MOA: Competitive direct thrombin inhibitor. Blocks pivotal part of common pathway

Gastric irritation (tartaric acid)

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.

5% PO bioavailability

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

35% protein bound

99% protein bound, predominantly albumin

Vd 0.1L/Kg

Rapidly metabolized to active Dabigitran by hepatic and plasma esterases
Not metabolized further

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

Renal excretion

Metabolites excreted in urine and feces

T1/2= 12-17 hours

T1/2= 40 hours

Bleeding

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

Anticoagulants

Anticoagulants

1. Non-valvular AF
2. VTE prophylaxis in orthopaedic
3. VTE treatment

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

Competitive Direct Thrombin Inhibitor

Coumarin derivative

Level 2

Level 1

PO (Dabigitran etexilate- prodrug)

Monitor:
Direct assays of Thrombin activity:
- Thrombin time (TT)
- Ecarin clotting time (ECT)
- APTT 2.5x >control= increased risk of bleeding

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)

Reversal:
Idarucizumab

Cons:
1. Many drug interactions
2. Excretion dependent on renal function

Pros:
1. Predictable kinetics not affected by age, weight or gender
2. Oral
3. Monitoring generally not indicated
4. Reversal agent available
5. Lower bleeding risk than warfarin

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