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

860 Bivalirudin contains the sequence Phe 1 –Pro 2 –Arg 3 –Pro 4 ,
which occupies the catalytic site of thrombin, followed by a
tetraglycine linker and a hirudin-like sequence that binds to exosite I.
Thrombin slowly cleaves the Arg 3 –Pro 4 peptide bond and thus
regains activity.
Bivalirudin is administered intravenously and is used as an
alternative to heparin in patients undergoing coronary angioplasty
or cardiopulmonary bypass surgery. Patients with heparin-induced
thrombocytopenia or a history of this disorder also can be given
bivalirudin instead of heparin during coronary angioplasty. The t 1/2
of bivalirudin in patients with normal renal function is 25 minutes;
dosage reductions are recommended for patients with moderate or
severe renal impairment.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Argatroban. Argatroban, a synthetic compound based
on the structure of l-arginine, binds reversibly to the
catalytic site of thrombin.
Argatroban is administered intravenously and has an immediate
onset of action. Its t 1/2
is 40-50 minutes. Argatroban is metabolized
by hepatic CYPs and is excreted in the bile; therefore, dosage
reduction is required for patients with hepatic insufficiency. The
dosage is adjusted to maintain an aPTT of 1.5-3 times the baseline
value. Argatroban can be used as an alternative to lepirudin for prophylaxis
or treatment of patients with, or at risk of developing,
heparin-induced thrombocytopenia. In addition to prolonging the
aPTT, argatroban also prolongs the PT, which can complicate the
transitioning of patients from argatroban to warfarin. A chromogenic
factor X assay can be used instead of the PT to monitor warfarin in
these patients.
Drotrecogin Alfa. Drotrecogin alfa (XIGRIS) is a recombinant
form of human activated protein C that inhibits
coagulation by proteolytic inactivation of factors Va and
VIIIa. It also has anti-inflammatory effects (Esmon,
2003).
A 96-hour continuous infusion of drotrecogin alfa decreases
mortality in adult patients who are at high risk for death from
severe sepsis if given within 48 hours of the onset of organ dysfunction
(e.g., shock, hypoxemia, oliguria). The major adverse
effect is bleeding.
Antithrombin. Antithrombin (ATRYN) is a recombinant
form of human antithrombin produced from the milk
of genetically modified goats. It is approved as an anticoagulant
for patients with hereditary antithrombin
deficiency undergoing surgical procedures.
ORAL ANTICOAGULANTS
Warfarin
History. Following the report of a hemorrhagic disorder in cattle that
resulted from the ingestion of spoiled sweet clover silage, Campbell
and Link, in 1939, identified the hemorrhagic agent as bishydroxycoumarin
(dicoumarol). In 1948, a more potent synthetic congener
was introduced as an extremely effective rodenticide; the compound
was named warfarin as an acronym derived from the name of the
patent holder, Wisconsin Alumni Research Foundation (WARF).
Warfarin’s potential as a therapeutic anticoagulant was recognized
but not widely accepted, partly due to fear of unacceptable toxicity.
However, in 1951, an army inductee uneventfully survived an
attempted suicide with massive doses of a preparation of warfarin
intended for rodent control. Since then, these anticoagulants have
become a mainstay for prevention of thromboembolic disease.
Chemistry. Numerous anticoagulants have been synthesized as
derivatives of 4-hydroxycoumarin and of the related compound,
indan-1,3-dione (Figure 30–6). Only the coumarin derivatives are
widely used; the 4-hydroxycoumarin residue, with a nonpolar carbon
substituent at the position 3, is the minimal structural requirement for
activity. This carbon is asymmetrical in warfarin (and in phenprocoumon
and acenocoumarol). The R- and S-enantiomers differ in
anticoagulant potency, metabolism, elimination, and interactions
with other drugs. Commercial preparations of these anticoagulants
are racemic mixtures. No advantage of administering a single enantiomer
has been established.
Mechanism of Action. The oral anticoagulants are antagonists
of vitamin K (see the section on “Vitamin K,”
later). Coagulation factors II, VII, IX, and X and the
O
O
OH
4-Hydroxycoumarin
NO
O O
O O
OH
CH 2 CCH 3
H
C O
CH 2
ONa
CH 2 CCH 3
OH
Warfarin Sodium
Dicumarol
O O
O
H
C
OH
C 2 H 5
O
Phenprocoumon
Indan-1,3-dione
O
O O
H
2
C O
O OCH 3
Acenocoumarol
Anisindione
Figure 30–6. Structural formulas of the vitamin K antagonists.
4-Hydroxycoumarin and indan-1,3-dione are the parent molecules
from which the vitamin K antagonists are derived. The
asymmetrical carbon atoms in the coumarins are shown in red.
O O
OH