Heparin - instructions for use, dose, side effects, contraindications

The mechanism of action of heparin sodium is based, first of all, on its binding to antithrombin III, which is a natural inhibitor of activated blood coagulation factors - IIa (thrombin), IXa, Xa, XIa and XIIa. Sodium Heparin is bound by antithrombin III and causes conformational changes in its molecule. As a result, the binding of antithrombin III to blood coagulation factors IIa (thrombin), IXa, Xa, XIa, XIIa is accelerated, and their enzymatic activity is blocked.The binding of sodium heparin to antithrombin III is of an electrostatic nature and depends to a large extent on the length and composition of the molecule (a pentaccharide sequence containing 3-O-sulphated glucosamine).

The greatest value is the ability of heparin sodium in combination with antithrombin III to inhibit coagulation factors IIa (thrombin) and Ha. The ratio of heparin sodium activity with respect to factor Xa to its activity with respect to factor IIa is 0.9-1.1. Sodium Heparin reduces blood viscosity, reduces vascular permeability, stimulated bradykinin, histamine and other endogenous factors, and thus prevents the development of stasis. Sodium Heparin can sorb on the surface of membranes of the endothelium and blood cells, increasing their negative charge, which prevents adhesion and aggregation of platelets. Sodium Heparin slows hyperplasia of smooth muscles, activates lipoprotein lipase and, thus, has a hypolipidemic effect and prevents the development of atherosclerosis.

Heparin sodium binds some components of the complement system, reducing its activity, interferes with the cooperation of lymphocytes and the formation of immunoglobulins, binds histamine, serotonin (that is, it has anti-allergic effect). Sodium Heparin increases the renal blood flow, increases the resistance of cerebral vessels, reduces the activity of cerebral hyaluronidase, reduces the activity of the surfactant in the lungs, suppresses excessive synthesis of aldosterone in the adrenal cortex, binds adrenaline, modulates the ovarian response to hormonal stimuli, and enhances parathyroid hormone activity. As a result of interaction with enzymes heparin sodium can increase the activity of tyrosine hydroxylase of the brain, pepsinogen, DNA polymerase and reduce the activity of myosin ATPase, pyruvate kinase, RNA polymerase, pepsin. The clinical significance of these effects of sodium heparin remains uncertain and insufficiently studied.

In acute coronary syndrome without stable rise of the ST segment on the ECG (unstable angina, myocardial infarction without ST segment elevation) heparin sodium in combination with acetylsalicylic acid reduces the risk of myocardial infarction and mortality. With myocardial infarction with ST segment elevation on the ECG heparin sodium effective in primary percutaneous coronary revascularization in combination with inhibitors of glycoprotein IIb / IIIa receptor and streptokinase in thrombolytic therapy (increased frequency revascularization).

In high doses heparin sodium effective for pulmonary embolism and venous thrombosis, small - is effective for the prevention of venous thromboembolism, including after surgery.

After intravenous administration of drug action occurs almost immediately, no later than 10-15 minutes and lasts long -. 6.3 hours after subcutaneous administration of drug action begins slowly - over 40-60 min, but lasts 8 hours antithrombin III deficiency in the blood or plasma. at the site of thrombosis can reduce the anticoagulant effect of heparin sodium.

Pharmacokinetics:

The maximum concentration (C_max) after intravenous administration is achieved almost immediately, after subcutaneous administration - after 2-4 hours.

Communication with plasma proteins - up to 95% volume distribution is very small - 0.06 L / kg (not leave the bloodstream because strong binding to plasma proteins).

It does not penetrate the placental barrier and into breast milk.

Intensively captured by endothelial cells and cells of the mononuclear-macrophage system (cells of the reticuloendothelial system), it is concentrated in the liver and spleen. It is metabolized in the liver with the participation of N-desulfamidase and platelet heparinase, which is included in the metabolism of heparin at later stages. Participation in the metabolism of platelet factor IV (anti-heparin factor), as well as the binding of sodium heparin to the macrophage system, explains the rapid biological inactivation and short-term action. Desulfated molecules under the influence of kidney endoglycosidase are converted into low-molecular fragments. Half-life of the drug (T_1/2) is 1-6 hours (on the average - 1.5 hours); increases with obesity, hepatic and / or renal insufficiency; decreases with thromboembolism of the pulmonary artery, infections, malignant tumors.

It is excreted by the kidneys, mainly in the form of inactive metabolites, and only with the introduction of high doses is it possible to excrete (up to 50%) unchanged. It is not excreted by hemodialysis.

Indications:

- Prevention and treatment of venous thrombosis (including thrombosis of the superficial and deep veins of the lower extremities, thrombosis of the renal veins) and pulmonary embolism.

- Prevention and treatment of thromboembolic complications associated with atrial fibrillation.

- Prevention and treatment of peripheral arterial embolism (including those associated with mitral heart defects).

- Treatment of acute and chronic coagulopathy of consumption (including the first stage of DIC syndrome).

- Acute coronary syndrome without stable rise of the ST segment on the ECG (unstable angina, myocardial infarction without ST segment elevation on the ECG).

- Myocardial infarction with ST segment elevation: with thrombolytic therapy, with primary percutaneous coronary revascularization (balloon angioplasty with or without stenting) and with a high risk of arterial or venous thrombosis and thromboembolism.

- Prevention and treatment of microthrombogenesis and microcirculatory disorders, including hemolytic-uremic syndrome, glomerulonephritis (including lupus nephritis) and forced diuresis.

- Prevention of blood coagulation during blood transfusion, extracorporeal circulation systems (extracorporeal circulation in heart surgery, hemosorption, cytarapheresis) and hemodialysis.

- Treatment of peripheral venous catheters.

Contraindications:

- Hypersensitivity to sodium and other components of the drug.

- Heparin-induced thrombocytopenia (with or without thrombosis) in the anamnesis or at the present time.

- Bleeding (except when the benefits of sodium heparin outweigh the potential risk).

- Pregnancy and the period of breastfeeding.

Carefully:

Patients with a polyvalent allergy (including bronchial asthma).

In pathological conditions associated with an increased risk of bleeding, such as:

- Diseases of the cardiovascular system: acute and subacute infective endocarditis, severe uncontrolled arterial hypertension, exfoliation of the aorta, aneurysm of cerebral vessels.

- Erosive-ulcerative lesions of the gastrointestinal tract (GIT), varicose veins of the esophagus with cirrhosis of the liver and other diseases, prolonged use of gastric and intestinal drainage, ulcerative colitis, hemorrhoids.

- Diseases of the hemopoiesis and lymphatic system: leukemia, hemophilia, thrombocytopenia, hemorrhagic diathesis.

- Diseases of the central nervous system: hemorrhagic stroke, craniocerebral trauma.

- Malignant neoplasms.

- Congenital deficiency of antithrombin III and substitution therapy with antithrombin III (lower doses of heparin should be used to reduce the risk of bleeding).

Other physiological and pathological conditions: period of menstruation, threatening abortion, early postpartum period, severe liver disease with impaired protein-synthetical function, chronic renal failure, recent surgery for the eyes, brain or spinal cord, recent spinal puncture or epidural anesthesia , proliferative diabetic retinopathy, vasculitis, children under 3 years of age (included in the gasoline alcohol can cause t ksicheskih and anaphylactoid reactions), advanced age (over 60 years, especially the women).

Pregnancy and lactation:

Heparin sodium does not penetrate the placental barrier. To date, there are no data indicating the possibility of malformations of the fetus due to the use of heparin sodium during pregnancy; there are also no results of animal experiments,which would indicate the embryo or fetotoxic effect of sodium heparin. However, there is evidence of an increased risk of preterm labor and spontaneous abortion associated with bleeding. It is necessary to take into account the likelihood of complications when using heparin sodium in pregnant women with concomitant diseases, as well as in pregnant women receiving additional treatment.

Daily use of high doses of heparin sodium for more than 3 months may increase the risk of osteoporosis in pregnant women. Therefore, the continuous use of high doses of sodium heparin should not exceed 3 months.

Epidural anesthesia should not be used in pregnant women who undergo anticoagulant therapy. Anticoagulant therapy is contraindicated in case of threat of bleeding, for example, in case of threatening abortion.

Heparin sodium is not excreted in breast milk.

Daily use of high doses of heparin sodium for more than 3 months may increase the risk of osteoporosis in lactating women.

In case of need of application in the specified periods it is necessary to use other preparations of heparin of sodium,not containing petrol as an auxiliary substance (see "Composition", "Contraindications").

Dosing and Administration:

Heparin is administered subcutaneously, intravenously, bolus or drip.

Heparin is prescribed in the form of continuous intravenous infusion or in the form of regular intravenous injections, as well as subcutaneously (in the abdomen).

Heparin can not be administered intramuscularly.

A common place for hypodermic injections is the anterolateral wall of the abdomen (in exceptional cases, it is inserted into the upper region of the shoulder or thigh), using a thin needle that should be inserted deep, perpendicularly into the fold of the skin held between the thumb and forefinger until the end of the solution. Each time, alternate injection sites (to avoid the formation of a hematoma). The first injection should be performed 1-2 hours before the operation; in the postoperative period - enter within 7-10 days, and if necessary - for a longer time. The initial dose of Heparin administered for medicinal purposes is usually 5000 IU and is administered intravenously, after which the treatment is continued using subcutaneous injections or intravenous infusions.

Supporting doses are determined depending on the method of application:

- with continuous intravenous infusion, appoint 1000-2000 IU / h (24000-48000 IU / day), diluting Heparin 0.9% solution of sodium chloride;

- with regular intravenous injections appoint 5000-10000 ME Heparin every 4-6 hours;

- when administered subcutaneously, every 12 hours, 15,000 to 20,000 ME or every 8 hours to 8000-10000 ME.

Before the administration of each dose, it is necessary to conduct a study of blood coagulation time and / or activated partial thromboplastin time (APTT) in order to correct the subsequent dose.

Doses of Heparin for intravenous administration are selected so that the APTT is 1.5-2.5 times greater than the control one. An anticoagulant effect of Heparin is considered optimal if the clotting time is 2-3 times longer than normal, APTT and thrombin time are 2-fold (if APTTV is continuously monitored).

When subcutaneous administration of small doses (5000 IU 2-3 times a day) for the prevention of thrombosis, regular monitoring of APTT is not required, since it increases insignificantly.

Continuous intravenous infusion is the most effective way of using Heparin, better than regular (periodic) injections,since it provides a more stable hypocoagulation and less often causes bleeding.

Use of heparin sodium in special clinical situations

Primary percutaneous coronary angioplasty in acute coronary syndrome without ST segment elevation and myocardial infarction with ST segment elevation: heparin sodium is administered intravenously bolus at a dose of 70-100 IU / kg (unless the use of inhibitors of glycoprotein IIb / IIIa receptors is planned) or at a dose of 50-60 IU / kg (when combined with glycoprotein IIb / IIIa receptor inhibitors).

Thrombolytic therapy for myocardial infarction with ST segment elevation: heparin sodium is administered intravenously bolus in a dose of 60 IU / kg (maximum dose 4000 ME), followed by intravenous infusion at a dose of 12 IU / kg (not more than 1000 IU / h) for 24-48 hours. The target level of APTT is 50-70 sec, that in 1,5-2,0 times above the norm; control of APTT - at 3.6, 12 and 24 hours after initiation of therapy.

Prevention of thromboembolic complications after surgical interventions using low doses of heparin sodium: heparin sodium is injected subcutaneously, deep into the fold of the abdominal skin. The initial dose is 5000 IU for 2 hours before the operation. In the postoperative period - 5000 ME every 8-12 hours for 7 days or until the patient's mobility is completely restored (whichever comes first).When sodium heparin is used in low doses for the prevention of thromboembolic complications, it is not necessary to control the APTT.

Application in cardiovascular surgery in operations using the extracorporeal circulation system: the initial dose of heparin sodium is at least 150 IU / kg. Further heparin sodium is introduced by continuous intravenous infusion at a rate of 15-25 drops / min at 30,000 IU per 1 liter of the infusion solution. The total dose is usually 300 IU / kg (if the expected duration of the operation is less than 60 minutes) or 400 IU / kg (if the estimated duration of the operation is 60 minutes or more).

Application for hemodialysis: the initial dose of heparin sodium is 25-30 IU / kg (or 10,000 IU) intravenously bolus, then continuous infusion of heparin sodium 20000 IU / 100 ml 0.9% sodium chloride solution at a rate of 1500-2000 IU / h (unless otherwise specified in manual for the use of systems for hemodialysis).

The use of heparin sodium in pediatrics: adequate controlled trials of the use of heparin sodium in children have not been conducted. The recommendations are based on clinical experience: initial dose: 75-100 IU / kg intravenously bolus for 10 minutes,maintenance dose: children aged 1-3 months - 25-30 IU / kg / h (800 IU / kg / day), children aged 4-12 months - 25-30 IU / kg / h (700 IU / kg / day), children older than 1 year -18-20 ME / kg / h (500 IU / kg / day) intravenously drip.

The dose of heparin sodium should be selected taking into account the parameters of blood coagulation (the target level of APTT is 60-85 sec).

The duration of therapy depends on the indications and the way of application. For intravenous use, the optimal treatment duration is 7-10 days, followed by continued treatment with oral anticoagulants (oral anticoagulants recommended to appoint, starting from 1 day of treatment with sodium heparin or 5 to day 7, while use of sodium heparin terminate at 4-5 day combined therapy). With extensive thrombosis of the ileum-femoral veins, it is advisable to conduct longer courses of treatment with the drug Heparin.

Side effects:

Allergic reactions: hyperemia of the skin, drug fever, hives, rhinitis, pruritus and sensation of heat in the soles, bronchospasm, collapse, anaphylactic shock.

Bleeding: typical - from the gastrointestinal tract and urinary tract, at the site of injection, in areas subject to pressure,from operating wounds; hemorrhages in various organs (including adrenal glands, yellow body, retroperitoneal space).

Local reactions: pain, hyperemia, hematoma and ulceration at the injection site, bleeding.

Other potential side effects include: dizziness, headache, nausea, vomiting, decreased appetite, diarrhea, joint pain, increased blood pressure and eosinophilia.

At the beginning of treatment with Heparin, transient thrombocytopenia can sometimes be noted with a platelet count ranging from 80x10⁹/ l up to 150x10⁹/ l. Usually this situation does not lead to the development of complications and treatment with Heparin can be continued. In rare cases, severe thrombocytopenia (white clot syndrome) can occur, sometimes fatal. This complication should be assumed in case of a decrease in platelets below 80x10⁹/ l or more than 50% of the baseline level, the administration of Heparin in such cases is urgently discontinued. Patients with severe thrombocytopenia may develop coagulopathy of consumption (depletion of fibrinogen stores).

Against the background of heparin-induced thrombocytopenia: skin necrosis, arterial thrombosis, accompanied by the development of gangrene, myocardial infarction, stroke.

With prolonged use: osteoporosis, spontaneous bone fractures, calcification of soft tissues, hypoaldosteronism, transient alopecia, priapism.

Against the backdrop of therapy with Heparin, changes in biochemical blood parameters can be observed (increased activity of "hepatic" transaminases, free fatty acids and thyroxine in the blood plasma, hyperkalemia, recurrent hyperlipidemia with Heparin withdrawal, false increase in blood glucose concentration and false positive result of bromsulfalein test).

Overdose:

Symptoms: signs of bleeding.

Treatment: with small bleeding caused by an overdose of heparin, it is enough to stop using it. With extensive bleeding, excess heparin is neutralized with protamine sulfate (1 mg protamine sulphate per 100 IU sodium heparin). 1% (10 mg / ml) solution of protamine sulfate is administered intravenously very slowly. Every 10 minutes, you can not administer more than 50 mg (5 ml) of protamine sulfate. Given the rapid metabolism of heparin sodium, the required dose of protamine sulfate decreases with time. To calculate the required dose of protamine sulfate, it can be considered that T1 / 2 of sodium heparin is 30 minutes.When protamine sulfate was used, severe anaphylactic reactions with a lethal outcome were noted, and therefore the drug should be administered only under conditions of separation, equipped to provide emergency medical care for anaphylactic shock.

Hemodialysis is ineffective.

Interaction:

Pharmaceutical interaction: solution of sodium heparin is compatible only with 0.9% sodium chloride solution.

A solution of sodium heparin compatible with the following drugs solutions: alteplase, amikacin, amiodarone, ampicillin, penicillin, ciprofloxacin, cytarabine, dacarbazine, daunorubicin, diazepam, dobutamine, doxorubicin, droperidol, erythromycin, gentamicin, haloperidol, hyaluronidase, hydrocortisone, dextrose, idarubicin, kanamycin, methicillin sodium, netilmicin, opioids, oxytetracycline, polymyxin B, promazine, promethazine, streptomycin, sulfafurazole diethanolamine, tetracycline, tobramycin, efalotina, tsefaloridinom, vancomycin, vinblastine, nicardipine, fat emulsions.

Pharmacokinetic interaction: heparin sodium expels phenytoin, quinidine, propranolol and benzodiazepine derivatives from the sites of their binding to plasma proteins, which may lead to an increase in the pharmacological effect of these drugs. Sodium Heparin binds and is inactivated by protamine sulfate, polypeptides having an alkaline reaction, and tricyclic antidepressants.

Pharmacodynamic interaction: anticoagulant effect of sodium heparin is enhanced with simultaneous use with other drugs that affect hemostasis, including. with antiplatelet agents (acetylsalicylic acid, clopidogrel, prasugrel, ticlopidine, dipyridamole), anticoagulants of indirect action (warfarin, fenindion, acenocoumarol), thrombolytic drugs (alteplase, streptokinase, urokinase), non-steroidal anti-inflammatory drugs (including phenylbutazone, ibuprofen, indomethacin, diclofenac), glucocorticosteroids and dextran, which increases the risk of bleeding. In addition, the anticoagulant effect of sodium heparin can be enhanced when combined with hydroxychloroquine, ethacrylic acid, cytostatics, cefamandol, valproic acid, propylthiouracil.

The anticoagulant effect of sodium heparin decreases with simultaneous use with ACTH, antihistamine drugs, ascorbic acid, ergot alkaloids, nicotine, nitroglycerin, cardiac glycosides, thyroxine, tetracycline and quinine.

Heparin sodium can reduce the pharmacological effect of adrenocorticotropic hormone, glucocorticosteroids and insulin.

Special instructions:

Treatment in large doses is recommended in a hospital.

The control of the platelet count should be performed before the start of treatment, on the first day of treatment and at short intervals during the entire period of administration of sodium heparin, especially between 6 and 14 days after initiation of treatment. Immediately stop treatment with a sharp decrease in the number of platelets (see section "Side effect").

A sharp decrease in the number of platelets requires further investigation for the detection of heparin-induced immune thrombocytopenia. If this occurs, the patient should be informed that he can not use Heparin in the future (even low molecular weight heparin). If there is a high probability of heparin-induced immune thrombocytopenia, Heparin should be immediately withdrawn.When developing heparin-induced immune thrombocytopenia in patients receiving Heparin for thromboembolic disease or in the case of thromboembolic complications, other anticoagulant drugs should be used.

Patients with heparin-induced immune thrombocytopenia (white clot syndrome) should not undergo hemodialysis with heparinization. If necessary, alternative methods of treating renal failure should be used.

To avoid overdose, it is necessary to constantly monitor clinical symptoms indicating possible bleeding (bleeding of the mucous membranes, hematuria, etc.). In patients with a lack of response to Heparin or requiring the appointment of high doses of Heparin, it is necessary to monitor the level of antithrombin III.

The use of drugs containing benzyl alcohol as a preservative in newborns (especially in prematurity and in children with reduced body weight) can lead to serious undesirable phenomena (central nervous system depression, metabolic acidosis, gas-breathing) and death.Therefore, newborns and children under 1 year should use heparin sodium preparations that do not contain preservatives.

Resistance to sodium heparin is often observed with fever, thrombosis, thrombophlebitis, infectious diseases, myocardial infarction, malignant neoplasms, and also after surgical interventions and with the deficiency of antithrombin III. In such situations, more thorough laboratory monitoring (APTT monitoring) is required.

In women over 60 years of age, Heparin can increase bleeding, and therefore the dose of sodium heparin should be reduced in this category of patients.

When using heparin sodium in patients with hypertension should regularly monitor blood pressure.

Before starting therapy with sodium heparin, a coagulogram study should always be performed, with the exception of the use of low doses.

Patients who are transferred to oral anticoagulant therapy, the appointment of heparin sodium should be continued until the results of coagulation time and APTT are not in the therapeutic range.

Intramuscular injections are contraindicated.It should also be avoided as much as possible puncture biopsies, infiltration and epidural anesthesia and diagnostic lumbar punctures against the background of sodium heparin.

If there is a massive bleeding, you should cancel Heparin and examine the coagulogram indices. If the results of the analysis are within the limits of the norm, then the probability of development of this bleeding due to the use of Heparin is minimal.

Changes in the coagulogram tend to normalize after Heparin cancellation. A solution of Heparin can acquire a yellow tint, which does not change its activity or tolerability.

To dilute the drug use only 0.9% solution of sodium chloride!

Effect on the ability to drive transp. cf. and fur:Studies to assess the impact of Heparin on the ability to drive vehicles and engage in potentially hazardous activities were not conducted.

Form release / dosage:A solution for intravenous and subcutaneous administration of 5000 IU / ml.

Packaging:

For 5 ml in neutral glass bottles or 5 ml in neutral glass ampoules.

1 bottle with instructions for use in a pack of cardboard.

For 5 vials or ampoules in a contour plastic packaging (pallet) or in a planar cell package.

1, 2 contour plastic packages (pallets) or contour mesh packages together with instructions for use in a pack of cardboard.

5, 10 vials or ampoules together with instructions for use in a pack with a cardboard insert.

Packing for hospitals

10, 20 contour plastic packages (pallets) or contour mesh packages together with instructions for use in an amount equal to the number of primary packages with the preparation in a cardboard box.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002335

Date of registration:19.12.2013 / 01.07.2014

Expiration Date:19.12.2018

The owner of the registration certificate:BINERGIYA, CJSC BINERGIYA, CJSC Russia

Manufacturer: & nbsp

Armavir Biofactory, FKP

Information update date: & nbsp24.03.2017

Illustrated instructions

Instructions

Heparin (Heparin)