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

Before initiating iron dextran therapy, the total dose of iron
required to repair the patient’s iron-deficient state should be calculated.
Relevant factors are the hemoglobin deficit, the need to reconstitute
iron stores, and continued excess losses of iron, as seen with
hemodialysis and chronic GI bleeding. Iron dextran solution (50
mg/mL of elemental iron) can be administered undiluted in daily
doses of 2 mL until the total dose is reached or given off label as a
single total-dose infusion. In the latter case, the iron dextran should
be diluted in 250-1000 mL of 0.9% saline and infused over an hour
or more.
With repeated doses of iron dextran—especially multiple
total-dose infusions such as those sometimes used in the treatment
of chronic GI blood loss—accumulations of slowly metabolized iron
dextran stores in reticuloendothelial cells can be impressive. The
plasma ferritin level also can rise to levels associated with iron overload.
Although disease-related hemochromatosis has been associated
with an increased risk of infections and cardiovascular disease,
this has not been shown to be true in hemodialysis patients treated
with iron dextran (Owen, 1999). It seems prudent, however, to withhold
the drug whenever the plasma ferritin rises above 800 μg/L.
Sodium Ferric Gluconate. Sodium ferric gluconate is an intravenous
iron preparation with a molecular size of ~295,000 Da and an osmolality
of 990 mOsm/kg −1 (Balakrishnan et al., 2009). Administration
of ferric gluconate at doses ranging from 62.5-125 mg during
hemodialysis is associated with transferrin saturation exceeding
100% (Zanen et al., 1996). Hemodialysis patients who had ferritin
levels between 500 and 1200 ng/mL and transferrin saturations of
≤25% while undergoing treatment with erythropoietin had improved
hemoglobin values following treatment with ferric gluconate, resulting
in reduced requirements for erythropoietin (Kapoian et al., 2008).
Unlike iron dextran, which requires processing by
macrophages that may require several weeks, ~80% of sodium ferric
gluconate is delivered to transferrin with in 24 hours. Sodium ferric
gluconate also has a lower risk of inducing serious anaphylactic
reactions than iron dextran (Sengolge et al., 2005). No deaths were
reported with 25 million infusions of sodium ferric gluconate,
whereas there were 31 infusion-related deaths reported from approximately
half the number of patients treated with iron dextran (Faich
and Strobos, 1999). Thus, sodium ferric gluconate has become the
preferred agent for parenteral iron therapy. Currently iron dextran is
reserved for noncompliant patients or for those who are seriously
inconvenienced by the multiple infusions that may be required for
treatment with sodium ferric gluconate or iron sucrose.
Iron Sucrose. Iron sucrose is complex of polynuclear iron (III)-
hydroxide in sucrose with a molecular weight of 252,000 Da and an
osmolality of 1316 mOsm/kg −1 (Balakrishnan et al., 2009). Following
intravenous injection, the complex is taken up by the reticuloendothelial
system, where it dissociates into iron and sucrose. Iron sucrose is
generally administered in daily amounts of 100-200 mg within a
14-day period to a total cumulative dose of 1000 mg. It can be administered
repeatedly to hemodialysis patients as maintenance therapy
without inducing hypersensitivity (Aronoff et al., 2004).
Like sodium ferric gluconate, iron sucrose appears to be better
tolerated and to cause fewer adverse events than iron dextran
(Hayat, 2008). This agent is FDA-approved for the treatment of iron
deficiency in patients with chronic kidney disease. However, iron
sucrose has been used effectively to treat iron deficiency observed in
other clinical settings (al-Momen et al., 1996; Bodemar et al., 2004).
However, one study reported that iron sucrose may be most likely of
available parenteral iron preparations to induce renal tubular injury
because of its high renal uptake (Zager et al., 2004), potentially
resulting in tubulointerstitial damage with chronic repeated use
(Agarwal, 2006).
Copper
Copper deficiency is extremely rare because the amount
present in food is more than adequate to provide the
needed body complement of slightly more than 100 mg.
There is speculation that marginal deficiency of copper
can contribute to development or progression of a number
of chronic disorders, such as diabetes or cardiovascular
disease (Uriu-Adams and Keen, 2005). However,
there is no evidence that copper ever needs to be added
to a normal diet, either prophylactically or therapeutically.
Even in clinical states associated with
hypocupremia (sprue, celiac disease, and nephrotic syndrome),
effects of copper deficiency usually are not
demonstrable. Anemia due to copper deficiency has
been described in individuals who have undergone
intestinal bypass surgery (Zidar et al., 1977), in those
who are receiving parenteral nutrition (Dunlap et al.,
1974), in malnourished infants (Graham and Cordano,
1976), and in patients ingesting excessive amounts of
zinc (Hoffman et al., 1988).
Copper has redox properties similar to that of iron, which
simultaneously is essential and potentially toxic to the cell (Kim et
al., 2008). Cells have virtually no free copper. Instead copper is
stored by metallothioneins and distributed by specialized chaperones
to sites that make use of its redox properties (Lalioti et al.,
2009). Transfer of copper to nascent cuproenzymes is performed
by individual or collective activities of P-type ATPases, ATP7A
and ATP7B, which are expressed in all tissues (Linz and Lutsenko,
2007). In mammals, the liver is the organ most responsible for the
storage, distribution, and excretion of copper. Mutations in ATP7A
or ATP7B that interfere with this function have been found responsible
for Wilson’s disease or Menkes syndrome (steely hair syndrome)
(de Bie et al., 2007), respectively, which can result in life-threatening
hepatic failure.
Copper deficiency in experimental animals interferes with the
absorption of iron and its release from reticuloendothelial cells
(Gambling et al., 2008). The associated microcytic anemia is related
to a decrease in the availability of iron to the normoblasts, and perhaps
even more importantly, to decreased mitochondrial production of
heme. It may be that the specific defect in the latter case is a decrease
in the activity of cytochrome oxidase. Other pathological effects
involving the skeletal, cardiovascular, and nervous systems have been
observed in copper-deficient experimental animals. In humans, the
prominent findings have been leukopenia, particularly granulocytopenia,
and anemia. Concentrations of iron in plasma are variable, and
the anemia is not always microcytic. When a low plasma copper concentration
is determined in the presence of leukopenia and anemia, a
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CHAPTER 37
HEMATOPOIETIC AGENTS