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

Leucovorin should never be used for the treatment of pernicious
anemia or other megaloblastic anemias secondary to a deficiency of
vitamin B 12
. Just as is seen with folic acid, its use can result in an
apparent response of the hematopoietic system, but neurological
damage may occur or progress if already present. Leucovorin is marketed
as oral tablets and as products for intravenous infusion.
Untoward Effects. There have been rare reports of reactions to parenteral
injections of folic acid and leucovorin. If a patient describes
a history of a reaction before the drug is given, caution should be
exercised. Oral folic acid usually is not toxic. Even with doses as high
as 15 mg/day, there have been no substantiated reports of side effects.
Folic acid in large amounts may counteract the antiepileptic effect of
phenobarbital, phenytoin, and primidone, and increase the frequency
of seizures in susceptible children (Reynolds, 1968). Although some
studies have not supported these contentions, the FDA recommends
that oral tablets of folic acid be limited to strengths of ≤1 mg.
General Principles of Therapy. The therapeutic use of
folic acid is limited to the prevention and treatment of
deficiencies of the vitamin. As with vitamin B 12
therapy,
effective use of the vitamin depends on accurate
diagnosis and an understanding of the mechanisms that
are operative in a specific disease state. The following
general principles of therapy should be respected:
1. Prophylactic administration of folic acid should be
undertaken for clear indications. Dietary supplementation
is necessary when there is a requirement
that may not be met by a “normal” diet. The daily
ingestion of a multivitamin preparation containing
400-500 μg of folic acid has become standard practice
before and during pregnancy to reduce the incidence
of neural tube defects and for as long as a
woman is breast-feeding. In women with a history
of a pregnancy complicated by a neural tube defect,
an even larger dose of 4 mg/day has been recommended
(MRC Vitamin Study Research Group,
1991). Patients on total parenteral nutrition should
receive folic acid supplements as part of their fluid
regimen because liver folate stores are limited.
Adult patients with a disease state characterized by
high cell turnover (e.g., hemolytic anemia) generally
require larger doses, 1 mg of folic acid given
once or twice a day. The 1-mg dose also has been
used in the treatment of patients with elevated levels
of homocysteine.
2. As with vitamin B 12
deficiency, any patient with
folate deficiency and a megaloblastic anemia
should be evaluated carefully to determine the
underlying cause of the deficiency state. This
should include evaluation of the effects of medications,
the amount of alcohol intake, the patient’s
history of travel, and the function of the GI tract.
3. Therapy always should be as specific as possible.
Multivitamin preparations should be avoided
unless there is good reason to suspect deficiency of
several vitamins.
4. The potential danger of mistreating a patient who
has vitamin B 12
deficiency with folic acid must be
kept in mind. The administration of large doses of
folic acid can result in an apparent improvement
of the megaloblastic anemia, inasmuch as PteGlu
is converted by dihydrofolate reductase to
H 4
PteGlu; this circumvents the methylfolate
“trap.” However, folate therapy does not prevent
or alleviate the neurological defects of vitamin
B 12
deficiency, and these may progress and
become irreversible.
Treatment of the Acutely Ill Patient. As described in detail in the
section on vitamin B 12
, treatment of the patient who is acutely ill
with megaloblastic anemia should begin with intramuscular injections
of vitamin B 12
and folic acid. Inasmuch as the patient requires
therapy before the exact cause of the disease has been defined, it is
important to avoid the potential problem of a combined deficiency
of vitamin B 12
and folic acid. When the patient is deficient in both,
therapy with only one vitamin will not provide an optimal response.
Longstanding nontropical sprue is one example of a disease in
which combined deficiency of B 12
and folate is common. When
indicated, vitamin B 12
(100 μg) and folic acid (1-5 mg) should be
administered intramuscularly, and the patient should then be maintained
on daily oral supplements of 1-2 mg of folic acid for the next
1-2 weeks.
Oral administration of folate generally is satisfactory for
patients who are not acutely ill, regardless of the cause of the deficiency
state. Even the patient with tropical or nontropical sprue
and a demonstrable defect in absorption of folic acid will respond
adequately to such therapy. Abnormalities in the activity of pteroylγ-glutamyl
carboxypeptidase and the function of mucosal cells will
not prevent passive diffusion of sufficient amounts of PteGlu across
the mucosal barrier if the dosage is adequate, and continued ingestion
of alcohol or other drugs also will not prevent an adequate
therapeutic response. The effects of most inhibitors of folate transport
or dihydrofolate reductase are overcome easily by administration
of pharmacological doses of the vitamin. Folinic acid is the
appropriate form of the vitamin for use in chemotherapeutic protocols,
including “rescue” from methotrexate (Chapter 61). Perhaps
the only situation in which oral administration of folate will be
ineffective is when vitamin C is severely deficient. Patients with
scurvy may suffer from a megaloblastic anemia despite increased
intake of folate and normal or high concentrations of the vitamin
in plasma and cells.
The therapeutic response may be monitored by study of the
hematopoietic system in a fashion identical to that described for
vitamin B 12
. Within 48 hours of the initiation of appropriate therapy,
megaloblastic erythropoiesis disappears, and as efficient erythropoiesis
begins, the concentration of iron in plasma falls to
normal or below-normal values. The reticulocyte count begins
to rise on the second or third day and reaches a peak by the fifth to
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CHAPTER 37
HEMATOPOIETIC AGENTS