Tranquilizers

Tranquilizers are a class of drugs that initially combined drugs designed primarily to treat anxiety and sleep disorders. The absence of an antipsychotic effect in the range of psychopharmacological activity, as well as the ability to cause extrapyramidal disorders, served as the basis for their isolation from other psychotropic drugs. According to the chemical structure, tranquilizers are mainly represented by benzodiazepine derivatives, glycerol, trihydroxybenzoic acid; derivatives of azapiron and a number of other chemical compounds.

The 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 CNS, which are directly related to GABA, one of the main inhibitors of neurotransmitter systems. When GABA is combined with its receptors, the tubules of chlorine ions are opened and they enter the neuron, which forms its resistance to excitation. GABA is active mainly in the following parts of the brain: stellar intercalary neurons in the cerebral cortex, striary afferent pathways of globus pallidus and substantia nigra, Purkinje cells of the cerebellum. Benzodiazepine tranquilizers possess GABAergic action, i.e. Stimulate the production of this neurotransmitter and facilitate GABA-ergic transmission at the pre- and postsynaptic levels.

Clinical effects of benzodiazepine derivatives

Clinical effects of benzodiazepine derivatives include 6 major: tranquilizing or anxiolytic, sedative, central miorelaxing, anticonvulsant or anticonvulsant, hypnotic or hypnotic, vegetative stabilizing and 2 facultative: timoanaleptic, 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 given drug.

The use of benzodiazepine derivatives is advisable in cases of disadaptation caused by anxiety. The purpose 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 therapy, situational and acute anxiety, low-potency drugs with a long half-life are preferred, which reduces the risk of drug dependence and withdrawal symptoms, in particular, diazepam (not 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 somatic diseases, these drugs are used.

The most pronounced effect of benzodiazepine derivatives in the therapy of panic attacks is observed provided that they are not accompanied by persistent reactions of avoiding the situation on the part of patients. The rapid onset of anxiolytic effect allows to completely stop the panic attack or prevent it in the case of taking the drug immediately before a situationally significant event. Given the high incidence of relapse, most patients are prescribed combined therapy or the use of several drugs with a sequential shift during the course. Despite the relatively high safety of long-acting drugs, their therapeutic dose may be so high that it will cause excessive sedation. In the presence of symptoms of depression in the structure of panic disorder in combination therapy, antidepressants are used, preferring selective inhibitors of the reuptake of serotonin and norepinephrine.

In the treatment of generalized anxiety disorder, which according to various data has a higher degree of comorbidity with a greater depressive disorder than with other anxiety disorders, such symptom-specific clinical symptoms of anxiety as muscular tension, autonomic nervous system hyperactivity and increased level of wakefulness. In most cases, in this pathology, benzodiazepine derivatives are used in conjunction with SSRIs and dual-acting antidepressants (selective serotonin and noradrenaline reuptake inhibitors). And both with monotherapy with benzodiazepine derivatives, and with combined use, efficacy and safety are higher in prolonged drugs with a long half-life. On the contrary, when using powerful drugs with short T1 / 2 (eg, alprazolam), the risk of drug dependence and relapse of anxiety in the intervals between receptions is increased. It is advisable to use 15-30 mg / day of diazepam or another drug in an equivalent dose. Typically, long-term therapy (6 months or more) is effective and safe in most patients, although the dose of the drug must be reduced, controlling the possible appearance of symptoms of anxiety.

Benzodiazepine derivatives in the therapy of simple phobias are not considered drugs of choice in all cases, except anxiety expectations, when it is possible to use diazepam (10-30 mg / day) as a counter to phobic stimuli. The basis of treatment for this pathology, probably should be a behavior-oriented psychotherapy.

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, proceeding with the form of isolated dysfunction of certain organs, are subject to therapy with benzodiazepine derivatives only when taking into account the direct influence of these drugs on a variety of vegetative and algic components of the pathological condition. And the effectiveness of benzodiazepine derivatives is significantly higher with leading vegetative symptoms than with isolated algic symptoms.

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

At the phenomena of hypertension and shallow mania, the appointment of benzodiazepine derivatives promotes reduction of insomnic disorders accompanying manic affect, irritability, anger and sensations of bodily discomfort.

In the treatment of schizophrenia, tranquilizers are used in complex psychotropic effects as adjuvant drugs designed 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, and the peak concentration in the blood plasma of these compounds occurs within a few hours. Metabolic conversion of benzodiazepine derivatives occurs in the liver under the action of cytochromes P450 (CUR) ZA4, ZA7 and CYP 2S19. Most of the 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 removed from the body, which explains their significantly better tolerability and less risk of drug interactions. For the duration of the half-life, benzodiazepine derivatives are divided into long-acting drugs (T1 / 2 more than 20 hours): chlordiazepoxide, diazepam and medazepam; quick action (T1 / 2 less than 5 hours); average duration of action (T1 / 2 from 5 to 20 hours); lorazepam, bromazepam, oxazepam, and others.

Characterization of tranquilizers of benzodiazepine derivatives

Symptom	Benzodiazepine derivatives of short duration	Benzodiazepine derivatives of long duration
Potency	High	Low
Frequency of reception during the day	4 times a day (every 4-6 hours)	2 or 1 times a day
The appearance of anxiety in the intervals of the burden between receptions	Frequent	Rare
Cumulation	Minimal or absent	Characteristic of most drugs
Sedation	Missing or slightly pronounced	Moderate to moderate severity
Resuming alarm condition	Often	Rarely
The risk of dependence formation	Tall	Minor
The timing of the appearance of withdrawal signs	1-3 days	4-7 days
Duration of withdrawal syndrome	2-5 days	8-15 days
Severity of withdrawal syndrome	Expressive	Moderate to moderate severity
The onset of paradoxical action	Frequent	Rare
Formation of anterograde amnesia	Often	Rarely
Intramuscular injection	Rapid absorption	Slow absorption
Risk of complications with intravenous administration	Minor	High with jet injection
The presence of active metabolites	No or minimal	A large number of

Classification of tranquilizers

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

Classification of tranquilizers by the mechanism of action (Voronina Seredenin SV, 2002)

Mechanism of action	Representatives of
Traditional anxiolytics
Direct agonists of the GABA-benzodiazepine receptor complex	Benzodiazepine derivatives: with the predominance of the actual anxiolytic action (chlordiazepoxide, diazepam, phenazepam, oxazepam, lorazepam, etc.); with a predominance of sleeping pills (nitrazepam, flunitrazepam); with predominance of anticonvulsant action (clonazepam)
Preparations of different mechanism of action	Preparations of different structures: mebicar, meprobamate, benactysin, benzoclidine, etc.
New anxiolytics
Partial agonists of the GABA-benzodiazepine receptor, substances with different tropism to the subunits of the benzodiazepine receptor and GABA receptor	Abecarnil, imidazoliridines (allidem, zollide), imidazobenzodiazepines (imidazenil, bretazenil, flumazenil), divalon, hydazepam
Endogenous regulators (modulators) of the GABA-benzodiazepine receptor complex	Fragments of endozapines (in particular, DBI-Diazepam binding inhibitor, inhibitor of diazepam binding), beta-carboline derivatives (ambocarb, carbacetam), nicotinamide and its analogues

[10], [11],

Anxiolytics of the nonbenzodiazepine series

In spite of the fact that benzodiazepine derivatives occupy a position of excellence in the degree of study and breadth of use, other anxiolytics are also used in medical practice.

Afobazol (INN: morphoinoethylthioethoxybenzimidazole) is a domestic pharmacological drug from the anxiolytics group, the world's first selective anti-anxiety drug of the nonbendiazepine series. Afobazol deprived of side effects of benzodiazepine derivatives: hypnosediasis, myorelaxing effect, memory disorders, etc.

Afobazol has an anxiolytic effect with an activating component that is not accompanied by hypnose-sedative effects (the sedative effect of afobazole is detected in doses 40-50 times higher than ED50 for anxiolytic action). The drug lacks muscle relaxant properties, a negative effect on memory and attention indicators; no drug dependence is formed and withdrawal syndrome does not develop. Reducing or eliminating anxiety (anxiety, bad forebodings, fears, irritability), tensions (fearfulness, tearfulness, anxiety, inability to relax, insomnia, fear), and therefore somatic (muscle, sensory, cardiovascular, respiratory, gastrointestinal symptoms), vegetative (dry mouth, sweating, dizziness) and cognitive (difficulty concentrating, weakened memory), violations are observed after 5-7 days of treatment with afobazole. The maximum effect comes to the end of 4 weeks of treatment and remains in the post-therapy period on average 1-2 weeks.

The drug is indicated for use in the therapy of neurotic disorders. Especially appropriate is the appointment of afobazol to persons with predominantly asthenic personality traits in the form of anxious suspicion, uncertainty, increased vulnerability and emotional lability, a tendency to emotional-stressful reactions.

Afobazol is non-toxic (LD50 in rats is 1.1 g with ED50 - 0.001 g). The half-life of afobazole for oral administration is 0.82 hours, the average maximum concentration (Cmax) is 0.130 ± 0.073 μg / ml, the average retention time of the drug in the body (MRT) is 1.60 ± 0.86 h. Afobazol is intensively distributed over well-vascularized organs. Apply inside after eating. Optimal single doses of the drug - 10 mg, daily allowance - 30 mg, distributed over 3 doses during the day. The duration of the course use of the drug is 2-4 weeks. If necessary, the dose of the drug 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, improves cerebral circulation. This drug is used to treat anxiety disorders, including anxiety-depressive conditions (especially not pronounced and associated with cerebral circulatory insufficiency). In addition, benzoclidine is prescribed to elderly patients with atherosclerosis with cerebral disorders, arterial hypertension, paroxysmal tachycardia.

Hydroxisin is a blocker of central M-cholinergic receptors and H1 receptors. The expressed sedative and moderate anxiolytic action is associated with inhibition of activity of some subcortical structures of the central nervous system. For hydroxysin is characterized by a fairly rapid development of anxiolytic action (during the first week of treatment), lack of amnestinal effect. Unlike benzodiazepines with prolonged use of hydroxyzine does not cause addiction and dependence, there are no signs of withdrawal and recoil syndromes.

Benaktizin is a derivative of diphenylmethane, the anxiolytic effect of the drug is due to a reversible blockade of central M-cholinergic receptors. In connection with the pronounced influence on the central cholinoreactive structures, benactysin is referred to the group of central cholinolytics. The effect on the central nervous system is clinically manifested by a calming effect, depression of the convulsive and toxic effect of anticholinesterase and cholinomimetic substances, increased action of barbiturates and other hypnotics, analgesics, etc. Currently, due to the presence of effective tranquilizers, and also due to undesirable side effects associated with with atropinopodobnym action (dry mouth, tachycardia, mydriasis, etc.), Benaktizin is practically not used as an anxiolytic.

Representatives of 3rd generation anxiolytics - buspirone, oxymethylethylpyridine succinate (mexidol), etc. The anxiolytic effect of mexidol is related to 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 and 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 nucleus of the suture. In addition, it selectively blocks (antagonist) pre- and postsynaptic D2-dopamine receptors (moderate affinity) and increases the rate of excitation of dopamine neurons in the midbrain. Some data suggest that buspirone has an effect on other neurotransmitter systems. Effective in the treatment of mixed anxiety-depressive conditions, panic disorders, etc. The anxiolytic effect develops gradually, manifests itself after 7-14 days and reaches a maximum after 4 weeks. Unlike benzodiazepines, buspirone does not have a sedative effect, a negative effect on psychomotor functions, does not cause tolerance, drug dependence and withdrawal symptoms, does not potentiate the effect of alcohol.

In addition to drugs belonging to the group of anxiolytics, preparations of other pharmacological groups to some extent or another have anti-anxiety effects: some, tnf-adrenoblockers (propranolol, oxprenolol, acebutolol, timolol, etc.), a-adrenomimetics (clonidine). Thus, propranolol is effective in the treatment of anxiety conditions associated with the hyperreactivity of the sympathetic nervous system and accompanied by pronounced somatic and vegetative symptoms, clonidine has the ability to reduce somatovegetative manifestations in the abstinence syndrome of opiate addiction.

Currently, an intensive search for new drugs with anxiolytic effect and at the same time more safe and effective than existing medicines continues. Screening of benzodiazepine derivatives is aimed at identifying the most selectively acting drugs with the most pronounced anxiolytic effect with a minimum of side effects. Search is also carried out 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 is the sedative effect, which itself disappears within a few weeks as the anxiolytic action develops. Also, when using standard doses of drugs due to individual sensitivity, confusion, ataxia, agitation, exaltation, transient hypotension, dizziness and gastrointestinal disorders can 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. In their development, the leading role of alcohol in the joint use with benzodiazepine derivatives has been proved. The incidence of these disorders is less than 1%.

Violations of cognitive functions are noted in patients taking long-term minimal therapeutic doses of benzodiazepine derivatives. The quality of visual and spatial activities is reduced and attention is being impaired. As a rule, patients themselves do not feel this.

Overdose with tranquilizers

Cases of death in overdose is not described. Even with the injection of large doses, convalescence occurs quickly and without serious consequences. With the combined use of large doses with drugs that depress the central nervous system, other groups, the severity of intoxication depends more on the type and amount of concomitant than on the concentration of benzodiazepine derivatives in the blood.

When appointing benzodiazepine derivatives, special attention is paid to the personality characteristics and the behavioral profile of the patient, which avoids the abuse of these drugs.

Characteristics of persons taking benzodiazelin tranquilizers for the treatment and use of these drugs for non-medical purposes

Persons taking benzodiazepine derivatives for therapeutic purposes	Persons taking benzodiazepine derivatives with a toxicological purpose
More often women aged 50 years and over	More often men in the age of 20-35 years
Benzodiazepine derivatives are administered according to the prescription and under the supervision of the doctor for a particular disease	Accept benzodiazepine derivatives as prescribed by the doctor or without a prescription, but not for a specific disease, but independently prescribe drugs for the purpose of artificial stimulation
Usually only accept e prescribed dosages accepted only benzodiazepine derivatives	Exceed the recommended doses Usually, several drugs are abused, while benzodiazepine derivatives are taken in combination with alcohol, narcotics, etc.
Tolerance is usually not formed	Typically, tolerance is quickly formed, and patients tend to increase the dose to obtain the desired effect
Burdened sedating benzodiazepines rarely take diazepam at a dose greater than 40 mg / day (or other drugs and doses ekvialentnye) The risk of withdrawal expressed negligible Admission preparations does not cause significant physical or social problems not seek illegal recipes by	Strive to potentiate the sedative effect of benzodiazepine derivatives Often take diazepam at a dose of 80-120 mg / day or more Often there is a pronounced withdrawal syndrome Drug use leads to health problems and in the social sphere Often get drugs and prescriptions for them illegally

The withdrawal syndrome

All benzodiazepine derivatives may, to varying degrees, cause withdrawal symptoms. This pathological condition, as a rule, occurs in the form of various disorders of the digestive tract, hyperhidrosis, tremor, seizures, tachycardia, drowsiness, dizziness, cephalgia, hyperacia, irritability.

In a number of cases, with a sharp abolition of therapy, the appearance of such severe symptoms as pronounced and prolonged depression, acute developing psychotic conditions, hallucinations, opisthotonus. Choreoathetosis, myoclonus. Delirious states with catatonic inclusions, etc.

The withdrawal syndrome develops rarely if the course of therapy with benzodiazepine derivatives does not exceed 3-4 weeks. To the phenomena of cancellation include the so-called interdose symptomatology, or symptoms of a breakthrough - the resumption of symptoms between benzodiazepine derivatives (adapted from the American Psychiatric Association, 1990). When discontinuing treatment with benzodiazepine derivatives, it is important to follow the following basic guidelines.

• Develop a clear pattern of therapeutic use of the drug in order to avoid abusing it.
• Correctly consider the ratio of benefits and possible negative treatment points.
• Gradually reduce the dose, carefully monitor the appearance of possible withdrawal symptoms.
• Solve the issue of alternative treatment (psychotherapy, behavioral therapy or drug use).
• It is necessary to maintain a spirit of cooperation with the patient in order to strengthen compliance.

The general recommendation to reduce the daily dose of benzodiazepine derivatives to exclude the appearance of withdrawal syndrome is the possibility of a fairly rapid reduction of 50% of the intake of patients; however, the subsequent decrease should be made more slowly (by 10-20% of the new dosage every 4-5 days).