DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

anticoagulant proteins C and S are synthesized mainly
in the liver and are biologically inactive unless 9-13 of
the amino-terminal glutamate residues are carboxylated
to form the Ca 2+ -binding Gla residues. This reaction of
the descarboxy precursor protein requires CO 2
, O 2
, and
reduced vitamin K and is catalyzed by γ-glutamyl carboxylase
(Figure 30–7). Carboxylation is directly coupled
to the oxidation of vitamin K to its corresponding
epoxide.
Reduced vitamin K must be regenerated from the epoxide for
sustained carboxylation and synthesis of biologically competent proteins.
The enzyme that catalyzes this, vitamin K epoxide reductase
(VKOR), is inhibited by therapeutic doses of warfarin. Vitamin K (but
not vitamin K epoxide) also can be converted to the corresponding
hydroquinone by a second reductase, DT-diaphorase. This enzyme
requires high concentrations of vitamin K and is less sensitive to
coumarin drugs, which may explain why administration of sufficient
vitamin K can counteract even large doses of oral anticoagulants.
OH
OH
CH 3
R
Non-functional
prozymogens
reduced Vitamin K
Therapeutic doses of warfarin decrease by 30-50% the
total amount of each vitamin K-dependent coagulation factor
made by the liver; in addition, the secreted molecules are undercarboxylated,
resulting in diminished biological activity (10-40%
of normal). Congenital deficiencies of the procoagulant proteins
to these levels cause mild bleeding disorders. Vitamin K antagonists
have no effect on the activity of fully carboxylated molecules
in the circulation. Thus, the time required for the activity of
each factor in plasma to reach a new steady state after therapy is
initiated or adjusted depends on its individual rate of clearance.
The approximate t 1/2
(in hours) are as follows: factor VII, 6; factor
IX, 24; factor X, 36; factor II, 50; protein C, 8; and protein S, 30.
Because of the long t 1/2
of some of the coagulation factors, in
particular factor II, the full anti-thrombotic effect of warfarin is
not achieved for several days, even though the PT may be prolonged
soon after administration due to the more rapid reduction
of factors with a shorter t 1/2
, in particular factor VII. There is no
obvious selectivity of the effect of warfarin on any particular vitamin
K-dependent coagulation factor, although the anti-thrombotic
benefit and the hemorrhagic risk of therapy may be correlated
Functional
zygomens
oxidized Vitamin K
CPYs 1A1,
1A2, 3A4 R-warfarin S-warfarin CYP2C9
6-OH, 8-OH and
10-OH warfarin
NAD
γ-glutamyl
carboxylase
Vitamin K
cycle
(VKORC1)
vitamin K
reductase
X
warfarin
7-OH-warfarin
Figure 30–7. The vitamin K cycle and mechanism of action of warfarin. In the racemic mixture of S- and R-enantiomers, S-warfarin is more
active. By blocking vitamin K epoxide reductase encoded by the VKORC1 gene, warfarin inhibits the conversion of oxidized vitamin K
epoxide into its reduced form, vitamin K hydroquinone. This inhibits vitamin K-dependent γ-carboxylation of factors II, VII, IX, and X
because reduced vitamin K serves as a cofactor for a γ-glutamyl carboxylase that catalyzes the γ-carboxylation process, thereby converting
prozymogens to zymogens capable of binding Ca 2+ and interacting with anionic phospholipid surfaces. S-warfarin is metabolized by
CYP2C9. Common genetic polymorphisms in this enzyme can influence warfarin metabolism. Polymorphisms in the C1 subunit of vitamin
K reductase (VKORC1) also can affect the susceptibility of the enzyme to warfarin-induced inhibition, thereby influencing warfarin
dosage requirements.
NADH
O
O
CH 3
O
R
861
CHAPTER 30
BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS