Vitamin K antagonists

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The vitamin K antagonists (VKAs) are a group of anticoagulants. Most vitamin K antagonists are coumarins, so the terms are often used interchangeably. However, there exist some VKAs which are not coumarins. The most commonly used VKA by far is warfarin (Marevan®, Coumadin®). These drugs are administered orally.

Dicumarol is another VKA, but due to unpredictable absorption and significant GI side effects, it's been replaced by warfarin. Acenocoumarol is another VKA which is no longer used.

Following the introduction and establishment of direct oral anticoagulants (DOACs), VKAs are much less commonly used, as DOACs are safer and non-inferior to VKAs in most cases.

Indications

There are now only a few cases where VKAs are preferred compared to DOACs:

If the patient has contraindications to DOAC but not to warfarin (rare), warfarin can be used on the same indications as DOACs, including preventing stroke in atrial fibrillation, and treating or preventing venous thromboembolism.

Mechanism of action

VKAs inhibit vitamin K epoxide reductase, thereby decreasing the amount of “usable” vitamin K. This creates a condition similar to vitamin K deficiency, causing clotting factors II, VII, IX and X to be dysfunctional and therefore inactive. This creates a functional depletion of these clotting factors.

Because VKAs act on the synthesis of clotting factors they have a slow onset of action. Immediately after the first administration there are still functioning clotting factors present in the blood – the anticoagulant effect comes only after these functioning clotting factors have been eliminated, which takes around 4 days.

Pharmacokinetics

Warfarin has good oral absorption, strong plasma protein binding (97%) and is inactivated by CYP450 in the liver. Its duration of action is 4-5 days and the half-life is 40 hours.

Monitoring

The problem with coumarins is that people respond differently to the same dose. This is because polymorphisms in the gene for vitamin K epoxide reductase change the affinity of the VKAs to the enzyme and differences in vitamin K content of diet.

To monitor the anticoagulant effect of warfarin, the international normalised ratio (INR) is used. INR is a standardised form of prothrombin time which is normalised so that the result is similar between different laboratory methods and equipments. The prothrombin time is first measured and then normalised by a specific equation and factor.

It’s important to start with a low dose and continuously test the INR of the patient to make sure that they’re not receiving too much (and therefore bleed too easily) or too little (and therefore have suboptimal anticoagulant effect). The dose should always be adjusted so that the INR of the patient is between 2 and 3 (between 2,5 – 3,5 in case of mechanical heart valves). INR should be measured often, initially daily but later more and more rarely (but still regularly).

Contraindications

VKas are teratogenic and are therefore contraindicated in pregnancy. They’re also contraindicated in severe liver and kidney failure.

Interactions

Certain drugs decrease the effect of coumarins. Vitamin K is the obvious one – in fact vitamin K is the antidote to warfarin poisoning. Drugs that induce CYP450 enzymes like rifampicin and barbiturates increase the elimination of coumarins. Colestyramine decreases the absorption of them.

Because coumarins have strong plasma protein binding they can be displaced by other drugs who also bind strongly to plasma proteins.

Complications

Warfarin inhibits the synthesis of protein C and protein S as well, and these factors are depleted more quickly than the clotting factors. This causes an initial hypercoagulable state which can cause tissue infarction and necrosis. Warfarin-induced skin necrosis is a severe complication which can occur with warfarin treatment.

To prevent warfarin-induced necrosis we can use heparin to prevent the initial hypercoagulable state.

Reversal

The anticoagulant effect of VKA antagonists can be rapidly reversed by replacement, by administering prothrombin complex concentrate or fresh frozen plasma. Vitamin K administration also antagonises the effect but this occurs much more slowly.