Anticoagulants indirect-acting

Twenty to 24 million prescriptions of Coumadin were dispensed in the United States during 2003-2005. Coumadin is an anticoagulant that acts by preventing the synthesis of active vitamin K, a necessary cofactor for synthesizing active clotting factors. Thus, preventing the synthesis of active vitamin K indirectly inhibits the formation of active clotting factors, notably factor II (prothrombin), VII, IX, and X in the liver. Ironically, coumarins, of which Coumadin is a member, are also used as rodenticides. 

Indirect antithrombins. The action of heparin is complex, and it is sometimes referred to as an indirect-acting antithrombin, in as much as it works indirectly to inhibit the action of thrombin in the coagulation cascade. Dicoumarin anticoagulants, most notably warfarin, also act in an indirect... 

The oral anticoagulant drugs act indirectly on the process of Glu carboxylation of the vitamin K-dependent proteins. The vitamin K antagonists prevent the reduction of the reaction intermediate, vitamin K epoxide. Blockage of the epoxide reductase reaction results in the accumulation of vitamin K epoxide and other nonfunctional forms of vitamin K. Without regeneration of the vitamin K-related reaction intermediates through the cycle shown in Figure 36-22, a depletion of functional vitamin K occurs. 

The direct thrombin inhibitors (DTIs) exert their anticoagulant effect by directly binding to the active site of thrombin, thereby inhibiting thrombin s downstream effects. This is in contrast to indirect thrombin inhibitors such as heparin and LMWH (see above), which act through antithrombin. Hirudin and bivalirudin are bivalent DTIs in that they bind at both the catalytic or active site of thrombin as well as at a substrate recognition site. Argatroban and melagatran are small molecules that bind only at the thrombin active site. 

Heparin acts indirectly at multiple points within the coagulation cascade, Its major anticoagulant effect is via interaction with its requisite co-factor, antithrombin III (AT). The heparin-AT complex inactivates factors IXa, Xa, and XIla, and binds thrombin at its active site to prevent the conversion of fibrinogen to fibrin (3). Heparin also prevents fibrin stabilization through the inhibition of fibrin stabilization factor. Heparin has no fibrinolytic activity and therefore is ineffective as a thrombolytic (4,5). 

The two commonly administered anticoagulant therapies3 are parenteral heparin, a highly sulfated glycosaminoglycan, and oral warfarin 2, a vitamin K antagonist (which acts by indirectly inhibiting several steps of the coagulation pathway). The major... 

Inactive factors 1. Mechanism of action Heparin acts indirectly by binding to antithrombin III to cause a rapid anticoagulant effect. Maximal anticoagulation occurs within minutes after intravenous heparin injection (unlike vitamin K antagonist anticoagulants, such as war-... 

As a result of intensive research, derivatives of 4-hydroxycoumarin were found, which proved to be particularly efficient against rodents and resistant to anticoagulant rodenticides. Difenacoum (34) is a chronic rodenticide, which acts as a typical indirect blood anticoagulant similar to warfarin. However, it is effective against rats and mice, which are resistant to warfarin and other anticoagulant rodenticides, and is more toxic than warfarin to susceptible strains of these rodents. The chemical composition of difenacoum is 3-(3-p-biphenyl-1,2,3,4-tetrahydro-naphth-l-yI)-4-hydroxycoumarin. Its acute oral LD50 is 1.8 mg/kg for Norway rats (Hadler et al., 1975a,b). 

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