Pharmacology of Anemia and Hematopoietic Growth Factors Flashcards
1
Q
Example of a drug used to treat hypochromic microcytic anemia?
A
iron
2
Q
example of 2 drugs used to treat megaloblastic (macrocytic) anemia?
A
vitamin B12 and folate
3
Q
example of 3 drugs used to treat anemia of chronic renal disease?
A
epoetin alfa, hydroxyurea, and eculizumab
4
Q
4 drugs used to treat neutropenia?
A
filgrastim, pegfilgrastim, sargramostim, and plerixafor
5
Q
3 drugs used to treat thrombocytopenia?
A
oprelvekin, romiplastin, eltrombopag
6
Q
what is the most common nutritional cause of anemia?
A
iron deficiency anemia
7
Q
how do you treat iron deficiency anemia if it is severe?
A
with RBC transfusion
8
Q
more hepcidin leads to what?
A
block of iron uptake
9
Q
what are 2 examples of things that decrease hepcidin and therefore cause an increase in more iron uptake?
A
increased need for RBCs and hypoxia
10
Q
what are two examples of things that increase hepcidin and therefore cause a decrease in iron uptake?
A
iron and inflammation
11
Q
absorption of iron is regulated by what?
A
hepcidin
12
Q
What are 4 broad causes of microcytic anemia?
A
- reduced iron availability 2. reduced heme synthesis 3. reduced globin production 4. rare disorders
13
Q
what could lead to reduced heme synthesis?
A
lead poisoning or congenital or acquired sideroblastic anemias
14
Q
What could cause reduced globin production?
A
thalassemic disorders or other hemoglobinopathies
15
Q
iron through the diet is best absorbed from what 3 things?
A
meat, poultry, and fish
16
Q
what is the recommended iron therapy?
A
oral iron 200-400 mg of elemental ferrous iron/ day in a single dose with only water/juice
17
Q
what are some of the side effects of oral iron?
A
nausea, constipation, anorexia, heartburn, vomiting, and diarrhea
18
Q
what is the least expensive option for parenteral (colloidal) iron IV?
A
LMW dextran
19
Q
what is an iron medication that can be given quickly (e.g 5 min)?
A
ferumoxytol
20
Q
When does iron therapy begin to work?
A
expect reticulocytosis in a few days and an increase in Hb in 2 weeks
21
Q
What are the symptoms of acute iron toxicity?
A
necrotizing gastroenteritis with vomiting, abdominal pain and bloody diarrhea–> shock, lethargy, and dyspnea
22
Q
suggestion of improvement from acute iron toxicity may be noted and then followed by what?
A
severe metabolic acidosis, coma, and death
23
Q
what does treatment for acute iron toxicity include?
A
urgent!! includes whole bowel irrigation and parenteral deferoxamine (which is a potent iron-chelating compound)
24
Q
What is activated charcoal’s role in acute iron toxicity?
A
it does not bind to iron and it is ineffective
25
What is chronic iron toxicity?
when iron deposits in the heart, liver, and pancreas leading to organ failure and death; seen in patients with hereditary hemochromatosis and patients who receive many red cell transfusions
26
the interaction with vitamin B12 in the folic acid cycle is crucial for what?
the synthesis for methionine, which is needed for methylation reactions
27
a bone marrow aspirate from someone with megaloblastic anemia shows what?
erythroid hyperplasia with cells messed up at every stage of the maturation process
28
what is vitamin b12 important for?
for RBCs and CNS function
29
where is vitamin b12 found?
in animal products and fortified breakfast cereals
30
how much vitamin b12 do we need daily? and how much does the body store?
need ~2micrograms/daily; body stores 2-5 mg; because the normal body stores greatly exceed the daily requirement, it takes years to develop a vitamin b12 deficiency
31
what is the effect of nitrous oxide on vitamin b12?
it inactivates cyanocobalamin (a common form of b12); if body stores are depleted, there is a rapid onset of neurological dysfunction that may not fully reverse
32
the IF-Cbl complex binds where before being basorbed?
binds to a specific receptor- cubulin- in the ileum
33
what are four causes of pernicious anemia?
autoantibodies are formed blocking the IF-cbl interction or blocking the IF-cbl receptors in the ileum; chronic atrophic gastritis; gastrectomy; H. pylori infection
34
how would you treat vitamin b12 deficiency?
oral vitamin b12 supplementation- x500 daily need or if there are neurological symptoms present parenteral therapy
35
what are the best dietary sources for folate?
yeast, liver, kidney, and green leafy vegetables
36
what is the estimated daily requirement for folate? and what is the recommended daily allowance for folate?
5-50 micro grams a day; recommended 400 micrograms a day for adults and 800 micrograms a day for pregnant or lactating females
37
where is folate absorbed?
in the jejunum
38
when do plasma levels of folate begin to fall following inadequate intake?
within three weeks due to metabolism and urinary excretion
39
what are 2 usual causes of folate deficiency?
inadequate dietary intake or alcoholism
40
which causes neuropsychiatric symptoms: B12 or folate deficiency?
B12; FOLATE DEFICIENCY DOES NOT CAUSE NEUROPSYCHIATRIC SYMPTOMS
41
how do you treat folate deficiency?
typically 1 mg/day for 4 months; if folate malabsorption then dose of 1-5 mg/day
42
folate is generally well-tolerated at recommended doses; higher doses can cause what?
hypotension and hypoglycemia
43
hypoxia is sensed by what organ?
the kidneys
44
in response to hypoxia, what does the kidney do?
EPO is made by the renal cortical fibroblasts and with hypoxia the number of fibroblasts that are making EPO increases
45
What is the mechanism of action of epoetin alfa?
it is an erythropoiesis-stimulating glycoprotein
46
how is epoetin alfa manufactured?
recombinant DNA technology
47
what are the effects of epoetin alfa?
stimulates erythropoiesis; increases the reticulocyte count in less than 10 days; increased the RBC count, hemoglobin, and hematocrit in 2-6 weeks
48
what is also included in epoetin alfa treatment?
iron and folate
49
what are the clinical applications for epoetin alfa treatment?
anemia due to: chronic kidney disease, cancer chemotherapy, when using zidovudine tx for HIV;
50
how is epoetin alfa administered?
via IV or subcutaneously
51
what are some of the toxicities of epoetin alfa?
20-50% have increased diastolic BP; there is an increased risk of death, myocardial infarction, stroke, embolism, and tumor progression or recurrence
52
what is the half life of epoetin alfa? and what is an example of a similar drug with 3x a longer half life?
half life= 4-13 hours; darbepoetin alfa (half life is 21 hours)
53
what is the mechanism of action for hydroxyurea?
it targets ribonucleotide reductase, resulting in s-phase cell cycle arrest; it also somehow boosts the levels of fetal hemoglobin
54
what are the effects of hydroxyurea?
lowers the concentration of Hb S within a cell--> less polymerization of the abnormal hemoglobin
55
what are the clinical applications for hydroxyurea?
it is the only disease modifying therapy approved for sickle cell anemia
56
how is hydroxyurea administered?
orally--> it is readily absorbed
57
what are the toxicities associated with hydroxyurea?
neutropenia anemia, oral ulcers, mild GI upset, hyperpigmentation, rash, nail changes
58
what is the mechanism of action for eculizumab?
it is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity; it inhibits its cleavage to C5a and C5b; prevents generation of terminal complement complex C5b-9
59
what are the effects of eculizumab?
inhibits terminal complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria; inhibits complement-mediated thrombotic microangiopathy in patients with atypical hemolytic uremia syndrome
60
what are the clinical applications of eculizumab?
PNH, atypical hemolytic uremic syndrome; it is only available under a risk evaluation and mitigation strategy (REMS) to which prescribers must enroll
61
how is eculizumad administered?
given IV over 35 minutes once per week for 1st 4 weeks; maintenance doses then given IV every 2 weeks
62
what are the toxicities associated with eculizumab?
viral infections, life-threatening meningococcal infections (must give meningococcal vaccine 2 weeks before using); immunogenic
63
what are some common presenting symptoms of neutropenia?
low-grade fever, sore mouth, severe pain when swallowing, gingival pain, symptoms of PNA
64
What is filgrastim?
a human granulocyte colony-stimulating factor (G-CSF) produced by recombinant DNA technology
65
what is G-CSF produced by endogenously?
monocytes, fibroblasts, and endothelial cells
66
what are the effects of filgrastim?
it regulates the production of neutrophils within the bone marrow--> affects neutrophil progenitor proliferation and differentiation
67
what are the clinical applications of filgrastim?
indicated to decreased the incidence of infection as manifested by febrile neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs or in those receiving a bone marrow transplant; used to mobilize hematopoietic progenitor cells into the peripheral blood; used for those with severe chronic neutropenia
68
how is filgrastim administered?
as 4 or 24 hour IV infusion; wait 24 hours after chemotherapy and stop 24 hours before chemotherapy
69
what is the half life of filgrastim? and what similar medication has a longer half life?
3.5 hours; pegfilgrastim- due to conjugation with monomethoxypolyethylene glycol
70
what are the toxicities associated with filgrastim?
allergic reaction and bone pain sometimes
71
what is sargramostim?
a recombinant form of granulocyte-macrophage colony stimulating factor (GM-CSF) made in yeast
72
what are the effects of sargramostim?
acts in the bone marrow to increase production of neutrophils, eosinophils, and monocytes/macrophages
73
what are the clinical applications of sargramostim?
used to accelerate recovery of myeloid cells after autologous bone marrow transplantation; can be used to mobilize hematopoietic stem cells into peripheral blood; indicated for use following induction chemotherapy in patients> 55 years with AML to shorten time to neutrophil recovery
74
how is sargramostim administered?
given IV or subcutaneously
75
what is the half life of sargramostim?
60 minutes
76
what are the toxicities associated with sargramostim?
edema, sequestration of granulocytes in pulmonary circulation--> causing dyspnea; has worsened preexisiting renal and hepatic dysfunction
77
when comparing filgrastim versus sargramostim, which one wins?
filgrastim has fewer adverse effects, so filgrastim wins
78
what are the UpToDate recommendations on CSF use in cancer?
no role for CSF in afebrile patients with neutropenia; primary prophylaxis: use only if incidence of febrile neutropenia is estimated at >20%; secondary prophylaxis: only use if delay or reduction of chemotherapy dose would prevent full doses of potentially curative chemotherapy
79
what is plerixafor?
a partial agonist of the CXCR4 receptor
80
what is the CXCR4 receptor important for?
the homing of hematopoietic stem cells to the bone marrow
81
what are the effects of plerixafor?
it mobilizes hematopoietic stem cells from the bone marrow to the plasma
82
what are the clinical applications for plerixafor?
patients who do not mobilize sufficient stem cells
83
what is plerixafor known to be?
an orphan drug (it is expensive)
84
how is plerixafor administered?
subcutaneous injection
85
what is the metabolism like of plerixafor/ half life?
half life is 3-5 hours; it is not metabolized- it's eliminated by the kidneys
86
both thrombopoietin and its PEG-derivatized variant have been withdrawn from the market- why?
due to autoantibodies that caused severe thrombocytopenia
87
stem cell factor has potent synergistic actions on early progenitor cells, so why can't it be used clinically?
it is also found on mast cells, and administration causes severe allergic reactions
88
what is oprelvekin?
a recombinant form of IL-11
89
what is the effect of oprelvekin?
it increases platelet levels by promoting the formation and maturation of megakaryocytes
90
what are the clinical applications for oprelvekin?
does not have a major clinical use
91
what other interleukins increase platelet levels, but are too toxic to use?
IL-3 and IL-6
92
what is romiplostim?
a peptibody which binds to the TPO receptor but has no TPO homology
93
what are the effects or romiplostim?
increases the platelet count in: healthy individuals, patients with ITP, and patients with MDS
94
what are the clinical applications of romiplostim?
excess platelet destruction due to ITP; used after failure of glucocorticoids and immune globin, and splenectomy
95
how is romiplostim administered?
weekly as subcutaneous injection
96
what are the toxicities associated with romiplostim?
generally well-tolerated, but could have allergic reaction
97
what is eltrombopag?
a potent orally available non-peptide TPO receptor agonist
98
what are the effects of eltrombopag?
it increases the platelet count in healthy individuals, patients with ITP, and thrombocytopenia due to hepatitis C
99
what are the clinical applications for eltrombopag?
excess platelet destruction due to ITP or cirrhosis due to hepatitis C
100
how is eltrombopag administered?
orally given once per day
101
what are the toxicities associated with eltrombopag?
may cause hepatotoxicity when used in combination with interferon and ribavirin in patients with chronic hepatitis C
102
what are the first options used when treating ITP?
glucocorticoids and immune globin
103
what are the second options of treating ITP?
rituximab + splenectomy
104
what are the third options for treating ITP?
romiplostim and eltrombopag
