Pharmacodynamics and Dosing Considerations
Anticoagulant Activity. The anticoagulant activity of warfarin depends on the clearance of functional clotting factors from the systemic circulation after administration of the dose. The clearance of these clotting factors is determined by their half-lives. The earliest changes in the International Normalized Ratio (INR) are typically noted 24 to 36 hours after a dose of warfarin is administered. These changes are due to the clearance of functional factor VII, which is the vitamin K*dependent clotting factor with the shortest half-life (six hours). However, the early changes in the INR are deceptive because they do not actually affect the body's physiologic ability to halt clot expansion or form new thromboses.4
Antithrombotic Effect. The antithrombotic effect of warfarin, or the inability to expand or form clots, is not present until approximately the fifth day of therapy. This effect depends on the clearance of functional factor II (prothrombin), which has a half-life of approximately 50 hours in patients with normal hepatic function.
The difference between the antithrombotic and anticoagulant effects of warfarin need to be understood and applied in clinical practice. Because antithrombotic effect depends on the clearance of prothrombin (which may take up to five days), loading doses of warfarin are of limited value.4,12 Because warfarin has a long half-life, increases in the INR may not be noted for 24 to 36 hours after administration of the first dose, and maximum anticoagulant effect may not be achieved for 72 to 96 hours.4
Loading doses of warfarin (i.e., 10 mg or more per day) may increase the patient's risk of bleeding episodes early in therapy by eliminating or severely reducing the production of functional factor VII. The administration of loading doses is a possible source of prolonged hospitalization secondary to dramatic rises in INR that necessitate increased monitoring. Administration of loading doses has also been hypothesized to potentiate a hypercoagulable state because of severe depletion of protein C. The practice of using loading doses should be abandoned because it has no effect on the inhibition of thrombosis.4[corrected]
A potential paradoxic consequence of loading doses is the development of a hypercoagulable state because of a precipitous reduction in the concentration of protein C (approximate half-life of eight hours) during the first 36 hours of warfarin therapy.12 Thus, loading doses theoretically may cause clot formation and/or expansion by limiting the production of proteins C and S, which have shorter half-lives than prothrombin. Consequently, the concurrent use of heparin is extremely important.
The initial dose of warfarin should approximate the chronic maintenance dose that is anticipated. In most patients, the average maintenance dose is 4 to 6 mg per day. Dose has an inverse relation with age. In patients 50 years old, the average daily dose is 6.3 mg; in patients 70 years old, the average daily dose is 3.6 mg.
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