Warfarin

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

Indications of the warfarin

It is used to prevent the development or therapy of existing thromboses of any location:

• DVT (also proximal), thrombosis of cerebral vessels, as well as PE;
• development of thromboembolic complications in the case of performing blood vessel transplantation or implanting artificial valves inside the body;
• various damages to the heart valves;
• atrial fibrillation;
• prevention of secondary type with myocardial infarction or in the case of development of complications of thromboembolic type after its transfer;
• prevention of thrombosis after surgery.

[1], [2], [3]

Release form

The release is carried out in tablet form.

Warfarin nycomed is in tablets with a volume of 2.5 mg. Inside the plastic bottle contains 50 or 100 tablets. In the package - 1 bottle with tablets.

Warfarin orion - inside the vial contains 30 or 100 tablets. In a separate box - 1 bottle.

Warfarin-fs is produced on 10 tablets inside the blister plate. A single pack contains 1, 3 or 10 blister packs.

[4], [5], [6], [7], [8], [9], [10], [11]

Pharmacodynamics

Warfarin (substance 4-hydroxycoumarin) is an indirect anticoagulant that prevents the type-II vitamin-dependent binding of type 2, 7, 9, and 10, and also type C and S. Proteins. This occurs through a dose-dependent slowing down of C1 -subunit of K-epoxy-reductase, as a result of which the production of K1-epoxide decreases.

The half-life of the factors of blood coagulation:

• factor 2 - this indicator is 60 hours;
• factor 7 - about 4-6 hours;
• Factor 9 - is 24 hours;
• at the factor 10 - within the limits of 48-72 hours.

The half-life of type C proteins, and also S is approximately 8 and 30 hours, respectively. Consequently, in vivo tests, the active activity of factors 7, 9 is sequentially suppressed, and also 10 and P.

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

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

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

It should also be noted that anticoagulants do not have a direct effect on the already formed thrombus, nor can they repair tissues affected by ischemia. Under the condition of the already formed thrombus, anticoagulant treatment will consist in preventing the increase in thrombus size and the development of complications of thromboembolic type that can provoke serious disorders, up to the time of death.

[12], [13], [14], [15], [16], [17], [18], [19], [20]

Pharmacokinetics

Warfarin is a combination of R- as well as 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 ingestion, the substance is almost completely absorbed from the digestive tract, reaching a peak in the first 4 hours.

There are no significant differences in the values of the distribution volume for intravenous injection and ingestion. The distribution level is rather low - about 0.14 l / kg. The distribution stage is 6-12 hours. The substance can penetrate the placental barrier, reaching indicators that are close to the level of concentration in the mother, but it is not observed inside the mother's milk. About 99% of the drug is synthesized with a plasma protein.

The excretion of the substance takes place in the form of inactive decay products. The drug is stereoselectively metabolized using microsomal hepatic enzymes (hemoprotein type P-450), turning into inactive hydroxylated degradation products (mainly), and also reductase (this method forms warfarin alcohols). The latter have a weak anticoagulant effect.

The decay products of the active ingredient are excreted primarily through the kidneys, and a small part of them with bile. Discovered decay products of the substance: dehydrarfarine with two diastereoisomers of alcohol, and in addition 4'-, 6- and 7-, and also 8- and 10-hydroxyarfarin. Participants in the exchange processes are the following isoenzymes: 2C9 and 2C19 with 2C8, and in addition 2C18 with 1A2 and 3A4. Isoenzyme 2C9, most likely, should be considered the leading type of hemoprotein P-450 within the human liver, responsible for the anticoagulant effect of the substance in the form in vivo.

The terminal half-life of warfarin for one-time use is about the 1st week, but the real half-life is between 20-60 hours (the average is 40 hours). The R-warfarin clearance rate 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, and for the S-enantiomer, within 21-43 hours.

Tests using radioactively labeled warfarin demonstrated that in the urine, more than 92% of the ingested drug is observed. Only a small part of the substance is excreted unchanged; excretion is mainly carried out in the form of decay products.

[21], [22], [23], [24]

Dosing and administration

The medicine is consumed once a day at the same time of day. The duration of therapy is prescribed by the doctor, taking into account the indices of INR. Persons who had not taken a medicine earlier are given an initial daily dosage of 5 mg in the first 4 days. From the 5th day the treatment passes to the dosage of 2.5-7.5 mg per day (the more accurate figure depends on the patient's condition and its indices).

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

The initial pediatric dosage for the day is 0.1-0.2 mg / kg, taking into account hepatic function. The size of the maintenance dosage is selected in accordance with the level of INR.

Elderly people need to be treated under the careful supervision of a doctor (because they are likely to have side effects).

During therapy of persons suffering from functional hepatic disorders, it is required to constantly monitor the values of INR.

[35], [36]

Use of the 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 is information about developmental disorders, as well as congenital malformations in children whose mothers used the drug during pregnancy. It is necessary to carefully weigh the risk of using drugs in women who are at reproductive age. It is necessary to warn them about the need to use effective contraceptives.

There are data on the penetration of the substance into the mother's milk, but these quantities are very small and, therefore, often do not have an impact on babies' bloodspring in infants. Although in the case of using Warfarin in lactation, it is required to detect the MHO index in a child. When taking drugs in high doses should be abandoned breastfeeding.

Contraindications

Among the contraindications:

• intolerance of the constituent elements of the drug;
• the presence of bleeding in acute form;
• elevated blood pressure in a severe degree;
• cerebral hemorrhage;
• presence of thrombocytopenia;
• hepatic or renal pathologies;
• high risk of bleeding (cerebral hemorrhage, stomach ulcer or duodenal ulcer, bacterial endocarditis and severe injuries).

[25], [26], [27], [28], [29], [30], [31]

Side effects of the warfarin

As a result of using the medicine, such adverse reactions can occur: 

• the appearance of bleeding and hemorrhages;
• the development of anemia or eosinophilia;
• an increase in hepatic activity, abdominal pain with vomiting, diarrhea and nausea;
• rashes, vasculitis, cutaneous necrosis and itching, as well as alopecia and eczema;
• development of urolithiasis or nephritis.

[32], [33], [34]

Overdose

Because of an overdose, microhematuria or bleeding gums can develop.

For violations of mild degree, it will be sufficient to reduce the dosage of the drug or to abolish it for a short period of time. In case of development of severe bleeding, the introduction of I / V by the vitamin K-type and factors of blood turnover is required.

[37], [38], [39], [40], [41], [42]

Interactions with other drugs

Many drugs can interact with the substance warfarin (among them are salicylates and antibiotics with a large range of activity, and in addition clofibrate with phenytoin, as well as NSAIDs and oral hypoglycemic drugs).

[43], [44], [45], [46], [47], [48]

Storage conditions

Warfarin should be kept under standard conditions, with temperatures not exceeding 25 ° C.

[49], [50]

Shelf life

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

[51], [52], [53], [54]