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P A R T 8
Drugs acting on the cardiovascular system
Adverse effects
The adverse effects most commonly associated with
these drugs include the CNS effects of headache,
fatigue, asthenia and dizziness and the potential for
serious seizures. These effects may be the result of a
cellular response to the glycoprotein. Nausea, vomiting
and diarrhoea are also common effects. Cardio
vascular symptoms can include hypertension, oedema
and possible chest pain, all of which may be related
to the increase in RBC numbers changing the balance
within the cardiovascular system. People receiving
intravenous administration must also be monitored
for possible clotting of the access line related to direct
cellular effects of the drug. In 2005, post-marketing
studies showed that pure red cell aplasia associated with
erythropoietin-neutralising antibodies could occur with
all of these products. In 2008, after analyses of several
post-marketing studies, these drugs were required to add
black-box warnings
to their prescribing information.
Clinically important drug–drug interactions
These drugs should never be mixed in solution with
any other drugs because of a risk of interactions in the
solution.
Oxygen use
in tissues
Arterial
oxygen pressure
Erythropoietin
Stem cell
stimulation
O
2
carrying
capacity
RBCs
formed
Stimulation for
erythropoietin
from kidney
Arterial
oxygen pressure
FIGURE 49.3
Erythropoiesis controls the rate of blood cell production.
Safe medication administration
In late 2005, the makers of epoetin and darbepoetin sent out
warning letters to healthcare professionals to bring attention to
serious adverse effects that had been noted in post-marketing
studies. Cases of pure red cell aplasia (defective or insufficient
production) and severe anaemias, with or without cytopenias
(decreased levels of other blood cells), had been reported.
These cases were associated with the development of
neutralising antibodies to erythropoietin. Use of any therapeutic
protein brings with it the risk of antibody production. All of the
erythropoietic proteins (Aranesp, Eprex) now carry a warning
about the potential for this problem. If a person is being
treated with one of these drugs and develops a sudden loss of
response accompanied by severe anaemia and low reticulocyte
count, they should be assessed for the possible causes. Assays
for binding and neutralising antibodies should be done. If an
antibody-mediated anaemia is confirmed, the drug should be
permanently stopped and the person should not be switched
to another erythropoietic protein because cross-reaction could
occur. Most of the people in the reported cases had chronic
renal failure and were being treated with subcutaneous
injections. It is now recommended that people on haemodialysis
receive the drug intravenously rather than subcutaneously. If the
drug is started and there is no response, or if a person fails to
maintain a response, the dose should not be increased, and red
blood cell aplasia should be suspected. The person should be
evaluated with the appropriate tests and supported.
A target haemoglobin of no more than 12 g/dL is sought
when using these drugs. Higher levels have been associated
with cardiovascular events, including death, and increased rates
of tumour progression death in people with cancer in whom the
drug was being used to treat anaemia associated with toxic drug
therapy. Monitoring the haemoglobin levels is critical for safe
and therapeutic use of the erythropoiesis-stimulating agents.
An increase in tumour growth was also found in people with
cancer treated with these drugs when haemoglobin levels were
not kept within the guidelines of no more than 12 g/dL. This has
been added to the warnings for these drugs to alert caregivers
to carefully monitor haemoglobin levels to assure safety.
Prototype summary: Epoetin alfa
Indications:
Treatment of anaemia associated with
chronic renal failure, related to treatment of HIV
infection or to chemotherapy in people with cancer;
to reduce the need for allogenic blood transfusion
in people undergoing surgical procedures.
Actions:
Natural glycoprotein that stimulates RBC
production in the bone marrow.
Pharmacokinetics:
Route
Onset
Peak
Duration
Subcutaneous 7–14 days 5–24 hours 24 hours
T
1/2
:
4 to 13 hours; metabolised in serum and
excreted in urine.
Adverse effects:
Headache, arthralgias, fatigue,
asthenia, dizziness, hypertension, oedema, chest
pain, nausea, vomiting, diarrhoea.
