What Is Warfarin?

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

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 X, thereby exerting anticoagulant effect. The carboxylase in the liver mitochondria can convert the glutamate of the above-mentioned coagulation factors into -carboxyglutamic acid, which can then combine with calcium ions to exert its coagulation activity. The role of this drug is to inhibit carboxylase, and has no direct counteracting effect on the above factors that have been synthesized. You must wait for these factors to be exhausted in the body before they can exert anticoagulant effects. Therefore, this drug works slowly and is only effective in the body. The effect lasts longer after stopping the drug (the anticoagulant effect does not disappear until the vitamin K-dependent factor gradually returns to a certain concentration). In addition, the drug can still induce the liver to produce vitamin K-dependent coagulation factor precursor material and release it into the blood. The substance has the same antigenicity as related coagulation factors, but does not have coagulation function, but has anticoagulant effect. Can reduce thrombin-induced platelet aggregation response. Therefore, under the action of this drug, the synthesis of coagulation factors II, , , X, protein S, and protein C is reduced, and the "false coagulation factor", that is, the "vitamin K antagonist-induced protein" is increased, achieving an anticoagulant effect. The pharmacokinetic parameters of this medicine are relatively stable, and are superior to other oral anticoagulants (such as anisindione, phenprolactam and dicoumarin, etc.). Only when patients are intolerant to this drug, other oral anticoagulants should be used. In the prevention of stroke in patients with non-rheumatic atrial fibrillation, the efficacy of this drug is significantly better than aspirin. In the treatment or prevention of thrombosis or embolism in pregnant patients, subcutaneous or intravenous heparin is more effective than this drug (due to the large molecular weight of heparin, it is not easy to affect the fetus through the placenta).

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 Large blood drug concentration. The half-life of racemic warfarin is 36 to 42 hours, which circulates in the body by binding to plasma proteins (mainly albumin). Warfarin is almost completely eliminated by liver metabolism, and metabolites have a weak anticoagulant effect. It is excreted mainly through the kidney, rarely into the bile, and only a very small amount of warfarin is excreted from the urine in its original form, so patients with renal insufficiency do not have to adjust the dose of warfarin. Warfarin can pass through the placenta, and the fetal blood concentration is close to the maternal value, but no warfarin is found in human milk.

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 , And further inhibit the gamma-carboxylation of vitamin K-dependent coagulation factors. In addition, vitamin K antagonists can inhibit the carboxylation of anticoagulin C and S.

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 It is suitable for the prevention and treatment of thromboembolic diseases. It is only effective when taken orally, and its effect is slow and long-lasting. Only those who need to maintain anticoagulation for a long time should choose this product. When rapid anticoagulation is needed, heparin should be used, or it should be added on the basis of heparin treatment.

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 Oral 0.5-20mg on the first day, with the maintenance amount starting from the next day, 2.5-7.5mg daily.

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 response to this product varies with patients, and the dosage must be individualized. Adjust the dosage according to the prothrombin time. Generally maintain 1.5-2.5 times the normal control value. Because this product acts indirectly as an anticoagulant and has a long half-life, the effect can be stabilized after 5-7 days of administration. It is necessary to observe the 5-7 days to determine whether the amount is sufficient. When the prothrombin time has been significantly prolonged to more than 2.5 times normal, or a small tendency to bleeding occurs, it should be reduced or discontinued immediately. For severe hemorrhage, 2.5-20mg of vitamin K1 can be injected intravenously. The dosage is based on the ability to control bleeding. If necessary, frozen plasma sediment, whole blood, plasma or prothrombin complex can be given.

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 Missed. The main adverse reaction is bleeding, the most common being epistaxis, bleeding gums, skin bruising, hematuria, uterine bleeding, blood in the stool, bleeding from wounds and ulcers. The prothrombin time should be measured regularly during the medication and should be maintained at 25-30 seconds. The prothrombin activity should be at least 25% to 40% of the normal value. The above two indicators cannot be replaced with clotting time or bleeding time. When there are no conditions for measuring prothrombin time or prothrombin activity, do not use this product casually, to prevent excessive prothrombinemia and bleeding. When the prothrombin time exceeds 2.5 times the normal value (the normal value is 12 seconds), the prothrombin activity drops below 15% of the normal value, or bleeding occurs, the drug should be stopped immediately. In severe cases, vitamin K can be used orally (4-20mg) or slowly intravenously (10-20mg). The prothrombin time can be restored to a safe level 6 hours after administration. If necessary, fresh whole blood, plasma, or prothrombin complex can also be administered.

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 Aspirin, salicylic acid, prostaglandin synthase inhibitor, chlorpromazine, diphenhydramine, etc .; In addition, anticoagulant drugs include propylthiouracil, diazoxide, propyl Disopyramide, oral hypoglycemic agents, sulpyridone (anti-gout drugs), etc., the mechanism is not clear; Adrenocortical hormone and phenytoin can increase, but also weaken the anticoagulant effect, which may cause gastrointestinal tract The risk of bleeding is generally not suitable; can not be combined with streptokinase and urokinase, otherwise it may lead to severe bleeding.

(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 Activated factor X (factor Xa) activates prothrombin (factor II) into thrombin (factor IIa), while the factor III / VIIa complex also activates factor IX, which magnifies the coagulation waterfall response.

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.