14A21: Exam Report
Compare and contrast the mechanism of action, pharmacokinetics, adverse effects and monitoring of effect of dabigatran and warfarin.
29% of candidates passed this question.
Most candidates were able to provide some details about warfarin however dabigatran was less well known. The syllabus provides a guide to depth of knowledge required for listed drugs and so more detail was expected for Warfarin as a class “A” drug than was expected for dabigatran (a class “C” drug). It was however expected that candidates would provide more than just generalisation regarding “hepatic metabolism and renal excretion”when applied to both agents that actually have different modes of elimination.
Q2i / 14A21: Compare and contrast the mechanism of action, pharmacokinetics, adverse effects and monitoring of effect of dabigatran and warfarin
Warfarin
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
Dabigatran
A benzamidine based thrombin inhibitor (it is a non-peptide reversible thrombin inhibitor)
MoA
Warfarin
Inhibits production of Vit K dependent clotting factors & proteins
Formation of these requires y-CARBOXYLATION
Warfarin inhibits EPOXIDE REDUCTASE. This enzyme reduces oxidised Vit K so it may be used again
∴ no cofactor for carboxylation → ↓ synthesis clotting factor & protein C/S
PK
Warfarin
Dabigatran
A
Warfarin
High lipid solubility
100% OBA
Rapid absorption
Peak plasma 4h
Dabigatran
Low OBA 6.5% absorbed in acidic stomach & SI
D
Warfarin
99% PPB (albumin)
VD 0.1L/kg
Small due to high PPB
Dabigatran
VD 60 – 70L; Low PPB
M
Warfarin
Entirely by liver
Phase 1 & 2 reaction
CYP450
Metabolites then conjugated & glucoside
Dabigatran
Plasma + liver esterases convert to DABIGATRAN (active)
20% conjugated & excreted in biliary system
E
Warfarin
Metabolites excreted in urine & faeces
t ½ = 40hrs prolonged
Dabigatran
Rest renally excreted unchanged
↓
Dose adjustment for renal impairment
AE
Warfarin
Bleeding. Easier to reverse
- Cease warfarin!
- Vitamin K
- FFP
- Prothrombinex
- Activated FVII
Teratogenic
Dabigatran
Bleeding. Difficult to reverse;
Idarucizumab
Monitoring
Warfarin
Warfarin is reported by monitoring INR, which is the Prothrombin Time (ext & common pathway) according to International Reference Thromboplastin
Dabigatran
Linear relationship with both tests:
- Thrombin Clotting Time
- Ecarin Clotting Time
Marketed as an anticoag which doesn’t require monitoring but levels vary wide & BMJ exposed drug company as withholding info
Comparison
Warfarin
- Relatively easier to monitor
- Narrow ther index
- Multiple drug interactions
- No dose adjustment w renal impairment
- Easy reversal
- Cheaper & more common
Dabigatran
- Renal adjustment
- Difficult to monitor
- Expensive