Warfarin

Chemical

Synthetically derived coumarin anticoagulant

NB: coumarin is a chemical in many plants

The term comes from the French ‘tonka bean’ = COUMAROU, from where coumarin was first isolated

Use

  1. Prevent emboli in AF, value disease, prosthetic valves
  2. Tx DVT/PE

Presentation

Oral tablets 1 – 10mg

Racemix mixture

S-isomer x 4 potent

Dose / Route

5 – 10mg OD orally for 3 days

→ Daily bloods

→ Then alternate days for 1/52

→ Then fortnightly

 

Dose/route overlap for a minimum of 5 days, until target INR has been reached for at least two consecutive days (Pisters et al. 2010; Rossi 2015).

Because of the shorter half life of protein C and S they drop prior to the clotting factors and as such warfarin can produce an pro-thrombotic phenotype in the first few days

 

Target INR

AF 2 – 2.5

Prosthetic valve 2.5 – 3.5

All else 2 – 3

Onset

8 – 12hrs onset

  • Warfarin halts production of new clotting factors
  • No effect on already active factors
  • ∴requires hours for full effect (for all of those factors to be degraded) → mainly F II (PRO THROMBIN)

DoA

Half lives:

of Protein C/s → 7 → 9 → 10 → 2

=          7                 6    24      40     60hrs

DoA → effects last 2 – 5 days (life of clotting factors)

Very slow clearance 3mL/kg/min & new clotting factors need to be synthesised

MoA (mechanism)

  • Inhibits production of Vit K dependent clotting factors & proteins
  • Vit K is required to synthesise:
    • 4 clotting factors: II, VII, IX, X (TV channels)
    • ­­­2 anticoag proteins; Pr C & S
  • Formation of these requires y-CARBOXYLATION
  • Reduced Vit K (as cofactor)
  • Warfarin inhibits EPOXIDE REDUCTASE. This enzyme reduces oxidised Vit K so it may be used again
  • ∴ no cofactor for carboxylation → ↓ synthesis clotting factor & protein
Carboxylation

NB: y-CARBOXYLATION allows activated factors to chelate Ca2+ → binds phospholipids → procoagulant

PK

A

High lipid solubility

100% OBA

Rapid absorption

Peak plasma 4h

D

99% PPB (albumin)

VD 0.1L/kg

Small due to high PPB

M

Entirely by liver

Phase 1 & 2 reaction

CYP450

Metabolites then conjugated & glucoside 

E

Metabolites excreted in urine & faeces

t ½ = 40hrs prolonged

Predictability

Highly variable

  • VIT K AVAILABILITY
    • Diet
    • ↓synthesis
    • ↓absorption (requires bile salts)
    • Albumin alters Vit K absorption
  • LIVER DISEASE
    • ↓synthesis clotting factors
    • Altered metabolism of warfarin
  • METABOLISM
    • Fever/hyperthyroid → ↑breakdown coag factors
    • Myxoedema → ↓breakdown coag factors
  • DRUG INTERACTIONS
    • Susceptible due to high PPB & sole liver metabolism

Enhanced Effect

NSAIDs/Aspirin (high PPB)

EtOH → prolongs clearance

Other PPB competitors

  • Amiodarone
  • Cimetidine
  • Metronidazole
  • Erythromycin

Decreased Effect

Liver enzyme inducers

  • Barbituates
  • OCP
  • Phenytoin
  • Rifampicin

Adverse Effects

  • Bleeding (nose, urine, head, menstrual, GI etc)
  • Teratogenic → crosses placenta
  • Cutaneous necrosis → may occur in patients with ↓activity of Pr C

Monitoring

  • Warfarin is reported by monitoring INR, which is the Prothrombin Time (ext & common pathway) according to International Reference Thromboplastin

Reversal

  • Cease warfarin!
  • Vitamin K
  • FFP
  • Prothrombinex
  • Activated FVII