What Are Low-Molecular-Weight Heparins?

It is a low-molecular-weight glucosamine sulfate, with an average molecular weight of 4000 to 6000. It is a short-chain heparin preparation made by various depolymerization methods. It can be divided into different commercial preparations based on the molecular weight, chain end structure, and compound binding salts At present, the main products used in the Chinese market are dalteparin sodium, enoxaparin sodium and naltreparin calcium, which are colorless or pale yellow clear liquids.

Low molecular weight heparin, (1) prevents deep venous thrombosis and pulmonary embolism.

(2) Treatment of acute deep venous thrombosis that has developed.

(3) Prevent thrombus or blood coagulation in extracorporeal circulation system during hemodialysis or blood permeation.

(4) Treatment of unstable angina pectoris and non-ST segment elevation myocardial infarction.

Drug name: Low molecular weight heparin
Drug type: Essential medicines

English name: Low Molecular Heparin
Chinese alias: Low molecular weight heparin sodium; liver protection;
English alias: Calcium-Heparine; Cale-Hepin; Minihep-Calcium

Physicochemical properties of low molecular weight heparin

Low molecular weight heparin pharmacology

It has obvious and long-lasting antithrombotic effect, and its antithrombotic activity is stronger than anticoagulant activity. Therefore, the risk of bleeding is smaller when antithrombotic effects occur. The mechanism is to strengthen the inhibitory effect on factor Xa and thrombin by combining with antithrombin III (AT III) and its complex. However, due to its short molecular chain, it has a strong and long-term anti-Xa activity and has a weak inhibitory effect on thrombin. In addition, it can also promote the release of tissue-type plasmin activator (t-PA), exert fibrinolytic effect, and protect vascular endothelium, and enhance antithrombotic effect. Little effect on platelet function.

Low molecular weight heparin indication

(1) Prevention of deep venous thrombosis and pulmonary embolism. (2) Treatment of acute deep venous thrombosis that has developed. (3) Prevent thrombus or blood coagulation in extracorporeal circulation system during hemodialysis or blood permeation. (4) Treatment of unstable angina pectoris and non-ST segment elevation myocardial infarction.

Low molecular weight heparin usage and dosage

[Preparation and its characteristics and usage] (1) The average molecular weight of dalteparin sodium (faianmin, gepaline) and Dalteparin Sodium (FRAGMIN) is 5000. The ratio of anti-Xa / a activity in vitro was 2.2: 1. The bioavailability of subcutaneous injection is about 90%. Intravenous injection is effective for 3 minutes, t1 / 2 is about 2 hours; subcutaneous injection is effective for 2 to 4 hours, and t1 / 2 is 3 to 4 hours. For: Treatment of acute deep venous thrombosis: subcutaneous injection of 200U / kg, once a day, the daily dosage does not exceed 18000U. Patients with a higher risk of bleeding can be given 100 U / kg twice a day. Vitamin K antagonist can be taken orally immediately when using this product, and the combined treatment lasts at least 5 days. Prevention of deep vein thrombosis after operation: 2500U is injected subcutaneously 1 to 2 hours before surgery, 2500U is injected 12 hours after surgery, and then 2500U is injected once a day for 5 to 10 days. unstable angina pectoris and non-ST segment elevation myocardial infarction: subcutaneous injection of 120U / kg, 2 times a day, the maximum dose is 10,000U every 12 hours, the medication lasts 5 to 10 days. Continuous concurrent use of low-dose aspirin (70 ~ 165mg / d). Prevention of coagulation during hemodialysis and hemofiltration: chronic renal failure, rapid intravenous injection of 30-40 U / kg without known bleeding risk, followed by intravenous infusion of 10-15 U / kg per hour; acute renal failure has a high risk of bleeding For patients, rapid intravenous injection of 5 to 10 U / kg followed by intravenous infusion of 4 to 5 U / kg per hour. (2) Enoxaparin Sodium (Kexai), Enoxaparin Sodium (CLEXANE), ATC code BO1AB05, molecular weight 3500-5500. The ratio of anti-Xa / IIa activity in vitro was about 4: 1. After subcutaneous injection, the bioavailability is close to 100%, and the tmax is 3 to 5 hours. Metabolized mainly in the liver, the kidneys clear about 10% in their original form, and the total kidney clearance is 40%. For: Treatment of deep venous thrombosis: once daily, 150U / kg subcutaneously, or twice daily, 100U / kg. The course of treatment is usually 10 days, and oral anticoagulant therapy should be started at an appropriate time. Prevention of venous thromboembolic disease: when the surgical patient is at a moderate risk of thrombosis, subcutaneous injection of 2000U or 4000U, once a day, the first injection is given 2 hours before; surgical patients with a high tendency to thrombosis can be treated during surgery Dosing was started in the first 12 hours, once daily, 4000 daily, subcutaneously; for preventive application in medical patients, 4000U once daily, subcutaneously, for 6 to 14 days. Treatment of unstable angina pectoris or non-ST segment elevation myocardial infarction: 100U / kg daily, once every 12 hours, aspirin should be applied at the same time, the general course of treatment is 2-8 days. Prevent thrombosis of extracorporeal circulation of hemodialysis: 100U / kg, given by arterial vascular access at the beginning of dialysis. (3) Natraparin calcium (low-molecular-weight heparin calcium, Subilin, Limaiqing, Bo Xiqing), Nadroparin Calcium (Low-Molecular-Weight Heparins-Calcium, Fraxiparin Calcium), ATC code BO1AB06, average molecular weight is 3600 ~ 5000. The ratio of anti-Xa / IIa activity in vitro was 4: 1. The bioavailability of subcutaneous injection is close to 100%, tmax is 3 hours, and it is eliminated or formed by the kidney with a small amount of metabolism. t1 / 2 is about 3.5 hours. For: Treatment of thromboembolic diseases: subcutaneous injection, each time according to the patient's weight range at a dose of 0.1ml / 10kg, 12 hours apart, the treatment time should not exceed 10 days. Unless contraindicated, oral anticoagulants should be used as soon as possible. Prevention of thromboembolic diseases: subcutaneous injection. For general surgery, 0.3 ml once a day, usually lasting at least 7 days, the first dose should be administered 2 hours before surgery; the dosage for orthopedic surgery should be adjusted according to the patient's weight, once a day for at least 10 days. The drug was given 12 hours before surgery and 12 hours after surgery. prevent coagulation during hemodialysis: injection through a blood vessel. At the beginning of dialysis, a single dose was administered through the arterial end, the weight was <51 kg, 0.3 m each time; the weight was 51 to 70 kg, 0.4 ml each time; the weight was> 70 kg, 0.6 ml each time.

Low molecular weight heparin adverse reactions

Possible adverse reactions are skin mucous membrane, gum bleeding, occasional thrombocytopenia, elevated liver aminotransferase, and skin irritation.

Contraindications to low molecular weight heparin

It is prohibited in patients with severe coagulopathy, bleeding from tissue and organ damage, bacterial endocarditis, acute gastrointestinal and cerebral hemorrhage, and allergic to this product.

Low molecular weight heparin considerations

(1) It should be injected subcutaneously, not intramuscularly. For subcutaneous injection, the injection site is in the subcutaneous tissue of the anterolateral or posterolateral abdominal wall, alternating left and right, and the needle should go vertically into the pinched skin wrinkles. Use the thumb and index finger to pinch the skin wrinkles until the injection is completed. (2) In case of overdose, protamine can be used to antagonize. 1mg protamine sulfate can neutralize 100IU of this product. (3) Those with bleeding tendency should be used with caution in pregnant women and postpartum women. (4) Different low-molecular-weight heparin preparations have different characteristics and are not equivalent. Never use two different products in the same course of treatment. When using, you must comply with the instructions of the respective product's instruction manual.

Low molecular weight heparin drug interactions

(1) Heparin is used in combination with the following drugs to increase the risk of bleeding: coumarin and its derivatives, aspirin and non-steroidal anti-inflammatory analgesics, dipyridamole, dextran, adrenocorticoids, adrenocorticotropic hormones, tissue fibers Lysogen activator, urokinase, streptokinase, etc. (2) Heparin combined with sodium bicarbonate, sodium lactate and other drugs to correct acidosis can promote the anticoagulant effect of heparin. (3) Heparin can interact with insulin receptors, thereby changing the binding and effect of insulin. (4) Cannot be used in combination with alkaline drugs.

Low molecular weight heparin

Injection

Introduction to Low Molecular Weight Heparin Pharmacopeia

[Identification] (1) Take an appropriate amount of this product, add water to make a solution containing about 1000IU per 1ml, add 2ml of 5% hydrochloric acid solution and 0.2ml of 1% indole ethanol solution, heat in a water bath for 5 minutes, it should be orange yellow or orange red. (2) Take this product and measure according to (Attachment 1) and (Attachment 2) titer determination method. The ratio of the anti-Xa factor titer and anti-IIa factor titer ratio shall not be less than 1.5. (3) Identification of calcium salt in aqueous solution of this product (Appendix III of Part Two of Chinese Pharmacopoeia 2005 Edition). [Inspection] Take 0.10g of this product, add 10ml of water to dissolve it, and measure it according to law (Chinese Pharmacopoeia 2005 Edition, Appendix VI H). The pH value should be 5.5 ~ 8.0. The clarity and color of the solution should be taken in the appropriate amount. Add water to make a solution containing about 5000IU per 1ml, and it should be clear and colorless; if color is developed, it should be compared with the yellow colorimetric standard solution 2 (Chinese Pharmacopoeia 2005 Edition Appendix A) The first method) comparison must not be deeper. Take the product absorbance, add water to make a solution containing 4mg per 1ml, and measure according to ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2005 Edition Two Appendix IV A), the absorbance at the wavelength of 260nm shall not be greater than 0.20; at 280nm At the wavelength of, its absorbance shall not be greater than 0.15. Take 0.20g of nitrite, add 10ml of water to dissolve, take 1 drop of the above solution and place it on a white porcelain plate, add 1 ~ 2 drops of p-aminobenzenesulfonic acid-naphthylamine test solution, and it should not show purple red within 30 seconds. Nitrogen is taken from this product and measured according to the nitrogen determination method (Chinese Pharmacopoeia 2005 Edition, Appendix D Second Method). Based on the dry product, the total nitrogen content should be 1.5% to 2.5%. Mole ratio of sulfate ion to carboxylate ion: Take about 0.1g of this product, dissolve by adding 20ml of water, suck 2ml and pass through a cation exchange resin column (about 10cm × 1cm), slowly wash the human titration container with 10 ~ 15ml of water, conduct conductance titration Add about 50 l of sodium hydroxide titration solution (0.05 mol / L) each time until the end point. Draw the curve with the conductivity as the ordinate and the volume of the titrant as the abscissa. Make the best straight lines for the three linear part graphs that suddenly descend, climb slightly, and rise sharply. At the intersections of the first straight line and the second straight line, the second straight line and the third straight line, respectively, make vertical lines to the abscissa, and the foot of the intersection of the first and second straight lines is sodium sulfate consumption of sodium hydroxide The number of milliliters (V1) of the titration solution (0.05mol / L). The foot at the intersection of the second and third straight lines is the number of milliliters of sodium hydroxide titration solution (0.05mol / L) consumed by sulfate and carboxylate. V2), V2-V1 is the number of milliliters of sodium hydroxide titration solution consumed by the carboxylate, and the number of moles of sulfate ion and carboxylate ion is calculated, and the molar ratio must not be less than 1.8. The molecular weight and molecular weight distribution are determined by molecular exclusion chromatography (Chinese Pharmacopoeia 2005 Edition Appendix VH). The weight average molecular weight should be less than 8000, and the fraction with weight average molecular weight less than 8000 should be no less than 60% of the total. Preparation of reference solution The appropriate amount of a reference (Mna: 3700) for low molecular weight heparin molecular weight determination of the European Pharmacopoeia was accurately weighed, and a solution containing 10 mg per 1 ml was prepared using a mobile phase. Preparation of test product solution Take an appropriate amount of this product, add mobile phase and dilute to a solution containing about 10mg per 1ml. Chromatographic conditions and system calibration using hydrophilic bonded silica as a filler [such as TSK G2000SXXL (300mm x 7.8mm) or a corresponding column capable of separating protein with a molecular weight of 15,000 to 100,000]; 2.84% anhydrous sodium sulfate solution (using Dilute sulfuric acid adjusts pH to 5.0) as mobile phase; flow rate is 0.5ml per minute; column temperature is 35 ° C; ultraviolet detector and refractive index detector are connected in series to the outlet of the chromatographic column in order, and accurately measure the two detectors. The delay time is such that the two chromatograms correspond, and the detection wavelength is 234 nm. Take 25l of the reference solution and inject it into the liquid chromatograph. Record the UV and differential chromatograms. The calibration retention time should be the time of the differential detector. From the total peak area of the ultraviolet chromatogram (UV234) and the total peak area of the differential chromatogram (RI) (excluding the salt and solvent peaks from the main peak), calculate the ratio r according to formula (1): then calculate according to formula (2) f value. Calculate the molecular weight Mi of each time point on the differential chromatogram from the correction factor f according to formula (3): r = RI / UV234 (1) f = Mna / r (2) Mi = f × RIi / UV234i (3) In the formula, Mna is the number average molecular weight of the reference substance; RIi and UV234i are the difference and the peak height of the corresponding time in the UV chromatogram, respectively. The retention time was used to systematically correct the molecular weight using GPC software. 25l of the test solution was injected into the liquid chromatograph, and the differential chromatogram was recorded (to ensure that the main peak and the solvent peak can be completely eluted). The weight average molecular weight was calculated according to formula (4): Mw = (RIiMi) / RIi formula The RIi is the mass of the eluted i-fraction, that is, the peak height of the differential chromatogram; Mi The molecular weight of the i-fraction obtained by the calibration system. Loss on drying Take this product, use phosphorus pentoxide as a desiccant, dry under reduced pressure at 60 ° C for 3 hours (pressure does not exceed 670Pa), and lose weight must not exceed 10.0% (Chinese Pharmacopoeia 2005 Edition, Appendix II L). Take this product for heavy metals and inspect it according to law (Appendix H, the second method of the 2005 edition of the Chinese Pharmacopoeia). The content of heavy metals must not exceed 20 parts per million. Take this product for bacterial endotoxin and check it according to law (Appendix E of the Second Part of Chinese Pharmacopoeia 2005 Edition). The amount of endotoxin per 1IU should be less than 0.01EU. [Determination of titer] Take this product and measure it according to the anti-Xa factor titer assay (Appendix 1). [Category] Anticoagulant. [Storage] Sealed and stored in a cool and dark place. ^[1] ^[2] ^[3] ^[4]