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

Thank you for listening