Drugs that protect against stress

Strasprotective action, that is, protects against stress to varying degrees, has drugs of many pharmacological groups, but not all of them are for various reasons suitable for preventive and therapeutic use in shock, as their introduction to the victim must simultaneously provide the solution of several problems:

• protection of the central nervous system from the impact of the mental component of the trauma, including self-assessment of the severity of the condition, its future fate and other social factors, creating relative "psychological comfort" for the victim (anxiolytic and sedative effects, and, if necessary, antidepressant action);
• restriction of the expression of standard adaptive neuro-vegetative and neuroendocrine reactions, which, with strong stress and in conditions of pragmatic uncertainty, are included with maximum stress, leading to a number of undesirable manifestations (inadequate enhancement of cardiac activity, spasm of resistive vessels, decreased immunity, ulceration of the gastric mucosa and intestine and etc.);
• elimination of excitement, euphoria, potentiation of the action of simultaneously or sequentially administered analgesics.

The idea of a deep neurovegetative blockade (neuroplegia) at different levels of regulation of autonomic and endocrine functions in shock was first expressed by G. Labori (1970). It was meant to create a relative areoactivity of the body with the help of "lytic cocktails", the basis of which was a strong neuroleptic from the group of phenothiazines that had just been discovered then (chlorpromazine or lorgacyl, aminosine). Its powerful central psychosedative action was supplemented by adrenolytic action on the periphery; in the "cocktail" was also an antihistamine (diprazine or diphenhydramine) and m-holinolitik. The idea was to turn off all unwanted excess centrogenic and reflex responses to trauma, to reduce the level of metabolic processes, body temperature, oxygen consumption and thereby to translate the organism into a low energy level of functioning and reactivity with the help of neuroplegy.

However, "deep neuroplagia" was accompanied by significant negative effects, including weighting of circulatory disorders. In this form, the method of neurovegetative blockade in case of a shock trauma did not justify itself. The extreme degree of fascination with the method and the principal drawbacks of the strong neuroleptics phenothiazine series (aminazine, tizergin, etc.) with a pronounced and uncontrolled peripheral alpha-adrenergic action leading to dangerous arterial hypotension against the background of a circulating blood volume deficiency (BCC) and tachycardia compromised the idea. Later, aminazine in minimal doses (0.1-0.15 mg / kg) was sometimes used to control vasospasm and microcirculation disorders after replenishment of the BCC deficiency.

The use of neuroleptics as psychodegenerative drugs returned in the early 70's with the introduction of the clinical practice of derivatives of the bootosterophenone, in particular, droperidol. In the years 1959-1969. He was introduced into anesthesia practice in combination with a very strong analgesic fentanyl in the form of a method of "neuroleptanalgesia." From neuroplegia, this method fundamentally differs mainly in two qualities: neuroleptanalgesia is not aimed at reducing life processes; is caused by pharmacological drugs that do not exert such pronounced side effects as aminazine and "lytic cocktails." This method is widely used and is still used as a basis for shallow anesthesia, in particular, to provide emergency interventions in the case of shock injuries. Neuroleptanalgesia has been thoroughly studied by anesthesiologists and resuscitators, and its components, droperidol and fentanyl-steel have been specially used in clinics and (less often) in the pre-hospital stage of assisting victims with injuries, burns and patients with myocardial infarction.

Like phenothiazines, the central antipsychotic and antipsychotic effects of droperidol are associated with a dopaminolitic alpha-adrenergic property, in addition, droperidol has a mild antiserotonin effect, but is virtually devoid of the central antihistamine and m-cholinolytic action, which is inherent in one way or another to the phenothiazine derivative. The sum of the properties of droperidol is expressed in the form of a very strong "total" psycho-sedative effect, a state of total indifference to oneself and the environment, while preserving consciousness and critical attitude, in the loss of initiative and motivation. In other words, the central effect of droperidol in a sufficient dose is very similar to that of the phenothiazines of the sedative group. For a number of properties, droperidol is superior to aminazine, but perhaps the most important difference is the "mild" alpha-adrenolytic effect on the vessel wall. Therefore, in the absence of hypovolemia, it does not cause severe hypotension, and the removal of reactive vasospasm and a moderate decrease in total peripheral vascular resistance (OPS) are useful.

Medicines for stress of various groups used for the prevention and treatment of shock

Nature of activity	Aminazine, tizercin and other fetiazines	Droperidol and other butyro- phenones	Sibazon (seduxene) and other benzodiazepines	Sodium oxybutyrate (subnarcotic doses)
Generalized effect	+++	++++	++	++
Specific ankspoliticheskoe (streseprotektivnoe) dsjstlio			+++	+
Anterograde amnesia	-	-	+	-
Potentiation of anesthesia	+++	++++	++	++
Potentiation of analgesia	+++	++++	+	+
Potentiation of respiratory depression by analgesic	+++	+++	+	+
Own hypnotic (general anesthetic) effect			++	+++
Protection of the cardiovascular system from operational stress	+	+	+++	+
Arterial hypotension with reduced BCC, danger of collapse	++++	++	+	+
Antiemetic action	++	+++	-	-
Protective effect in the modeling of traumatic shock in animals	+	++	+++	++
Prevention of stressful tissue damage			+++	+

The content of the active substance in 1 ml of a solution of various drugs for neuroleptanalgesia (according to TM Darbinyan, 1969)

A drug	Active substance, mg / ml
Fentanyl	0.05
Droperidol	2.5
Talamonal	0.05 (fentanyl) + 2.5 (droperidol)
Innovan (Innovaar)	0.02 (fentanyl) + 1.0 (droperidol)

To carry out neuroleptanalgesia, mixtures consisting of neuroplegic and analgesic preparations were also proposed.

Studies have shown that in the fentanyl-droperidol mixture in a ratio of 1:50, the analgesic effect of fentanyl increases and its side effects are reduced (vomiting, increased muscle tone and a number of other cholinergic reactions). However, the use of drugs such as thalamonal or innovative in trauma and shock has no special advantages compared with the separate use of these pharmacological agents, since the pharmacokinetics of these drugs are different.

The general lack of neuroleptics is the absence (or small expression) of the selective anxiolytic effect, so they do not suppress the pathological "core" of fear, anxiety, negative emotions. The suppression of emotional and, in general, neurogenic somatic responses is secondary to their "total" psycho-sedative action. In actual doses used in shock, as well as with neuroleptanalgesia, if it is not supplemented by anesthesia, antipsychotics do not create reliable anterograde amnesia, and the memory of the patient remains episodes experienced in the intensive care unit and during surgery.

[1], [2], [3]

Benzodiazepines, as progressive drugs for stress

Relatively new and, perhaps, the most progressive approach to protecting the body from stress and its consequences in traumas, myocardial infarction and in other shockogenic situations is the use of anxiolytic agents of the benzodiazepine series. The first representatives of this vast group (today more than 20 benzodiazepines are used worldwide) were introduced into clinical practice in 1960-1963. (Librium, Valium). Later, in the experiments of many authors, the protective effect of benzodiazepine derivatives was demonstrated under severe stress and shockogenic trauma (Bazarevich G. Ya. Et al., 1984).

The duration of the drugs (in minutes) used for neuroleptanalgesia (according to TM Darbinyan, 1969)

A drug	Start of action		Maximum		Duration
	W / m	In / in	W / m	In / in	W / m	In / in
Fentanyl	5	0.5	15	2	45	Thirty
Droperidol	15	5	40	20	480	360

An important feature of benzodiazepines is the selective anxiolytic effect, which is practically absent in neuroleptics, and with increasing dosages - generalized, anticonvulsant, potentiating analgesia and hypnotic (from sleeping pills to general anesthetic) effects. These properties are due to the activation of special benzodiazepine receptors (BR), which facilitate the transmission of physiological limiting effects (by opening membrane channels for C1 ions) in inhibitory GABAergic synapses. The endogenous ligand of these receptors has not been accurately established, perhaps it is a modulating peptide released simultaneously with the mediator GABA-ergic endings. As a result of the modulating effect of the peptide (or benzodiazepines) on the GABA-receptor complex, the transmission of inhibitory signals in the synapses of the central nervous system is greatly facilitated and enhanced. Thus, in moderate doses, benzodiazepines increase the effectiveness of inhibitory transmission in the brain where it is physiologically necessary and is included in this place and at the moment. Studies of neurochemists have shown that this primarily restricts short-axis intercalation neurons based on the feedback principle at different levels of the central nervous system (primarily in the limbic emotional system, in the cerebral cortex and cerebellum); believe that 30 to 50% of all brain synapses are inhibitory GABA-ergic. If we take into account the inhibitory synapses of the brain with a different transmission (peptidergic, purinergic, serotonin, etc.), this percentage increases substantially. In other words, there is a powerful and branched (short- and long-axle) braking system in the central nervous system at various levels, designed to limit excess excitation signals, differentiation and the detection of significant signals. It is its use in the emergency activation of afferent systems in conditions of a shockogenic injury that represents a real pharmacological pathway for protecting the brain and the body as a whole.

Based on the pharmacological analysis, at least two types of BR are now isolated. Type I receptors are mainly localized in the limbic system and, apparently, in the cerebral cortex. With their activation, the anxiolytic effect and anticonvulsant effect are associated, whereas type II BR are responsible for sedative properties, the hypnotic effect obviously does not carry such a selective function and barbiturates can interact with them. There is reason to believe that the potentiation of analgesia and anesthesia, sometimes observed respiratory depression, is also due to the interaction of drugs with Type II receptors. These properties of benzodiazepines (with the exception of respiratory depression) in the case of a shock injury are not superfluous and with moderate manifestation are useful. Benzodiazepine preparations differ somewhat in the spectrum of pharmacological activity. An important advantage of them is the ability to serve not only as a means of preventing shock in the prehospital stage of care, but also with medication and even anesthesia in the clinic. It is on these properties of benzodiazepines (more commonly used sibazone - seduxen, diazepam) built one of the modern versions of "balanced anesthesia" (tranquilloanalgesia, ataroanalgesia). In fact, this method differs from neuroleptanalgesia only by replacing the antipsychotic with an anxiolytic. However, it does not only give a certain advantage in safety, but has a number of additional useful properties: a lesser threat of hypotension (there are no peripheral alpha-adrenolytic effects). However, based on sibazone (like droperidol), it is not possible to build a complete surgical anesthesia: hypnotic properties are not sufficiently expressed. Not suitable for this and fenozepam.

One of the most promising drugs for carrying out the victim through all stages of medical care, including urgent surgical, is considered to be rohypnol (flunitrosepam), which has the necessary qualities for this. However, all three substances - sibazone, fenozepam and rohypnol - have a significant duration of action (T0.5 from 19 to 60 h), which makes their effect uncontrollable and the elimination of excessive or residual post-cannabis depression presents significant difficulties. Depression caused by benzodiazepines is nonspecifically and only partially removed by adenosine antagonists (theophylline or euphyllin). In recent years, a specific benzodiazepine antagonist (anexate or flumazenil) -imidazole derivative of benzodiazepine has been obtained and successfully tested in the clinic. The drug is low-toxic, reliable and removes all the effects of benzodiazepines for a period of 3-5 hours. Thus, the problem of stopping the excessive psychodegressive action of benzodiazepines can be considered fundamentally solved.

The comparative activity of diazepam (sibazone) and rohypnol (according to Bergmann H., 1978)

Effects	Diazepam	Rohypnol
Analgesia	-	-
Potentiation of analgesics	+	++++
Sedative action	+	+++
Hypnotic (general anesthetic effect)	-	-n-
Amnesia	+	++
Anticonvulsant effect	+	+++

Moderate psycho-sedative effect of drugs of this group, not accompanied by additional hemodynamic disorders, on the contrary, protecting it from negative centrogenic influences, can be useful in cardiogenic shock, in agitated victims with mechanical injuries and burns. The disadvantages of sibazone, fenozepam and rohypnol include insolubility in water. The use of solutions on propylene glycol is accompanied by tissue irritation and can cause phlebitis (3-5%). The possibility of obtaining water-soluble benzodiazepines, devoid of irritant properties, was demonstrated with the example of midazolam and opened the way for further searches.

Thus, by the mechanism of action and the sum of the pharmacological properties, the benzodiazepine derivatives today are better than other stress protective means to meet the requirements of the clinic as an essential component of complex shock prevention at the prehospital stage, with early therapy in the intensive care unit, and as a component of balanced anesthesia in urgent surgical interventions . The discovery of a specific antidote to benzodiazepines makes their use safer.

Another approach to the prevention and therapy of shock by neurotropic drugs is associated with the use of direct agonists of GABA-receptors (sodium oxybutyrate, phenibut, pantogamma, etc.). Unlike GABA itself, they penetrate well through the BBB and create the necessary concentrations in the brain, and unlike benzodiazepines, they cause not "selective incorporation" of GABA receptors where it is physiologically justified at the moment, but ubiquitous activation in proportion to the dose, substituting for natural mediator. This gives a different gradation of psycho-sedative effect from sedation to anesthesia; The stress-protective effect is manifested against sedation and less selective than with the administration of benzodiazepines.

In the experiments and clinic, the anti-shock effect of sodium oxybutyrate is better than the others. It manifests itself clearly in smaller narcotic and close to them doses. In these doses, the drug also has a distinct antihypoxic effect due to the formation in the cells of redoxiparas due to the partial conversion of oxybutyrate to semialdehyde succinic acid. The antihypoxic properties of oxybutyrate contribute to the anti-shock effect. In general, the stress-protective effect of sodium oxybutyrate is not as selective as in benzodiazepines, and anti-shock and antihypoxic properties correlate more with general and hypnotic.

[4], [5]