Core pharmacology

Class Group

Anticoagulants

Legacy Cicm Level

Level 1

Introduction

Coumarin derivative

Indications Uses

1. AF
2. Thromboprophylaxis in rheumatic or prosthetic valves
3. Prophylaxis and treatment of DVT/PE

Presentation

Racemic mixture of warfarin sodium (S enantiomer is 2-5x more potent)
0.5/1/3/5mg tablets
Maximum effect 18-72 hours after dose

Monitor:
INR aim generally 2.0-4.5 depending on indication (most commonly 2-3)

Mechanism of action

Vitamin K is responsible for the gamma-carboxylation of glutamic residues of inactive precursors of clotting factors 2,7,9,10. Warfarin prevents the return of vitamin K to its reduced form, inhibiting the activation of these factors.

Adverse Effects Toxicity

1. Hemorrhage
2. Teratogenicity - More common and serious in first trimester
3. In third trimester it may cross the placenta and cause fetal hemorrhage.

Absorption

- Rapidly and completely orally absorbed with bioavailability of 100%
- Onset 8 hours post dose

Protein binding

99% protein bound, predominantly albumin

Volume of distribution

Vd 0.1L/Kg

Metabolism

Completely hepatically metabolized
Oxidation of L-form and reduction of D-form. Then conjugated with glucuronide.

Excretion

Metabolites excreted in urine and feces

Half-life

T1/2= 40 hours

Special Points

Reversal:
1. Vitamin K
2. FFP
3. 4-factor PCC (Prothrombinex: 3-factor PCC available in Australia)

Increase effect:
1. Cyp inhibitors- many antibiotics, cimetidine, amiodarone
2. Competitive plasma protein binding (Amiodarone, NSAIDs)
3. Decreased intake of vitamin K
CYP2C9 genetic polymorphism

Decrease effect:
1. CYP inducers- rifampicin, phenytoin, carbamazepine
2. Increased dietary intake of vitamin K
CYP2C9 genetic polymorphism