WARFARIN

  • Important drug – know the PK, PD, drug interactions and the toxicity of warfarin.
Structure/class
  1. Oral anticoagulant (coumarin)
Pharmacodynamics
  1. Functions by blocking the γ (gamma) carboxylation of several glutamate residues in factors II, VII, IX and X. Also blocks the endogenous anticoagulants Protein C and Protein S.
  2. Also inhibits the reduction of inactive Vit K epoxide to its active hydroxyquinone form.
  3. Action of warfarin is delated by 8-12 hours. This is due to the partially inhibited synthesis, but unaltered degradation of the Vit K dependent factors (II, VII, IX and X)
Absorption/administration
  1. PO or IV, 2-10mg.
  2. Warfarin has a bioavailability of 100%.
Distribution
  1. It is 99% bound to plasma albumin, and therefore has very small Vd (0.12L/kg)
  2. It has a very long half-life of 36 hours.
Metabolism
  1. Liver – bound to glucuronides.
Excretion
  1. Excreted via enterohepatic circulation, in the stool and in urine.
Indications
  1. Hypercoagulable states – DVT/PE
  2. AF and prevention of ischaemic stroke.
  3. Prevention of clotting on prosthetic valves
Contraindications
  1. Active bleeding
  2. Any potential for serious life-threatening bleed
  3. Pregnancy (absolute CI).
    • Due to risk of haemorrhage in fetus and development of birth defects.
Special precautions  
Interactions
  1. Warfarin has many interactions with other drugs or disease states, due to changes in PK/PD.
Drugs/situations that increase PT/INR Drugs/situations that decrease PT/INR
PK PD PK PD
MetronidazoleFluconazoleBactrim

Amiodarone

Disulfiram

Cimetidine

 AspirinHeparinCephalosporins (esp. 3rd gen)

Body factors, like

Hepatic dysf(x) and

Hyperthyroidism

 BarbituratesRifampicinCholestyramine DiureticsVitamin KBody factors, like hereditary resistance and hypothyroidism
  • Diuretics (e.g. spironolactone) decrease PT due to concentration of clotting factors.
  • Hypo/hyperthyroidism both reduce/increase turnover of Vit K dependent factors.
  • 3rd generation cephalosporins eliminate GI bacteria that produce Vit K.
Adverse effects
Dosing/administration
  1. Titrate to INR 2-3, or 2.5-3.5 if prosthetic valve
Toxicology
  1. Bleeding
    • Cease drug.
    • Use Vitamin K/Prothrombin Complex Concentrate (Prothrombinex)/FFP/Recombinant Factor VII (NovoSeven)
  2. Hypercoagulable states
    • This is due to inhibition of protein C.
    • May cause tissue necrosis (especially cutaneous/breast/intestine)
Withdrawal syndrome  
Special notes
  1. Note that ethanol, phenothiazines, benzodiazepines, paracetamol, opioids, indomethacin and most other antibiotics (other than the ones listed above) are thought to have no significant effects on anti-coagulation.