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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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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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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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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


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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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.

Documents

6748024-Anemias95