Ref. Atlas P 140 Drugs For The Treatment Of Anemias

‡ 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 stimulated 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 erythropoietin,. 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(macrocytichyperchromic 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 administration 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.