Vitamin K antagonist

Warning label on a tube of "brown rat" poison laid on a dike of the Scheldt river in Steendorp, Belgium. The tube contains bromadiolone, a second-generation ("super-warfarin") anticoagulant. The label in Dutch states, in part: Contains an anticoagulant with prolonged activity. Antidote Vitamin K1.

Vitamin K₂ (menaquinone). In menaquinone the side chain is composed of a varying number of isoprenoid residues.

Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. They are used as anticoagulant medications in the prevention of thrombosis, and in pest control, as rodenticides.

Mechanism of action

These drugs deplete the active form of the vitamin by inhibiting the enzyme vitamin K epoxide reductase and thus the recycling of the inactive vitamin K epoxide back to the active reduced form of vitamin K. The drugs are structurally similar to vitamin K and act as competitive inhibitors of the enzyme. The term "vitamin K antagonist" is a misnomer, as the drugs do not directly antagonise the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K.

Vitamin K is required for the proper production of certain proteins involved in the blood clotting process. For example, it is needed to carboxylate specific glutamic acid residues on prothrombin. Without these residues carboxylated, the protein will not form the appropriate conformation of thrombin, which is needed to produce the fibrin monomers that are polymerized to form clots.

The action of this class of anticoagulants may 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.

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

Coumarins (4-hydroxycoumarins)

Main article: 4-hydroxycoumarins

Coumarins (more accurately 4-hydroxycoumarins) are the most commonly used VKAs.

In medicine, the most commonly used VKA is warfarin. 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. 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 coumarins used as pharmaceuticals and rodenticides, see the main article on 4-hydroxycoumarins.

• Warfarin.svg

  Warfarin (Coumadin)

• 

  Coumatetralyl

• Phenprocoumon.svg

  Phenprocoumon

• 

  Acenocoumarol

• 

  Dicoumarol

• 

  Tioclomarol

• 

  Brodifacoum

Other VKAs

Not all VKAs are coumarins; many of the non-coumarin VKAs are 1,3-indandione derivatives. Although these are loosely termed VKAs, these molecules share a separate mechanism of action, inhibiting the enzyme vitamin K epoxide reductase. Such therapeutic agents may themselves be antagonized by administration of vitamin K. Examples include phenindione, Clorindione, diphenadione, and fluindione.

• 

  Phenindione

• 

  Clorindione

• 

  Diphenadione

See also

• Vitamin K deficiency
• Category:Vitamin K antagonists

Further reading

• Published reviews, 2011-2016, regarding Vitamin K antagonists.
• Note, because this issue foreword is over a decade old, its statements regarding limited available oral anticoagulants is no longer accurate.