Vitamin K antagonist

Vitamin K antagonist

Vitamin K antagonists (VKA) are a group of drugs that reduce blood clotting by inhibiting vitamin K epoxide reductase and thus the recycling of vitamin K epoxide back to the active reduced form of vitamin K. These drugs reduce the action of vitamin K by depleting the active form of the vitamin. The term "vitamin K antagonist" is a misnomer, as the drugs don't directly antagonise the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K. For this reason vitamin K antagonizes the drug's effect (rather than vice versa), and this has led to the loose terminology of vitamin K antagonism.

On the basis of its mechanism of action, the action of this class of anticoagulants in all cases may thus be reversed by administering vitamin K for the duration of the anticoagulant's residence in the body, and the daily dose needed for reversal is the same for all drugs in the class. However, in the case of the second generation "super warfarins" intended to kill warfarin resistant rodents, the time of vitamin K administration may need to be prolonged to months, in order to combat the long residence time of the poison.[1]

The vitamin K antagonists can cause birth defects (teratogens).[2]

Coumarins (4-hydroxycoumarins)

Main article: 4-hydroxycoumarins

Coumarins (more accurately 4-hydroxycoumarins) are the most commonly used VKA (they are a subset of VKAs), and sometimes the terms are loosely used synonymously (though this also is not quite accurate).

In medicine, the most commonly used VKA is warfarin.[3] The primary mechanism of warfarin is the inhibition of vitamin K epoxide reductase. The VKAs are not pharmacological antagonists of vitamin K. They are inhibitors of the enzymatic conversion of inactive vitamin K epoxide to its reduced active form. Vitamin K inhibits the overall action of these drugs, but the drugs do not inhibit the direct action of vitamin K. The same dose of vitamin K therefore is antedotal for all the drugs, but may need to be given for a much longer time in the case of drugs that have longer residence times in tissue, as is typical of modern rodenticides.

Warfarin was initially used as a rodenticide, but made the transition to pharmaceutical. Eventually some rodents developed resistance to it. The "second generation" VKAs for dedicated use as rodenticides are sometimes called "super warfarins." These VKAs are enhanced to kill warfarin-resistant rodents. The enhancement to the molecule takes the form of a larger lipophilic group to enhance the fat solubility of the poison and greatly increase the time it acts within the animal's body.[4] However, as described above, the super-warfarins do not inhibit vitamin K and their effect is easily inhibited by vitamin K. Nevertheless, oral vitamin K may need to be given for times that may exceed a month, in order to counter the effect of second-generation VKAs that have very long residence times in the fat of animals and humans.

For a more complete list of VKA's used is pharmaceuticals and rodenticides, see the main article above.

Other VKAs

Not all VKAs are coumarins. For example, fluindione is a VKA,[5] but not a coumarin.

Another example is phenindione.[6]

Many of the non-coumarin VKAs are 1,3-indandione derivatives. Nevertheless, all of these molecules share the same mechanism of action, and are inhibitors (antagonists) of vitamin K epoxide reductase, even though loosely called "vitamin K antagonists." The action of all of them may be antagonized by administration of vitamin K.

See also