Anti-Anemia Drugs

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Anti-Anemia Drugs

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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.

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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.

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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.

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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)

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Sites of action for EPO
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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

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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

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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,
  granulocyte-macrophage and high proliferative
  potential (HPP) colonies
• Induces release of granulocytes from marrow

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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 (SACHEcells) in bone
  marrow.
• Produces an increase in megakaryocytes
  endomitosis.
• Increases platelet size and number in plasma.

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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

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Mechanism of Iron Absorption
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Therapeutic uses of Iron

• Iron Deficient Anemia
• Pregnancy
• Premature Babies
• Blood loss

• Hookworn infestation
• Malabsorption Syndrome
• GI Bleeding due to
• Ulcers
• Aspirin
• Excess consumption of coffee

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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

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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

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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.

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Treatment of Iron Overdose

• Toxic levels
• ALD 200-300mgkg, plasma iron gt 300ug/dl
• ABCs supportive care
• Bicarbonate for acidosis
• Fluids for blood loss
• Ipecac or lavage
• Chelation with Deferoxamine

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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

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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.

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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.

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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.

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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.

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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.

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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.