The English name of Warfarin is Coumadin, Chinese translation: 华法法, Warfarin. Chemical structure: 3-(a-phenylacetone)-4-hydroxycoumarin. Its mechanism of action one is by inhibiting hepatic epoxide reductase, so that the inactive oxidized (epoxide type) vitamin K (VK) cannot be reduced to the active reduced (hydroquinone type) VK, preventing the circulating application of VK, interfering with the carboxylation of VK-dependent coagulation factors II, VII, IX, X, so that these coagulation factors cannot be activated and only stay in the precursor stage (antigenic, inactive), and achieve the purpose of anticoagulation. and the purpose of anticoagulation is achieved.
Secondly, warfarin inhibits the synthesis of anticoagulant protein C and protein S at the same time as anticoagulation. In layman’s terms, warfarin inhibits the formation of new thrombi by inhibiting the activation of coagulation factors, limits the expansion and extension of thrombi, inhibits the formation of new thrombi on top of thrombi, inhibits the occurrence of thrombus shedding and embolism, and facilitates the body’s fibrinolytic system to clear the formed thrombi. Warfarin itself has no thrombolytic effect. Cheng Delei, Department of Interventional Radiology, Anhui Provincial Hospital
The anticoagulant effect of warfarin does not take effect immediately after oral administration. The antithrombotic effect of warfarin depends on a significant decrease in prothrombin (factor II), which has a half-life of about 72 h. Therefore, it takes at least 3 days for oral warfarin to have a real effect. In the plasma it is mainly bound to albumin. Fetal blood concentrations are close to maternal values, so warfarin should be used with caution in pregnant women. However, warfarin has not been found to be present in human breast milk and therefore does not interfere with breastfeeding. Warfarin is almost completely metabolized by the liver, so there is no need to adjust the warfarin dose in patients with renal insufficiency.
The most critical aspect of warfarin use is the adjustment of the appropriate dose. The dose-response (International Normalized Ratio INR) relationship for warfarin is highly variable and is influenced by many factors and therefore needs to be monitored closely.
According to the theory, warfarin affects the activity of coagulation factors IIa, VIIa, IXa and Xa, which are related to the exogenous coagulation system, so the dose is adjusted by monitoring its effect on the exogenous coagulation system (prothrombin time, PT) after oral administration of warfarin. However, clinically used prothrombin reagents have different sources and the coagulogenic activity of each batch of prothrombin is different, so that even for the same plasma, different PT measured with different reagents cannot be compared and standardized, which does not facilitate clinical diagnosis and dosing monitoring.
Therefore, a standardized PT, or international normalized ratio (INR), is used clinically to adjust the dose of warfarin. The antithrombotic effect of warfarin is dependent on a significant decrease in prothrombin (factor II), which has a half-life of about 72 h. Therefore, it takes at least 3 days for oral warfarin to have a real effect before the original factor II level in the body is significantly reduced. Due to the short half-life of factor VII and protein C (6~8h), the level of factor VII and protein C decreases quickly after the application of warfarin, and the PT (INR) measured at this time mainly reflects the level of plasma factor VII, and the INR at this time cannot reflect the real antithrombotic level in the body.
It is also very important for the first dose and when to stop heparin. Increasing the initial dose of warfarin cannot achieve effective antithrombotic levels quickly because warfarin cannot accelerate the clearance of the already synthesized factor II. A high initial dose can lead to a hypercoagulable state in the initial phase of drug administration due to the reduced synthesis and rapid clearance of protein C and protein S, and even to skin necrosis and other complications.
Acute antithrombotics should be administered first with low-molecular heparin, and the heparinoids should be discontinued only after at least 4 days of crossover between the two (preferably maintaining INR at therapeutic range for more than two days) so that effective antithrombotic levels can be achieved with Warfarin after discontinuation of heparin.
The following are tips and experiences with Warfarin dosing and dose adjustment. A target INR value of 2.0 to 3.0 is preferred for Warfarin use. Older adults older than 75 years and patients at high risk for bleeding should start with 2 to 2.5 mg orally once daily, and the target INR can be maintained at 1.6 to 2.5.
The initial dose of warfarin is generally recommended to be 3 mg, and a larger starting dose is not recommended because a large starting dose means exceeding the maintenance dose for many patients and having to gradually reduce from the large dose to a smaller dose to achieve the target INR, which not only increases the risk but also increases the difficulty of dose adjustment and forces the INR to be measured daily. the initial shock dose is also not recommended, as it may cause a decrease in protein C activity This not only increases the risk but also makes it more difficult to adjust the dose and forces daily INR measurements.
If the INR is below 1.5 at this time, the dose should be increased by 0.5 mg/d; if the INR is above 1.5, the dose can be temporarily not increased and wait for the results of INR measurement after 7 days; if the INR does not change significantly compared to the basal level, the dose can be increased by 1 mg/d. Experience has shown that the starting dose of 2 mg is too small and increases the time required to reach the standard and increases the measurement time. time needed to reach the target and increase the number of INR measurements, which can increase the psychological burden and financial burden on the patient.
If the INR is too high or too low, or if the dose of Warfarin is changed for any reason, the next dose of Warfarin should be determined according to the INR and dose adjustment. If the INR is too high or low, or if the dose of Warfarin is changed for some reason, the time of the next INR observation should be determined according to the INR value and dose adjustment.
Dose adjustment should be based on the INR value, with each increase or decrease of 0.5 to 1 mg/d. Before each dose adjustment, the reason for the change in INR should be carefully searched for, and the INR value measured in a previous period should be referred to.
If the INR has been stable in the past and there is an occasional increase in INR, as long as the INR does not exceed 3.5~4.0, the dose can be temporarily not adjusted and the INR should be checked again in 3~7 days. the INR measurement should not be too diligent either.
There are many factors that affect INR, including travel, diet, environment, physical condition, having other diseases and medication use, all of which can cause changes in INR. Therefore, in order to ensure the safety and effectiveness of medication use, it is important to provide guidance on the patient’s life and medication use. If the patient has cognitive problems, medication administration must be in the hands of a nearby guardian or caregiver, and the wrong medication should be avoided.
When factors affecting medication response are present, such as aspirin in patients with colds, discontinuation of medication for any reason, or irregular dosing, additional INRs should be done several times so that the medication dose can be adjusted in a timely manner to maintain the INR within the target range for treatment.
Certain drugs can affect the pharmacokinetics of warfarin by inhibiting VK-dependent coagulation factor synthesis, increasing metabolic clearance, and interfering with other hemostatic pathways.
These drugs are.
(i) Broad-spectrum antibiotics: Inhibit intestinal flora, decrease vitamin K levels in the body, and enhance the efficacy of oral anticoagulant drugs;
(ii) Anti-platelet drugs such as aspirin: can have synergistic effects with oral anticoagulants, with increased bleeding side effects;
(iii) chloral hydrate, hydroxyproteasone, methylsulfonylurea, quinidine, etc. can increase the concentration of plasma warfarin due to the replacement of plasma proteins and enhance the effect;
(iv) Salicylate, promethazine, metronidazole, cimetidine, etc. can enhance the effect of oral anticoagulants by inhibiting hepatic enzymes and reducing the hepatic metabolism of warfarin;
(v) Barbiturates, phenytoin sodium, carbamazepine, rifampicin, etc. increase the metabolism of warfarin due to induction of hepatic enzymes, which diminishes its effect;
(vi) Oral contraceptive drugs may increase the coagulation activity and weaken the effect of Warfarin.
Fluctuations in the intake and absorption of VK in food affect the efficacy of warfarin. Hepatic insufficiency impairs the synthesis of VK-dependent coagulation factors and enhances the response to warfarin. Hypermetabolic states, such as hyperthyroidism, increase the metabolism of clotting factors and enhance the efficacy of warfarin. Vitamin K is able to antagonize the anticoagulant effect of warfarin, thereby reducing the anticoagulant effect.
In order to maintain the stable anticoagulant strength of warfarin, it is necessary for the patient to maintain a relatively balanced diet, especially a relatively balanced intake of VK-rich green vegetables. Examples of drug effects on warfarin are as follows: clearance of the racemic isomer R is slightly lower in the elderly than in the young, while clearance of the isomer S is not affected by age. The anticoagulant response to warfarin in older adults than 60 years of age is stronger than that shown by PT/INR, and appropriate dose reduction can produce the same anticoagulant effect.
The application of warfarin should be strictly indicated, possible contraindications should be excluded and aspirin should be discontinued in most cases. The patient’s age, physical condition, medical history, treatment and medication history, and lifestyle should be understood, especially if there is a history of hematologic or bleeding disorders, especially if there are risk factors for bleeding, such as uncontrolled hypertension, previous history of traumatic brain injury or cerebral hemorrhage, and recent active ulcer disease. Routine blood tests, urine and stool tests and occult blood tests should be performed prior to drug administration, and other relevant tests such as brain CT and gastroscopy should be performed if necessary.
Although warfarin is safe when used properly, it is best not to use it until the physician has mastered its use, especially in places where INR monitoring is not available. Fixed small doses of unmonitored use of warfarin, which has been shown in foreign studies to be less effective in anticoagulation, do not reduce the risk of bleeding.
How to deal with increased INR or bleeding conditions?
The following method is for reference: It has been observed that a moderately elevated INR (4.0-10.0), 1.0-2.5 mg of vitamin K1 orally, can bring down the elevated INR rapidly within 24 hours.
1. If INR is greater than the target value but less than 5.0, there is no bleeding, and there is no need for rapid recovery of INR (e.g. surgery), then the dose can be reduced or discontinued only once, and the dose is reduced and applied after the INR has recovered the target value; mildly elevated INR does not even need to be reduced.
2. If the INR is above 5.0 and less than 9.0 without significant bleeding, there are two ways to deal with it: one way is to stop warfarin 1~2 times if there are no other risk factors causing bleeding, and after the INR is restored to the target value, re-dose the dose orally; if the patient has other risk factors for bleeding, he should stop warfarin once while taking vitamin K1 1~2.5mg orally; if it is necessary to rapid reversal of INR, such as surgery or tooth extraction, vitamin K1 2~4mg can be given orally with a view to bringing down INR significantly within 24 hours, and if it is still high, vitamin K1 1~2mg can be given orally again.
3. If the INR exceeds 9.0 and there is no clinical bleeding, a high dose of vitamin K1 3~5mg should be given orally with a view to bringing down the INR significantly within 24~48 hours, and the oral vitamin K1 can be repeated if needed; if the INR needs to be reversed quickly or there is severe bleeding or the INR exceeds 20, then vitamin K1 10mg should be given intravenously with appropriate supplementation of fresh plasma or plasminogen concentrate, and vitamin K1 IV can be repeated every 12 hours. After stopping warfarin (INR 2.0~3.0), it takes about 4 days for INR to return to normal levels.
Although warfarin is the most widely used anticoagulant, its use is still considered contraindicated in the following situations.
(1) Pregnancy Warfarin can cause fetal neurodevelopmental malformations and hemorrhage and is generally contraindicated in women who are pregnant or may become pregnant. If it is indeed necessary, the application of warfarin to such patients should be carefully weighed in accordance with the needs of the condition and the actual situation of the patient. Warfarin is generally used within 6 weeks of early pregnancy with relatively little effect on the fetus, and is contraindicated from 6 to 12 weeks. If anticoagulation is necessary, it should be changed to heparin or low molecular heparin, and warfarin can be used after 12 weeks.
(2) Recent or intended surgery on: 1. central nervous system 2. eye surgery 3. major traumatic surgery
(3) Bleeding or bleeding tendency 1. gastrointestinal, genitourinary and respiratory 2. hematologic disorders 3. retinal disorders 4. cerebral hemorrhage 5. intracranial aneurysm 6. aortic aneurysm or aortic coarctation 7. pericardial effusion 8. bacterial endocarditis
(4) Pre-eclampsia, pre-eclampsia and eclampsia
(5) Lack of PT/INR monitoring equipment
(6) Unsupervised elderly, alcoholism, psychosis, and patient noncooperation
(7) Frequent syncope or epilepsy that is not easily controlled, frequent falls or unsteady gait, and susceptibility to trauma
(8) Lumbar puncture, other medical operations where bleeding is not easily controlled
(9)severe hypertension or uncontrollable blood pressure
(10) Allergic to warfarin or other bicoumarins
(11) Engaged in intense collision sports or work environment