Heparin

General characteristics. Structure:

Active ingredient: 5000 ME heparin sodium.

Excipients: petrol alcohol, sodium chloride, solution of Acidum hydrochloricum of 1 M or solution of sodium hydroxide 1M to pH 5,0 - 7,5, water for injections.

Pharmacological properties:

Pharmacodynamics. Anticoagulant of direct action, concerns to group of middlemolecular heparins, slows down formation of fibrin. The anticoagulating effect is found in vitro and in vivo, comes directly after intravenous use.

The mechanism of effect of heparin is based first of all on its linkng with antithrombin III - inhibitor of the activated blood-coagulation factors: thrombin, IXa, Ha, HIA, HIIA (ability to inhibit thrombin and the activated factor of X is especially important).

Increases a renal blood stream; increases brain vascular resistance, reduces activity of brain hyaluronidase, activates lipoproteinlipase and possesses hypolipidemic action.

Reduces activity of surfactant in lungs, suppresses excessive synthesis of Aldosteronum in bark of adrenal glands, connects adrenaline, modulates reaction of ovaries to hormonal incentives, increases activity of parathormone. As a result of interaction with enzymes can increase activity of a tyrosinehydroxylase of a brain, a pepsinogen, DNA polymerase and to reduce miozinovy Atfaza's activity, пирув^киназы, RNA polymerases, pepsin.

At patients with an ischemic heart disease (coronary heart disease) (in a combination with ASK (acetylsalicylic acid) reduces risk of development of acute thromboses of coronary arteries, a myocardial infarction and sudden death. Reduces the frequency of repeated heart attacks and a lethality of the patients who had a myocardial infarction.

In high doses it is effective at thromboembolisms of a pulmonary artery and venous thrombosis, in small - for prevention of venous thromboembolisms, including after surgeries.

At intravenous administration a blood coagulation is slowed down almost at once, at intramuscular - in 15-30 min., at hypodermic - in 20-60 min., after inhalation at most of effect - in a day; duration of anticoagulating effect respectively - 4-5, 6, 8 h and 1-2 weeks, therapeutic effect - prevention of a thrombogenesis - remains much longer.

Deficit of antithrombin III in plasma or in the place of thrombosis can reduce antitrombichesky effect of heparin.

Pharmacokinetics. After hypodermic introduction of TCmax - 4-5 h. Communication with proteins of plasma - to 95%, distribution volume very small - 0,06 l/kg (does not leave a vascular bed because of strong linkng with proteins of plasma). Does not get into a placenta and into breast milk. It is intensively taken endothelial cells and cells of mononuklearno-macrophagic system (RES cells (reticuloendothelial system), concentrates in a liver and a spleen. It is metabolized in a liver with participation of N-desulfamidazy and haparinase of thrombocytes joining in metabolism of heparin at later stages. Participation in metabolism of a platelet factor of IV (an anti-heparin factor), and also linkng of heparin with system of macrophages explain a bystry biological inactivation and short duration of action. Desulfatirovanny molecules under the influence of endoglycosidase of kidneys turn into low-molecular fragments. T1/2 - 1-6 h (on average 1,5 h); increases at obesity, a liver and/or renal failure; decreases at a thromboembolism of a pulmonary artery, infections, malignant tumors.

It is allocated with kidneys, it is preferential in the form of inactive metabolites, and only at introduction of high doses removal (to 50%) in an invariable look is possible. It is not removed by means of a hemodialysis.

Indications to use:

Fibrinferments, thromboembolisms (prevention and treatment), the prevention of a blood coagulation (in cardiovascular surgery), fibrinferments of coronary vessels, the disseminated intravascular blood coagulation, the postoperative period at patients with thromboembolisms in the anamnesis. Prevention of a blood coagulation during operations with use of extracorporal methods of blood circulation.

Route of administration and doses:

Heparin is appointed in the form of continuous intravenous infusion or in the form of subcutaneous or intravenous injections.

The initial dose of the heparin entered in the medical purposes makes 5000 ME and is entered intravenously then treatment continues, using subcutaneous injections or intravenous infusions.

Maintenance doses are defined depending on a route of administration:
- at continuous intravenous infusion to enter in a dose of 15 ME/kg of body weight in an hour, dissolving heparin in 0,9% NaCl solution;
- at regular intravenous injections each 4-6 h appoint 5000-10000 ME heparins;
- at hypodermic introduction each 12 h on 15000-20000 ME or each 8 h enter 8000 - 10000 ME.

Before introduction of each dose it is necessary to conduct a research of a blood clotting time and/or the activated partial tromboplastinovy time (APTT) for the purpose of correction of the subsequent dose. It is preferable to carry out subcutaneous injections in the field of a front abdominal wall, by way of exception it is possible to use also other injection sites (a shoulder, a hip). The anticoagulating effect of heparin is considered optimum if the blood clotting time is extended by 2-3 times in comparison with a normal indicator, the activated partial tromboplastinovy time (APTT) and thrombin time increase twice (at a possibility of continuous control of AChTV).

To the patients who are on extracorporal blood circulation, heparin is appointed in a dose of 150-400 ME/kg of body weight or 1500-2000 ME/500 of ml of stored blood (a whole blood, a packed red cells).

To the patients who are on dialysis, dose adjustment is carried out by results of a koagulogramma.

To children the drug is administered intravenously kapelno: at the age of 1-3 months-800 МЕ/кг/сут, 4-12 months - 700 МЕ/кг/сут, are more senior than 6 years - 500 МЕ/кг/сут under control APTT (the activated partial tromboplastinovy time).

Features of use:

Treatment by high doses is recommended to be carried out in the conditions of a hospital. Control of quantity of thrombocytes should be carried out before an initiation of treatment, in the first day of treatment and through short intervals during the entire period of purpose of heparin, especially between the 6 and 14 day after an initiation of treatment. It is necessary to stop immediately treatment at sharp decrease in number of thrombocytes (see. "Side effects").

Sharp decrease in number of thrombocytes demands a further research regarding identification heparin - the induced immune thrombocytopenia. If that takes place, the patient should report that he cannot appoint heparin in the future (even low-molecular heparin). If there is a high probability heparin - the induced immune thrombocytopenia, heparin should be cancelled immediately.

At development heparin - the induced thrombocytopenia at the patients receiving heparin concerning a clotting disease or in case of development of tromboembolic episodes should use other antitrombotichesky means.

Patients about heparin - the induced immune thrombocytopenia (a syndrome of formation of white blood clot) should not be exposed to a hemodialysis with a geparinization. If necessary, at them alternative methods of treatment of a renal failure have to be used.

In order to avoid overdose it is necessary to watch the clinical symptoms indicating possible bleeding (bleeding of mucous membranes, a hamaturia, etc.) constantly. Persons with absence have reactions to heparin or the high doses of heparin demanding appointment it is necessary to control antithrombin III level.

Though heparin does not get through a placental barrier and is not defined in breast milk, at appointment in therapeutic doses it is necessary to watch pregnant women and the nursing mothers carefully.

Extra care should be observed within 36 hours after the delivery. Carrying out the corresponding control laboratory researches (a blood clotting time, the activated partial tromboplastinovy time and thrombin time) is necessary.

At women 60 years heparin are more senior can increase bleeding.

When using heparin at patients with arterial hypertension it is necessary to control arterial pressure constantly.

Before therapy by heparin the koagulogramma research, except for use of low doses always has to be conducted.

Patients who are transferred to peroral anticoagulating therapy should continue purpose of heparin until results the blood clotting time and the activated partial tromboplastinovy time (APTT) are not in therapeutic range.

Intramuscular injections have to be excluded at purpose of heparin in the medical purposes. It is also necessary to avoid whenever possible puncture biopsies, infiltration and epidural anesthesia and diagnostic lumbar punctures.

If there is massive bleeding, it is necessary to cancel heparin and to investigate koagulogramma indicators. If results of the analysis within norm, then the probability of development of the given bleeding owing to use of heparin is minimum; Changes in a koagulogramma tend to normalization after heparin cancellation.

Protamin sulfate is a specific antidote of heparin. One ml of protamin of sulfate neutralizes 1000 ME heparins. Doses of protamin have to korrigirovatsya depending on results of a koagulogramma as the excess amount of this drug in itself can provoke bleeding.

Side effects:

Allergic reactions: a dermahemia, medicinal fever, a small tortoiseshell, rhinitis, a skin itch and feeling of heat in soles, a bronchospasm, a collapse, an acute anaphylaxis.

Other potential side effects include dizziness, a headache, nausea, a loss of appetite, vomiting, diarrhea, joint pains, increase in arterial pressure and an eosinophilia.

In an initiation of treatment by heparin passing thrombocytopenia (6% of patients) with quantity of thrombocytes in the range from 80x109/l up to 150Õ109/l can sometimes be noted. Usually this situation does not lead to development of complications and treatment by heparin can be continued. In rare instances heavy thrombocytopenia (a syndrome of formation of white blood clot), sometimes with a lethal outcome can be noted. This complication should be assumed in case of decrease in quantity of thrombocytes lower than 80x109/l or more than for 50% of initial level, administration of heparin in such cases is urgently stopped. At patients with heavy thrombocytopenia the consumption coagulopathy (exhaustion of reserves of fibrinogen) can develop.

Against the background of heparin - the induced thrombocytopenia: a skin necrosis, the arterial thrombosis which is followed by a gangrenosis, a myocardial infarction, a stroke.

At prolonged use: osteoporosis, spontaneous fractures of bones, calcification of soft tissues, hypoaldosteronism, passing allopecia.

Against the background of therapy changes of biochemical parameters of blood can be observed by heparin (increase in activity of "hepatic" transaminases, free fatty acids and thyroxine in a blood plasma; a reversible delay of potassium in an organism; false decrease in level of cholesterol; false increase in level of glucose of blood and a mistake in results of the bromsulfaleinovy test). Local reactions: irritation, pain, a hyperemia, a hematoma and ulcerations in an injection site, bleeding.

Bleedings: typical - from a GIT (digestive tract) and uric ways, in a drug injection site, in the areas which are exposed to pressure from operational wounds; hemorrhages in various bodies (including adrenal glands, a yellow body, retroperitoneal space).

Interaction with other medicines:

Before any surgical interventions, using heparin, not less than in 5 days peroral anticoagulants (for example, Dicumarinums) and antiagregant (for example, acetylsalicylic acid, Dipiridamolum) have to be cancelled as they can strengthen bleeding during operations or in the postoperative period.

Simultaneous use of ascorbic acid, antihistaminic drugs, digitalis or tetracyclines, alkaloids of an ergot, nicotine, nitroglycerine (intravenous administration), thyroxine, AKTG (adenokortikotropny hormone), alkaline amino acids and polypeptides, protamin can reduce effect of heparin.

The dextran, phenylbutazone, indometacin, сульфйнпиразон, пробенецид, intravenous administration of Acidum etacrynicum, penicillin and tsitostatik can exponentiate effect of heparin.

Heparin replaces Phenytoinum, quinidine, propranolol, benzodiazepines and bilirubin in places of their linkng with proteins. Mutual decrease in efficiency happens at simultaneous use of tricyclic antidepressants since they can contact heparin.

Because of potentially possible precipitation of active ingredients heparin should not mix up with other medicines.

Contraindications:

Hypersensitivity to heparin, the diseases which are followed by the raised bleeding (hemophilia, thrombocytopenia, a vasculitis, etc.), bleeding, aneurism of vessels of a brain, the stratified aortic aneurysm, a hemorrhagic stroke, an anti-phospholipidic syndrome, an injury, especially craniocereberal), erosive cankers, tumors and polyps of a GIT (digestive tract); subacute bacterial endocarditis; the expressed abnormal liver functions and kidneys; the cirrhosis which is followed by a gullet varicosity, heavy uncontrollable arterial hypertension; hemorrhagic stroke; recently performed brain and backbone, eyes, prostate, liver or biliary tract operations; states after a puncture of a spinal cord, a proliferative diabetic retinopathy; the diseases which are followed by decrease in a blood clotting time; the menstrual period, the menacing abortion, childbirth (including recent), pregnancy, the lactation period; thrombocytopenia; hyperpermeability of vessels; pulmonary bleeding.

With care. To the persons having a polyvalent allergy (including bronchial asthma), arterial hypertension, dental manipulations, a diabetes mellitus, an endocarditis, a pericardis, VMK (intrauterine contraception), active tuberculosis, radiation therapy, a liver failure, CRF (chronic renal failure), advanced age (60 years, especially are more senior than the woman).

Overdose:

Symptoms: symptoms of bleeding.

Treatment: at the small bleedings caused by heparin overdose it is enough to stop its use. At extensive bleedings excess of heparin is neutralized protamin sulfate (1 mg of protamin of sulfate on 100 ME heparins). It must be kept in mind that heparin is quickly removed and if protamin sulfate is appointed in 30 min. after the previous dose of heparin, it is necessary to enter only a half of a necessary dose; the maximum dose of protamin of sulfate makes 50 mg. The hemodialysis is inefficient.

Storage conditions:

In the place protected from light at a temperature from 15 to 25 °C. To store in the places unavailable to children. A period of validity - 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous and hypodermic administration of 5000 ME/ml in ampoules on 5 ml or in bottles on 5 ml. Packaging: on 5 ampoules in a blister strip packaging. 1 blister strip packaging with the application instruction of drug, a knife or the scarificator ampoule in a pack from a cardboard. On 30 or 50 blister strip packagings with a foil with 30 or 50 application instructions of drug respectively, knives or scarificators ampoule in boxes from a cardboard or in boxes from corrugated fibreboard (for a hospital). When packaging ampoules with notches, rings or points of a break knives or scarificators ampoule do not put. On 5 bottles in a blister strip packaging. 1 blister strip packaging with the application instruction of drug in a pack from a cardboard. On 30 or 50 blister strip packagings with a foil with 30 or 50 application instructions of drug respectively in boxes from a cardboard or in boxes from corrugated fibreboard (for a hospital).