Drug Therapy of Anemias

Structure of hemoglobin: With 4 hemes attached to 1 globin, the molecule carries 8 atoms of oxygen.

Biosynthesis of hemoglobin: The RLS for synthesis of hemoglobin (in mitochondria) is 2-alpha-ketoglutaric acid+glycine –(ALA sythetase)pyrrole, which can be enhanced by heme, barbiturates, estrogen, and sulfonamides; can lead to acute intermediate porphyria.

Areas of the body producing RBCs: Yolk sac (1st trimester); liver, spleen, and lymph nodes (2nd trimester); bone marrow (all bones until age 5, membranous bones such as sternum, pelvis, ribs, and vertebrae after age 20).

Aging of RBCs: Hb synthesis and glucose metabolism occur in immature and early RBCs only. Structural changes occur due to declining glycolytic activity.

RBC replacement: The formation of many new cells necessitates high mitotic activity and a high rate of DNA synthesis. Decrease in DNA synthesis will result in an insufficiency in RBC formation (anemia).

Pathophysiology: Physiologic adjustments include tachycardia, augmented CO, accelerated velocity of blood flow, increased alveolar ventilation, and increased 2,3-DPG. A normal person may tolerate as much as a 50% reduction in RBC mass without conspicuous untoward affects.

Erythropoietin – growth factor produced by kidney that controls RBC production; triggered by hypoxia (oxygen sensing cell), resulting in production of nitric oxide; NO stimulates guanylate cyclase in EPO producing cell to increase cGMP, which ultimately increases expression of EPO mRNA.

• Targets: Early erythroid colony-forming unit (CFU-E) and late burst erythroid colony forming unit (BFU-E).

• Indications: Anemia due to chronic renal failure, AIDS patients treated with AZT, cancer patients treated with chemotherapy, and patients undergoing elective surgery to increase RBC production.

• Side effects: Increased clotting in dialysis patients, hypertension, seizures.

Myeloid growth factors (G-CSF, GM-CSF, M-CSF) – glycoproteins that stimulate proliferation and differentiation of hematopoietic precursors.

• Side effects: Bone, joint, and muscle pain.

Iron: Main storage form is hemoglobin (75%) and myoglobin; other storage forms include ferritin and hemosiderin. Normal male individual needs 1 mg of iron per day; menstruating or pregnant females need more (2.0-2.5 mg). Children need 0.5-1.0 mg per day. In the U.S. an average person absorbs only 10-30% of dietary iron to balance loss (can be increased to 60% if necessary). Factors that increase iron absorption include vitamin C; factors that decrease absorption include antacids and tetracycline.

Iron Deficiency Anemia: Hypochromic microcytic anemia; only anemia resulting from iron deficiency and therefore is the only anemia that responds to iron.

Ferrous sulfate – treatment of choice for hypochromic microcytic anemia (180 mg/day).

Ferrous gluconate – tolerated better.

• Indications: Hypochromic microcytic anemia.

• Route: Oral AS EFFECTIVE as parenteral.

• Toxicity: Acute iron poisoning (1 g in kids) can lead to death due to hepatic injury; treat with deferoxamine, which is a potent iron chelator but a poor calcium chelator.

• Side effects: Constipation, diarrhea, nausea, epigastric pain.

Iron dextran

• Indications: Hypochromic microcytic anemia who do not respond to oral therapy (idiopathic)

• Route: Parenteral.

• Side effects: Hypertension, headache, tachycardia, pain at injection site.

Megaloblastic Anemia: Deficiency of vitamin B12 and/or folate impairs DNA synthesis and is reflected in mitotic activity. The primary defect appears to be decreased mitotic activity consequent to lengthening of the intermitotic interval. Large, oval RBCs are characteristic. Therapy with either vitamin B12 or folate can usually reverse the symptoms. Once difference is that vitamin B12 deficiency produces neurological symptoms that can be corrected by vitamin B12 but not folates. Folate deficiency does not result in nerve damage.

Vitamin B12: Absorption takes place in distal ileum and requires intrinsic factor, which can bind 2 molecules of B12. Vitamin B12 has a cobalt requirement. B12 requirement is 2g/day assuming 60-80% GI absorption.

Folate (pteroylglutamic acid/PGA): Occur most abundantly in fresh green vegetables, liver, kidney, eggs, yeast, dried beans, nuts, grains, and certain fruits. Minimum requirement is 50-100 g/day. Folate is absorbed in the proximal jejunum in an energy-dependent process. Anticonvulsants (phenytoin, primidone, ethanol), trimethoprim, and methotrexate can cause a folate deficiency and thus precipitate megalobalastic anemia. A folate deficient megaloblastic anemia can also occur in association with scurvy because vitamin C is involved in conversion of folic acid to folinic acid.

Vitamin B12 – the patient with pernicious anemia should be placed on vitamin B12 for life.

1. Indications: Megaloblastic anemia due to vitamin B12 deficiency due to vegetarianism, impaired absorption, gastric or small bowel disease, tapeworm, blind loop syndrome, or functional damage to ileum (also malnutrition, alcoholism, or pregnancy).

2. Route: Injection appears more dependable (IM).

Folate – folic acid CANNOT correct the neurological disorders due to vitamin B12 deficiency. May also give vitamin C concurrently (antioxidant).

1. Indications: Megaloblastic anemia due to folate deficiency due to NO vegetables in diet, impaired utilization, anticonvulsants, vitamin C deficiency, hyperthyroidism, malignant tumor, or dialysis (also malnutrition, alcoholism, or pregnancy).

Anemias Related to Marrow Defects: The bone marrow failure may be idiopathic, or it may be secondary to known toxic or inhibiting agents.

Hemolytic Anemias: Hereditary (spherocytosis corrected by splenectomy) or acquired (immune or nonimmune). Immune varieties include autoimmune hemolytic anemia, erythoblastosis fetalis, and transfusion reactions. Immune hemolytic anemias respond to corticosteroids. Hemolytic anemias are associated with a positive Coombs test. Nonimmune acquired hemolytic anemias include those caused by various chemical, bacterial, or protozoal agents. Hemolysis by ordinary doses of drugs is usually due to G6PDH deficiency.

Category: Pharmacology Notes