"Heparin" is one of the oldest drugs widely used and is currently in clinical practice. The entire pharmacological family is named for the active substance that provides the medicinal properties of the drug. In the pharmacy you can find drugs for both external and internal use. This is a heterogeneous mixture of branched glycosaminoglycans, which has antithrombotic properties.
Reason for medical use
It was found that the dog’s liver extract (the heparin was first isolated from this organ) is a coagulation inhibitor. In the beginning, heparin was an indirect anticoagulant requiring a plasma cofactor. In 1968, this cofactor was named Abildgaard Antithrombin III and is now called AT.
The main anticoagulant effect of heparin is provided by the interaction of AT.
Mechanism of action and pharmacology
The active substance in the composition of the drug is heterogeneous in molecular size, anticoagulant activity and pharmacokinetic properties. The masses of these molecules range from 5,000 to 30,000 Da (Dalton).
Contraindications "Heparin" has a minimum with external consumption. The pharmacological properties and speed of the ointment are significantly different from those observed when using the medication orally or for injection.
Only about a third of the administered dose of heparin binds to antibodies. This fraction is responsible for most of its anticoagulant activity. The drug produces its main therapeutic effect by inactivating thrombin and activated factor X.
How does the active substance in the drug
Heparin in the composition of the drug binds to antithrombin via pentasaccharide with high similarity, which leads to conformational changes.
Antithrombin inhibits the activity of several coagulation factors, including IXa, Xa and XIIa and thrombin. The complex not only prevents the formation of fibrin, but also inhibits the activation of factors V and VIII.
Heparin capsules have limited contraindications. The composition of the medication may include other active groups, which avoids serious negative reactions and complications with prolonged treatment.
In order for the molecule, which is part of the drug in the form of an active substance, to inactivate thrombin, it must form a triple complex. This is done by binding the substance to antithrombin, which causes a conformational change in the structure of the harmful factor, leading to the formation of blood clots.
Heparin molecules with their 18 saccharides are not enough chain length to connect thrombin and antithrombin. This is done only by those molecules that contain more than 18 saccharides. To achieve the optimal effect, there are a series of drugs for both external and internal consumption.
The instructions for "Heparin 1000" contain the basic rules for using the substance. This gel is for external use, which is great for venous thrombosis on the legs and arms. The dosage of use and frequency is determined only by the attending physician.
The active substance is heparin. Auxiliary - ethanol, lavender oil, trometamol, methyl parahydroxybenzoate, orange blossom oil, water.
The drug is an almost transparent gel with a characteristic odor.
Instructions for use of the Heparin gel reports that the medication is used externally for hematomas, mastitis, thrombophlebitis (superficial), lymphangitis, phlebitis after injection, hemorrhoidal vein thrombosis, edema, elephantiasis, bruises, localized infiltrates, injuries of tissues, joints and tendons.
From what the active substance is obtained in preparations
Commercially available active substance medications are obtained from the intestinal mucosa or pig lung. Although there are some differences between the two methods of preparation, no differences in antithrombotic activity have been demonstrated.
There are no strict contraindications to “Heparin” in the form of a gel. Overdoses are also not observed. However, practice shows that with internal consumption of the drug, sharp jumps in blood pressure can occur. In addition, the load on the kidneys and liver increases further.
However, there is an important point when using it. The International Institute for the Safe Practice of Medicines includes heparin in the list of medicines that have an increased risk of causing significant harm to patients when used by mistake.
Pharmacokinetic properties of drugs
The biological activity and bioavailability of UFH (unfractionated heparin) is limited by its biological tendency to bind to plasma proteins, platelet factor 4, macrophages, fibrinogen, lipoproteins and endothelial cells.
In contraindications to "Heparin" it is noted that the remedy should not be used by pregnant women. From an early date it is advisable to abandon the injection use of the medication. In contraindications to the use of Heparin, it is not indicated that the active substance can be harmful when the fetus is formed in pregnant women. However, chemical properties can increase the burden on the mother's body.
This may be the probable cause of significant variability between the various stages of the disease in the anticoagulation response to UFH treatment. Rapid changes in the level of circulating above-mentioned heparin-binding proteins occur in patients who have active thrombosis. These people often have heparin resistance, which requires higher doses of the drug to achieve a therapeutic response.
Due to its large molecular size and anionic structure, the active substance is not fully absorbed in the gastrointestinal tract when taken orally. Intramuscular administration is not recommended due to unstable absorption and can lead to large hematomas.
Injection dosage
The bioavailability of subcutaneous UFH is dose dependent. This indicator varies from 30% at lower doses to 70% at higher. After subcutaneous injection, the anticoagulant effect is usually one to two hours. When there is a need for rapid inhibition of blood coagulation, Heparin can be administered intravenously. After this injection, anticoagulant activity occurs immediately or occurs during the onset of continuous intravenous infusion of an incoming dose of the drug.
The active substance is widely associated with low density lipoproteins, globulins and fibrinogen. UFH does not cross the placenta and does not spread into breast milk. The dose required to achieve a therapeutic anticoagulant response correlates with weight.
Heparin 5000 is an injectable solution used based on the patient’s weight. Obese people do not have a proportional increase in blood volume relative to body weight. When calculating the initial doses of Heparin for such patients, it is unclear whether the actual or adjusted weight of their body should be used. Therefore, you can not inject yourself. You should consult your doctor to determine the exact dosage of the drug for injections.
The duration of the drug
The half-life of the active substance from plasma in adults is from 30 to 90 minutes. However, the half-life is dose dependent. Several studies using sodium heparin have shown a shorter half-life in patients with pulmonary thromboembolism compared with healthy people and those with other thrombotic disorders. In patients with hepatic impairment, the plasma half-life is also reduced. However, the period when the substance begins to act will increase in patients with cirrhosis.
In contraindications to the use of "Heparin" no restrictions are indicated for people suffering from alcohol dependence. However, alcohol should not be taken during treatment.
The metabolism of UFH has not been fully studied, but it is known that the drug is excreted from the body mainly by the reticuloendothelial system and can be localized on the arterial and venous endothelium. There are two main mechanisms for eliminating UFH. Depending on the dose and size of UFH, excretion is associated with these two mechanisms.
Above, we indicated the area of application of the Heparin gel. The instructions noted that its medicinal properties allow a point effect on venous thrombi with external use. However, this is not always effective. Low doses of UFH are eliminated mainly through a zero order process. At the same time, heparinases and desulfatases enzymatically inactivate the molecules of the substance that are associated with endothelial cells and macrophages, turning them into smaller and less sulfated particles. The drug is also excreted by the kidneys. This is a first order process, which is slower and unsaturated and mainly occurs in very high doses.
Clinical use and dosage
Instructions for use of the gel "Heparin" does not contain the exact dosage of its use. The active substance, which is part of many drugs, is used to prevent and treat venous thrombosis diseases.
UFH can be used for the prevention and treatment of:
- Pulmonary thromboembolism.
- Treatment of embolization associated with arrhythmia or replacement of a heart valve prosthesis.
- For the prevention and treatment of peripheral arterial embolism.
- For the prevention of postoperative deep vein thrombosis and pulmonary thromboembolism in patients who have undergone serious abdominal or thoracic surgery, which faces thromboembolism.
- In the diagnosis and treatment of acute and chronic consumer coagulopathies.
The drugs can also be used to prevent the activation of the coagulation mechanism during arterial and cardiac surgery, as well as in cases where blood passes through the extracorporeal circuit in dialysis procedures. In addition, UFH is used in blood samples taken for laboratory purposes, and as an anticoagulant for blood transfusion. Adjunctive antithrombotic therapy with UFH is also used in patients with unstable angina pectoris.
The dose and route of administration of UFH by injection is based on the indications, therapeutic goals and individual patient response to therapy. To prevent venous thromboembolism, UFH is administered by subcutaneous injection into the abdominal fat layer.
An intravenous bolus dose based on weight followed by continuous infusion is preferred when the patient requires immediate and complete anticoagulation.
The scientific community has reported a relationship between the administered dose of UFH and its efficacy and safety. The dose of UFH should be adjusted according to the activated partial thromboplastin time (APTT). Although the patient’s weight-based approach to dosing UFH is successful, some clinicians still use time-tested standard drug regimens.
Heparin solution for injections is calculated not only by the patient’s body weight. The complexity of the disease is also taken into account. Clinical trial data demonstrate that weight-based dosing protocols increase the proportion of patients who have a therapeutic response in the first 24 hours after using the drug.
Side effects
Hemorrhage is the main adverse manifestation in the treatment of UFH. It can range from minor local bruises to serious hemorrhagic complications. "Heparin" in ampoules has the most serious effect on the body.
Although there is a strong correlation between the subtherapeutic values of APTT (activated partial thromboplastin time) and recurrent thromboembolism, the relationship between this factor and bleeding has not been fully studied. The frequency of complications of this kind in patients receiving UFH is approximately 1.5% to 20%.
Heparin ampoules may increase the risk of hemorrhage with active and prolonged treatment. Serious bleeding occurs mainly at the maximum dose. More often negative reactions are observed with intermittent intravenous injection than with continuous infusion of the drug. The risk of using ointments with the active substance is minimal. When taking capsules, a negative reaction may occur if a person exceeds the dosage.
Another common side effect of Heparin treatment is thrombocytopenia, which is determined when the platelet count is less than 150,000 / cu. mm This side effect has no clinical significance, observed with a frequency of 30% or lower. Thrombocytopenia in the treatment of UFH is not dose related and is more often observed when heparin G is used, obtained from bovine lung tissue, and not from pig's intestinal mucosa.
Indications and contraindications for "Heparin" depend on the percentage of the drug and its use. Heparin-associated thrombocytopenia usually occurs during the first few days of treatment in patients who have not previously received this substance in any medication. Platelet count rarely drops below 100,000 / cu. mm Mild thrombocytopenia may remain stable even if UFH therapy continues.
Another form of side effect is heparin-induced thrombocytopenia, which usually occurs 5-10 days after starting treatment with UFH. This condition caused by heparin is a serious drug problem that requires immediate intervention. It is accompanied by a progressive decrease in platelet count. Their number in patients receiving UFH therapy should be monitored every one to two days. In addition, it should be checked whether or not heparin-induced thrombocytopenia is present if the platelet count drops by 50% or more or below 100,000 / cubic meter. mm
On contraindications to "Heparin" in the injections, the instructions say that during the treatment period a high load on the internal organs is created. Long-term treatment with the use of UFH causes alopecia, priapism and suppression of aldosterone synthesis with subsequent hyperkalemia. Suppression of renal function is also noted after prolonged therapy. Osteoporosis and possible spinal injuries have been reported in patients receiving large daily doses of 10,000 mg UFH for more than six months.
The occurrence of allergic reactions to heparin is rare. Hypersensitivity, which can be generalized, is sometimes manifested by chills, fever, itching, hives, asthma, rhinitis, lacrimation, headache, nausea, vomiting, and anaphylactoid reactions, including shock.
Therapeutic monitoring
Due to unpredictable anticoagulant reactions in patients receiving UFH, careful monitoring during the use of these agents is required. Several tests are available to monitor drug therapy, including blood coagulation time, APTT, antifactor Xa activity, and plasma heparin concentration.
In the instructions to "Heparin" contraindications and side effects are described in great detail. Each of the restrictions in use depends on the form and type of agent used. Each medical type of substance is subject to testing and monitoring to identify all side factors.
APTT is the most widely used test to determine the extent of anticoagulation with UFH using conventional therapeutic doses. It is cheap, automated and usually available 24 hours a day. When very high doses of UFH are used in combination with coronary interventions and circulatory surgery, the activated coagulation time is used to control therapy.
When studying blood coagulation in seconds, an indicator was set in the range from 1.5 to 2.5 from the control value. This range is known to be associated with a reduced risk of recurrent thromboembolism. After that, the therapeutic range of APTT was 1.5-2.5 times higher than the control value, having received wide clinical recognition.
Contraindications to the appointment of "Heparin" for myocardial infarction are that you should refrain from injecting the drug during the treatment of the heart. Before prescribing a drug, it is necessary to pass a complex of tests.
Over the past 25 years, the reagents and tools used to determine APTT have changed.Today, more than 300 laboratory methods are used, as well as more than 30 combinations of reagents. Therefore, there is a wide variation in sensitivity to anticoagulants in different laboratories.
This variability is emphasized by the observation that, at a plasma heparin concentration of 0.3 units / ml (for factor Xa inhibition), the average test results range from 48 to 108 seconds.
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Instructions for use with "Heparin 1000" contains the basic requirements for the frequency of use and dosage per day. Many nomograms with dose adjustment of UFH have been developed, but not one of them can be applied to all APTT reagents. Therefore, the therapeutic range must be appropriately adapted.
Standardization can be achieved by calibrating the concentration of the active substance in the plasma using a therapeutic range from 0.3 to 0.7 units / ml based on an analysis of the anti-factor Xa heparin or its level from 0.2 to 0.4 units / ml by titration of protamine sulfate.
The use of Heparin gel can also be dosed. The volume of the drug is necessary for the targeted effect on thrombosis in a specific area. The studies used the APTT ranges, which were 1.5 times higher than the control value, which is associated with subtherapeutic levels of UFH. The results showed that the true effectiveness of the active substance in the drug in clinical trials of venous thromboembolism was underestimated, since most studies used invalid ranges of APTT therapy and improper dosage of the drug.
Heparin antifactorial analysis in treatment monitoring
The choice of analysis used to monitor UFH therapy is based on clinical preferences and facility accessibility. Monitoring of UFH therapy can also be assessed by measuring heparin levels. The two most common research systems available for measuring active substance levels are neutralization assays and functional assays.
Analysis of protamine titration, which is a form of neutralization, is very laborious, inconvenient and inaccessible to most patients. Functional tests for heparin-anti-factor XA become automated and affordable.
Output
In conclusion, it should be noted: numerous studies have shown that APTT is not a useful substitute for heparin. APTV restrictions have long been established. They do not always reliably correlate with the concentration of heparin in the blood or antithrombotic effects.
Despite this, the vast majority of hospitals continue to use the APTT test. Using modern diagnostic methods, an automatic antifactorial analysis for heparin can be carried out on a basic basis. According to research results, current recommendations for the use of anti-factor Xa levels of a substance should be expanded, since UFH therapy, controlled by dosage levels, can be more effective and safe.
It is not worth it to take Heparin for treatment on your own, even pills or ointment. The exact dosage must be determined. This can only be done by a qualified doctor based on studies and blood tests.