appear during anxiety and emotional stress reactions [6].

Thanks to this, fabomotizol has a pronounced anxiolytic, vegetative-stabilizing effect. At the same time, the drug in therapeutic doses does not exhibit a sedative or muscle relaxant effect, and does not affect memory and attention. Drug dependence does not develop with its use. Another important feature of fabomotizol is that it belongs to the OTC group. Pervostolniki can recommend the drug when requests for remedies for increased anxiety, feelings of tension, including in combination with memory impairment, decreased concentration [5].

Another popular anxiolytic of this subgroup is ethylmethylhydroxypyridine succinate, which, like fabomotizol, was synthesized at the Research Institute of Pharmacology of the Russian Academy of Medical Sciences. In addition to the anxiolytic effect, the drug exhibits anti-alcohol, antihypoxic and vegetotropic effects. However, it does not have a sedative or muscle relaxant effect, which is considered a significant advantage compared to benzodiazepines. Ethylmethylhydroxypyridine succinate fights learning and memory disorders. The drug exhibits the most pronounced effect in the treatment of acute and chronic cerebrovascular accidents, including strokes [7].

Serotonergic anxiolytics

In particular, buspirone has a high affinity for serotonin 5‑HT1A receptors. Despite the fact that the anti-anxiety effect of buspirone is not associated with an effect on GABA-benzodiazepine receptors, its anxiolytic activity is comparable to benzodiazepines, for example, diazepam and lorazepam. But, unlike them, it does not cause drug dependence, cognitive and psychomotor impairment, and does not exhibit a sedative or muscle relaxant effect [8].

The effect of buspirone develops gradually over 7–14 days, reaching a maximum after 4 weeks of use. The drug is usually prescribed for generalized anxiety disorder, panic disorder, alcohol withdrawal, and as part of a combination treatment for depression [9].

aminophenylbutyric acid occupies an intermediate position in the classification by mechanism of action.

. It is a non-selective GABA agonist and acts on both GABAA and GABAB receptors [8]. The drug was synthesized by Soviet professor V.V. Perekalin and studied at the Institute of Experimental Medicine of the USSR Academy of Medical Sciences in the 70s of the last century [10].

The mechanism of action of aminophenylbutyric acid is based on the effect on GABAergic receptors, facilitating GABA-mediated transmission of nerve impulses to the central nervous system. The drug is characterized by both a tranquilizing and antihypoxic effect, as well as nootropic and vasotropic (elimination of headaches, dizziness) activity [10]. It has been proven that aminophenylbutyric acid increases mental performance, improves well-being, increases interest and initiative, and motivation for mental activity without sedation or agitation [4]. Indications for the use of aminophenylbutyric acid are wide: from stuttering and enuresis in children to insomnia, night anxiety and motion sickness [4].

When describing new anxiolytics, one cannot fail to mention representatives of H1 blockers - in particular, hydroxyzine. It does not inhibit the cerebral cortex, but it suppresses the activity of certain zones of the subcortical region of the central nervous system. The drug has a sedative effect and reduces anxiety. Used to treat anxiety disorders, as well as itching associated with allergies.

Treatment with hydroxyzine, like other anxiolytics, should only be carried out under medical supervision. In addition, it is worth emphasizing several common features for representatives of the group, about which it is important to warn the visitor with a prescription for these drugs.

Use by drug addicts

People with drug addiction resort to the use of pharmaceuticals with psychotropic effects to obtain euphoria and drug intoxication. Despite the fact that benzodiazepines are used in narcology to treat addiction to ethanol, amphetamines, opiates and hallucinogens, drug addicts do not use them for therapy, but, on the contrary, to get a high. The mechanism of action of benzodiazepines on the nervous system is similar to narcotic substances and ethyl alcohol. Most often, for their purposes, they choose Phenazepam, Diazepam, Lorazepam, Nozepam, etc.

Symptoms of benzodiazepine addiction are determined by the chemical effects of the drugs. Immediately after taking them, a person looks lethargic and lethargic, he practically sleeps, since all processes in his brain slow down sharply. After the effects of the medications wear off, consciousness gradually returns, while the drug addict exhibits excessive irritability and aggression against the background of weakened reflexes, altered gait and speech.

With prolonged abuse of benzodiazepines, seizures, drug-induced parkinsonism, vomiting, weight loss and consciousness disorders are recorded as a result of destructive changes in brain tissue. At the same time, drug addicts are not limited to one type of psychotropic drugs. They choose medications from different pharmacological groups and constantly alternate them with each other. The dose of benzodiazepines required to achieve drug intoxication is much higher than the therapeutic dose.

The result of such abuse is the destruction of personality against the background of intellectual, moral and behavioral disorders. A person degrades by showing disrespect for loved ones, forgetting about basic ethics and norms of society. He loses his ability to work, unable to cope with mental and physical stress.

What should you warn the client about?

When taking axinolytics, drinking alcoholic beverages is unacceptable, since alcohol enhances the inhibitory effect of the drugs on the central nervous system. This may be accompanied by a number of side effects, including respiratory depression, loss of consciousness, as well as paradoxical reactions - agitation, aggressive behavior, and so on.

In addition, it should be borne in mind that anxiolytics can potentiate the effects of other drugs that depress the central nervous system, in particular, hypnotics, antipsychotics with sedative effects, antihistamines with sedative effects, muscle relaxants and others.

Sources

1. Polkovnikova Yu. A., Stepanova E. F. Possibilities of creating prolonged dosage forms of afobazole: review. — 2011.
2. Voronina T. A., Seredenin S. B. Prospects for the search for new anxiolytics // Experimental and clinical pharmacology, 2002. T. 65. No. 5. P. 4–17.
3. Clinical pharmacology and pharmacotherapy: textbook. — 3rd ed., add. and processed / ed. V. G. Kukesa, A. K. Starodubtseva. - M.: GEOTAR-Media, 2012. - 832 p.
4. Dyukova G. M. Grandaxin in clinical practice // Treatment of nervous diseases, 2005. No. 2. P. 25–29.
5. According to GRLS data as of 06/06/2021.
6. Avedisova A. S. Afobazole is a safe drug for the treatment of anxiety in general practice // Russian Medical Journal, 2006. T. 14. No. 22. P. 1–3.
7. Voronina T. A. Mexidol: main neuropsychotropic effects and mechanism of action // Pharmateka, 2009. T. 6. P. 28–31.
8. Levin O. S. Use of buspirone in clinical practice // Journal of Neurology and Psychiatry named after. S. S. Korsakova, 2015. T. 115. No. 4. P. 83–87.
9. Zyablitseva E. A., Pavlova I. V. Effect of the GABA receptor agonist phenibut on the impulse and interaction of neocortical and hippocampal neurons in emotionally negative situations // Russian Physiological Journal named after. IM Sechenov, 2009. T. 95. No. 9. P. 907–918.
10. Brachkova D. S., Kolesnik V. A., Mironchenko S. I. Phenibut - a new stage in the development of nootropic drugs, 2014.

Benzodiazepines

Some people, in order to cope with feelings of anxiety and panic attacks that have arisen in connection with the coronavirus (COVID-19) pandemic, begin to take benzodiazepine tranquilizers (phenazepam, diazepam, alprazolam, clonazepam, etc.). In order to understand how useful these drugs are, it is worth delving into their pharmacology. At the same time, these drugs cause respiratory depressant effects, which are especially exaggerated in patients with chronic obstructive pulmonary disease. If we consider the fact that phenazepam, like other benzodiazepines, is especially dangerous in older people, it becomes clear that it is extremely dangerous for patients with COVID-19. I hope this post on my Blog can be useful, not only for doctors, but also for patients.

Phenazepam is a benzodiazepine with a short elimination period, so it causes dependence relatively quickly. The mechanisms of action of many benzodiazepines (BZDs) are now widely studied, and BZDs of varying potency and duration of action are now developed and marketed. BZDs are used for many indications, including anxiety spectrum disorders, insomnia, muscle relaxation, relief from spasticity caused by central nervous system disorders, and epilepsy. BZDs are also used during surgery for their anxiolytic properties. Tolerance, dependence, age-related physiological changes, and drug interactions are all important factors in benzodiazepine therapy.

In any patient taking a BZD, the prescribing physician should carefully evaluate the risks and benefits of such treatment; high-risk patients, such as the elderly or those with pulmonary, hepatic, or renal impairment, require special caution and understanding of the pharmacology of benzodiazepines.

Gamma-aminobutyric acid (GABA) is the most abundant neurotransmitter in the central nervous system, found in high concentrations in the cortex and limbic system. GABA is inhibitory in nature and thus reduces neuronal excitability. GABA has a calming effect on the brain. The three GABA receptors are designated A, B, and C.

The GABA-A receptor complex consists of 5 glycoprotein subunits, each of which has several isoforms. GABA-A receptors contain 2 α-subunits, 2 β-subunits and 1 γ-subunit. Each receptor complex has 2 GABA-binding sites, but only 1 BZD-binding site. The benzodiazepine binding site is located in a specific pocket at the site of pairing (intersection) of the α and γ subunits. Within the α-subunit of isoforms 1, 2, 3 and 5 there is a histidine residue (H101, H101, H126 and H105, respectively), which has a high affinity for benzodiazepines. Isoforms 4 and 6 of the α subunit contain an arginine residue and have no affinity for BZD. BZDs bind to the pocket created by the α and γ subunits and induce conformational changes in the GABA-A receptor. This change in turn causes a conformational change in the chloride channel of the GABA-A receptor, which hyperpolarizes the cell and accounts for the inhibitory effect of GABA throughout the central nervous system.

BZDs act as positive allosteric modulators at the gamma-aminobutyric acid (GABA)-A receptor. The GABA-A receptor is a ligand-gated chloride-selective ion channel.

The BZD receptor has been classified into several types based on the α-subunit isoforms and the clinical effects associated with each type. The BZ1 receptor contains the α1 isoform. The BZ1 receptor is highly concentrated in the cortex, thalamus, and cerebellum; it is responsible for the sedative effects of benzodiazepines and anterograde amnesia, as well as some of the anticonvulsant effects of diazepam. 60% of GABA-A receptors contain the α1 subunit. Therefore, amnesia is a common side effect of BZD use since most GABA-A receptors contain the BZ1 receptor responsible for amnesia. A major factor in predicting the risk of amnesia is lipid solubility; The higher the lipid solubility, the higher the risk of developing amnesia. BZDs with high lipid solubility have higher absorption rates and faster onset of clinical effects than BZDs with low lipid solubility.

BZ2 receptors contain the α2 isoform and mediate the anxiolytic and largely muscle relaxant effects of BZD. BZ2 receptors are highly concentrated in areas such as the limbic system, motor neurons and the spinal horn. The anxiolytic effects of BZDs are thought to be mediated through BZ2 receptors located in the limbic system, and the muscle relaxant properties are mediated through α2-containing receptors in the spinal cord and motor neurons. Not all BZDs interact with the same type of BZ receptor or with the same affinity for a particular receptor. These differences in α-subunit isoforms, BZ receptor type affinity, and location in the central nervous system explain the different effects of different BZDs.

The pharmacokinetic properties of the drug determine its onset and duration of action. Specifically, pharmacokinetics describes the absorption, distribution, metabolism, and elimination of a drug (that is, what the body does with the drug). Pharmacokinetics (determining the onset of action and duration of action of a drug) depends on the route of administration, absorption and volume of distribution. BZD can be administered as intramuscular, intravenous, oral, sublingual, intranasal, or rectal gel forms. Drug characteristics, including lipid solubility, plasma protein binding, and molecular size, influence the volume of distribution.

Pharmacodynamics describes how receptors respond to a drug and the mechanism by which these effects occur (that is, what the drug does to the body). People respond differently to the same drug, and often these different responses reflect pharmacokinetics and/or pharmacodynamics in different patients. The pharmacodynamics and pharmacological effects of drugs are described in terms of dose-response curves, which depict the relationship between dose and the resulting pharmacological effect. Dose-response curves predict the effect of a drug on a patient as the dose is increased. Titration of the drug should be based on expected pharmacodynamics.

Pre-existing diseases and age-related changes affect the half-life of the drug, which is especially important when using benzodiazepines. The half-life is the time required for the plasma concentration of a drug to decrease to 50% during the elimination phase. Because the half-life is directly proportional to the volume of distribution and inversely proportional to its clearance, kidney and liver disease (altered volume of distribution and/or clearance) affects the half-life. The half-life does not reflect the time to recovery from drug effects. Half-life is an estimate of the time required for the plasma concentration of a drug to decrease by half. After approximately 5 half-lives, the drug is almost completely eliminated from the body. Therefore, drug accumulation is likely if dosing intervals are shorter than this time period.

From a pharmacological point of view, benzodiazepines are usually well absorbed from the gastrointestinal tract after oral administration. After intravenous administration, benzodiazepines rapidly distribute to the brain and central nervous system.

Some BZDs exert additional effects through the production of active metabolites, which is an important consideration when prescribing these agents. Midazolam, one of the short-acting BZDs, does not produce active metabolites. However, diazepam, a long-acting BZD, produces active metabolites oxazepam, desmethyldiazepam, and temazepam. These metabolites further increase the duration of action of the drug and should be an important consideration in the treatment of certain patient groups, especially the elderly and patients with extensive liver disease.

Benzodiazepines are classified in terms of their half-life. Short-acting BZDs have a mean half-life of 1-12 hours, intermediate-acting BZDs have a mean half-life of 12-40 hours, and long-acting BZDs have a mean half-life of 40-250 hours. As noted previously, 5 half-lives are generally required for removing the agent from the body, which significantly increases the number of hours during which the drug remains in the body.

Another way to characterize benzodiazepines is by relative strength of effect. The first BZDs had low to moderate activity. These include the long-acting chlordiazepoxide, the first benzodiazepide discovered, as well as oxazepam and temazepam. Because of their effectiveness and relatively low toxicity, they have become first-line drugs for conditions such as insomnia and anxiety. Later, highly effective benzodiazepines (alprazolam, lorazepam and clonazepam) were discovered. These new drugs have led to new indications for use: as a treatment for panic disorder, as an adjunct to selective serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder, and as an adjunct to antipsychotics for the treatment of acute mania or agitation. The new high-potency BZDs have shown improved therapeutic effects as well as faster onset of action, making them the preferred BZDs for most indications. However, as potency increases, the risk of unwanted effects increases. Therefore, when prescribing drugs in this group of BZDs, clinicians must consider individual properties such as absorption, distribution, half-life, and lipid solubility.

Alprazolam

Alprazolam is a highly effective, short-acting BZD with a half-life of 6–27 hours. Alprazolam was first studied for use in panic disorders and was found to be well tolerated and effective. Alprazolam is commonly prescribed for panic disorders and anxiety. The recommended dose for anxiety starts with 0.25-0.5 mg tablets administered orally 3 times a day. The maximum recommended daily dose of alprazolam for anxiolysis should not exceed 4 mg. For panic disorders, it is recommended to use the same tablet form and route of administration to the maximum recommended. A common problem with alprazolam is restlessness and anxiety that occurs during drug withdrawal, which occurs when the drug is abruptly stopped due to the drug's short half-life.

Clonazepam

Clonazepam was the second highly effective BZD. Clonazepam behaves as a GABA-A receptor agonist, as a highly effective long-acting drug, and as a serotonin agonist. Clonazepam has anticonvulsant and anxiolytic effects. One study found that clonazepam was at least as effective as lithium for treating acute mania. When combined with serotonin reuptake blockers, clonazepam appears to speed up the treatment response to panic disorder. In another study, clonazepam was found to be as effective for treating panic disorders as alprazoles, but discontinuation did not produce withdrawal symptoms due to the long half-life of clonazepam. Because clonazepam exhibits low lipid solubility, it is less likely to cause anterograde amnesia compared to other highly effective BZDs. For example, clonazepam is half as lipid soluble as alprazolam, so side effects are reduced in amnesic patients. Clonazepam also has a relatively lower binding affinity for GABA-A receptors than other high-potency BZDs.

Clonazepam used to treat panic disorder should be started with a dose of 0.25 mg tablets taken orally twice daily for 3 days, after which the dose should be increased to 0.5 mg tablets twice daily. The maximum daily dose should not exceed 1-4 mg. For the treatment of seizure disorders in adults, start with 0.5 mg tablets taken orally 3 times daily. In the pediatric population, starting at a dose of 0.01-0.03 mg/kg, it is recommended that oral administration be divided into 2 or 3 doses. The maximum dose in this population should not exceed 0.1-0.2 mg/kg in 3 divided doses.

Diazepam

Diazepam is a long-acting, intermediate-potency BZD that is used as an anticonvulsant and for anxiolysis, sedation, and muscle relaxation. Diazepam, one of the most common benzodiazepines used for anxiety, is available in intramuscular, intravenous, oral, and rectal gel forms. Diazepam interacts with all BZD-sensitive receptors in the central nervous system with equal affinity. Anxiolytic effects are observed at low doses due to the interaction of diazepam with α2-containing receptors in the limbic system. At higher doses, diazepam may provide muscle relaxation in addition to anxiolysis; The muscle relaxant effect is primarily mediated through α2-containing receptors in the spinal cord and motor neurons and, to a lesser extent, through interaction with α3-containing receptors. Of course, at higher doses, sedation and anterograde amnesia are also observed, but these effects are α1-mediated. Diazepam is unique in that its metabolism in the liver produces the active metabolites oxazepam, temazepam and desmethyldiazepam, each of which has its own effect. These metabolites and their actions explain the long half-life of diazepam, which increases by approximately 1 hour for each year of age over 40 years (for example, the half-life of diazepam in a 75-year-old child is approximately 75 hours).

Thus, when prescribing this drug, clinicians should consider potential side effects associated with accumulation of the active metabolite, such as overdose and anterograde amnesia. These side effects can be serious and long-lasting, especially in older adults and those with impaired liver or kidney function. For intravenous administration, diazepam must be prepared in a solution with propylene glycol to be water soluble. Diazepam, used for anxiety, can be prescribed as 2-10 mg orally 2-4 times daily depending on the severity of symptoms and the age of the patient. Both intramuscular and intravenous forms are also available for anxiolysis and should be administered in doses of 2-10 mg every 3-4 hours, depending on the severity of symptoms and age factors. As an adjunct to antiseize therapy or for muscle relaxation, it is recommended to take 2-10 mg orally up to 4 times daily. For status epilepticus, doctors initially give 5 to 10 mg IV every 15 minutes to a maximum dose of 30 mg. If necessary, this dose can be repeated after 2-4 hours.

Side effects of benzodiazepines

Common side effects among all BZDs include drowsiness, lethargy, and fatigue. At higher dosages, loss of motor coordination, dizziness, slurred speech, blurred vision, mood swings and euphoria, aggression and agitation in some cases may occur. BZDs are slowly eliminated from the body, so repeated doses over a long period can lead to significant accumulation in fatty tissues. Thus, some symptoms of long-term benzodiazepine treatment (impaired thinking, disorientation, confusion, slurred speech) may appear over time. Tolerance, dependence, and withdrawal symptoms are the adverse effects associated with long-term use of these drugs.

Interaction with other drugs, especially psychotropic drugs, is another problem with benzodiazepines. They are metabolized in the liver via the cytochrome p450 system and then glucuronidated and excreted by the kidneys. Drugs that weaken (oral contraceptive pills, antifungals, and some antibiotics) or potentiate (carbamazepine, phenytoin, rifampin, St. John's wort) cytochrome p450 enzymes either increase or decrease the half-life of BZD, respectively.

Serious side effects can occur when BZD is administered with other drugs such as opioids. When combined with opioids, cardiovascular and hemodynamic compromise becomes more significant. The effects of respiratory depression on spontaneous ventilation are dramatically increased when opioids are used in combination with BZDs, and these effects are dose dependent. Respiratory depressant effects are also exaggerated in patients with chronic obstructive pulmonary disease. Vein irritation can occur with diazepam and lorazepam; both drugs are usually administered in hospital or palliative care settings as intravenous drugs.

Use of benzodiazepines in the elderly

As people age, there is a continuous decline in the function of the homeostatic mechanisms in the body, especially the central nervous system, liver and kidneys. Research has shown that numerous changes occur in the central nervous system as a function of aging, including the death of neurons and their replacement by proliferating glial cells, reduction of intracellular enzymes, and reduction of dendritic synapses.

Physiological changes of aging in the liver lead to prolonged drug clearance. Decline in renal function begins after age 40 at a rate of approximately 1% per year or a decrease in creatinine clearance of 1 ml/min/year. Taken together, these aging-related physiological changes are particularly important in terms of BZD accumulation. In general, hypersensitivity to benzodiazepines includes mental disorganization and disorientation, leading to more hazardous effects of BZDs in older adults compared to younger adults. This increased sensitivity is directly related to the accumulation of BZDs and their associated active metabolites. In older adults, the intensity of BZD-mediated responses and the duration of BZD-mediated effects subsequently increase.

Benzodiazepine toxicity

Cognitive impairment is a broad term that covers several symptoms of BZD-induced central nervous system toxicity, such as anterograde amnesia, sedation, somnolence, motor disturbances, inattention, and ataxia. These symptoms are usually more severe in older adults due to metabolic changes, associated with normal aging. The consequences of cognitive impairment can lead to serious consequences, including an increased risk of falls, as well as higher rates of motor vehicle accidents. Injury is a leading cause of death among older adults, with the majority of fatal injuries resulting from falls. In addition to cognitive impairment, BZD has a risk of addiction. Withdrawal symptoms usually occur after sudden cessation of use, especially at higher doses.

Amnesia

Sensory and short-term memory do not seem to be affected by BZD use. Long-term memory, on the other hand, is affected by BZD. The subcategories of long-term memory are explicit (intentional, conscious memories) and implicit (unconscious, unintentional memories). Within explicit memory is a subcategory called episodic memory; these are memories of personally experienced events, including recall and recognition of information such as words, stories, pictures, etc. Benzodiazepines impair episodic memory. Another type of explicit memory is semantic memory; it includes stored knowledge of information such as speech and rules that does not need to be remembered in any specific context. Semantic memory is not impaired by benzodiazepines. Implicit memory is also impaired by BZD, but not as much as explicit memory. Numerous studies evaluating BZD-induced memory impairment have demonstrated a “differential time course” of BZD-induced impairment in implicit and explicit memory. This means that impairments in implicit memory tend to coincide with peak plasma BZD levels and do not last as long as impairments in explicit memory. Impairments in explicit memory occur earlier (due to medication) and last longer than implicit memory impairments.

Two hypotheses have been proposed to explain this observation: (1) impairments in implicit memory require relatively higher serum drug levels than explicit memory impairments, and (2) a specific type of BZD receptor is activated only at higher drug levels, making this receptor partially responsible for implicit memory impairment. Thus, BZDs impair long-term memory, more specifically anterograde memory (amnesia for events occurring after the inciting event of drug absorption). Currently, no literature supports any significant evidence that benzodiazepines cause retrograde amnesia (amnesia for events that occurred before taking benzodiazepines). In the perioperative period, BZDs are used specifically for their amnesic properties, but in almost all other cases, amnesia is an undesirable side effect. Although amnesia can occur in any patient, it is of particular concern in the aging population. This problem can lead to the accumulation of toxic BZDs and their breakdown products, resulting in morbidity and even mortality. In many cases, a patient prescribed a BZD for an indication (eg, anxiety, muscle spasms, or sleep disturbances) at a dose that appears to be safe experiences severe memory impairment or confusion after just a few doses. This effect occurs because many BZDs are eliminated relatively slowly from the body due to their lipophilic properties, and they accumulate in fatty tissues. Therefore, taking even a small, standard dose, a patient may have significant memory loss. The patient may be unable to recognize loved ones and/or friends and may have difficulty remembering significant portions of life, sometimes even up to several years. Cognitive impairment may also limit a patient's ability to work effectively.

Another unwanted potential consequence that may result from benzodiazepine-induced amnesia is sexual assault. Typically, sexual violence occurs in 64/100,000 women per year. Many of these cases occur when a pharmacological drug (such as a date rape drug) is administered, some of which are BZDs. This scenario most often occurs in combination with alcohol use, when the victim knowingly ingested a BZD, or when the assailant secretly placed the drug in the victim's drink . The latter is commonly referred to as drug-assisted sexual assault (DFSA). In one case, a woman took an alcoholic drink that, unknown to her, contained 1 mg of flunitrazepam. She was subsequently sexually assaulted and, due to the anterograde amnesia effect of flunitrazepam, had no memory of the event.

Disinhibition

Another related effect of the accumulation of toxic BZDs and their metabolic by-products is loss of inhibition or disinhibition, which can cause a person to behave in an unnatural manner, putting them in dangerous situations due to impaired understanding of risk. Common scenarios include high-risk sexual behavior and reckless driving. One study found that BZD use approximately doubles the risk of traffic accidents. Additionally, automotive studies have shown that the attenuating effects of BZD and related compounds may still be present after 1 week of daily treatment (demonstrated for diazepam, lorazepam, alpidem, and suriclone), although tolerance may develop.

Delirium

Another adverse effect of BZDs commonly observed in intensive care settings is delirium, an acute confusion of consciousness characterized by impaired attention and cognition, hallucinations, etc. Benzodiazepines increase the risk of delirium, especially in elderly patients in the intensive care unit. Studies have demonstrated a surprising 78-87% incidence of delirium in elderly patients in the intensive care unit. Delirium is a serious problem that can lead to increased mortality and prolonged hospital stays. Morbidity and mortality increase because the risk of hospital-acquired infections increases the longer a patient is in the hospital. One study found that BZDs prescribed before admission to the intensive care unit were associated with delirium in the first 48 hours after admission.

Other drugs, including opioids, alcohol, and over-the-counter sleep aids, may have additive or synergistic effects on the central nervous system and respiratory function.

Features of the treatment of neuroses

When selecting a dose of tranquilizers, they are guided by the rule of the minimum sufficient dose. When choosing an initial dose, it must be remembered that patients suffering from any type of anxiety disorder have a significantly lower sensitivity to tranquilizers than healthy people experiencing a severe stressful situation. If effectiveness is insufficient, the dose should be gradually increased, adding a dose equal to the minimum every 3 days. Typically, panic attacks require higher doses than anxiety disorders. Throughout the entire period of treatment, attempts are constantly made to reduce the dose if the patient's condition allows it.

Due to rapid and complete absorption in the gastrointestinal tract, tranquilizers are convenient to use orally. However, if it is necessary to achieve a particularly rapid tranquilizing effect, the medicine can be administered intramuscularly, intravenously, intravenously by drip or rectally. The duration of treatment with this administration should not exceed 3–5 days, after which, if necessary, they switch to taking the drug orally (orally).

Due to the risk of withdrawal syndrome (return of anxiety after abruptly stopping the drug), tranquilizers are discontinued gradually, in the same mode in which the dose was increased.

Tranquilizers can cause mental, physical dependence and addiction (reduced effect of the drug in the initial dose). In this case, it will be necessary to constantly increase the dose, which increases the risk of side effects.