3.20.14 Sweatman - Pharmacologic Approaches to Anemia

Question 1

What is the most common cause of anemia?

Answer 1

iron, B12 or folic acid deficiency needed for RBC production.

Question 2

Hematopoietic factors

Answer 2

growth factors that stimulate blood cell production

Question 3

iron deficiency anemias

Answer 3

microcytic hypochromic anemia

Question 4

b12 deficiency anemias

Answer 4

Pernicious anemiamegaloblastic anemias

Question 5

Pernicious anemia

Answer 5

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.

Question 6

What are the proteins that bind iron?

Answer 6

transfer protein in the blood: transferrinstorage protein: ferritin

Question 7

How does the body reduce iron stores?

Answer 7

there is no mechanism for excretion. Regulation is done through modulation of absorption in the intestine

Question 8

What happens after ferrous iron is taken up by intestinal epithelial cells?

Answer 8

a. stored by ferritin within the cellb. transported out of the cell by ferroportin and oxidized to ferric iron )3+) by ferroxidase

Question 9

What cells can store iron bound to ferritin?

Answer 9

gastrointestinal epithelial cellsmacrophageshepatocytes(in gross overload, parenchymal cells of skin, heart, organs)

Question 10

Describe the absorption, transport, and storage of iron.

Answer 10

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.

Question 11

What are the types of iron supplementation?

Answer 11

ferrous sulfate, ferrous gluconate, ferrous fumarateparenteral iron preparations: iron detran, dosium ferric gluconate complex, iron sucrose

Question 12

When is iron supplementation contraindicated?

Answer 12

hemolytic anemia because iron stores are elevated.

Question 13

Acute iron intoxicationa. symptomsb. treatment

Answer 13

a. necrotizing gastrienteritis, shock, metabolic acidosis, coma, deathb. parenteral admin of deferoxamine (chelates circulating iron)

Question 14

Chronic iron overload, hemochromatosisa. symptomsb. etiologyc. treatment

Answer 14

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)

Question 15

Function of B12 and Folic acid

Answer 15

needed for DNA synthesis. Deficiencies manifest first as anemia.

Question 16

Absorption and storage of B12

Answer 16

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)

Question 17

What reactions use B12

Answer 17

a. conversion of methylamonyl CoA to succinyl CoAb. conversion of homocystein to methionine

Question 18

What happens in B12 deficiency? What happens if you administer folate? Ideal way to treat B12 deficiency?

Answer 18

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.

Question 19

pernicious anemia

Answer 19

megaloblastic anemia caused by B12 deficiency

Question 20

Folic acid deficiency

Answer 20

a. megaloblastic anemia due to lack of DNA synthesisb. especially prevalent during pregnancy, causes neural tube defects in fetus

Question 21

Absorption and storage of folic acid

Answer 21

absorbed readily, not stored much, so loss of dietary folic acid results in anemia within months.

Question 22

What reactions use folic acid?

Answer 22

Folic acid -(DHFR)-> THF

Question 23

a. Erythropoetinb. ESA therapy

Answer 23

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

Question 24

Myeloid growth factors

Answer 24

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.

Question 25

Megakaryocyte Growth Factors

Answer 25

a. Oprelvekin (IL-11) stimulates growth of megakeyocytic progenitors and increases peripheral platelets (for thrombocytopenia)b. Romiplotim (thrombopoietin receptor agonist) for thrombocytopenia

Question 26

Microcytic anemia

Answer 26

commonly cause by iron deficiency

Question 27

Megaloblastic anemia

Answer 27

commonly cause by B12 or folic acid deficiency

Question 28

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

Answer 28

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.

Question 29

pale conjunctive is an indicator of

Answer 29

anemia

Question 30

3 main causes of anemia

Answer 30

decreased productionincreased destructiondecreased absorption of precursors

Question 31

what can lead to inadquate RBC production

Answer 31

drugs (antimetabolites)decreased Epo ; kidney diseaseiron deficiencyB12, folate deficiencycancer: increase hepcidin in chronic inflammatory malignant states

Question 32

When is parenteral iron therapy preferable to oral treatment of anemia?

Answer 32

malabsorption (atrophic gastritis, H. pylori, celiac disease, losing blood in the stomach)Low acid: proton pump inhibitors or Tumspostsurgery: small bowel resectioninflammatory bowel disease

Question 33

bone marrrow sample with many blue cells is caused by?

Answer 33

vitamin B12 or folate (both look the same)

Question 34

what test can you do for B12 deficiency?

Answer 34

serum B12/folateseum or urine homocysteine or methylmalonate (these are very good when previous test is borderline, these values are accurate in deficiency)

Question 35

B12 deficiency creates an apparent folate deficiency by trapping which folate intermediate?

Answer 35

N5-methyl THF

Question 36

Most common cause of B12 deficiency

Answer 36

malabsorption (vegetarians, interferon deficiency)

Question 37

What are the problems associated with B12 deficiency

Answer 37

posterior column problemsproprioceptionperipheral neuropathy

Question 38

what is the appropriate way to administer B12?

Answer 38

oral, IM, deep SC

Question 39

Deferoxamine causes iron to be eliminated via the kidney. Is it normally eliminated by this route?

Answer 39

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.

Question 40

Why are hematopoietic growht factor drugs administered by injection?

Answer 40

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.

Question 41

How is the production of erythropoietin regulated?

Answer 41

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).

Question 42

You’ve been giving a patient erythropoietin but the effect is poor; what is wrong?

Answer 42

Something is wrong with the red cell production otherwise (iron/folate/B12 deficiency is most common, or myelodysplasia).

Question 43

What is the recommended Hgb treatment target for erythropoietin?

Answer 43

lowest dose sufficient to reduce need for RBC transfusion? Don’t want too many RBC (coagulation, HTN, CV problems). Not advised in some malignancies.

Question 44

What is the significant difference between epoetin and darbepoietin?

Answer 44

modified structure, longer half life. Both eliminated renally.(neither is removed by hemodialysis because they are too large