3.20.14 Sweatman - Pharmacologic Approaches to Anemia Flashcards
Pre-study In-class PPT Lecture Notes+ Reading (Katzung Ch. 33)
What is the most common cause of anemia?
iron, B12 or folic acid deficiency needed for RBC production.
Hematopoietic factors
growth factors that stimulate blood cell production
iron deficiency anemias
microcytic hypochromic anemia
b12 deficiency anemias
Pernicious anemiamegaloblastic anemias
Pernicious anemia
caused by defect in synthesis ofintrinsic factor,a protein needed for B12 dietary absorption (genetic or surgical removal of part of stomach that secrete intrinsic factor.
What are the proteins that bind iron?
transfer protein in the blood: transferrinstorage protein: ferritin
How does the body reduce iron stores?
there is no mechanism for excretion. Regulation is done through modulation of absorption in the intestine
What happens after ferrous iron is taken up by intestinal epithelial cells?
a. stored by ferritin within the cellb. transported out of the cell by ferroportin and oxidized to ferric iron )3+) by ferroxidase
What cells can store iron bound to ferritin?
gastrointestinal epithelial cellsmacrophageshepatocytes(in gross overload, parenchymal cells of skin, heart, organs)
Describe the absorption, transport, and storage of iron.
Intestinal epithelial cells actively absorb inorganic iron via the divalent metaltransporter 1 (DMT1) and heme iron via the heme carrier protein 1 (HCP1). Iron that is absorbed or released from absorbed heme iron in theintestine is actively transported into the blood by ferroportin (FP) or complexed with apoferritin (AF) and stored as ferritin (F). Inthe blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) orto hepatocytes for storage as ferritin. The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors andhepatocytes and is internalized. After release of iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophagesthat phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin. Hepatocytes use several mechanisms to take up iron and store the iron as ferritin. FO, ferroxidase.
What are the types of iron supplementation?
ferrous sulfate, ferrous gluconate, ferrous fumarateparenteral iron preparations: iron detran, dosium ferric gluconate complex, iron sucrose
When is iron supplementation contraindicated?
hemolytic anemia because iron stores are elevated.
Acute iron intoxicationa. symptomsb. treatment
a. necrotizing gastrienteritis, shock, metabolic acidosis, coma, deathb. parenteral admin of deferoxamine (chelates circulating iron)
Chronic iron overload, hemochromatosisa. symptomsb. etiologyc. treatment
a. damages organs that store excess iron (heart, liver, pancreas)b. patients with inherited abnormality of iron absorption; patients who receive frequent transfusions for treatment of hemolytic disorders (thal major)c. phlebotomy, iron chelator (deferoxamine or deferasirox)
Function of B12 and Folic acid
needed for DNA synthesis. Deficiencies manifest first as anemia.
Absorption and storage of B12
B12 is only produced by bacteria. Absorbed from GI tract in presence of intrinsic factor (from parietal cells). Transported into plasma by transcobalmin II. Stored in the liver. There are two avaliable forms cyanocobalimin and hydroxocobalmin (longer circulating half-life)
What reactions use B12
a. conversion of methylamonyl CoA to succinyl CoAb. conversion of homocystein to methionine
What happens in B12 deficiency? What happens if you administer folate? Ideal way to treat B12 deficiency?
a. folate accumulates as N5-methylTHF and the supply of THF is depleted, production of RBC slows down.b. folate with restore THF pool and partially/fully correct the anemia (although B12 deficiency in the brain will cause defects)c. Because it is almost always due to lack of absorption, you would not supplement B12, give it parenterally.
pernicious anemia
megaloblastic anemia caused by B12 deficiency
Folic acid deficiency
a. megaloblastic anemia due to lack of DNA synthesisb. especially prevalent during pregnancy, causes neural tube defects in fetus
Absorption and storage of folic acid
absorbed readily, not stored much, so loss of dietary folic acid results in anemia within months.
What reactions use folic acid?
Folic acid -(DHFR)-> THF
a. Erythropoetinb. ESA therapy
a. Erythropoietin- produced by the kidney (anemia due to renal failure).b. Erythropoiesis-Stimulating agent (ESA) therapy is used to treat anemia. Complications include HTN and thrombosis
Myeloid growth factors
Both stimulate the production/function of neutrophils. GM-CSF also stimulates production of other myeloid and megakaryocyte progenitors. Used in treatment for neutropenia.a. Filgrastim (granulocyte colony-stimulating factor; G-CSF) mobilizes hematopoietic stem cells (increases their concentration in peripheral blood). May be conjugated to polyethylene glycol to increasr half-life.b. Sargramostim (grnulocyte-macrophage colony-stimulating factor; GM-CSF) may cause fever, arthralgias, capillary damage with edema.
Megakaryocyte Growth Factors
a. Oprelvekin (IL-11) stimulates growth of megakeyocytic progenitors and increases peripheral platelets (for thrombocytopenia)b. Romiplotim (thrombopoietin receptor agonist) for thrombocytopenia
Microcytic anemia
commonly cause by iron deficiency
Megaloblastic anemia
commonly cause by B12 or folic acid deficiency
The megaloblastic anemia that results from vitamin B12deficiency is due to inadequate supplies of which of thefollowing?(A) Cobalamin(B) dTMP(C) Folic acid(D) Homocysteine(E) N 5-methyltetrahydrofolate
Deficiency of vitamin B12 (cobalamin) leads to a deficiencyin tetrahydrofolate and subsequently a deficiency of thedTMP required for DNA synthesis. Homocysteine andN 5-methyltetrahydrofolate accumulate. The answer is B.
pale conjunctive is an indicator of
anemia
3 main causes of anemia
decreased productionincreased destructiondecreased absorption of precursors
what can lead to inadquate RBC production
drugs (antimetabolites)decreased Epo ; kidney diseaseiron deficiencyB12, folate deficiencycancer: increase hepcidin in chronic inflammatory malignant states
When is parenteral iron therapy preferable to oral treatment of anemia?
malabsorption (atrophic gastritis, H. pylori, celiac disease, losing blood in the stomach)Low acid: proton pump inhibitors or Tumspostsurgery: small bowel resectioninflammatory bowel disease
bone marrrow sample with many blue cells is caused by?
vitamin B12 or folate (both look the same)
what test can you do for B12 deficiency?
serum B12/folateseum or urine homocysteine or methylmalonate (these are very good when previous test is borderline, these values are accurate in deficiency)
B12 deficiency creates an apparent folate deficiency by trapping which folate intermediate?
N5-methyl THF
Most common cause of B12 deficiency
malabsorption (vegetarians, interferon deficiency)
What are the problems associated with B12 deficiency
posterior column problemsproprioceptionperipheral neuropathy
what is the appropriate way to administer B12?
oral, IM, deep SC
Deferoxamine causes iron to be eliminated via the kidney. Is it normally eliminated by this route?
No (there are very stringent ways to absorp and store iron, but there is not a way to excrete it)Deferozamine is an oral chelating agent.
Why are hematopoietic growht factor drugs administered by injection?
acid instability. These are proteins, which cannot survive the stomach. Half life is longer if by subcutaneous or IM, because diffusion from the injection site is the rate limiting step rather than elimination.
How is the production of erythropoietin regulated?
hypoxia in peritubular capilaries? HIF production (5-7 days) is a transcription factor, making lag time for response. HIF will increase Epo production (causes angiogenesis in cancer).
You’ve been giving a patient erythropoietin but the effect is poor; what is wrong?
Something is wrong with the red cell production otherwise (iron/folate/B12 deficiency is most common, or myelodysplasia).
What is the recommended Hgb treatment target for erythropoietin?
lowest dose sufficient to reduce need for RBC transfusion? Don’t want too many RBC (coagulation, HTN, CV problems). Not advised in some malignancies.
What is the significant difference between epoetin and darbepoietin?
modified structure, longer half life. Both eliminated renally.(neither is removed by hemodialysis because they are too large
