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

proliferation, and maturation are dramatically stimulated.
This finely tuned feedback loop can be disrupted by
kidney disease, marrow damage, or a deficiency in iron or
an essential vitamin. With an infection or an inflammatory
state, erythropoietin secretion, iron delivery, and progenitor
proliferation all are suppressed by inflammatory
cytokines, but this accounts for only part of the resultant
anemia; interference with iron metabolism also is an
effect of inflammatory mediator effects on the hepatic
protein hepcidin (Nemeth et al., 2004).
Recombinant human erythropoietin (epoetin alfa) is nearly
identical to the endogenous hormone except for two subtle differences.
First, the carbohydrate modification pattern of epoetin alfa
differs slightly from the native protein, but this difference apparently
does not alter kinetics, potency, or immunoreactivity of the drug.
However, modern assays can detect these differences (Skibeli et al.,
2001) and identify athletes who use the recombinant product for
“blood doping.” The second difference probably is related to the
manufacturing process because one commercially available form of
the drug was recently associated with the development of antirecombinant
erythropoietin antibodies that cross-react with the
patient’s own erythropoietin, potentially causing pure red-cell aplasia
(Macdougall, 2004). Most of these cases were caused by one
preparation of the drug shortly after albumin was removed from the
formulation (Casadevall, 2003).
Preparations. Available preparations of epoetin alfa
include EPOGEN, PROCRIT, and EPREX, supplied in singleuse
vials containing 2000-40,000 units/mL for intravenous
or subcutaneous administration. When injected
intravenously, epoetin alfa is cleared from plasma with
a t 1/2
of 4-8 hours. However, the effect on marrow progenitors
lasts much longer, and once-weekly dosing can
be sufficient to achieve an adequate response. Although
allergic reactions have been reported with the administration
of epoetin alfa, no consistent pattern of significant
allergic reactions has emerged; except as noted
earlier, antibodies have not been detected even after
prolonged administration.
More recently, a novel erythropoiesis-stimulating
protein, darbepoetin alfa (ARANESP), has been approved
for clinical use in patients with indications similar to
those for epoetin alfa. It is a genetically modified
form of erythropoietin in which four amino acids have
been mutated such that additional carbohydrate side
chains are added during its synthesis, prolonging
the circulatory survival of the drug to 24-26 hours
(Jelkmann, 2002).
Therapeutic Uses, Monitoring, and Adverse Effects.
Recombinant erythropoietin therapy, in conjunction
with adequate iron intake, can be highly effective in a
number of anemias, especially those associated with a
poor erythropoietic response. There is a clear
dose–response relationship between the epoetin alfa
dose and the rise in hematocrit in anephric patients,
with eradication of their anemia at higher doses
(Eschbach et al., 1987). Epoetin alfa also is effective in
the treatment of anemias associated with surgery, AIDS,
cancer chemotherapy, prematurity, and certain chronic
inflammatory conditions. Darbepoetin alfa also has
been approved for use in patients with anemia associated
with chronic kidney disease and is under review
for several other indications.
During erythropoietin therapy, absolute or functional
iron deficiency may develop. Functional iron
deficiency (i.e., normal ferritin levels but low transferrin
saturation) presumably results from the inability to
mobilize iron stores rapidly enough to support the
increased erythropoiesis. Virtually all patients eventually
will require supplemental iron to increase or maintain
transferrin saturation to levels that will adequately
support stimulated erythropoiesis. Supplemental iron
therapy is recommended for all patients whose serum
ferritin is <100 μg/L or whose serum transferrin saturation
is <20%.
During initial therapy and after any dosage adjustment, the
hematocrit is determined once a week (HIV-infected and cancer
patients) or twice a week (renal failure patients) until it has stabilized
in the target range and the maintenance dose has been established;
the hematocrit then is monitored at regular intervals. If the
hematocrit increases by >4 points in any 2-week period, the dose
should be decreased. Due to the time required for erythropoiesis and
the erythrocyte half-life, hematocrit changes lag behind dosage
adjustments by 2-6 weeks. The dose of darbepoetin should be
decreased if the hemoglobin increase exceeds 1 g/dL in any 2-week
period because of the association of excessive rate of rise of hemoglobin
with adverse cardiovascular events.
During hemodialysis, patients receiving epoetin alfa or
darbepoetin may require increased anticoagulation. Serious thromboembolic
events have been reported, including migratory thrombophlebitis,
microvascular thrombosis, pulmonary embolism, and
thrombosis of the retinal artery and temporal and renal veins. The
risk of thrombotic events, including vascular access thromboses, was
higher in adults with ischemic heart disease or congestive heart failure
receiving epoetin alfa therapy with the goal of reaching a normal
hematocrit (42%) than in those with a lower target hematocrit of
30%. A large meta-analysis indicated that there was a relative risk
of 1.6 for developing venous thromboembolic events associated
with erythropoietic therapies (Bennett et al., 2008). The higher risk
of cardiovascular events from erythropoietic therapies may be associated
with higher hemoglobin or higher rates of rise of hemoglobin.
The hemoglobin level should be managed to avoid exceeding a target
level of 12 g/dL. ESA use is associated with increased rates of
cancer recurrence and decreased on-study survival in patients in
whom the drugs are administered for cancer-induced or for
chemotherapy-induced anemia. The magnitude of the effect was
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CHAPTER 37
HEMATOPOIETIC AGENTS