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

1084 follows usual oral doses. Common indications are iron
malabsorption (e.g., sprue, short bowel syndrome),
severe oral iron intolerance, as a routine supplement to
total parenteral nutrition, and in patients who are receiving
erythropoietin (Eschbach et al., 1987). In particular,
when hemodialysis patients are started on erythropoietin,
oral iron therapy alone generally is insufficient to
provide an optimal hemoglobin response. It therefore
is recommended that sufficient parenteral iron be given
to maintain a plasma ferritin level between 100 and
800 μg/L and a transferrin saturation of 20-50%
(Goodnough et al., 2000).
Parenteral iron also has been given to iron-deficient
patients and pregnant women to create iron stores,
something that would take months to achieve by the
oral route. The belief that the response to parenteral
iron, especially iron dextran, is faster than oral iron is
open to debate. In otherwise healthy individuals, the
rate of hemoglobin response is determined by the balance
between the severity of the anemia (the level of
erythropoietin stimulus) and the delivery of iron to the
marrow from iron absorption and iron stores. When a
large intravenous dose of iron dextran is given to a
severely anemic patient, the hematologic response can
exceed that seen with oral iron for 1-3 weeks.
Subsequently, however, the response is no better than
that seen with oral iron.
Parenteral iron therapy should be used only when
clearly indicated because acute hypersensitivity, including
anaphylactic and anaphylactoid reactions, can occur
in 0.2-3% of patients (Faich and Strobos, 1999). Other
reactions to intravenous iron include headache, malaise,
fever, generalized lymphadenopathy, arthralgias,
urticaria, and in some patients with rheumatoid arthritis,
exacerbation of the disease.
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
Four iron formulations are available in the U.S. These are
iron dextran (DEXFERRUM or INFED), sodium ferric gluconate (FER-
RLECIT), ferumoxytol (FERAHEME), and iron sucrose (VENOFER).
Ferumoxytol is a semisynthetic carbohydrate-coated superparamagnetic
iron oxide nanoparticle that is approved for treatment of irondeficiency
anemia in patients with chronic kidney disease
(Balakrishnan et al., 2009). The indications for the iron dextran
preparations include treatment of any patient with documented iron
deficiency and intolerance or irresponsiveness to oral iron. In contrast,
the indications for the ferric gluconate and iron sucrose are
limited to patients with chronic kidney disease who have a documented
iron deficiency, although broader applications are being
advocated (Wish, 2008). Iron dextran is the only preparation that can
be given as a total-dose infusion, which is the entire dose of elemental
iron required to replace iron stores. However, ferric gluconate
and iron sucrose are administered as a fixed dose every week for several
weeks until total iron stores are replenished.
Iron Dextran. Iron dextran injection (INFED or DEXFERRUM) is a colloidal
solution of ferric oxyhydroxide complexed with polymerized
dextran (molecular weight, ~180,000 Da) that contains 50 mg/mL of
elemental iron. The use of low-molecular-weight iron dextran has
reduced the incidence of toxicity relative to that observed with high
molecular weight preparations (IMFERON) (Auerbach and Al Talib,
2008). Iron dextran can be administered by either intravenous (preferred)
or intramuscular injection. When given by deep intramuscular
injection, it is gradually mobilized via the lymphatics and
transported to reticuloendothelial cells; the iron then is released from
the dextran complex. Intravenous administration gives a more reliable
response. Given intravenously in a dose <500 mg, the iron
dextran complex is cleared exponentially with a plasma t 1/2
of
6 hours. When ≥1 g is administered intravenously as total dose
therapy, reticuloendothelial cell clearance is constant at 10-
20 mg/hour. This slow rate of clearance results in a brownish discoloration
of the plasma for several days and an elevation of the serum
iron for 1-2 weeks.
Once the iron is released from the dextran within the reticuloendothelial
cells, it is either incorporated into stores or transported
via transferrin to the erythroid marrow. Although a portion of the
processed iron is rapidly made available to the marrow, a significant
fraction is only gradually converted to usable iron stores. All of the
iron eventually is released, although many months are required
before the process is complete. During this time, the iron dextran
stores in reticuloendothelial cells can confuse the clinician who
attempts to evaluate the iron status of the patient.
Intramuscular injection of iron dextran should only be initiated
after a test dose of 0.5 mL (25 mg of iron). If no adverse reactions
are observed, the injections can proceed. The daily dose
ordinarily should not exceed 0.5 mL (25 mg of iron) for infants
weighing <4.5 kg (10 lb), 1 mL (50 mg of iron) for children weighing
<9 kg (20 lb), and 2 mL (100 mg of iron) for other patients. Iron
dextran should be injected only into the muscle mass of the upper
outer quadrant of the buttock using a z-track technique (displacement
of the skin laterally before injection). However, local reactions
and the concern about malignant change at the site of injection
(Weinbren et al., 1978) make intramuscular administration inappropriate
except when the intravenous route is inaccessible.
A test injection of 0.5 mL of undiluted iron dextran or an
equivalent amount (25 mg of iron) diluted in saline also should precede
intravenous administration of a therapeutic dose of iron dextran.
The patient should be observed for signs of immediate
anaphylaxis and for an hour after injection for any signs of vascular
instability or hypersensitivity, including respiratory distress,
hypotension, tachycardia, or back or chest pain. When widely spaced
total-dose infusion therapy is given, a test dose injection should be
given before each infusion because hypersensitivity can appear at
any time. Furthermore, the patient should be monitored closely
throughout the infusion for signs of cardiovascular instability.
Delayed hypersensitivity reactions also are observed, especially in
patients with rheumatoid arthritis or a history of allergies. Fever,
malaise, lymphadenopathy, arthralgias, and urticaria can develop
days or weeks following injection and last for prolonged periods of
time. Therefore, iron dextran should be used with extreme caution in
patients with rheumatoid arthritis or other connective tissue diseases,
and during the acute phase of an inflammatory illness. Once hypersensitivity
is documented, iron dextran therapy must be abandoned.