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 RBC’s Anemia's

Microcytic anemia – deficiency of Fe
 RBC’s 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 RBC’s 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 AZT’s
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, CFUMeg, 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

Hookworn infestation

Pregnancy

Malabsorption
Syndrome

Premature Babies

GI Bleeding due to:

Blood loss
 Ulcers
 Aspirin
 Excess consumption of
coffee
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

ABC’s 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 Will’s
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.