Tranquilizers. Pharmacological properties, areas of improvement, Problems of safety of use
Tranquilizers (from Lat. tranquillium — “tranquility”) represent one of the most important groups of psychotropic drugs. Recently, they are increasingly called anxiolytics (from the Latin. anxius — “anxious” and Greek. lysis — “dissolution”). There are other, less common names — ataractics (from the Greek ataraxia — “equanimity”), psychosedative, anti-neurotic drugs.
In the general classification of psychotropic drugs, tranquilizers, together with neuroleptics, traditionally belong to the class of psycholeptics, i.e. drugs of a depressing, depressing type of action in general. However, as will be shown later, a significant number of drugs from different groups are able to exhibit anti-anxiety (actually tranquilizing) properties. In particular, such properties are inherent in some antidepressants — drugs that generally have a stimulating effect on mental processes. At the same time, such a classic tranquilizer as dipazepam has an antidepressant effect. These overlapping spectra of pharmacological activity of seemingly completely different drugs indicate the polymodality of psychotropic effects, the exceptional complexity of the mechanisms of various mental disorders that occur with the participation of many neurotransmitters, and the commonality of some neurochemical and neurophysiological links of these disorders.
Tranquilizers have been known for about 50 years. The development of the first drugs of this group dates back to the 50s of the twentieth century – the period of the birth of scientific psychopharmacology. The history of the use of anxiolytics began with the introduction into clinical practice of meprobamate (meprotan) in 1955, chlordiazepoxide (elenium) in 1959. A year after chlordiazepoxide, diazepam (seduxen, sibazone, relanium) appeared on the pharmaceutical market. Today, the group of tranquilizers has more than 100 drugs. Their active search and improvement continues. Only in the most popular range of 1,4-benzodiazepine derivatives, more than 3 thousand compounds have been synthesized, of which more than 40 are used in clinical practice .
The most important property of tranquilizers is the elimination of anxiety, feelings of anxiety and fear, reduction of internal tension, increased irritability, insomnia and other manifestations of neurotic, neurosis—like, psychopathic and psychopathic states, autonomic dysfunctions. Therefore, the main target of the use of tranquilizers are various anxiety-phobic syndromes of non—psychotic level – both acute and chronic, developing within the framework of the so-called borderline states .
In addition to the actual anxiolytic, the main clinical and pharmacological effects of tranquilizers include sedative, muscle relaxant, anticonvulsant, hypnotic, vegetostabilizing, as well as amnesic. Many anxiolytics are also capable of causing drug dependence. However, in individual tranquilizers, these properties are expressed to varying degrees, which should always be taken into account when choosing a drug for a particular patient. The improvement of the group under consideration is carried out in the direction of creating drugs with isolated anxiolytic properties, which leads to minimizing side effects. Indeed, the sedative and hypnotic effect of many classical tranquilizers leads to undesirable lethargy, drowsiness, decreased attention (unless we are talking about their use as hypnotics). Muscle relaxant action is important in the treatment of nervous diseases accompanied by increased muscle tone, as well as in anesthesiology; in patients with borderline mental disorders, it is usually undesirable. As for the amnesic properties, i.e. the ability to impair memory, they are almost always a manifestation of a side effect.
Among psychotropic drugs, tranquilizers are the most widely used in both inpatient and outpatient treatment. The scope of their use goes far beyond psychiatry, covering many somatic diseases, neurology, surgery, anesthesiology (premedication, ataralgesia), oncology, dermatology, gerontology, pediatrics, obstetrics and gynecology, narcology (for the relief of alcohol withdrawal), a number of other areas of medicine. These drugs are also used by practically healthy people to relieve the negative effects of emotional stress. As V. I. Borodin points out, from 10 to 15% of the total population in various countries of the world receive prescriptions for one or another tranquilizer once a year. Benzodiazepines are especially often prescribed. About 2% of the population takes them for a long time.
Given such a wide prevalence and high importance of tranquilizers, it is advisable to systematize current information about this group of drugs, including classification, mechanisms of action, pharmacological effects, as well as side effects and safety of use. The latter is due to the fact that currently in psychopharmacology priority is given to the safety of treatment, attention is focused on the importance of comparing clinical efficacy (benefit of treatment) and undesirable, side effects or tolerability of drugs (risk of treatment).
Classification of tranquilizers. Most of the early classifications of tranquilizers are based on the features of their chemical structure, duration of action, and clinical use.
Thus, benzodiazepine derivatives are leading in the number of drugs, among which there are long-acting drugs (for example, diazepam, phenazepam, cinazepam, nitrazepam, flunitrazepam), medium-duration drugs (chlordiazepoxide, lorazepam, nosepam, alprazolam, etc.) and short-acting drugs (midazolam, triazolam). Derivatives of diphenylmethane include benactisine (amisyl), derivatives of 3-methoxybenzoic acid — trioxazine, esters of substituted propanediol — meprobamate, derivatives of quinuclidine — oxylidine, derivatives of azaspyrodecanedione — buspiron.
Traditionally, the so—called “daytime tranquilizers” are distinguished, in which the actual anxiolytic effect prevails and sedative, hypnotic, muscle relaxant effects are minimally pronounced – mesapam (rudotel), trioxazine, tofizopam (grandaxin); the anxiolytic effect prevails in gidazepam, tofizopam, dikali clorazepate (tranksen). These drugs can be prescribed on an outpatient basis during the day.
Such an approach to classification, however, does not take into account the mechanism of action of tranquilizers, which is especially important both for understanding the pharmacodynamics and the essence of the side effect, and for determining the main directions of the development of a new generation of drugs. Progressive classifications of anxiolytics based on the mechanism of action are beginning to appear not only in scientific publications, but also in the latest editions of the educational literature on pharmacology. In particular, Prof. D. A. Harkevich classifies the most important tranquilizers into benzodiazepine receptor agonists (diazepam, phenazepam, etc.), serotonin receptor agonists (buspirone) and drugs of different types of action (amizil, etc.).
Table 1. Classification of the most important tranquilizers
| Mechanism of action | Representatives |
|---|---|
| Traditional anxiolytics | |
| Direct GABA agonistsAnd-benzodiazepine receptor complex (GABA – γaminobutyric acid) |
Benzodiazepine derivatives:
|
| Drugs of different mechanisms of action | Preparations of different structures – mebicar, meprobamate, benactizine, oxylidine etc. |
| New anxiolytics | |
| Partial benzodiazepine receptor agonists (MDD), substances with various tropism to the subunits of MDD and GABAAnd-Receptor | Abecarnyl, imidazopyridiny (alpidem, zolpidem), imidazobenzodiazepines (imidazenil, bretazenil ), divalon, gidazepam |
| Endogenous regulators (modulators) of GABAAnd-benzodiazepine receptor complex | Fragments of endozepines (in particular, DBI – Diazepam binding inhibitor, i.e., a diazepam binding inhibitor), β-carboline derivatives (ambocarb, carbacetam), nicotinamide and its analogues |
| GABA agonistsIn-receptor complex | Phenibut, GABA (aminalone), baclofen |
| GABA membrane modulatorsAnd-benzodiazepine receptor Complex | Mexidol, afobazole, ladasten, tofisopam |
| Glutamatergic anxiolytics | NMDA receptor antagonists (ketamine, phencyclidine, cyclazocin), antagonists AMPA receptor (ifenprodil), glycine site ligands (7-chlorokynurenic acid) |
| Serotonergic anxiolytics | Agonists and partial agonists of serotonin 1A receptors (buspirone, gepyron, ipsapirone), antagonists of 1C-, 1D-receptors, 2A-, 2B-, 2C-receptors (ritanserin, altanserin), serotonin 3A receptors (zacoride, ondansetron) |
As can be seen from the table. 1, due to the effect on various neurotransmitters systems involved in the pathogenesis of anxiety states, tranquilizing effect inherent not only in “classical” anxiolytics, but also in means, belonging to different clinical and pharmacological groups. These are, in particular, nootropic and cerebrovascular drug aminalon (sometimes referred to as tranquilonotropics), muscle relaxant, antispastic and analgesic agent baclofen, antiemetic The drug Ondansetron (Zofran), the antioxidant Mexidol, the anesthetic drug ketamine (calypsol). Most of these drugs are not currently prescribed Especially for the correction of anxiety-phobic states. Structural homologue of ketamine phencyclidine, which has a similar mechanism of action (antagonism with glutamate NMDA receptors), is a hallucinogenic agent and is not used at all in clinical medicine as a medicine.
In addition, the table does not include the numerous drugs described by the authors, at different stages of development and clinical application. Some Of these, they are used only in experimental medicine. For them, tranquilizing Action is only one facet of pharmacological activity. These are β-blockers (propranolol, etc., which have lipophilicity and penetrate well into the head brain), since the activation of adrenergic systems contributes to increased anxiety and fear; The use of β-blockers is especially indicated when combined anxiety with somatic pathology – angina pectoris, arrhythmias, arterial Hypertension; nucleic acid metabolites (uridine, potassium orotate); Substances affecting the energy status of the brain, ligands of adenosine receptors (lithonite, nicogamol, rubidium nicotinate); hormonal substances (corticotropin-releasing hormone, pineal hormone melatonin); cholecystokinin-B receptor antagonists; Neuropeptides (neuropeptide Y, enkephalins, selank, noopept, prolylene endopeptidase inhibitors, etc.); histamine H agonists3-Receptors; Antidepressants – tricyclic and MAO-A inhibitors (such as moclobemide, pyrazidol), DOPA decarboxylase inhibitors. Anti-anxiety component in the spectrum of pharmacological Some antipsychotics, narcotic analgesics, nootropics also have activities and actoprotectors, hypnotics, lithium salts, calcium channel blockers, range vitamin complexes. Analysis of the pharmacological properties of these drugs comes out beyond the scope of this publication.
Factors affecting the action of tranquilizers. Along with the peculiarities of the mechanism of action, dose and duration of use The effect of tranquilizers is significantly influenced by the pharmacogenetic factor – genetically determined type of the body’s response to emotional stress. In animal experiments, it has been shown that with an active type of reaction in action benzodiazepine tranquilizers predominate dose-dependent sedative effect, inhibition of behavioral reactions, and with the opposite type (the so-called freezing-reaction – “solidification”), on the contrary, activation is noted Behavior. According to S. B. Seredenin, clinical studies have established that that in asthenic patients with neuroses there is a tranquilo-activating, and in sthenic – tranquilo-sedative effect of benzodiazepines. In healthy volunteers with high efficiency of operator activity In an emotionally stressful environment, benzodiazepines cause sedation, and in the case of the disorganizing effect of stress – an increase in performance. Dependence The effect of the phenotype of the emotional-stress reaction also occurs in afobazole.
As evidenced by the results of our research, on the effect of tranquilizers Such a factor as the mineral composition of the diet can also influence, in particular, the level of food intake of sodium chloride. The experiments were performed on mice (test intraspecific aggression of males caused by isolation for 1 week). A male from a general cage was planted in a cage to an isolated mouse, in relation to which the isolyant shows pronounced aggression. Data table. 2 show that in animals, within 1–2 months prior to the experiment consuming increased amount of NaCl, aggressive behavior was less pronounced than in controls mice fed a normal salt diet. Latent time of open attack lengthened by a factor of 15 compared to the control (p<0.05), Moreover, during this period, the isolates almost did not pay attention to the partner. The total number of attacks tended to decrease relative to the control level (an average of 17%). Diazepam even in a small dose (0.1 mg / kg intraperitoneally 30 minutes before the experiment) significantly reduced aggressive behavior in the control group. This was manifested in an increase in latent time attacks by 21 times (p<0.05) and a decrease in the number of attacks by 77% (p<0.05) compared with the background index of mice to which the drug was not administered (Table 2). 0). However, in conditions of excessive consumption of table salt, the specific The effect of the anxiolytic was weakened. The latent period of aggression was half as short, than in control animals after administration of diazepam (p<05.29), and unreliable (56%) less than the background indicator with a hypersodium diet. Number of attacks After the introduction of diazepam, it decreased in comparison with the background by <>%, i.e. to a lesser extent than in a normal diet.
Table 2. The effect of increased consumption of table salt on aggressiveness mice induced by prolonged isolation and modulation of the effect of diazepam
| Mineral additive | Background indicator | Diazepam | ||
|---|---|---|---|---|
| Latency period, min. | The number of attacks in 1 hour |
Latency period, min. | The number of attacks in 1 hour |
|
| No additives (control) | 1,1±0,5 | 30±8 | 23,4±9,6 # | 7±4 # |
| NaCl | 16,9±7,4 * | 25±7 | 12,0±8,8 * | 11±2 # |
The decrease in the effectiveness of the anxiolytic is obviously due to the fact that the increased consumption of sodium chloride contributes to the weakening of GABAergic inhibitory processes.
Tranquilizer Side Effects and Safety Concerns their applications. In general, tranquilizers, unlike others psychotropic drugs (neuroleptics, antidepressants), characterized by the absence of severe side effects and good tolerability. V. I. Borodin [4] allocates The following are the main side effects that occur with the use of tranquilizers and belonging to type A :
- hypersedation – dose-dependent daytime sleepiness, decreased wakefulness, impaired coordination of attention, forgetfulness, etc.;
- muscle relaxation – relaxation of skeletal muscles, manifested by a general weakness, weakness in certain muscle groups;
- “behavioral toxicity” is a mild impairment of cognitive functions and psychomotor skills, manifested even in small doses and detected in neuropsychological testing;
- “paradoxical” reactions – increased aggressiveness and agitation (agitated state), sleep disturbances, usually passing spontaneously or after dose reduction;
- mental and physical dependence that occurs with long-term use (6-12 months continuously), the manifestations of which resemble neurotic anxiety.
These manifestations of side effects are most characteristic of benzodiazepines, which In addition, they can cause arterial hypotension (especially with parenteral introduction), dry mouth, neuralgia (nausea, vomiting, diarrhea or constipation), increased appetite and food intake, dysuria (urination disorders), impaired sexual desire and potency. Benzodiazepines may increase intraocular pressure, therefore, contraindicated in angle-closure glaucoma. With prolonged tolerance is possible. Allergic reactions are rare.
In terms of frequency, lethargy, drowsiness, occurring in about 10%, are leading cases, including the next day as part of “residual effects” after taking the drug in the evening the day before. 5-10 times less common dizziness and ataxia (impaired coordination of movements) associated with muscle relaxation. However, in old age, the side effects in question become more frequent. In connection with these properties, a contraindication to the use of tranquilizers is myasthenia gravis.
The deepening of sleep and muscle relaxation caused by tranquilizers cause such a contraindication to their use as sleep apnea syndrome – long breathing pauses in sleep, usually occurring in snoring patients. In this case, hypoxia occurs, myocardial ischemia may develop. Tranquilizers make it difficult to awaken when breathing stops, and muscle relaxation is soft the palate, sagging and preventing the flow of air into the larynx and beyond into the trachea, leads to aggravation of hypoxia. In this regard, It is appropriate to recall the old recommendation to refrain from using any sleeping pills in snoring patients.
Memory impairment refers to manifestations of “behavioral toxicity” and are characterized by episodes of anterograde amnesia (decreased memory for events, occurring after taking the drug), especially in the case of taking benzodiazepines tranquilizers with a pronounced hypnosedative effect, including dipotassium clorazepate (tranxen). Reversible memory impairment is also possible and reproduction of information against the background of long-term use of classical benzodiazepines drugs such as diazepam, phenazepam, but not new generation drugs – alprazolam (Xanax) or buspirone.
Increased aggressiveness as a manifestation of “paradoxical” reactions can cause triazolam, and therefore it is recommended to take this drug no more than 10 days only as a sleeping pill, as well as dipotassium clorazepate. Increased aggressiveness or agitation can be quite difficult clearly associated with the use of tranquilizers, it can be a manifestation of the course of the disease, and not the side effects of the drugs in question.
Due to the adverse effects on the intrauterine fetus of anxiolytics Contraindicated in pregnancy. Tranquilizers, primarily benzodiazepine, Easily penetrate the placenta. Thus, the concentration of diazepam in the blood of the umbilical cord exceeds its concentration in maternal blood. Levels of diazepam and oxazepam in the blood of an intrauterine child increases slowly due to a high degree of the connection of these drugs with the blood proteins of a pregnant woman, but subsequently They create a higher concentration in the baby’s serum, firmly binding to its proteins. Elimination of these drugs and their metabolites occurs several times slower than in adults. Children, especially in the prenatal and early postnatal period, have increased sensitivity to depressing effects on the central nervous system, and tranquilizers in their body easily cumulated. Therefore, in newborns whose mothers during pregnancy took anxiolytics, respiratory depression is possible until it stops – apnea (in some cases, on the contrary, tachypnea is noted), hypothermia, decreased muscle tone, inhibition of reflexes, including sucking (sometimes possible hyperreflexia), tremor, hyperactivity, increased irritability, violations sleep, vomiting. The duration of these phenomena without treatment reaches 8–9 months. Such violations (with some peculiarity of the clinical picture) are described also for chlordiazepoxide and for meprobamate. They can be mistaken for manifestations drug intoxication. The appearance of the described violations was noted, in particular, with regular intake of 10-15 mg of diazepam during the last trimester pregnancy. Sometimes the term “benzodiazepine babies” is even used. The so-called “behavioral teratogenesis” of tranquilizers, i.e. postnatal disorders of the higher nervous activity of the offspring, established in numerous experimental studies on animals.
In a retrospective study of more than 20,12 women who took meprobamate During pregnancy, morphological abnormalities (deformities) were detected in 9% newborns, which indicates an increased risk of teratogenic effect.
Regarding the safety of single use of diazepam during childbirth for anesthetic purposes, it does not lead to significant deviations in the condition of a newborn.
Tranquilizers penetrate into breast milk. In particular, diazepam creates a 10 times lower concentration in it than in the blood. In case the need to use tranquilizers by a lactating woman breastfeeding must be stopped.
The problem of drug dependence to tranquilizers is interpreted by specialists ambiguously. As noted by A. S. Avedisova, opinions abound here and insufficiently verified data. However, the addiction is clinical Reality. Most authors agree that its risk is directly proportional duration of treatment with tranquilizers. Addiction is especially likely to occur to benzodiazepines, including lorazepam. Dangerous in this relation and meprobamate, the peculiarity of which is the development of euphoria.
The occurrence of physical dependence is indicated by withdrawal syndrome. Its manifestations are gastrointestinal disorders, sweating, tremors, drowsiness, dizziness, headache, intolerance to sharp sounds and smells, tinnitus, irritability, anxiety, insomnia, depersonalization (feeling of loss one’s own self and the experience of lack of emotional involvement in relation to loved ones, to work, etc.). Usually It is not severe. The severity and duration of withdrawal disorders can to be underestimated and mistaken for neurotic manifestations of the disease Patient. At the same time, examples of long-term (months and even years) are not uncommon the use of benzodiazepines without the difficulties of subsequent withdrawal, which is facilitated by certain tactics of treatment and discontinuation of the drug. To prevent With long-term treatment, lower doses, fractional doses should be used short courses of therapy, and cancellation should be carried out within 1-2 months against the background of psychotherapy or taking a placebo. It is possible to recommend a replacement for short-acting on a long-acting drug in equivalent doses (Table 3), and the pace dose reductions should be approximately 25% for every quarter of the withdrawal period; . Long-term treatment (with good tolerability and lack of tolerance) possibly in elderly patients who have benzodiazepines in small doses well stop the symptoms, and in patients who are helped by the drugs improve the quality of life .
Table 3. Equivalent doses of some tranquilizers for adults
| Drugs | Dose, mg |
|---|---|
| Diazepam (sibazone, seduxen, relanium) | 10 |
| Chlordiazepoxide (Elenium) | 25 |
| Lorazepam (loraphen, merlite) | 2 |
| Alprazolam (Xanax) | 1 |
| Clonazepam (antelopsin) | 1,5 |
| Oxazepam (tazepam) | 30 |
| Mezapam (rudotel) | 30 |
| Nitrazepam (radedorm, eunoctin) | 10 |
| Meprobamate (meprotan, andaxin) | 400 |
| Buspirone (spitomine) | 5 |
In the origin of addiction, the role of psychological mechanisms is great. Probability Its occurrence is highest in individuals with cognitive and behavioral disorders, excessive fixation on somatic symptoms, irrational belief in the power of drugs and the expectation of severe withdrawal symptoms.
Discussing the safety problems of the use of tranquilizers, it is impossible to leave without attention poisoning with these drugs. Due to the widespread use of They (especially benzodiazepines) are the leaders in frequency among drug poisoning depriming action [10]. However, due to the great breadth of therapeutic Actions lethal outcomes in case of poisoning by them are rare, unless they are used combinations of these drugs with alcohol, barbiturates, neuroleptics, antidepressants. The toxic effects of these drugs tranquilizers potentiate. Very dangerous and combination with cardiac glycosides, since with combined The effect of the tranquilizer can mask the effects of the second substance. Rapid intravenous administration of benzodiazepines, resulting in to a decrease in blood pressure, a sharp depression of breathing and work heart until it stops. A particularly significant reduction in pressure can call meprobamate. The course of poisoning is heavier in persons with diseases liver, since the rate of excretion of the drug from the body is significantly reduced. In patients with a powerful development of subcutaneous fat, poisoning Even with a slight severity, it can take a long time, so the risk increases development of hypostatic pneumonia.
When ingesting a large number of tranquilizer tablets in the stomach Their conglomerates can be formed, the mass of which reaches 25 g. They are fixed in the folds of the mucous membrane and are not removed by washing. Water used for washing, can bring them into the small intestine. This leads to a protracted the course of poisoning. Therefore, after gastric lavage, if the patient’s condition worsens, endoscopy is recommended, the appointment of enterosorbents, saline laxatives, cleansing enemas.
As already noted, the peculiarity of pharmacokinetics and, accordingly, toxicokinetics benzodiazepines is a high degree of binding to blood proteins that makes them practically non-dialyzable substances. Most of the drugs of this Groups are little excreted through the kidneys. Therefore, in case of poisoning, such methods of detoxification, Both hemodialysis and forced diuresis are usually ineffective. Dialysis is ineffective and with an overdose of buspirone. Treatment is focused on repeated washing stomach, infusion therapy, the use of plasma substitutes, vasopressor drugs, high-dose nootropics, including piracetam, oxygen therapy, in severe In cases, mechanical ventilation is used. Prevention of pneumonia is necessary. A specific benzodiazepine antagonist, flumazenil, is used only in the absence of drugs, alcohol, antidepressants in the body, history of convulsive conditions (flumazenil can cause convulsions). Enter flumazenil intravenously. As for meprobamate, poisoning which occurs rarely, it is much weaker than benzodiazepines, binds to proteins blood and is excreted to a greater extent in the urine. Therefore, hemodialysis and forced Diuresis in case of poisoning with meprobamate is effective.
After removing the patient from the acute phase of poisoning, rehabilitation is necessary due to long-term impairment of cognitive functions, autonomic innervation, condition of the lungs, liver, kidneys, immune system. It has been established that within a year after poisoning with tranquilizers, vaccinations against infectious diseases are ineffective .
Regarding drug interactions of tranquilizers, it should be noted that any (even anxioselective) drugs in this group should not be combined with alcohol. Severe drowsiness, psychomotor retardation are possible and even respiratory depression. Due to the potentiation of the depressing effect on CNS should not combine benzodiazepines with phenothiazine neuroleptics. Buspirone is incompatible with antidepressants – MAO inhibitors (nialamide etc.), since the development of a hypertensive crisis is possible. Cimetidine is able to increase the concentration of diazepam and chlordiazepoxide (but not ocazepam or lorazepam) in the blood by 50%, slowing down their metabolism and clearance. High doses of caffeine, including in beverages, reduces anxiolytic effect of benzodiazepines.
Accounting for side effects, contraindications, drug interactions of tranquilizers is necessary to improve the safety of the use of these most widespread psychotropic drugs.