Medications that protect against stress

Many pharmacological groups of drugs have a stress-protective effect, that is, protection against stress to varying degrees, but not all of them, for various reasons, are suitable for prophylactic and therapeutic use in shock, since their administration to the victim must simultaneously provide a solution to several problems:

• protection of the central nervous system from the impact of the mental component of trauma, including self-assessment of the severity of the condition, one’s future fate and other social factors, creating relative “psychological comfort” for the victim (anxiolytic and sedative effects, and later, if necessary, an antidepressant effect);
• limitation of the expression of standard adaptive neurovegetative and neuroendocrine reactions, which, under severe stress and in conditions of pragmatic uncertainty, are activated with maximum tension, which leads to a number of undesirable manifestations (inadequate increase in cardiac activity, spasm of resistive vessels, decreased immunity, ulceration of the gastric and intestinal mucosa, etc.);
• elimination of excitement, euphoria, potentiation of the action of simultaneously or sequentially administered analgesics.

The idea of deep neurovegetative blockade (neuroplegia) at different levels of regulation of vegetative and endocrine functions in shock was first put forward by G. Labori (1970). It was intended to create a relative areactivity of the organism with the help of "lytic cocktails", the basis of which was a strong neuroleptic from the then newly discovered group of phenothiazines (chlorpromazine or largactil, aminozine). Its powerful central psychosedative action was supplemented by an adrenolytic effect on the periphery; the "cocktail" also included an antihistamine (diprazine or diphenhydramine) and m-anticholinergic. The idea was to use neuroplegia to switch off all unwanted excess centrogenic and reflex responses to trauma, to reduce the level of metabolic processes, body temperature, oxygen consumption and thereby transfer the organism to a low energy level of functioning and reactivity.

However, "deep neuroplegia" was accompanied by significant negative effects, including aggravation of circulatory disorders. In this form, the method of neurovegetative blockade in shock-producing trauma did not justify itself. The extreme degree of enthusiasm for the method and the fundamental shortcomings of strong phenothiazine neuroleptics (chlorpromazine, tizercin, etc.) with a pronounced and uncontrolled peripheral alpha-adrenolytic effect, leading to dangerous arterial hypotension against the background of a deficit in the circulating blood volume (CBV) and tachycardia compromised the idea. Subsequently, chlorpromazine in minimal doses (0.1-0.15 mg/kg) was sometimes used to combat vasospasm and microcirculation disorders after replenishment of the CBV deficit.

The use of neuroleptics as psychosedatives was resumed in the early 1970s with the introduction of buterophenone derivatives, in particular droperidol, into clinical practice. In 1959-1969, it was introduced into anesthesiology practice in combination with a very strong analgesic, fentanyl, in the form of the "neuroleptanalgesia" method. This method differs fundamentally from neuroplegia mainly in two qualities: neuroleptanalgesia is not aimed at reducing vital processes; it is caused by pharmacological drugs that do not have such pronounced side effects as aminazine and "lytic cocktails". This method has become widespread and is still used as a basis for shallow anesthesia, in particular, to ensure emergency interventions in shock-producing injuries. Neuroleptanalgesia has been studied in great detail by anesthesiologists and resuscitators, and its components, droperidol and fentanyl, have begun to be used specifically in clinics and (less frequently) at the pre-hospital stage of providing assistance to victims of trauma, burns, and patients with myocardial infarction.

Like phenothiazines, the central neuroleptic and antipsychotic action of droperidol is associated with the dopaminolitic alpha-adrenolytic property, in addition, droperidol has a moderate antiserotonin effect, but is virtually devoid of the central antihistamine and m-anticholinergic action inherent to some extent in phenothiazine derivatives. The sum of the properties of droperidol is expressed in the form of a very strong "total" psychosedative effect, a state of complete indifference to oneself and the environment while maintaining consciousness and a critical attitude, in the loss of initiative and motivation. In other words, the central action of droperidol in a sufficient dose is very similar to that of phenothiazines of the sedative group. Droperidol is superior to aminazine in a number of properties, but perhaps the most important difference is the "soft" alpha-adrenolytic effect on the vascular wall. Therefore, in the absence of hypovolemia, it does not cause severe hypotension, and the relief of reactive vasospasm and a moderate decrease in total peripheral vascular resistance (TPR) are beneficial.

Anti-stress medications of various groups used for the prevention and treatment of shock

Nature of activity	Aminazine, tizercin and other fetiazines	Droperidol and other butyrophenones	Sibazon (seduxen) and other benzodiazepines	Sodium oxybutyrate (subnarcotic doses)
General sedative effect	+++	++++	++	++
Specific anxpolitical (stress-protective) disposition			+++	+
Anterograde amnesia	-	-	+	-
Potentiation of anesthesia	+++	++++	++	++
Potentiation of analgesia	+++	++++	+	+
Potentiation of respiratory depression by analgesics	+++	+++	+	+
Own hypnotic (general anesthetic) effect			++	+++
Protection of the cardiovascular system from surgical stress	+	+	+++	+
Arterial hypotension with decreased circulating blood volume, risk of collapse	++++	++	+	+
Antiemetic effect	++	+++	-	-
Protective effect in modeling traumatic shock in animals	+	++	+++	++
Prevention of stress-induced tissue damage			+++	+

Content of active substance in 1 ml of solution of various drugs for neuroleptanalgesia (according to T. M. Darbinyan, 1969)

Preparation	Active ingredient, mg/ml
Fentanyl	0.05
Droperidol	2.5
Thalamonal	0.05 (fentanyl) + 2.5 (droperidol)
Innovan (innovar)	0.02 (fentanyl) + 1.0 (droperidol)

For the implementation of neuroleptanalgesia, mixtures consisting of neuroplegic and analgesic drugs have also been proposed.

Studies have shown that a mixture of fentanyl and droperidol in a ratio of 1:50 enhances the analgesic effect of fentanyl and reduces its side effects (vomiting, increased muscle tone and a number of other cholinergic reactions). However, the use of drugs such as thalamonal or innovan in trauma and shock does not have any particular advantages over the separate use of these pharmacological agents, since the pharmacokinetics of these drugs are different.

A common disadvantage of neuroleptics is the absence (or low intensity) of a selective anxiolytic effect, as a result of which they do not suppress the pathological "core" of fear, anxiety, and negative emotions. Suppression of emotional and generally neurogenic somatic responses is secondary to their "total" psychosedative effect. In the doses actually used in shock, as well as in neuroleptanalgesia, if it is not supplemented with anesthesia, neuroleptics do not create reliable anterograde amnesia and episodes of what was experienced in the intensive care unit and during surgery remain in the patient's memory.

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Benzodiazepines as progressive stress medications

A relatively new and perhaps the most progressive approach to protecting the body from stress and its consequences in trauma, myocardial infarction and other shock-producing situations is the use of benzodiazepine anxiolytics. The first representatives of this large group (today more than 20 benzodiazepines are used in the world) were introduced into clinical practice in 1960-1963 (Librium, Valium). Later, in experiments by many authors, the protective effect of benzodiazepine derivatives in severe stress and shock-producing trauma was demonstrated (Bazarevich G. Ya. et al., 1984).

Duration of action of drugs (in minutes) used for neuroleptanalgesia (according to T. M. Darbinyan, 1969)

Preparation	Beginning of action		Maximum		Duration
	V/m	I/V	V/m	I/V	V/m	I/V
Fentanyl	5	0.5	15	2	45	30
Droperidol	15	5	40	20	480	360

An important feature of benzodiazepines is their selective anxiolytic action, which is practically absent in neuroleptics, and with increasing dosages - general sedative, anticonvulsant, analgesic potentiating and hypnotic (from hypnotic 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 GABA-ergic synapses. The endogenous ligand of these receptors has not been precisely established; it may be a modulating peptide released simultaneously with the mediator by 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 CNS synapses is significantly facilitated and enhanced. Thus, in moderate doses, benzodiazepines enhance the efficiency of inhibitory transmission in the brain where it is physiologically necessary and is included in a given place and at a given moment. Research by neurochemists has shown that these are primarily the feedback-based limiting short-axon interneurons at different levels of the CNS (primarily in the limbic emotiogenic system, in the cerebral cortex and cerebellum); it is believed 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 significantly. In other words, in the CNS at different levels there is a powerful and ramified (short- and long-axon) inhibitory system designed to limit excess excitatory signals, differentiate and identify significant signals. It is precisely its use in extreme activation of afferent systems in conditions of shock-induced trauma that represents a real pharmacological way to protect the brain and the body as a whole.

Based on pharmacological analysis, at least two types of BR are currently distinguished. Type I receptors are mainly localized in the limbic system and, apparently, in the cerebral cortex. Their activation is associated with anxiolytic effect and anticonvulsant action, while type II BRs are responsible for sedative properties, hypnotic effect, apparently do not have such a selective function and can interact with barbiturates. There is reason to believe that potentiation of analgesia and anesthesia, sometimes observed depression of the respiratory center are also due to the interaction of drugs with type II receptors. These properties of benzodiazepines (except for respiratory depression) are not excessive in shockogenic trauma and are useful in moderate manifestations. Benzodiazepine drugs differ somewhat from each other in the spectrum of pharmacological activity. An important advantage of them is the ability to simultaneously serve not only as means of shock prevention at the prehospital stage of care, but also as drugs for sedation and even anesthesia in the clinic. It is on these properties of benzodiazepines (sibazon - seduxen, diazepam are most often used) that one of the modern versions of "balanced anesthesia" (tranquiloanalgesia, ataranalgesia) is built. In essence, this method differs from neuroleptanalgesia only by replacing the neuroleptic with an anxiolytic. However, it provides a certain gain not only in safety, but also has a number of additional useful properties: a lower risk of hypotension (there are no peripheral alpha-adrenolytic effects). However, it is not possible to build complete surgical anesthesia on the basis of sibazon (as well as droperidol): its hypnotic properties are not sufficiently expressed. Phenazepam is not suitable for this either.

One of the most promising drugs for guiding a victim through all stages of medical care, including emergency surgery, is considered to be Rohypnol (flunitrazepam), which has the necessary qualities for this. However, all three substances - sibazon, phenazepam and Rohypnol - have a significant duration of action (T0.5 from 19 to 60 hours), which makes their effect uncontrollable and the elimination of excess or residual post-anesthetic depression presents significant difficulties. Depression caused by benzodiazepines is non-specifically and only partially relieved by adenosine antagonists (theophylline or euphylline). In recent years, a specific benzodiazepine antagonist (anexate or flumazenil) - an imidazole derivative of benzodiazepine - has been obtained and successfully tested in the clinic. The drug is low-toxic, reliable and removes all effects of benzodiazepines for a period of 3-5 hours. Thus, the problem of stopping the excessive psychodepressant effect of benzodiazepines can be considered fundamentally solved.

Comparative activity of diazepam (sibazon) and rohypnol (according to Bergmann H., 1978)

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

Moderate psychosedative effect of drugs of this group, not accompanied by additional hemodynamic disorders, on the contrary, protecting it from negative centrogenic effects, can be useful in cardiogenic shock, in agitated victims with mechanical injuries and burns. Disadvantages of sibazon, phenazepam 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 irritating properties was demonstrated using midazolam as an example and opened the way for further searches.

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

Another approach to the prevention and treatment of shock with neurotropic agents 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 do not cause "selective activation" of GABA receptors where it is physiologically justified at the moment, but their widespread activation proportional to the dose, replacing the natural mediator. This gives a different gradation of the psychosedative effect from sedation to anesthesia; the stress-protective effect manifests itself against the background of sedation and is less selective than with the introduction of benzodiazepines.

The anti-shock effect of sodium oxybutyrate has been studied better than others in experiments and clinical studies. It manifests itself clearly in smaller narcotic and similar doses. In these doses, the drug also has a distinct anti-hypoxic effect due to the formation of a redox pair in cells due to the partial conversion of oxybutyrate into succinic acid semialdehyde. The anti-hypoxic properties of oxybutyrate make a certain contribution to the anti-shock effect. In general, the stress-protective effect of sodium oxybutyrate is not as selective as that of benzodiazepines, and the anti-shock and anti-hypoxic properties correlate rather with general sedative and hypnotic ones.

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