Pharmacological properties
Pharmacodynamics. Heparin is a glycosaminoglycan (mucopolysaccharide) consisting of sulfated residues of d-glucosamine and d-glucuronic acid.
Heparin is a direct-acting anticoagulant. In solution, heparin has a negative charge, which facilitates its interaction with proteins involved in the blood clotting process. Heparin binds to antithrombin III (heparin cofactor) and inhibits the blood clotting process by inactivating factors V, VII, IX, X. In this case, factors that activate blood clotting (kallikrein, IXa, Xa, XIa, XIIa) are neutralized, and the transition of prothrombin to thrombin is disrupted. When the process of thrombus formation has already begun, large amounts of heparin can inhibit further coagulation by inactivating thrombin and inhibiting the conversion of fibrinogen to fibrin. Heparin also prevents the formation of stable fibrin clots by inhibiting the activation of fibrin-stabilizing factor. When administered parenterally, heparin slows down blood clotting, activates the fibrinolysis process, inhibits the activity of certain enzymes (hyaluronidase, phosphatase, trypsin), slowing down the effect of prostacyclin on platelet aggregation caused by the action of adenosine diphosphate.
Pharmacokinetics. After intravenous injection, C max in blood plasma is reached after a few minutes, after slow intravenous infusion - no later than 2-3 minutes, after subcutaneous injection - after 40-60 minutes. The volume of distribution of heparin corresponds to the volume of blood plasma and significantly increases with increasing dose of the drug. Plasma proteins at a heparin concentration of 2 IU / ml of blood bind up to 95% of the drug, at higher concentrations - less. Heparin is partially metabolized in the liver. About 20% is determined in the urine in the form of unchanged heparin and uroheparin (has an activity of 50% of the active substance). The biological half-life is 1.32-1.72 hours. T ½ from blood plasma is 30-60 minutes. With liver failure, heparin accumulates. Heparin does not penetrate into breast milk and does not penetrate the placenta well.
Indication
Prevention and treatment of thromboembolic diseases and their complications (acute coronary syndrome, thrombosis and embolism of major veins and arteries, brain vessels, eyes, phase I of DIC syndrome, permanent form of atrial fibrillation with embolization).
For the prevention of postoperative venous thrombosis and pulmonary embolism (in a low-dose regimen) in patients who have undergone surgery or in individuals with other risk factors for the development of thromboembolic diseases.
To prevent blood clotting during laboratory tests, dialysis, extracorporeal circulation, heart and vascular surgery, and direct blood transfusion.
Application
Heparin-Indar is administered as a jet or intermittent i/v or s/c injection. Before administering the drug, blood clotting time, thrombin and APTT, and platelet count should be determined. Only 0.9% sodium chloride solution is used to dilute heparin.
In adults with acute thrombosis, treatment begins with the administration of 10,000-15,000 IU of Heparin-Indar under the control of venous blood coagulation, thrombin time and APTT. After that, 5,000-10,000 IU of Heparin-Indar should be administered every 4-6 hours. In this case, the dose of Heparin-Indar is considered adequate, at which the blood clotting time is prolonged by 2.5-3 times, and the APTT - by 1.5-2 times.
For the prevention of acute thrombosis, Heparin-Indar is administered subcutaneously at 5000 IU every 6-8 hours. In the first phase of DIC in adults, heparin is administered subcutaneously for a long time in a daily dose of 2500-5000 IU under the control of thrombin time. 1-2 days before discontinuation of Heparin-Indar, the dose is gradually reduced.
During open-heart surgery with the connection of an extracorporeal circulation apparatus, patients are administered Heparin-Indar in an initial dose of at least 150 IU / kg of body weight. When the procedure lasts 60 minutes, a dose of 300 IU / kg is prescribed, and when the procedure lasts 60 minutes, 400 IU / kg is prescribed.
For prophylactic purposes, Heparin-Indar is administered subcutaneously at a dose of 5000 IU 2 hours before surgery, then 5000 IU every 6-8 hours for 7 days.
As an adjunct to streptokinase, Heparin-Indar 5000 IU 3 times a day or 10,000-12,500 IU 2 times a day may be indicated for patients at increased risk of developing thrombotic complications:
with repeated myocardial infarction; with a permanent form of atrial fibrillation with embolization.
In acute coronary syndrome (unstable angina or myocardial infarction), first 5000 IU of Heparin-Indar are injected intravenously, then switched to intravenous drip administration of the drug at a rate of 1000 IU/h. The infusion rate must be selected in such a way that during the first 2-3 days the APTT is maintained at a level 1.5-2 times higher than its normal value.
Children are prescribed Heparin-Indar according to the following scheme: the initial dose is 50 IU / kg (iv injection / infusion), the maintenance dose is 100 IU / kg every 4 hours. The average daily dose for children is 300 IU / kg.
Infants are given 2 to 10 IU/kg/h IV (boosted or intermittently). Infants are given heparin subcutaneously at a dose of 200-300 IU/kg, divided into 4-6 injections.
In all cases, when using Heparin-Indar, indirect anticoagulants are prescribed for 1-3 days before its discontinuation.
Hypersensitivity to heparin and/or benzyl alcohol, hemophilia, hemorrhagic diathesis, suspected heparin-immune thrombocytopenia, gastric and duodenal ulcers, severe acute pancreatitis, cirrhosis of the liver accompanied by esophageal varicose veins, severe renal and hepatic failure, bacterial endocarditis, menstruation, recent surgical interventions, especially neurosurgical and ophthalmological, ulcerative colitis, malignant neoplasms, hemorrhagic stroke (first 2-3 days), craniocerebral trauma, retinopathy, hemorrhage into the eye tissue, destructive pulmonary tuberculosis; encephalomalacia, hemorrhagic pancreatic necrosis; Bleeding of any location (open stomach ulcer, intracranial bleeding), except for hemorrhage resulting from embolic pulmonary infarction (hemoptysis) or renal infarction (hematuria), a history of recurrent bleeding, regardless of location; increased vascular permeability (e.g., Verlhof's disease), shock; threatened abortion.
Heparin should not be used: in patients who have taken high doses of alcohol; in the form of i / m injections, in acute and chronic leukemia; aplastic and hypoplastic anemias, in acute aortic aneurysm; during operations on the brain or spinal cord, eyeball, organ of hearing; after surgical operations in areas where the development of bleeding is dangerous to the patient's life, in diabetes mellitus, during epidural anesthesia during childbirth. For patients who use heparin for therapeutic purposes, during planned surgical operations, conduction anesthesia is contraindicated, since the use of heparin in rare cases can cause epidural or spinal hematomas, as a result of which prolonged or permanent paralysis may develop.
Side effects
The most common adverse reactions include hemorrhage, elevated liver enzymes, reversible thrombocytopenia, and various dermatological disorders. Isolated cases of generalized allergic reactions, skin necrosis, and priapism have also been reported.
From the blood system: thrombocytopenia type I and II; epidural and spinal hematomas.
Mental disorders: depression.
From the nervous system: headache.
Gastrointestinal tract: nausea, vomiting, diarrhea.
On the part of the hepatobiliary system: increased levels of hepatic transaminases (ALT and AST), LDH, gamma-glutamyltransferase and hyperlipidemia (these disorders are reversible and disappear upon discontinuation of the drug).
Skin and subcutaneous tissue disorders: rash (erythematous, maculopapular), urticaria, itching and burning in the area of the skin of the feet, skin necrosis, erythema multiforme, alopecia.
Musculoskeletal system: osteoporosis, bone demineralization.
From the reproductive system: priapism.
On the part of the immune system: skin rash, conjunctivitis, lacrimation, rhinitis, bronchospasm, asthma, tachypnea, cyanosis, urticaria, allergic angiospasm in the extremities, anaphylactoid reactions, anaphylactic shock.
On the part of the endocrine system and metabolism: hypoaldosteronism, hyperkalemia, increased thyroxine levels, decreased cholesterol levels, increased blood glucose levels.
From the cardiovascular system: hemorrhages and hematomas in any organ or organ system (subcutaneous, intramuscular, retroperitoneal, nasal, intestinal, gastric, uterine).
Injection site reactions: irritation, ulceration, tenderness, hemorrhage, hematoma, and atrophy at the injection sites.
Others: rhinorrhea, fever.
Thrombocytopenia as a complication of heparin therapy is noted in 6% of patients. It can occur as a direct consequence of platelet aggregation under the influence of heparin or as a result of an immune reaction when the antibody affects platelets and endothelium. Reactions of the first type, as a rule, manifest themselves in a mild form and disappear after cessation of therapy, and reactions of the second type are severe. As a result of thrombocytopenia, skin necrosis and thrombosis in the arteries ("white clot") may occur, which are accompanied by recurrence of venous thromboembolism, the development of gangrene, myocardial infarction, stroke. If severe thrombocytopenia occurs (a decrease in the number of platelets by 2 times from the initial number), it is necessary to stop using heparin.
Possible increase in transaminase activity (ALT and AST), free fatty acid and thyroxine levels; reversible potassium retention.
Special instructions
When prescribing heparin for therapeutic purposes, it is forbidden to administer the drug intramuscularly. Biopsy, epidural anesthesia, and diagnostic lumbar puncture should be avoided.
Use with caution in patients with a history of hypersensitivity reactions to LMWH.
Platelet counts should be determined before treatment, on day 1 of treatment, and every 3-4 days during the entire period of heparin use. A sudden decrease in platelet count requires immediate discontinuation of the drug and further investigation to clarify the etiology of thrombocytopenia. If heparin-induced thrombocytopenia type I or II is suspected, heparin treatment should be discontinued.
When switching from heparin therapy to indirect anticoagulants, heparin should be discontinued only when the anticoagulants provide an increase in prothrombin time to therapeutic limits for at least 2 consecutive days.
When using heparin, it is recommended to monitor hematological parameters, as well as observe the patient's clinical condition and the features of the development of hemorrhagic complications.
In patients over 60 years of age, heparin can cause hemorrhage (especially in women) and in patients with impaired renal function.
Patients sensitive to animal proteins may also be sensitive to heparin.
If a hypersensitivity reaction is suspected, a diluted test dose of 1000 IU should be administered slowly intravenously a few minutes before the full dose.
Special care should be taken within 36 hours after delivery.
In patients with hypertension, blood pressure should be monitored.
In patients with diabetes mellitus, renal failure, metabolic acidosis, increased blood potassium concentration, or those taking potassium supplements, frequent monitoring of blood potassium levels is recommended when using the drug, given the increased risk of developing hyperkalemia.
Use during pregnancy and breastfeeding. Heparin is not contraindicated during pregnancy. The drug does not penetrate the placenta. Although heparin does not penetrate into breast milk, its administration to breastfeeding women in some cases caused rapid (within 2-4 weeks) development of osteoporosis and spinal damage. The feasibility of using the drug is decided individually, taking into account the benefit to the mother / risk to the fetus.
Children. The drug is used in children according to body weight. Do not use in premature or newborns! The development of allergic reactions, including toxic ones, is possible in children under 3 years of age.
The ability to influence the reaction rate when driving vehicles or working with other mechanisms. No data.
Interactions
Anticoagulants of direct and indirect action enhance the effect of heparin. Antihistamines and digitalis preparations, tetracyclines, nicotine, nitroglycerin, corticotropin, thyroxine weaken the anticoagulant effect of the drug. Agents that reduce platelet aggregation (acetylsalicylic acid, dextrin, phenylbutazone, ibuprofen, metindol, dipyridamole, hydroxychloroquine, fibrinolytics, ascorbic acid, ergot alkaloids, indomethacin, sulfinpyrazone, probenecid, cephalosporins, ketorolac, epoprostenol, clopidogrel, ticlopidine, streptokinase, intravenous administration of penicillins, ethacrynic acid, cytostatics), with simultaneous therapy with heparin can cause hemorrhages, so they should be used very carefully. The risk of hemorrhage also increases with combined heparin therapy with drugs that have ulcerogenic properties, immunosuppressants, and thrombolytic drugs.
Heparin can displace phenytoin, quinidine, propranolol, benzodiazepines and bilirubin from plasma protein binding sites. With simultaneous use, alkaline drugs, enaprilat, tricyclic antidepressants can bind to heparin, which leads to a mutual decrease in effectiveness.
ACE inhibitors, angiotensin II antagonists: possible development of hyperkalemia.
Alcohol: simultaneous consumption of alcoholic beverages can significantly increase the risk of bleeding.
Overdose
In case of overdose, bleeding may occur. In case of minor bleeding, it is enough to reduce the dose of the drug or temporarily stop its administration. In case of significant bleeding, it is necessary to urgently cancel the administration of heparin and prescribe an antidote - 1% protamine sulfate solution (injected intravenously slowly) based on the fact that 1 mg of protamine sulfate neutralizes 85 IU of heparin.
Storage conditions
At a temperature of 2-8 °C, in a place protected from light.
Current information
Heparin is the oldest anticoagulant used in clinical medicine. Paradoxically, heparin was discovered by Jay McLean in 1916 while trying to isolate thromboplastic factor. Heparin is a polysaccharide of natural origin, belonging to the group of glycosaminoglycans (mucopolysaccharides). Further work on its study ultimately led to its introduction into clinical use in 1935. Since then, the use of heparin has been studied for various indications and in various modifications (Eziafa I. Oduah et al., 2016).
Heparin is a basic drug and the most widely used clinical anticoagulant in the world. Newer anticoagulants, developed for specific uses in most medical settings, have not significantly replaced heparin and its anticoagulants. However, in the last decade, there has been growing concern about the safety of heparin. The international heparin crisis (heparin scandal), which occurred in 2007-2008, was associated with more than 80 deaths in the United States alone. Unfortunately, most of the world's supply of heparin is obtained from a single species of animal, pigs, and in a single country, China.
Blood in a healthy person circulates freely through the arteries and veins. A normally functioning vascular endothelium acts as an antithrombotic surface. Under conditions that are dangerous to human health and life, the hemostasis system is triggered and immediately becomes active (a cascade of reactions). When the blood vessel wall is damaged, platelets and fibrin combine to prevent hemorrhage. Although rapid hemostasis is necessary to prevent blood loss, excessive blood clots can lead to serious thrombotic complications.
The primary mechanism of hemostasis is platelet aggregation and adhesion to the injured vessel. Secondary hemostasis is mediated by plasma coagulation factors, which undergo a biochemical cascade leading to the formation of platelet-fibrin clots.
Primary hemostasis - platelets
After vascular injury, platelets adhere to endothelial collagen, forming a “platelet plug,” which leads to primary hemostasis. Von Willebrand factor promotes platelet adhesion and aggregation. Activated platelets degranulate bioactive substances, including serotonin, adenosine diphosphate (ADP), and thromboxane A2 (TXA2). Serotonin and thromboxane A2 have vasoconstrictor effects. In addition, activated platelets (their receptors) bind to fibrinogen in such a way that a platelet plug (platelet thrombus) is formed. This thrombus allows activated blood clotting factors to collect on its surface, and then secondary hemostasis, which involves the plasma coagulation cascade, follows.
Secondary hemostasis - biochemical cascade reactions
Secondary hemostasis involves a cascade of biochemical reactions. This cascade consists of inactive zymogens (or proenzymes), called clotting factors, which are activated by serine proteases (i.e., factor X is converted to factor Xa), which can then activate subsequent clotting factors (i.e., factor Xa activates factor II to form factor IIa), which ultimately converts the soluble protein fibrinogen into the insoluble protein fibrin (containing the clot). There are two traditional major secondary coagulation cascade pathways: intrinsic and extrinsic. The intrinsic pathway, also called the contact pathway, is initiated by factors XII and XI. When factor XII comes into contact with a negatively charged surface (phospholipids at the site of vascular injury), there is a local increase in its (factor) concentration, which is then automatically activated to factor XIIa. Factor XIIa then catalyzes the conversion of prekallikrein to high molecular weight kininogen and factor XI to XIa. These activations then lead to the formation of factor IXa.
The extrinsic pathway, also called the tissue factor pathway, is the initial step in hemostasis. The interaction of tissue factor (TF) with factor VII (proconvertin) initiates the extrinsic pathway of blood coagulation, forming the TF-VIIa complex. Alternatively, the extrinsic pathway can also be initiated when monocytes and smooth muscle cells are exposed to cytokines or other inflammatory mediators. This process also triggers the release of tissue factor. Once the TF-VIIa complex is formed, it converts factor IX to factor X; factor IXa to factor Xa, respectively.
Once factor IXa is formed by either the intrinsic or extrinsic pathway, a tenase complex consisting of factor IXa, factor VIIIa, calcium, and phospholipids is generated. This tenase complex activates factor X. After the tenase complex is formed, a prothrombinase complex consisting of factor Xa, factor Va, calcium ions, and anionic platelet phospholipids is formed. Although factor Xa alone can catalyze prothrombin (factor II) to thrombin (factor IIa), this activation is greatly accelerated by factor Va and the prothrombinase complex as a whole. Thrombin (clotting factor II) is a serine protease produced in the coagulation cascade and is a critical component of the blood clotting system. Thrombin activates various components of the coagulation pathway, such as platelets, factors V, VIII, and IX, C-reactive protein, and fibrinolysis inhibitors to enhance the coagulation cascade. And most importantly, thrombin converts fibrinogen into fibrin, ultimately creating a clot.
The conversion of soluble fibrinogen to insoluble fibrin is the final stage of the coagulation process. Factor XIIIa catalyzes the crosslinking of fibrin monomers, the process of forming a stabilized fibrin clot. In parallel, the fibrinolytic system is activated to control the size of fibrin clots. Fibrinolysis involves the dissolution of fibrin. Fibrinolysis prevents blood vessels from being blocked by fibrin clots. Plasmin is the enzyme responsible for fibrinolysis.
Antithrombin (AT), formerly known as antithrombin III, is a serine protease inhibitor that inactivates various activated serine proteases, including factors IXa, Xa, the TF-VIIa complex, and thrombin. AT covalently binds to serine residues of serine proteases, causing their inactivation. However, in the presence of heparin or heparan sulfate (HS), the ability of AT to inhibit serine proteases is markedly enhanced, and in this case, a heparin-AT-thrombin complex is formed.
Heparin is a direct-acting anticoagulant. It binds to antithrombin III and inhibits the blood clotting process by inactivating factors V, VII, IX, X. This neutralizes a whole chain of factors that activate blood clotting (kallikrein, IXA, Xa, XIa, XIIa), disrupts the transition of prothrombin to thrombin. The ratio of anti-Xa activity to anti-IIa activity of different heparins is different. Shorter heparin chains with low molecular weight demonstrate higher anti-Xa / anti-IIa ratios. The molecular weight of heparin affects the mechanisms and pathways of clearance and may prevent the use of a particular heparin in patients with renal failure (Onishi A. et al., 2016).
Pharmacokinetics
In the body, Heparin binds well to globulins, fibrinogen, and low-density lipoproteins. The liver and reticuloendothelial system are the sites of heparin biotransformation, but its metabolism has not been properly studied. A small portion of unchanged heparin is excreted in the urine. Heparin is not amenable to hemodialysis. T ½ - 1.5 h.
T ½ of heparin from blood plasma increases from 60 min (when administered at a dose of 100 IU/kg) to 150 min (when administered at a dose of 400 IU/kg).
indication
Heparin is indicated for the prevention and treatment of venous thrombosis and its further spread, the prevention of postoperative deep venous thrombosis and pulmonary embolism, and for the prevention of blood clotting in arterial and cardiac surgery. In cardiology, it is used to prevent embolism in patients with atrial fibrillation and as an additional antithrombin therapy in patients with unstable angina and / or myocardial infarction without a Q wave (i.e. acute coronary syndrome without ST segment elevation), in patients receiving glycoprotein (IIb / IIIa) - a membrane protein that plays an important role in platelet aggregation, which is the target of antithrombotic drugs. In addition, heparin is used to prevent blood clotting during dialysis and surgical procedures, helping to prevent coagulation during blood transfusion in vitro and in blood samples taken for laboratory studies.
In addition to its use as an anticoagulant, there has been increasing interest in the potential use of Heparin for other medical purposes over the years. These applications range from anti-inflammatory and anti-tumor treatment to the prevention of infectious diseases and use as nanocarriers for drug delivery (Eziafa I. Oduah et al., 2016).
routes of administration
Heparin must be administered parenterally because it is not absorbed through the gastrointestinal mucosa. It is usually administered intravenously or deep subcutaneously. Its effect occurs immediately after intravenous injection, but after subcutaneous injection - after 20-60 minutes.
anticoagulant comparison
When choosing anticoagulant drugs, important factors are their cost, availability of antidotes, route of administration, safety, and efficacy. Two other critical factors are their therapeutic indications and contraindications.
Heparins are much cheaper than direct inhibitors. Heparins remain the drugs of choice. The route of administration is another important factor to consider when choosing an anticoagulant. Heparins are commonly used in the treatment of venous thromboembolism in its acute phase.
conclusion
For centuries since its discovery, heparin has been successfully used and continues to be one of the most commonly used anticoagulants. To date, there have been many breakthroughs in understanding the mechanisms of action and the spectrum of biological activity of heparin. Scientists have demonstrated new data on potential routes in the bioengineering and synthesis of heparin and heparin-like molecules. All studies have been aimed at meeting the current need for safety and mitigating the problem of shortages of current heparin supplies. Despite the mass of achievements in this area, there is a huge range of directions for further study. Some of these include a better understanding of the structure-function relationships of the compound itself, the potential diversification of the compound for the inclusion of its molecule in the structure of anti-cancer, anti-inflammatory drugs and/or the introduction of heparin in the therapy of infectious diseases. Surface modification of heparin nanoparticles can also be used for diagnostic and therapeutic purposes in the field of oncology. Nanomedicine is a new direction in medicine, and additional research is still needed on safety and efficacy at both preclinical and clinical levels (Eziafa I. Oduah et al., 2016).
