Q2i / 14A21: Dabigatran v warfarin

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

Dabigatran

UNIVALENT THROMBIN INHIBITOR (reversible)

PRODRUG:

Dabigatran etexilate

Pro drug

Dabigatran

 

Binds free & clot bound THROMBIN on catalytic site

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