Warfarin Drug Info

Warfarin Uses | Indications
Warfarin is a blood thinning agent (anticoagulant) used to reduce the formation of blood clots (thrombosis) by inhibiting clotting factors in the body. It is indicated for prevention of disease associated with thrombosis including heart attacks, strokes, atrial fibrillation, deep vein thrombosis (DVT) and pulmonary embolism (PE). Embolism is an abnormal formation and migration of blood clots (thrombosis) where it would result in blocking supply to a vital organ. Warfarin is one of the most widely used and practised oral anticoagulant drug in North America.


Besides, warfarin is purposed for areas with slow flowing blood such as in veins and pool of blood in artificial and natural valves, and also in dysfunctional cardiac atria. Plus, warfarin may be used for secondary prevention of myocardial infarctions, though it is less effective in preventing the formation of new thromboses in coronary arteries.


Warfarin Mechanism of Actions | How it works
Warfarin works by inhibiting the vitamin K-dependent synthesis of calcium-dependent clotting factors (which are of active forms) include factors II, VII, IX and X (2,7,9,10). Furthermore, the regulatory factors of protein C, cofactor protein S, and protein Z would be inhibited as well. However, proteins that are not clotting factors may be influenced to a certain extent, such as osteocalcin and matrix Gla protein.


Before we go into details for mechanism of action of warfarin, we have to understand normal mechanism of clotting process. From the diagram above, we can see that the precursors of the clotting factors mentioned above (prothrombin precursor) require carboxylation of their glutamic acid residues catalyzed by gamma-glutamyl carboxylase to become active form (prothrombin), before being able to bind to phospholipid membrane on vascular endothelium of blood vessels. (The newly formed Gla residues from Glu chelate strongly and selectively with calcium ion in which the latter would form ion bridges with the anionic phosphate groups of phospholipid membrance surfaces)


However, the carboxylation process will only be able to proceed in the presence of reduced form of vitamin K (or known as vitamin K hydroquinone). The vitamin K cycle involves enzyme Vitamin KO reductase (or vitamin K epoxide reductase) which reduce oxidized vitamin K (or vitamin K epoxide) to vitamin K which would be then converted to vitamin K hydroquinone by enzyme vitamin k reductase.


Warfarin is a vitamin K antagonist which inhibits epoxide reductase step. Hence, vitamin K cannot be formed and thus would diminish availalbe vitamin K hydroquinone in the tissues, lead to the inhibition of carboxylation activity of glutamyl carboxylate. Active clotting factors no longer can be formed and the final result would be anticoagulation effect. However, the anticoauglation activity of warfarin can only be seen apparent after 3 to 5 days due to the half life of previously produced active factors which degrade over several days before replaced by new inactive actors. Furthermore, due to the inhibition of protein C and protein S (vitamin K dependent) which play their role in anticlotting as well, warfarin may cause formation of clot temporarily leading to prothrombic state. 
Hence, it is normally practised to co-administer heparin intravenously to the patient which help reduce the risk of thromosis together with warfarin therapy for 4 to 5 days, with the purpose to have heparin anticoagulation effect before the full activitly of warfarin is achieved.


Warfarin Side Effects
Hemorrhage
The most common side effects of warfarin due to its blood thinning effect would be hemorrhage (bleeding). However, mild bleeding is commonly reported and most of them can be managed and controlled well while the risk of severe bleeding is small (estimate of 0.9% to 2.7% has been reported annually). Hence, it is important to evaluate the beneifts over risk ratio before starting any warfarin therapy. The common bleeding side effects associated would be hemoptysis (coughing or spitting blood), excessive or unusual bleeding, gums or nose bleeding, bleeding from vagina or rectum, bloody / black urine or stool.


The risks of bleeding would be higher if warfarin is concurrently taken with other antiplatelet or anticoauglant (fibrinolytic) agents which include aspirin, clopidogrel or NSAIDs (eg. ibuprofen, indomethacin). Also, The risk of bleeding would be higher in elderly patients or patients undergoing hemodialysis while on warfarin therapy.


Skin Necrosis
Warfarin induced necrosis would be one of the rare but serious complication of warfarin treatment. This normally occurs shortly after starting warfarin therapy in patients with protein C defiency. This is because Protein C is an innate anticogulant (vitamin K dependent) which play its role similar to other procogulant factors. Also, protein C requires Vitamin K for its carboxylation activity. And since warfarin initially reduces protein C levels faster than other coagulation factors, paradoxcially it would raise up blood's tendency to coagulate during starting of treatment. This may lead to skin necrosis and gangrene of limbs due to massive thrombosis. Due to this, heparin is normally given to patient for 3 to 5 days to counter this problem before warfarin full activily is achieved.
Similary, protein S deficiency may be affects in the same way as what happen to protein C deficiency.


Osteoporosis
Long-term use of warfarin is associated witth osteoporosis-related fractured. Study of 572 women in 1999 showed that risk of vertebral fracture and rib fracture was increased in patients taking warfarin for deep vein thrombosis. Also, retrospective study of 14564 Medicare recipients for more than 1 year demonstrated 60% increased risk of osteoporosis-related fracture in men, however, there was no association in women. The mechanism was thought due to the reduced intake of vitamin K responsible for bone health.


Purple toe syndrome
This is a rare side effects of warfarin which may occur during 3 to 8 weeks after starting of warfarin treatment. The mechanism was thought to result from cholesterol embolism that flow into the blood vessels in the skin of feet and obstruct it, leading to blueish purple color which may be painful.


Drug-Drug Interactions
Increase INR value which increases risk of bleeding
Analgesics (acetaminophen, aspirin, topical salicylates, tramadol)
Antiarrhythimics (amiodraone, propafenone)
Antibiotics (examples include amoxicillin, cephalosporins, isoniazid, fluoroquinolones, macrolides, metronidazole, sulfonamides, telithromycin, tetracyclines)
Anticonvulsants (phenytoin which is biphasic, increase initially and decrease in long term, sodium valproate)
Antidepressants (duloxetine, venlafaxine, SSRI e.g. fluoxetine, fluvoxamine, setraline, paroxetine and citalopram)
Antifungals (itraconazole, fluconazole, ketoconazole, miconazole, voriconazole)
Antihyperlipidemics (fenofibrate, ezetimibe, fluvastatin, gemfibrozil, simvastatin)
Others include allopurinol, cimetidine, oral corticosteroids, proton pump inhibitors and thyroid supplements


Decrease INR value which increase risk of blood clotting
Antibiotics (rifampin)
Antidepressants (trazodone)
Antiepileptics (phenytoin, carbamazepine, phenobarbitone, primodone)
Other include antithyroid agents,cholestyramine


Drug Foods Interactions / herbs & supplements
Increase INR value
Alcohol (excessive), Dansh, glucosamine (with or without chondroitin), Birch, Dong Quai, grapefruit, Chitosan, fish oil, mango, cranberry juice, garlic supplement, papaya extract
Decrease INR value
Alcohol (chronic), smoking, coenzyme q10, ginseng, St. John's Wort, high dose of Vitamin C, Vitamin K (greeny vegetables)


Warfarin Dosage
Initial dose (loading dose) would be 5 mg/day for 3 to 5 days. For rapid anticoagulation effect, 10 mg/day for 2 days. After INR value is obtained, warfarin dose should be adjusted based on the INR or prothrombin time. Usual maintenance dose would be 2-10 mg daily depending on INR. Lower initial dose should be given to elderly patient, or to the patient concurrently taking medications / supplement that would increase INR value.