32. Drug Interactions with Warfarin: Potentiation
Level of
Evidence Potentiation
Alcohol (if concomitant liver disease) amiodarone (anabolic steroids,
cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600
mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam,
propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition)
Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram,
itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen,
tetracycline, flu vaccine
Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide, ketoprofen,
iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin,
propoxyphene, sulindac, tolmetin, topical salicylates
Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole
I
II
III
IV
†In a small number of volunteer subjects, an inhibitory drug interaction occurred.
33. Drug Interactions with Warfarin: Inhibition
Level of
Evidence Inhibition
Barbiturates, carbamazepine, chlordiazepoxide,
cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate
Dicloxacillin
Azathioprine, cyclosporine, etretinate, trazodone
I
II
III
IV
34. Drug Interactions with Warfarin: No Effect
Level of
Evidence No Effect
Alcohol, antacids, atenolol, bumetadine, enoxacin,
famotidine, fluoxetine, ketorolac metoprolol, naproxen,
nizatidine, psyllium, ranitidine‡
Ibuprofen, ketoconazole
Diltiazem, tobacco, vancomycin
I
II
III
IV
53. Signs of Warfarin Overdosage
Any unusual bleeding:
Blood in stools or urine
Excessive menstrual bleeding
Bruising
Excessive nose bleeds/bleeding gums
Persistent oozing from superficial injuries
Bleeding from tumor, ulcer, or other lesion
65. Managing Patients with High INR Values/
Minor or No Bleeding
Clinical Situation
INR >therapeutic range but <5.0,
no clinically significant bleeding,
rapid reversal not indicated for
reasons of surgical intervention
Guidelines
Lower the dose or omit the next dose; resume warfarin
therapy at a lower dose when the INR approaches desired
range
If the INR is only minimally above therapeutic range, dose
reduction may not be necessary
Patients with no additional risk factors for bleeding; omit
the next dose or two of warfarin, monitor INR more
frequently, and resume warfarin therapy at a lower dose
when the INR is in therapeutic range
Patients at increased risk of bleeding: omit the next dose
of warfarin, and give vitamin K1 (1.0 to 2.5 mg orally)
Patients requiring more rapid reversal before urgent
surgery or dental extraction: vitamin K1 (2–4 mg orally); if
the INR remains high at 24 h, an additional dose of 1–
2 mg
INR >5.0 but <9.0, no clinically
significant bleeding
66. Managing Patients with High INR Values/
Serious Bleeding
Clinical Situation
INR >9.0, no clinically significant
bleeding
Life-threatening bleeding or serious
warfarin overdose
Continuing warfarin therapy
indicated after high doses of
vitamin K1
Guidelines
Vitamin K1 (3–5 mg orally); closely monitor the INR; if the
INR is not substantially reduced by 24–24 h, the vitamin K1
dose can be repeated
Serious bleeding, or major warfarin overdose (e.g., INR
>20.0) requiring very rapid reversal of anticoagulant effect:
Vitamin K1 (10 mg by slow IV infusion), with fresh plasma
transfusion or prothrombin complex concentrate,
depending upon urgency; vitamin K1 injections may be
needed q12h
Prothrombin complex concentrate, with vitamin K1 (10 mg
by slow IV infusion); repeat if necessary, depending upon
the INR
Heparin, until the effects of vitamin K1 have been reversed,
and patient is responsive to warfarin
Editor's Notes
The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway).
Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by Ixa (in the presence of Factor VIII).
The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor Ixa then activates Factor X.
Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin.
Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide.
Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 4–5 days when starting therapy.
The four Vitamin K dependent clotting factors are synthesized in the liver.
The Vitamin K dependent clotting factors are carboxylated in a reaction that is linked to the oxidation of the reduced form of the vitamin . The non carboxylated forms of these clotting factors are inactive because they cannot bind calcium. When Vitamin K is deficient, non-carboxylated prothrombin is secreted and this protein is non functional. Carboxylation of terminal glutamic acid side chains (known as the Glu to Gla conversion) allows the clotting factors to bind calcium which in turn bridges the clotting factors to phospholipid surfaces, a necessary requirement for their activity.
Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity.
Warfarin works by interfering with internal recycling of oxidized Vitamin K to the reduced form. When warfarin is given, the oxidized form of Vitamin K builds up in the blood leading to a deficiency of reduced Vitamin K and a decrease in carboxylation of prothrombin.
Warfarin interferes with g–carboxylation of terminal glutamic acids on the procoagulant proteins, Factors II, VII, IX, and X. g–carboxylation from the Glu to the Gla form of these proteins in a critical step in the biosynthesis of these proteins that is required their normal function in coagulation.
g–carboxylation is a post-translational step that is Vitamin K dependent and linked to the oxidation of hydroquinone (the active cloting form of Vitamin K) to the Vitamin K epoxide. The reaction uses molecular oxygen for the conversion of hydroquinone to the epoxide, and CO2, for the g–carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive Glu to the active Gla form.
Under normal physiologic circumstances, Vitamin K is absorbed as the quinone form (Vitamin K1). The quinone is reduced to the hydroquinone (the reduced form), which in turn is oxidized to Vitamin K epoxide (the oxidized form). The active cofactor form of Vitamin K (hydroquinone) is then regenerated through two reduction steps. First the 2–3 epoxide is reduced to the quinone (the dietary source of Vitamin K1). This is then reduced to the hydroquinone which, when recycled to the epoxide, acts as the cofactor for the Glu to Gla conversion of the Vitamin K dependent coagulation factors by blocking both reduction steps, thereby depleting the stores of the hydroquinone form of Vitamin K.
Virchow’s Triad defines the pathophysiology of thrombotic disease. Thrombosis occurs when one or more of the three components of Virchow’s Triad are present. Accordingly, thrombosis is caused by abnormalities of blood flow (stasis), abnormalities of blood vessels (endothelial injury), or abnormalities of the blood itself (a hypercoagulable state).
This slide lists the various drugs that have been reported to interact with and potentate warfarin The strength of the evidence is shown in the left hand column with level I being strongest and level IV the weakest based on the study design of the report.
This slide lists the various drugs and foods that have been reported to interact with and inhibit warfarin. The strength of the evidence is shown in the left hand column.
This slide lists the venous drugs and foods that have been reported to have no effect on warfarin The strength of the evidence is shown in the left hand column. With excessive consumption, alcohol potentiates the effect (Slide 33), but when limited to two glasses of wine /day, it has been reported not to influence the ant/coagulant effect of warfarin.
The signs of warfarin overdosage are listed on this slide.
Hemorrhagic complications from warfarin therapy are more likely to occur with excessive degrees of anticoagulation, but even with an INR in the therapeutic range, bleeding can occur. Because of the likelihood of finding an underlying lesion in an individual who has gastrointestinal bleeding or significant genito-urinary bleeding in the face of therapeutic levels of anticoagulation, one is advised to consider and evaluate for underlying abnormalities predisposing to the bleeding. The return on such evaluations in the face of an excessive degree of anticoagulation diminishes, and one must use judgement whether or not to pursue an evaluation.
An approach to the management of patients who are excessively over anticoagulated and either have minor bleeding or no obvious bleeding is outlined on this slide.
In all cases, warfarin treatment should be interrupted the INR checked and warfarin restarted at a lower dose when the INR returns to the therapeutic range.
If the INR is above 5 but below 9, oral Vitamin K, should be considered if the patient is at excessive risk of bleeding.
If the INR is between 9 and 20; oral Vitamin K1 should be administered in a dose of 2.5 mg.
If the INR is >20 more aggressive measures should be used. Vitamin K should be administered by slow intravenous infusion over 10 minutes in a dose of at least 5 mg, an infusion of fresh frozen plasma and hospitalization should be considered, and the hematocrit checked for hidden bleeding.
If the INR is excessively out of range and dose not make sense with the recent trend in INR results in individual patients, the clinician is advised to consider the possibility of laboratory error before a dose adjustment is made. In this case, it is optimal to repeat the INR before a dose change is made to verify the results.
If there is serious bleeding, the patient should be hospitalized. Vitamin K should be administered by slow intravenous infusion over 10 minutes in a dose of 5–10 mg, an infusion of fresh frozen plasma should be given Prothrombin concentrate should be considered if bleeding is life-threatening.
