In this post, I hope to break down at a macroscopic level use of oral direct thrombin inhibitors DTI. In my next post, I will review Factor Xa inhibitors. Fibrin clots form after activation of the intrinsic and extrinsic pathways. Tissue injury initiates the intrinsic pathway and compromises the vast majority of the coagulation cascade.
Warfarin acts across both the extrinsic and intrinsic pathways to prevent thrombus formation. Direct thrombin inhibitors and Factor Xa inhibitors both work in the common pathway of coagulation. Most DTIs are administered parenterally and used in patients with ACS and in treatment of patients with heparin-induced thrombocytopenia.
Oral DTIs have been slower to reach the market. While several are under development, dabigatran received FDA approval in for prevention of stroke in patients with nonvalvular AF.
The RE-LY trial, published in ,showed that low-dose dabigatran mg twice daily was noninferior to warfarin for preventing stroke in patients with intermediate risk nonvalvular AF mean CHADS2 score 2.
High-dose dabigatran mg twice daily was superior to warfarin in this population. The risk for major bleeding compared with warfarin was lower in the low-dose dabigatran group and similar in the high-dose dabigatran group.
The clotting of blood requires certain key substances to be present in the blood stream:. As well as the anticoagulant proteins C and S. The chart above show that Warfarin interferes with the vitamin K cycle. It interacts with the reductase enzyme which means that oxidised vitamin K cannot be converted back to vitamin K. This in turn means, as shown above, that the amount of reduced vitamin K will also decrease. Laboratory Monitoring of Anticoagulation Because Factor VII has the shortest half-life of the pro-coagulant factors affected by warfarin, its effective concentration declines the fastest upon administration of warfarin.
Consequently, the PT and INR are the first coagulation parameters which will begin to lengthen and these are used to monitor the anticoagulant effect of warfarin. Pharmacokinetics Overview Warfarin is orally available and thus it is frequently used for chronic, outpatient purposes. Warfarin is metabolized by the hepatic Cytochrome P system.
A long list of drugs can interact with this system, either by inducing increased synthesis of P and thus enhanced metabolism of warfarin, or by interfering with P metabolism of warfarin and thus increasing its blood concentration.
It is important to know some of the most common interacting drugs given the common use of warfarin and the potentially disastrous adverse effects of supra-therapeutic levels.
Potentiators of P Metabolism : Decreased effective Warfarin concentration Acute Alcohol Intoxication, Cimetidine, Chloramphenicol , Disulfiram, Metronidazole Inhibitors of P Metabolism : Increased effective Warfarin concentration Chronic Alcohol Intake, Barbiturates, Rifampin , Griseofulvin Reversal The anticoagulant effect of warfarin can be reversed by the parenteral administration of Vitamin K; however, improved coagulation requires the synthesis of new coagulation factors and thus takes several days to occur.
If immediate reversal is clinically necessary then this can be done solely by parenteral supplementation with exogenous coagulation factors. In general, this is done by administration of Fresh Frozen Plasma FFP Adverse Effects Bleeding Diathesis Predictably, supra-therapeutic doses of warfarin can result in abnormal or excessive bleeding, a potentially fatal complication Teratogenicity Warfarin should never be administered during pregnancy as it can cross the placenta and act as a potent teratogen.
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