Anti-Anemia Drugs

Anemia

2nd most presenting manifestation of disease, with pain being the first. It is defined as: low hemoglobin, low RBC count and low RBC mass. Usually presents with pallor, fatigability, weakness and pale conjunctivae In order to properly treat the anemia, you must determine the cause.

Causes of Anemia

1. Diminished production and or replacement of red blood cells.

2. Excessive breakdown and loss of red blood cells. Hemodilution while not a cause of anemia, it does cause an anemia-like effect.

1. Diminished Production/Replacement of RBCs Anemia's

Microcytic anemia deficiency of Fe

RBCs appear pale and smaller, and we see more reticulocytes in circulation. Can be caused by the chronic use of aspirin, which irritates the stomach GI blood loss.

Normocytic anemia deficiency of Erythropoietin

Caused by compromised renal function.

Macrocytic Anemia- deficiency of folic acid and B12

Diminished cell division and release of larger cells in circulation.

2. Breakdown of RBCs Anemia

Bleeding: can be due to an ulcer or in females blood loss due to their menstrual cycle Use of drugs that irritate the GI tract (aspirin) Hemolysis (Hemolytic Anemia) can be caused by:
Autoimmune disease Mechanical (heart valves, microvascular disease) Toxins (e.g., snake venom)

Sites of action for EPO

Therapeutic Uses of EPO

Anemia of end stage renal disease To treat AIDS anemia caused by AZTs suppression of bone marrow Anemia related to cancer chemotherapy Others
To increase RBC levels for autologous blood donation Anemia associated with rheumatoid arthritis

Biological Actions of Other Hematopoietic Growth Factors

1. Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF)- Sargramostim

Acts synergistically with IL-3 to stimulate the formation and proliferation of colony forming cells: CFU-GEMM, BFU-E, CFU-Meg, CFU-GM, CFU-M, CFU-E Increases cytotoxic phagocytic activity of mature granulocytes

2. Interleukin 3 (IL-3)
Acts synergistically with GM-CSF to stimulate the formation of granulocytes, macrophages, eosinophils and megakaryocytes. Acts synergistically with EPO to stimulate formation of BFU-E colonies Induces CFU-S and leukemic blast cells into cell cycle

More Hematopoietic Growth Factors

3. Colony stimulating Factor-1 (CSF-1 or M-CSF)

Acts synergistically with GM-CSF and IL-3 to stimulate monocyte/macrophage colony formation and function

4. Granulocyte Colony Stimulating Factor (G-CSF) - filgrastim

Acts synergistically with IL-3, GM-CSF and CSF-1 to
stimulate formation of megakaryocytes, granulocytemacrophage and high proliferative potential (HPP) colonies Induces release of granulocytes from marrow

More Hematopoietic Growth Factors

5. Thrombopoietin (TSF)
Increases the size and number of megakaryocytes. (IL-11 also useful in stimulating production)
Increases the concentration of early megakaryocytes cells (SACHE+cells) in bone marrow. Produces an increase in megakaryocytes endomitosis.

Increases platelet size and number in plasma.

Iron Cycle

5 - 10% of ingested iron is absorbed

Once ingested the acid in the stomach:

1. Aids in ionization of iron 2. Splits chelated food iron from chelator 3. Maintains iron in soluble form 4. Allows iron to remain in the absorbable form Fe3+

Mechanism of Iron Absorption

Therapeutic uses of Iron

Iron Deficient Anemia Pregnancy Premature Babies

Hookworn infestation Malabsorption Syndrome GI Bleeding due to:

Ulcers Aspirin Excess consumption of coffee

Blood loss

Iron Preparations

Oral Iron
Ferrous Sulfate (Feosol) 300 mg tid Side Effects are extremely mild:
Nausea, upper abdominal pain, constipation or diarrhea.

Cheapest form of Iron and one of the most widely used

Parenteral
Iron Dextran (Imferon) IM or IV Indicated for patients who cannot tolerate or absorb oral iron or where oral iron is insufficient to treat the condition ie. Malabsorption syndrome, prolonged salicylate therapy, dialysis patients

Toxicity of Iron Overdose

5000 deaths/year in the US, usually in children 20% of children presenting with iron toxicity will die 1 to 2 grams are sufficient to cause death At high doses, Iron is absorbed through passive diffusion with no regulation

Iron Clinical Effects

Early changes

Vomiting, diarrhea Blood Volume HR TPR (reflex) Acidosis from Iron oxidation, Krebs cycle and anaerobic metabolism citric acid and lactic acid

Intermediate changes

Improvement (short lived) profound shock and CV Collapse Hepatic Failure, jaundice, pulmonary edema and death

Late Stage

Intestinal scarring, fatty acid degeneration of liver, cirrhosis and death.

Treatment of Iron Overdose

Toxic levels

ALD 200-300mgkg, plasma iron > 300ug/dl

ABCs supportive care Bicarbonate for acidosis Fluids for blood loss Ipecac or lavage

Chelation with Deferoxamine

Vitamin B12

Source: In food, especially in liver and kidneys. GI Microorganism synthesis, Vitamin Supplements (Cyanocobalamin) Necessary for normal DNA synthesis Absorption of B12
1. Intrinsic Factor (low dose): a protein made by stomach parietal cells that binds to B12 and delivers it from the ileum via a calcium mediated event. 2. Mass Action (High dose): 1000mg/day, absorbed via passive diffusion

B12 Deficiency

A B12 deficiency will cause peripheral neuropathy and a macrocytic anemia, a pernicious anemia. Folic Acid administration can correct the macrocytic anemia but will fail to correct the peripheral neuropathy.

To treat the neuropathy, Vit B12 must be utilized.

Mechanism for Peripheral Neuropathy

Cobalamin is a cofactor for the enzyme Methylmalonyl-CoA mutase which converts methylmalonyl-CoA to succinyl-CoA. Succinyl-CoA enters the Krebs cycles and goes into nerves to make myelin. If no Vitamin B12, methylmalonyl-CoA goes on to form abnormal fatty acids and causes subacute degeneration of the nerves. Only B12 can correct this problem.

Therapeutic Uses of B12

Daily Requirements - 0.6-1.0mh/day; T1/2 ~ 1 year

Pernicious Anemia
Impaired GI absorption of B12

Gastrectomy
Corrosive Injury of GI mucosa

Fish tape worm: worm siphons off B12

Placebo abuse with B12, especially in elderly patients.

Folic Acid

Source in food yeast, egg yolk, liver and leafy vegetables

Folic Acid (F.A.) is absorbed in the small intestines.

F.A. is converted to tetrahydrofolate by dihydrofolate reductase.

Folic Acid deficiency (F.A. Deficiency) is also called Wills Disease. Deficiency may produce megaloblastic anemia; neural tube defect in fetus.

Therapeutic Uses of Folic Acid

1. Megaloblastic Anemia due to inadequate dietary intake of folic acid

Can be due to chronic alcoholism, pregnancy, infancy, impaired utilization: uremia, cancer or hepatic disease.

2. To alleviate anemia that is associated with dihydrofolate reductase inhibitors.

i.e. Methotrexate (Cancer chemotherapy), Pyrimethamine (Antimalarial) Administration of citrovorum factor (methylated folic acid) alleviates the anemia.

Therapeutic Uses of Folic Acid (cont)

3. Ingestion of drugs that interfere with intestinal absorption and storage of folic acid.
Mechanism- inhibition of the conjugases that break off folic acid from its food chelators. Ex. phenytoin, progestin/estrogens (oral contraceptives)

4. Malabsorption Sprue, Celiac disease, partial gastrectomy. 5. Rheumatoid arthritis increased folic acid demand or utilization.