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Section IVOther important drugsKinetics
Warfarin is completely absorbed from the gut and highly protein bound (>95%). It
undergoes complete hepatic metabolism by oxidation and reduction to products
that are subsequently conjugated and excreted in the urine.Monitoring warfarin therapy
Prothrombin time (PT) is a measure of the extrinsic system (VII) and factors com-
mon to both systems. Tissue thromboplastin (a brain extract) and Ca^2 +are added to
citrated plasma. Clotting normally takes place in 10–14 seconds. The international
normalized ratio (INR) is a ratio of the sample PT to a control international standard
PT. Warfarin treatment should aim to increase the PT so that the INR is raised to
between 2.0 and 4.5 depending on the clinical situation.Ximelagatran
Ximelagatran is an oral direct thrombin inhibitor. It is a prodrug, which is converted
to the active form – melagatran – in the liver. Melagatran is a potent competitive
inhibitor ofα-thrombin, which is highly selective for thrombin rather than other
serine proteases.
Itis taken twice a day and blood tests are not required to monitor its effects. How-
ever, in contrast to warfarin there is no antidote to reverse its effects should that
become necessary. Overdose may be treated with prothrombin complex concen-
trates, fresh frozen plasma or recombinant factor VIIa. Ximelagatran may find its
niche where warfarin is currently used and has proven efficacy in these areas (atrial
fibrillation and venous thromboembolism). It requires no further precautions over
LMWH when used alongside neuraxial blockade.Kinetics
The oral bioavailability of meligatran after oral ximelagatran (compared with sub-
cutaneous melagatran) is about 20%. It has a volume of distribution of 2 l/kg, and
an elimination half-life of 3–5 hours, and as it is not metabolized further it is almost
exclusively excreted via the kidneys. It has no interactions with drugs metabolized
bythe hepatic P450 system.Drugs affecting the fibrinolytic system
FibrinolyticsStreptokinase
Streptokinase is an enzyme produced by group Cβ-haemolytic streptococci.