Introduction

Warfarin is widely used as an anticoagulant used in the management of atrial fibrillation and venous thromboembolism. Many patients who would previously have been prescribed warfarin are now given direct oral
anticoagulants (DOACs).

Mechanism of action

Warfarin is an oral anticoagulant which inhibits epoxide reductase preventing the reduction of vitamin K to its active hydroquinone form, which in turn acts as a cofactor in the carboxylation of clotting factor II, VII, IX and X (mnemonic = 1972) and protein C.

Indications

  • Venous thromboembolism: target INR = 2.5, if recurrent 3.5
  • Atrial fibrillation, target INR = 2.5
  • Mechanical heart valves, target INR depends on the valve type and location. Mitral valves generally require a higher INR than aortic valves.

Adverse effects

  • Haemorrhage
  • Teratogenic, although can be used in breastfeeding mothers
  • Skin necrosis: when warfarin is first started biosynthesis of protein C is reduced. This results in a temporary procoagulant state after initially starting warfarin, normally avoided by concurrent heparin administration. Thrombosis may occur in venules leading to skin necrosis
  • Purple toes

Contraindications

General factors that may potentiate warfarin
  • Liver disease
  • P450 enzyme inhibitors (see below)
  • Cranberry juice
  • Drugs which displace warfarin from plasma albumin, e.g. NSAIDs
  • Inhibit platelet function: NSAIDs

Drugs which either inhibit or induce the P450 system may affect the metabolism of warfarin and hence the INR:

Inducers of the P450 system include - INR will decreaseInhibitors of the P450 system include - INR will increase
  • Antiepileptics: phenytoin, carbamazepine
  • Barbiturates: phenobarbitone
  • Rifampicin
  • St John's Wort
  • Chronic alcohol intake
  • Griseofulvin
  • Smoking (affects CYP1A2, reason why smokers require more aminophylline)
  • Antibiotics: ciprofloxacin, erythromycin
  • Isoniazid
  • Cimetidine,omeprazole
  • Amiodarone
  • Allopurinol
  • Imidazoles: ketoconazole, fluconazole
  • SSRIs: fluoxetine, sertraline
  • Ritonavir
  • Sodium valproate
  • Acute alcohol intake
  • Quinupristin

Monitoring

Patients on warfarin are monitored using the INR (international normalised ration), the ratio of the prothrombin time for the patient over the normal prothrombin time. Warfarin has a long half-life and achieving a stable INR may take several days. There a variety of loading regimes and computer software is now often used to alter the dose.