‡ Atlas p 140 Drugs for the Treatment of Anemias

Anemia denotes a reduction in red blood cell count or hemoglobin content, or both.

Erythropoiesis (A) Blood corpuscles develop from stem cells through several cell divisions (n =
17!). He- moglobin is then synthesized and the cell nucleus is extruded. Erythropoiesis is stimu-
lated by the hormone erythropoietin (a gly- coprotein), which is released from the kid- neys
when renal oxygen tension declines. A nephrogenic anemia can be ameliorated by parenteral
administration of recombinant erythropoietin (epoetin alfa) or hyperglyco- sylated
erythropoietin (darbepoetin; longer half-life than epoetin). Even in healthy humans, formation
of red blood cells and, hence, the oxygen transport capacity of blood, is augmented by erythro-
poietin,. This effect is equivalent to high-al- titude training and is employed as a doping method
by high-performance athletes. Erythropoietin is inactivated by cleavage of sugar residues, with
a biological half-life of ~5hoursafter intravenous injection and a t½ > 20 hours after
subcutaneous injection. Given adequate production of erythro- poietin, a disturbance of
erythropoiesis is due to two principal causes. (1) Cell multi- plication is inhibited because DNA
synthe- sis is insuf cient. This occurs in deficiencies of vitamin B12 or folic acid(macrocytichyper-
chromic anemia). (2) Hemoglobin synthesis is impaired. This situation arises in iron de- ficiency,
since Fe2+ is a constituent of hemo- globin (microcytic hypochromic anemia).

Vitamin B12 (B) Vitamin B12 (cyanocobalamin) is produced by bacteria; vitamin B12 generated
in the colon, however, is unavailable for absorp- tion. Liver, meat, fish, and milk products are
rich sources of the vitamin. The minimal requirement is about 1 µg/day. Enteral ab- sorption
ofvitamin B12 requirestheso-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, trans- cobalamin, vitamin B12 is destined for stor- age in the liver or uptake
into tissues. A frequent cause ofvitamin B12 defi- ciency is atrophic gastritis leading to a lack of
intrinsic factor. Besides megaloblastic ane- mia, damage to mucosal linings and degen- eration
of myelin sheaths with neurological sequelae will occur (pernicious anemia). The optimal
therapy consists in parenteral administration of cyanocobalamin or hy- droxycobalamin
(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
~50 µg/day. Polyglutamine-FA in food is hy- drolyzed to monoglutamine-FA prior to being
absorbed. Causes of deficiency in- clude insuf cient intake, malabsorption, and increased
requirements during preg- nancy (hence the prophylactic administra- tion during pregnancy).
Antiepileptic drugs and oral contraceptives may decrease FA ab- sorption, presumably by
inhibiting the for- mation of monoglutamine-FA. Inhibition of dihydro-FAreductase (e.g., by
methotrexate, p.300) depresses the formation of the active species, tetrahydro-FA. Symptoms
of defi- ciency are megaloblastic anemia and mu- cosal damage. Therapy consists in oral ad-
ministration of FA. Administration of FA can mask a vitamin B12 deficiency.Vitamin B12
isrequired for the conversion of methyltetrahydro-FA to tetra- hydro-FA, which is important for
DNA-syn- thesis (B). Inhibition of this reaction due to vitamin 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 dif cult to diagnose by the
absence of hematologicalchanges.Indiscriminate use of FA-containing multivitamin
preparations can, therefore, be harmful.