Pharm 101: Warfarin

Class

Anticoagulant

Pharmacodynamics

• Two mechanisms of action
  • Blocks y-carboxylation of factors II (prothrombin), VII, IX, X, as well as endogenous proteins C and S, resulting in incomplete, inactive coagulation factor molecules
  • Inhibits recycling of Vitamin K by blocking reduction of inactive Vitamin K to active form
• 8-12 hour delay in action, as anticoagulant effect results from balance between the above two mechanisms
• Resulting inhibition of coagulation is dependent on degradation half-lives in circulation of Vitamin K dependent clotting factors
  • 6, 24, 40, and 60 hours for factors VII, IX, X and II respectively
  • Protein C has a half life of 7 hours

Pharmacokinetics

• 100% oral bioavailability
• 99% bound to plasma proteins
• Small volume of distribution
• Small urinary excretion of unchanged drug
• Half life 36 hours

Clinical uses

• The International Normalised Ratio (INR) is used to measure circulating effective levels of warfarin
  • It is the prothrombin time ratio
  • Prothrombin time should be increased to a level representing a reduction of prothrombin activity to 25% of normal and maintained therefore for long-term therapy

Adverse effects

• Bleeding in toxicity
• Pregnancy (see below)
• Reversal of toxicity
  • Cessation
  • Vitamin K: oral or IV 1-10mg
  • Fresh frozen plasma
  • Prothrombinex
  • Recombinant factor VIIa
  • Note due to the long half life of Warfarin, a single dose of vitamin K or rFVIIa may not be sufficient

Precautions/contraindications

• Pregnancy
  • First trimester: hypoplastic nasal bridge and chrondrodysplasia
  • Second trimester: central nervous system malformations
  • Third trimester: bleeding
• Drug interactions are common in the context of warfarin and can potentiate toxicity or reduce effectiveness of anticoagulation
• INR can be decreased in the setting of:
  • CYP enzyme inducers such as barbiturates, cholestyramine, rifampin
  • Drugs that increase synthesis of clotting factors, such as diuretics and vitamin K
  • Hypothyroidism
• INR can be increased in the setting of:
  • CYP enzyme inhibitors such as amiodarone, bactrim, cimetidine, disulfiram, metronidazole, fluconazole
  • Third generation cephalosporins (eliminate bacteria that produce Vitamin K)
  • Other drugs affecting haemostats such as heparin, apixaban, and high dose aspirin
  • Hepatic disease
  • Hyperthyroidism

Further Reading

• Long N. Warfarin toxicity. LITFL
• Nickson C. Warfarin deliberate self poisoning. LITFL
• Nickson C. Little Johnny and Grandad’s warfarin. LITFL
• Nickson C. Supratherapeutic INR. LITFL
• Nickson C. Warfarin CCC. LITFL