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

1092 neurological signs or symptoms, the administration of vitamin B 12
alone will suffice. Moreover, therapy may be delayed until other
causes of megaloblastic anemia have been excluded and sufficient
studies of GI function have been performed to reveal the underlying
cause of the disease. In this situation, a therapeutic trial with small
amounts of parenteral vitamin B 12
(1-10 μg per day) can confirm the
presence of an uncomplicated vitamin B 12
deficiency.
In contrast, patients with neurological changes or severe
leukopenia or thrombocytopenia associated with infection or bleeding
require emergency treatment. The older individual with a
severe anemia (hematocrit <20%) is likely to have tissue hypoxia,
cerebrovascular insufficiency, and congestive heart failure.
Effective therapy must not wait for detailed diagnostic tests. Once
the megaloblastic erythropoiesis has been confirmed and sufficient
blood collected for later measurements of vitamin B 12
and folic
acid, the patient should receive intramuscular injections of 100 μg
of cyanocobalamin and 1-5 mg of folic acid. For the next 1-2 weeks
the patient should receive daily intramuscular injections of 100 μg
of cyanocobalamin, together with a daily oral supplement of 1 to
2 mg of folic acid. Because an effective increase in red-cell mass
will not occur for 10-20 days, the patient with a markedly
depressed hematocrit and tissue hypoxia also should receive a
transfusion of 2-3 units of packed red blood cells. If congestive
heart failure is present, diuretics can be administered to prevent
volume overload.
Patients usually report an increased sense of well-being
within the first 24 hours of the initiation of therapy. Objectively,
memory and orientation can improve dramatically, although full
recovery of mental function may take months, or it may never occur.
In addition, even before an obvious hematologic response is apparent,
the patient may report an increase in strength, a better appetite,
and reduced soreness of the mouth and tongue.
The first objective hematologic change is the disappearance
of the megaloblastic morphology of the bone marrow. As the ineffective
erythropoiesis is corrected, the concentration of iron in plasma
falls dramatically as the metal is used in the formation of hemoglobin.
This usually occurs within the first 48 hours. Full correction of
precursor maturation in marrow with production of an increased
number of reticulocytes begins about the second or third day and
peaks 3-5 days later. When the anemia is moderate to severe, the
maximal reticulocyte index will be between three and five times the
normal value (i.e., a reticulocyte count of 20-40%). The ability of
the marrow to sustain a high rate of production determines the rate
of recovery of the hematocrit. Patients with complicating iron deficiency,
an infection or other inflammatory state, or renal disease may
be unable to correct their anemia. Therefore it is important to monitor
the reticulocyte index over the first several weeks. If it does not
continue at elevated levels while the hematocrit is <35%, plasma
concentrations of iron and folic acid should again be determined and
the patient reevaluated for an illness that could inhibit the response
of the marrow.
The degree and rate of improvement of neurological signs and
symptoms depend on the severity and the duration of the abnormalities.
Those that have been present for only a few months usually disappear
relatively rapidly. When a defect has been present for many
months or years, full return to normal function may never occur.
Long-Term Therapy with Vitamin B 12
. Once begun, vitamin B 12
therapy
must be maintained for life. This fact must be impressed on the
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
patient and family, and a system must be established to guarantee
continued monthly injections of cyanocobalamin.
Intramuscular injection of 100 μg of cyanocobalamin every
4 weeks is sufficient to maintain a normal concentration of vitamin
B 12
in plasma and an adequate supply for tissues. Patients with severe
neurological symptoms and signs may be treated with larger doses of
vitamin B 12
in the period immediately after the diagnosis. Doses of
100 μg per day or several times per week may be given for several
months with the hope of encouraging faster and more complete recovery.
It is important to monitor vitamin B 12
concentrations in plasma
and to obtain peripheral blood counts at intervals of 3-6 months to
confirm the adequacy of therapy. Because refractoriness to therapy
can develop at any time, evaluation must continue throughout the
patient’s life. Intranasal preparations are available for maintenance
following normalization of vitamin B 12
–deficient patients without
nervous system involvement (CALOMIST, NASCOBAL) or as a supplement
for vitamin B 12
deficiencies of various etiologies (NASCOBAL).
Other Therapeutic Uses of Vitamin B 12
. Vitamin B 12
has been used in
the therapy of a number of conditions, including trigeminal neuralgia,
multiple sclerosis and other neuropathies, various psychiatric
disorders, poor growth or nutrition, and as a “tonic” for patients complaining
of tiredness or easy fatigue. There is no evidence for the
validity of such therapy in any of these conditions. Maintenance therapy
with vitamin B 12
has been used with some apparent success in
the treatment of children with methylmalonic aciduria.
Folic Acid
Chemistry and Metabolic Functions. The structural formula of
pteroylglutamic acid (PteGlu) is shown in Figure 37–9. Major portions
of the molecule include a pteridine ring linked by a methylene
bridge to para-aminobenzoic acid, which is joined by an amide linkage
to glutamic acid. Although pteroylglutamic acid is the common
pharmaceutical form of folic acid, it is neither the principal folate
congener in food nor the active coenzyme for intracellular metabolism.
After absorption, PteGlu is rapidly reduced at the 5, 6, 7, and
8 positions to tetrahydrofolic acid (H 4
PteGlu), which then acts as an
acceptor of a number of one-carbon units. These are attached at
either the 5 or the 10 position of the pteridine ring or may bridge
these atoms to form a new five-membered ring. The most important
forms of the coenzyme that are synthesized by these reactions are
listed in Figure 37–9. Each plays a specific role in intracellular
metabolism, summarized as follows (see “Relationships Between
Vitamin B 12
and Folic Acid,” as well as Figure 37–6).
Conversion of Homocysteine to Methionine. This reaction requires
CH 3
H 4
PteGlu as a methyl donor and uses vitamin B 12
as a cofactor.
Conversion of Serine to Glycine. This reaction requires tetrahydrofolate
as an acceptor of a methylene group from serine and uses pyridoxal
phosphate as a cofactor. It results in the formation of 5,10-CH 2
H 4
PteGlu,
an essential coenzyme for the synthesis of thymidylate.
Synthesis Of thymidylate. 5,10-CH 2
H 4
PteGlu donates a methylene
group and reducing equivalents to deoxyuridylate for the synthesis
of thymidylate—a rate-limiting step in DNA synthesis.
Histidine Metabolism. H 4
PteGlu also acts as an acceptor of a
formimino group in the conversion of formiminoglutamic acid to
glutamic acid.
Synthesis of Purines. Two steps in the synthesis of purine nucleotides
require the participation of 10-CHOH 4
PteGlu as a formyl donor in