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

Pharmacodynamics:Anticoagulant direct action, refers to the group of medium-molecular heparins, slows the formation of fibrin. The mechanism of action is based, first of all, on the binding of sodium heparin to antithrombin III, an inhibitor of activated blood coagulation factors: thrombin, IXa, Xa, XIa, XIIa (especially the ability to inhibit thrombin and activated factor X). Increases renal blood flow; increases the resistance of cerebral vessels, reduces the activity of brain hyaluronidase, activates lipoprotein lipase and has lipid-lowering action.
Reduces the activity of the surfactant in the lungs, suppresses the excessive synthesis of aldosterone in the adrenal cortex, binds adrenaline, modulates the ovarian response to hormonal stimuli, and increases the activity of parathyroid hormone. As a result of the interaction with enzymes, it can increase the activity of the tyrosine hydroxylase of the brain, pepsinogen, DNA polymerase and reduce the activity of myosin ATPase, pyruvate kinase, RNA polymerase, pepsin.
Heparin is not able to dissolve the thrombus (not fibrinolytic), but it can reduce the size of the thrombus, stopping its growth, and in this case part of the thrombus dissolves under the action of the fibrinolytic enzyme-plasmin. With ischemic heart disease (in combination with acetylsalicylic acid) reduces the risk of developing acute coronary thrombosis, myocardial infarction and sudden death. Reduces the frequency of recurrent myocardial infarction and mortality of patients with myocardial infarction.
In high doses it is effective for pulmonary embolism and venous thrombosis, in small doses for the prevention of venous thromboembolism, including after surgical operations.
With intravenous administration, blood clotting slows down almost immediately, with subcutaneous - in 20-60 minutes; the duration of anticoagulant action is 4-5 and 8 hours, respectively, and the therapeutic effect - prevention of thrombus formation - lasts much longer.
Deficiency of antithrombin III in plasma or in the place of thrombosis can reduce the antithrombotic effect of heparin.

Pharmacokinetics:After subcutaneous administration, the time to reach the maximum concentration (TCmax) is 4-5 hours. The connection with plasma proteins is up to 95%, the volume of distribution is 0.06 l / kg (does not leave the vascular bed due to significant binding to plasma proteins). It does not penetrate the placenta 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 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. The half-life 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:Treatment and prevention: deep vein thrombosis, pulmonary thromboembolism (including peripheral veins), coronary thrombosis, thrombophlebitis, unstable angina, acute myocardial infarction, atrial fibrillation (including accompanied by embolization), disseminated syndrome intravascular coagulation, prophylaxis and therapy of microthrombogenesis and microcirculation disorders, renal vein thrombosis, hemolyticuremic syndrome, mitral heart disease (thrombogenesis prophylaxis), bacterial ny endocarditis, glomerulonephritis, lupus nephritis.
Prevention of blood coagulation during operations with extracorporeal circulation techniques, during hemodialysis, hemosorption, peritoneal dialysis, cytapheresis, Forced diuresis by washing venous catheters.

Contraindications:Hypersensitivity to heparin, diseases accompanied by increased hemorrhage (including hemophilia, thrombocytopenia, vasculitis), bleeding, cerebral aneurysm, exfoliating aortic aneurysm, hemorrhagic stroke, antiphospholipid syndrome, trauma (especially craniocerebral), uncontrolled arterial hypertension , erosive and ulcerative lesions of the gastrointestinal tract; cirrhosis of the liver, accompanied by varicose veins of the esophagus; menstrual period, threatening miscarriage, childbirth (including recent), recent surgery on the eyes, brain, prostate, liver and biliary tract, conditions after spinal puncture, pregnancy, lactation, children under the age of 1 month.

Carefully:Persons suffering from polyvalent allergy (incl.bronchial asthma), arterial hypertension, dental manipulation, diabetes mellitus, endocarditis, pericarditis, use of intrauterine contraceptives, active tuberculosis, radiation therapy, hepatic insufficiency, chronic renal failure (CRF), elderly (over 60 years, especially women).

Dosing and Administration:Heparin is administered subcutaneously, intravenously (bolus or drip).
Heparin can not be administered intramuscularly!
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).
For prophylactic purposes, subcutaneously, 5,000 IU per day, at intervals of 8-12 hours. The usual place for subcutaneous injections is an anterolateral area of the abdomen (in exceptional cases, they are inserted into the upper region of the shoulder or thigh), using a thin A needle that should be inserted deeply, perpendicularly, into the fold of the skin held between the thumb and index finger 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, administer within 7-10 days, and if necessary - for a longer time.
The initial dose of heparin administered for therapeutic purposes is usually 5,000 ME and is administered intravenously, after which the treatment is continued using intravenous infusions.
Supporting doses are determined depending on the method of application:
- with continuous intravenous infusion, appoint 1-2 thousand IU / h (24-48 thousand IU / day), diluting heparin in a 0.9% solution of sodium chloride;
- with periodic intravenous injections appoint 5-10 thousand IU of heparin every 4 hours.
Doses of heparin for intravenous administration are selected so that the activated partial thromboplastin time (APTT) was 1.5-2.5 times greater than the control one. When subcutaneous administration of small doses (5 thousand ME 2-3 times a day) for the prevention of thrombosis, regular monitoring of APTTV is not required, it increases slightly.
Continuous intravenous infusion is the most effective way of using heparin, better than regular (periodic) injections, because provides more stable hypocoagulation and less often causes bleeding. Intravenous injection is recommended to be administered only with the use of initial doses or if for any reason it is not possible to use intravenous infusion or subcutaneous injection.Repeated intravenous injections cause significant fluctuations in hemostatic parameters and often cause dangerous bleeding, therefore they are prescribed only when absolutely necessary.
Adults with thromboses of mild to moderate severity, the drug is administered intravenously at a dose of 40000-50000 IU / day for 3-4 injections; with severe thrombosis and embolism
- intravenously in a dose of 80000 IU / day, divided into 4 times with an interval of 6 hours. By "vital" indications, intravenously administered once 25000 ME (5 ml), then by
20000 IU every 4 hours until a daily dose of 80000-120000 ME is achieved. When intravenous drip introduction to the daily volume of the infusion solution, it is necessary to add at least 40,000 IU of heparin.
When performing extracorporeal circulation, the drug is administered at a dose of 140-400 IU / kg or 1.5-2 thousand IU per 500 ml of blood. In hemodialysis, 10,000 IU intravenously are administered first, then in the middle of the procedure, another 30-50 thousand ME. For the elderly, especially women, the dose should be reduced.
For children, the drug is administered intravenously drip: an initial dose of 50 IU / kg, maintaining a dose of 100 IU / kg every 4 hours (under the control of APTT). At the age of 1-3 months - 800 IU / kg / day, 4-12 months - 700 IU / kg / day, over 6 years - 500 IU / kg / day; The dose should be selected so that the clotting time is 20 minutes.
The duration of therapy with heparin depends on the indications and the way of application.With intravenous application, the optimal duration of treatment is 7-10 days, after which the therapy is continued with oral anticoagulants (it is recommended to appoint oral anticoagulants starting from the first day of treatment with heparin or from 5 to 7 days, and stopping the use of heparin on 4-5 days of combined therapy). In cases of extensive thrombosis of the ileum-femoral veins, longer courses of heparin treatment are advisable.
The procedure for working with a polymer ampoule:
1. Take the ampoule and shake it, holding it by the neck.
2. Press the ampoule with your hand, while the drug should not be isolated, and rotate and separate the valve with rotating movements.
3. Connect the syringe to the ampoule immediately through the opening.
4. Turn over the ampoule and slowly fill the syringe with its contents.
5. Put the needle on the syringe.

Side effects:Allergic reactions: skin hyperemia, drug fever, urticaria, rhinitis, pruritus and heat sensation in the soles, bronchospasm, collapse, anaphylactic shock, dizziness, headache, nausea, decreased appetite, vomiting, diarrhea. Thrombocytopenia (6% of patients) with fatal outcome.Against the background of heparin-induced thrombocytopenia: skin necrosis, arterial thrombosis, accompanied by the development of gangrene, myocardial infarction, stroke. With the development of severe thrombocytopenia (2 times the initial number or less than 100 thousand / mm3), heparin is rapidly stopped.
With prolonged use: osteoporosis, spontaneous bone fractures, calcification of soft tissues, hypoaldosteronism, transient alopecia, increased activity of "liver" transaminases.
Local reactions with subcutaneous administration: irritation, pain, hyperemia, hematoma and ulceration at the injection site, bleeding.
Bleeding: typical - from the gastrointestinal tract and urinary tract, at the site of injection, in areas undergoing pressure, from surgical wounds; hemorrhages in various organs (including adrenal glands, yellow body, retroperitoneal space).

Overdose:Symptoms: 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 by administration of protamine sulfate (the dose is calculated depending on the method of administration of sodium heparin and the time elapsed from its administration,an average of 1 mg of protamine sulfate neutralizes 100 IU of sodium heparin). It must be borne in mind that heparin sodium It is quickly displayed, and if Protamine sulfate appointed 30 minutes after the previous dose of heparin, only half the required dose should be administered; The maximum dose of protamine sulfate is 50 mg. Hemodialysis is ineffective.

Interaction:Before any surgical interventions with the use of heparin sodium, oral anticoagulants (coumarin derivatives) and medicines that have antiaggregant effect should be canceled no less than for 5 days (incl. acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine), since they can increase bleeding during surgery or in the postoperative period.
The simultaneous use of ascorbic acid, antihistamines, digitalis or tetracyclines, ergot alkaloids, nicotine, nitroglycerin (intravenous administration), thyroxine, ACTH (adrenocorticotropic hormone), alkaline amino acids and polypeptides, protamine may reduce the effect of heparin sodium. Dextran, phenylbutazone, indomethacin, sulfinpyrazone, probenecid, intravenous administration of ethacrynic acid, penicillins and cytostatics may enhance the action of sodium heparin. Sodium Heparin replaces phenytoin, quinidine, propranolol, benzodiazepines and bilirubin in the places of their binding with proteins. Mutual reduction in efficacy occurs with the simultaneous use of tricyclic antidepressants, since they can bind to sodium heparin.
Due to the potentially possible precipitation of the active ingredients heparin sodium should not be mixed with other drugs.

Special instructions:Heparin can not be administered intramuscularly, since it is possible to form a hematoma at the injection site.
Treatment in large doses is recommended in a hospital. Control of platelet count is recommended before the start of treatment, on the 1st day of treatment and at short intervals during the entire period of heparin treatment, especially between 6 and 14 days of therapy. With a sharp decrease in the number of platelets, treatment is immediately stopped. A sharp decrease in the number of platelets requires further research on the development of heparin-induced thrombocytopenia.
Patients with heparin-induced immune thrombocytopenia 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 individuals with no response to heparin or requiring the use of high doses of heparin, it is necessary to monitor the activity of antithrombin III.
Particular care should be taken when using heparin for 36 hours after delivery. It is necessary to conduct appropriate control laboratory tests (clotting time, activated partial thromboplastin time and thrombin time).
In women over 60 years of age, heparin can increase bleeding. When using heparin in patients with concomitant arterial hypertension, one should constantly monitor blood pressure.
Before starting therapy with 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 administration of heparin should continue until the results of clotting time and activated partial thromboplastin time will not be in the therapeutic range. A solution of heparin can acquire a yellow tint, which does not change its activity or tolerability.
When prescribing heparin for therapeutic purposes, its dose is selected depending on the value of APTT (activated partial thromboplastin time).
During the application of heparin, other medications should not be administered intramuscularly, organ biopsies, infiltration and epidural anesthesia, diagnostic lumbar puncture should be performed.
For dilution of heparin, only 0.9% sodium chloride solution is used.

Effect on the ability to drive transp. cf. and fur:During the period of treatment it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Solution for intravenous and subcutaneous injection 5 thousand IU / ml.

Packaging:5 ml each in polymeric ampoules, produced by the technology of "blow-fill-seal" "blow-fill-seal".
For 5 or 10 polymer ampoules, along with the instructions for medical use, put in a pack of cardboard.

Storage conditions:In a dry, dark place at a temperature of 12 to 15 ° C.
Keep out of the reach of children.

Shelf life:3 years.
Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000958

Date of registration:18.10.2011 / 29.07.2015

The owner of the registration certificate:SLAVYANSKAYA APTEKA, LLC SLAVYANSKAYA APTEKA, LLC Russia

Manufacturer: & nbsp

SLAVYANSKAYA APTEKA, LLC Russia

Information update date: & nbsp2016-01-10

Illustrated instructions

Instructions

Heparin (Heparin)