Warfarin

Common indications

• Prevention of thrombus extension or recurrent thrombosis in deep vein thrombosis and pulmonary embolism.
• Prevention of thromboembolism during atrial fibrillation.
• Prevention of thromboembolism after heart valve replacement.

 

Mechanisms of action

1. Warfarin inhibits vitamin K epoxide reductase.
2. Oxidised vitamin K is reduced (and therefore reactivated) at a lower rate.
3. There is insufficient reduced vitamin K available for the synthesis of vitamin K dependent coagulation factors. 
4. There is reduced activation of clotting factors II, VII, IX and X. There is also reduced activation of anticoagulation factors protein C and protein S.

 

Important adverse effects

• Bleeding
• Warfarin necrosis 
• Osteoporosis
• Blue toe syndrome
• Valve calcification 

 

Warnings

• As there is a fine line between thrombosis and haemorrhage in patients taking warfarin, potential risks and benefits must be carefully balanced.
• Warfarin is contraindicated in patients at immediate risk of haemorrhage, including after trauma and in patients requiring surgery.
• Patients with liver disease who are less able to metabolise the drug are at risk of over-anticoagulation/bleeding.
• In pregnancy, warfarin should not be used in the first trimester as it causes fetal malformations, including cardiac and cranial abnormalities. It should not be used towards term, when it may cause maternal haemorrhage at delivery.

 

Important interactions

• The plasma concentration of warfarin required to prevent clotting is very close to the concentration that causes bleeding (low therapeutic index). Small changes in hepatic warfarin metabolism by cytochrome P450 enzymes can cause clinically significant changes in anticoagulation. 
• Cytochrome P450 inhibitors (e.g. fluconazole, macrolides, protease inhibitors) decrease warfarin metabolism and increase bleeding risk. 
• Cytochrome P450 inducers (e.g. phenytoin, carbamazepine, rifampicin) increase warfarin metabolism and risk of clots. 
• Many antibiotics can increase anticoagulation in patients on warfarin by killing gut flora which synthesise vitamin K.