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

858 For therapeutic purposes, heparin also can be administered
subcutaneously on a twice-daily basis. A total daily dose of ~35,000
units administered as divided doses every 8-12 hours usually is sufficient
to achieve an aPTT of twice the control value (measured midway
between doses). Monitoring generally is unnecessary once a
steady dosage schedule is established. For low-dose heparin therapy
(to prevent DVT and thromboembolism in hospitalized medical or
surgical patients), a subcutaneous dose of 5000 units is given two to
three times daily. Laboratory monitoring of heparin administered in
this way usually is unnecessary because low-dose regimens have
negligible effects on the aPTT.
LMWH preparations include Enoxaparin (LOVENOX), dalteparin
(FRAGMIN), tinzaparin (INNOHEP, others), ardeparin (NORMIFLO),
nadroparin (FRAXIPARINE, others), and reviparin (CLIVARINE) (the latter
three are not available in the U.S. currently). These agents differ considerably
in composition, and one cannot assume that two preparations
that have similar anti-factor Xa activity will have equivalent antithrombotic
effects. The more predictable pharmacokinetic properties of
LMWH, however, permit administration in a fixed or weight-adjusted
dosage regimen once or twice daily by subcutaneous injection.
Because LMWHs produce a relatively predictable anticoagulant
response, monitoring is not done routinely. Patients with
renal impairment may require monitoring with an anti-factor Xa
assay because this condition may prolong the t 1/2
and slow the elimination
of LMWHs. Obese patients and children given LMWHs
also may require monitoring. Specific dosage recommendations
for various LMWH preparations may be obtained from the manufacturer’s
literature.
Fondaparinux (ARIXTRA) is administered by subcutaneous
injection, reaches peak plasma levels in 2 hours, and is excreted in
the urine (t 1/2
~17 h). It should not be used in patients with renal failure.
Because it does not interact significantly with blood cells or
plasma proteins other than antithrombin, fondaparinux can be given
once a day at a fixed dose without coagulation monitoring.
Fondaparinux appears to be much less likely than heparin or LMWH
to trigger the syndrome of heparin-induced thrombocytopenia (see
later in the chapter). Fondaparinux is approved for thromboprophylaxis
in patients undergoing hip or knee surgery or surgery for hip
fracture (Buller et al., 2003) and in general medical or surgical
patients. It also can be used for initial therapy in patients with pulmonary
embolism or DVT.
Idraparinux, a hypermethylated version of fondaparinux,
underwent phase III clinical testing. This drug has a t 1/2
of
80 hours and is given subcutaneously on a once-weekly basis. To
overcome the lack of an antidote, a biotin moiety was added to idraparinux
to generate idrabiotaparinux, which can be neutralized with
intravenous avidin. Ongoing phase III clinical trials are comparing
idrabiotaparinux with warfarin for treatment of pulmonary embolism
or for stroke prevention in patients with atrial fibrillation.
Idraparinux, idrabiotaparinus, and avidin are not available for routine
clinical use.
Heparin Resistance. The dose of heparin required to produce a therapeutic
aPTT varies due to differences in the concentrations of
heparin-binding proteins in plasma, such as histidine-rich glycoprotein,
vitronectin, and large multimers of von Willebrand factor and
platelet factor 4; these proteins competitively inhibit binding of
heparin to antithrombin. Some patients do not achieve a therapeutic
aPTT unless very high doses of heparin (>50,000 units/day) are
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
administered. Such patients may have “therapeutic” concentrations
of heparin in plasma at the usual dose when measured using an antifactor
Xa assay. This “pseudo” heparin resistance occurs because
these patients have short aPTT values prior to treatment, as a result
of increased concentrations of factor VIII. Other patients may require
large doses of heparin because of accelerated clearance of the drug,
as may occur with massive pulmonary embolism. Patients with
inherited antithrombin deficiency ordinarily have 40-60% of the
usual plasma concentration of this inhibitor and respond normally to
intravenous heparin. However, acquired antithrombin deficiency,
where concentrations may be <25% of normal, may occur in patients
with hepatic cirrhosis, nephrotic syndrome, or disseminated intravascular
coagulation; large doses of heparin may not prolong the aPTT
in these individuals.
Because LMWHs and fondaparinux exhibit reduced binding
to plasma proteins other than antithrombin, heparin resistance rarely
occurs with these agents. For this reason, routine coagulation monitoring
is unnecessary. Occasional patients, particularly those with
underlying cancer, develop recurrent thrombosis despite therapeutic
doses of a LMWH. Anti-factor Xa assays often are subtherapeutic
in these patients, and higher doses of LMWH are needed to
achieve a therapeutic response.
Toxicity and Adverse Events
Bleeding. Bleeding is the primary untoward effect of
heparin. Major bleeding occurs in 1-5% of patients
treated with intravenous heparin for venous thromboembolism
(Hirsh et al., 2001). The incidence of bleeding is
somewhat less in patients treated with LMWH for this
indication. Although the risk of bleeding appears to
increase with higher total daily doses of heparin and
with the degree of prolongation of the aPTT, these
correlations are weak, and patients can bleed with
aPTT values that are within the therapeutic range.
Often an underlying cause for bleeding is present,
such as recent surgery, trauma, peptic ulcer disease,
or platelet dysfunction.
The anticoagulant effect of heparin disappears within hours
of discontinuation of the drug. Mild bleeding due to heparin usually
can be controlled without the administration of an antagonist. If lifethreatening
hemorrhage occurs, the effect of heparin can be reversed
quickly by the intravenous infusion of protamine sulfate, a mixture
of basic polypeptides isolated from salmon sperm. Protamine binds
tightly to heparin and thereby neutralizes its anticoagulant effect.
Protamine also interacts with platelets, fibrinogen, and other plasma
proteins and may cause an anticoagulant effect of its own. Therefore,
one should give the minimal amount of protamine required to neutralize
the heparin present in the plasma. This amount is approximately
1 mg of protamine for every 100 units of heparin remaining in the
patient; protamine (up to a maximum of 50 mg) is given intravenously
at a slow rate (over 10 minutes).
Protamine is used routinely to reverse the anticoagulant effect
of heparin after cardiac surgery and other vascular procedures.
Anaphylactic reactions occur in about 1% of patients with diabetes
mellitus who have received protamine-containing insulin (NPH insulin