| Indication |
For the treatment of retinal vascular occlusion, pulmonary
embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral
embolism, transient cerebral ischaemia, arterial embolism and
thrombosis. |
| Pharmacodynamics |
Warfarin, a coumarin anticoagulant, is a racemic mixture of two
active isomers. It is used in the prevention and treatment of
thromboembolic disease including venous thrombosis, thromboembolism, and
pulmonary embolism as well as for the prevention of ischemic stroke in
patients with atrial fibrillation (AF). |
| Mechanism of action |
Warfarin inhibits vitamin K reductase, resulting in depletion of
the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor
for the carboxylation of glutamate residues on the N-terminal regions of
vitamin K-dependent proteins, this limits the gamma-carboxylation and
subsequent activation of the vitamin K-dependent coagulant proteins. The
synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X
and anticoagulant proteins C and S is inhibited. Depression of three of
the four vitamin K-dependent coagulation factors (factors II, VII, and
X) results in decreased prothrombin levels and a decrease in the amount
of thrombin generated and bound to fibrin. This reduces the
thrombogenicity of clots. |
| Absorption |
Rapidly absorbed following oral administration with considerable interindividual variations. Also absorbed percutaneously. |
| Volume of distribution |
|
| Protein binding |
99% bound primarily to albumin |
| Metabolism |
Metabolized stereo- and regio-selectively by hepatic microsomal
enzymes. S-warfarin is predominantly metabolized by cytochrome P450
(CYP) 2C9 to yield the 6- and 7-hydroxylated metabolites. R-warfarin is
metabolized by CYP1A1, 1A2, and 3A4 to yield 6-, 8-, and 10-hydroxylated
metabolites. Hydroxylated metabolites may be further conjugated prior
to excretion into bile and urine. UGT1A1 appears to be responsible for
producing the 6-O-glucuronide of warfarin, with a possibly contribution
from UGT1A10. Five UGT1As may be involved in the formation of
7-O-glucuronide warfarin. S-warfarin has higher potency than R-warfarin
and genetic polymorphisms in CYP2C9 may dramatically decrease clearance
of and increase toxicity of the medication. |
| Route of elimination |
The elimination of warfarin is almost entirely by metabolism. Very
little warfarin is excreted unchanged in urine. The metabolites are
principally excreted into the urine; and to a lesser extent into the
bile. |
| Half life |
R-warfarin t1/2=37-89 hours; S-warfarin t1/2=21-43 hours. |
| Clearance |
- 0.065 +/- 0.025 mL/min/kg [CYP2C9 Genotype 1/1]
- 0.041 +/- 0.021 [CYP2C9 Genotype 1/2 or 1/3]
- 0.020 +/- 0.011 [CYP2C9 Genotype 2/2, 2/3, or 3/3]
|
| Toxicity |
LD50=374 (orally in mice) |
