Question 21

Compare and contrast the mechanism of action, pharmacokinetics, adverse effects and  monitoring of effect of dabigatran and warfarin.

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College Answer

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 generalisations regarding “hepatic metabolism and renal excretion” when applied to both agents that actually have different modes of elimination.


  Warfarin Dabigatran
Class Vitamin K antagonist Direct thrombin inhibitor
Chemistry Coumarin derivative Small molecule polypeptide
Routes of administration Oral only Oral only
Absorption Rapidly absorbed
High oral bioavailablility (~ 100%)
Maximum blood concentration about 90 minutes after administration
Available as dabigatran etexilate, which is a pro-drug; dabigatran on its own is mch too polar to be absorbed effectively.
The exetilate is rapidly absorbed
High oral bioavailablility (~ 100%)
Maximum blood concentration about 90-180 minutes after administration
Solubility pKa 5.87; practically insoluble in water pKa 4.0, solubility in water is not very good
Distribution VOD=0.08-0.12, 99% protein-bound VOD=1.0L/kg; 35% protein-bound
Target receptor vitamin K epoxide reductase complex 1 Thrombin
Metabolism The more potent S-isomer is metabolised by hepatic CYP2C9 to 7-hydroxywarfarin, an inactive hydroxylated metabolite.
Another route is through reductases, into reduced metabolites (warfarin alcohols) with minimal anticoagulant activity.
Mainly renally excreted as unchanged drug; but about 20% is conjugated
with glucuronic acid to form acylglucuronides.
These conjugates are pharmacologically active and demonstrate almost identical properties of free, unconjugated dabigatran.
Elimination All of the metabolites ultimately make their way out in the urine. 92% of the radiolabelled dose is recovered in urine after 1 week.
Minimal free warfarin is renally excreted
80% renal excretion of unchanged drug
20% biliary excretion of acylglucouronides
Time course of action Terminal half-life of warfarin after a single dose is approximately 1 week;
Effective half-life ranges from 20 to 60 hours
Mean half-life is about 36-42 hours.
Half life = 12-14 hours
Mechanism of action Warfarin interferes with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the γ-carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins.Vitamin K-dependent coagulation factors II, VII, IX, and X require γ-carboxylation for their procoagulant activity; thus warfarin therapy results in the hepatic synthesis of ineffective factors. Dabigatran interacts with the active site of thrombin, and acts as a competitive inhibitor of thrombin. It inactivates thrombin, including fibrin-bound thrombin.
This is a reversible reaction.
Some thrombin remains active to produce haemostasis.
Clinical effects Bleeding, skin necrosis, systemic microemboli, calciphylaxis Bleeding, insomnia, fever, periphral oedema
Single best reference for further information TGA PI document TGA PI document


Tran, Huyen, et al. "New oral anticoagulants: a practical guide on prescription, laboratory testing and peri‐procedural/bleeding management." Internal medicine journal 44.6 (2014): 525-536.

Yeh, Calvin H., James C. Fredenburgh, and Jeffrey I. Weitz. "Oral direct factor Xa inhibitors.Circulation research 111.8 (2012): 1069-1078.

Ansell, Jack, et al. "The pharmacology and management of the vitamin K antagonists." Chest 126.suppl 3 (2004): 204S-233S.

Scaglione, Francesco. "New oral anticoagulants: comparative pharmacology with vitamin K antagonists." Clinical pharmacokinetics 52.2 (2013): 69-82.

Stangier, Joachim, and Andreas Clemens. "Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor." Clinical and Applied Thrombosis/Hemostasis (2009).