Lecture 11: Pharmacology of Anemia and Hematopoietic Growth Factors Flashcards

1
Q

What drugs are given to treat Hypochromic-Microcytic Anemia?

A

IRON (oral or parenteral)

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2
Q

What drugs are given to treat Megablastic Anemia?

A

vitamin B12 and/or folate

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3
Q

What 4 drugs are given to treat Neutropenia? (FPSP)

A

figrastim, pegfilgrastim, sargramostim, plerixafor

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4
Q

What 3 drugs are given to treat Thrombocytopenia? (ORE)

A

oprelvekin, romiplastin, eltrombopag

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5
Q

What are hydroxyurea and eculizumab used to treat?

A

H –> sickle cell anemia

E –> paroxysmal nocturnal hemoglobinuria

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6
Q

Why is hepcidin important in iron absorption and what conditions increase and decrease its synthesis?

A
  • hepcidin blocks absorption of iron because excess iron can be toxic to the body (blocks ferroportin)

inc. hepcidin = excess iron, inflammation
- bacteria needs iron
dec. hepcidin = inc. erythroid demand, hypoxia

no renal mechanism for iron elimination

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7
Q

What is Microcytic Anemia and what are 3 things that it leads to?

A
  • small, pale RBCs caused by not having enough hemoglobin
  • red. iron availability (severe deficiency, anemia of inflamm, copper def.)

caused by: reduced iron availability, reduced heme synthesis (lead poisoning), and reduced globin production (thalassemic disorders)

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8
Q

Oral Iron:

What foods do you get iron from, how should oral iron be taken, and what side effects does it cause (6)?

A
  • best absorbed from meat, fish, poultry
  • take 200-400 mg of ferrous (Fe2+)/day in 2-3 doses w/water or juice (not enteric-coated and not-sustained release (only get 25% absorption)
  • nausea, constipation, anorexia, vomiting, diarrhea, dark stool (food helps dec. irritation but inhibs absorp)
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9
Q

Parenteral (colloidal) Iron:

What are 3 options that can be given and what is a new one that tolerated better?

A

use iron dextran, sodium ferric gluconate, iron-sucrose (all have iron oxyhydroxide core)

new: Ferumoxytol (nanoparticle iron)
- administered quick and easier than dextran
- side effects similar to oral

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10
Q

Acute Iron Toxicity vs Chronic Iron Toxicity:

Who is at risk, what are symptoms, and how are they treated?

A

A: children (10 tablets = lethal)

  • necrotizing gastroenteritis, vomit, bloody diarrhea
  • use whole bowel irrigation and deferoxamine

C: hemochromatosis or chronic RBC transfusions
- iron deposits in heart, liver, pancreas (organ fails)

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11
Q

How do folate and Vitamin B12 affect the CNS?

A
  • they form methionine from homocysteine
    for methylation reactions (mainly B12 tho)
  • used to make purines and thymidylate
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12
Q

What is a common cellular feature of Megaloblastic Macrocytic Anemia that is NOT related to RBCs themselves?

A
  • appearance of HYPERSEGMENTED neutrophils in blood smears
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13
Q

Vitamin B12:

Where do we get it from, how much do we store, and how can it be depleted?

A
  • found in animal products and fortified breakfast cereal
  • need 2 ug/day, but can store 2-5 mgs (half in liver)
  • takes years for deficiency to develop after, but leads to rapid onset neuro dysfunction that may not fully reverse
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14
Q

What agent can inactivate B12 in our bodies?

A

Nitrous Oxide (given during analgesia before surgery)

  • inactivates Cyanocobalamin
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15
Q

How is Cobalamin absorbed in our bodies?

A
  • binds to R-factor in gastric juice, but is freed in alkaline duodenum by pancreatic enzymes
  • then binds to Intrinsic Factor (parietal cells), then binds as a complex to cubulin (receptor) in the Ileum
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16
Q

What are 3 common causes of Vitamin B12 Deficiency? (PGH)

A
  1. Pernicious Anemia (elderly white/black women/men)
    • caused by autoantibodies to IF-Cbl or their receptor
    • caused by chronic atrophic gastritis (Abs vs parietal)
  2. gastrectomy or gastritis
  3. H. pylori infection
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17
Q

What are common cutaneous, GI, hematologic, and neuro symptoms of B12 deficiency?

A

C: vitiligo, hyperpigmentation
GI: glossitis (thick, smooth, red tongue)
H: anemia, neutropenia, thrombocytopenia
N: symmetric numbness, weakness, gait

18
Q

Oral vs Parental treatment of Vitamin B12 Deficiency

A

O: 1-2 mg/day for 2 wks, then 1 mg daily
- works w/Pernicious (alternate absorption pathway)

P: cyanocobalamin @ 1 mg/day for 1 wk, then weekly for 1 month, then monthly
- use if NEUROLOGICAL symptoms are present

19
Q

Folate (Vitamin B9):

Where do we get it, how much do we need, and what are two causes of deficiency?

A

from yeast, organ meat, leafy greens; absorbed by jejunum

  • 400 ug/adults and 800 ug/day pregnant/lact. women (prevent congenital malformation)

deficiency from: inadequate intake or alcoholism

20
Q

What are pregnancy, cutaneous, GI, and hematologic symptoms of Folate Deficiency?

A

P: neural tube defects
C: jaundice
GI: mouth ulcers
H: anemia, neutropenia, thrombocytopenia

NO NEURO SYMPTOMS –> exam purposes

21
Q

Oral Folate Treatment:

How much should be given and what can it cause at high doses (2)?

A
  • 1 mg/day x 4 months (malabsorption = 1-5 mg doses)

- high doses cause hypotension/hypoglycemia

22
Q

What are the Hct and hemoglobin outcomes for Megaloblastic Anemia treatment?

How are reticulocytes and neuro symptoms affected by treatment?

A

Hct - inc. < 2wks w/folate, normalize in 2 mths
Hb - inc. in 1 wk w/B12, normalize in 1-2 mths

reticulocytosis in 3-5 days

neuro: takes longer and may be irreversible
- should NOT worsen during treatment

23
Q

Where is EPO made and what does it do?

A

made by renal cortical fibroblasts of the kidneys (stimulated by hypoxia)

  • stimulates red bone marrow to enhance erythropoiesis and inc. RBC counts (inc. oxygen carrying ability of blood)
24
Q

Epoetin Alfa:

What is its MOA, effects, and clinical applications (2)?

A

MOA: 165 AA erythropoiesis-stimulating glycoprotein
- looks like EPO

Effects: inc. RBCs, inc. reticulocytes (<10 days)

Apps: treat anemia caused by chronic kidney disease and chemotherapy (No Olympic uses)

25
Q

Epoetin Alfa:

How is it administered and what are 4 toxic effects it can have? (DMSV)

A
  • administered IV or SubQ
  • can cause death, MI, stroke, venous thromboembolis

darbepoetin alfa has 3x LONGER HALF LIFE (21hrs)

26
Q

Hydroxyurea:

What is its MOA, effects, and clinical applications?

How is it administered?

A

MOA: S-phase cell cycle arrest, boosts HbF levels

Effects: lowers HbS concentration in a cell

Apps: only therapy approved for Sickle Cell Disease

  • administered orally, readily absorbed or distributed widely (in erythrocytes/leukocytes)
27
Q

Eculizumab:

What is its MOA, effects (2), and clinical applications?

A

MOA: Ab binds to protein C5, prevents MAC formation

Effects: inhibits terminal complement intravascular hemolysis (PNH) AND inhibits thrombotic microangiopathy (AHUS)
- used for Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome

**only available under REMS to which you must enroll

28
Q

Eculizumab:

How is it given and what are toxicities associated with it?

A
  • 35 min IV once per week x 4 weeks, then maintenance doses every 2 wks (MOST EXPENSIVE DRUG ON MARKET)
  • viral infections, meningococcal infections (vaccine 2 wks prior), upper respiratory tract infections, hypertension, headache, anemia/leukopenia
29
Q

What is the classification of SEVERE neutropenia?

A

Absolute Neutrophil Count < 500 cells/ul

30
Q

What are common presenting signs of Neutropenia?

A

low-grade fever, sore mouth, odynophagia (severe pain when swallowing), skin abcesses, recurrent bacterial infections

31
Q

Filgrastim:

What is its MOA, effects, and clinical applications?

A

MOA: 175-AA G-CSF

Effect: regulates neutrophil production

Apps: dec. infection in pts w/nonmyeloid malignancies on anticancer drugs or bone marrow transplant

  • also mobilizes progenitor cells into blood and can be used to treat severe chronic neutropenia
32
Q

Filgrastim:

How is it administered and what are its toxicities (3 - ABR)?

A

Admin: 4 or 24 hr infusion/continuous SC infusion
- wait 24 hrs after chemo or stop 24 hrs before

Causes: allergic rxn, bone pain, acute RDS

**pegfilgrastim - longer lasting version (15-80 hrs vs 3.5)

33
Q

Sargramostim:

What is its MOA, effects, and clinical application (3)?

A

MOA: 127-AA GM-CSF (differs by Leu at postion 23)

Effect: inc. neutrophils/eosinophils/monocytes

App: inc. myeloid recovery after bone marrow transplant (autologous and allogeneic)

  • also mobilizes stem cells into periphery for collection
  • also for chemo in >55yo pts with AML
34
Q

Sargramostim:

How is it given and what are its toxicities (4 - EDHG)?

A
  • given in IV or SC (60 min 1/2 life)
    causes: edema, dyspnea (sequestration), worsened hepatic/renal dysfunction, “gasping syndrome” in infants (benzyl alcohol)
35
Q

Plerixafor:

What is its MOA, effects, and clinical application?

A

MOA: partial agonist of CXCR4 (HSC homing to bone)

Effect: mobilize HSC into plasma from bone

App: for pts that don’t mobilize enough stem cells for autologous transplant w/G-CSF alone
- pts: lymphoma, multiple myeloma

given SubQ; can mobilize leukemia cells

36
Q

Oprelvekin (IL-11):

What is its MOA, effects, and clinical application?

What are potential toxicities (4 - EDAB)?

A

MOA: IL-11, MOA is unknown

Effect: promotes formation of megakaryocytes

App: does not have major clinical use; treat thrombocytopenia (SC once daily)

  • can cause edema, cardiac dysrhythmias, allergic rxns, and “bloodshot” eyes
37
Q

Why are IL-3 and IL-6 not given to increase platelet levels? Why were thrombopoietin and stem cell factor c-Kit not used either?

A

TOO TOXIC

  • thrombopoietin has autoantibodies to it, and c-Kit triggers severe allergic rxns (found on mast cells)
38
Q

Romiplostim:

What is its MOA, effects, and clinical application?

What are potential toxicities?

A

MOA: peptibody (2 Fc fragments covalently bound w/two identical peptide sequences) - bind TPO receptor (NO HOMOLOGY tho)

Effects: inc. platelets in health pts and those with ITP

Apps: use in pts with idiopathic thrombocytopenic purpura (after glucocorticoids fail) via SC injection

well-tolerated but can cause allergic rxns

39
Q

Eltrombopag:

What is its MOA, effects, and clinical application?

What is a major toxic problem it can cause?

A

MOA: potent, oral non-peptide TPO agonist (oral once daily)

Effect: inc. platelet count (healthy, ITP, Hep C)

Apps: excess platelet destruction (ITP) or cirrhosis (Hep C)

**can cause hepatotoxicity due to drug-drug interactions in pts with Chronic Hep C)

40
Q

When are Romiplostim and Eltrombopag used?

A

3rd line of defense

1st: glucocorticoids/immune globin (fails)
2nd: rituximab +/- splenectomy (fails)