Anticoagulants, competition

In contrast to heparin, the coumarinic acid anticoagulants are inactive in vitw ]6k.e heparin they are active in vivo. The phenylindanedione-type compounds (7) (36) and warfarin (2) produce their in vivo inhibitory effect on the coagulation system by competitively antagonizing the normal activity of vitamin (8) (37—44). 

Fluindione, ap-fluoro phenindione, is a vitamin K competitive antagonist used as an anticoagulant. The plasma haE-life of phenindione is strongly increased by the fluorine substitution (from 10 to 30 h). 

Coumarins are competitive inhibitors of vitamin K, which is required for the formation in the liver of the amino acid, gamma-carboxyglutamic acid. This is necessary for the synthesis of prothrombin and factors VII, IX and X (Figure 17.1). After starting treatment the anticoagulant effect is delayed until the concentration of normal coagulation factors falls (36-72 h). The effects can be reversed by vitamin K (slow maximum effect only after 3-6 h) or by whole blood or plasma (fast). Gut bacteria synthesise vitamin K and thus are an important source of this vitamin. Consequently, antibiotics can cause excessive prolongation of the prothrombin time in patients otherwise adequately controlled on warfarin. 

It was found that rivaroxaban competitively inhibits human FXa and prothrombinase activity (/C50 = 2.1 nM). It inhibits endogenous FXa more potently in human and rabbit plasma (/C50 = 21 nM) than in rat plasma (/C50 = 290 nM). Rivaroxaban has demonstrated anticoagulant effects in human plasma, doubling the prothrombin time (PT) and activated partial thromboplastin time (APTT) at 0.23 and 0.69 pM, respectively. In vivo, rivaroxaban reduced venous thrombosis dose dependency (EDS0 = 0.1 mg/kg i.v.) in a rat venous stasis model. The pharmacological actions of rivaroxaban have been described in more detail by Perzbom et al.12... 

CICLOSPORIN ANTICOAGULANTS-ORAL 1. J ciclosporin levels when co-administered with warfarin or acenocoumarol 2.1 anticoagulant effect with warfarin and variable effect with acenocoumarol Competitive metabolism by CYP3A4 1. Watch for i efficacy of ciclosporin 2. Monitor INR at least weekly until stable... 

ANTICOAGULANTS-ORAL PARACETAMOL Possible t anticoagulant effect when paracetamol is taken regularly (but not occasionally) Uncertain possibly due to competitive inhibition of CYP-mediated metabolism of warfarin Monitor INR closely for the first 1-2 weeks of starting or stopping regular paracetamol... 

Warfarin and dicoumarol are used clinically as anticoagulants. Warfarin is also a common rat poison, causing death by internal bleeding. These compounds prevent clotting by inhibiting the enzyme that reduces vitamin K epoxide to vitamin KH2, thereby preventing the carboxylation of glutamate. The enzyme caimot tell the difference between these two compounds and vitamin K epoxide, so the compounds act as competitive inhibitors. 

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