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

effect (see the warfarin “Clinical Use” and “Monitoring
Anticoagulant Therapy” sections later in the chapter).
Heparin, LMWH, or fondaparinux also can be used
in the initial management of patients with unstable
angina or acute myocardial infarction. For most of
these indications, LMWHs and fondaparinux have
replaced continuous heparin infusions because of
their pharmacokinetic advantages, which permit subcutaneous
administration once or twice daily in fixed
or weight-adjusted doses without coagulation monitoring.
By contrast, full-dose heparin usually requires
continuous intravenous infusion and frequent aPTT
monitoring to ensure that a therapeutic level of anticoagulation
has been achieved.
Because they do not require routine laboratory monitoring,
LMWHs or fondaparinux can be used for out-of-hospital management
of patients with venous thrombosis or pulmonary embolism, an
approach that reduces healthcare expenditures. Patients who develop
these disorders due to cancer often are treated with long-term
LMWH instead of warfarin because nausea and vomiting from
chemotherapy, involvement of the liver with cancer, and poor venous
access can render therapy with warfarin problematic.
Heparin and LMWH are used during coronary balloon angioplasty
with or without stent placement to prevent thrombosis.
Fondaparinux is not used in this setting because of the risk of
catheter thrombosis, a complication caused by catheter-induced activation
of factor XII; longer heparin molecules are better than shorter
ones for blocking this process. Cardiopulmonary bypass circuits also
activate factor XII, which can cause clotting of the oxygenator.
Heparin remains the agent of choice for surgery requiring cardiopulmonary
bypass because it blocks this process and because the
heparin can rapidly be neutralized with protamine sulfate after the
procedure. Heparin also is used to treat selected patients with disseminated
intravascular coagulation. While low-dose heparin,
LMWH, or fondaparinux regimens all are effective, subcutaneous
administration of low-dose heparin remains the recommended regimen
for the prevention of post-operative deep venous thrombosis
(DVT) and pulmonary embolism in patients undergoing major
abdominothoracic surgery or who are at risk of developing thromboembolic
disease. Specific recommendations for heparin use have
been reviewed (Geerts et al., 2008).
In contrast to warfarin, heparin, LMWH, and fondaparinux do
not cross the placenta and have not been associated with fetal malformations;
therefore, these are the drugs of choice for anticoagulation
during pregnancy. LMWH or fondaparinux is used most often in this
setting because these agents need only be given once daily by subcutaneous
injection. In addition, the risk of heparin-induced thrombocytopenia
or osteoporosis is lower with LMWHs or fondaparinux
than with heparin. Heparin, LMWH, and fondaparinux do not appear
to increase fetal mortality or prematurity. If possible, the drugs
should be discontinued 24 hours before delivery to minimize the risk
of postpartum bleeding.
Absorption and Pharmacokinetics. Heparin, LMWHs,
and fondaparinux are not absorbed through the GI
mucosa and therefore must be given parenterally.
Heparin is given by continuous intravenous infusion,
intermittent infusion every 4-6 hours, or subcutaneous
injection every 8-12 hours. Heparin has an immediate
onset of action when given intravenously. In contrast,
there is considerable variation in the bioavailability of
heparin given subcutaneously, and the onset of action is
delayed 1-2 hours. LMWH and fondaparinux are
absorbed more uniformly after subcutaneous injection.
The t 1/2
of heparin in plasma depends on the dose administered.
When doses of 100, 400, or 800 units/kg of heparin are
injected intravenously, the half-lives of the anticoagulant activities
are approximately 1, 2.5, and 5 hours, respectively (see Appendix II
for pharmacokinetic data). Heparin appears to be cleared and
degraded primarily by the reticuloendothelial system; a small
amount of undegraded heparin also appears in the urine. LMWHs
and fondaparinux have longer biological half-lives than heparin,
4-6 hours and ~17 hours, respectively. Because these smaller heparin
fragments are cleared almost exclusively by the kidneys, the drugs
can accumulate in patients with renal impairment, which can lead to
bleeding. Both LMWH and fondaparinux are contraindicated in
patients with a creatinine clearance <30 mL/min. In addition, fondaparinux
is contraindicated in patients with body weight <50 kg
undergoing hip fracture, hip replacement, knee replacement surgery,
or abdominal surgery.
Administration and Monitoring. Full-dose heparin therapy usually
is administered by continuous intravenous infusion. Treatment of
venous thromboembolism is initiated with a fixed-dose bolus
injection of 5000 units or with a weight-adjusted bolus, followed
by 800-1600 units/hour delivered by an infusion pump. Therapy
routinely is monitored by measuring the aPTT. The therapeutic
range for heparin is considered to be that which is equivalent to a
plasma heparin level of 0.3-0.7 units/mL, as determined with an
anti-factor Xa assay (Hirsh et al., 2001). The aPTT value that corresponds
to this range varies depending on the reagent and instrument
used to perform the assay. An aPTT two to three times the
normal mean aPTT value generally is assumed to be therapeutic;
however, values in this range obtained with some aPTT assays
may overestimate the amount of circulating heparin and therefore
be subtherapeutic. The risk of recurrence of thromboembolism is
greater in patients who do not achieve a therapeutic level of anticoagulation
within the first 24 hours. Initially, the aPTT should
be measured and the infusion rate adjusted every 6 hours; dose
adjustments may be aided by use of nomograms; weight-based
nomograms appear to outperform those that used fixed doses
(Hirsh et al., 2001). Once a steady dosage schedule has been
established in a stable patient, daily laboratory monitoring usually
is sufficient.
Very high doses of heparin are required to prevent coagulation
during cardiopulmonary bypass. The aPTT is infinitely prolonged
over the dosage range used. A less sensitive coagulation test,
such as the activated clotting time, is employed to monitor therapy in
this situation. Because the activated clotting time can be performed
in a point-of-care fashion, patients undergoing coronary angioplasty
also typically have their heparin therapy monitored this way.
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CHAPTER 30
BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS