Vitamin K antagonists (VKA) are a group of substances that reduce

blood clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechan ...

by reducing the action of

vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...

. The term "vitamin K antagonist" is technically 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. They are used as

anticoagulant Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where t ...

medications in the prevention of

thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (th ...

, and in

pest control Pest control is the regulation or management of a species defined as a pest; any animal, plant or fungus that impacts adversely on human activities or environment. The human response depends on the importance of the damage done and will range ...

, as

rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despi ...

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 A misnomer is a name that is incorrectly or unsuitably applied. Misnomers often arise because something was named long before its correct nature was known, or because an earlier form of something has been replaced by a later form to which the name ...

, 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

superwarfarin Superwarfarins are highly potent vitamin K antagonist anticoagulants that are used as rodenticides. They are called superwarfarins because they are much more potent and long acting than warfarin. Examples *Brodifacoum *Bromadiolone *Difenacoum *Flo ...

s 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). K1 vitamin Mechanism of Action

Coumarins (4-hydroxycoumarins)

Coumarins (more accurately

4-hydroxycoumarins 4-Hydroxycoumarins belong to a class of vitamin K antagonist (VKA) anticoagulant drug molecules derived from coumarin by adding a hydroxy group at the 4 position to obtain 4-hydroxycoumarin, then adding a large aromatic substituent at the 3-p ...

) are the most commonly used VKAs. In medicine, the most commonly used VKA is

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

. 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

s. 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 superwarfarins 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 (cases have been described needing as much as nine months vitamin K supplementation), 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

. File:Warfarin.svg,

Warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

(Coumadin) File:Coumatetralyl.svg, Coumatetralyl File:Phenprocoumon.svg, Phenprocoumon File:Acenocoumarol.svg, Acenocoumarol File:Dicumarol.svg, Dicoumarol File:Tioclomarol.svg, Tioclomarol File:Brodifacoum.png,

Brodifacoum Brodifacoum is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide, but is also used to control larger ...

Indandiones

Another group of VKAs are 1,3-indandione derivatives. Pindone,

chlorophacinone Chlorophacinone is an anticoagulant used as a rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks ...

, and

diphacinone Diphenadione is a vitamin K antagonist that has anticoagulant effects and is used as a rodenticide against rats, mice, voles, ground squirrels and other rodents. The chemical compound is an anti-coagulant with active half-life longer than warfari ...

are used as rodenticides. They are categorised as "first-generation" anticoagulants, and have similar effects as warfarin. They have been largely superseded by second-generation anticoagulants because warfarin-resistant rodents have become more common. Anisindione, fluindione, and phenindione are oral anticoagulant medicines with actions similar to warfarin. However, the indandiones are generally more toxic than warfarin, with hypersensitivity reactions involving many organs and sometimes resulting in death. They are therefore now rarely used. File:Pindone_Structural_Formula_V.1.svg, Pindone File:Chlorophacinone.svg,

Chlorophacinone Chlorophacinone is an anticoagulant used as a rodenticide Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks ...

File:Diphenadione2.svg,

Diphacinone Diphenadione is a vitamin K antagonist that has anticoagulant effects and is used as a rodenticide against rats, mice, voles, ground squirrels and other rodents. The chemical compound is an anti-coagulant with active half-life longer than warfari ...

File:Anisindione skeletal.svg, Anisindione File:Fluindione.png, Fluindione File:Phenindione.svg, Phenindione

Mechanism of action

Coumarins (4-hydroxycoumarins)

Indandiones

See also

References

Further reading