Warfarin therapy

A patient has a CT-confirmed retroperitoneal haemorrhage. He is on warfarin for

atrial fibrillation. His international normalised ratio (INR) is usually stable between

two and three. It is now eight, and this may be explained by the recent commencement

of a new drug. Of the following drugs, which is the LEAST LIKELY to be

responsible for the derangement?

a) Clopidogrel

b) Paracetamol

c) Amiodarone

d) Fluconazole

e) Metronidazole

Answer: A

Explanation

Warfarin inhibits the effective synthesis of biologically active forms of the vitamin Kdependent

clotting factors: II, VII, IX and X, as well as the regulatory factors: protein C,

protein S and protein Z. The precursors of these factors require carboxylation of their

glutamic acid residues to allow the coagulation factors to bind to phospholipid surfaces.

This carboxylation is linked to oxidation of vitamin K to form vitamin K epoxide,

which is in turn recycled back to the reduced form by the enzyme vitamin K epoxide

reductase (VKOR). Warfarin inhibits VKOR thereby diminishing available vitamin K

stores and inhibiting production of functioning coagulation factors. Most clinically

relevant drug interactions with warfarin involve drugs from only a few classes and

occur by only a handful of mechanisms. Drugs that impair platelet function (e.g.

acetylsalicylic acid, clopidogrel and interestingly some selective serotonin reuptake

inhibitors) increase the risk of bleeding in patients on warfarin but without raising the

INR, hence option (a) is incorrect. The effect of NSAIDs on the gastric mucosa is

another important cause of increased bleeding risk in a warfarinised patient with an

INR within therapeutic range. Many antibiotics enhance the effects of warfarin by

either reducing vitamin K levels by altering the intestinal microflora or by directly

inhibiting hepatic warfarin metabolism. Commercially produced warfarin exists as a

racemic mixture of two isomers, the S-isomer of which is five times more active and is

metabolised by the cytochrome P450 isoenzyme 2C9. Drugs reducing the activity

of this enzyme, e.g. antifungals, fluoxetine, metronidazole and amiodarone, will

therefore lead to elevated warfarin levels and raised INR. The other major drug

interaction of warfarin is with paracetamol. Research evidence suggests that N-acetyl

(P)-benzoquinoneimine (the highly reactive paracetamol metabolite that causes hepatocellular

injury in paracetamol overdose) inhibits vitamin K-dependent carboxylase

thus interrupting the vitamin K cycle and augmenting the clinical effect of warfarin.

For reasons that are unclear, some patients may experience a rapid rise in INR following

standard doses of paracetamol.

Reference

Juurlink D. Drug interactions with warfarin: what clinicians need to know. Can Med

Assoc J 2007; 177(4): 369–71.