Hepatic synthesis of coagulation factors II, VII, IX, and X, as well as proteins C and S, requires the presence of vitamin K. These clotting factors are physiologically activated by the addition of carboxyl groups to key glutamic acid residues within the proteins' structure. In the process, "active" vitamin K is oxidatively converted to an "inactive" form, which is then subsequently re-activated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin competitively inhibits the subunit 1 of the multi-unit VKOR complex, thus depleting functional vitamin K reserves and hence reduces synthesis of active clotting factors. However, the anticoagulant effect of warfarin is not established until the pre-existing factors have been degraded through their natural cycle. This process usually takes 5-7 days.In patients with thromboembolic disorder; warfarin can therefore prolonging the time it takes for blood to clot (Prothrombin Time) thereby reducing episodes or risk of thromboembolism.
How Pharmacokinetics and Pharmacodynamics of Warfarin are altered in different Disease states
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Warfarin is a racemic mixture of two optically active isomers, the R and S forms in roughly equal proportion. The S isomer is five times more potent than the R isomer. These two isomers are metabolised by different pathways in the liver. Whereas the S isomer is metabolised by the cytochrome P450 (CYP) 2C9 enzyme, the R isomer is metabolised by CYP 3A4. The absorption of warfarin from the gastrointestinal tract is both rapid and complete (Breckenridge, 1978). The effective elimination half-life of warfarin averages about 40 hours and shows considerable interindividual variation (range: 20-60 hours). Warfarin in the blood is about 99% bound to plasma proteins (mainly albumen), and accumulate in the liver where the two isomers are metabolised by the different pathways (O'Reilly, 1986). Different disease states may alter warfarin pharmacokinetic and pharmacodynamic functions, thereby dictating dose adjustment in those conditions.
Thyroid dysfunction has been reported to alter the disposition of several drugs. Frequently, the rate of elimination of medications is depressed in hypothyroid states and increased during hyperthyroid states. However, the effects of thyroid dysfunction on warfarin pharmacokinetics do not follow this typical pattern. Stephens et al reported a case of a 45-year-old woman taking warfarin (10 mg) daily for a history of recurrent deep vein thrombosis and pulmonary embolism. Two years after treatment of hyperthyroidism with 131I, the patient was admitted to the hospital with hypothyroidism and a possible pulmonary embolism. The dosage of warfarin required to achieve a therapeutic PTR increased to 27.5 mg daily. After achieving a euthyroid state with levothyroxine, the dose requirement of warfarin returned to 10 mg daily.
Vagenakis et al were the first to describe increased response to warfarin, in a hyperthyroid patient with Grave's disease. The patient showed increased sensitivity to maintenance warfarin therapy during two episodes of hyperthyroidism. Warfarin dosing requirements returned to baseline when the patient was euthyroid. Self et al also described enhanced warfarin response in a patient with hyperthyroidism.
The liver is the most important organ for the synthesis of plasma proteins, including plasma clotting factors. Liver disease is well-documented as causing defective haemostasis, including prolongation of the prothrombin time (PT).[3-7] The PT is an excellent marker of liver dysfunction. Gallus et al studied coagulation in 104 hospitalized patients with acute infectious hepatitis. Patients with or without liver failure were evaluated separately. A mild coagulation defect (prolonged PT and reduced levels of factors V, VII, and X and plasminogen) was reported in 57 of the 78 patients without liver failure and was not associated with bleeding. A severe coagulation defect was reported in all 26 patients with liver failure, and bleeding occurred in 15 patients (10 patients required treatment).
Congestive Heart Failure
While further study is needed, it appears that some patients with decompensated CHF have an increased responsiveness to oral anticoagulants.[6,8,24-33] One possible mechanism for this interaction is CHF-induced hepatic congestion. In 1949, Stats and Davison evaluated the effect of CHF on dicumarol. The researchers studied 23 patients with right-sided CHF and 48 control patients. Prothrombin times were evaluated at baseline and on 3 successive days after a single 150 mg dose of dicumarol. Results of the study showed a greater prolongation of the PT in patients with moderate to severe right ventricular failure as compared with control patients and those with only mild cardiac disease. Patients with more severe cardiac disease also had a more gradual decline in PT. Liver congestion induced by CHF was mentioned as one likely mechanism for this effect on dicumarol. Similar results were reported by Killip and Payne in a review of the effects of heart disease on hepatic function.
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The efficacy and safety of oral anticoagulation was evaluated in patients with cancer (n = 44) and compared with a control population (n = 64). The proportion of time in which INRs were in the target range (2.0 to 3.0) was significantly different (42.3% of patients with cancer vs 56.9% controls; P < .0001). Among cancer patients with INR values outside the therapeutic range, 42% had high INRs, and 58% had low INRs. It was concluded that metastatic liver disease, malnutrition, use of chemotherapy, or noncompliance might be the possible reasons for the significant difference. There was no significant difference in bleeding and recurrent thrombotic events between groups. In a retrospective evaluation of predictors of major bleeding, Landefeld et al reported that patients with two or more comorbid risk factors had a nearly 20-fold increased risk of bleeding compared with patients with no comorbid conditions. Co-morbid conditions included cancer, serious cardiac illness, liver dysfunction, active renal disease, and severe anemia.
Although the following reports are of isolated cases, we have included them for completeness. Dietary vitamin K is absorbed from the proximal small intestine. Malabsorption due to diarrhea could cause a deficiency of vitamin K, resulting in an enhanced response to warfarin. In one case, anticoagulation had been maintained within the therapeutic range (INR 2.0 to 3.0). After more than 1 week of diarrhea due to giardiasis, an INR of 4.6 was reported. The elevated INR was accompanied by a large ecchymosis on the left calf. Further evaluation of the effect of diarrhea on response to warfarin is needed.
Note any significant drug-drug and drug-food interactions that must be avoided and the mechanism(s) of these
The effect of co-prescribed drugs on the activity of warfarin depends on the particular enzymatic pathway affected. Metronidazole may result in significant rise in INR because of the inhibition of the S isomer via CYP2C9 pathway. Drugs interfering with the R isomer (e.g. dilitazem) may have a modest effect on INR. However, drugs that interfere with the clearance of both isomers like amiodarone (almog, et al., 1985) may profoundly increase INR. If both drugs are administered concurrently, anticoagulant dose need to be adjust base on carefully monitored prothrombin activity. Hepatic inducers like phenytoin and some antiepileptic drugs may result in reduction in INR if co-prescribed