Medicines that protect biological membranes from damage

Pathogenetic factors that cause cell damage in shock and ischemia are numerous. Cells of various organs and tissues are unequally sensitive to these factors, and in the same tissue (organ), lesions are most often focal in nature, reflecting the spatial distribution of local microcirculation disorders and the effects of cytoaggressive substances, metabolic and ATP synthesis disorders, "slag" and pH shifts, other difficult-to-account changes. As a result of a complex of structural and functional disorders (in the beginning - reversible), a state is formed that has been called the "shock cell".

Among the many interrelated factors in the pathogenesis of the "shock cell," it seems methodologically useful to selectively artificially those that are amenable to a positive pharmacological effect and allow us to formulate a number of additional approaches to the pharmacotherapy of shock. These approaches have been extensively studied experimentally, but only partially realized in clinical practice. The need for additional approaches is explained by the fact that measures and means that correct violations of systemic and regional blood flow, respiration and oxygen transport function of blood, hemocoagulation, acid-base state and other therapeutic interventions of the systemic level belong to the crucial importance in preventing the transition of the cell to a "shock state". Taking into account this situation, it is possible to single out the following known and promising directions, mainly the cellular level of pharmacological prophylaxis and therapy of shock disorders:

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

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

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

1. antihypoxic drugs (antihypoxic drugs);
2. oxidation substrates and macroergic compounds.

Different in structure and functional significance, cell membranes (plasma, endoplasmic, mitochondrial, microsomal, lysosomal, along with embedded or strongly sorbed proteins) constitute over 80% of the dry cell mass. They create a structural basis for the ordered arrangement and optimum operation of the enzymes of electron transport in the respiratory chain and oxidative phosphorylation, adaptive and repair synthesis of proteins of different purposes and nucleotides, enzymes (various ATP-as), carrying out volatile transport of electrolytes (Na, Ca, K , Cl, aqueous and hydroxyl, phosphate and other ions) and a number of metabolites. The specific functional activity of different types of cells is closely related to cell membranes.

Naturally, violations of the integrity and functional capacity of membranes in shock and hypoxia of different nature lead to severe disruption of the activity and viability of cells, in particular:

• further deterioration of the energy status of the cells due to the separation of respiration and phosphorylation and reduction of ATP production per unit consumed 02;
• development of electrolyte imbalance due to disruption of the function of membrane ATP-as (various ion pumps) and ion transport through the semipermeable membrane lost in accordance with the ion gradient (cytoplasmic overload by Na, Ca ions, depletion of K ions, and other more subtle shifts in trace element 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 into the cytoplasm contained in organelles of proteolytic and other hydrolytic enzymes is known to bind the processes of autolysis in reversibly damaged cells and the transfer of damage to irreversible ones.

This, far from complete list of violations sufficiently brightly illustrates the importance of the problem of pharmacological protection of biological membranes in shock. However, the purposeful development of the problem has been launched relatively recently and practical success has so far been possible to assess as very modest.

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

[1], [2], [3], [4], [5]

Antioxidants

The peroxide oxidation of lipids (LPO) of various membranes has recently been given great importance in the mechanism of irreversible cell damage in the zones of reduced blood supply bordering with necrosis and in the reperfusion of tissues. LPO is carried out in a non-enzymatic way, mainly iron complexes with the participation of oxygen and chemically aggressive free radicals, which can be formed during the disturbed metabolism. In intact tissues there is a rather powerful antioxidant system, including a number of enzymes (superoxide dismutase, catalase, peroxidase) and redox systems with high reducing activity, intercepting free radicals (glutathione, tocopherol, etc.). Cofactor in a rather complex system of endogenous antioxidant protection is selenium. Between the complex of LPO factors and the body's antioxidant system there is a dynamic balance.

As exogenous pharmacological antioxidants, synthetic substances (dibunol, 3-hydroxypyridine derivatives, sodium selenite, etc.) and natural antioxidants (tocopherol, plant catechins of the vitamin P group, reduced glutathione, etc.) can act as exogenous pharmacological antioxidants. Drugs of the second group are less toxic, able to be included in the endogenous system of antioxidant reactions and, apparently, even with a relatively long-term use, do not reduce the activity of antioxidant enzymes. 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 be applied only a short course at the altitude of LPO activation.

There are many publications that experimentally confirm the feasibility of suppressing LPO in the modeling of acute myocardial ischemia followed by reperfusion, with septic, endotoxin, hemorrhagic and traumatic shock. Since the use of natural antioxidants (except reduced glutathione) in acute situations is technically impossible because of their insolubility in water, synthetic experiments with higher antioxidant potentials were usually used in experiments of different authors. The results of these rather numerous experiments can be assessed positively: a decrease in the size of the focus of necrosis in myocardial ischemia was observed due to the preservation of border zones, a decrease in the frequency of severe rhythm disturbances, and in the case of shock, longevity of experimental animals and survival at a fixed time. Thus, this direction of pharmacological protection of biological membranes from damage in case of shock and myocardial infarction (as a cause of possible cardiogenic shock) should be considered promising. Despite a good theoretical justification for the need to use antioxidants as traps of hydroxyl radicals, the experience of their clinical application is too small and the results are in many ways contradictory.

[6], [7], [8], [9], [10]

Inhibitors of proteolytic enzymes

The meaning of the use of drugs of this group (trasilol, countercracker, halidor, etc.) consists in inhibiting the secondary damaging autolytic action of lysosomal proteolytic enzymes that are released due to increased permeability of the lysosome membranes by blood cells and tissue elements due to hypoxia, acidosis, in violation of their integrity 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 promote the transfer of "shock cells" into a state of irreversible damage.

The positive effect of inhibitors of proteolytic enzymes on the course of shock of different genesis, myocardial infarction has been shown by many authors in various experiments. This provided a basis for the practical application of proteolysis inhibitors in shock and myocardial infarction with satisfactory results. Not solving, of course, the problem as a whole, these remedies are useful additional factors of shock therapy.

Glucocorticoids and preparations 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 application of macrocoses of glucocorticoids (methylprednisolone, dexamethasone, etc.) with myocardial infarction and cerebral ischemia, the first overly optimistic evaluations of clinicians have been replaced by a restrained attitude and even denial of the usefulness of the drugs. From the many-sided action of glucocorticoids on the body in this section, it is advisable to isolate the protective effect of them 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, which inhibit the action of lysosomal phospholipases. Other putative mechanisms of the membrane-stabilizing action 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 inhibits the release of arachidonic acid from the membranes and its involvement in the metabolic cascade with the formation of leukotrienes, prostaglandins and their secondary products (thromboxanes, prostacyclin). Thus, simultaneously the function of these chemical intermediaries in allergic, inflammatory and thrombotic processes is inhibited.

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

Another factor damaging the membrane in shock and myocardial infarction are non-esterified fatty acids (NEFC) with a long (C12-C22) carbon chain, which exert a detergent effect on biological membranes. With the stress accompanying this pathology, there are quite favorable conditions - ejection of catecholamines and ACTH. These stress hormones are carried out (catecholamines through beta-AR) activation of adenylate cyclase in adipocytes with the transfer into the active form of lipases, the splitting of fat stores and the release of significant amounts of NEFLC into the blood. The latter not only have a damaging effect on membranes, but also competitively inhibit the utilization of glucose by cells. Stress-protective agents and beta-adrenolytics (anaprilin or propranolol, etc.) have the most distinct inhibitory effect on the yield of NEFLC. The use of beta-adrenoceptors is limited to the initial stage of myocardial infarction, if for them there are no contraindications. In this case, their contribution can be significant, however, stress protective means are more common.

Another way to reduce excess NLC is to increase their utilization by cells in the overall final oxidation pathway in the mitochondria. One of the stages that limit the utilization of NEFIC is its transport through the internal membrane of the mitochondria. The process is carried out with the help of transferase and a low-molecular transport carrier - carnitine. Synthesis of carnitine is quite simple and its use in the experiment and clinic for myocardial ischemia and shock can reduce the level of NEF in the blood by more intensive utilization of them in tissues and helps to reduce the size of the focus of necrosis in the heart, more favorable to the course of shock.

A group of medicinal substances with antihypoxic properties, which increase in one way or another the energy potential of the cells, possesses a membrane stabilizing action. Since the constant flow of ATP energy is required to maintain the semipermeability of biological membranes and the operation of various transport ATP-as (ion pumps), the preservation of the functional structure of membranes, their surface charge, the ability of membrane receptors to react to mediators and hormones, and mitochondria to carry out oxidative phosphorylation, with the energy potential of the cell. Consequently, the specific antihypoxic effect of the drugs of this group, as well as of exogenous high-energy compounds, already contributes to the stabilization of membranes under conditions of hypoxia accompanying any kind of shock. In addition, some antihypoxic drugs (gutimine, amtizol, etamerzol, etc.) are also associated with antihypoxic activity, which is clearly superior to tocopherol, a kind of antioxidant standard. Unlike antihypoxic agents (antihypoxic agents), for which antioxidant properties are not necessary and are a useful addition to their basic activity, typical antioxidants (dibunol, oxymetacin, tocopherol, etc.) are completely devoid of antihypoxic effect.