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Agents for Anemia and Hematopoiesis
Kevin Kern, PharmD Block VI, Week 7
Terms in this set (93)
What is hematopoiesis?
The formation and maturation of blood cells and their derivatives
What are the three primary blood cell components?
3. Leukocytes (PMNs, lymphocytes, monocyte/macs, eosinophils, plasma cells, and basophils)
What are hematopoietic growth factors?
Glycoproteins produced by a number of marrow cells and peripheral tissues
Does a hematopoietic growth factor usually have an effect on only one cell line?
What does stem cell factor (SCF) do?
Stimulates early pluripotent and committed stem cells
What does EPO do?
Stimulates proliferation and maturation of committed erythroid progenitors to increase RBC production
What do interleukins do (in terms of hematopoiesis)?
Work synergisticallly with other factors to promote differentiation and maturation of all cell lines
What does thrombopoietin do?
1. Stimulates stem cell differentiation into megakaryocyte progenitors
2. Selectively stimulates megakaryocytopoiesis
3. Works with other growth factors (IL-6 and IL-11)
Granulocyte/marcophage colony-stimulating factor (GM-CSF) stimulates what 3 CFUs? What is it's function?
Enhances migration, phagocytosis, superoxide production, and antibody-dependent cell mediated toxicity of PMNs, monocytes, and eosinophils.
What does G-CSF do?
Stimulates CFU-G to increase PMN production and enhances phagocytic and cytotoxic activities of PMNs
What does M-CSF do?
Stimulates CFU-M to increase monocyte precursors and activates and enhance function of monocytes/macs.
How are pharm. GM-CSF and G-CSF made?
Recombinant DNA technology
What is the drug name of GM-CSF?
What does Sargramostim do?
Stimulates production of all granulocytes and monocytes/macrophages. Promotes proliferation of magakaryocytes and erythroid progenitors.
What the the drug name of G-CSF?
What does Filgrastim do?
Promotes proliferation and maturation of PMNs and enhances their phagocytic and cytotoxic functions
What are the 3 primary indications for GM-CSF and G-CSF use?
1. Myelosuppressive chemotherapy
-to decrease the incidence of infection secondary to neutropenia and decreases the severity and duration of neurtropenia.
2. Bone Marrow Transplant
-To reduce the duration of neutropenia in patients with non-myeloid malignancies undergoing myeloblative chemo followed by BMT
3. Peripheral blood progenitor cell collection
-For mobilization of hematopoietic progenitor cells into the peripheral blood for leukapheresis collection
severe chronic neutropenia, HIV-associated and/or drug-induced neutropenia, to increase WBC counts in patients with myelodysplastic syndromes or aplastic anemia, or durg-induced bone marrow suppression
Can you give GM-CSF within 24 hours of chemo or radiation?
What is the most frequent adverse reaction of GM-CSF therapy?
*Can be prevented with analgesics and antipyretics
What is the 1st dose effect of GM-CSF therapy?
A syndrome of respiratory distress, hypoxia, flushing, hypotension, syncope, or tachycardia with the first dose.
*Usually does not recur with subsequent doses in the same dosing cycle but may occur with the first dose of each cycle.
Done not happen with G-CSF
What can lead to a capillary leak syndrome?
Prolonged administration of GM-CSF- peripheral edema, pleural and pericardial effusions.
Caution in patients with history of CHF
Name three adverse effects of GM-CSF treatment (besides flu-like syndrome and first dose effect).
1. Capillary leak syndrome
2. Marked leukocytosis
3. May act as a growth factor for any tumor type (esp. myeloid malignancies)
What is a contraindication to using GM-CSF?
Excessive leukemic myeloid blasts in the bone marrow or peripheral blood (>10%)
What drugs will GM-CSF interact with?
Drugs that may potentiate the myeloproliferative effects (steroids- should be used cautiously)
What is the most frequent adverse effect of G-CSF treatment?
Name 4 adverse effects of G-CSF.
3. Act as a growth factor for any tumor type (esp. myeloid malignancies)
4. Local skin reactions (rash)
What is Plerixafor?
A hematopoietic stem cell mobilizing drug (CXCR4 chemokine receptor antagonist)
What do you use Plerixafor for?
combination with G-CSF
to mobilize peripheral SCs in adults with MM or non-Hodgkin's lymphoma before high-dose chemo with autologous stem cell rescue
What is Oprelvekin?
What does Oprelvekin do?
Stimulates megakaryocytopoiesis and thrombopoiesis
What is the main therapeutic use of Oprelvekin?
- to prevent and reduce the need for platelet transfusions following myelosuppresive chemo in patients with nonmyeloid malignances who are a high risk of severe thrombocytopenia
With any of the hemotopoietic drugs are we trying to reach the normal levels of cells?
No- will reach for a level lower than physiologically normal
Name 3 major categories of adverse effects of Oprelvekin use?
1. Fluid retention- reverses upon discontinuation of therapy
-Closely monitor patients that are chronic diuretic therapy (CHF)
2. Transient atrial arrhythmias
3. Ophthalmologic effects- visual blurring, papilledema
What is Romiplostim?
A thrombopoietin (TPO) mimetic peptibody- given subq
What is the MOA of Romiplostim?
Bind to the TPO receptor and mimics the effects of TPO stimulating platelet production
What is Eltrombopag?
Oral non-peptide TPO receptor antagonist.
- Increases platelet production by binding and activating the TPO receptor
What is the indication of Eltrobopag or Romplostim?
Thrombocytopenia in splenectomized and non-splenectomized adults with chronic immune thrombocytopenic purpura (ITP)
What are some of the most common adverse drug reactions to Eltrobopag and Romplostim?
Myalgia, arthralgia, dizziness, insomnia, pain in extremities, and abdominal pain
What is one adverse effect of Eltrobopag and Romplostim that we need to look out for?
Excessive platelet counts can lead to thrombotic and/or thromboembolic complications
What is the black box warning for Eltrobopag?
Hepatotoxicity and cataracts
Name 4 agents we can use to treat anemia?
3. Folic Acid
4. Vit B12
What is the most important regulator of the proliferation of committed progenitors of RBC production (CSF-E)?
Where is the majority of EPO produced? What triggers its release?
In the peritubular cells of the renal cortex and released in response to hypoxemia
Name 4 functions of EPO?
1. Stimulates stem cells to differentiate into proerythroblasts
2. Increase the rate of mitosis
3. Increases release of reticulocytes from marrow
4. Induces Hgb formation
What should you give in combo with EPO?
What is Epoietin Alfa?
What lab values should you monitor when give Epoietin therapy?
Hgb and Hct to see if the therapy is working- should respond in about a month after initiation
Name 4 conditions in which Epoietin therapy is used?
1. Anemia of chronic renal failure (CRF)
2. Anemia in cancer patients on chemo (non-myeloid)
3. Anemia associated with zidovudine therapy (anti-retroviral)
4. Reduction of allogenic blood transfusion in surgery patients (not done much anymore)
What should you evaluate prioir to epoietin therapy and during therapy?
What should ferritin levels be for non-HD CKD and HD-CKD in epoietin therapy?
Non-HD CKD: >100
HD CKD: >200
What should transferrin saturation be in epoietin therapy?
What is the goal of therapy in CRF patients on epoietin therapy?
To maintain Hgb levels that will reduce the need for transfusions
What is the maximum Hgb level for CRF patients on epoietin therapy?
*should be assessed monthly
Are CA patients on or off chemo when receiving epoietin?
*Do not start is Hgb >10
What is the primary cause of resistance to epoietin therapy?
Name some others.
Underlying infections or inflammation, occult blood loss, vitamin deficiencies, aluminum toxicity, hyperparathyroidism, increased zidovudine dose
Name 5 risk factors of epoietin therapy>
3. May act as a growth factor for any tumor type, esp. myeloid malignancies
4. Thrombotic events (clotting)
Black box warning
-associated with higher hematocrits and Hgb (> 11 or 12)
5. Flu-like symptoms
What is the purpose of giving Epoietin therapy?
Decreased need for blood transfusions
What form is dietary iron in? What form do we absorb it in?
Absorb: Fe2+ (Fe
Where does absorption of iron primarily occur?
Name 3 things that increase the absorption of iron.
1. Gastric acid
2. Ascorbic acid
3. Other dietary components (meat)
Name 2 things that decrease the absorption of iron?
1. Dietary compounds that form insoluble complexes or chelate with iron (phytates, tannates, and phosphate)
2. Drugs (antacids, phosphate-binders, H2 antagonists, and PPIs)
What is the most common form or iron given?
What is the preferred iron product?
Non0enteric coated ferrous salt (also least tolerable)
Do slow-release iron products work well?
No- result in insufficeint dissolution until they reach the small intestine and often will release material after the duodenum where absorption is reduced.
What does the dose of iron depend on?
The patient's ability to tolerate it
Should you take iron on an empty stomach or with food?
Preferably on an empty stomach (food decreases the absorption by up to 50%) but if unable to tolerate can give with meals
How much should Hgb values increase weekly when on iron therapy?
If an increase of <2gm% over 3 weeks of iron therapy happens what does this mean?
You need to re-evaluate the patient because something other than IDA is going on.
What is the main adverse effect of iron therapy?
GI- dark stools, constipation, diarrhea, N/V
Name 4 reasons why a patient would fail to response to oral iron therapy.
4. Chronic blood loss (occult GI bleed)
What are the indications for parental iron therapy? (4)
3. Long-term compliance problems
4. Commonly given with EPO to patients receiving chronic dialysis
What kind of IV iron do you need to do a test dose for? Why?
Iron dextran (old product)- risk of anaphylaxis
What are 3 adverse effects of parental iron therapy?
1. Anaphylaxis (mostly iron dextran)
2. Flu like symptoms
3. Hypotension, flusing
What is a pro and a con of newer parental iron agents?
Pro: may be better tolerated
Con: More expensive
How long should you wait to check iron indices after giving parental iron?
What does Vit B12 and folate deficiency cause?
Defective synthesis of DNA in any cell where chromosomal replicaiton and division are taking place (affects those tissues with the higher cellular turnover rate the greatest, i.e. the hematopoietic system)
What does Vit B12 and folate deficiency result in?
Is folate or Vit B12 deficiency associated with neurological sequelae?
Vit B12- may not be reversible
Name three circumstances that would result in a Vit B12 deficiency.
1. Inadequate intake (rare and would take 3-4 years to manifest)
2. Decreased absorption (pernicious anemia)
3. Inadequate utilization (transcobolamin II deficiency, very rare)
What do you order to diagnose B12 deficiency
Serum B12 levels
Is the intrinsic factor dependent pathway or the -independent pathway more effective?
Intrinsic factor dependent pathway
Can the intrinsic factor independent pathway be relied upon for B12 supplementation in pernicious anemia?
What method of dosing is the best for B12 deficiency?
Parenteral- Subq or IM
Not IV because risk of anaphylaxis
or pee it out (water soluble vitamin)
How quickly do patients respond to Vit B12 therapy?
Rapidly- reticulocytosis within 2-3 days and Hgb begins to increase after 1st week
What are some adverse effects of B12 therapy?
Hyperuricemia and hypokalemia
Rebound thrombocytosis >> thrombotic events
What are humans dependent on for folate requirements?
Dietary intake- cannot synthesize the total daily folate
How long would cessation of intake of folic acid take to manifest?
How do you diagnose folic acid deficiency?
Serum or RBC folate levels
What 3 conditions can result in inadequate intake of folate?
2. Being old (elderly)
3. Food fads
How can you get decreased absorption of folate?
Nontropical and tropical sprue, Chrohn's, extensive small bowel resection
Why do pregnant women become folate deficient?
Hyperutilization because the rate of cellular division is increased
(same scenario in hemolytic anemia)
What kind of drugs can induce a folic acid deficiency?
When will you see the Hct rise in folic acid therapy?
Within 2 weeks (should normalize in 2 months)
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