Agents Used in Anemias;

Hematopoietic growth Factors

Anemia: a deficiency in oxygen-carrying erythrocytes

Thrombocytopenia

Neutropenia
 Agents Used in Anemias
Iron

Basic Pharmacology Iron-porphyrin heme ring

Microcytic hypochromic anemia

Pharmacokinetics

growing children
pregnant women
menstruating women
Heme iron in food Transport, storage, elimination
meat
Nonheme iron in food
chelators
complexing agent

apotransferrin

ferritin: liver
spleen
bone
plasma

transferrin receptor
Clinical Pharmacology

I. Indications for the use of iron : iron deficiency

1. Infants, especially premature infants
2. Children during rapid growth periods
3. Pregnant and lactating women
4. Blood loss: menstruting women
gastrointestinal bleeding
II. Treatment
1. Oral iron therapy
Failure to respond
2. Parenteral iron therapy

Iron dextran: ferric hydroxide and

low molecular-weight dertran
i.m.: local pain, tissue staining
i.v.
Hypersensitvity

Clinical Toxicity
I. Acute iron toxicity: young children
necrotizing gastroenterities
shock, lethargy, dyspnea, metabolic acidosis, coma, death

Treatment: activated charcoal, deferoxamine

II. Chronic Iron Toxicity

Hemochromatosis: heart, liver, pacreas and other organs

inherited hemochromatosis: excessive iron absorption

red cell transfusions over a long period of time

Treatment: intermittent phlebotomy

Vitamin B12
Deficiency: anemia
gastrointestinal symptoms
neurologic abnormalities
due to abnormal absorption of dietary Vit B12

Chemistry
prophyrin-like ring + Co

Active form:
Deoxyadenosylcobalamin
Methylcobalamin
Food: cyanocobalamin
hydroxycobalamin

microbial synthesis
animals or plants: not
meat, eggs, dairy products
extrinsic factor

Pharmacokinetics

intrinsic factor: glycoprotein secreted by the parietal cell

Vit B12 + Intrinsci factor: receptoy-mediated transport system

distal ileum
Pharmacodynamics
dTMP: deoxythymidylate
Clinical Pharmacology
1. Neurologic syndrome:
degeneration of myelin sheath⇒disruption of axon
peripheral nerves: paresthesia, spasticity
central nervous system

2. Megaloblastic anemia: vitamin B12 or folic acid

3. Pernicious anemia: defective secretion of intrinsic
factor
gastric atrophy
partial gastrectomy
distal ileum: inflammation
surgical resection
bacterial overgrowth of the small bowel
chronic pancreatitis and thyroid disease
4. Treatment

Parenteral injection:
Cyanocobalamin
Hydroxocobalamin: protein-bound

Oral

bone marrow: 48 hr
reticulocytosis: second or third day
hemoglobin: begins to increase in the first week and
return to normal by 1-2 months
Folic Acid
Chemistry
polyglutamates
Pharmacokinetics
the richest sources: liver, kidney, green vegetables

unaltered folic acid: proximal jejunum

dietary folates: polyglutamate forms of
N5-methyltetrahydrofolate
Pharmacodynamics
Clinical Pharmacology

1. no neurologic syndrome
2. Inadequate dietary intake: elderly patients,
poor patients,
food faddist
3. Liver disease
4. Pregnant women
patient with hemolytic anemia
5. Fetal neural tube defect: spina bifida
6. Phenytoin, oral contraceptives, isoniazide
7. Methotrexate, trimethoprim, pyrimethamine
dihydrofolate reductase
High-risk patient: pregnant women, alcoholics, patient
with hemolytic anemia, liver disease
renal dialysis, certain skin disease
Hematopoietic Growth Factors
Erythropoietin

Chemistry & Pharmacokinetics

1. First human hematopoietic growth factor
2. the urine of patient with severe anemia
3. Recombinant DNA technology
4. Glycosylated peptide

Pharmacodynamics
Clinical Pharmacology
1. Chronic renal failure
iron deficiency
folate supplementation
2. Primary bone marrow disorders and secondary anemias
aplastic anemia
chronic inflammation
3. HIV infection: Zidovudin
Phlebotomies
4. Athletes

Toxicity
hematocrit and hemoglobin
hypertension and thrombotic complication
 G-CSF:granulocyte colony-
Myeloid Growth Factors stimulating factor

GM-CSF: granulocyte-
macrophage colony-
stimulating factor
Chemistry and Pharmacokinetics
Filgrastim: G-CSF
Sargramostim:GM-CSF

Pharmacodynamics
1. receptor on various myeloid progenitor cells:
tyrosine kinase in the JAK/STAT pathway
2. G-CSF: stimulate the production and function of neutrophil
mobilize hematopoietic stem cells
3. GM-CSF: neutrophil
early and late granulocytic progenitor cells
erythroid and megakaryocyte progenitor
T cell proliferation (+ IL-2)
peripheral blood stem cell

4. Stem cell factor (SCF): early pluipotent progenitor cell

Clinical Pharmacology
1.Neutropenia : myelosuppressiove chemtherapy
G-CSF: prior episode of febrile neutropenia
GM-CSF: itself can induce fever
2. Acute myeloid leukemia : postchemotherapy supportive care
G-CSF; GM-CSF
3.Secondary and primary neutropenia
aplastic anemia, congenital neutropenia
cyclic neutropenia, myelodysplasia
4. Autologus stem cell transplantation
5. Mobilize peripheral blood stem cell
autologus and allogeneic transplantation
G-CSF

Toxicity
GM-CSF: more sever side effect
G-CSF:bone pain
Megakaryocyte Growth factor

Chemistry and Pharmacokinetics

Interleukin: fibroblasts and stromal cell in bone marrow

Oprelvekin: recombinant
Thrombopoietin: hepatocyte
recombinant

Pharmacodynamics
IL-11: primitive megakaryocytic progenitors
increases the number of peripheral platelets
and neutrophil
Thrombopoietin: primitive megakaryocytic progenitors
mature megakaryocytes
Clinical Pharmacology

1. IL-11
thrombocytopenia
no effect on leukopenia and neutropenia
2. Thrombopoietin: investigational agent

Toxicity
Cardiovascular effect: anemia, dyspenia,
transient atrial arrhythmia
fluid retention
Objectives

1. Describe the normal mechanism of regulation or iron absorption

and storage in the body.
2. List anemias for which iron supplementation is indicated and
those for which it is contraindicated.
3. Describe the acute and chronic toxicity of iron.
4. Sketch the dTMP cycle and show folic acid and vitamin B12
affect the cycle.
5. Describe the clinical application of vitamin B12 and folic acid.
6. Describe the major hazard involved in the use of folic acid as sole
therapy for megaloblastic anemia.
7. Name the major hematopoietic growth factors and describe their
Clinical uses.