What Is the Connection Between Warfarin and Vitamin K?
This product is a type of coumarin anticoagulant, which has an anti-vitamin K effect in the body. Can inhibit vitamin K involved in the synthesis of coagulation factor , , , X in the liver. It has no resistance to the existing coagulation factors , , , in the blood. Therefore, it cannot be used as an anticoagulant in vitro, and anticoagulant in vivo must be consumed after active coagulation factors are consumed, and the effect and maintenance time are longer after onset. It is mainly used to prevent and treat thromboembolic diseases.
- Drug Name
- Warfarin
- Drug alias
- Benzylacetone coumarin sodium, warfarin sodium
- English name
- Warfarin
- Drug description
- Injection: 50mg, 75mg
- This product is a type of coumarin anticoagulant, which has an anti-vitamin K effect in the body. Can inhibit vitamin K involved in the synthesis of coagulation factor , , , X in the liver. It has no resistance to the existing coagulation factors , , , in the blood. Therefore, it cannot be used as an anticoagulant in vitro, and anticoagulant in vivo must be consumed after active coagulation factors are consumed, and the effect and maintenance time are longer after onset. It is mainly used to prevent and treat thromboembolic diseases.
Warfarin Basic Information
- Chinese name Warfarin
- Chinese alias: warfarin; farwarin; rodentin; rodentin; 4-hydroxy-3- (3-oxo-1-phenylbutyl) -2H-1-benzopyran-2-one
- English name: Warfarin
- English alias: warfarin; 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; Unifyl; accurb; austyn;
- 4-hydroxy-3- (3-oxo-1-phenylbutyl) -2H-1-benzopyran-2-one; Elixex; Nuelin; X 115; zocoumarin; duraphy;
- 4-hydroxy-3-[(1RS) -3-oxo-1-phenylbutyl] coumarin; Slo-PhyllinTM; (RS) -3- (-acetonylbenzyl) -4-hydroxycoumarin;
- unidur; 1,3-dimethylxanthine; rac-4-hydroxy-3-[(1R) -3-oxo-1-phenylbutyl] -2H-1-benzopyran-2-one;
- 2H-1-Benzopyran-2-one, 4-hydroxy-3- (3-oxo-1-phenylbutyl)-; asmax
- CAS number: 81-81-2
- Molecular formula: C 19 H 16 O 4
- Exact mass: 308.10500
- PSA: 67.51000
- LogP: 3.60960 [1]
- Structural formula:
Warfarin physical and chemical properties
- Appearance and properties: white to off-white crystalline powder
- Density: 1.307 g / cm 3
- Melting point: 162-164 ° C (lit.)
- Boiling point: 356 ° C
- Flash point: 188.8ºC
- Storage conditions: storeroom is ventilated, low temperature and dry, and stored separately from food materials
Warfarin safety information
- Packing level: I
- Hazard category: 6.1 (a)
- Dangerous Goods Transport Code: UN 2811 6.1 / PG 1
- WGK Germany: 3
- Danger category code: R61; R48 / 25; R52 / 53
- Safety instructions: S53-S45-S61-S52
- RTECS number: GN4550000
- Dangerous goods mark: T [1]
Warfarin pharmacological action
- This drug is an indirect coumarin oral anticoagulant, which inhibits vitamin K to synthesize coagulation factors II, , , ,
- Warfarin
Warfarin Pharmacokinetics
- Warfarin is a racemic mixture consisting of two optically active isomers, R and S, in equal proportions. It is rapidly absorbed through the digestive tract and has high bioavailability. It is administered orally by healthy volunteers. You can reach the maximum in the body within 90 minutes after the medicine
- Warfarin
- The dose-response (international normalized ratio) relationship of warfarin varies widely and is affected by many factors, so it needs to be closely monitored. The dose-response relationship of warfarin is affected by genetic and environmental factors, including mutations in the cytochrome P450 gene locus, and the activity of liver enzymes on the oxidative metabolism of warfarin S-type isomers. Compared with the wild-type enzyme CYP2C9, gene polymorphisms of liver enzymes have been thought to be associated with a higher incidence of bleeding complications caused by low-dose warfarin.
Warfarin mechanism
- Warfarin is a biscoumarin derivative with a chemical structure of 3- (a-phenylacetone) -4-hydroxycoumarin. There is no anticoagulant effect in the test tube, that is, it does not participate in in vitro anticoagulation. It mainly inhibits the synthesis of vitamin K-dependent coagulation factors , , , and X in the liver microparticles, but the effect occurs slowly, and the maximum effect is 3-5 days. Within. Vitamin K can promote the carboxylation of amino-terminal glutamic acid of vitamin K-dependent coagulation factors , , , and X to -carboxyglutamic acid. Carboxylation can promote the binding of vitamin K-dependent coagulation factors to the surface of phospholipids. Can accelerate blood clotting. Gamma-carboxylation requires the participation of reduced vitamin K (vitamin KH2). Dicoumarin blocks vitamin KH2 production by inhibiting vitamin K epoxide reductase activity
- Warfarin molecule
- The anticoagulant effect of warfarin can be antagonized by small doses of vitamin K1 (phytonadione). Large doses of vitamin K1 (usually greater than 5 mg) can resist the effects of warfarin for more than a week, because vitamin K1 accumulated in the liver can Reduced by vitamin K epoxide reductase by bypass.
- Warfarin can also interfere with the carboxylation of gamma-carboxyglutamate proteins synthesized in bone. Warfarin treatment in pregnant women can cause severe skeletal abnormalities in the fetus, but there is no evidence that warfarin administration in adults or children directly affects bone metabolism.
- Warfarin inhibits the formation of new thrombus by inhibiting the activation of coagulation factors, limits the expansion and extension of thrombus, inhibits the formation of new thrombus based on the thrombus, inhibits the occurrence of thrombus shedding and embolism, and facilitates the body's fibrinolytic system to clear the formation Blood clots. Warfarin has no thrombolytic (thrombolytic) effect. The use of warfarin to reduce or even disappear thrombus is the result of the mechanism (fibrinolysis) of the body's elimination of thrombus while inhibiting new thrombosis.
Warfarin adaptation symptoms
- Warfarin pills
- 1. Prevention and treatment of thromboembolic diseases can prevent thrombosis and development, such as the treatment of thromboembolic phlebitis, reduce the incidence and mortality of pulmonary embolism, reduce major surgical operations, rheumatic heart disease, hip fixation, artificial replacement Incidence of venous thrombosis in heart valve surgery, etc.
- 2. Adjuvant medication for myocardial infarction.
Warfarin dosage
- Warfarin pills
- Usual dose for adults: 10mg daily for 3 days. The prothrombin activity in the first 1-2 days mainly reflected the disappearance of short-lived factor , and the anticoagulant effect was unstable at this time. After about 3 days, factors II, IX, and X are exhausted to fully display the anticoagulant effect. Prothrombin time also more accurately reflects the reduction in vitamin K-dependent coagulation factors, which can be used to determine maintenance.
- Pediatric commonly used amount: should be based on individual needs.
- Medication for pregnant and lactating women:
- 1. Easy to pass through the placenta and cause teratogenicity. The use of this product during pregnancy can cause "fetal warfarin syndrome" with an incidence rate of 5-30%. Presented as epiphyseal separation, nasal hypoplasia, optic nerve atrophy, mental retardation, heart, liver, spleen, gastrointestinal tract, head and other deformities. Application in late pregnancy can cause bleeding and stillbirth, so this product is contraindicated in the first 3 months of pregnancy and in the third month of pregnancy. Pregnant women with hereditary thromboembolism can be given a small dose of heparin when receiving this product and undergo strict experimental monitoring.
- 2. A small amount of warfarin can be secreted by milk. Breastfeeding women take 5-10mg daily. The blood drug concentration is generally 0.48-1.8 g / ml. The drug concentration in milk and infant plasma is extremely low, which has little effect on infants.
Warfarin banned with caution
- (1) This product can easily pass through the placenta and cause teratology and central nervous system abnormalities. Abortion or stillbirth rates are as high as 16-17%. Application in the third trimester of pregnancy can cause maternal and fetal bleeding and stillbirth. Therefore, this product is disabled during pregnancy. Anticoagulation therapy can be given in small doses of heparin.
- (2) Appropriate reduction in elderly consumption.
- (3) The contraindications are the same as those of dicoumarin, in particular for patients with liver and kidney insufficiency, severe hypertension and bleeding tendency.
- Patients with bleeding tendency, hemophilia, thrombocytopenic purpura, severe liver and kidney disease, active peptic ulcer, brain, spinal cord and ophthalmic surgery are contraindicated. Cachexia, weakness, fever, chronic alcoholism, active tuberculosis, congestive heart failure, severe hypertension, subacute bacterial endocarditis, menstruation, threatened abortion, etc. are used with caution.
Warfarin administration instructions
- Strictly grasp the indications. Do not abuse this product without the conditions of prothrombin measurement. Do not
- Warfarin pills
- The individual differences of this product are obvious. Excessive bleeding may cause excessive bleeding. During the treatment, oral mucosa, nasal cavity, and subcutaneous bleeding should be closely observed to reduce unnecessary surgical operations and avoid excessive fatigue and injury-prone activities. The prothrombin time, fecal occult blood and urinary occult blood should be followed during the course of treatment. During the long-term application of the minimum maintenance amount, if surgery is needed, vitamin K1 50mg can be injected intravenously, but the drug should be discontinued before the central nervous system and ophthalmic surgery. After gastrointestinal surgery, fecal occult blood should be checked.
Warfarin adverse reactions
- Consistent with oral anticoagulants, overdose is likely to cause bleeding. There may be early ecchymosis, purpura, bleeding gums, epistaxis, wound bleeding, permanent bleeding, and more menstruation. Bleeding can occur anywhere, especially the urinary and digestive tracts. Intestinal wall hematoma can cause subacute intestinal obstruction, and is also found in subdural and intracranial. Any puncture can cause hematoma, and severe local compression symptoms are obvious in severe cases. Uncommon adverse reactions include nausea, vomiting, diarrhea, itchy rash, allergic reactions, and skin necrosis. A large amount of oral administration has even been reported for bilateral breast necrosis, microangiopathies or hemolytic anemia, and large-scale skin gangrene; it is particularly dangerous when the dose is too large.
- Can cause bleeding, hematuria, ecchymosis, blood in the stool, etc. Can cause liver and kidney damage, symptoms disappear after withdrawal
- Warfarin pills
Warfarin interaction
- (1) Drugs that can enhance anticoagulant effect when used in combination with this product include: Stronger affinity with plasma proteins than this product, and the competition results in increased free biscoumaryl ethyl esters, such as aspirin, butytaxel, hydroxybutyrol, Mefenamic acid, chloral hydrate, clobetyl (amtoxamine), sulfa drugs, probenecid, etc .; Inhibit liver microsomal enzymes, reduce the metabolism of this product and increase efficiency, such as chloramphenicol, allopurin Alcohols, monoamine oxidase inhibitors, metronidazole (metridin), cimetidine, etc .; drugs that reduce absorption of vitamin K and affect prothrombin synthesis, such as various broad-spectrum antibiotics, long-term use of liquid paraffin, or test Enamines (cholestyramine), etc .; drugs that can promote the binding of this product to the receptor, such as quinidine, thyroxine, anabolic hormones, phenformin; drugs that interfere with platelet function and promote more obvious anticoagulation, Such as high doses
- Warfarin pills
- (2) Drugs that can reduce the anticoagulant effect when used in combination with this product: Inhibit the absorption of oral anticoagulants, including antacids, laxatives, griseofulvin, rifampicin, and glummit (hypnotic) , Meprobamate (anning), etc .; Vitamin K, oral contraceptives and estrogen, etc., compete for related enzyme proteins and promote the synthesis of factors , , , X.
Warfarin considerations
- Overdose can easily cause bleeding. Contraindications are the same as heparin. Disable pregnant women.
- Warfarin can penetrate the placental barrier and cause fetal bone retardation.
- In the following cases, the drug should be stopped first and the hospital should be treated immediately
- 1. More bleeding while brushing or after cutting
- 2. Unexplained bruising and expansion
- 3. Coughing up blood, vomiting blood, hematuria, bloody or black stools
- 4. Severe headache, stomach pain
- 5. Excessive menstrual flow during women's physiological period
- 6. If a woman has a pregnancy plan, first inform the doctor
- 7. Patients with bleeding tendency (such as hemophilia, thrombocytopenic purpura) within 3 days after surgery, late pregnancy, lactation, severe liver and kidney disease, active peptic ulcer, patients with brain, spinal cord and ophthalmic surgery are prohibited.
- 8. Caution should be used in the following cases: cachexia, weakness, fever, chronic alcoholism, active tuberculosis, congestive heart failure, severe hypertension, subacute bacterial endocarditis, menstruation, threatened abortion, etc.
- 9. During the long-term application of the minimum maintenance amount, if surgery is required, vitamin K1150mg can be injected intravenously, but the drug should be discontinued before the central nervous system and ophthalmic surgery. After gastrointestinal surgery, fecal occult blood should be checked.
Warfarin clinical monitoring
- The advantage of this product is that it is effective orally and has a long acting time. The disadvantage is that the effect is slow, the effect is too long, and it is not easy to control. For those who need rapid anticoagulation, heparin should be used for treatment before warfarin is used to maintain the effect. Warfarin combined with antiplatelet drugs can reduce the incidence of venous thromboembolism in major surgery, rheumatic heart disease, and prosthetic valve replacement. The prothrombin time must be measured during the medication, and it is generally better to control it within 25-30 seconds. Tissue factor (factor III) released from injury combines with factor VII to form a complex activating factor X,
- Warfarin pills
- Warfarin affects the activity of coagulation factors IIa, VIIa, IXa, and Xa related to the exogenous coagulation system, so it is adjusted by monitoring its effect on the exogenous coagulation system (prothrombin time, PT) after oral warfarin dose. The determination of PT is to add exogenous thromboplastin to the plasma, activate the exogenous coagulation system in vitro, and calculate the time that the plasma coagulates. The longer the PT, the more obvious the degree of inhibition of coagulation factors.
- There are different sources of thromboplastin reagents used clinically, and the coagulant activity of thromboplastin in each batch is different, so even if the same plasma has different PTs measured with different reagents, it can not be compared and standardized. Not convenient for clinical diagnosis and medication monitoring. The standardized PT, the International Normalized Ratio (INR), is used clinically to adjust the dose of warfarin. INR = PTR ISI , where ISI is the international sensitivity index and represents the procoagulant activity (sensitivity) of thromboplastin; PTR is the ratio of the subject's PT to normal plasma PT. Although the PT measured by different reagents in the same plasma is different, the results are the same when using INR. In principle, the closer the ISI is to 1, the better.