Tranquilizers

Tranquilizers are a class of drugs that initially united agents intended primarily for the treatment of anxiety symptoms and sleep disorders. The absence of both an antipsychotic effect and the ability to cause extrapyramidal disorders in the range of psychopharmacological activity served as the basis for their isolation from other psychotropic drugs. In terms of chemical structure, tranquilizers are mainly represented by derivatives of benzodiazepine, glycerol, trioxybenzoic acid; derivatives of azapiron and a number of other chemical compounds.

Mechanism of action of benzodiazepine derivatives

The mechanism of action of benzodiazepine derivatives became known in 1977, when benzodiazepine receptors were discovered and localized in the central nervous system, which are directly linked to GABA, one of the main inhibitors of neurotransmitter systems. When GABA binds to its receptors, chloride ion channels open and they enter the neuron, which forms its resistance to excitation. GABA is active mainly in the following parts of the brain: stellate interneurons in the cortex of the hemispheres, striatal afferent pathways of the globus pallidus and substantia nigra, and Purkinje cells of the cerebellum. Benzodiazepine tranquilizers have a GABAergic effect, i.e. they stimulate the production of this neurotransmitter and facilitate GABAergic transmission at the pre- and postsynaptic levels.

Clinical effects of benzodiazepine derivatives

The clinical effects of benzodiazepine derivatives include 6 main ones: tranquilizing or anxiolytic, sedative, central muscle relaxant, anticonvulsant or anticonvulsant, hypnotic or hypnotic, vegetative stabilizing and 2 optional: thymoanaleptic, antiphobic. The degree of expression of various effects in the spectrum of psychotropic activity of various benzodiazepine derivatives is not the same, which forms the individual profile of a particular drug.

The use of benzodiazepine derivatives is advisable for maladaptation phenomena caused by anxiety. The use of these drugs is not recommended in cases where the severity of anxiety is low and does not go beyond the normal response to a stressful situation. In the therapy of situational, acutely developed anxiety, preference is given to low-potency drugs with a long half-life, which reduces the risk of drug dependence and withdrawal symptoms, in particular diazepam (no more than 30 mg / day). The duration of the course is determined by the time of exposure to the stress factor that contributed to the development of anxiety. In the treatment of anxiety in the context of somatic diseases, the same drugs are used.

The most pronounced effect of benzodiazepine derivatives in the treatment of panic attacks is observed provided that they are not accompanied by persistent reactions of avoidance of the situation on the part of patients. The rapid onset of the anxiolytic effect allows for a complete relief of a panic attack or its prevention if the drug is taken immediately before a situationally significant event. Given the high frequency of relapses, most patients are prescribed combination therapy or the use of several drugs with a sequential change during the course. Despite the relatively greater safety of long-acting drugs, their therapeutic dose can be so high that it will cause an excessive sedative effect. In the presence of symptoms of depression in the structure of panic disorder, antidepressants are used in combination therapy, giving preference to selective serotonin and norepinephrine reuptake inhibitors.

In the treatment of generalized anxiety disorder, which according to various data has a higher degree of comorbidity with major depressive disorder than with other anxiety disorders, the target symptoms are such clinical phenomena of anxiety specific to this nosology as muscle tension, hyperactivity of the autonomic nervous system and increased level of wakefulness. In most cases of this pathology, benzodiazepine derivatives are used together with SSRIs and dual-action antidepressants (selective serotonin and norepinephrine reuptake inhibitors). Moreover, both in monotherapy with benzodiazepine derivatives and in combined use, the efficacy and safety are higher for prolonged drugs with a long half-life. On the contrary, when using potent drugs with a short T1/2 (for example, alprazolam), the risk of drug dependence and relapses of anxiety in the intervals between doses is increased. It is advisable to use 15-30 mg/day of diazepam or another drug in an equivalent dose. As a rule, long-term therapy (6 months or more) is effective and safe in most patients, although the dose of the drug should be reduced, monitoring the possible emergence of anxiety symptoms.

Benzodiazepine derivatives are not considered drugs of choice in the treatment of simple phobias in all cases except for anticipatory anxiety, when diazepam (10-30 mg/day) can be used to counteract phobic stimuli. Behaviourally oriented psychotherapy should probably be the basis of treatment for this pathology.

In the treatment of obsessive-compulsive disorders, benzodiazepine derivatives are less effective than SSRIs and selective serotonin and norepinephrine reuptake inhibitors in combination with psychotherapy.

Somatoform disorders occurring as isolated dysfunction of certain organs are subject to therapy with benzodiazepine derivatives only if the direct influence of these agents on various vegetative and algic components of the pathological condition is taken into account. Moreover, the effectiveness of benzodiazepine derivatives is significantly higher with leading vegetative symptoms than with isolated algic symptoms.

Despite the widespread clinical use of benzodiazepine derivatives in depressive states, their own antidepressant activity is low even in cases where anxiety is clearly present in the clinical picture (anxiety-depressive disorders). In such patients, benzodiazepine derivatives should be used only as concomitant therapy to enhance the activity of antidepressants. In other words, therapy for anxious depression begins with the use of antidepressants and, for the period necessary for the development of their therapeutic effect, a course of tranquilizers lasting 1-4 weeks is additionally prescribed. A special place in the therapy of depressive disorders is occupied by insomnias resistant to antidepressant therapy. In such cases, a longer administration of benzodiazepine derivatives (diazepam, phenazepam in average therapeutic doses) is indicated.

In cases of hyperthymia and shallow mania, the administration of benzodiazepine derivatives helps to reduce insomnia disorders, irritability, anger, and sensations of physical discomfort associated with manic affect.

In the treatment of schizophrenia, tranquilizers are used in complex psychotropic effects as adjuvant agents intended to relieve psychotic anxiety and to reduce the manifestations of neuroleptic akathisia.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ]

Pharmacokinetics of benzodiazepine derivatives

Most benzodiazepines are completely absorbed when taken orally, with peak plasma concentrations of these compounds occurring within a few hours. Metabolic conversion of benzodiazepine derivatives occurs in the liver under the action of cytochromes P450 (CYP) 3A4, 3A7 and CYP 2C19. Most drugs in this group (alprazolam, diazepam, medazepam, chlordiazepoxide) form active metabolites, which significantly increases their half-life. Compounds that do not form active metabolites (oxazepam, lorazepam) immediately bind to glucuronic acid and are quickly eliminated from the body, which explains their significantly better tolerability and lower risk of drug interactions. Based on the duration of the half-life, benzodiazepine derivatives are divided into long-acting drugs (T1/2 more than 20 hours): chlordiazepoxide, diazepam and medazepam; fast-acting (T1/2 less than 5 hours); medium-acting (T1/2 from 5 to 20 hours); lorazepam, bromazepam, oxazepam, etc.

Characteristics of benzodiazepine derivative tranquilizers

Sign	Short-acting benzodiazepine derivatives	Long-acting benzodiazepine derivatives
Potency	Tall	Low
Frequency of administration during the day	4 times a day (every 4-6 hours)	2 or 1 time per day
The appearance of anxiety in the intervals between doses	Frequent	Rare
Cumulation	Minimal or none	Typical for most drugs
Sedation	Absent or slightly expressed	Mild to moderate severity
Renewal of the state of anxiety	Often	Rarely
Risk of developing addiction	High	Minor
Timing of withdrawal symptoms	1-3 days	4-7 days
Duration of withdrawal syndrome	2-5 days	8-15 days
Severity of withdrawal syndrome	Expressed	Mild to moderate severity
The emergence of paradoxical action	Frequent	Rare
Formation of anterograde amnesia	Often	Rarely
Intramuscular injection	Fast absorption	Slow absorption
Risk of complications with intravenous administration	Minor	High with jet injection
Presence of active metabolites	None or minimally	A large number

Classification of tranquilizers

The main groups of tranquilizers, divided according to their mechanism of action, are shown in the table.

Classification of tranquilizers by mechanism of action (Voronina Seredenin S.V., 2002)

Mechanism of action	Representatives
Traditional anxiolytics
Direct agonists of the GABAA-benzodiazepine receptor complex	Benzodiazepine derivatives: with a predominance of the actual anxiolytic effect (chlordiazepoxide, diazepam, phenazepam, oxazepam, lorazepam, etc.); with predominantly hypnotic effect (nitrazepam, flunitrazepam); with predominantly anticonvulsant action (clonazepam)
Drugs with different mechanisms of action	Preparations of different structures: mebicar, meprobamate, benactizine, benzoclidine, etc.
New anxiolytics
Partial agonists of the GABA-benzidiazepine receptor, substances with different affinities for the subunits of the benzodiazepine receptor and the GABA receptor	Abecarnil, imidazoliridines (allidem, zollidem), imidazobenzodiazepines (imidazenil, bretazenil, flumazenil), divalon, gidazepam
Endogenous regulators (modulators) of the GABA-benzodiazepine receptor complex	Fragments of endosepines (in particular, DBI - Diazepam binding inhibitor), beta-carbol derivatives (ambocarb, carbacetam), nicotinamide and its analogues

[ 10 ], [ 11 ]

Non-benzodiazepine anxiolytics

Despite the fact that benzodiazepine derivatives occupy a leading position in terms of the degree of study and breadth of application, other anxiolytics are also used in medical practice.

Afobazole (INN: morphoinoethylthioethoxybenzimidazole) is a domestic pharmacological drug from the group of anxiolytics, the world's first selective anti-anxiety drug of the nebendiazepine series. Afobazole is devoid of the side effects of benzodiazepine derivatives: hypnosedative action, muscle relaxant effect, memory disorders, etc.

Afobazole has an anxiolytic effect with an activating component, not accompanied by hypnosedative effects (the sedative effect of afobazole is detected in doses 40-50 times exceeding ED50 for anxiolytic effect). The drug has no muscle relaxant properties, negative impact on memory and attention; drug dependence is not formed and withdrawal syndrome does not develop. Reduction or elimination of anxiety (concern, bad feelings, fears, irritability), tension (timidity, tearfulness, feeling of restlessness, inability to relax, insomnia, fear), and therefore somatic (muscular, sensory, cardiovascular, respiratory, gastrointestinal symptoms), vegetative (dry mouth, sweating, dizziness) and cognitive (difficulty concentrating, weakened memory) disorders are observed after 5-7 days of treatment with afobazole. The maximum effect occurs by the end of 4 weeks of treatment and persists in the post-therapeutic period for an average of 1-2 weeks.

The drug is indicated for use in the treatment of neurotic disorders. It is especially advisable to prescribe Afobazole to people with predominantly asthenic personality traits in the form of anxious suspiciousness, insecurity, increased vulnerability and emotional lability, a tendency to emotional-stress reactions.

Afobazole is non-toxic (LD50 in rats is 1.1 g with ED50 being 0.001 g). The half-life of afobazole when taken orally is 0.82 h, the average maximum concentration (Cmax) is 0.130±0.073 μg/ml, and the average drug retention time (MRT) is 1.60±0.86 h. Afobazole is intensively distributed throughout well-vascularized organs. It is taken orally after meals. The optimal single dose of the drug is 10 mg, the daily dose is 30 mg, divided into 3 doses during the day. The duration of a course of treatment with the drug is 2-4 weeks. If necessary, the dose can be increased to 60 mg/day.

Benzoclidine inhibits the activity of cortical neurons and the reticular formation of the brainstem, reduces the excitability of the vasomotor center, and improves cerebral circulation. This drug is used to treat anxiety disorders, including anxiety-depressive states (especially mild ones and those associated with cerebral circulatory insufficiency). In addition, benzoclidine is prescribed to elderly patients with atherosclerosis with cerebral disorders, arterial hypertension, and paroxysmal tachycardia.

Hydroxyzine is a blocker of central M-cholinergic receptors and H1 receptors. The pronounced sedative and moderate anxiolytic effect is associated with the suppression of the activity of some subcortical structures of the central nervous system. Hydroxyzine is characterized by a fairly rapid development of anxiolytic action (during the first week of treatment), the absence of an amnestic effect. Unlike benzodiazepines, with prolonged use, hydroxyzine does not cause addiction and dependence, and no withdrawal or rebound syndromes have been noted.

Benactyzine is a diphenylmethane derivative, the anxiolytic effect of the drug is due to the reversible blockade of central M-cholinergic receptors. Due to the pronounced effect on central cholinergic structures, benactyzine is classified as a central anticholinergic. The effect on the central nervous system is clinically manifested by a calming effect, suppression of the convulsive and toxic effect of anticholinesterase and cholinomimetic substances, increased action of barbiturates and other hypnotics, analgesics, etc. Currently, due to the availability of effective tranquilizers, as well as because of undesirable side effects associated with atropine-like action (dry mouth, tachycardia, mydriasis, etc.), benactyzine is practically not used as an anxiolytic.

Representatives of the third generation of anxiolytics are buspirone, oxymethylethylpyridine succinate (mexidol), etc. The anxiolytic effect of mexidol is associated with its modulating effect on membranes, including the GABA receptor complex, and is manifested by an improvement in synaptic transmission.

Buspirone is a partial agonist of serotonin receptors, has a high affinity for serotonin 5-HT1a receptors. The mechanism of action is not fully understood. It is known that buspirone reduces the synthesis and release of serotonin, the activity of serotonergic neurons, including in the dorsal raphe nucleus. In addition, it selectively blocks (antagonist) pre- and postsynaptic D2-dopamine receptors (moderate affinity) and increases the rate of excitation of dopamine neurons of the midbrain. Some data indicate that buspirone has an effect on other neurotransmitter systems. It is effective in the treatment of mixed anxiety-depressive states, panic disorders, etc. The anxiolytic effect develops gradually, appears after 7-14 days and reaches a maximum after 4 weeks. Unlike benzodiazepines, buspirone does not have a sedative effect, does not negatively affect psychomotor functions, does not cause tolerance, drug dependence and withdrawal symptoms, and does not potentiate the effects of alcohol.

In addition to drugs belonging to the anxiolytic group, drugs of other pharmacological groups have an anti-anxiety effect to varying degrees: some TNF-adrenoblockers (propranolol, oxprenolol, acebutolol, timolol, etc.), alpha-adrenomimetics (clonidine). Thus, propranolol is effective in the treatment of anxiety states associated with hyperreactivity of the sympathetic nervous system and accompanied by pronounced somatic and vegetative symptoms, clonidine has the ability to reduce somatovegetative manifestations in the withdrawal syndrome of opiate addiction.

Currently, an intensive search for new drugs with anxiolytic action and at the same time safer and more effective than existing drugs continues. Screening of benzodiazepine derivatives is aimed at identifying the most selectively acting drugs with the most pronounced anxiolytic action with a minimum of side effects. The search is also conducted among substances that affect serotonergic transmission, antagonists of excitatory amino acids (glutamate, aspartate), etc.

[ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ]

Side effects of tranquilizers

At the early stage of therapy, the most significant effect is considered to be the sedative effect, which disappears on its own within a few weeks as the anxiolytic effect develops. Also, when using standard doses of drugs, due to individual sensitivity, confusion, ataxia, agitation, exaltation, transient hypotension, dizziness and gastrointestinal disorders may occur.

Mental disinhibition is the most serious side effect of benzodiazepine derivatives, characterized by hostility, dysphoria, and loss of control over one's own actions. The leading role of alcohol in their development has been proven when used together with benzodiazepine derivatives. The incidence of these disorders is less than 1%.

Cognitive impairment is observed in patients who have been taking minimal therapeutic doses of benzodiazepine derivatives for a long time. The quality of visual-spatial activities decreases and attention deteriorates. As a rule, the patients themselves do not notice this.

Tranquilizer overdose

There are no reported cases of fatal overdose. Even with injection of large doses, convalescence occurs fairly quickly and without severe consequences. When combined with large doses of CNS depressants of other groups, the severity of intoxication depends to a greater extent on the type and amount of the accompanying substance than on the concentration of benzodiazepine derivatives in the blood.

When prescribing benzodiazepine derivatives, special attention is paid to the personality traits and behavioral profile of the patient, which helps to avoid cases of abuse of these drugs.

Characteristics of individuals taking benzodiazepine tranquilizers for treatment and using these drugs for non-medical purposes

Persons taking benzodiazepine derivatives for therapeutic purposes	Persons taking benzodiazepine derivatives for toxicomanic purposes
More often women aged 50 years and older	Most often men aged 20-35 years
Benzodiazepine derivatives are taken as prescribed and under the supervision of a physician for a specific disease.	They take benzodiazepine derivatives as prescribed by a doctor or without a prescription, but not for a specific disease, but independently prescribe drugs for themselves for the purpose of artificial stimulation
Usually taken only in prescribed dosages. Only benzodiazepine derivatives are taken.	Exceeding the recommended doses Usually, several drugs are abused, with benzodiazepine derivatives taken in combination with alcohol, narcotic drugs, etc.
Tolerance is usually not developed	Tolerance usually develops quickly, and patients tend to increase the dose to achieve the desired effect.
They are burdened by the sedative effect of benzodiazepine derivatives They rarely take diazepam in doses exceeding 40 mg/day (or other equivalent drugs and doses) The risk of developing a pronounced withdrawal syndrome is insignificant Taking the drugs does not cause significant somatic or social problems They do not seek to obtain prescriptions illegally	They seek to potentiate the sedative effect of benzodiazepine derivatives. They often take diazepam at a dose of 80-120 mg/day or more. They often have a severe withdrawal syndrome. The use of drugs leads to health and social problems. They often obtain drugs and prescriptions for them illegally.

Withdrawal syndrome

All benzodiazepine derivatives can cause withdrawal syndrome to varying degrees. This pathological condition usually manifests itself in the form of various gastrointestinal disorders, hyperhidrosis, tremors, convulsions, tachycardia, drowsiness, dizziness, cephalgia, hyperacusis, irritability.

In some cases, with abrupt discontinuation of therapy, severe symptoms such as severe and prolonged depression, acutely developing psychotic states, hallucinations, opisthotonus, choreoathetosis, myoclonus, delirious states with catatonic episodes, etc. are noted.

Withdrawal syndrome is rare if the course of therapy with benzodiazepine derivatives does not exceed 3-4 weeks. Withdrawal phenomena also include so-called interdose symptoms, or breakthrough symptoms - resumption of symptoms between doses of benzodiazepine derivatives (adapted from data from the American Psychiatric Association, 1990). When discontinuing treatment with benzodiazepine derivatives, it is important to follow the following basic recommendations.

• Develop a clear scheme for the therapeutic use of the drug in order to avoid its abuse.
• It is important to correctly consider the balance between the benefits and possible negative aspects of treatment.
• Gradually reduce the dose, carefully monitoring for possible withdrawal symptoms.
• Resolve the issue of alternative treatment (psychotherapy, behavioral therapy or medication).
• It is necessary to maintain a spirit of cooperation in the relationship with the patient to strengthen compliance.

The general recommendation for reducing the daily dose of benzodiazepine derivatives to avoid the occurrence of withdrawal syndrome is the possibility of a fairly rapid reduction by 50% of the dose taken by the patient; however, subsequent reduction should be carried out more slowly (by 10-20% of the new dosage every 4-5 days).