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

About 10-15 glycosaminoglycan chains, each containing
200-300 saccharide units, are attached to a core protein and yield a
proteoglycan with a molecular mass of 750-1,000 kDa. The glycosaminoglycan
then undergoes a series of modifications, which
include the following: N-deacetylation and N-sulfation of glucosamine
residues, epimerization of D-glucuronic acid to L-iduronic acid,
O-sulfation of iduronic and glucuronic acid residues at the C2 position,
and O-sulfation of glucosamine residues at the C3 and C6 positions.
Each of these modifications is incomplete, yielding a variety of
oligosaccharide structures. After transport of the heparin proteoglycan
to mast cell granules, an endo-β-D-glucuronidase slowly degrades
the glycosaminoglycan chains to fragments of 5-30 kDa (mean, ~15 kDa,
corresponding to ~40 saccharide units).
Source. Heparin is commonly extracted from porcine intestinal
mucosa, which is rich in mast cells, and preparations may contain
small amounts of other glycosaminoglycans. Despite the heterogeneity
in composition among different commercial preparations of
heparin, their biological activities are similar (~150 USP units/mg).
A USP unit reflects the quantity of heparin that prevents 1 mL of
citrated sheep plasma from clotting for 1 hour after the addition of
0.2 mL of 1% CaCl 2
. Although North American heparin manufacturers
have traditionally quantified heparin potency in USP units,
European manufacturers measure potency with an anti-factor Xa
assay. This assay involves monitoring the activity of factor Xa added
to human citrated plasma with a synthetic factor Xa–directed substrate
that changes color when cleaved by the enzyme. The higher the
heparin concentration in the sample, the less the residual factor Xa
activity detected. To determine heparin potency, residual factor Xa
activity in the sample is compared with that detected in controls containing
known concentrations of an international heparin standard.
When assessed this way, heparin potency is expressed in international
units per mg.
Effective October 1, 2009, the new USP unit dose has been
harmonized to the international unit dose. Contamination of heparin
with oversulfated chondroitin sulfate, a non-heparin glycosaminoglycan,
prompted this shift because this contaminant eludes detection
with the USP assay but not with the anti-factor Xa assay. As a
result, the new USP unit dose is less potent than the old USP unit
dose by ~10%, and heparin doses using the new USP units will have
to increase slightly to achieve the same level of anticoagulation. This
likely is of little or no clinical consequence for subcutaneous administration,
due to the low and variable bioavailability of heparin when
administered by this route. However, for intravenous administration,
dosing adjustments and more frequent monitoring of aPTT may be
necessary.
Heparin Derivatives. Derivatives of heparin in current use include
low-molecular-weight heparins (LMWHs) and fondaparinux. The features
that distinguish these derivatives from heparin are outlined in
Table 30–1. Several LMWH preparations are marketed (e.g., daltaparin
[FRAGMIN], enoxaparin [LOVENOX], tinzaparin [INNOHEP]), but all
are fragments of heparin ranging in molecular weight from 1-10 kDa
(mean ~5 kDa, ~17 saccharide units). LMWH preparations differ from
heparin and, to a lesser extent, from each other in their pharmacokinetic
properties. The potency of LMWH is assessed with anti-factor
Xa assays, which use an international LMWH standard for reference
purposes.
In contrast to heparin and LMWHs, which are biologicals
derived from animal tissues, fondaparinux (ARIXTRA) is a synthetic
five-saccharide analog of a natural pentasaccharide sequence that is
found in heparin and LMWHs and mediates their interaction with
antithrombin. Fondaparinux has unique pharmacokinetic properties
that distinguish it from LMWH. The potency of fondaparinux also
is assessed with an anti-Xa assay.
Mechanism of Action. Heparin, LMWHs, and fondaparinux
have no intrinsic anticoagulant activity. Instead, these
agents bind to antithrombin and accelerate the rate at which
it inhibits various coagulation proteases. Antithrombin is
a glycosylated, single-chain polypeptide composed of
432 amino acid residues (Olson and Chuang, 2002).
Synthesized in the liver, antithrombin circulates in
plasma at an approximate concentration of 2.6 μM.
Antithrombin inhibits activated coagulation factors
involved in the intrinsic and common pathways but has
relatively little activity against factor VIIa. Antithrombin
is a “suicide substrate” for these proteases; inhibition
occurs when the protease attacks a specific Arg–Ser
peptide bond in the reactive center loop of antithrombin
and becomes trapped as a stable 1:1 complex.
Table 30–1
Comparison of the Features of Heparin, LMWH, and Fondaparinux
FEATURES HEPARIN LMWH FONDAPARINUX
Source Biological Biological Synthetic
Molecular weight (Da) 15,000 5000 1500
Target Xa and IIa Xa and IIa Xa
Bioavailability (%) 30 90 100
t 1/2
(h) 1 4 17
Renal excretion No Yes Yes
Antidote effect Complete Partial None
Thrombocytopenia <5% <1% <1%