I. Drugs that have synergistic effects with Warfarin
1.The combination of fluoroquinolones and warfarin can cause coagulation disorders
Canadian Adverse Drug Reaction Bulletin (2004, Issue 3) said that the combination of fluoroquinolone antibiotics and Warfarin led to increased anticoagulant activity has been reported repeatedly. The anticoagulant mechanisms of the interaction are: substitution of warfarin from the protein binding site; reduction of the intestinal flora that produces vitamin K and coagulation factors and decreased metabolism of warfarin.
Most fluoroquinolone antibiotics inhibit cytochrome P450-mediated metabolism and therefore have the potential to cause toxic reactions to other drugs applied concomitantly, especially those with a narrow therapeutic index, such as warfarin, by decreasing drug clearance. Therefore, it is believed that fluoroquinolone antibiotics may enhance the effect of warfarin or its derivatives, and patients’ prothrombin time and INR should be closely monitored, especially in elderly patients, and the dosage of warfarin should be adjusted at any time. 2006, a similar report was made in Australia.
2. The combination of macrolides and warfarin has an increased risk of bleeding
The Australian Adverse Drug Reaction Bulletin reported receiving reports of interactions between Warfarin and all four macrolide antibiotics (azithromycin, clarithromycin, erythromycin and roxithromycin). In contrast to this report, McCall et al. at Texas Tech University Health Sciences Center reported no significant change in INR after the addition of azithromycin in people taking Warfarin (Pharmacotherapy 2004, 24: 188). There are also case reports of increased INR and hematuria associated with amoxicillin (Davydov et al., Ann Pharmacother 2003, 37: 367).
3. Tramadol and Warfarin have synergistic effects
The Australian Adverse Drug Reaction Bulletin stated that tramadol caused an increase in INR and bleeding events in patients taking warfarin. Patients on a stable dose of warfarin had an onset 3 to 7 days (median time 4 days) after the addition of tramadol. Recovery was within 1 to 4 days after discontinuation of tramadol (no change in warfarin dose).
Boeijinga et al. conducted a pharmacodynamic study and the results suggested that anticoagulation was associated with metabolic variability in a small number of patients. The Australian Council on Adverse Drug Reactions advises physicians that INR should be monitored for the first few days to a week after the addition of tramadol in patients treated with warfarin to prevent untoward events. Interferon has also been reported to increase the anticoagulant effect of warfarin.
4.Fish oil and warfarin have interaction
Fish oil is an omega-3 polyunsaturated fatty acid, which can affect platelet aggregation and/or vitamin K-dependent coagulation factors, reduce thromboxane A2 content in platelets, and also reduce factor VII levels, which can enhance the anticoagulant effect of Warfarin after proper supplementation.
5. Antiphospholipid antibodies can cause an increase in INR
Ashley et al. of the University of California Davis Medical Center reported that the researchers noted that INR values are often used to evaluate the degree of anticoagulation, and that an elevated INR represents a decrease in the activity of coagulation factors II, VII, and X. In rare cases, the presence of non-vitamin K-dependent inhibitors or interfering substances can interfere with the INR determination. In such cases, the anticoagulant effect of warfarin can be evaluated by direct determination of coagulation factor concentrations.
6. Genetic variants increase the risk of bleeding during anticoagulation with warfarin
A study at the University of Washington showed that variants in two genes related to warfarin metabolism increase the risk of bleeding during warfarin anticoagulation therapy. The CYP2C9*2 and CYP2C9*3 genes are known to express key enzymes for warfarin metabolism, and variants in these two genes increase the risk of bleeding during warfarin anticoagulation.
Drugs that reduce the effect of warfarin
1.Western ginseng
A randomized, double-blind, placebo-controlled clinical trial conducted by Yuan et al. at the University of Chicago showed that American ginseng reduced the anticoagulant effect of warfarin. The results showed that the INR of the American ginseng group was significantly lower than that of the placebo group after 2 weeks. Therefore, it is recommended that physicians should ask detailed questions about the use of American ginseng before administering warfarin to patients.
2.Ribavirin
Schulman from Sweden reported that a 61-year-old male patient who had undergone heart valve replacement and had been taking Warfarin for a long time was treated with Ribavirin for hepatitis C due to blood transfusion infection, and it was found that the dosage of Warfarin needed to be increased by 40% to maintain the desired anticoagulant effect. The mechanism of action is not known. Weekly monitoring of prothrombin time is recommended during the use of ribavirin. Warfarin has a narrow therapeutic window and a minor effect on anticoagulation can have significant consequences.