Inhibition of platelet aggregation. Antiplatelet agents. Translate the phrase “Nootropil inhibits the aggregation of activated platelets and restores configurational properties”

Platelet aggregation is the desire of blood platelets, fragments of megakaryocytes called platelets or Bizzocero plaques, “sensing” an emergency situation accompanied by blood loss to come together in order to, with the help of other “liquidators” (present or formed in the process), close the damage in the vessel.

A small injury with a violation of the integrity of small vessels, as a rule (if everything is in order with the hemostasis system), does not threaten big troubles. The blood flowing from the wound stops after some time, and in such cases people, denying their participation, say: “It stopped on its own.” And, probably, not everyone knows such a process as platelet aggregation, which plays an important role in stopping bleeding and preventing the loss of precious fluid for the body.

Platelet aggregation is one of the stages of stopping bleeding

Behind such a seemingly trifle as stopping bleeding from the vessels of the microvasculature (arterioles, venules, capillaries) there are complex, sequential processes:

• In response to damage, the microcirculatory vessels spasm and thereby partially impede the free flow of blood;
• Blood platelets - platelets, which attach to the damaged area, rush to the scene of the accident, trying to close the “gap” ( platelet adhesion);
• The number of platelets at the site of injury increases rapidly (accumulation), they begin to crowd together and form conglomerates - this occurs platelet aggregation, which represents the initial but very important stage of blood clot formation;
• As a result of the aggregation of blood platelets, a loose platelet plug (irreversible platelet aggregation), this plug, although impenetrable to plasma, is not very stable and reliable - touch it a little and blood will flow again;
• The blood clot contracts under the influence of the contractile protein of platelets (thromboplastin), fibrin threads make the blood clot dense, which stops bleeding ( retraction of thrombin thrombus).

stages of blood clot formation

Obviously, platelet aggregation is not the final stage of stopping bleeding, it is just one of the stages of the process, but this does not make it any less important. How this reaction is carried out, what components are involved in this will be described in the following sections, but, first of all, the reader should be informed that platelet aggregation, while performing a protective function in healthy people, can also have a downside. Platelets do not always behave this way - sitting quietly and calmly for the time being, they are quickly activated, stick to the walls of blood vessels and stick together if necessary (if the blood vessel from which blood flows is damaged).

Increased platelet aggregation implies the excessive intensity of the actions of these blood platelets, when they are unnecessarily activated (in the absence of bleeding), stick together and thus contribute to the formation of blood clots unnecessary for the body, which subsequently, moving through the bloodstream, close the blood vessel and disrupt the nutrition of the tissues of vital organs. This can happen anywhere: in the vessels supplying blood to the heart (myocardial infarction), lungs (pulmonary infarction), brain (ischemic stroke), etc., which is why medicinal forms of antiplatelet agents are so widely prescribed for the prevention and treatment of these pathological conditions.

Thromboembolism of leading arteries often has a sad outcome, but it all started with a small thing - with spontaneous platelet aggregation, but, unfortunately, when such an important (aggregation) function for some reason has already undergone pathological changes...

Platelet aggregation in blood tests

To study the aggregation ability of platelets, conditions close to natural (circulation in the bloodstream) are created for the cells. Testing is carried out on glass using inducer substances taken in certain concentrations (induced platelet aggregation), which, in general, are involved in this process in a living organism (in vivo) with bleeding-stimulated aggregation of blood platelets (ADP, collagen, thrombin , adrenaline). In some laboratories, substances that are not present in the body but have the ability to cause aggregation, for example, ristomycin (ristocetin), are used for analysis. It should be noted that each inductor has its own limits of normal values, which can be found by looking at the table. But just get acquainted, because the norm is given only tentatively, it can expand or narrow its scope in different laboratories - this depends on the reference values ​​of each CDL.

Table: normal platelet aggregation ability depending on the inducer substance

Of particular importance for the diagnosis of pathological conditions (especially cardiovascular diseases) is spontaneous platelet aggregation (SAT), when an excessive number of blood platelets glued together circulate freely through the blood vessels, causing a number of disorders, and this occurs, first of all, in the microcirculation zone :

1. Spontaneous platelet aggregation over a long period of time threatens to lead to changes in the walls of blood vessels (especially for microvasculature vessels);
2. SAT creates conditions for increasing the ability of platelets to form aggregates, thereby increasing the risk of developing cardiovascular pathology, its progression and the occurrence of serious complications and consequences against this background.

Most often, spontaneous platelet aggregation in laboratory conditions is determined by:

• Measuring the optical density of a platelet suspension;
• Through morphological (visual) assessment of aggregated blood platelets.

In order to diagnose and determine the nosological form of thrombocytopathies, it is undoubtedly better to use special modern equipment - aggregometers (optical, recording the aggregation of blood platelets in plasma enriched with them, or conductometric, which measure this indicator in whole blood). These devices continuously record everything that happens to the blood platelets, and then display their measurements graphically (curve - aggregogram). Such diagnostic methods are quite reliable, however, they are labor-intensive and require large quantities of plasma for research.

Deviations from the norm create problems during pregnancy

Both low and high aggregation capacity are equally bad. In this regard, in specific circumstances, when platelet aggregation may be increased or decreased compared to the norm, a blood test that calculates this indicator becomes mandatory.

One of these circumstances is the examination of women who are in a state of bearing a child, because in obstetrics, deviations of platelet aggregation ability from the norm often have bad consequences. During the gestational period, a woman’s body begins to prepare for the upcoming blood loss long ago, so coagulation rates increase slightly, but a moderate degree of increase is noted, which should not indicate hyperaggregation.

Increased platelet aggregation can cause thrombosis, but on the other hand, if it is reduced, there is a risk of bleeding. For a favorable pregnancy, you need a middle...

The normal platelet aggregation capacity during pregnancy usually ranges from 30 to 60%(regardless of the inductor substance used) and again: everything is approximate - the results should be obtained from the laboratory that performed the analysis, where specialists will compare them with reference values ​​and report deviations, if any. Only in such cases can one expect not to encounter either hypo- or hyperaggregation and avoid thrombosis and bleeding.

Platelet aggregation with inducers

A blood test that determines the aggregation ability of representatives of the platelet link should be carried out with several inducers at once (there must be at least four of them) in order to know at what level of the process the failure occurs.

Aggregation of blood platelets with ADP

The study of platelet aggregation ability with ADP is carried out in order to identify spontaneous platelet aggregation or diagnose thrombotic conditions that occur in a certain pathology:

1. Atherosclerotic process;
2. Arterial hypertension;
3. IHD, myocardial infarction;
4. Cerebral circulation disorders;
5. Diabetes mellitus;
6. Hyperlipoproteinemia (changes in the lipid spectrum, increased low-density lipoproteins, increased atherogenicity coefficient);
7. Hereditary thrombopathy;
8. Thrombocytopathies accompanying hemoblastosis;
9. When taking certain medications that can inhibit the activity of platelet cells.

The downward deviation is given by:

• Glanzmann's thrombasthenia (hereditary pathology caused by the absence or defect of the membrane receptor for fibrinogen and glycoproteins IIb-IIIa);
• Essential atrombia (differs from thrombasthenia by incomplete impairment of the functional abilities of platelets;
• Wiskott-Aldrich syndrome (a rare sex-linked recessive disease characterized by changes in the shape and decrease in cell size);
• Aspirin-like syndrome (pathology associated with a violation of the “release reaction” and the 2nd phase of aggregation);
• Thrombocytopathy in uremic syndrome;
• Secondary thrombocytopathies (with hematological malignancies, hypothyroidism, treatment with antiplatelet agents, NSAIDs - non-steroidal anti-inflammatory drugs, antibiotics, diuretics and drugs that lower blood pressure).

An increase in indicators is observed when:

• Viscous platelet syndrome (tendency to adhesion, increased platelet aggregation);
• Activation of cells of the platelet part of the coagulation system, caused by various factors: psycho-emotional stress, medications, formation of immune complexes for certain reasons, etc.;
• Resistance to acetylsalicylic acid.

Induced aggregation with collagen

Deviation from the norm when using a reaction with collagen may indicate that disturbances already occur at the level of adhesion. Indicators tend to decrease, in principle, with the same pathology as in samples with ADP. Increased platelet aggregation is observed in viscous platelet syndrome and vasculitis of various origins.

Determination of platelet aggregation ability in a test with adrenaline

Adrenaline, being an inducer of the general aggregation activity of blood platelets, acts as the most informative indicator of all internal activation mechanisms, including the very important, but very vulnerable, “release reaction.” A downward shift in values ​​is observed in conditions typical for analysis with ADP and collagen, so there is no point in listing everything again. As for the increase in the aggregation activity of blood platelets, there is nothing new here either: increased platelet viscosity and activation of platelet hemostasis in certain situations (stress, medications, etc.).

Study of ristocetin cofactor activity

The values ​​of this indicator reflect the activity of von Willebrand factor; the test is mainly used to diagnose a disease with the same name.

It should be noted that carrying out this testing using inductors is useful not only for determining the ability of blood platelets to aggregate. These tests allow you to evaluate the effectiveness of antiplatelet drugs during treatment and make it possible to select the correct doses of drugs.

Information for the curious

Meanwhile, the reader can rightly reproach that, having begun the description of the topic with tests, variants of their norm and pathological changes, the author said too little about the blood plates themselves, their functions and behavior during bleeding-stimulated aggregation. The text does not highlight the mechanisms of platelet activation, nor does it explain the essence of all the reactions behind cell gluing and the formation of a hemostatic plug.

All this can be easily corrected by allowing people with increased interest to follow the entire process described in the sections below, from beginning to end, independently understand the individual subtleties and indicate the importance of each of the components of the reaction.

The important role of platelets

Platelets are very important in the implementation of vascular-platelet hemostasis, which is reflected in the name of the process. In general, their functions consist of solving the following tasks:

1. Blood plates, performing an angiotrophic function, maintain the normal structure and functional abilities of the walls of small-caliber vessels;
2. Having adhesive-aggregation abilities, which consist in the fact that cells gather in “clumps” and stick to damaged areas of blood vessels (adhesion), quickly forming a hemostatic plug (platelet aggregation), they can stop minor bleeding in 1 – 2 minutes;
3. The tasks of the blood plates include maintaining the spasm of injured hemocapillaries at the proper level - these cells do not allow the vessels to relax, because this will cause increased bleeding;
4. Platelets are not only present, but also take an active part in the coagulation processes, and, in addition, affect the fibrinolysis reaction.

The functions of platelet adhesion and aggregation are inextricably linked and combined into one - adhesive-aggregation (this ability of blood cells was discovered at the end of the year before last - the 9th century). The fact is that a platelet plug begins to form even before the moment when platelets arrive in place and begin to stick to the basement membrane of the vascular walls.

Although the attachment of platelets to the walls of capillaries is facilitated by various connective tissue components, collagen is recognized as the main stimulator of the first stage of vascular-platelet hemostasis.

By changing their “look” they acquire new opportunities

It is interesting that the blood platelets, having “learned” about an emergency situation in the body, begin to intensively prepare before arriving at the scene of the incident:

• In a split second, they change their appearance: from flat disc-shaped cells they turn into spherical shapes, throwing out pseudopodia (long processes that were not there before and which urgently became needed to cling to tissue and communicate with each other);
• Platelets arrive to a damaged vessel fully equipped, that is, well prepared for both adhesion and aggregation, so it takes them up to 5 seconds to attach.
• At the same time, platelets circulating in the bloodstream “do not sit idle”, they search and quickly find their “brothers”, gather in groups (from 3 to 20 cells) and stick together, forming conglomerates;
• Conglomerates are sent to the damaged area to connect with platelets that were the first (primarily adherent) to arrive at the scene and adhere to the exposed basement membrane of the blood vessel.

All these actions are carried out by platelets in order to very quickly increase the size of the hemostatic plug, which within a short time (from 1 to 3 minutes) will become capable of closing any gap in the blood vessel of the microvasculature in order to stop bleeding.

Behind aggregation is a complex biochemical process

Adhesion and aggregation of platelets is not such a simple reaction as it might seem at first glance. This is a complex multi-stage biochemical process that occurs with the participation of various exogenous (external) and endogenous (internal, coming from the blood plates themselves) factors: reaction stimulants, energy consumption, significant restructuring of Bizzocero plaques. For example, for full functioning, platelets require von Willebrand factor (a glycoprotein, a plasma cofactor for the adhesion of blood platelets to collagen), its production occurs in the vascular walls. So, platelets, moving through blood vessels, stock up on this glycoprotein for future use, storing it in their granules so that, if necessary (when activated), they release it into the environment.

Platelet aggregation is impossible without the participation of a number of stimulants, which are simultaneously activated when the reaction starts:

1. Collagen is the main stimulator of platelet adhesion;
2. ADP - this component takes on a leading role in the first stage of aggregation: first, ADP is released in small quantities from the injured vessel wall and red blood cells (erythrocytes), which are also present at the scene of the accident. Then the hemostasis zone is supplied with this stimulator by the Bizzocero plaques themselves (ATP → ADP), which have managed to initially adhere and activate (the “release reaction” characteristic of platelets);
3. In parallel with ADP, other aggregation agonists - adrenaline and serotonin - come from platelet granules; membrane enzymes are activated in the blood plates, promoting the formation of powerful reaction stimulants - arachidonic acid (C 20 H 32 O 2) and its derivatives, among which is the most active aggregating substance - thromboxane;
4. A significant link in the regulation of platelet aggregation abilities is the prostaglandin system: in the active mode, prostaglandin endoperoxides are formed in the endothelium and smooth muscle cells; they can also be converted into thromboxane. However, at the last stage of aggregation, when it is no longer necessary, these substances change direction and begin to provide the release of the vasodilator prostacyclin (PGI 2) into the blood, which dilates blood vessels and significantly suppresses platelet aggregation;
5. The “release reaction” of intraplatelet factors, strengthening and increasing the strength of the hemostatic plug with fibrin, is completed by a very strong aggregating agent - thrombin, which is capable of causing aggregation in doses that are tiny compared to those needed for blood to clot.

Of course, the listed mechanisms are in the area of ​​attention of doctors of a certain profile, however, perhaps they will also be of interest to particularly inquisitive readers who have set the goal of thoroughly understanding the complex reactions of platelet hemostasis. In addition, such an acquaintance will help to understand the origin of a number of diseases associated with blood clotting disorders at this stage.

Vulnerabilities

Disturbances in certain parts of platelet hemostasis form a number of pathological conditions (hereditary and acquired).

The most vulnerable in the mechanism of platelet aggregation turned out to be a very significant “release reaction” - without it, the process of crowding and gluing of cells ends as soon as it begins. A hemostatic plug, of course, does not form in such cases.

In addition, for high-quality blood clotting in the microcirculation zone, there is a need for the presence of various substances of a non-protein (Ca 2+, Mg 2+, phospholipid factor), as well as protein (albumin, fibrinogen, individual components of the gamma fraction, etc.) nature.

Proteins are needed by platelets in order to create comfortable conditions for them, the so-called “plasmic atmosphere”, and only then will the blood platelets efficiently perform the tasks assigned to them. However, many protein breakdown products (in particular, those obtained from the breakdown of fibrinogen and fibrin) interfere with platelet aggregation and significantly inhibit it.

Meanwhile, provided that all participants in platelet hemostasis are functioning normally, platelet aggregation is quite capable of stopping bleeding in the microcirculation zone, but in large vessels, where the pressure on the walls is higher, a plug not reinforced with fibrin will be untenable and, simply put, will “fly out” resuming bleeding.

Antiplatelet agents(Greek anti- against + Lat. aggregans, aggregantis adding) - drugs that inhibit platelet aggregation. Due to the lack of drugs that selectively block platelet aggregation, drugs that have a concomitant antiaggregation effect are used as antiplatelet drugs in medical practice. These include the non-narcotic analgesic acetylsalicylic acid (see. Analgesics ), anti-gout drug anturan (see. Antigout drugs ), some vasodilators and antispasmodics (for example, dipyridamole, pentoxifylline, xanthinol nicotinate). as well as the blood substitute rheopolyglucin.

The mechanisms of action of A. may be due to the ability of drugs to disrupt the metabolism of arachidonic acid, increase the intracellular level of cyclic AMP (cAMP), change the state of the cytoplasmic membrane of platelets, etc.

Acetylsalicylic acid irreversibly inhibits prostaglandin H-synthetase (cyclooxygenase) by acetylation of the active centers of this enzyme. As a result, the formation of prostaglandin H2 and thromboxane A2 from arachidonic acid, which are endogenous inducers of platelet aggregation, is blocked. Inhibition of platelet aggregation develops after 1-3 h after taking this drug orally and continues for several days. The latter is due to the fact that restoration of cyclooxygenase activity after irreversible inhibition of this enzyme by acetylsalicylic acid is possible only due to the formation of a new enzyme, and platelets do not have the ability to synthesize proteins, including enzymes, because are anucleate cells. Thus, after a single dose of acetylsalicylic acid, the duration of its antiaggregation effect corresponds to the average lifespan of a platelet (8-11 days). In this regard, as A. acetylsalicylic acid is prescribed at 0.05-0.1 G 1 time a day or 1-1.5 G 2-3 times a week; use in higher doses or with greater frequency is inappropriate, because At the same time, acetylsalicylic acid inhibits cyclooxygenase in the vascular wall for a long time and thereby disrupts the formation of prostacyclin from arachidonic acid, which is an endogenous antagonist of thromboxane A 2 in its effect on platelet aggregation and vascular tone. Restoration of cyclooxygenase activity of the vascular wall in humans after a single dose of acetylsalicylic acid at a dose of 0.5 G occurs within 6 h due to the formation of cyclooxygenase in the endothelium and vascular intimal cells. The aggregation ability of blood after discontinuation of acetylsalicylic acid is restored slowly (within several days) and occurs due to a change in the population of platelets with blocked cyclooxygenase to newly formed platelets with unimpaired cyclooxygenase activity.

According to the mechanism of action on platelet aggregation, anturan is somewhat different from acetylsalicylic acid.

The sulfide metabolites of anturanium formed in the body have the ability to reversibly block cyclooxygenase. However, this is apparently not the main reason for its antiaggregation effect, because with a single dose, anturan is reversible, and with long-term use, it irreversibly inhibits platelet aggregation. The latter is due to the fact that with prolonged use, anturan causes irreversible changes in the cytoplasmic membrane of platelets. As a result, the adhesion of platelets to the vascular endothelium is weakened, and the processes of release of a number of substances from these cells (ADP, serotonin, thromboxane) that induce platelet aggregation are disrupted. The antiaggregation effect of anturan develops gradually and reaches a maximum after several months of its constant use. When the drug is discontinued after long-term (for 3 months) use, inhibition of platelet aggregation persists for 1-2 weeks. As A. anturan is prescribed in a daily dose of 0.6-0.8 G(usually in 2-4 doses).

Dipyridamole (synonym: chimes, persantine), xanthinol nicotinate (synonym: complamin, xavin, theonicol) and pentoxifylline (synonym: trental) inhibit platelet aggregation by increasing the content of cAMP in them, because These drugs inhibit the activity of cAMP phosphodiesterase, an enzyme that metabolizes cAMP. As A. dipyridamole is prescribed orally (for 1 h before meals) usually 0.1 G 4 times a day; pentoxifylline - at the beginning of treatment, 0,

2-0,4 G 3 times a day, then in a maintenance dose (0.1 G 3 times a day). If it is necessary to achieve a rapid antiaggregation effect, dipyridamole is administered intravenously at 0.01-0.02 G. Sometimes they resort to drip intravenous administration 0.1 G pentoxifylline at 250-500 ml 5% glucose solution or isotonic sodium chloride solution (at a rate of 30-60 drops per 1 min). Pentoxifylline can also be used intra-arterially in doses of 0.1-0.3 G(at a speed of 0.01 G in 1 min). Xanthinol nicotinate in emergency cases is administered intravenously at 0.3-0.6 G per day. For maintenance therapy it is prescribed orally, less often intramuscularly. Unlike cyclooxygenase inhibitors, these A., which increase the content of cAMP, not only do not inhibit, but even somewhat stimulate the antiaggregation activity of the vascular wall. However, their effect on platelet aggregation is not stable, and therefore A. of this group is usually used in combination with acetylsalicylic acid.

Prostacyclin has pronounced antiaggregation properties. It increases the level of cAMP in platelets by activating adenylate cyclase, which stimulates the formation of cAMP. However, the effect of prostacyclin is very short-lived (a few minutes), and therefore it has not received widespread practical use. A search is underway for new active A. among prostacyclin analogues, which differ from it in a longer duration of action.

Sometimes, to achieve a rapid anti-aggregation effect, the blood substitute rheopolyglucin, which is a low-molecular-weight dextran preparation, is used. The mechanism of its action is little studied and, apparently, is largely due to hemodilution.

Indications for use of A. are prethrombotic conditions, thrombosis, microcirculation disorders of various localizations. In particular, A. are indicated for myocardial infarction, ischemic

For example, when a blood vessel is damaged, platelets, using membrane glycoprotein receptors, quickly adhere to the accessible components of the subendothelial space (collagen); this process is regulated by von Willebrand factor. Following platelet adhesion to the vascular wall, the contents of their cytoplasmic granules (including calcium, ADP, serotonin and thrombin) are released. Platelet activation and secretion of granule contents are stimulated when they bind to agonists (in particular collagen and thrombin). During this process, platelet activation induces de novo synthesis and secretion of thromboxane A2 (TXA2), a potent vasoconstrictor and inducer of aggregation (Fig. 17.17). ADP, thrombin and TXA2 promote platelet aggregation and thereby contribute to the formation of the primary blood clot. During platelet activation, important conformational changes occur in the glycoprotein membrane receptors Ilb/IIIa. These changes lead to the fact that previously inactive Hb/Sha receptors bind fibrinogen molecules, as a result of which platelets are firmly connected to each other, forming aggregates.

The regulation of platelet activation is largely due to the release of Ca++ from the platelet depot. As a result, the calcium concentration in the cell cytosol increases, protein kinases are activated, and, ultimately, phosphorylation of regulatory proteins inside platelets occurs. An increase in [Ca++] in the cell cytosol also stimulates phospholipase A2, causing the release of arachidonic acid, the precursor of TXA2 (Fig. 17.17). Calcium release is regulated by several factors. When thrombin and other agonists bind to the corresponding receptors on the platelet membrane, intermediate compounds are formed that stimulate the release of calcium from the depot. TXA2 increases the level of intracellular [Ca++] by binding to its receptor on the surface of platelets, which suppresses the activity of adenylate cyclase, thereby reducing the production of cAMP and increasing the release of [Ca++] from the depot (Fig. 17.17). In contrast, prostacyclin (PGI2) produced by endothelial cells stimulates the activity of adenylate cyclase, increases the concentration of cAMP in platelets and inhibits the secretion of [Ca++] from the depot.

Rice. 17.17. Platelet activation is mediated by intracellular [Ca++]. Factors that accelerate and inhibit the release of calcium from its depot in platelets are shown. Thrombin and serotonin, by binding to specific receptors, stimulate the production of inositol triphosphate (ITP) from phosphatidylinositol diphosphate (PIFg) under the action of phospholipase C (PLS). IFZ enhances the release of calcium into the cell cytoplasm. Thromboxane Ag (TXA2) also promotes the release of calcium: it inhibits the activity of adenylate cyclase (AC), which is accompanied by a decrease in the production of cyclic AMP (cAMP). Under normal conditions, cAMP prevents the release of [Ca++] from the ER, so the decrease in this effect due to the action of TCAg increases the release of calcium into the cytoplasm. Prostacyclin formed in endothelial cells has the opposite effect: by stimulating AC activity and the formation of cAMP, it reduces the release of calcium inside platelets. Calcium enhances the activity of phospholipase Kj (PLA2), under the influence of which TXAg precursors are formed from phospholipids of the cell membrane. When platelets are activated, [Ca++] changes, as a result of which the contents of calcium stores are released, the cytoskeleton is reorganized and the conformation of glycoprotein Ib/Sha receptors significantly changes, i.e., processes necessary for platelet aggregation occur. ADP also makes a certain contribution to platelet aggregation, but the mediators of this process have not yet been identified

Modern antiplatelet drugs affect platelet function at different stages of the processes of their activation and aggregation. The most common antiplatelet drug is aspirin. Other drugs used clinically include dipyridamole and ticlopidine. Potential new drugs that block platelet IIb/Sha receptors are being actively studied, and their significance in the treatment of cardiovascular diseases is being clarified.

Platelet aggregation inhibitors (excluding heparin) - ATC classification of drugs

This section of the site contains information about drugs from the group - B01AC Platelet aggregation inhibitors (excluding heparin). Each drug is described in detail by specialists of the EUROLAB portal.

The Anatomical Therapeutic Chemical Classification (ATC) is an international drug classification system. The Latin name is Anatomical Therapeutic Chemical (ATC). Based on this system, all drugs are divided into groups according to their main therapeutic use. The ATC classification has a clear, hierarchical structure, which makes it easier to find the right drugs.

Each medicine has its own pharmacological action. Correctly identifying the right medications is a fundamental step for successfully treating diseases. In order to avoid undesirable consequences, before using certain medications, consult your doctor and read the instructions for use. Pay special attention to interactions with other medications, as well as conditions of use during pregnancy.

ATX B01AC Platelet aggregation inhibitors (excluding heparin):

Medicines group: Platelet aggregation inhibitors (excluding heparin)

• Aggregal (Tablets)
• Aklotin (Tablets)
• Aspigrel (Capsule)
• Aspicor (Oral tablets)
• Aspinat (Oral tablets)
• Aspinat (Effervescent tablets)
• Aspirin (Oral tablets)
• Aspirin 1000 (Effervescent tablets)
• Aspirin Cardio (Oral tablets)
• ATROGREL (Oral tablets)
• Acecardol (Oral tablets)
• Acetylsalicylic acid "York" (Oral tablets)
• Acetylsalicylic acid Cardio (Oral tablets)
• Acetylsalicylic acid Cardio (Capsule)

• Acetylsalicylic acid-LekT (Oral tablets)
• Acetylsalicylic acid-Rusfar (Oral tablets)
• Acetylsalicylic acid-UBF (Oral tablets)
• Ventavis (Aerosol)
• Detromb (Oral tablets)
• Dipyridamole (Oral suspension)
• Dipyridamole (Oral tablets)
• Zylt (Oral tablets)
• Ibustrin (Oral tablets)
• Ilomedin (Concentrate for solution for infusion)
• CardiASK (Oral tablets)
• Cardiomagnyl (Oral tablets)
• Coplavix (Oral tablets)
• Listab 75 (Oral tablets)

• Lopirel (Oral tablets)
• Mikristin (Oral tablets)
• Parsedyl (Dragée)
• Persantine (Concentrate for solution for infusion)
• Plavix (Oral tablets)
• Plagril (Oral tablets)
• Plidol 100 (Oral tablets)
• Plogrel (Oral tablets)
• Sanomil-Sanovel (Oral tablets)
• Tagren (Oral tablets)
• Targetek (Oral tablets)
• Tiklid (Oral tablets)
• Tiklo (Oral tablets)
• Thrombo ACC (Oral tablets)

If you are interested in any other medicines and preparations, their descriptions and instructions for use, synonyms and analogues, information about the composition and form of release, indications for use and side effects, methods of use, dosages and contraindications, notes on the treatment of children with medicines, newborns and pregnant women, prices and reviews of medications, or you have any other questions and suggestions - write to us, we will definitely try to help you.

Hot Topics

• Treatment of hemorrhoids Important!
• Solving problems of vaginal discomfort, dryness and itching Important!
• Comprehensive treatment of colds Important!
• Treatment of the back, muscles, joints Important!
• Comprehensive treatment of kidney diseases Important!

Other services:

We are in social networks:

Our partners:

ATC (ATS) - classification of drugs and medical products on the EUROLAB portal.

The EUROLAB™ trademark and trademark are registered. All rights reserved.

Platelet aggregation is an important indicator of blood clotting

Platelets, colorless blood cells, play a vital role in protecting the body from blood loss. They can be called ambulances, since they instantly rush to the site of damage and block it. This process is called aggregation.

Platelet aggregation - what is it?

Platelet aggregation is a process in which cells stick together. This forms a plug that closes the wound. At the initial stage, blood cells stick together and later adhere to the walls of the vessel. The result is a blood clot called a thrombus.

In a healthy body, aggregation is protective: platelets clog the wound and bleeding stops. In some cases, the formation of blood clots is undesirable because they block blood vessels in vital organs and tissues.

1. Increased activity of colorless blood cells can lead to stroke and heart attack.
2. Decreased platelet production often leads to large blood loss. Frequent bleeding that does not stop for a long time leads to exhaustion and anemia (anemia).

According to statistics, one in 250 people die from thrombosis every year.

In order to prevent the disease, it is necessary to control the level of platelets and their ability to aggregate.

• frequent bleeding - uterine, from the nose;
• the appearance of bruises from the slightest injury;
• poorly healing wounds;
• swelling.

Normal indicators

Normally, aggregation is 25–75%. Such indicators indicate good hematopoiesis and sufficient oxygen supply to tissues and organs.

Platelet norm - table

Child under one year old

Men over 18 years old

Women over 18 years old

Platelet Aggregation Test

A blood test allows you to identify deviations from the norm and diagnose pathologies of the hematopoietic and cardiovascular systems. In addition, the procedure is prescribed to monitor the dynamics of a number of diseases and prescribe appropriate treatment.

The analysis is carried out in laboratory conditions. To do this, blood is taken from a vein. Before the study, the patient is recommended:

• follow a diet prepared by a specialist for 1–3 days;
• 8 hours before the procedure, avoid foods high in fat, as well as take medications, including Voltaren gel (if possible);
• 24 hours in advance, avoid the use of immunostimulants, including coffee, alcohol, garlic, and stop smoking.

The study is carried out in the morning on an empty stomach. Before the procedure, you are allowed to drink only clean, still water.

After collecting venous blood, special substances are added to it - inducers, which in their composition are similar to the cells of the human body, promoting thrombus formation. For this purpose use:

The method for determining aggregation is based on transmitting light waves through blood plasma before and after clotting. The nature, shape and speed of the light wave are also taken into account.

It should be noted that the study is not carried out if there is an inflammatory process in the body.

The indicator depends on the substance that was added to the blood and its concentration.

Aggregation rate depending on the inductor - table

Types of aggregation

Doctors distinguish several types of aggregation:

• spontaneous - determined without an inductor substance. To determine the aggregation activity of platelets, blood taken from a vein is placed in a test tube, which is placed in a special device, where it is heated to a temperature of 37°C;
• induced - the study is carried out with the addition of inducers to the plasma. Typically, four substances are used: ADP, collagen, epinephrine and ristomycin. The method is used to determine a number of blood diseases;
• moderate - observed during pregnancy. Caused by placental circulation;
• low - occurs in pathologies of the circulatory system. A decrease in platelet levels can lead to various types of bleeding. Observed in women during menstruation;
• increased - leads to increased thrombus formation. This manifests itself in the form of swelling and a feeling of numbness.

Platelet hyperaggregation

If the level of aggregation (hyperaggregation) increases, increased thrombus formation occurs. In this condition, the blood moves slowly through the vessels and clots quickly (the norm is up to two minutes).

Hyperaggregation occurs when:

• diabetes mellitus;
• hypertension - high blood pressure;
• cancer of the kidneys, stomach, blood;
• vascular atherosclerosis;
• thrombocytopathy.

Increased levels of aggregation can lead to the following conditions:

• myocardial infarction - an acute disease of the heart muscle that develops due to insufficient blood supply;
• stroke - cerebrovascular accident;
• thrombosis of the veins of the lower extremities.

Ignoring the problem can be fatal.

Treatment methods depend on the complexity of the disease.

Drug therapy

At the initial stage, it is recommended to take medications whose action is aimed at thinning the blood. Regular aspirin is suitable for this purpose. To prevent bleeding, the drug in a protective shell is taken after meals.

The use of special medications will help prevent the formation of new blood clots. All medications are taken only after consultation with the attending physician.

After additional studies, the patient is prescribed:

• anticoagulants - medications that prevent rapid blood clotting;
• novocaine blockade, painkillers;
• drugs that promote vasodilation.

Diet

It is very important to maintain a drinking regime, since an insufficient amount of fluid causes vasoconstriction, as a result of which the blood thickens even more. You should consume at least 2–2.5 liters of water per day.

Avoid foods that promote hematopoiesis:

Prohibited products - gallery

ethnoscience

To treat increased platelet aggregation, non-traditional treatment methods are used. Before using decoctions and infusions, you should consult your doctor, since many medicinal herbs are prohibited for thrombocytosis.

1. Sweet clover. Pour 1 tbsp boiling water over a glass. l. ground herbs, leave for 30 minutes. Divide the liquid into 3-4 equal parts and drink throughout the day. The course of therapy is a month. If necessary, repeat treatment.
2. Peony. Grind the root and pour 70% alcohol in a proportion of 1 tbsp. l. for 250 ml. Leave in a dark place for 21 days. Take 30 drops before meals 3 times a day for two weeks. Then you need to take a break for a week and repeat the course.
3. Green tea. Mix 1 tsp. ginger root and green tea, pour 500 ml of boiling water, add cinnamon on the tip of a knife. Infuse tea for about 15 minutes. You can add lemon for taste. Drink during the day.
4. Oranges. It is recommended to drink 100 ml of freshly squeezed orange juice daily. Can be mixed with pumpkin juice in a 1:1 ratio.

About thick blood and blood clots in blood vessels - video

Platelet hypoaggregation

A reduced level of aggregation is no less dangerous for the health and life of the patient. Insufficient platelet aggregation (hypoaggregation) causes poor blood clotting (thrombocytopenia). As a result, the formation of clots (thrombi) does not occur, which leads to severe bleeding.

Doctors distinguish between hereditary and acquired platelet hypoaggregation.

According to WHO, the disease affects about 10% of the world's population.

Low aggregation ability is activated by a viral or bacterial infection, physiotherapy, or taking medications.

Hypoaggregation occurs when:

• renal failure;
• chronic leukemia - a malignant disease of the circulatory system;
• decreased thyroid function;
• anemia (anemia).

Diet

Nutrition is an important factor in normalizing platelet levels. The diet should contain foods that promote hematopoiesis:

• buckwheat;
• fish;
• red meat - prepared in any way;
• beef liver;
• eggs;
• greenery;
• salads with carrots, nettles, bell peppers, beets;
• pomegranates, bananas, rowan berries, rosehip juice.

In this case, you should reduce or completely eliminate the consumption of ginger, citrus fruits, and garlic.

Traditional treatment

In advanced cases, treatment is carried out only in a hospital setting. The patient is prescribed:

1. Aminocaproic acid solution 5% intravenously.
2. Sodium adenosine triphosphate intramuscularly or subcutaneously.
3. Preparations: Emosint, Dicynone, Tranexamic acid.

In case of severe bleeding, a transfusion of donor platelet mass is performed.

Patients should avoid taking medications that thin the blood:

Drugs for the treatment of hypoaggregation - gallery

Unconventional treatment

Traditional methods of treatment are used as an adjuvant, since it is impossible to raise the platelet count only with the help of medicinal herbs.

1. Nettle. Grind 1 tbsp. l. plants, pour a glass of boiling water and put on low heat for 10 minutes. Cool the liquid and filter. Take before every meal. The course is one month.
2. Beetroot juice. Grate raw beets, add 1 tbsp. l. granulated sugar. Leave the paste overnight. In the morning, squeeze the juice and drink before breakfast. Duration of treatment is 2–3 weeks.
3. Sesame oil. Used for both treatment and prevention. Take 3-4 times a day after meals.

Features during pregnancy

The level of aggregation during pregnancy is of great importance. The fact is that disruption of this process leads to serious consequences.

The norm during pregnancy is considered to be 150–380 x 10^9/l.

A slight increase in the indicator is associated with placental blood circulation and is considered normal. The upper threshold should not exceed 400 x 10^9/l.

The normal level of aggregation with the addition of any inductor is 30–60%.

Hyperaggregation

Platelet hyperaggregation is dangerous not only for the mother, but also for the baby, as it can cause miscarriage or spontaneous abortion in the early stages. Doctors name the main reasons for increased platelet aggregation during pregnancy:

• dehydration of the body as a result of vomiting, frequent bowel movements, insufficient drinking regimen;
• diseases that can provoke a secondary increase in platelet levels.

Pregnant women must undergo a medical examination and undergo regular tests. Only in this way can a deviation from the norm be noticed in time and appropriate measures taken.

With a moderate increase in the level of coagulation, it is recommended to adjust the diet. You should consume foods that thin your blood plasma. These are flaxseed and olive oils, onions, tomato juice. The diet should include magnesium-containing foods:

If the diet does not bring results, drug treatment is prescribed.

Hypoaggregation

A decrease in aggregation capacity is no less dangerous for the health of a pregnant woman and the fetus than hyperaggregation. In this condition, the vessels become fragile, bruises appear on the body, and the gums begin to bleed. This occurs due to a violation of the qualitative composition of blood cells or their insufficient production. Hypoaggregation can cause uterine bleeding during and after childbirth.

A decrease in platelet levels is provoked by the following factors:

• taking medications - diuretics, antibacterials;
• autoimmune and endocrine diseases;
• allergy;
• severe toxicosis;
• poor nutrition;
• lack of vitamins B12 and C.

To improve the synthesis of blood cells, a woman is recommended to consume foods rich in vitamins B and C:

The doctor prescribes special medications that have a beneficial effect on the hematopoietic system without having a negative effect on the baby.

To avoid the negative consequences and risks associated with hyper- or hypoaggregation, doctors recommend conducting a study on platelet aggregation ability even when planning pregnancy.

Features in children

Despite the fact that increased aggregation capacity is usually found in the adult population, recently there has been an increase in cases of the disease in children.

1. Hyperaggregation can be either hereditary or acquired. The causes of elevated platelet levels are not much different in adults. Mainly:
   • diseases of the circulatory system;
   • infectious and viral diseases;
   • surgical intervention.

In children under one year of age, hyperaggregation can be caused by dehydration and anemia. In adolescence, stressful situations and physiological growth of the body play an important role.

Treatment begins with finding out the cause of the deviation from the norm in platelet aggregation ability. Sometimes adjusting your diet and drinking regime is enough. In some cases, treatment of the disease that caused the abnormality is required.

If necessary, a hematologist will conduct an additional examination and prescribe medication according to the patient’s age and severity of the disease.

Why platelet levels drop - video

A study of the level of platelet aggregation is an important diagnostic procedure that allows you to identify serious diseases, reduce the risk of complications and carry out timely therapy.

• Print

The material is published for informational purposes only and under no circumstances can it be considered a substitute for medical consultation with a specialist in a medical institution. The site administration is not responsible for the results of using the posted information. For questions of diagnosis and treatment, as well as prescribing medications and determining their dosage regimen, we recommend that you consult a doctor.

27.1. Drugs that reduce platelet aggregation (antiplatelet agents)

Platelets are small, disc-shaped blood elements that are formed as fragments of bone marrow megakaryocytes. Platelets circulate in the blood for 6-12 days and are then taken up by tissue macrophages.

Vascular endothelium influences the functional activity of platelets. Endothelial cells release prostacyclin (prostaglandin I 2) and endothelial relaxing factor, which is identified with nitric oxide - NO, into the bloodstream. These substances prevent platelet aggregation. In addition, endothelial cells secrete substances that reduce blood clotting and promote clot lysis. All this ensures the antithrombogenic properties of intact vascular endothelium.

When the vascular endothelium is damaged, which can be caused by various factors (mechanical trauma, infections, atherosclerotic changes in the vascular wall, increased blood pressure, etc.), the antithrombogenic properties of the endothelium are reduced, which creates conditions for the formation of a blood clot. The synthesis of prostacyclin and endothelial relaxing factor is disrupted and this facilitates contact

platelets with damaged endothelial surface. Platelets accumulate at the site of damage and interact with the vascular subendothelium: directly or through von Willebrand factor (secreted by activated platelets and endothelial cells), they bind to collagen and other proteins of the subendothelium with the participation of specific glycoproteins localized in the platelet membrane. Von Willebrand factor binds to glycoprotein Ib, and collagen binds to glycoprotein Ia of the platelet membrane (see Fig. 27-1). The impact of collagen (as well as thrombin, which is formed in small quantities locally already at the initial stage of thrombus formation) on platelets causes a change in their state - activation. Platelets change their shape (from disc-shaped they become spread out with many processes - pseudopodia) and cover the damaged surface of the vessel.

When activated, platelets release various biologically active substances, which in non-activated platelets are located in granules (α-granules, dense granules). Dense granules are a repository of substances that stimulate platelet aggregation: ADP and serotonin. The release of these substances from platelet granules occurs as a result of an increase in the intracellular concentration of Ca 2+ due to the action of collagen, thrombin and other aggregation inducers, including ADP itself, on platelets. ADP released into the bloodstream stimulates specific (purinergic) receptors localized in the platelet membrane. Through G-protein coupled receptors (P2Y 12 purinergic receptors), ADP causes inhibition of adenylate cyclase and a decrease in cAMP levels, which leads to an increase in Ca 2 levels in the cytoplasm of platelets (Fig. 27-2).

In addition, when platelets are activated, the activity of platelet membrane phospholipase A2, an enzyme involved in the formation of arachidonic acid from membrane phospholipids, increases. In platelets, cyclic endoperoxides (prostaglandins G2/H2) are first synthesized from arachidonic acid under the influence of cyclooxygenase, and from them, with the participation of thromboxanesine-

Thetase produces thromboxane A 2, an active stimulator of platelet aggregation and a vasoconstrictor. Once released into the bloodstream, thromboxane A 2 stimulates thromboxane receptors on platelet membranes. As a result, phospholipase C is activated through Cq proteins associated with these receptors and the formation of

Rice. 27-1. Adhesion and aggregation of platelets during damage to the vascular wall: EC - endothelial cell; VW - von Willebrand factor; TxA 2 - thromboxane A 2; PGI 2 - prostacyclin; NO - endothelial relaxing factor; GP - glycoproteins; GP llb/llla - glycoproteins llb/llla (From: Katzung B.G. Bazic and Clinical Pharmacology - NY, 2001, as amended)

inositol-1,4,5-triphosphate, which promotes the release of Ca 2+ from the intracellular depot of platelets (the role of the calcium depot in platelets is performed by a system of dense tubules). This leads to an increase in the cytoplasmic concentration of Ca 2+ (Fig. 27-2). Thromboxane A 2 causes an increase in the concentration of Ca 2+ in vascular smooth muscle cells, which leads to vasoconstriction.

Rice. 27-2. Mechanisms of action of antiplatelet agents (acetylsalicylic acid, ticlopidine and epoprostenol): EC - endothelial cell; PL - phospholipids of cell membranes; AA - archidonic acid; PLA 2 - phospholipase A 2; COX - cyclooxygenase; TS - thromboxane synthetase; PS - prostacyclin synthetase; PGG 2 /H 2 - cyclic endoperoxides; TxA 2 - thromboxane A 2; PGI 2 - prostacyclin; AC - adenylate cyclase; PLS - phospholipase C; IP 3 - inositol-1, 4, 5-triphosphate

Thus, ADP and thromboxane A 2 increase the level of Ca 2+ in the cytoplasm of platelets. Cytoplasmic Ca 2+ causes a change in the conformation of glycoproteins IIb/IIIa in the platelet membrane, as a result of which they acquire the ability to bind fibrinogen. One molecule of fibrinogen has two binding sites for glycoproteins IIb/IIIa and thus can unite two platelets (Fig. 27-3). The joining of many platelets by fibrinogen bridges leads to the formation of platelet aggregates.

Prostacyclin (prostaglandin I 2) has the opposite effect on platelet aggregation. Like thromboxane, prostacyclin

is formed from cyclic endoperoxides, but under the action of another enzyme - prostacyclin synthetase. Prostacyclin is synthesized by endothelial cells and released into the bloodstream, where it stimulates prostacyclin receptors in the platelet membrane and adenylate cyclase associated with them through the G s protein. As a result, the level of cAMP in platelets increases and the concentration of cytoplasmic Ca 2+ decreases (see Fig. 27-2). This prevents the conformation of glycoproteins IIb/IIIa from changing and they lose their ability to bind fibrinogen. Thus, prostacyclin prevents platelet aggregation. Under the influence of prostacyclin, the concentration of Ca 2+ in vascular smooth muscle cells decreases, which leads to vasodilation.

The following sequence of main events leading to platelet aggregation can be distinguished (see Diagram 27-1).

The main focus of the action of antiplatelet agents, which are currently used in clinical practice, is associated with the elimination of the action of thromboxane A 2 and ADP, as well as with the blockade of glycoproteins IIb/IIIa of platelet membranes. Substances with a different mechanism of action are also used, which increase the concentration of cAMP in platelets and, therefore, reduce the concentration of Ca 2+ in them.

The following groups of agents that reduce platelet aggregation are distinguished.

Agents that inhibit the synthesis of thromboxane A2. - Cyclooxygenase inhibitors:

Scheme 27.1. Mechanism of platelet aggregation

Cyclooxygenase and thromboxane synthetase inhibitors: indobufen.

Agents that stimulate prostacyclin receptors:

Agents that interfere with the effect of ADP on platelets:

Agents that inhibit platelet phosphodiesterase:

Agents that block glycoproteins IIb/IIIa of platelet membranes.

Monoclonal antibodies: abciximab.

Synthetic blockers of glycoproteins IIb/IIIa: eptifibatide; tirofiban.

Agents that inhibit the synthesis of thromboxane A 2

Acetylsalicylic acid (aspirin*) is a well-known anti-inflammatory, analgesic and antipyretic agent. Currently widely used as an antiplatelet agent. The antiplatelet effect of acetylsalicylic acid is associated with its inhibitory effect on the synthesis of thromboxane A 2 in platelets.

Acetylsalicylic acid irreversibly inhibits cyclooxygenase (causes irreversible acetylation of the enzyme) and thus disrupts the formation of cyclic endoperoxides, precursors of thromboxane A2 and prostaglandins from arachidonic acid. Therefore, under the influence of acetylsalicylic acid, not only the synthesis of thromboxane A 2 in platelets, but also the synthesis of prostacyclin in vascular endothelial cells decreases (see Fig. 27-2). However, by selecting the appropriate doses and regimen, it is possible to achieve a preferential effect of acetylsalicylic acid on the synthesis of thromboxane A 2 . This is due to significant differences between platelets and endothelial cells.

Platelets - anucleate cells - do not have a protein resynthesis system and, therefore, are not able to synthesize cyclooxygenase. Therefore, with irreversible inhibition of this enzyme, the disruption of thromboxane A2 synthesis persists throughout the life of the platelet, i.e. within 7-10 days. Due to the formation of new platelets, the antiplatelet effect of acetylsalicylic acid lasts for a shorter period of time, and therefore, to achieve a stable effect of the drug (i.e., a stable decrease in thromboxane levels), it is recommended to prescribe it once a day.

Cycloxygenase is resynthesized in vascular endothelial cells, and the activity of this enzyme is restored within a few hours after taking acetylsalicylic acid. Therefore, when prescribing the drug once a day, there is no significant reduction in prostacyclin synthesis.

In addition, approximately 30% of acetylsalicylic acid undergoes first-pass metabolism in the liver, so its concentration in the systemic circulation is lower than in the portal blood. As a result, acetylsalicylic acid acts on platelets circulating in the portal bloodstream in higher concentrations than on endothelial cells of systemic vessels. Therefore, to suppress the synthesis of thromboxane A2 in platelets, smaller doses of acetylsalicylic acid are required than to suppress the synthesis of prostacyclin in endothelial cells.

For these reasons, with an increase in the dose and frequency of administration of acetylsalicylic acid, its inhibitory effect on prostacyclin synthesis becomes more pronounced, which can lead to a decrease in the antiplatelet effect. In connection with these features, acetylsalicylic acid as an antiplatelet agent is recommended to be prescribed in small doses (on average 100 mg) once a day.

As an antiplatelet agent, acetylsalicylic acid is used for unstable angina, for the prevention of myocardial infarction, ischemic stroke and peripheral vascular thrombosis, to prevent the formation of blood clots during coronary artery bypass grafting and coronary angioplasty. Acetylsalicylic acid is prescribed orally in doses of mg (for certain indications - in the dose range from 50 to 325 mg) once a day for a long time. Currently, doctors have at their disposal acetylsalicylic acid preparations intended for the prevention of thrombosis, which contain mg of the active substance, including enteric-coated tablets - Acecardol *, Aspicor *, Cardiopyrin *, Aspirin Cardio *, Novandol *, Thrombo ACC * and others. The antiplatelet effect of acetylsalicylic acid occurs quickly (within minutes). Enteric-coated dosage forms begin to act more slowly, but with long-term use their effectiveness is practically no different from that of conventional tablets. To achieve a faster effect, acetylsalicylic acid tablets should be chewed.

The main side effects of acetylsalicylic acid are associated with inhibition of cyclooxygenase. This disrupts the formation of prostaglandins E 2 and I 2, which have an antisecretory and gastroprotective effect (reduce the secretion of hydrochloric acid by the parietal cells of the stomach, increase the secretion of mucus and bicarbonates). As a result, even with short-term use, acetylsalicylic acid can cause damage to the epithelium of the stomach and duodenum (ulcerogenic effect). The effect on the gastric mucosa is less pronounced when using enteric-coated dosage forms. When using acetylsalicylic acid, gastrointestinal bleeding and other hemorrhagic complications are possible. The risk of such complications is lower when acetylsalicylic acid is prescribed at a dose of 100 mg/day or less. Selective inhibition of COX leads to activation of the lipoxygenase pathway for the conversion of arachidonic acid and the formation of leukotrienes, which have bronchoconstrictor properties. In patients with bronchial asthma, acetylsalicylic acid can provoke the onset of an attack (“aspirin asthma”). Allergic reactions are possible.

To reduce the ulcerogenic effect of acetylsalicylic acid, a combination drug Cardiomagnyl * containing magnesium hydroxide has been proposed. Magnesium hydroxide neutralizes hydrochloric acid in the stomach (antacid effect), reducing its damaging effect on the mucous membrane. The drug is used for the same indications as acetylsalicylic acid, including for the secondary prevention of ischemic stroke.

Indobufen (ibustrin *) reduces the synthesis of thromboxane A 2, while simultaneously inhibiting cyclooxygenase and thromboxane synthetase. Unlike acetylsalicylic acid, indobufen causes reversible inhibition of cyclooxygenase. When taking this drug, there is a relative increase in the amount of prostacyclin (the prostacyclin/thromboxane A 2 ratio increases). Indobufen inhibits platelet adhesion and aggregation. Indications for use and side effects are the same as for acetylsalicylic acid.

Agents that stimulate prostacyclin receptors

Another way to reduce platelet aggregation is stimulation of prostacyclin receptors. For this purpose they use

prostacyclin preparation e p o pro s t e n o l * . The effect of prostacyclin is opposite to the effect of thromboxane A 2 not only on platelets, but also on vascular tone. It causes vasodilation and a decrease in blood pressure. This effect of prostacyclin is used in pulmonary hypertension. Since prostacyclin is quickly destroyed in the blood (t 1/2 about 2 minutes) and therefore does not act for long, the drug is administered by infusion. Due to its short action, epoprostenol* has not found widespread use as an antiplatelet agent. A possible area of ​​use of the antiplatelet effect of epoprostenol is the prevention of platelet aggregation during extracorporeal circulation.

Agents that interfere with the action of ADP on platelets

Ticlopidine (ticlid*), a thienopyridine derivative, inhibits platelet aggregation caused by ADP. Ticlopidine is a prodrug; its antiplatelet effect is associated with the formation of an active metabolite with the participation of microsomal liver enzymes. The ticlopidine metabolite contains thiol groups, through which it irreversibly binds to P2Y 12 purinergic receptors in the platelet membrane. This leads to the elimination of the stimulating effect of ADP on platelets and a decrease in the concentration of cytoplasmic Ca 2+ in them. As a result, the expression of glycoproteins IIb/IIIa in the platelet membrane and their binding to fibrinogen decreases (see Fig. 27-2). Due to the irreversible nature of its action, ticlopidine has a long-lasting antiplatelet effect.

The maximum effect with constant use of ticlopidine is achieved after 7-11 days (the time required for the formation and development of the action of the active metabolite) and after discontinuation of the drug it persists throughout the entire lifespan of platelets (7-10 days).

Ticlopidine is prescribed for the secondary prevention of ischemic stroke, to prevent thrombosis in obliterating diseases of the lower extremities, during coronary artery bypass grafting and stenting of the coronary arteries. The drug is effective when taken orally, prescribed 2 times a day with meals.

The use of ticlopidine is limited due to its side effects. Possible loss of appetite, nausea, vomiting, diarrhea (20%), abdominal pain, skin rashes (11-14%). Noted

increase in the blood plasma level of atherogenic lipoproteins. Bleeding is a common complication when using antiplatelet agents. A dangerous complication is neutropenia, which occurs during the first three months of treatment in 1-2.4% of patients. Thrombocytopenia, agranulocytosis, and very rarely aplastic anemia are possible. In this regard, during the first months of treatment, systematic monitoring of the blood picture is necessary.

Clopidogrel (Plavix*, Zilt*) is similar to ticlopidine in chemical structure, main effects and mechanism of action. Like ticlopidine, it is a prodrug and undergoes conversion in the liver to form an active metabolite. Significant inhibition of platelet aggregation was noted from the second day of treatment, the maximum effect is achieved after 4-7 days. After discontinuation of the drug, its effect lasts for 7-10 days. Clopidogrel is superior to ticlopidine in activity - at a daily dose of 75 mg it causes the same decrease in platelet aggregation and prolongation of bleeding time as ticlopidine at a daily dose of 500 mg.

Clopidogrel is used for the same indications as acetylsalicylic acid, in case of intolerance. Take orally 1 time per day, regardless of meals. Clopidogrel can be combined with acetylsalicylic acid, since the drugs inhibit different mechanisms of platelet aggregation and therefore enhance the effect of each other (however, with this combination there is a higher risk of hemorrhagic complications).

Compared with ticlopidine, the side effects of clopidogrel are less pronounced (diarrhea - 4.5%, rash - 6%). The use of clopidogrel is associated with a lower risk of such a serious complication as neutropenia (0.1%), and thrombocytopenia occurs less frequently. As a rare complication, as with ticlopidine, thrombotic thrombocytopenic purpura may develop.

Platelet phosphodiesterase inhibitors

Dipyridamole (curantyl*, persantine*) was first proposed as a coronary dilator. Later, its ability to inhibit platelet aggregation was revealed. Currently, dipyridamole is used mainly as an antiplatelet agent for the prevention of thrombosis. The antiplatelet effect of dipyridamole is associated with an increase in the level of cAMP in platelets, as a result of which the concentration of cytoplasmic Ca 2+ in them decreases. This happens for several reasons. First, dipyridamole inhibits phosphodiesterase, which inactivates cAMP. In addition, dipyridamole inhibits the uptake of adenosine by endothelial cells and erythrocytes and its metabolism (inhibits adenosine deaminase), thereby increasing the level of adenosine in the blood (Fig. 27-4). Adenosine stimulates platelet A 2 receptors and increases the activity of adenylate cyclase associated with these receptors, as a result, the formation of cAMP in platelets increases and the level of cytoplasmic Ca 2+ decreases. Dipyridamole also increases cAMP levels in vascular smooth muscle cells, causing vasorelaxation.

Dipyridamole is used to prevent ischemic stroke, as well as for diseases of peripheral arteries (mainly in combination with acetylsalicylic acid, since dipyridamole itself has a weak antiplatelet effect). Prescribed orally 3-4 times a day 1 hour before meals. In combination with oral anticoagulants, dipyridamole is prescribed to prevent the formation of blood clots in mitral heart disease.

When using dipyridamole, headache, dizziness, arterial hypotension, dyspeptic symptoms,

skin rashes. The risk of bleeding is less than with the use of acetylsalicylic acid. Dipyridamole is contraindicated in cases of angina pectoris (possible “steal syndrome”).

Rice. 27-4. Mechanism of antiplatelet action of dipyridamole: EC - endothelial cell; A 2 -P - adenosine A 2 receptor; PDE - cAMP phosphodiesterase; AC - adenylate cyclase; GP IIb/IIIa - glycoproteins IIb/IIIa

Pentoxifylline (agapurine*, trental*), like dipyridamole, inhibits phosphodiesterase and increases cAMP levels. As a result, the level of cytoplasmic Ca 2 + in platelets decreases, which leads to a decrease in their aggregation. Pentoxifylline also has other properties: it increases the deformability of red blood cells, reduces blood viscosity, and has a vasodilating effect, improving microcirculation.

Pentoxifylline is used for cerebrovascular accidents, peripheral circulatory disorders of various origins, and vascular pathology of the eyes (see the chapter “Drugs used for cerebrovascular accidents”). Possible side effects: dyspeptic symptoms, dizziness, redness of the face, as well as a decrease in blood pressure, tachycardia, allergic reactions, bleeding. Like dipyridamole, it can provoke attacks during angina pectoris.

Agents blocking glycoproteins IIb/IIIa of platelet membranes

This group of antiplatelet agents, which directly interact with glycoproteins IIb/IIIa of platelet membranes and disrupt their binding to fibrinogen, has appeared relatively recently.

Abciximab (reopro*) - the first drug from this group is a “chimeric” mouse/human monoclonal antibody (Fab fragment of mouse antibodies to glycoproteins IIb/IIIa combined with the Fc fragment of human Ig). Abciximab non-competitively inhibits the binding of fibrinogen to glycoproteins IIb/IIIa on the platelet membrane, disrupting their aggregation (see Fig. 27-3). Platelet aggregation normalizes 48 hours after a single dose. The drug is administered intravenously (as an infusion) to prevent thrombosis during angioplasty of the coronary arteries. When using abciximab, bleeding is possible, including internal (gastrointestinal, intracranial, bleeding from the genitourinary tract), nausea, vomiting, hypotension, bradycardia, allergic reactions up to anaphylactic shock, thrombocytopenia.

The search for less allergenic drugs with the same mechanism of action led to the creation of synthetic blockers of glycoproteins IIb/IIIa. Based on barborin (a peptide isolated from the venom of the pygmy rattlesnake), the drug e p t i f i b a t i d (integrilin *) was obtained - a cyclic hectapeptide that imitates the amino acid sequence of the fibrinogen chain, which directly binds to glycoproteins IIb/IIIa. Eptifibatide competitively displaces fibrinogen from binding to receptors, causing a reversible disorder of platelet aggregation. The drug is administered intravenously as an infusion; the antiplatelet effect occurs within 5 minutes and disappears 6-12 hours after cessation of administration. The drug is recommended for the prevention of thrombus formation during percutaneous coronary angioplasty, for unstable angina, and for the prevention of myocardial infarction. A dangerous complication when using eptifibatide is bleeding; thrombocytopenia is possible.

Tirofiban (agrastat*) is a non-peptide blocker of glycoproteins IIb/IIIa, an analogue of tyrosine. Like eptifibatide, tirofiban competitively blocks glycoprotein IIb/IIIa receptors. The drug is administered intravenously (infusion). The speed of onset of effect, duration of action and indications for use are the same as for eptifibatide. Side effects - bleeding, thrombocytopenia.

To expand the possibilities of using drugs in this group, blockers of glycoproteins IIb/IIIa were created that are effective when administered orally - xemilofiban *, sibrafiban *, etc. However, tests of these drugs revealed their insufficient effectiveness and a side effect in the form of severe thrombocytopenia.

To continue downloading, you need to collect the image:

Drugs that reduce platelet and erythrocyte aggregation. Features of pharmacokinetics. Side effects. 19.1.1. DRUGS THAT REDUCE PLATELET AGGREGATION (ANTI-PLATELETS)

Platelet aggregation is largely regulated by the thromboxane-prostacyclin system. Both compounds are formed from cyclic endoperoxides, which are products of the transformation of arachidonic acid in the body (see diagram 24.1), and act on thromboxane and prostacyclin receptors, respectively.

Thromboxane A 2 (TXA 2) increases platelet aggregation and causes severe vasoconstriction (Fig. 19.1). It is synthesized in platelets. The mechanism of increased platelet aggregation is obviously associated with stimulation of phospholipase C due to the activating effect of thromboxane on thromboxane receptors. This increases the formation of inositol 1,4,5-triphosphate and diacylglycerol and thus increases the Ca 2+ content of platelets. Thromboxane is a very unstable compound (t 1/2 = 30 s at 37? C).

Along with thromboxane, platelet aggregation stimulators also include vascular wall collagen, thrombin, ADP, serotonin, prostaglandin E 2, and catecholamines.

The exact opposite role is played by prostacyclin (prostaglandin I 2; PG1 2). It inhibits platelet aggregation and causes vasodilation. It is the most active endogenous inhibitor of platelet aggregation. In high concentrations, it inhibits the adhesion (sticking) of platelets to the subendothelial layer of the vascular wall (prevents their interaction with collagen). Synthesis

Prostacyclin is produced mainly by the vascular endothelium; its greatest quantity is contained in the intima of blood vessels. Prostacyclin also circulates in the blood. Its main effect is that it stimulates prostacyclin receptors and the adenylate cyclase associated with them and increases the cAMP content in platelets and the vascular wall (the content of intracellular Ca 2 + decreases).

In addition to prostacyclin, aggregation is reduced by prostaglandins E 1 and D, nitric oxide (NO), heparin, AMP, adenosine, serotonin antagonists, etc.

For practical purposes, agents that prevent platelet aggregation are of great importance. They act in the following directions:

I. Inhibition of the activity of the thromboxane system

1. Decreased thromboxane synthesis

A. Cyclooxygenase inhibitors (acetylsalicylic acid)

b. Thromboxane synthetase inhibitors (dazoxiben)

2. Thromboxane receptor block 1

3. Substances of mixed action(1b + 2; ridogrel)

II. Increased activity of the prostacyclin system

1. Agents that stimulate prostacyclin receptors(epoprostenol)

III. Agents that inhibit the binding of fibrinogen to platelet glycoprotein receptors (GP IIb/IIIa)

1 A number of thromboxane receptor blockers have been obtained and are at the research stage (Daltroban).

1. Antagonists of glycoprotein receptors(abciximab, tirofiban)

2. Drugs that block platelet purine receptors and prevent the stimulating effect of ADP on them (glycoprotein receptors are not activated)(ticlopidine, clopidogrel)

IV. Agents of different types of action (dipyridamole, anturan).

The most common antiplatelet agent in practice is acetylsalicylic acid (aspirin) (see Chapters 8; 8.2 and 24). It is an inhibitor of cyclooxygenase, as a result of which the synthesis of cyclic endoperoxides and their metabolites thromboxane and prostacyclin is disrupted. However, platelet cyclooxygenase is more sensitive than a similar enzyme in the vascular wall. Therefore, the synthesis of thromboxane is suppressed to a greater extent than prostacyclin. This difference in effect is especially clear when using the drug in small doses. As a result, the antiplatelet effect predominates, which can last for several days, which is explained by the irreversibility of the inhibitory effect of acetylsalicylic acid on platelet cyclooxygenase. Platelets do not synthesize cyclooxygenase again. It is replenished only in the process of formation of new platelets (the “life” of platelets is measured at 7-10 days). At the same time, cyclooxygenase of the vessel wall restores its activity within several hours. Therefore, the duration of reduction in thromboxane levels is longer than that of prostacyclin.

A new drug, nitroaspirin, has been synthesized, which eliminates nitric oxide in the body. As is known, the latter is one of the endogenous antiplatelet compounds. Thus, the inhibition of platelet aggregation by nitroaspirin is due to inhibition of cyclooxygenase (which leads to a decrease in thromboxane biosynthesis) and NO production. The negative effect on the mucous membrane of the digestive tract of nitroaspirin is less pronounced than that of acetylsalicylic acid (aspirin). In addition, due to the release of NO, the drug has an antihypertensive effect.

Research aimed at creating substances that inhibit thromboxane synthase, i.e., has attracted considerable interest. substances that selectively reduce the synthesis of thromboxane (see Fig. 19.1). Such agents should theoretically suppress platelet aggregation more specifically and effectively. In principle, this problem was solved: an imidazole derivative called dazoxyben was synthesized, which selectively blocks thromboxane synthase. However, expectations were not met, since monotherapy with dazoxiben was ineffective. This is obviously due to the accumulation of proaggregating substances (cyclic endoperoxides) against the background of its action, formed in the cyclooxygenase pathway for the conversion of arachidonic acid, which stimulate thromboxane receptors. In practical medicine, dazoxyben is used in combination with acetylsalicylic acid. Blockers of thromboxane platelet receptors (daltroban) and especially drugs that combine this action with inhibition of thromboxane synthase (ridogrel) are more promising, but they require more careful study.

The above drugs reduce platelet aggregation by inhibiting the thromboxane system. The second possibility is to activate the prostacyclin system. This can be done by influencing the corresponding receptors or by increasing the activity of prostacyclin synthase.

The principle of the antiplatelet action of prostacyclin is discussed above. In addition, the drug causes vasodilation and lowers blood pressure. Taking into account its low stability (t 1/2 = 3 min at 37°C), it was tried to be administered to patients in the form of a long-term (many hours) intra-arterial infusion for vascular diseases of the lower extremities. Prostacyclin caused a persistent (within 3 days) improvement in blood circulation in muscles and other tissues, eliminated ischemic pain and promoted the healing of trophic ulcers. This effect is associated with local inhibition of platelet aggregation and vasodilation. The prostacyclin drug is called epoprostenol.

A chemically more stable prostacyclin analogue, carbacyclin, has been synthesized. However, it also turned out to be unstable in a biological environment. Carbacycline, when administered intravenously, reduces platelet aggregation. The experiment showed that the effect persists for the duration of the infusion and no more than 10 minutes after its cessation. Due to their short duration of action, both substances are unsuitable for practical use. It is desirable to create long-acting drugs that are effective through different routes of administration. However, epoprostenol has found its area of ​​application: it is recommended to be used during hemodialysis (instead of heparin), since it reduces platelet adhesion on the dialysis membrane and does not cause bleeding. The drug is also used for hemosorption and extracorporeal circulation. In addition, it is used for pulmonary hypertension (vasodilator + antiplatelet effect).

The idea of ​​creating antiplatelet agents that selectively activate the synthesis of endogenous prostacyclin is of undoubted interest. Prostacyclin synthase, which ensures this process, is found in endothelial cells and is absent in platelets and can be a “target” for the action of pharmacological substances. However, drugs of this kind have not yet been obtained.

In recent years, substances acting on glycoprotein receptors (GP IIb/IIIa) of platelets have attracted much attention (Fig. 19.2). These receptors play a critical role in platelet aggregation. Drugs that affect their activity are divided into 2 groups. The first is competitive or non-competitive blockers of glycoprotein receptors (abciximab, tirofiban, etc.). The second group is represented by drugs that interfere with the activating effect of ADP on platelets and the expression of their glycoprotein receptors (ticlopidine, clopidogrel). In both cases, the binding of fibrinogen and a number of other factors to glycoprotein receptors does not occur or decreases, which underlies the antiplatelet effect of these substances.

Glycoprotein receptor blockers according to their chemical structure belong to the following groups:

1. Monoclonal antibodies- abciximab.

2. Synthetic peptides- eptifibatide.

3. Synthetic non-peptide compounds- tirofiban.

The first drug of this group introduced into medical practice was abciximab (reopro), a non-competitive blocker of glycoprotein receptors (IIb/IIIa) of platelets. It prevents fibrinogen and a number of other compounds from binding to these receptors. Thanks to this, the drug reduces platelet aggregation and subsequent formation of blood clots. The maximum antiplatelet effect is observed when at least 80% of glycoprotein receptors are bound. The drug also has anticoagulant activity.

Abciximab is a fragment of a special monoclonal antibody.

It is administered intravenously at once or by infusion. Binding to receptors occurs quickly (within 5-30 minutes). The maximum effect develops after approximately 2 hours. After stopping the drug administration, the pronounced effect lasts up to 1 day, and residual effects of blockade of glycoprotein receptors can persist for more than 10 days.

It is used for surgical interventions on coronary vessels, for angina pectoris, and myocardial infarction. Often combined with heparins, as well as fibrinolytics.

The most common side effect is increased bleeding of various locations. Allergic reactions, thrombocytopenia, hypotension, bradycardia, dyspepsia, etc. are possible.

Further searches for glycoprotein receptor antagonists were aimed at creating drugs obtained by chemical synthesis. A number of such antiplatelet agents are now known for intravenous and enteral administration. One of them is the cyclic peptide eptifibatide (integrilin). It specifically binds to glycoprotein IIb/IIIa receptors, preventing fibrinogen from interacting with them. It is administered intravenously. It acts faster and has a shorter duration than abciximab. After stopping the infusion, the effect disappears within 2-8 hours;

1.5-2.5 hours. About 25% of the substance binds to blood plasma proteins. Partially metabolized in the liver. 40-50% is excreted by the kidneys, mostly unchanged.

The group of competitive blockers of glycoprotein receptors also includes the non-peptide compound tirofiban (agrastat). The mechanism for reducing platelet aggregation and indications for use are similar to those for abciximab.

The drug is administered intravenously. It has a shorter duration of action than abciximab. After stopping the infusion, platelet aggregation is restored within 4-8 hours. Metabolized to a small extent. = approximately 2 hours. Excreted mainly unchanged by the kidneys (65%) and intestines (25%).

Synthetic drugs can also cause bleeding, thrombocytopenia, and allergic reactions.

The second group of substances (ticlopidine, clopidogrel) acts according to a different principle. They do not directly affect glycoprotein receptors. The mechanism of their antiplatelet effect is that they interfere with the stimulating effect of ADP on purine receptors (P 2Y) of platelets. At the same time, platelets and glycoprotein receptors are not activated, which prevents the interaction of the latter with fibrinogen.

Ticlopidine (ticlid) has pronounced antiplatelet activity. Effective when administered enterally. The effect develops gradually and reaches a maximum after 3-5 days. Ticlopidine itself is inactive. In the liver it is quickly metabolized and active compounds are formed from it, i.e. Ticlopidine is a prodrug. Used for unstable angina to prevent myocardial infarction, to reduce the incidence of thrombotic complications after operations on the heart and blood vessels, etc. Side effects are observed quite often. These include dyspepsia, skin rash, and increased blood levels of atherogenic lipoproteins. Leukopenia, agranulocytosis and pancytopenia sometimes occur, so systematic blood monitoring is necessary. At the first signs of a violation of leukopoiesis, the drug should be discontinued. Ticlopidine is usually prescribed for intolerance to acetylsalicylic acid.

Clopidogrel also belongs to the ticlopidine group of drugs. Is a prodrug. In the liver, an active metabolite is formed from it, which provides an antiplatelet effect. It selectively and irreversibly blocks the receptors with which ADP interacts, and similarly to ticlopidine, eliminates the activation of glycoprotein receptors GP IIb/IIIa. As a result, platelet aggregation is impaired.

The drug is administered orally once a day. Absorbed quickly, but not completely (about 50%). The maximum concentration in the blood accumulates after approximately 1 hour. Most of the substance and metabolites bind to plasma proteins

blood. They are excreted by the kidneys and intestines. t 1/2 metabolite

8 hours. With daily administration of the drug, the maximum antiplatelet effect (inhibition by 40-60%) develops after 3-7 days.

The drug is relatively well tolerated. Compared with ticlopidine, side effects on the skin (various rashes), digestive tract (bleeding), and peripheral blood composition (neutropenia) are less common. Less common than acetylsalicylic acid, it causes gastrointestinal bleeding and ulceration of the mucous membrane, but diarrhea and skin rashes are more common.

Group of drugs different types of action includes dipyridamole and anturan.

Dipyridamole (Curantyl) is known as a coronary dilator (see Chapter 14.3). However, it has some antiplatelet activity. The mechanism of its action is not well understood. It is known that it inhibits phosphodiesterase and significantly increases the content of cAMP in platelets. In addition, it potentiates the effect of adenosine, which inhibits platelet aggregation and has a vasodilating effect. The latter is due to the fact that dipyridamole inhibits the uptake and metabolism of adenosine by erythrocytes and endothelial cells. In addition, it potentiates the action of prostacyclin. The most common side effects are headache, dyspepsia, and skin rash. Typically, dipyridamole is used in combination with indirect anticoagulants or acetylsalicylic acid.

The drug anturan (sulfinpyrazone) is an anti-gout drug (see Chapter 25). Along with this, it inhibits platelet adhesion 1 and has antiplatelet activity. Perhaps the latter is associated with inhibition of cyclooxygenase and/or an effect on the platelet membrane, as well as a decrease in the release of ADP and serotonin, which promote platelet aggregation. The effectiveness of the drug is low.

46. ​​Agonists of central α-adrenergic receptors. Classification. Mechanism of action. Pharmacodynamics, pharmacokinetics. Indications, contraindications, side effects. Possible interactions with drugs from other groups. Central alpha2-adrenergic receptor agonists

Agonists of central α 2 -adrenergic receptors stimulate α 2 -adrenergic receptors in the region of the nucleus of the solitary tract with subsequent inhibition of sympathetic impulses in the medulla oblongata. This leads to a decrease in the activity of the sympathetic nervous system and an increase in the tone of the vagus nerve, which causes a decrease in total peripheral vascular resistance and cardiac output. As a result, blood pressure decreases.

This group of drugs includes guanfacine (Estulik), clonidine (Gemiton, Catapressin, Clonidine), methyldopa (Aldomet, Dopegit).

Guanfacine, when taken orally, is almost completely absorbed from the gastrointestinal tract. The maximum concentration in the blood is created after 2 hours, and in the brain structures - after 4 hours. The half-life of guanfacine is hours, so it can be taken 1-2 times a day. A stable level of guanfacine in the blood is established on the 4th day after starting the drug. After its discontinuation, blood pressure returns to its original level within 2-4 days.

Clonidine is well absorbed after oral administration. Its maximum concentration in plasma is reached after 3-5 hours. The half-life of the drug is hours, the duration of action ranges from 2 to 24 hours. After oral administration, 60% of the drug is excreted by the kidneys, mainly in an inactive form.

After oral administration of methyldopa, about 50% of the substance enters the systemic circulation. The maximum hypotensive effect occurs 4-6 hours after oral administration and continues for hours. With a course of treatment, the hypotensive effect occurs on the 2-5th day. The drug is excreted relatively quickly in the urine, mainly unchanged.

§ Place in therapy

α 2 -adrenergic receptor agonists are used to treat arterial hypertension.

Guanfacine may be used for opioid withdrawal symptoms.

Clonidine is also prescribed for open-angle glaucoma (as monotherapy or in combination with other drugs that lower intraocular pressure).

The following side effects may occur during the use of central α2-adrenergic receptor agonists:

§ From the digestive system: dry mouth, loss of appetite, nausea, vomiting, stomach cramps, constipation, decreased gastric secretion.

§ From the central nervous system: drowsiness, dizziness, headache, fainting, slowing of the speed of mental and motor reactions, weakness, depression, anxiety, tension, nervousness, psychomotor agitation, tremor of the hands and fingers, confusion.

§ From the cardiovascular system: orthostatic hypotension, bradycardia.

§ From the organ of vision: conjunctivitis (dryness, itching, burning in the eyes).

§ Other: sweating, nasal congestion, decreased potency, decreased libido.

If you abruptly stop taking guanfacine and clonidine, withdrawal syndrome may occur (increased blood pressure, nervousness, headaches, tremor, nausea).

Methyldopa can lead to the development of myocarditis, hemolytic anemia, leukopenia, thrombocytopenia, lupus-like syndrome, and liver diseases.

With long-term use of methylodopa (1.5-3 months), tachyphylaxis may develop. In these cases, it is necessary to increase the dose of the drug.

Contraindications to the use of drugs in this group are: hypersensitivity, arterial hypotension, cardiogenic shock, cardiac conduction disorders, depression, pregnancy, lactation.

Methyldopa is contraindicated in active liver diseases, severe renal dysfunction, parkinsonism, pheochromocytoma, porphyria.

Central α 2 -adrenergic receptor agonists are prescribed with caution in cases of severe atherosclerosis of the coronary arteries and cerebral vessels, after a recent myocardial infarction.

A decrease in the antihypertensive effect of guanfacine is possible with simultaneous use with α2-adrenergic receptor antagonists (phentolamine, yohimbine), nonsteroidal anti-inflammatory drugs, and estrogens. An increase in the antihypertensive effect of guanfacine is observed when used simultaneously with diuretics, β-blockers, and peripheral vasodilators.

When guanfacine is used simultaneously with antipsychotics, the sedative effect of this drug may be enhanced.

Sympatholytics (reserpine and guanethidine) deplete norepinephrine reserves in the adrenergic endings of sympathetic fibers and inhibit the hypotensive effect of clonidine. The hypotensive effect of clonidine is reduced when used simultaneously with tricyclic antidepressants (imipramine, clomipramine, desipramine).

Tricyclic antidepressants and beta-blockers increase the risk of developing hypertension after discontinuation of clonidine.

When clonidine is prescribed simultaneously with propranolol and atenolol, an additive hypotensive effect is observed, dry mouth appears, and the sedative effect of the drug increases.

The sedative effect of clonidine becomes more pronounced with the simultaneous use of oral hormonal contraceptives.

Against the background of combined use of clonidine and cyclosporine, the concentration of the latter in the blood plasma may increase.

Strengthening the antihypertensive effect of methyldopa is possible with simultaneous use with tranquilizers, fenfluramine, chlorpromazine.

A decrease in the antihypertensive effect of methyldopa is observed when combined with tricyclic antidepressants, non-steroidal anti-inflammatory drugs, iron salts (iron sulfate, iron gluconate).

When methyldopa is prescribed with beta-blockers, orthostatic hypotension may develop. When administering anesthesia (fluorotane, sodium thiopental) during methyldopa therapy, collapse is possible.

Methyldopa is not recommended to be prescribed concomitantly with MAO inhibitors and levodopa. In the latter case, this is because there may be an increase in the antiparkinsonian effect of levodopa and the hypotensive effect of mitildopa.

47. Angiotensin-converting enzyme inhibitors. Angiotensin receptor blockers. Classification. Mechanism of action. Pharmacodynamics, pharmacokinetics. Indications, contraindications, side effects. Possible interactions with drugs of other groups. ACE inhibitors (angiotensin-converting enzyme inhibitors, ACE inhibitors) are a group of natural and synthetic chemical compounds used for the treatment and prevention of cardiac (usually in doses that do not reduce blood pressure) and renal failure, to lower blood pressure, in plastic surgery, for protection from ionizing radiation. Discovered by studying peptides contained in the venom of the common jararaka ( Bothrops jararaca). ACE inhibitor drugs are most widely used to treat hypertension and heart failure.

ACE inhibitors inhibit the action of the angiotensin-converting enzyme, which converts biologically inactive angiotensin I into the hormone angiotensin II, which has a vasoconstrictor effect. As a result of the impact on the renin-angiotensin system, as well as enhancing the effects of the kallikrein-kinin system ACE inhibitors have a hypotensive effect.

ACE inhibitors slow the breakdown of bradykinin, a strong vasodilator that stimulates the dilation of blood vessels through the release of nitric oxide (NO) and prostacyclin (prostaglandin I2).

Classification of ACE inhibitors

· Preparations containing sulfhydryl groups: captopril, zofenopril.

· Dicarboxylate-containing drugs: enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril.

· Phosphonate-containing drugs: fosinopril.

· Natural ACE inhibitors.

Casokinins and lactokinins are breakdown products of casein and whey that occur naturally after consuming dairy products. The role in lowering blood pressure is unclear. Lactotripeptides Val-Pro-Pro and Ile-Pro-Pro are produced by probiotics Lactobacillus helveticus or are breakdown products of casein and have an antihypertensive effect. ACE inhibitors reduce blood pressure by reducing total peripheral vascular resistance. Cardiac output and heart rate do not change much. These drugs do not cause reflex tachycardia, characteristic of direct vasodilators. The absence of reflex tachycardia is achieved by setting the level of baroreceptor activation to a lower level or by activating the parasympathetic nervous system.

Clinical benefits of ACE inhibitors

ACE inhibitors reduce proteinuria, therefore they are especially important for the treatment of patients with chronic kidney disease. This effect is also important in patients diagnosed with diabetes mellitus, which is why these drugs have the status of drugs of choice for the treatment of hypertension in patients with diabetes. These effects appear to be associated with improved renal hemodynamics and a decrease in the resistance of efferent arterioles, which reduces pressure in the glomerular capillaries. These drugs also reduce mortality from myocardial infarction and heart failure. The benefit of ACE inhibitors has been demonstrated for all degrees of HF severity, as well as in patients with asymptomatic left ventricular dysfunction; benefit has also been demonstrated in patients with previous myocardial infarction. Overall, there was a significant reduction in myocardial infarction and HF hospitalizations (odds ratio 0.72, 95% CI 67–78%). This means that treating 100 patients will prevent at least one event in 7 patients.

ACE inhibitors are well tolerated as they cause fewer idiosyncratic reactions and have no metabolic side effects compared to beta blockers and diuretics.

Range of side effects: hypotension, dry cough, hyperkalemia, acute renal failure (in patients with bilateral renal artery stenosis), fetopathic potential (contraindicated in pregnancy), rashes, dysgesia, angioedema, neutropenia, hepatotoxicity, decreased libido, Stevens-Johnson syndrome.

Canadian researchers report that use of ACE inhibitors increases patients' risk of falls and fractures by 53%. It is assumed that this effect of the drugs may be associated both with changes in bone structure and with the likelihood of a significant decrease in pressure when changing body position.

Slow calcium channel blockers. Classification. Mechanism of action. Pharmacodynamics, pharmacokinetics. Indications, contraindications, side effects. Possible interactions with drugs from other groups. Calcium channel blockers

Calcium channel blockers (calcium antagonists) effectively eliminate the symptoms of many cardiovascular diseases, help reduce the severity of pathological disorders, and in some cases have a beneficial effect on the prognosis.

The classification of calcium antagonists is based on differences in chemical structure and tissue selectivity. First generation calcium antagonists include conventional tablets and capsules of nifedipine, verapamil and idiltiazem. Second-generation calcium antagonists are represented by new dosage forms of nifedipine, verapamil and diltiazem, as well as new derivatives dihydropyridine-lodipine and lacidipine, which are sometimes classified as third-generation calcium antagonists.

New dosage forms of calcium antagonists are represented by retardated tablets or capsules, biphasic release tablets or drug therapeutic systems.

Calcium antagonists are selective blockers of “slow calcium channels” (L-type), localized in the sinoatrial, atrioventricular tracts, Purkinje fibers, myocardial myofibrils, vascular smooth muscle cells, and skeletal muscles. They have a pronounced vasodilating effect and have the following main effects:

1. antianginal, anti-ischemic;

3. organoprotective (cardioprotective, nephroprotective);

6. decreased pressure in the pulmonary artery and dilatation of the bronchi - some calcium antagonists (dihydropyridines);

7. decreased platelet aggregation.

The antianginal effect is associated both with the direct effect of calcium antagonists on the myocardium and coronary vessels, and with their effect on peripheral hemodynamics. By blocking the entry of calcium ions into the cardiomyocyte, they reduce the conversion of phosphate-bound energy into mechanical work, thus reducing the ability of the myocardium to develop mechanical tension, and consequently reducing its contractility. The action of these drugs on the wall of the coronary vessels leads to their expansion (antispastic effect) and an increase in coronary blood flow. Due to this, the supply of oxygen to the myocardium increases, and the effect on the peripheral arteries (arterial vasodilation) leads to a decrease in peripheral resistance and blood pressure (reduction of afterload), which reduces the work of the heart and the myocardium’s need for oxygen. In this case, the antianginal effect is combined with a cardioprotective effect (for example, during myocardial ischemia, the mechanism of which is to prevent the load of cardiomyocytes with calcium ions).

The hypotensive effect of calcium antagonists is associated with peripheral vasodilation, which not only reduces blood pressure, but also increases blood flow to vital organs - the heart, brain, kidneys. The hypotensive effect is combined with moderate natriuretic and diuretic effects, which leads to an additional decrease in vascular resistance and circulating blood volume. In addition, calcium antagonists have a beneficial effect on morphological changes in blood vessels and other target organs of hypertension. The cardioprotective effect of calcium antagonists in patients with hypertension is associated with their ability to lead to regression of left ventricular myocardial hypertrophy and improvement of myocardial diastolic function. These effects are based on a hemodynamic effect (reduction of afterload) and a decrease in the overload of cardiomyocytes with calcium ions.

As a result of lowering blood pressure, calcium antagonists can have a triggering effect on the renin-angiotensin-aldosterone and sympathoadrenal systems, leading to the development of side effects and, as a result, poor tolerability. This is especially true for short-acting forms of nifedipine (not recommended for routine treatment of hypertension). Today, long-acting dosage forms of dihydropyridines have been created, which, due to a slow increase in plasma concentration, do not cause activation of counter-regulatory mechanisms and show better tolerability.

The nephroprotective effect of calcium antagonists is based on eliminating vasoconstriction of renal vessels and increasing renal blood flow. In addition, calcium antagonists increase the glomerular filtration rate. As a result of intrarenal redistribution of blood flow, Na + -uresis increases, complementing the hypotensive effect of calcium antagonists. It is important to note that calcium antagonists are effective even in patients with initial manifestations of nephroangiosclerosis and, due to their ability to suppress the proliferation of mesangium cells, provide nephroprotection. Other mechanisms of the nephroprotective effect of calcium antagonists include inhibition of renal hypertrophy and prevention of nephrocalcinosis by reducing the overload of renal parenchyma cells with calcium ions.

The antiatherogenic effect of calcium antagonists has been confirmed in clinical studies and occurs due to the following mechanisms:

1. ↓ monocyte adhesion;

2. ↓ proliferation and migration of SMCs;

3. ↓ deposition of cholesterol esters;

4. cholesterol outflow;

5. ↓ platelet aggregation;

6. ↓ release of growth factors;

7. ↓ superoxide production;

8. ↓ lipid peroxidation;

9. ↓ collagen synthesis.

Verapamil and diltiazem have a tropism for both the myocardium and blood vessels; dihydropyridines have a greater tropism for the vessels, and some of them have a selective tropism for the coronary (nisoldipine) or cerebral vessels (nimodipine).

Such tissue selectivity of calcium antagonists determines the difference in their effects:

1. moderate vasodilation in verapamil, which has negative chronotropic, dromotropic and inotropic effects;

2. pronounced vasodilation in nifedipine and other dihydropyridines, which have virtually no effect on the automaticity, conductivity and contractility of the myocardium;

3. The pharmacological effects of diltiazem are intermediate.

Most calcium antagonists are given orally. Verapamil, diltiazem, nifedipine, nimodipine have forms for parenteral administration.

Calcium antagonists are lipophilic drugs. After oral administration, they are characterized by a rapid rate of absorption, but significantly variable bioavailability, which is associated with the presence of a “first pass effect” through the liver. In blood plasma, drugs are strongly bound to proteins, mainly albumins and, to a lesser extent, lipoproteins. The rate of achieving maximum concentration in blood plasma (Cmax) and TS depend on the dosage form of calcium antagonists: from 1-2 hours for drugs of the first generation, to 3-12 hours for drugs of the second-third generation.

Since the hemodynamic effects of calcium antagonists are dose dependent, an important pharmacokinetic characteristic of long-acting calcium antagonists is the ratio of Cmax to Cmin in the blood plasma.

The closer the ratio of Cmax to Cmin is to unity, the more stable the plasma concentration is during the day; there are no sharp “peaks” and “declines” in the concentration of drugs in the plasma, which, on the one hand, ensures the stability of the effect, and on the other hand, does not stimulate stress systems of the body.

Place in clinical practice

The characteristics of the pharmacological activity of individual representatives of calcium antagonists determine the indications for their use in various cardiovascular diseases.

The pharmacological action of diltiazem and especially verapamil is in many ways similar to beta-blockers. Therefore, these calcium antagonists are often used in patients who do not have heart failure or significant reduction in myocardial contractility, in cases where beta blockers are contraindicated, not tolerated, or are not effective enough.

Dihydropyridines (nifedipine GITS, lacidipine, amlodipine) are the drugs of choice for the treatment of hypertension in patients with carotid artery lesions.

In addition, there is reason to believe that in patients with hypertension, some dihydropyridines (lacidipine, nifedipine GITS) can not only effectively control the symptoms of the disease and prevent cardiovascular complications, but also slow down the progression of atherosclerosis.

Contraindications for the prescription of calcium antagonists are due to their adverse effects on myocardial function (bradycardic, decreased myocardial contractility - verapamil and diltiazem) and hemodynamics, especially in acute conditions accompanied by a tendency to hypotension and increased activity of the sympathoadrenal system.

The following side effects are common to all calcium antagonists:

1. effects associated with peripheral vasodilation: headache, hyperemia of the skin of the face and neck, palpitations, swelling of the legs, arterial hypotension;

2. conduction disorders: bradycardia, atrioventricular block;

3. gastrointestinal disorders: constipation, diarrhea.

The frequency of occurrence of individual side effects depends on the characteristics of the drug used. When taking a short-acting dosage form of nifedipine, along with arterial hypotension, tachycardia and the occurrence or worsening of myocardial ischemia are possible; When using long-acting derivatives of dihydropyridine, verapamil and diltiazem, such a reaction does not occur. Severe arterial hypotension often develops with intravenous administration or the use of high doses of drugs. The appearance of edema of the legs, as a rule, is associated with dilatation of arterioles and is not a manifestation of heart failure. They decrease with a decrease in the drug dose, but often go away without changing therapy when physical activity is limited.

Cases of overdose of calcium antagonists when using therapeutic doses are still unknown. Treatment is with an intravenous infusion of calcium chloride.

Pharmacodynamic interactions are manifested by a change in the severity of the antihypertensive effect (increase or decrease) and an increase in cardiodepressive effects (decreased myocardial contractility, slower conduction along pathways, etc.).

Such interactions are observed at the level of changes in metabolic activity in the liver (verapamil and diltiazem inhibit cytochrome P450) and binding to plasma proteins (for drugs with high binding and a narrow therapeutic index).

49. Beta-blockers. Classification. Mechanism of action. Pharmacodynamics, pharmacokinetics. Indications, contraindications, side effects. Possible interactions with drugs from other groups. Beta blockers Beta blockers are drugs that reversibly (temporarily) block various types (β 1 -, β 2 -, β 3 -) adrenergic receptors.

The importance of beta blockers can hardly be overestimated. They are the only class of drugs in cardiology for the development of which the Nobel Prize in Medicine was awarded. In awarding the prize in 1988, the Nobel Committee called the clinical significance of beta-blockers " greatest breakthrough in the fight against heart disease since the discovery of digitalis 200 years ago».

Digitalis preparations (Foxglove plants, Latin Digitalis) are a group of cardiac glycosides (digoxin, strophanthin, etc.), which have been used to treat chronic heart failure since approximately 1785.

Article 00206

Readiness time for tests in express mode (Cito)

Due time		Readiness
Weekdays	Weekend
Clinic at the CIR Laboratory on Dubrovka
08:00-17:00	09:00-17:00	2-4 hours
Maryino, Novokuznetskaya, Voikovskaya
08:00-12:00	09:00-12:00	4-6 hours
Butovo
08:00-12:00	09:00-12:00	until 17:00
Podolsk
08:00-09:00	09:00-10:00	until 15:00
09:00-11:00	10:00-11:00	until 17:00

The value of tests

To assess platelet function, the CIR Laboratories perform an analysis for induced platelet aggregation. This is a high-quality analysis performed on an automatic aggregometer. Since this test changes dramatically when taking drugs that affect blood clotting (antiplatelet agents, for example, aspirin, thromboass, anticoagulants, for example, heparin), it is advisable to take it before starting to take these drugs. For each aggregogram, the laboratory doctor issues a conclusion.

Platelet aggregation testing is recommended in the following cases: miscarriage, unsuccessful IVF attempts, a history of severe pregnancy complications, infertility of unknown origin, as well as increased bleeding: easy bruising, menorrhagia, nosebleeds.

The aggregation curve evaluates the amplitude of aggregation, the shape of the curve, the presence of one or two waves, and the presence of disaggregation.

The sample shown shows: 1 - zeroing of the device, 2 - before adding the inductor, 3 - peak associated with dilution of the sample by the inductor, 4 - reference point, first wave, 5 - second wave, 6 - disaggregation.

Important information: the combination of taking foods, herbal medicines and nutritional supplements containing components from this list with taking antiplatelet agents (thromboASS) and anticoagulants (heparin) is a dangerous combination due to the risk of bleeding (category D according to the FDA classification). The risk of bleeding in most cases outweighs the potential benefit.

In the CIR Laboratories, platelet aggregation is performed with the following inducers:

• Aggregation with ADP
  
• Aggregation with arachidonic acid
• Aggregation with adrenaline (epinephrine)
• Aggregation with ristocetin.
  The first three inducers make it possible to evaluate the function of platelets from different sides; they complement each other. Aggregation with ristocetin allows one to suspect a dangerous bleeding condition - von Willebrand disease (von Willebrand factor deficiency). When planning a pregnancy, this analysis is important to eliminate the risk of bleeding during childbirth.

Aggregation with ADP (blue line) and arachidonic acid. The aggregation response is sharply reduced. There is virtually no disaggregation.

Aggregation with ADP.
The aggregation response is reduced. There is virtually no disaggregation.

Also, platelet aggregation with ADP and adrenaline may decrease.

Aggregation with ADP, response reduced. Partial disaggregation.

Aggregation with ristocetin, the aggregation response is sharply reduced.

The analysis is given in Maryino on weekdays and Saturdays from 9.00 to 11.00, on Tretyakovskaya and Voykovskaya on weekdays from 8.00 to 10.00.

What medications affect platelet aggregation?

Pathogenetic mechanism	The way to realize the impact	Drugs
Inhibitors of thromboxane A2 formation
Phospholipase inhibitors	Prevents the formation of arachidonic acid, inhibit collagen, ADP and adrenaline aggregation	Quinacarpine, high-dose corticosteroids
COX inhibitors	Acythelate platelet and COX membranes, block the formation of prostacyclin in the endothelium, inhibiting aggregation and release reactions. Against the background of drugs that block COX, arachidonic acid levels are sharply reduced.	PVP (aspirin, indomethacin, butadione, ibuprofen, sulpirazone), indocid, fenoprofen
Thromboxane synthetase inhibitors	They block the synthesis of thromboxane A2 without affecting the synthesis of prostacyclin.	Prostacyclin and its synthetic analogues, imidazole and its derivatives (individual sensitivity)
Competitive antagonists of thromboxane A2	Block thromboxane receptors and inhibit aggregation. Inhibits aggregation under the influence of arachidonic acid	1,3-Azoprostanoic acid and its derivatives
Drugs that increase cAMP levels in platelets
Adenylate cyclase stimulators	They block the synthesis of thromboxane A2 without affecting the synthesis of prostacyclin. Inhibits aggregation under the influence of arachidonic acid.	Prostacyclin, PGE, diterpene foscolin
Phosphodiesterase inhibitors	Prevents cAMP degradation. Inhibit platelet adhesion to the subendothelium, the second wave of aggregation, disrupt the release reaction	Dipyridamole, papaverine, aminophylline, intensain
Stimulators of prostacyclin synthesis	They enhance the synthesis of prostacyclin, its release from the endothelium, and weaken its degradation	Anabolic steroids, nicotinic acid, vasopressin
Drugs that interfere with calcium transport
	Suppress second wave of aggregation	Isoptin, nifedipine
	Violate adhesive-aggregation function platelets	Furosemide in high concentrations
	Disrupts the initial and second wave of ADP-collagen- and adrenaline-platelet aggregation	Nitrofurantoin, aminazine, imipramine, amitriptyline, antihistamines, α- and β-blockers, high (over 20 million units/day) doses of penicillin, carbenicillin
Drugs of different groups
Anticoagulants	In high concentrations they reduce aggregation	Pelentan, warfarin
Dextrans	Reduce platelet aggregation	Reopoliglyukin
Anesthetics	Reduce ADP aggregation	Nitrous oxide, cyclopropane, phenobarbital
Alcohol	Reduces collagen and ADP aggregation
Antiplatelet agents	Reduce all types of aggregation, significantly enhance the effect of prostacyclin, disrupt the connection between platelets and fibrinogen	Tiklid

Presentation "Platelet aggregation"

• what is platelet aggregation
• What are platelet granules and what do they contain?
• what platelet activators are there in a living organism and what does the laboratory use?
• requirements for conducting research
• factors affecting platelet aggregation
• interpretation of aggregograms

Platelets are involved in the process of primary bleeding control. Their activation includes three stages: 1) adhesion to the affected area, 2) release reaction (secretion of platelet products and activation of key receptors) and 3) aggregation.

For example, when a blood vessel is damaged, platelets, using membrane glycoprotein receptors, quickly adhere to the accessible components of the subendothelial space (collagen); this process is regulated by von Willebrand factor. Following platelet adhesion to the vascular wall, the contents of their cytoplasmic granules (including calcium, ADP, serotonin and thrombin) are released. Platelet activation and secretion of granule contents are stimulated when they bind to agonists (in particular collagen and thrombin). During this process, platelet activation induces de novo synthesis and secretion of thromboxane A2 (TXA2), a potent vasoconstrictor and inducer of aggregation (Fig. 17.17). ADP, thrombin and TXA2 promote platelet aggregation and thereby contribute to the formation of the primary blood clot. During platelet activation, important conformational changes occur in the glycoprotein membrane receptors Ilb/IIIa. These changes lead to the fact that previously inactive Hb/Sha receptors bind fibrinogen molecules, as a result of which platelets are firmly connected to each other, forming aggregates.

The regulation of platelet activation is largely due to the release of Ca++ from the platelet depot. As a result, the calcium concentration in the cell cytosol increases, protein kinases are activated, and, ultimately, phosphorylation of regulatory proteins inside platelets occurs. An increase in [Ca++] in the cell cytosol also stimulates phospholipase A2, causing the release of arachidonic acid, the precursor of TXA2 (Fig. 17.17). Calcium release is regulated by several factors. When thrombin and other agonists bind to the corresponding receptors on the platelet membrane, intermediate compounds are formed that stimulate the release of calcium from the depot. TXA2 increases the level of intracellular [Ca++] by binding to its receptor on the surface of platelets, which suppresses the activity of adenylate cyclase, thereby reducing the production of cAMP and increasing the release of [Ca++] from the depot (Fig. 17.17). In contrast, prostacyclin (PGI2) produced by endothelial cells stimulates the activity of adenylate cyclase, increases the concentration of cAMP in platelets and inhibits the secretion of [Ca++] from the depot.

Rice. 17.17. Platelet activation is mediated by intracellular [Ca++]. Factors that accelerate and inhibit the release of calcium from its depot in platelets are shown. Thrombin and serotonin, by binding to specific receptors, stimulate the production of inositol triphosphate (ITP) from phosphatidylinositol diphosphate (PIFg) under the action of phospholipase C (PLS). IFZ enhances the release of calcium into the cell cytoplasm. Thromboxane Ag (TXA2) also promotes the release of calcium: it inhibits the activity of adenylate cyclase (AC), which is accompanied by a decrease in the production of cyclic AMP (cAMP). Under normal conditions, cAMP prevents the release of [Ca++] from the ER, so the decrease in this effect due to the action of TCAg increases the release of calcium into the cytoplasm. Prostacyclin formed in endothelial cells has the opposite effect: by stimulating AC activity and the formation of cAMP, it reduces the release of calcium inside platelets. Calcium enhances the activity of phospholipase Kj (PLA2), under the influence of which TXAg precursors are formed from phospholipids of the cell membrane. When platelets are activated, [Ca++] changes, as a result of which the contents of calcium stores are released, the cytoskeleton is reorganized and the conformation of glycoprotein Ib/Sha receptors significantly changes, i.e., processes necessary for platelet aggregation occur. ADP also makes a certain contribution to platelet aggregation, but the mediators of this process have not yet been identified

Modern antiplatelet drugs affect platelet function at different stages of the processes of their activation and aggregation. The most common antiplatelet drug is aspirin. Other drugs used clinically include dipyridamole and ticlopidine. Potential new drugs that block platelet IIb/Sha receptors are being actively studied, and their significance in the treatment of cardiovascular diseases is being clarified.

Platelet aggregation inhibitors (excluding heparin) - ATC classification of drugs

This section of the site contains information about drugs from the group - B01AC Platelet aggregation inhibitors (excluding heparin). Each drug is described in detail by specialists of the EUROLAB portal.

The Anatomical Therapeutic Chemical Classification (ATC) is an international drug classification system. The Latin name is Anatomical Therapeutic Chemical (ATC). Based on this system, all drugs are divided into groups according to their main therapeutic use. The ATC classification has a clear, hierarchical structure, which makes it easier to find the right drugs.

Each medicine has its own pharmacological action. Correctly identifying the right medications is a fundamental step for successfully treating diseases. In order to avoid undesirable consequences, before using certain medications, consult your doctor and read the instructions for use. Pay special attention to interactions with other medications, as well as conditions of use during pregnancy.

Translate the phrase “Nootropil inhibits the aggregation of activated platelets and restores configurational properties”

increased platelet aggregation is accompanied by ischemic heart disease and the development of myocardial infarction.

i.e. weakens, reduces the hardness of blood vessels, gives red blood cells the opportunity

change its shape to make it easier to pass through the vessels..

In large vessels, nothing prevents the movement of red blood cells, but in capillaries, when the blood is thick and there are a lot of platelets that have formed lumps, the red blood cells can no longer move. This is where hypoxia occurs.

then find out what configuration properties the outer membranes have

rigid red blood cells. (Rigid red blood cells are red blood cells overloaded with cholesterol, right?) http://humbio.ru/humbio/har/0069e456.htm

Spur-shaped red blood cells cannot pass through the red pulp of the spleen - this is a configurational property.

Write each definition in your own words, connect everything according to its meaning - and you're done!

What is platelet aggregation inhibition?

These are drugs that inhibit the initial process of thrombus formation, i.e. aggregation (gluing platelets together) and adhesion (gluing platelets to the surface of the walls of blood vessels), normalizing the rheological properties of blood and tissue microcirculation.

These include acetylsalicylic acid, dipyridamole, ticlopidine (ticlid), etc.

Acetylsalicylic acid affects the initial phase of thrombus formation in small doses of 0.08-0.3 g once a day or every other day for a long time. At such doses, the drug disrupts the synthesis of thromboxane A by acetylation of platelet cyclooxygenase. The antiplatelet effect lasts for several days, because the inhibitory effect of acetylsalicylic acid on platelet cyclooxygenase is irreversible. Cyclooxygenase is restored only during the formation of new platelets. The level of this enzyme in the vascular wall is restored within several hours, so normalization of thromboxane A2 levels occurs within a few days, and prostacyclin levels much faster. As the dose increases, acetylsalicylic acid begins to inhibit the formation of prostacyclin in vascular endothelial cells, which counteracts platelet aggregation, and the antiplatelet effect of the drug decreases.

Indications for use: thrombophlebitis, thrombosis of retinal vessels, cerebrovascular accidents, for the prevention of postoperative blood clots and the prevention of thromboembolic complications in angina pectoris and myocardial infarction.

Dipyridamole (curantyl), like acetylsalicylic acid, inhibits platelet aggregation and counteracts the formation of blood clots in blood vessels by inhibiting phosphodiesterase, which promotes the accumulation of cAMP in platelets. This leads to a decrease in the release of serotonin thromboxane aggregation activators, ADP. It also inhibits adenosine deaminase. Promotes the accumulation of adenosine in erythrocytes and platelets, which is accompanied by vasodilation and inhibition of platelet aggregation. Dipyridamole is better tolerated than acetylsalicylic acid and does not have an ulcerogenic effect. In some cases, facial redness, tachycardia, and allergic skin rash are observed. The drug is contraindicated in atherosclerosis of the coronary arteries.

Ticlopidine (ticlid), clopidogrel (Plavika) inhibit ADP-dependent platelet aggregation (phases I, II), interfere with the formation of fibrin bridges between platelets due to inhibition of glycoprotein receptors II B / III A (impairing the binding of fibrinogen, von Willebrand factor to glycoprotein receptors), and also enhances the formation of antiplatelet prostaglandins J2, D2, E through the platelet cAMP system.

Pentoxifylline (trental) inhibits phosphodiesterase, reduces platelet and erythrocyte aggregation, increases fibrinolysis, reduces blood viscosity, and improves microcirculation.

Other xanthine derivatives also have antiplatelet properties - theophylline, theobromine, aminophylline, which inhibit phosphodiesterase.

27.1. Drugs that reduce platelet aggregation (antiplatelet agents)

Platelets are small, disc-shaped blood elements that are formed as fragments of bone marrow megakaryocytes. Platelets circulate in the blood for 6-12 days and are then taken up by tissue macrophages.

Vascular endothelium influences the functional activity of platelets. Endothelial cells release prostacyclin (prostaglandin I 2) and endothelial relaxing factor, which is identified with nitric oxide - NO, into the bloodstream. These substances prevent platelet aggregation. In addition, endothelial cells secrete substances that reduce blood clotting and promote clot lysis. All this ensures the antithrombogenic properties of intact vascular endothelium.

When the vascular endothelium is damaged, which can be caused by various factors (mechanical trauma, infections, atherosclerotic changes in the vascular wall, increased blood pressure, etc.), the antithrombogenic properties of the endothelium are reduced, which creates conditions for the formation of a blood clot. The synthesis of prostacyclin and endothelial relaxing factor is disrupted and this facilitates contact

platelets with damaged endothelial surface. Platelets accumulate at the site of damage and interact with the vascular subendothelium: directly or through von Willebrand factor (secreted by activated platelets and endothelial cells), they bind to collagen and other proteins of the subendothelium with the participation of specific glycoproteins localized in the platelet membrane. Von Willebrand factor binds to glycoprotein Ib, and collagen binds to glycoprotein Ia of the platelet membrane (see Fig. 27-1). The impact of collagen (as well as thrombin, which is formed in small quantities locally already at the initial stage of thrombus formation) on platelets causes a change in their state - activation. Platelets change their shape (from disc-shaped they become spread out with many processes - pseudopodia) and cover the damaged surface of the vessel.

When activated, platelets release various biologically active substances, which in non-activated platelets are located in granules (α-granules, dense granules). Dense granules are a repository of substances that stimulate platelet aggregation: ADP and serotonin. The release of these substances from platelet granules occurs as a result of an increase in the intracellular concentration of Ca 2+ due to the action of collagen, thrombin and other aggregation inducers, including ADP itself, on platelets. ADP released into the bloodstream stimulates specific (purinergic) receptors localized in the platelet membrane. Through G-protein coupled receptors (P2Y 12 purinergic receptors), ADP causes inhibition of adenylate cyclase and a decrease in cAMP levels, which leads to an increase in Ca 2 levels in the cytoplasm of platelets (Fig. 27-2).

In addition, when platelets are activated, the activity of platelet membrane phospholipase A2, an enzyme involved in the formation of arachidonic acid from membrane phospholipids, increases. In platelets, cyclic endoperoxides (prostaglandins G2/H2) are first synthesized from arachidonic acid under the influence of cyclooxygenase, and from them, with the participation of thromboxanesine-

Thetase produces thromboxane A 2, an active stimulator of platelet aggregation and a vasoconstrictor. Once released into the bloodstream, thromboxane A 2 stimulates thromboxane receptors on platelet membranes. As a result, phospholipase C is activated through Cq proteins associated with these receptors and the formation of

Rice. 27-1. Adhesion and aggregation of platelets during damage to the vascular wall: EC - endothelial cell; VW - von Willebrand factor; TxA 2 - thromboxane A 2; PGI 2 - prostacyclin; NO - endothelial relaxing factor; GP - glycoproteins; GP llb/llla - glycoproteins llb/llla (From: Katzung B.G. Bazic and Clinical Pharmacology - NY, 2001, as amended)

inositol-1,4,5-triphosphate, which promotes the release of Ca 2+ from the intracellular depot of platelets (the role of the calcium depot in platelets is performed by a system of dense tubules). This leads to an increase in the cytoplasmic concentration of Ca 2+ (Fig. 27-2). Thromboxane A 2 causes an increase in the concentration of Ca 2+ in vascular smooth muscle cells, which leads to vasoconstriction.

Rice. 27-2. Mechanisms of action of antiplatelet agents (acetylsalicylic acid, ticlopidine and epoprostenol): EC - endothelial cell; PL - phospholipids of cell membranes; AA - archidonic acid; PLA 2 - phospholipase A 2; COX - cyclooxygenase; TS - thromboxane synthetase; PS - prostacyclin synthetase; PGG 2 /H 2 - cyclic endoperoxides; TxA 2 - thromboxane A 2; PGI 2 - prostacyclin; AC - adenylate cyclase; PLS - phospholipase C; IP 3 - inositol-1, 4, 5-triphosphate

Thus, ADP and thromboxane A 2 increase the level of Ca 2+ in the cytoplasm of platelets. Cytoplasmic Ca 2+ causes a change in the conformation of glycoproteins IIb/IIIa in the platelet membrane, as a result of which they acquire the ability to bind fibrinogen. One molecule of fibrinogen has two binding sites for glycoproteins IIb/IIIa and thus can unite two platelets (Fig. 27-3). The joining of many platelets by fibrinogen bridges leads to the formation of platelet aggregates.

Prostacyclin (prostaglandin I 2) has the opposite effect on platelet aggregation. Like thromboxane, prostacyclin

is formed from cyclic endoperoxides, but under the action of another enzyme - prostacyclin synthetase. Prostacyclin is synthesized by endothelial cells and released into the bloodstream, where it stimulates prostacyclin receptors in the platelet membrane and adenylate cyclase associated with them through the G s protein. As a result, the level of cAMP in platelets increases and the concentration of cytoplasmic Ca 2+ decreases (see Fig. 27-2). This prevents the conformation of glycoproteins IIb/IIIa from changing and they lose their ability to bind fibrinogen. Thus, prostacyclin prevents platelet aggregation. Under the influence of prostacyclin, the concentration of Ca 2+ in vascular smooth muscle cells decreases, which leads to vasodilation.

The following sequence of main events leading to platelet aggregation can be distinguished (see Diagram 27-1).

The main focus of the action of antiplatelet agents, which are currently used in clinical practice, is associated with the elimination of the action of thromboxane A 2 and ADP, as well as with the blockade of glycoproteins IIb/IIIa of platelet membranes. Substances with a different mechanism of action are also used, which increase the concentration of cAMP in platelets and, therefore, reduce the concentration of Ca 2+ in them.

The following groups of agents that reduce platelet aggregation are distinguished.

Agents that inhibit the synthesis of thromboxane A2. - Cyclooxygenase inhibitors:

Scheme 27.1. Mechanism of platelet aggregation

Cyclooxygenase and thromboxane synthetase inhibitors: indobufen.

Agents that stimulate prostacyclin receptors:

Agents that interfere with the effect of ADP on platelets:

Agents that inhibit platelet phosphodiesterase:

Agents that block glycoproteins IIb/IIIa of platelet membranes.

Monoclonal antibodies: abciximab.

Synthetic blockers of glycoproteins IIb/IIIa: eptifibatide; tirofiban.

Agents that inhibit the synthesis of thromboxane A 2

Acetylsalicylic acid (aspirin*) is a well-known anti-inflammatory, analgesic and antipyretic agent. Currently widely used as an antiplatelet agent. The antiplatelet effect of acetylsalicylic acid is associated with its inhibitory effect on the synthesis of thromboxane A 2 in platelets.

Acetylsalicylic acid irreversibly inhibits cyclooxygenase (causes irreversible acetylation of the enzyme) and thus disrupts the formation of cyclic endoperoxides, precursors of thromboxane A2 and prostaglandins from arachidonic acid. Therefore, under the influence of acetylsalicylic acid, not only the synthesis of thromboxane A 2 in platelets, but also the synthesis of prostacyclin in vascular endothelial cells decreases (see Fig. 27-2). However, by selecting the appropriate doses and regimen, it is possible to achieve a preferential effect of acetylsalicylic acid on the synthesis of thromboxane A 2 . This is due to significant differences between platelets and endothelial cells.

Platelets - anucleate cells - do not have a protein resynthesis system and, therefore, are not able to synthesize cyclooxygenase. Therefore, with irreversible inhibition of this enzyme, the disruption of thromboxane A2 synthesis persists throughout the life of the platelet, i.e. within 7-10 days. Due to the formation of new platelets, the antiplatelet effect of acetylsalicylic acid lasts for a shorter period of time, and therefore, to achieve a stable effect of the drug (i.e., a stable decrease in thromboxane levels), it is recommended to prescribe it once a day.

Cycloxygenase is resynthesized in vascular endothelial cells, and the activity of this enzyme is restored within a few hours after taking acetylsalicylic acid. Therefore, when prescribing the drug once a day, there is no significant reduction in prostacyclin synthesis.

In addition, approximately 30% of acetylsalicylic acid undergoes first-pass metabolism in the liver, so its concentration in the systemic circulation is lower than in the portal blood. As a result, acetylsalicylic acid acts on platelets circulating in the portal bloodstream in higher concentrations than on endothelial cells of systemic vessels. Therefore, to suppress the synthesis of thromboxane A2 in platelets, smaller doses of acetylsalicylic acid are required than to suppress the synthesis of prostacyclin in endothelial cells.

For these reasons, with an increase in the dose and frequency of administration of acetylsalicylic acid, its inhibitory effect on prostacyclin synthesis becomes more pronounced, which can lead to a decrease in the antiplatelet effect. In connection with these features, acetylsalicylic acid as an antiplatelet agent is recommended to be prescribed in small doses (on average 100 mg) once a day.

As an antiplatelet agent, acetylsalicylic acid is used for unstable angina, for the prevention of myocardial infarction, ischemic stroke and peripheral vascular thrombosis, to prevent the formation of blood clots during coronary artery bypass grafting and coronary angioplasty. Acetylsalicylic acid is prescribed orally in doses of mg (for certain indications - in the dose range from 50 to 325 mg) once a day for a long time. Currently, doctors have at their disposal acetylsalicylic acid preparations intended for the prevention of thrombosis, which contain mg of the active substance, including enteric-coated tablets - Acecardol *, Aspicor *, Cardiopyrin *, Aspirin Cardio *, Novandol *, Thrombo ACC * and others. The antiplatelet effect of acetylsalicylic acid occurs quickly (within minutes). Enteric-coated dosage forms begin to act more slowly, but with long-term use their effectiveness is practically no different from that of conventional tablets. To achieve a faster effect, acetylsalicylic acid tablets should be chewed.

The main side effects of acetylsalicylic acid are associated with inhibition of cyclooxygenase. This disrupts the formation of prostaglandins E 2 and I 2, which have an antisecretory and gastroprotective effect (reduce the secretion of hydrochloric acid by the parietal cells of the stomach, increase the secretion of mucus and bicarbonates). As a result, even with short-term use, acetylsalicylic acid can cause damage to the epithelium of the stomach and duodenum (ulcerogenic effect). The effect on the gastric mucosa is less pronounced when using enteric-coated dosage forms. When using acetylsalicylic acid, gastrointestinal bleeding and other hemorrhagic complications are possible. The risk of such complications is lower when acetylsalicylic acid is prescribed at a dose of 100 mg/day or less. Selective inhibition of COX leads to activation of the lipoxygenase pathway for the conversion of arachidonic acid and the formation of leukotrienes, which have bronchoconstrictor properties. In patients with bronchial asthma, acetylsalicylic acid can provoke the onset of an attack (“aspirin asthma”). Allergic reactions are possible.

To reduce the ulcerogenic effect of acetylsalicylic acid, a combination drug Cardiomagnyl * containing magnesium hydroxide has been proposed. Magnesium hydroxide neutralizes hydrochloric acid in the stomach (antacid effect), reducing its damaging effect on the mucous membrane. The drug is used for the same indications as acetylsalicylic acid, including for the secondary prevention of ischemic stroke.

Indobufen (ibustrin *) reduces the synthesis of thromboxane A 2, while simultaneously inhibiting cyclooxygenase and thromboxane synthetase. Unlike acetylsalicylic acid, indobufen causes reversible inhibition of cyclooxygenase. When taking this drug, there is a relative increase in the amount of prostacyclin (the prostacyclin/thromboxane A 2 ratio increases). Indobufen inhibits platelet adhesion and aggregation. Indications for use and side effects are the same as for acetylsalicylic acid.

Agents that stimulate prostacyclin receptors

Another way to reduce platelet aggregation is stimulation of prostacyclin receptors. For this purpose they use

prostacyclin preparation e p o pro s t e n o l * . The effect of prostacyclin is opposite to the effect of thromboxane A 2 not only on platelets, but also on vascular tone. It causes vasodilation and a decrease in blood pressure. This effect of prostacyclin is used in pulmonary hypertension. Since prostacyclin is quickly destroyed in the blood (t 1/2 about 2 minutes) and therefore does not act for long, the drug is administered by infusion. Due to its short action, epoprostenol* has not found widespread use as an antiplatelet agent. A possible area of ​​use of the antiplatelet effect of epoprostenol is the prevention of platelet aggregation during extracorporeal circulation.

Agents that interfere with the action of ADP on platelets

Ticlopidine (ticlid*), a thienopyridine derivative, inhibits platelet aggregation caused by ADP. Ticlopidine is a prodrug; its antiplatelet effect is associated with the formation of an active metabolite with the participation of microsomal liver enzymes. The ticlopidine metabolite contains thiol groups, through which it irreversibly binds to P2Y 12 purinergic receptors in the platelet membrane. This leads to the elimination of the stimulating effect of ADP on platelets and a decrease in the concentration of cytoplasmic Ca 2+ in them. As a result, the expression of glycoproteins IIb/IIIa in the platelet membrane and their binding to fibrinogen decreases (see Fig. 27-2). Due to the irreversible nature of its action, ticlopidine has a long-lasting antiplatelet effect.

The maximum effect with constant use of ticlopidine is achieved after 7-11 days (the time required for the formation and development of the action of the active metabolite) and after discontinuation of the drug it persists throughout the entire lifespan of platelets (7-10 days).

Ticlopidine is prescribed for the secondary prevention of ischemic stroke, to prevent thrombosis in obliterating diseases of the lower extremities, during coronary artery bypass grafting and stenting of the coronary arteries. The drug is effective when taken orally, prescribed 2 times a day with meals.

The use of ticlopidine is limited due to its side effects. Possible loss of appetite, nausea, vomiting, diarrhea (20%), abdominal pain, skin rashes (11-14%). Noted

increase in the blood plasma level of atherogenic lipoproteins. Bleeding is a common complication when using antiplatelet agents. A dangerous complication is neutropenia, which occurs during the first three months of treatment in 1-2.4% of patients. Thrombocytopenia, agranulocytosis, and very rarely aplastic anemia are possible. In this regard, during the first months of treatment, systematic monitoring of the blood picture is necessary.

Clopidogrel (Plavix*, Zilt*) is similar to ticlopidine in chemical structure, main effects and mechanism of action. Like ticlopidine, it is a prodrug and undergoes conversion in the liver to form an active metabolite. Significant inhibition of platelet aggregation was noted from the second day of treatment, the maximum effect is achieved after 4-7 days. After discontinuation of the drug, its effect lasts for 7-10 days. Clopidogrel is superior to ticlopidine in activity - at a daily dose of 75 mg it causes the same decrease in platelet aggregation and prolongation of bleeding time as ticlopidine at a daily dose of 500 mg.

Clopidogrel is used for the same indications as acetylsalicylic acid, in case of intolerance. Take orally 1 time per day, regardless of meals. Clopidogrel can be combined with acetylsalicylic acid, since the drugs inhibit different mechanisms of platelet aggregation and therefore enhance the effect of each other (however, with this combination there is a higher risk of hemorrhagic complications).

Compared with ticlopidine, the side effects of clopidogrel are less pronounced (diarrhea - 4.5%, rash - 6%). The use of clopidogrel is associated with a lower risk of such a serious complication as neutropenia (0.1%), and thrombocytopenia occurs less frequently. As a rare complication, as with ticlopidine, thrombotic thrombocytopenic purpura may develop.

Platelet phosphodiesterase inhibitors

Dipyridamole (curantyl*, persantine*) was first proposed as a coronary dilator. Later, its ability to inhibit platelet aggregation was revealed. Currently, dipyridamole is used mainly as an antiplatelet agent for the prevention of thrombosis. The antiplatelet effect of dipyridamole is associated with an increase in the level of cAMP in platelets, as a result of which the concentration of cytoplasmic Ca 2+ in them decreases. This happens for several reasons. First, dipyridamole inhibits phosphodiesterase, which inactivates cAMP. In addition, dipyridamole inhibits the uptake of adenosine by endothelial cells and erythrocytes and its metabolism (inhibits adenosine deaminase), thereby increasing the level of adenosine in the blood (Fig. 27-4). Adenosine stimulates platelet A 2 receptors and increases the activity of adenylate cyclase associated with these receptors, as a result, the formation of cAMP in platelets increases and the level of cytoplasmic Ca 2+ decreases. Dipyridamole also increases cAMP levels in vascular smooth muscle cells, causing vasorelaxation.

Dipyridamole is used to prevent ischemic stroke, as well as for diseases of peripheral arteries (mainly in combination with acetylsalicylic acid, since dipyridamole itself has a weak antiplatelet effect). Prescribed orally 3-4 times a day 1 hour before meals. In combination with oral anticoagulants, dipyridamole is prescribed to prevent the formation of blood clots in mitral heart disease.

When using dipyridamole, headache, dizziness, arterial hypotension, dyspeptic symptoms,

skin rashes. The risk of bleeding is less than with the use of acetylsalicylic acid. Dipyridamole is contraindicated in cases of angina pectoris (possible “steal syndrome”).

Rice. 27-4. Mechanism of antiplatelet action of dipyridamole: EC - endothelial cell; A 2 -P - adenosine A 2 receptor; PDE - cAMP phosphodiesterase; AC - adenylate cyclase; GP IIb/IIIa - glycoproteins IIb/IIIa

Pentoxifylline (agapurine*, trental*), like dipyridamole, inhibits phosphodiesterase and increases cAMP levels. As a result, the level of cytoplasmic Ca 2 + in platelets decreases, which leads to a decrease in their aggregation. Pentoxifylline also has other properties: it increases the deformability of red blood cells, reduces blood viscosity, and has a vasodilating effect, improving microcirculation.

Pentoxifylline is used for cerebrovascular accidents, peripheral circulatory disorders of various origins, and vascular pathology of the eyes (see the chapter “Drugs used for cerebrovascular accidents”). Possible side effects: dyspeptic symptoms, dizziness, redness of the face, as well as a decrease in blood pressure, tachycardia, allergic reactions, bleeding. Like dipyridamole, it can provoke attacks during angina pectoris.

Agents blocking glycoproteins IIb/IIIa of platelet membranes

This group of antiplatelet agents, which directly interact with glycoproteins IIb/IIIa of platelet membranes and disrupt their binding to fibrinogen, has appeared relatively recently.

Abciximab (reopro*) - the first drug from this group is a “chimeric” mouse/human monoclonal antibody (Fab fragment of mouse antibodies to glycoproteins IIb/IIIa combined with the Fc fragment of human Ig). Abciximab non-competitively inhibits the binding of fibrinogen to glycoproteins IIb/IIIa on the platelet membrane, disrupting their aggregation (see Fig. 27-3). Platelet aggregation normalizes 48 hours after a single dose. The drug is administered intravenously (as an infusion) to prevent thrombosis during angioplasty of the coronary arteries. When using abciximab, bleeding is possible, including internal (gastrointestinal, intracranial, bleeding from the genitourinary tract), nausea, vomiting, hypotension, bradycardia, allergic reactions up to anaphylactic shock, thrombocytopenia.

The search for less allergenic drugs with the same mechanism of action led to the creation of synthetic blockers of glycoproteins IIb/IIIa. Based on barborin (a peptide isolated from the venom of the pygmy rattlesnake), the drug e p t i f i b a t i d (integrilin *) was obtained - a cyclic hectapeptide that imitates the amino acid sequence of the fibrinogen chain, which directly binds to glycoproteins IIb/IIIa. Eptifibatide competitively displaces fibrinogen from binding to receptors, causing a reversible disorder of platelet aggregation. The drug is administered intravenously as an infusion; the antiplatelet effect occurs within 5 minutes and disappears 6-12 hours after cessation of administration. The drug is recommended for the prevention of thrombus formation during percutaneous coronary angioplasty, for unstable angina, and for the prevention of myocardial infarction. A dangerous complication when using eptifibatide is bleeding; thrombocytopenia is possible.

Tirofiban (agrastat*) is a non-peptide blocker of glycoproteins IIb/IIIa, an analogue of tyrosine. Like eptifibatide, tirofiban competitively blocks glycoprotein IIb/IIIa receptors. The drug is administered intravenously (infusion). The speed of onset of effect, duration of action and indications for use are the same as for eptifibatide. Side effects - bleeding, thrombocytopenia.

To expand the possibilities of using drugs in this group, blockers of glycoproteins IIb/IIIa were created that are effective when administered orally - xemilofiban *, sibrafiban *, etc. However, tests of these drugs revealed their insufficient effectiveness and a side effect in the form of severe thrombocytopenia.