Anemia and Hematopoietic Growth Factor Pharmacology Flashcards
What is the distribution of iron in your body?
Hemoglobin 70%
Myoglobin 10%
Ferritin and Hemosiderin (storage) 10-20%
Enzymes 1%
Describe the absorption of heme iron
Itron from animal sources (heme iron) may be absorbed intact
What form must non-heme iron be in for absorption?
Must be converted to ferrous (Fe2+) form
What is the protein transporter involved in iron absorption from the GI lumen?
DMT1
What will iron complex with if its destination is the bone marrow? What is that iron used for?
Transferrin.
That iron will be used for blood cell precursors.
What will iron complex with for storage?
Ferritin
Where is ferritin mainly present in the body?
Liver
Spleen
Plasma
What is the function of ferroportin?
Involved in the export of iron in the intestinal epithelium
How does hepcidin affect iron?
In what disease would high hepcidin play a role?
Hepcidin downregulates ferroportin, which can prevent macrophages in bone marrow from exporting iron to blood cell precursors. High levels of hepcidin play a role in ANEMIA OF CHRONIC DISEASE
Describe the pathogenesis of hemochromatosis
Low hepcidin levels lead to lots of iron being absorbed and released into the circulation. Leads to iron deposits in the lungs, heart, and liver, which is toxic
May cause organ failure
How does iron deficiency affect ferritin levels? Transferrin?
Low ferritin
High transferrin
How does iron overload affect ferritin levels? Transferrin?
High ferritin
Low transferrin
What are indications for iron therapy?
Prevention or treatment of iron deficient anemia
- Increased requirements (premature infants, children, pregnant women)
- Inadequate absorption
- Blood loss (GI, menstrual)
How may iron therapy be administered?
Oral or parenteral (IM, IV)
When is parenteral iron indicated above oral iron?
When oral iron is not tolerated
Post GI resection
Malabsorption syndrome
Adverse Effects of Oral Iron therapy
Nausea
Vomiting
Black stools
What is a common cause of acute iron toxicity? How can acute iron toxicity be fatal?
Overingestion of iron tablets. Could be fatal due to necrotizing gastroenteritis
What could cause chronic iron toxicity?
Hemochromatosis
Multiple RBC transfusions
What could chronic iron toxicity lead to?
Organ failure
How should you treat acute iron toxicity?
Gastric aspiration
Gastric lavage with phosphate or carbonate solns
Iron chelation therapy (deferoxamine)
How should you treat chronic iron toxicity?
Intermittent phlebotomy (if no anemia present)
Iron chelation (deferoxamine, deferasirox)
What is required for B12 absorption? Where is the complex absorbed?
Complexation with IF.
Absorbed in the distal ileum
After B12 absorption, how does it get transported to the sites where it is needed?
Complexation with transcobalamin II
How is folic acid absorbed? Where is it stored?
Absorbed as monoglutamate. Stored mainly in the liver
What are some signs of a B12 or folate deficiency?
Deficient DNA synthesis Megaloblastic anemia Leukopenia with hypersegmented granulocytes Atrophic glossitis Chronic gastritis
B12 deficiency can cause CNS symptoms with subacute combined degeneration
Treatment for B12 Deficiency
Pareneteral (IM) injections of cyanocobalamin or hydroxycobalamin
Now there is some evidence that oral B12 can be effective, even without IF
Treatment for Folic Acid Deficiency
Oral folic acid
What is the physiological function of Erythropoietin (EPO)?
Where is EPO made?
Stimulates proliferation and differentiation of erythroid cells
Stimulates release of reticulocytes form bone marrow
Produced in the kidney
Indications for EPO Therapy
Chronic Renal Failure Aplastic anemia Leukemias HIV/AIDS Associated anemias Cancer Anemia of prematurity Post-phlebotomy
What improvements should you expect to see after EPO injection?
Reticulocytes seen around 10 days
Increase in hemoglobin in 2-6 weeks
EPO Toxicity and Black Box Warnings
HTN
Thrombosis
Anaphylaxis
Increased risk of tumor progression and recurrence
G-CSF/GM-CSF
What is their physiological function?
Growth factors stimulating the proliferation and differentiation of myeloid, erythroid, and megakaryocytic cells
Promote release of hematopoietic cells into the peripheral circulation
G-CSF/GM-CSF
What are the two pharmacological recombinant forms?
Filgastim Pegfilgastim (longer 1/2 life)
G-CSF/GM-CSF
What are the therapeutic indications?
After chemotherapy to increase PMN counts
Used after chemo for AML (causes growth of normal cells that will outcompete the leukemia cells)
Mobilize blood stem cells into the periphery for easier collection for stem cell transplant
G-CSF/GM-CSF
Toxicity
G-CSF: bone pain, allergies
GM-CSF: Fever, arthralgia, peripheral edema, pleural or pericardial effusion, allergy
G-CSF is generally preferred
IL-11
Physiological function
Normally produced by bone marrow stromal cells to promote megakaryocytic progenitor proliferation.
Increases peripheral platelet counts
Is recombinant TPO (thrombopoietin) useful?
No. It often induced an immune response from patients and did not ultimately increase peripheral platelet levels
IL-11
Indications
Thrombocytopenia after chemo
IL-11
Toxicity
Fatigue HA Dizziness Dyspnea Arrhythmias Hypokalemia
What are the two new agents for treating thrombocytopenia?
Romiplostim
Eltrombopag
Romiplostim
MOA
“Peptibody”
Peptide domain binds the TPO receptor
Antibody Fc domain increases its half life
Eltrombopag
MOA
Small molecule TPO-receptor agonist
What are the indications for Romiplostim and Eltrombopag?
ITP
Eltrombopag may also be used in aplastic anemia
Romiplostim and Eltrombopag
Adverse Effects
Headache
Myalgia
Bone marrow fibrosis (reversible)
