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

Pharm 101 700

Pharmacology 101

Top 200 drugs

MBBS (UWA) CCPU (RCE, Biliary, DVT, E-FAST, AAA) Emergency Medicine Advanced Trainee in Melbourne, Australia. Special interests in diagnostic and procedural ultrasound, medical education, and ECG interpretation. Editor-in-chief of the LITFL ECG Library. Twitter: @rob_buttner

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