Drugs that protect biological membranes from damage

Pathogenetic factors causing cell damage during shock and ischemia are numerous. Cells of different organs and tissues are unequally sensitive to these factors, and in the same tissue (organ) damage is most often focal, reflecting the spatial distribution of local microcirculation disorders and the effects of cytoaggressive substances, metabolic disorders and ATP synthesis, removal of "slags" and pH shifts, and other changes that are difficult to account for. As a result of a complex of structural and functional disorders (initially reversible), a condition is formed that is called a "shock cell".

Among the many interrelated factors of the pathogenesis of the "shock cell", it seems methodologically useful to single out, to a certain extent artificially, those that are amenable to positive pharmacological action and allow formulating a number of additional approaches to the pharmacotherapy of shock. These approaches have been studied quite thoroughly experimentally, but only partially implemented in clinical practice. The need for additional approaches is explained by the fact that the decisive role in preventing the transition of the cell to the "shock state" belongs to measures and means that correct disorders of systemic and regional blood flow, respiration and oxygen transport function of the blood, hemocoagulation, acid-base balance and other therapeutic interventions at the systemic level. Taking this into account, the following known and promising directions, mainly at the cellular level, of pharmacological prevention and therapy of disorders in shock can be identified:

Development and study of drugs that protect biological membranes from damage:

1. antioxidants (natural and synthetic);
2. proteolytic enzyme inhibitors;
3. glucocorticoids and drugs of other pharmacological groups.

Development and study of drugs that increase the energy potential of cells:

1. antihypoxants (antihypoxic drugs);
2. oxidation substrates and high-energy compounds.

Cell membranes of various structures and functional significance (plasma, endoplasmic, mitochondrial, microsomal, lysosomal together with proteins embedded or firmly sorbed on them) make up over 80% of the dry mass of the cell. They create the structural basis for the ordered arrangement and optimum operation of enzymes of electron transport in the respiratory chain and oxidative phosphorylation, adaptive and reparative synthesis of proteins of various purposes and nucleotides, enzymes (various ATPases) that carry out energy-dependent transport of electrolytes (ions Na, Ca, K, Cl, water and hydroxyl, phosphate and other ions) and a number of metabolites. Specific functional activity of different types of cells is closely related to cell membranes.

Naturally, disruptions in the integrity and functional capacity of membranes during shock and hypoxia of various natures lead to severe disruptions in the activity and viability of cells, in particular:

• further deterioration of the energy status of the cell due to the uncoupling of respiration and phosphorylation and a reduction in ATP production per unit of consumed O2;
• the development of electrolyte imbalance due to disruption of the function of membrane ATPases (various ion pumps) and the movement of ions through a membrane losing semipermeability in accordance with the ion gradient (overload of the cytoplasm with Na, Ca ions, depletion of K ions, and other more subtle shifts in the microelement composition);
• disorders of the functioning of the biosynthetic apparatus and a decrease in the reparative capacity of the cell in the post-shock period;
• an increase in the permeability of lysosomal membranes with the release of proteolytic and other hydrolytic enzymes contained in organelles into the cytoplasm is known to link the processes of autolysis in reversibly damaged cells and the transition of damage to irreversible ones.

This far from complete list of violations quite vividly illustrates the importance of the problem of pharmacological protection of biological membranes in shock. However, targeted development of the problem began relatively recently and practical successes can be assessed as very modest.

The factors of pathogenesis of membrane damage in ischemia and shock, the formation and action of which can potentially be targeted by pharmacological agents, are different. Accordingly, drugs with a protective effect can be conditionally divided into several groups.

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Antioxidants

Lipid peroxidation (LPO) of various membranes has recently been given great importance in the mechanism of irreversible cell damage in the areas of reduced blood supply bordering necrosis and during tissue reperfusion. LPO is carried out non-enzymatically, mainly by iron complexes with the participation of oxygen and chemically aggressive free radicals that can form during impaired metabolism. Intact tissues have a fairly powerful antioxidant system, including a number of enzymes (superoxide dismutase, catalase, peroxidase) and redox systems with high restorative activity that intercept free radicals (glutathione, tocopherol, etc.). Selenium acts as a cofactor in a rather complex system of endogenous antioxidant protection. There is a dynamic balance between the complex of LPO factors and the antioxidant system of the body.

Synthetic substances (dibunol, 3-oxypyridine derivatives, sodium selinite, etc.) and natural antioxidants (tocopherol, plant catechins of the vitamin P group, reduced glutathione, etc.) can act as exogenous pharmacological antioxidants. The drugs of the second group are less toxic, have the ability to be included in the endogenous system of antioxidant reactions and, apparently, do not reduce the activity of antioxidant enzymes even with relatively long-term use. Synthetic antioxidants are not only more toxic, but also gradually inhibit the activity of tissue antioxidant enzymes, limiting the possibility of physiological protection. Therefore, they can only be used for a short course at the height of LPO activation.

There are many publications experimentally confirming the expediency of LPO suppression in modeling acute myocardial ischemia with subsequent reperfusion, in septic, endotoxin, hemorrhagic and traumatic shock. Since the use of natural antioxidants (except for reduced glutathione) in acute situations is technically impossible due to their insolubility in water, in experiments by different authors, synthetic drugs were usually used, which also had a higher antioxidant potential. The results of these fairly numerous experiments can be assessed positively: a decrease in the size of the necrosis focus in myocardial ischemia due to the preservation of border zones, a decrease in the frequency of severe rhythm disturbances, and in shock - an extension of the life expectancy of experimental animals and an increase in survival in fixed periods were observed. Thus, this direction of pharmacological protection of biological membranes from damage in shock and myocardial infarction (as a cause of possible cardiogenic shock) should be recognized as promising. Despite the good theoretical justification for the need to use antioxidants as hydroxyl radical scavengers, experience with their clinical use is too small and the results are largely contradictory.

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Proteolytic enzyme inhibitors

The purpose of using drugs of this group (trasilol, contrical, halidore, etc.) is to inhibit the secondary damaging autolytic action of lysosomal proteolytic enzymes, which are released due to increased permeability of lysosome membranes by blood cells and tissue elements due to hypoxia, acidosis, when their integrity is compromised, and under the influence of a number of locally formed biologically active substances (autacoids). The released proteolytic enzymes in turn begin to destroy the protein complexes of the membranes and also contribute to the transfer of "shock cells" to a state of irreversible damage.

The positive effect of proteolytic enzyme inhibitors on the course of shock of various genesis and myocardial infarction has been demonstrated by many authors in various experiments. This has provided grounds for the practical use of proteolysis inhibitors in shock and myocardial infarction with satisfactory results. Without solving the problem as a whole, of course, these agents are useful additional factors in shock therapy.

Glucocorticoids and drugs of other pharmacological groups

Glucocorticoids have a multifaceted effect on the body, and their effectiveness in septic and anaphylactic shock is not in doubt today. As for the shock use of macrodoses of glucocorticoids (methylprednisolone, dexamethasone, etc.) in myocardial infarction and cerebral ischemia, the first overly optimistic assessments of clinicians have been replaced by a reserved attitude and even denial of the usefulness of the drugs. From the multifaceted effect of glucocorticoids on the body, in this section it is advisable to single out their protective effect on biological membranes. This effect is largely (or unambiguously) due to the ability of glucocorticoids through the genetic apparatus of cells to activate the synthesis of specific proteins - lipocortins, inhibiting the action of lysosomal phospholipases. Other supposed mechanisms of the membrane-stabilizing effect of glucocorticoids do not yet have a sufficiently serious justification.

Phospholipases (A and B) of lysosomes attack the main components of biological membranes (plasma and organelle membranes) - phospholipids, causing their destruction, structural and functional disintegration of various membranes. Inhibition of phospholipase A also slows down the release of arachidonic acid from membranes and its involvement in the metabolic cascade with the formation of leukotrienes, prostaglandins and their secondary products (thromboxanes, prostacyclin). Thus, the function of these chemical mediators in allergic, inflammatory and thrombotic processes is simultaneously suppressed.

It should be emphasized, however, that under conditions of energy deficiency, the very energy-intensive synthesis of lipocortins may be difficult and the mechanism of mediated inhibition of phospholipases may prove unreliable. This has forced researchers to search for simple synthetic substances capable of selectively inhibiting the hydrolytic effects of phospholipases. The first successes in this direction allow us to optimistically assess the prospects of such an approach to protecting "shock cells" from autolytic damage to membrane structures.

Another factor damaging membranes in shock and myocardial infarction are non-esterified fatty acids (NEFA) with a long (C12-C22) carbon chain, which have a detergent effect on biological membranes. During stress accompanying this pathology, there are quite favorable conditions - the release of catecholamines and ACTH. These stress hormones (catecholamines - through beta-AR) activate adenylate cyclase in adipocytes with the conversion of lipases into an active form, the breakdown of fat reserves and the release of significant amounts of NEFA into the blood. The latter not only have a damaging effect on membranes, but also competitively inhibit the utilization of glucose by cells. The most pronounced inhibitory effect on the release of NEFA is exerted by stress-protective agents and beta-adrenolytics (anaprilin or propranolol, etc.). The use of beta-adrenolytics is limited to the initial stage of myocardial infarction, unless there are contraindications for them. In this case, their contribution can be significant, but stress-protective agents are of more general importance.

Another way to reduce the excess of NEFA is to increase their utilization by cells in the general final oxidation pathway in mitochondria. One of the stages limiting the utilization of NEFA is their transport through the inner mitochondrial membrane. The process is carried out with the help of transferase and a low-molecular shuttle carrier - carnitine. The synthesis of carnitine is quite simple and its use in experiments and clinical practice in myocardial ischemia and shock allows to reduce the level of NEFA in the blood due to their more intensive utilization in tissues and helps to reduce the size of the necrotic focus in the heart, a more favorable course of shock.

A group of medicinal substances with antihypoxic properties, which increase the energy potential of cells in one way or another, also have a membrane-stabilizing effect. Since a constant influx of ATP energy is necessary to maintain the semipermeability of biological membranes and the operation of various transport ATPases (ion pumps), maintaining the functional structure of membranes, their surface charge, the ability of membrane receptors to respond to mediators and hormones, and mitochondria to carry out oxidative phosphorylation, are directly related to the energy potential of the cell. Consequently, the specific antihypoxic effect of drugs in this group, as well as exogenous high-energy compounds, already in its essence contributes to the stabilization of membranes in conditions of hypoxia accompanying any type of shock. In addition, some antihypoxic drugs (gutimin, amtizol, etamerzol, etc.) also have antihypoxic activity, significantly exceeding tocopherol, a kind of standard of antioxidants. Unlike antihypoxic agents (antihypoxants), for which antioxidant properties are not necessary and are a useful addition to their main activity, typical antioxidants (dibunol, oxymethacin, tocopherol, etc.) are completely devoid of antihypoxic effect.