Antianemics

Drugs for the Treatment of Anemias
Anemia denotes a reduction in red
blood cell count, hemoglobin content,
or both. Oxygen (O2) transport capacity
is decreased.
Erythropoiesis (A). Blood corpuscles
develop from stem cells through
several cell divisions. Hemoglobin is
then synthesized and the cell nucleus is
extruded. Erythropoiesis is stimulated
by the hormone erythropoietin (a glycoprotein),
which is released from the
kidneys when renal O2 tension declines.
Given an adequate production of
erythropoietin, a disturbance of erythropoiesis
is due to two principal causes:
1. Cell multiplication is inhibited because
DNA synthesis is insufficient. This
occurs in deficiencies of vitamin B12 or
folic acid (macrocytic hyperchromic
anemia). 2. Hemoglobin synthesis is
impaired. This situation arises in iron
deficiency, since Fe2+ is a constituent of
hemoglobin (microcytic hypochromic
anemia).
Vitamin B12 (B)
Vitamin B12 (cyanocobalamin) is produced
by bacteria; B12 generated in the
colon, however, is unavailable for absorption
(see below). Liver, meat, fish,
and milk products are rich sources of
the vitamin. The minimal requirement
is about 1 μg/d. Enteral absorption of vitamin
B12 requires so-called “intrinsic
factor” from parietal cells of the stomach.
The complex formed with this glycoprotein
undergoes endocytosis in the
ileum. Bound to its transport protein,
transcobalamin, vitamin B12 is destined
for storage in the liver or uptake into tissues.
A frequent cause of vitamin B12 deficiency
is atrophic gastritis leading to a
lack of intrinsic factor. Besides megaloblastic
anemia, damage to mucosal linings
and degeneration of myelin
sheaths with neurological sequelae will
occur (pernicious anemia).
Optimal therapy consists in parenteral
administration of cyanocobalamin
or hydroxycobalamin (Vitamin
B12a; exchange of -CN for -OH group).
Adverse effects, in the form of hypersensitivity
reactions, are very rare.
Folic Acid (B). Leafy vegetables and
liver are rich in folic acid (FA). The minimal
requirement is approx. 50 μg/d.
Polyglutamine-FA in food is hydrolyzed
to monoglutamine-FA prior to being absorbed.
FA is heat labile. Causes of deficiency
include: insufficient intake, malabsorption
in gastrointestinal diseases,
increased requirements during pregnancy.
Antiepileptic drugs (phenytoin,
primidone, phenobarbital) may decrease
FA absorption, presumably by inhibiting
the formation of monoglutamine-
FA. Inhibition of dihydro-FA reductase
(e.g., by methotrexate, p. 298)
depresses the formation of the active
species, tetrahydro-FA. Symptoms of deficiency
are megaloblastic anemia and
mucosal damage. Therapy consists in
oral administration of FA or in folinic
acid when deficiency is caused
by inhibitors of dihydro—FA—reductase.
Administration of FA can mask a
vitamin B12 deficiency. Vitamin B12 is required
for the conversion of methyltetrahydro-
FA to tetrahydro-FA, which is
important for DNA synthesis (B). Inhibition
of this reaction due to B12 deficiency
can be compensated by increased FA
intake. The anemia is readily corrected;
however, nerve degeneration progresses
unchecked and its cause is made
more difficult to diagnose by the absence
of hematological changes. Indiscriminate
use of FA-containing multivitamin
preparations can, therefore, be
harmful.


Iron Compounds
Not all iron ingested in food is equally
absorbable. Trivalent Fe3+ is virtually
not taken up from the neutral milieu of
the small bowel, where the divalent Fe2+
is markedly better absorbed. Uptake is
particularly efficient in the form of
heme (present in hemo- and myoglobin).
Within the mucosal cells of the gut,
iron is oxidized and either deposited as
ferritin (see below) or passed on to the
transport protein, transferrin, a !1-glycoprotein.
The amount absorbed does
not exceed that needed to balance losses
due to epithelial shedding from skin
and mucosae or hemorrhage (so-called
“mucosal block”). In men, this amount
is approx. 1 mg/d; in women, it is approx.
2 mg/d (menstrual blood loss),
corresponding to about 10% of the dietary
intake. The transferrin-iron complex
undergoes endocytotic uptake
mainly into erythroblasts to be utilized
for hemoglobin synthesis.
About 70% of the total body store of
iron (~5 g) is contained within erythrocytes.
When these are degraded by macrophages
of the reticuloendothelial
(mononuclear phagocyte) system, iron
is liberated from hemoglobin. Fe3+ can
be stored as ferritin (= protein apoferritin
+ Fe3+) or returned to erythropoiesis
sites via transferrin.
A frequent cause of iron deficiency
is chronic blood loss due to gastric/intestinal
ulcers or tumors. One liter of
blood contains 500 mg of iron. Despite a
significant increase in absorption rate
(up to 50%), absorption is unable to keep
up with losses and the body store of iron
falls. Iron deficiency results in impaired
synthesis of hemoglobin and anemia.
The treatment of choice (after the
cause of bleeding has been found and
eliminated) consists of the oral administration
of Fe2+ compounds, e.g., ferrous
sulfate (daily dose 100 mg of iron
equivalent to 300 mg of FeSO4, divided
into multiple doses). Replenishing of
iron stores may take several months.
Oral administration, however, is advantageous
in that it is impossible to overload
the body with iron through an intact
mucosa because of its demand-regulated
absorption (mucosal block).
Adverse effects. The frequent gastrointestinal
complaints (epigastric
pain, diarrhea, constipation) necessitate
intake of iron preparations with or after
meals, although absorption is higher
from the empty stomach.
Interactions. Antacids inhibit iron
absorption. Combination with ascorbic
acid (Vitamin C), for protecting Fe2+
from oxidation to Fe3+, is theoretically
sound, but practically is not needed.
Parenteral administration of Fe3+
salts is indicated only when adequate
oral replacement is not possible. There
is a risk of overdosage with iron deposition
in tissues (hemosiderosis). The
binding capacity of transferrin is limited
and free Fe3+ is toxic. Therefore, Fe3+
complexes are employed that can donate
Fe3+ directly to transferrin or can
be phagocytosed by macrophages, enabling
iron to be incorporated into ferritin
stores. Possible adverse effects are,
with i.m. injection: persistent pain at
the injection site and skin discoloration;
with i.v. injection: flushing, hypotension,
anaphylactic shock.