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Agents Used in Anemias;
Hematopoietic growth Factors
Anemia: a deficiency in oxygen-carrying erythrocytes
Thrombocytopenia
Neutropenia
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Agents Used in Anemias
Iron
Basic Pharmacology
Microcytic hypochromic anemia
Iron-porphyrin heme ring
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Pharmacokinetics
growing children
pregnant women
menstruating women
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Heme iron in food
meat
Nonheme iron in food
chelatorscomplexing agent
apotransferrin
ferritin: liver
spleen
boneplasma
transferrin receptor
Transport, storage, elimination
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Clinical Pharmacology
I. Indications for the use of iron : iron deficiency1. Infants, especially premature infants
2. Children during rapid growth periods
3. Pregnant and lactating women
4. Blood loss: menstruting women
gastrointestinal bleeding
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II. Treatment
1. Oral iron therapy
Failure to respond
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2. Parenteral iron therapy
Iron dextran: ferric hydroxide andlow 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
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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
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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
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Pharmacodynamics
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dTMP: deoxythymidylate
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Clinical Pharmacology
1. Neurologic syndrome:
degeneration of myelin sheathdisruption of axon
peripheral nerves: paresthesia, spasticity
central nervous system
2. Megaloblastic anemia: vitamin B12 or folic acid3. Pernicious anemia: defective secretion of intrinsic
factor
gastric atrophy
partial gastrectomydistal ileum: inflammation
surgical resection
bacterial overgrowth of the small bowel
chronic pancreatitis and thyroid disease
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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
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Folic Acid
Chemistrypolyglutamates
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Pharmacokinetics
the richest sources: liver, kidney, green vegetables
unaltered folic acid: proximal jejunum
dietary folates: polyglutamate forms of
N5-methyltetrahydrofolate
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Pharmacodynamics
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Clinical Pharmacology
1. no neurologic syndrome
2. Inadequate dietary intake: elderly patients,poor patients,
food faddist
3. Liver disease
4. Pregnant womenpatient 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 dial sis, certain skin disease
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Hematopoietic Growth Factors
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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
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Clinical Pharmacology
1. Chronic renal failure
iron deficiency
folate supplementation
2. Primary bone marrow disorders and secondary anemias
aplastic anemia
chronic inflammation3. HIV infection: Zidovudin
Phlebotomies
4. Athletes
Toxicity
hematocrit and hemoglobin
hypertension and thrombotic complication
G CSF l t l
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Myeloid Growth Factors
GM-CSF: granulocyte-
macrophage colony-
stimulating factor
G-CSF:granulocyte colony-
stimulating factor
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Chemistry and Pharmacokinetics
Filgrastim: G-CSF
Sargramostim:GM-CSF
Pharmacodynamics1. 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
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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 chemtherapyG-CSF: prior episode of febrile neutropenia
GM-CSF: itself can induce fever
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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 cellautologus and allogeneic transplantation
G-CSF
ToxicityGM-CSF: more sever side effect
G-CSF:bone pain
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Megakaryocyte Growth factor
Chemistry and Pharmacokinetics
Interleukin: fibroblasts and stromal cell in bone marrow
Oprelvekin: recombinant
Thrombopoietin: hepatocyterecombinant
Pharmacodynamics
IL-11: primitive megakaryocytic progenitorsincreases the number of peripheral platelets
and neutrophil
Thrombopoietin: primitive megakaryocytic progenitors
mature megakaryocytes
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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
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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 B12affect 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.
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