Agents Used in Agents Used in Anemias; Hematopoietic Anemias; Hematopoietic Growth Factor Growth Factor Sakura, MD Sakura, MD Department of Pharmacology Department of Pharmacology Hasanuddin University Hasanuddin University
Jan 27, 2016
Agents Used in Anemias; Agents Used in Anemias; Hematopoietic Growth Hematopoietic Growth
FactorFactor
Sakura, MDSakura, MDDepartment of PharmacologyDepartment of Pharmacology
Hasanuddin UniversityHasanuddin University
HematopoiesisHematopoiesis
Require three essential nutrients :Require three essential nutrients :
- iron- iron
- vitamin B12- vitamin B12
- folic acid- folic acidAnemia : deficiency in oxygen Anemia : deficiency in oxygen
carrying-erythrocytecarrying-erythrocyte
IRONIRON Iron deficiency : the most common cause Iron deficiency : the most common cause
of chronic anemiaof chronic anemia Leads to : pallor, fatigue, dizziness, Leads to : pallor, fatigue, dizziness,
exertional dyspnea, etcexertional dyspnea, etc Forms : the nucleus of the iron-porphyrin Forms : the nucleus of the iron-porphyrin
heme ring, which 2gether with globin heme ring, which 2gether with globin chains forms hemoglobinchains forms hemoglobin
Hb : binds oxygen & provides the critical Hb : binds oxygen & provides the critical mechanism for oxygen delivery from lungs mechanism for oxygen delivery from lungs to other tissuesto other tissues
PharmacokineticsPharmacokinetics
AbsorptionAbsorption absorbed in duodenum, proximal absorbed in duodenum, proximal
jejunumjejunum A normal individual (without iron A normal individual (without iron
deficiency) absorbs 5-10% (0,5-1 deficiency) absorbs 5-10% (0,5-1 mg daily) of iron ; average diet in mg daily) of iron ; average diet in USA (10-15 mg daily)USA (10-15 mg daily)
Total iron absorption increase to 1-2 Total iron absorption increase to 1-2 mg in normal menstruating womanmg in normal menstruating woman
Tabel 1. Iron distribution in normal adult
Iron content (mg)
Men Women
Hemoglobin 3050 1700
Myoglobin 430 300
Enzymes 10 8
Transport (transferrin)
8 6
Storage (ferritin & other forms)
750 300
Total 4248 2314
Available abundant in meatAvailable abundant in meatAbsorption is decreased by the Absorption is decreased by the
presence of chelators or presence of chelators or complexing agents in intestine complexing agents in intestine lumenlumen
Absorption increased in the Absorption increased in the presence of hydrochloric acid & presence of hydrochloric acid & vitamin Cvitamin C
TransportTransport
Iron is transported in the plasma Iron is transported in the plasma bound to transferrinbound to transferrin
Crosses the intestinal mucosal cell by Crosses the intestinal mucosal cell by active transportactive transport
Increased erythropoiesis is Increased erythropoiesis is associated with an increase the associated with an increase the number of transferrin receptorsnumber of transferrin receptors
StorageStorage
Binds avidly to a protein Binds avidly to a protein apoferritin, apoferritin, forms complex forms complex ferritinferritin
It is stored in intestinal mucosal cell, It is stored in intestinal mucosal cell, macrophages in the liver, spleen, macrophages in the liver, spleen, bonebone
Apoferritin synthesis is regulated by Apoferritin synthesis is regulated by the levels of free ironthe levels of free iron
EliminationElimination
No mechanism for excretion of ironNo mechanism for excretion of ironSmall amounts are lost by exfoliation Small amounts are lost by exfoliation
of IMC into the stoolof IMC into the stoolTrace amounts are excreted in bile, Trace amounts are excreted in bile,
urine, and sweaturine, and sweatNo more than No more than 1 mg1 mg of iron lost per of iron lost per
dayday
Clinical PharmacologyClinical Pharmacology
The only clinical indication : treatment or The only clinical indication : treatment or prevention of iron deficiency anemiaprevention of iron deficiency anemia
Iron deficiency can be found in : infants (premature Iron deficiency can be found in : infants (premature infants), rapid growth period, pregnant, lactating infants), rapid growth period, pregnant, lactating woman, post gastrectomy, patient with severe woman, post gastrectomy, patient with severe small bowel disease that result in generalized small bowel disease that result in generalized malabsorptionmalabsorption
Iron deficiency is diagnosed : (laboratory Iron deficiency is diagnosed : (laboratory measurement)measurement)- serum iron - serum iron < 40 µg/dl< 40 µg/dl- TIBC > 400 µg/dl- TIBC > 400 µg/dl- iron binding saturation < 10 %- iron binding saturation < 10 %- serum ferritin < 10 µg/L- serum ferritin < 10 µg/L
Tabel 1. Some Commonly used oral iron preparation
Preparation Tablet sizeElemental
iron per tablet
Usual adult dosage tablet per day
Ferrous sulfate, hydrated
325 mg 65 mg 3 - 4
Ferrous sulfate, desiccated
200 mg 65 mg 3 - 4
Ferrous gluconate
325 mg 36 mg 3 - 4
Ferrous fumarate 200 mg 66 mg 3 - 4
Ferrous fumarate 325 mg 106 mg 2 - 3
TreatmentTreatment
1.1. Oral iron therapyOral iron therapy2.2. Parenteral iron therapyParenteral iron therapy
Indication :Indication :- various postgastrectomy condition- various postgastrectomy condition- previous small bowel resection- previous small bowel resection- inflammatory bowel disease - inflammatory bowel disease - malabsorption syndrome- malabsorption syndrome- Consist of : iron dextran (complex of ferric - Consist of : iron dextran (complex of ferric hydroxide), iron-sucrose complex, iron hydroxide), iron-sucrose complex, iron sodium gluconate complex (deep IM, IV sodium gluconate complex (deep IM, IV infusion)infusion)- Dosage for iron dextran : 20 – 40 ml (IV)- Dosage for iron dextran : 20 – 40 ml (IV)
Clinical ToxicityClinical Toxicity
Acute iron toxicityAcute iron toxicityNecrotizing gastroenteritis (vomiting, Necrotizing gastroenteritis (vomiting,
abdominal pain, bloody diarrhea abdominal pain, bloody diarrhea followed by shock, lethargy, followed by shock, lethargy, dyspnea) dyspnea)
Should be given DeferoxamineShould be given DeferoxamineChronic iron toxicityChronic iron toxicityHemochromatosisHemochromatosisR/ PhlebotomyR/ Phlebotomy
VITAMIN B12VITAMIN B12
CofactorCofactorDeficiency leads to anemia, Deficiency leads to anemia,
gastrointestinal symptoms, gastrointestinal symptoms, neurologic abnormalitiesneurologic abnormalities
Consist of a porphyrin-like ring with a Consist of a porphyrin-like ring with a central cobalt atomcentral cobalt atom
Cyanocobalamin & Cyanocobalamin & hydroxocobalaminhydroxocobalamin
Pharmacokinetics of Vitamin B12Pharmacokinetics of Vitamin B12
Once absorbed, Vit B12 is bound to Once absorbed, Vit B12 is bound to transcobalamin II and transported transcobalamin II and transported to various cells of the bodyto various cells of the body
Average diet (USA) contain 5-30 Average diet (USA) contain 5-30 µg µg of vit B12 daily; 1-5 µg of which is of vit B12 daily; 1-5 µg of which is absorbedabsorbed
Pharmacodynamics of Vit B12Pharmacodynamics of Vit B12
Cofactor for several reaction in the body :Cofactor for several reaction in the body : conversion of the major dietary and conversion of the major dietary and
storage folate to tetrahydrofolatestorage folate to tetrahydrofolate DNA synthesisDNA synthesis isomerization of methylmalonyl-CoA to isomerization of methylmalonyl-CoA to
avoid neurologic disorderavoid neurologic disorderClinical useClinical useR/ for pernicious anemia & anemia caused R/ for pernicious anemia & anemia caused
by gastric resectionby gastric resection
FOLIC ACIDFOLIC ACID
Cofactor for transfer reaction of one Cofactor for transfer reaction of one carboncarbon
Play a role in normal DNA synthesisPlay a role in normal DNA synthesis Deficiency : megaloblastic anemiaDeficiency : megaloblastic anemia Deficiency in pregnancy : increase risk of Deficiency in pregnancy : increase risk of
neural tube defects in fetus (spina bifida)neural tube defects in fetus (spina bifida) FA deficiency associated with : Cancer, FA deficiency associated with : Cancer,
leukemia, myeloproliferative disorders, leukemia, myeloproliferative disorders, certain chronic skin disease, certain chronic skin disease,
Drugs that can interfere the absorption & metabolism of FA : - Phenytoin (Abs)- Some anticonvulsant (Abs)- Oral contraceptives (Abs)- Isoniazid (Abs)- Methotrexate- Trimethoprim & Pyrimethamine (inhibit dehydrofolate reductase)
PharmacodynamicPharmacodynamic
Converted to tetrahydrofolate by Converted to tetrahydrofolate by dehydrofolate reductasedehydrofolate reductase
Hematopoietic Growth Factors
Erythropoietin Produced by the kidney Stimulates the production of red cells &
increases their release from the bone marrow Routinely used for : the anemis associated
with renal failure, primary bone marrow disorders, bone marrow transplantation, anemias secondary to cancer chemotherapy
Toxicity : minimal
Myeloid Growth Factor Consist of :
- granulocyte colony-stimulating fc; G-CSF- granulocyte-macrophage colony- stimulating fc; GM-CSF
Stimulates the production & function of neutrophils Stimulates the production of other myeloid and
megakaryocyte progenitors Function :
- accelerate the recovery of neutrophils after Ca chemotherapy- treat other form of secondary & primary neutropenia (aplastic anemia, congenital neutropenia)
SE : bone pain, fever, arthralgias, capilarry damage with edema, allergic reaction
Megakaryocyte Growth FactorStimulates the growth of primitive
megakaryocyte progenitor --> increase the number of peripheral platelets
Consist of thrombopoietin & interleukin-11
IL-11 : for treatment of patients who have had a prior episode of thrombocytopenia after a cycle of Ca chemotherapy
SE : fatigue, headache, dizziness, fluid retension
Other Hematopoietic Growth Factor Consist of :
- Monocyte colony stimulating factor (M-CSF)- Stem cell factor ( SCF)- Interleukin-3, -6, -9
SCF & IL-3 have the broadest progenitor cell line effect, including red cell, granulocyte, monocyte-macrophage, megakaryocyte, eosinophil, basophil cell lines
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