Acetylsalicylic acid mechanism of action of antiplatelet

The main interface in the group of antiplatelet agents passes along the point of their influence on the formed elements of the blood. There are platelet (Heparin, Aspirin, Dipyridamole) and erythrocyte (Pentoxifylline (contraindicated in patients after a heart attack), Reopoliglyukin) drugs.

There are drugs of combined action: Cardiomagnyl, Aspigrel, Agrenox.

In addition, platelet disaggregants (antiplatelet agents) are divided according to the mechanism of action on:

  1. Drugs that directly block platelet receptors:
  • ADP receptor blockers;
  • PAR receptor blockers
  1. Agents that inhibit platelet enzymes:
  • COX inhibitors;
  • PDE inhibitors.

It should be noted that this is not a final classification. In the near future, the list may be supplemented with new subgroups, since pharmacologists are constantly working on improving the means used in modern medicine.

Herbal remedies

ASA inhibits platelet aggregation by acetylation and inhibition of cyclooxygenase (COX) (B). This reaction is very specific: irreversible acetylation of the enzyme in the blood occurs in the celiac nerve, that is, before it enters the liver. Since ASA is subjected to presystemic deacetylation, it does not affect COX localized in areas after passage of the liver (for example, in the endothelium). In addition, platelets cannot synthesize COX on their own, since they do not have a nucleus. Therefore, the effect of ASA on them is especially strong.

On the pharmacological market are antiplatelet agents of plant origin based on ginkgo biloba. There are two representatives of this group available on the market:

  • Ginkio (Bilobil, Bilobil forte) – 45 rubles;
  • Ginos (Ginkoum) – 149 rubles.

The properties declared by manufacturers (normalization of metabolism in cells, improvement of rheological properties of blood, microcirculation, cerebral circulation, supply of oxygen and glucose to the brain, obstruction of red blood cell aggregation, inhibition of platelet activating factor) do not have scientific evidence for mono-use of drugs.

contraindications

Antiplatelet agents are prescribed by a doctor, because there are many reasons for their use, all are different. Indications for admission are:

  • atherosclerosis;
  • unstable angina;
  • prevention of cerebral or heart ischemia;
  • rehabilitation after ischemic stroke or heart attack;
  • high blood pressure;
  • obliteration of vessels of the lower extremities;
  • IHD therapy;
  • tendency to thrombosis, including hereditary;
  • transient blood flow disorders;
  • cardiac surgery;
  • insect bite (grind a tablet, mix with a small amount of water, apply the mixture to the bite);
  • acne, acne residues, black spots (local use of tablets):
  • corns, corns, rough skin on the heels (also local).

Only a qualified specialist can calculate the optimal dose of the drug, the duration of use, the participation of the drug in the complex therapy regimen of a disease. Dazaggregants are recommended after a complete clinical and laboratory examination, when all questions about the diagnosis have been removed, differential diagnosis has been carried out.

I must say that the list of indications is rather approximate. Doctors use antiplatelet agents for numerous complications of coronary heart disease, circulatory disorders, and blood coagulation systems. Each specific prescription is a doctor’s area of ​​responsibility (taking into account possible fatal complications). In this aspect, it is important to pay attention to the use of drugs with antiplatelet properties in combination with other agents. Strengthen the disaggregant effect:

  • non-steroidal anti-inflammatory drugs (Voltaren, Nurofen, Diclofenac);
  • cytostatics (Adalimumab, Infliximab, Etanercept);
  • anticoagulants (Apixaban, Rivaroxaban, Dabigatran);
  • SSRIs (Sertraline, Paroxetine, Escitalopram);
  • other antiplatelet agents.

In addition, some diseases enhance the effect of antiplatelet agents:

Reduce the anticoagulant effect: Carbamazepine, Erythromycin, Fluconazole, Omeprazole.

Antiplatelet agents are substances that have many side effects, so they are always prescribed with great care, carefully weighing the pros and cons. But there are several pathological conditions, the presence of which in the patient is an absolute ban on the use of drugs:

  • idiosyncrasy;
  • stomach ulcer, duodenal ulcer and all erosive and ulcerative diseases of the digestive system;
  • functional failure of the liver or kidneys;
  • hemorrhagic diathesis;
  • hemorrhagic stroke;
  • bleeding of internal organs of unknown genesis;
  • severe cardiovascular failure;
  • pregnancy, especially of the third trimester;
  • lactation;
  • age to 18.

Hypersensitivity, incl. Aspirin triad, aspirin asthma; hemorrhagic , deficiency of glucose-6-phosphate dehydrogenase, pregnancy (I and III trimester), breastfeeding, children and adolescents up to 15 years when used in achestve antipyretic (risk of Reye’s syndrome in children with fever on a background of virus diseases).

Pharmacological group of the substance Acetylsalicylic acid

The list, which includes the most popular and effective antiplatelet agents, antiplatelet agents exists quite wide. The list of drugs of the group that affect platelets and red blood cells using various mechanisms is presented below.

Acetylsalicylic acid has the ability to activate platelets. Therefore, antiplatelet therapy using the means of this group is pathogenetically substantiated.

Antiplatelet action is a key moment in the pathogenesis of cardiovascular complications, which determine the severity of circulatory disorders of organs and tissues (heart, brain, peripheral vessels). The main drugs of the group are cyclooxygenase inhibitors (COX). The main “nuisance” in the appointment of disaggregants of this group is the development of uncontrolled internal bleeding.

Most often, these are popular tablets:

  • Aspirin is an outdated, but still used by patients remedy: dangerous uncontrolled bleeding with prolonged use. Today, an improved modification is used – Aspirin-Cardio, a medicine that is recommended for the complex treatment of heart and vascular diseases (80 rubles);
  • Thrombo-ACC: a complete analogue of Aspirin-Cardio, but less aggressive for the stomach, because it has a special membrane that prevents the rapid absorption of acid in the digestive tract (40 rubles);
  • CardiAsk – antiplatelet agent with antipyretic, analgesic and anti-inflammatory properties (55 rubles);
  • Thrombopol – suppresses platelet aggregation (46 rubles);
  • Aspikor – NSAIDs with the properties of a disaggregant (47 rubles);
  • Cardiomagnyl is an antiplatelet agent in which magnesium hydroxide, which is part of the composition, protects the gastrointestinal mucosa from exposure to acetylsalicylic acid (108 rubles).

Sometimes there are cases of resistance of pathological processes associated with thrombosis to ASA. This may be due to the COX gene polymorphism affecting the active center of the enzyme. Then use a combination of ASA with thienopyridines or ADP blockers.

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ADP blockers

Antiplatelet drugs of the group, unlike ASA, act on both phases of platelet aggregation – aggregation and adhesion, which allows inactivation of a special substance, adenosine phosphate, destroying its connection with fibrinogen.

In addition, thienopyridines increase the plasticity (deformability) of red blood cells, helping to improve the rheological properties of blood and microcirculation. Therefore, today antiplatelet agents of this group are used as the main component of the complex therapy of obliterating endarteritis and diabetic foot. Side effects: extrasystoles, increased serum creatinine concentration and dyspnea.

The funds in this group include:

    Ticlop >

The mechanism of action of antiplatelet drugs that are able to inhibit DGP (platelet glycoprotein receptors) is mild. The essence of the “work” is the platelet command, which prohibits adhesion. In this case, maximum efficiency is achieved with minimal changes in the rheological properties of the blood.

The target of drugs is the last stage of platelet aggregation. Medicines compete with von Willebrand factor and fibrinogen for binding to the IIb / IIIa glycoprotein receptor. The effect does not last long, therefore, funds are used either for emergency care, or with the calculation of a clear dosage of admission according to an individual scheme. Side effects: bleeding, atrioventricular block, hypotension, nausea, vomiting, pneumonia, edema, anemia, anaphylaxis.

Disaggregants of the pharmaceutical group of GPR blockers:

  • Eptifibatide (Integrilin) ​​- an infusion drug, a synthetic cyclic peptide that reversibly blocks platelet IIb / IIIa receptors, is contraindicated in case of hypersensitivity, bleeding, cerebrovascular accident (3 rubles);
  • Tirofiban (Agrastat) – a derivative of tyrosine of a non-peptide nature, is the drug of choice for emergency care (31 rubles);
  • Abciximab (Reopro) – irreversibly blocks glycoprotein receptors on platelets (80% 2 hours after an infusion into a vein), is used for coronary angioplasty in men with acute coronary syndrome (15 416,85 rubles).

Due to the minimum of side effects, modern pharmacologists have recently been actively developing new drugs in this group. Many promising combinations with antiplatelet properties were found: Cefrafiban, Orbofigan, Sibrofiban, Xenilofiban. The drugs are undergoing clinical trials. There is also a medicine that has already found its practical use – this is Lamifiban injection solution, not available on the Russian market.

Another group of drugs that demonstrate the properties of antiplatelet agents is synthetic substances that affect the mechanism of blood clot formation by blocking blood enzymes. The safest of all the above groups are used during the recovery of rehabilitation after acute conditions, surgical interventions.

Antiplatelet agents of this group are:

  • Dipyridamole (Dipyridamole-FPO, Sanomil-Sanovel) – combines the properties of a disaggregant and a vasodilator. It is active as an angioprotector, immunomodulator. The drug has an inhibitory effect on platelet aggregation, improves microcirculation. The tool is almost completely associated with blood proteins. Accumulation occurs in myocardiocytes, erythrocytes (302 rubles);
  • Curantyl is an immunomodulator and a vasodilator. “Works” in the coronary blood flow system, when taken in high doses – in other parts of the circulatory system. Unlike organic nitrates, calcium antagonists do not cause expansion of larger coronary vessels (586 rubles);
  • Parsedil is a myotropic vasodilator with disaggregant properties. Expands coronary vessels (mainly arterioles), causes a significant increase in volumetric blood flow velocity (290 rubles);
  • Pentoxifylline – a structural analogue of theobromine, prevents the loss of potassium ions by red blood cells, and gives resistance to hemolysis. With peripheral arterial occlusion (intermittent claudication), it leads to an increase in walking distance, elimination of night cramps of calf muscles and pain. Available in tablets and injection (Tablets – 251 rubles, injections – 45 rubles for 10 ampoules of a 2% solution);
  • Cilostazol (Pletal) – has an antiplatelet and vasodilation effect (4 960 rubles);
  • Triflusal (Disgren) is an inhibitor of COX-1 and PDE, has not been studied much, is available to order in an online pharmacy.

Antiplatelet agents that reduce the synthesis of arachidonic acid have antithrombotic activity, but they have many side effects and require strict control, therefore they are rarely used.

By the mechanism of action – analogues of the previous group, but differ in specificity, binding exclusively to receptors of this acid. In addition, the drugs of the group are able to stop inflammation, stimulate the immune system. Side effects include individual intolerance.

Representatives of the pharmacological group of drugs:

  • Indobufen (Ibustrin) – platelet aggregation corrector with painkiller and anti-inflammatory effect (1390 rubles);
  • Zafirlukast is an antiaggregant with anti-inflammatory effect (1306,8 rubles).

Representatives of this group of antiplatelet agents are found in other classes of drugs of this type. Most often in the clopidogrel group. The essence of the action of drugs (for example, Ridogrel, Picotamide, Vapipros) is a decrease in the synthesis of thromboxane factor in the formation of blood clots. The medicines found their use in the complex therapy of vascular and cardiac pathology, cerebral ischemia, impaired blood flow in the vessels of the limbs, after cases of thrombosis and thrombophlebitis.

Side effects

The main thing is to inform the attending physician at the first signs of discomfort. Side effects are:

  • unmotivated fatigue;
  • sternal discomfort of a burning character;
  • severe headaches, migraine;
  • dyspepsia;
  • any bleeding;
  • soreness in the epigastrium;
  • an allergic reaction up to anaphylaxis;
  • urticaria, hemorrhage;
  • constant nausea, periodic vomiting;
  • impaired speech, swallowing, breathing;
  • arrhythmias, tachycardia;
  • yellowness of the skin and mucous membranes;
  • hyperthermia of unknown origin;
  • prodromal syndrome with increasing weakness;
  • arthralgia;
  • hallucinations;
  • noise in ears;
  • symptoms of intoxication.

Cancellation of drugs in such cases is required.

From the cardiovascular system and blood (hematopoiesis, hemostasis): thrombocytopenia, anemia, leukopenia.

From the digestive tract: NSAID-gastropathy (dyspepsia, epigastric pain, heartburn, nausea and vomiting, severe bleeding in the digestive tract), decreased appetite.

Allergic reactions: hypersensitivity reactions (bronchospasm, laryngeal edema and urticaria), the formation on the basis of the hapten mechanism of “aspirin” bronchial asthma and “aspirin” triad (eosinophilic rhinitis, recurrent nasal polyposis, hyperplastic sinusitis).

Other: impaired liver and / or kidney function, Reye syndrome in children (encephalopathy and acute fatty degeneration of the liver with the rapid development of liver failure).

With prolonged use – dizziness, headache, tinnitus, hearing loss, impaired vision, interstitial nephritis, prerenal azotemia with increased blood creatinine levels and hypercalcemia, papillary necrosis, acute renal failure, nephrotic syndrome, blood diseases, aseptic meningitis, enhancement symptoms of congestive heart failure, edema, increased levels of aminotransferases in the blood.

Interactions with other active substances

Active substance methylethylpyridinol:

  • Vixipin;
  • Methyl ethyl pyridinol (Methyl ethyl pyridinol-Eskom, Methyl ethyl pyridinol hydrochloride);
  • Emoxy-optician (Emoxibel, Emoksipin-AKOS, Emoksipin-Akti, Emoksipin, Cardioksipin).

The active principle of xanthinol nicotinate:

  • Complamine;
  • Xanthinol nicotinate, Xanthinol nicotinate-UBF, Xanthinol nicotinate injection 15%, Xanthinol nicotinate tablets 0,15 g

Drugs with another active principle:

  • Agrilin (Anagrelide);
  • Brilinta (Ticagrelor);
  • Ventavis (Iloprost);
  • Ticagrelor (Ticagrelor);
  • Thromboreductin (Anagrelide);
  • Cilostazolum (Cilostazolum).

Monitoring antiplatelet therapy

The main issue of patient safety when prescribing antiplatelet agents remains monitoring of complications. Evaluation of the effectiveness of therapy should be correlated with the absence of negative aspects. The techniques may be different:

  • optical – visual determination of platelet aggregation;
  • bedside tests (express tests);
  • stable monitoring of urine metabolites;
  • photospectrometry;
  • monitoring with aggregometers (expensive procedure, therefore unpopular).

The question of total testing of patients receiving antiplatelet agents remains unresolved, since almost all patients suffering from ischemic heart disease, circulatory system disorders, and vascular pathologies take them. The importance of such a decision can hardly be overestimated, since complications from uncontrolled administration of drugs for their overdose can be fatal.

Pharmacology

It inhibits cyclooxygenase (COX-1 and COX-2) and irreversibly inhibits the cyclooxygenase pathway of arachidonic acid metabolism, blocks the synthesis of PG (PGA2, PGD2, PGF2 alpha, PGE1, PGE2, etc.) and thromboxane. Reduces hyperemia, exudation, capillary permeability, hyaluronidase activity, limits the energy supply of the inflammatory process by inhibiting ATP production.

Affects the subcortical centers of thermoregulation and pain sensitivity. A decrease in the content of PG (mainly PGE1) in the center of thermoregulation leads to a decrease in body temperature due to the expansion of blood vessels of the skin and increased sweating. The analgesic effect is due to the effect on the centers of pain sensitivity, as well as peripheral anti-inflammatory action and the ability of salicylates to reduce the algogenic effect of bradykinin.

A decrease in the thromboxane A2 content in platelets leads to an irreversible suppression of aggregation, somewhat dilates blood vessels. The antiplatelet effect persists for 7 days after a single dose. A number of clinical studies have shown that significant inhibition of the adhesion of blood plates is achieved at doses up to 30 mg.

After oral administration, it is sufficiently absorbed. In the presence of an enteric-soluble membrane (resistant to the action of gastric juice and does not allow the absorption of acetylsalicylic acid in the stomach), it is absorbed in the upper part of the small intestine. During absorption, it undergoes a presystemic elimination in the intestinal wall and in the liver (deacetylated).

The absorbed part is hydrolyzed very quickly by special esterases; therefore, T1 / 2 of acetylsalicylic acid is no more than 15–20 min. It circulates in the body (75–90% due to albumin) and is distributed in tissues as an anion of salicylic acid. Cmax is reached after about 2 hours. Acetylsalicylic acid practically does not bind to plasma proteins.

During biotransformation, metabolites are formed in the liver that are found in many tissues and urine. The excretion of salicylates is carried out mainly by active secretion in the tubules of the kidneys in an unchanged form and in the form of metabolites. The excretion of unchanged substances and metabolites depends on the pH of the urine (with alkalization of urine, ionization of salicylates increases, their reabsorption worsens, and excretion increases significantly).

Application in pregnancy and lactation

The use of large doses of salicylates in the first trimester of pregnancy is associated with an increased frequency of defects in fetal development (cleft palate, heart defects). In the II trimester of pregnancy, salicylates can be prescribed only with regard to risk and benefit assessment. The appointment of salicylates in the third trimester of pregnancy is contraindicated.

Salicylates and their metabolites in small quantities pass into breast milk. Accidental reception of salicylates during lactation is not accompanied by the development of adverse reactions in the child and does not require discontinuation of breastfeeding. However, with long-term use or appointment in high doses, breastfeeding should be discontinued.

Interactions with other active substances

It enhances the toxicity of methotrexate, decreasing its renal clearance, the effects of narcotic analgesics (codeine), oral antidiabetic drugs, heparin, indirect anticoagulants, thrombolytics and platelet aggregation inhibitors, and reduces the effect of uricosuric drugs (benzbromarone phosphonurethiramide, dihydrophenyl sulfonate, dihydroperonol sulfonate, dihydrophenyl sulfonate, dihydrogen sulfonate, sulfonylurethane, diurethiurethane, .

Paracetamol, caffeine increase the risk of side effects. Glucocorticoids, ethanol and ethanol-containing drugs increase the negative effect on the gastrointestinal mucosa and increase clearance. Increases the concentration of digoxin, barbiturates, lithium salts in plasma. Antacids containing magnesium and / or aluminum slow down and impair the absorption of acetylsalicylic acid. Myelotoxic drugs enhance the manifestations of hematotoxicity of acetylsalicylic acid.

Overdose

May occur after a single dose of a large dose or with prolonged use. If a single dose is less than 150 mg / kg, acute poisoning is considered mild, 150-300 mg / kg – moderate, with higher doses – severe.

Symptoms: salicilism syndrome (nausea, vomiting, tinnitus, blurred vision, dizziness, severe headache, general malaise, fever – a poor prognostic sign in adults). More severe poisoning is stupor, convulsions and coma, non-cardiogenic pulmonary edema, severe dehydration, impaired ASH (first, respiratory alkalosis, then metabolic acidosis), renal failure and shock.

In chronic overdose, the plasma concentration is poorly correlated with the severity of intoxication. The greatest risk of developing chronic intoxication is observed in elderly people with a dose of more than 100 mg / kg / day for several days. In children and elderly patients, the initial signs of salicylism are not always noticeable, so it is advisable to periodically determine the concentration of salicylates in the blood.

Treatment: provocation of vomiting, administration of activated charcoal and laxatives, monitoring of acid-base balance and electrolyte balance; depending on the state of metabolism – the introduction of sodium bicarbonate, a solution of sodium citrate or sodium lactate. Increased reserve alkalinity enhances the elimination of acetylsalicylic acid due to alkalization of urine.

Urine alkalization is indicated for salicylates above 40 mg%, provided by iv infusion of sodium bicarbonate – 88 meq in 1 liter of 5% glucose solution, at a rate of 10-15 ml / kg / h. Recovery of bcc and induction of diuresis (achieved by the introduction of bicarbonate in the same dose and dilution, repeat 2-3 times); it should be borne in mind that intensive fluid infusion in elderly patients can lead to pulmonary edema.

The use of acetazolamide for alkalization of urine is not recommended (it can cause acidemia and enhance the toxic effect of salicylates). Hemodialysis is indicated for salicylates of more than 100-130 mg%, and in patients with chronic poisoning – 40 mg% or less if indicated (refractory acidosis, progressive deterioration, severe damage to the central nervous system, pulmonary edema, and renal failure).

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Svetlana Borszavich

General practitioner, cardiologist, with active work in therapy, gastroenterology, cardiology, rheumatology, immunology with allergology.
Fluent in general clinical methods for the diagnosis and treatment of heart disease, as well as electrocardiography, echocardiography, monitoring of cholera on an ECG and daily monitoring of blood pressure.
The treatment complex developed by the author significantly helps with cerebrovascular injuries and metabolic disorders in the brain and vascular diseases: hypertension and complications caused by diabetes.
The author is a member of the European Society of Therapists, a regular participant in scientific conferences and congresses in the field of cardiology and general medicine. She has repeatedly participated in a research program at a private university in Japan in the field of reconstructive medicine.

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