Lecture 11: Pharmacology of Anemia and Hematopoietic Growth Factors Flashcards
What drugs are given to treat Hypochromic-Microcytic Anemia?
IRON (oral or parenteral)
What drugs are given to treat Megablastic Anemia?
vitamin B12 and/or folate
What 4 drugs are given to treat Neutropenia? (FPSP)
figrastim, pegfilgrastim, sargramostim, plerixafor
What 3 drugs are given to treat Thrombocytopenia? (ORE)
oprelvekin, romiplastin, eltrombopag
What are hydroxyurea and eculizumab used to treat?
H –> sickle cell anemia
E –> paroxysmal nocturnal hemoglobinuria
Why is hepcidin important in iron absorption and what conditions increase and decrease its synthesis?
- 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
What is Microcytic Anemia and what are 3 things that it leads to?
- 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)
Oral Iron:
What foods do you get iron from, how should oral iron be taken, and what side effects does it cause (6)?
- 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)
Parenteral (colloidal) Iron:
What are 3 options that can be given and what is a new one that tolerated better?
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
Acute Iron Toxicity vs Chronic Iron Toxicity:
Who is at risk, what are symptoms, and how are they treated?
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)
How do folate and Vitamin B12 affect the CNS?
- they form methionine from homocysteine
for methylation reactions (mainly B12 tho) - used to make purines and thymidylate
What is a common cellular feature of Megaloblastic Macrocytic Anemia that is NOT related to RBCs themselves?
- appearance of HYPERSEGMENTED neutrophils in blood smears
Vitamin B12:
Where do we get it from, how much do we store, and how can it be depleted?
- 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
What agent can inactivate B12 in our bodies?
Nitrous Oxide (given during analgesia before surgery)
- inactivates Cyanocobalamin
How is Cobalamin absorbed in our bodies?
- 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
What are 3 common causes of Vitamin B12 Deficiency? (PGH)
- Pernicious Anemia (elderly white/black women/men)
- caused by autoantibodies to IF-Cbl or their receptor
- caused by chronic atrophic gastritis (Abs vs parietal)
- gastrectomy or gastritis
- H. pylori infection
What are common cutaneous, GI, hematologic, and neuro symptoms of B12 deficiency?
C: vitiligo, hyperpigmentation
GI: glossitis (thick, smooth, red tongue)
H: anemia, neutropenia, thrombocytopenia
N: symmetric numbness, weakness, gait
Oral vs Parental treatment of Vitamin B12 Deficiency
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
Folate (Vitamin B9):
Where do we get it, how much do we need, and what are two causes of deficiency?
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
What are pregnancy, cutaneous, GI, and hematologic symptoms of Folate Deficiency?
P: neural tube defects
C: jaundice
GI: mouth ulcers
H: anemia, neutropenia, thrombocytopenia
NO NEURO SYMPTOMS –> exam purposes
Oral Folate Treatment:
How much should be given and what can it cause at high doses (2)?
- 1 mg/day x 4 months (malabsorption = 1-5 mg doses)
- high doses cause hypotension/hypoglycemia
What are the Hct and hemoglobin outcomes for Megaloblastic Anemia treatment?
How are reticulocytes and neuro symptoms affected by treatment?
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
Where is EPO made and what does it do?
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)
Epoetin Alfa:
What is its MOA, effects, and clinical applications (2)?
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)
Epoetin Alfa:
How is it administered and what are 4 toxic effects it can have? (DMSV)
- administered IV or SubQ
- can cause death, MI, stroke, venous thromboembolis
darbepoetin alfa has 3x LONGER HALF LIFE (21hrs)
Hydroxyurea:
What is its MOA, effects, and clinical applications?
How is it administered?
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)
Eculizumab:
What is its MOA, effects (2), and clinical applications?
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
Eculizumab:
How is it given and what are toxicities associated with it?
- 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
What is the classification of SEVERE neutropenia?
Absolute Neutrophil Count < 500 cells/ul
What are common presenting signs of Neutropenia?
low-grade fever, sore mouth, odynophagia (severe pain when swallowing), skin abcesses, recurrent bacterial infections
Filgrastim:
What is its MOA, effects, and clinical applications?
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
Filgrastim:
How is it administered and what are its toxicities (3 - ABR)?
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)
Sargramostim:
What is its MOA, effects, and clinical application (3)?
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
Sargramostim:
How is it given and what are its toxicities (4 - EDHG)?
- given in IV or SC (60 min 1/2 life)
causes: edema, dyspnea (sequestration), worsened hepatic/renal dysfunction, “gasping syndrome” in infants (benzyl alcohol)
Plerixafor:
What is its MOA, effects, and clinical application?
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
Oprelvekin (IL-11):
What is its MOA, effects, and clinical application?
What are potential toxicities (4 - EDAB)?
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
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?
TOO TOXIC
- thrombopoietin has autoantibodies to it, and c-Kit triggers severe allergic rxns (found on mast cells)
Romiplostim:
What is its MOA, effects, and clinical application?
What are potential toxicities?
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
Eltrombopag:
What is its MOA, effects, and clinical application?
What is a major toxic problem it can cause?
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)
When are Romiplostim and Eltrombopag used?
3rd line of defense
1st: glucocorticoids/immune globin (fails)
2nd: rituximab +/- splenectomy (fails)
