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The processes of formation of atherosclerotic plaque and thrombus formation are closely related, therefore, pathogenetically it makes sense to conduct antithrombotic , antiplatelet treatment for all manifestations of atherosclerosis.
Acetylsalicylic acid (aspirin) . as an antiplatelet , has a large evidence base of effectiveness, easy to use and accessible.
Antiaggregant ( antithrombotic ) effect of acetylsalicylic acid is associated with blockade of cyclooxygenase-1 activity and synthesis of prostaglandins. The blockade of cyclooxygenase-1 leads to a decrease in the synthesis of thromboxane A2-strong vasoconstrictor and a powerful aggregation stimulator. Also, acetylsalicylic acid stimulates fibrinolysis and blocks the synthesis of fibrin.
An important point is that acetylsalicylic acid stabilizes an atherosclerotic plaque, suppressing the inflammatory processes leading to its rupture. Stability of antisclerotic plaque is also achieved by the antioxidant effect of acetylsalicylic acid by stimulating the production of ferritin , which in turn binds the free radicals (R) of iron in the blood.
To use acetylsalicylic acid as an antiaggregant should be in small doses (50-150 milligrams), since the synthesis of prostaglandin I2, which is an antiaggregant and a vasodilator , is less inhibited . The use of enteric-soluble drug form of acetylsalicylic acid reduces complications from the gastrointestinal tract to a minimum.
The appointment of aspirin, according to research, at a dosage of 75-150 milligrams reduces the risk of repeated cardiovascular crises by 25 percent. Patients with hypertension . having cardiovascular crises, it is also rational to prescribe antiplatelet therapy, but an important (adequate) control of arterial pressure is an important condition.
To reduce the incidence of complications on the gastrointestinal tract, it is not recommended to use a dose of acetylsalicylic acid more than 80 milligrams per day. It is also recommended to use proton pump inhibitors.
With all the above recommendations, acetylsalicylic acid is an effective antiplatelet agent for the prevention of complications of cardiovascular disease.
Aspirin is the most effective antiplatelet agent available today . Aspirin is the most studied antiaggregant . It acetylates cyclooxygenase platelets, thereby reducing the formation of platelets of thromboxane A2 - prostaglandin, which causes platelet aggregation and vasoconstriction . This effect persists throughout the life of platelets . that is, within 8 days . At the same time, aspirin inhibits the formation of endothelial cells of prostacyclin -prostaglandin . preventing the aggregation of platelets and causing vasodilation . This effect is temporary: once the aspirin disappears from the blood, the endothelial cells begin to synthesize prostacyclin again . In low doses and once a day, aspirin inhibits the formation of thromboxane A2. almost without affecting the synthesis of prostacyclin . Usually, aspirin is prescribed in a dose of 300 mg / day or less.
Antiaggregants are used in the treatment of arterial diseases and thromboembolism (Table 119.5). Due to its pharmacological features, aspirin is best studied. With a single admission, it is irreversibly acetylated cyclooxygenase . inhibiting the formation of thromboxane A2 in platelets. If other cells (for example, endothelial cells) can synthesize new molecules of the enzyme, then the platelets are unable to do this because of the absence of the nucleus and remain inactive throughout the life span.
To block the synthesis of thromboxane A2 and platelet aggregation, it is enough to take aspirin at a dose of 160 mg once a day or 325 mg every other day.
In patients with unstable angina, the risk of myocardial infarction is very high. Two large studies have shown that early administration of aspirin dramatically reduces the risk of myocardial infarction in these patients, although the frequency, severity, and duration of angina attacks do not change thereafter. The frequency of repeated myocardial infarctions with aspirin is reduced by 25%.
Another study in male doctors showed that with a daily intake of aspirin, the risk of the first myocardial infarction also decreases.
According to preliminary data from major clinical and epidemiological studies, similar results can be expected in women.
Thanks to these data, aspirin is now widely used for the prevention of myocardial infarction.
Aspirin in combination with dipyridamole when administered in the preoperative period increases the permeability of coronary shunts; the same combination reduces the frequency of embolism of the brain vessels in patients with prosthetic heart valves. receiving warfarin .
Much indicates that the combination of aspirin with dipyridamole is effective only due to aspirin. Therefore, the addition of dipyridamole to aspirin is hardly advisable.
Aspirin also reduces the frequency of transient cerebral ischemia in atherosclerosis of cerebral vessels; In the treatment of such patients, aspirin almost completely replaced the indirect anticoagulants. The frequency of repeated strokes with aspirin is reduced by 25%.
In combination with dipyridamole, aspirin slows the progression of some forms of glomerulonephritis (although nephrologists rarely use these drugs).
In addition, aspirin helps maintain the patency of arteriovenous shunts in patients on hemodialysis. At the same time, to maintain the patency of the vessels after the percutaneous angioplasty aspirin is ineffective.
For decades, it was believed that aspirin has three main effects: anti-inflammatory, antipyretic and less pronounced anesthetic. It is this triad of effects that characterizes a class of non-steroidal anti-inflammatory drugs (NSAIDs). where except the aspirin and other salicylates are well-known drugs of different chemical structure (Ortophenum. indomethacin, phenylbutazone and others.). To steroidal anti-inflammatory drugs are preparations of the adrenal cortex, such as hydrocortisone, prednisolone.
How do these effects of aspirin occur or, as experts in drug research - pharmacologists say, what are the mechanisms of action? They are complex, interrelated and still not sufficiently studied [1, 2 ].
The most distinctly suppressed second, exudative phase of inflammation, characterized by the release of the liquid part of the blood through the vascular wall, which leads to tissue swelling. Aspirin reduces the formation and influence on the vessels of inflammatory mediators . such as histamine, bradykinin , hyaluronidase , prostaglandins. As a result, the permeability of the vessels decreases and the exudation is weakened. Salicylates disrupt the synthesis of ATP, worsening the energy supply of the inflammatory process (sensitive to lack of energy). in particular the migration of leukocytes. The stabilizing effect on the cell membranes of lysosomes prevents the release of aggressive lysosomal enzymes and thereby weakens the destructive phenomena in the focus of inflammation. It is interesting that aspirin suppresses inflammatory edema of the extremities of experimental animals when introduced into the lateral ventricle of the brain, which also indicates the effect on the central mechanisms of regulation of peripheral inflammation.
Still, the main role in the implementation of the anti-inflammatory effect of aspirin, like all NSAIDs, is the ability to inhibit the biosynthesis of some of the main mediators of inflammation - prostaglandins (PG). These endogenous biologically active substances are the products of the transformation of arachidonic acid and are formed in various cells of the body under the action of the enzyme cyclooxygenase (COX) . which is blocked by aspirin. Arachidonic acid is released from membrane phospholipids by phospholipase A 2 .
However, the mechanism of inhibition of COX by aspirin and other NSAIDs is not the same. Aspirin, covalently bound to the remainder of the amino acid serine in the enzyme molecule, inhibits it irreversibly. As a result, steric hindrance arises to the attachment of the substrate ( arachidonic acid) to the active center of the COX. Unlike aspirin, voltaren , ibuprofen and other NSAIDs bind the COX reversibly. In inflamed tissue, mainly PGE 2 and PGI 2 . They act on the vascular wall themselves and increase the influence of other mediators of inflammation: histamine, bradykinin , serotonin.
New opportunities in the drug regulation of inflammation open in connection with the study of mediators of immunity - immunocytokines . It was found that aspirin inhibits the expression of the tumor necrosis factor gene (TNF-a). He among other effects activates neutrophils and macrophages that can support inflammation. There are data on the limitation of IL-1 production . which along with the activation of macrophages and neutrophils has its own pro-inflammatory ability - induce the synthesis of acute phase proteins. Influencing the late, proliferative stage of inflammation, aspirin inhibits the formation of granulomas (inflammatory proliferation of connective tissue in the form of a knot or tubercle). especially characteristic of rheumatism. It is believed that this action is associated with the elimination of the stimulating fibroblast effect of serotonin and bradykinin .
As has recently been established, an important contribution to the therapeutic effect of aspirin on inflammation is the metabolite of arachidonic acid lipoxin (LX) A4 ( trihydro-eicosotetraenoic acid). It is generated by various types of cells, including active participants in the inflammatory process of neutrophils and macrophages. The starting point in the induction of synthesis (LX) A4 is the acetylation of COX by aspirin. It has been established that lipoxins regulate the cellular reactions of inflammation and immunity. It has been proved, in particular, that lipoxins dramatically inhibit the release of IL-8 . which causes accelerated maturation, chemotaxis, transendothelial migration, activation of neutrophilic leukocytes, activates also macrophages and T-lymphocytes.
Antipyretic effect, apparently, is also associated with inhibition of PG synthesis. NSAIDs, and aspirin among them, do not affect normal or elevated temperature (heat stroke) body temperature. Other conditions occur with infectious diseases. Endogenous pyrogen , mainly IL-1. mobilize from leukocytes and increase in the center of thermoregulation, located in the hypothalamic region of the brain, the level of PGE 2 . As a result, the normal ratio of Na and Ca 2 ions is disrupted . which changes the activity of neurons in the thermoregulatory structures of the brain. The consequence is an increase in heat production and a decrease in heat transfer. Suppressing the formation of PGE 2 and thereby restoring the normal activity of neurons, aspirin reduces body temperature. Decrease in temperature is due to an increase in heat transfer as a result of the expansion of the vessels of the skin, which comes on command from the center of thermoregulation. At present, based on the notion of the protective role of temperature increase, it is rarely reduced specially. Usually this is achieved as a result of influencing the causative factor (the most frequent situation is the destruction of the pathogen by the antibiotics ).
However, children are prescribed antipyretic drugs at a temperature of 38.5-39 ° C, which disrupts the general state of the body, and children with cardiovascular pathology and prone to convulsions - at a temperature of 37.5-38 ° C. At the same time, it is considered that in children with viral infections (influenza acute respiratory infections, chicken pox), aspirin intake threatens the development of Ray's syndrome, which is characterized by brain and liver damage and often leads to death. Therefore, pediatricians use ibuprofen, naproxen and especially paracetamol.
The mechanism of analgesic (analgesic) action consists of two components: peripheral and central.
It is known that PG (PGE 2 . PGF 2a . PGI 2 ) . having a moderate own ability to cause a sensation of pain, significantly increase the sensitivity (sensitize) the endings of nerve fibers to various effects, including inflammatory mediators - bradykinin , histamine, etc. Therefore, a violation of biosynthesis of PG leads to an increase in the threshold of pain sensitivity, especially with inflammation. The central component, possibly also associated with the inhibition of PG synthesis, is inhibition of pain impulses along the ascending neural pathways, mainly at the level of the spinal cord. In comparison with other NSAIDs, the analgesic effect of salicylates is rather weakly expressed.
The foregoing makes it clear that the combination of anti-inflammatory, analgesic and antipyretic properties in one drug can not be considered accidental, since the action of the PG themselves, which influence the formation of which is the main effect of aspirin and other NSAIDs, is multifaceted.
The use of aspirin in certain cardiovascular diseases, and primarily in coronary heart disease (CHD) . is based on its ability to have an antithrombotic effect, expressed in preventing the formation of thrombi - thrombosis. A thrombus, a blood clot of different densities, formed in blood vessels, can obstruct or completely block the bloodstream in the vessel, which leads to a violation of the blood supply (ischemia) of the relevant organ or part thereof. Depending on the degree of ischemia, the possibility of compensating for the deficiency of blood supply at the expense of neighboring vessels, the importance of the organ, the consequences for the body can be different up to a fatal heart attack or brain. A thrombus or a fragment of it can come off, move by a current of blood and cork another vessel (embolism) with similar consequences.
Therefore, an increased tendency to thrombosis plays an extremely important role in the course of many cardiovascular diseases. Equally obvious is the urgent need for antithrombotic agents. There are three groups of such drugs: fibrinolytic , anticoagulants and antiplatelet , or antiplatelet agents . Fibrinolytics are esigned only to dissolve an already formed thrombus. Actively used anticoagulants, drugs that reduce blood clotting. But they require careful monitoring of blood coagulability, since they can cause dangerous bleeding in an overdose. The most widely used antiplatelet drugs, among which the unconditional leader is our familiar aspirin.
The formation of a thrombus is the result of a complex interaction between the components of the vascular wall, platelets and plasma proteins of the coagulating and anti- convolving blood systems . Platelets are unable to settle on the intact endothelium, which is a layer of flattened cells lining the inside of the walls of blood and lymphatic vessels. But if the integrity of the endothelial layer is violated, they easily adhere to subendothelial structures, especially collagen (adhesion) . which is ensured by the presence on the membranes of platelets receptors glycoprotein nature. In this case, platelets release some substances, including adenosine diphosphate (ADP) and thromboxane , which are powerful aggregates . As a result, a close accumulation of platelets is formed with the formation of fibrinogen bridges between them (aggregation). There is a further release of ADP and thromboxane , activating inactive cells, the mass of platelets increases (the phenomenon of snowballs). there is a platelet thrombus. Platelet granules release enzymes, vasoactive peptides, clotting factors, blood clotting increases, proteins of the coagulating system impregnate a platelet thrombus, one of them - fibrinogen converts into fibrin, imparts thrombus density, thrombus formation ends.
The two most important participants in these events are thromboxane and prostacyclin (PGI 2 ) . which are formed from arachidonic acid under the influence of COX, thromboxane - in platelets, prostacyclin - in endothelial cells. But their effects are antagonistic: prostacyclin dilates blood vessels and inhibits platelet aggregation, thromboxane acts the opposite ( Figure 2 ) . These effects are realized through a well-known mediator (messenger) of signaling inside the cell- cAMP . Prostacyclin increases the content of cAMP , which retains Ca 2+ in the bound state, which leads to inhibition of adhesion and platelet aggregation, as well as to a decrease in the release of thromboxane . Under the influence of thromboxane , on the contrary, the level of cAMP in platelets decreases.
The intact endothelium, producing prostacyclin , does not attract platelets. There are other explanations. Endothelial cells and platelets have a negative charge and are repulsed mutually. Synthesized by endothelial cells, the so-called endothelium - dependent relaxation factor, like prostacyclin , inhibits the adhesion and aggregation of platelets. Finally, an ADPase enzyme is localized on the surface of endothelial cells , which destroys a powerful platelet activator ADP (the AMP formed, on the contrary, inhibits platelet adhesion and aggregation) . In the formation of a defect in the endothelium ( for example , due to atherosclerosis), the exposed subendothelial tissues, deprived of these factors, become attractive for platelets.
Aspirin irreversibly acetylates COX platelets, which, being non-nuclear, are unable to synthesize new molecules of this enzyme, as well as other proteins. As a result, the formation of metabolites with arachidonic acid, including thromboxane , is sharply suppressed in thrombocytes during their entire life (up to 10 days). The irreversibility of COX inhibition is the fundamental difference between aspirin and all other NSAIDs that oppress COX reversibly. Consequently, they would have to be prescribed much more often than aspirin, which is uncomfortable, and fraught with complications.
Aspirin causes an antithrombotic effect. How is it achieved? In the circulatory system, aspirin does not circulate for long, therefore relatively little affects the COX of the vascular wall, where prostacyclin synthesis continues . In addition, endothelial cells, unlike platelets, are able to synthesize new molecules of COX. But the predominant effect on platelet COX is provided by the use of small doses of aspirin - about 50-325 mg per day, which is much less than the doses used for inflammation (2.0-4.0 g per day) . and, naturally, more secure. Aspirin has another useful property: as a vitamin K antagonist, it inhibits the synthesis of the precursor thrombin, the main factor in blood coagulation, in the liver.
Aspirin is prescribed for a long time with thrombophlebitis, cerebral circulation disorders and especially to prevent thromboembolic complications in coronary heart disease and myocardial infarction. Aspirin is indispensable for the prevention of thrombosis in cardiac and vascular surgery. In the unfavorable course of pregnancy, hypertension often occurs, which can go to pre-eclampsia (headache, visual disturbances, edema, convulsions). At the heart of these complications is the hyperproduction of thromboxane in prostacyclin deficiency . Excess thromboxane causes platelet hyperaggregation and vasospasm. Therefore, prevention of preeclampsia with success is carried out with aspirin, especially its long-acting dosage forms.
Recent studies reveal new aspects of the beneficial effects of aspirin in cardiovascular disease. It is known that an important endothelial damaging factor is the oxygen radicals formed during peroxide oxidation of lipids, as well as in activated neutrophils and macrophages. It has been established that aspirin protects the endothelium from such damage, which is associated with increased synthesis of the cytoprotective ferritin protein , which sequestrates from the cytosol iron ions, the main catalyst for the formation of oxygen radicals. It is interesting that other NSAIDs do not possess this property. Aspirin induces the formation of synthetase NO, and thereby increases the production of NO, the most important factor in vasodilatation and the improvement in blood flow in them. These effects are useful in various cardiovascular diseases. With atherosclerosis, they successfully supplement the known ability of aspirin to slow the formation of atherosclerotic plaques, protecting low-density lipoproteins from oxidation.
Aspirin is widely used to treat not only rheumatic diseases, but also with dental and headache, migraine, neuralgia and some other pathological conditions, accompanied by inflammation, pain and high fever.
Unfortunately, the main undesirable effects of aspirin - the formation of stomach ulcers and the toxic effect on the kidneys - are also a violation of the synthesis of PG, which underlies the therapeutic effect. The reason is that with COX blockade, simultaneous with the inhibition of the synthesis of harmful pro-inflammatory PH, the useful GHGs, in particular, protect the gastric mucosa from damaging factors, and primarily from the hydrochloric acid produced by the stomach. Naturally, these complications were perceived as inevitable. However, recently in-depth study of the mechanism of action of aspirin found that COX has two isoforms : COX-1 and COX-2. COX-1 is a structural enzyme that synthesizes PG regulating the normal (physiological) functions of various cells, whereas COX-2 is activated by pro-inflammatory stimuli and forms PGs involved in the development of the inflammatory process. A clear and far from a single example, when a drug acts as a tool for studying fundamental phenomena.
Aspirin and aspirin-like drugs block as COX-2 . and COX-1. which explains the nature of side effects. The discovery of COX isoforms is the theoretical basis for the development of anti-inflammatory drugs of a fundamentally new type - selective blockers of COX-2. and consequently , devoid of typical for them severe side effects. And such substances have already been obtained, they undergo clinical trials [4 ].
In connection with the recent detection of antiproliferative (anti-multiplication) effects on the mucosa of the colon, intensive use of aspirin in the treatment of colorectal cancer has been intensively studied  . cells of which express COX-2. Proceeding from the involvement of the inflammatory component in the development of Alzheimer's disease (a variant of the rapid development of dementia in the elderly), the feasibility of using NSAIDs in its treatment is being studied.
Given that the most frequent side effect of aspirin is damage to the mucous membrane of the stomach, it is clear the desire to reduce it to a minimum. The damaging effect of aspirin on the stomach is realized at two levels: the systemic, which was already mentioned above, and local. The local effect is a direct damaging effect on the gastric mucosa, as the substance, poorly soluble in water and acidic stomach contents, precipitates in the folds of the mucous membrane.
Local irritating effect, especially inherent in the usual ASA tablets, can be significantly weakened by covering the tablets with a coating that dissolves only in the intestine. Similar effects have microencapsulated tablets. However, at the same time the absorption of the drug is delayed, which, however, does not matter for the anti-aggregate effect. A rapid and more pronounced action with a reduced risk of damage to the stomach is provided by soluble tablets, which contain special substances that increase the solubility of ASA in water. But in the stomach ( pH 1.5-2.5) part of the dissolved substance can be recrystallized . To prevent this from happening, the tablets include substances with buffer properties - sodium hydrogen carbonate, sodium citrate, etc. Complex compounds of ASA with good water solubility have been obtained . Thus, lysine acetylsalicylate (drugs aspizol and laspal ) is administered intravenously and intramuscularly. Perspective transdermal forms of ASA are very promising - in the form of a patch applied to the skin. Such a dosage form, according to preliminary data, provides not only a prolonged intake of the drug into the systemic circulation and a decrease in the side effect on the stomach, but also a relatively selective inhibition of COX of platelets while maintaining prostacyclin synthesis .
Alexandra 17:27 | 02/13/2018
Many thanks to you for your valuable, practically, exhaustive publications about medicines! Success to you in everything! Health!