Vitamin K is contained in the phylloquinones in many green vegetables. It is also produced by bacteria from substrates within the intestinal tract and subsequently recycled enterohepatically as absorbable menaquinones. As vitamin K is absorbed from the intestine, it is stored in the liver for the production of clotting factors and anti-clotting proteins. Administration blocks the oxidation of vitamin K within the liver (Figure 1). Ultimately, warfarin elicits its therapeutic effect by limiting the activation of vitamin K-dependent clotting proteins that are synthesized and secreted by the liver.

Numerous compounds are involved in the complicated clotting cascade. The anticoagulant effect of warfarin is attained by blocking the activation of the intrinsic clotting factors VII, IX, X, and II. However, warfarin also has a simultaneous procoagulant effect, caused by blocking the activation of two endogenous anticoagulants, protein C and protein S. Over time, warfarin therapy results in reduced amounts of all of these factors in the circulation. eriacta 100 mg

Table 1 Vitamin K-Dependent Clotting Factors

Name Function


Protein C Anticoagulant

8 hours

Protein S Anticoagulant

30 hours

Factor VII Procoagulant

7 hours

Factor IX Procoagulant

24 hours

Factor X Procoagulant

36 hours

Factor II Procoagulant

50 hours

As shown in Table 1, relative to all factors other than factor VII, protein C has a very short half-life. Therefore, protein C is depleted quickly after the initiation of warfarin therapy. Because both proteins C and S are anticoagulants, a rapid depletion of these proteins leads to a transient hypercoagulable state in the first one to two days of warfarin therapy. Therefore, by causing rapid and precipitous declines in circulating protein C, the use of high loading doses may actually potentiate this phenomenon.

Indeed, one possible sign of this transient hypercoagulable state is sometimes manifested as an ischemia-related skin necrosis reaction. Caused by thrombosis of venules or capillaries within the subcutaneous fat, this phenomenon is usually apparent between the third and eighth days of therapy. The most commonly cited risk factors are a high initial warfarin dose, obesity, and female sex. Although sometimes referred to as the “purple toe syndrome,” the red painful plaques, hemorrhagic blisters, or necrotic scars are often found in such fatty areas as the breasts, hips, and buttocks. The syndrome affects only about one in 10,000 patients receiving warfarin, but it exacts a high mortality rate if it is not treated promptly. Treatment consists of vitamin K reversal, heparin anticoagulation, and monoclonal antibody-purified protein C concentrate. Surgical debridement may also be necessary.
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Figure 1 Warfarin and the vitamin K cycle. (Reproduced with permission from Hirsch J, Dalen J, Anderson DR, et al. Chest 2001;119[1 Suppl]:8S-l2S.)

During the first two to three days of warfarin therapy, it should be remembered that a rapid increase in INR reflects only a reduction of the shorter half-life of factors VII and IX, whereas clinically significant reductions of factors X and II have yet to occur. Because factor II (prothrombin) has the longest half-life (Figure 2), the optimal potential of warfarin to inhibit the expansion and development of the clot is determined after the final clearance of factor II. This delayed effect on adequately depleting activated factor II is the principal reason why the overlap of heparin therapy with warfarin must be at least four to five days if patients are in the throes of an acute thromboembolic event, even when a target therapeutic INR is attained earlier than this time. Of course, this overlap is not required in patients with chronic atrial fibrillation who have not shown any evidence of an acute thromboembolic event.

Next, we need to consider the half-life of warfarin itself. Warfarin’s S and R isomers are metabolized hepatically by cytochrome P-450 (CYP450). The S-enantiomer has a half-life of about one to two days; the R-enantiomer’s half-life is approximately 1.5 to four days (Figure 3).

The S-enantiomer exhibits two to five times more anticoagulant activity than the R-enantiomer in humans, but it also has a slightly more rapid clearance than the R-enantiomer. Even though the pharmacokinetic characteristics are similar in older and younger patients, the elderly appear to manifest a greater than expected prothrombin time and INR response to the anticoagulant effects of warfarin. One explanation is the enhanced receptor site sensitivity for warfarin in these patients. Another contributing factor may be the effect of age on liver volume.

Figure 2 Changes in clotting factor concentrations upon initiation of warfarin. INR = International Normalized Ratio; Pro = prothrombin. (Reproduced with permission from Katzung BG,ed. Basic and Clinical Pharmacology, 8th ed. New York: McGraw-Hill; 200l:57l.)

Wynne et al. noted that as a person’s age increases, liver volume decreases, thus leading to a reduction in warfarin dosing requirements. Hodges et al. found that the availability of vitamin K in elderly patients was less than that seen in younger patients. Not surprisingly, to tie it all together, Shepherd et al. found that the rate of clotting factor synthesis was lower in older patients than in their younger counterparts. Therefore, when dosing warfarin for elderly patients, clinicians should anticipate lower initiation and maintenance dose requirements than for younger people. They should also be especially vigilant in looking for exaggerated responses to dosing changes and for an increased sensitivity to drug interactions.
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Other issues that might be overlooked include acute changes in a patient’s condition or diet. Even subacute changes in vitamin K intake can make a significant difference in the response to warfarin. Of course, because of consequential reductions in procoagulant synthesis or turnover, parenchymal liver damage and acute biliary obstruction also potentiate warfarin’s effects. Passive hepatic congestion caused by exacerbations of congestive heart failure also reduce warfarin clearance, although alleviating the heart failure with diuretics can reverse this process.

Hypermetabolic events such as hyperthyroidism and fever are thought to potentiate canadian warfarin by increasing the catabolism of clotting proteins. Conversely, interferons or other inflammatory mediators released during sepsis may down-regulate various CYP450 isozymes, thereby slowing the metabolism of warfarin and potentiating a supratherapeutic response.