Antagonist
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The first vitamin K-antagonists
were discovered in the late 1920s as a result of investigations
in the occurrence of fatal hemorrhages in cattle. The cause of the
bleeding was found to be the feeding of cattle with hay made from
sweet clover. If the hay was improperly cured a compound named dicumarol
(see
Since the early 1950s oral anticoagulant treatment is frequently used for the treatment of hypercoagulability and for preventing thrombosis and related disorders such as myocardial infarction and pulmonary embolism. The treatment is based on the vitamin K-antagonistic effect of drugs derived of 4-hydroxycoumarin (known as oral anticoagulants), by which the procoagulant activity of a number of blood coagulation factors is reduced. All oral anticoagulants inhibit KO-reductase, so they block the recycling of vitamin K. Well known examples of these drugs are warfarin, phenprocoumon, and acenocoumarol, which are all used for therapeutic treatment of patients. Because they prevent the re-use of vitamin K, the KH2 stores are rapidly depleted, which leads to an apparent vitamin K-deficiency. Brodifacum, with a very long half-life time is used as rodenticide.
The critical step that is blocked in the vitamin
K cycle is the reduction of vitamin K epoxide into vitamin K quinone.
The only enzyme known to be capable of this conversion is the coumarin-sensitive
KO-reductase. The second step in the recycling of vitamin K is the
conversion of the quinone in a hydroquinone, and this step may be
accomplished by both KO-reductase and the coumarin-insensitive DT-diaphorase.
The main difference between the various therapeutically used oral anticoagulants is their biological half-life time, which is 10 h for acenocoumarol, 30-80 h for warfarin, and 70-120 h for phenprocoumon. Recommended literature:
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