Warfarin

Warfarin is an indirect anticoagulant that reduces the risk of blood clots.

Indications Warfarin

It is used for the prevention of development or treatment of existing thromboses of any location:

• DVT (also proximal type), cerebral vascular thrombosis, and pulmonary embolism;
• development of thromboembolic complications in the case of blood vessel transplantation or implantation of artificial valves into the body;
• various lesions of the heart valves;
• atrial fibrillation;
• prevention of secondary type in myocardial infarction or in case of development of thromboembolic type complications after its occurrence;
• prevention of thrombosis after surgery.

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Release form

It is released in tablet form.

Warfarin nicomed - in tablets of 2.5 mg. Inside the plastic bottle there are 50 or 100 tablets. In the package - 1 bottle with tablets.

Warfarin Orion - the bottle contains 30 or 100 tablets. In a separate box - 1 bottle.

Warfarin-FS is available in 10 tablets per blister. A separate pack contains 1, 3 or 10 blister packs.

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Pharmacodynamics

Warfarin (4-hydroxycoumarin) is an indirect anticoagulant that inhibits vitamin K-dependent binding of coagulation factors 2, 7, 9, and 10, as well as proteins C and S. This occurs through dose-dependent inhibition of the C1 subunit of K-epoxide reductase, resulting in decreased K1-epoxide production.

Half-life of blood coagulation factors:

• for factor 2, this figure is 60 hours;
• for factor 7 – approximately 4-6 hours;
• for factor 9 it is 24 hours;
• for factor 10 – within 48-72 hours.

The half-life of proteins of type C and S is approximately 8 and 30 hours, respectively. As a result, in vivo tests result in a sequential suppression of the activity of factors 7, 9, as well as 10 and II.

Vitamin K is an important cofactor in the processes of postribosomal binding of blood coagulation factors dependent on it (vitamin). The substance helps in the processes of binding of γ-carboxyglutamic acid residues within proteins required for the development of bioactivity.

Warfarin affects the binding of blood coagulation factors by slowing down the regeneration processes of vitamin K1 epoxide. The strength of the suppression depends on the size of the dose used. Medicinal dosages of the substance reduce the total amount of active types of each of the factors of the blood coagulation system of vitamin K, produced by the liver - by approximately 30-50%.

The anticoagulant effect develops 24 hours after taking the drug. But the drug reaches its maximum effectiveness after 72-96 hours. The duration of action with a single use of the racemate mixture of the substance warfarin is within 2-5 days. The effect of the component increases after daily use of the drug.

It should also be noted that anticoagulants do not have a direct effect on an already formed thrombus, and also cannot restore tissues affected by ischemia. If a thrombus has already formed, anticoagulant treatment will consist of preventing an increase in the size of the thrombus and the development of thromboembolic complications, which can provoke serious disorders, including death.

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Pharmacokinetics

Warfarin is a combination of R- and S-enantiomers. The human S-enantiomer is more active than the R-enantiomer (2-5 times), but the half-life of the latter is longer.

After oral administration, the substance is almost completely absorbed from the gastrointestinal tract, reaching a peak level during the first 4 hours.

There are no significant differences in the distribution volume values for intravenous injection and oral administration. The distribution level is quite low – approximately 0.14 l/kg. The distribution phase is 6-12 hours. The substance can penetrate the placental barrier, reaching values that are close to the concentration level in the mother, but it is not observed in breast milk. About 99% of the drug is synthesized with plasma protein.

The excretion of the substance occurs in the form of inactive decay products. The drug is stereoselectively metabolized by microsomal liver enzymes (hemoprotein type P-450), turning into inactive hydroxylated decay products (mainly), as well as reductases (this method forms warfarin alcohols). The latter have a weak anticoagulant effect.

The breakdown products of the active ingredient are excreted mainly through the kidneys, and a small part of them – with bile. The detected breakdown products of the substance: dehydrowarfarin with two alcohol diastereoisomers, and also 4'-, 6- and 7-, as well as 8- and 10-hydroxywarfarin. The participants in the exchange processes are the following isoenzymes: 2C9 and 2C19 with 2C8, and also 2C18 with 1A2 and 3A4. Isoenzyme 2C9 should most likely be considered the leading type of hemoprotein P-450 in the human liver, responsible for the anticoagulant effect of the substance in vivo.

The terminal half-life of warfarin after a single dose is about 1 week, but the actual half-life ranges from 20-60 hours (average 40 hours). The clearance rate of R-warfarin is half that of S-warfarin, but because their distribution volumes are similar, the half-life of the R-enantiomer is longer than that of the S-enantiomer. The half-life of the R-enantiomer is about 37-89 hours, while that of the S-enantiomer is within 21-43 hours.

Tests using radioactively labeled warfarin have shown that more than 92% of the drug ingested is recovered in the urine. Only a small portion of the drug is excreted unchanged; excretion occurs primarily in the form of breakdown products.

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Dosing and administration

The medicine is taken once a day at the same time of day. The duration of therapy is prescribed by the doctor, taking into account the INR indicators. People who have not previously taken the medicine are prescribed an initial daily dosage of 5 mg for the first 4 days. From the 5th day, the treatment switches to taking a dosage of 2.5-7.5 mg per day (a more accurate figure depends on the patient's condition and indicators).

For people who have previously taken Warfarin, the required initial dosage is equal to the double maintenance dose (in this format, the drug is taken for 2 days, after which treatment is continued with the above maintenance dosage). From the 5th day of therapy, dosages are adjusted taking into account the INR values.

The initial daily dose for children is 0.1-0.2 mg/kg, taking into account liver function. The maintenance dose is selected in accordance with the INR level.

Elderly people need to be treated under close supervision of a doctor (because they are more likely to experience side effects).

During therapy of individuals suffering from functional liver disorders, it is necessary to constantly monitor INR values.

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Use Warfarin during pregnancy

Pregnant women are prohibited from using Warfarin. The active component can pass through the placenta and provoke the development of bleeding in the fetus. There are reports of developmental disorders, as well as congenital defects in children whose mothers used the drug during pregnancy. It is necessary to carefully weigh the risk of using the drug in women of reproductive age. They must be warned about the need to use effective contraceptives.

There is data on the penetration of the substance into mother's milk, but these quantities are very small and therefore often do not affect blood clotting in infants. Although in the case of using Warfarin during lactation, it is necessary to determine the INR indicator in the child. When taking the drug in large doses, breastfeeding should be abandoned.

Contraindications

Among the contraindications:

• intolerance to the components of the drug;
• presence of acute bleeding;
• severely elevated blood pressure;
• cerebral hemorrhage;
• presence of thrombocytopenia;
• liver or kidney pathologies;
• high risk of bleeding (cerebral hemorrhage, gastric ulcer or duodenal ulcer, bacterial endocarditis and severe injuries).

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Side effects Warfarin

The following side effects may occur as a result of using the medicine:

• the appearance of bleeding and hemorrhages;
• development of anemia or eosinophilia;
• increased activity of liver elements, abdominal pain with vomiting, diarrhea and nausea;
• rashes, vasculitis, skin necrosis and itching, as well as alopecia and eczema;
• development of urolithiasis or nephritis.

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Overdose

Overdose may cause microhematuria or bleeding gums.

In case of mild disorders, it will be enough to reduce the dosage of the drug or cancel it for a short period of time. In case of severe bleeding, intravenous administration of vitamin type K and blood clotting factors is required.

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Interactions with other drugs

Many drugs can interact with warfarin (including salicylates and broad-spectrum antibiotics, as well as clofibrate and phenytoin, as well as NSAIDs and oral hypoglycemic drugs).

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Storage conditions

Warfarin must be kept under standard conditions, at temperatures no higher than 25°C.

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Shelf life

Warfarin can be used for a period of 5 years from the date of manufacture of the drug.

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