Compare and contrast the mechanism of action, pharmacokinetics, adverse effects and monitoring of effect of dabigatran and warfarin.
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.
|Class||Vitamin K antagonist||Direct thrombin inhibitor|
|Chemistry||Coumarin derivative||Small molecule polypeptide|
|Routes of administration||Oral only||Oral only|
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).