• Inhibits vitamin-K reduction after its oxidation by inhibiting the enzyme epoxide reductase 
• This inhibits blood clotting by interfering with hepatic synthesis of vitamin K-dependent clotting factors II (prothrombin), VII, IX, and X, and anti-coagulation proteins C and S
• Has NO in-vitro anticoagulant effects like heparin
• Warfarin is an anti-coagulant!!!

• Vitamin-K is activated in the liver by a cycle of oxidation+ reduction to form active vitamin-K 
• Vitamin-K convert glumatic acid residues in clotting factors II, VII, IX, and X to gamma-carboxygluatmic acid residues
• Gamma-carboxygluatmic acid has a high affinity for Ca++ and phospholipid

Pharmacokinetics of warfarin 

Onset

Absorption

Duration

Termination

• Onset:  Considerably delayed (36-72 hours). Because the shortest half-life of clotting factors is 6 hours (for factor VII)
• Absorption:  Completely absorbed in the GI tract and HIGHLY fat soluble. 99% is bound to albumin (really well known interaction) 
• Duration:  Prolonged with a high-life of 36 hours 
• Termination:  There is slow drug elimination rate so delayed elimination.  Also prothrombin + other factors need to be synthesized (which takes time).  Warfarin is inactivated to a metabolite form in the liver + kidney.  Elimated via stool + urine.  

• Hemorrhage
• Anorexia/nausea/vomitting/diarrhea 
• Cutaneous lesions:  

          Skin necrosis

          Dermatitis

          Alopecia

          Purpura 

• Same as heparin but also includes pregnancy + unrealiable patients 
• Recent eye/brain/spinal cord surgery 
• Head injury 
• Uncontrolled bleeding 
• Severe HTN (high risk for bleeding)
• Suspected aneurysm (high risk for bleeding) 

• General:  Hospitals start patients on heparin in the hospital and follow with warfarin for long-term therapy
• DVT 
• PE
• A. Fib (ONLY in older patients)
• MI (prevent mural thrombosis + systemic embolism)
• Rheumatic heart disease (b/c risk of embolism) 
• Mechanical prosthetic valve/bioprosthetic mitral valve  

Risk of warfarin toxicity if used over long periods outweights the beneficial effects of using warfarin in younger patients 

Warfarin ROA 

Factors influencing warfarin treatment?

• ONLY given orally
• There are many factors that influence the effectiveness of warfarin:  

          -Differences in absorption

          -Sensitivity to drug

          -Elimination

          -Drug-drug interactions (there are LOTS of these)

          -Age/clinical state/dietary intake of vitamin K/Dietary intake of              fat/presence of vitamin-K synthesizing microflora  

• Warfarin is monitoried during INR (PT-test)
• This should be determined BEFORE starting dose and then daily until response is stabilized.  And then weekly until maintenace dose is established

INR = 2.0-3.0 is the usual target for less intense therapy

This causes a 2X or 3X of the normal clotthing time

• Effects can be reversed by:

1. Withdrawel of the drug (but remember there is a prolonged elimination of the drug)
2. Administration of vitamin K1 
3. If necessary, infusion of fresh-frozen plasma or plasma rich in factors II, VII, IX, and X