Drugs for the treatment of anemia Flashcards
(81 cards)
1
Q
oprelvekin, IL-11
A
megakaryocyte growth factor
2
Q
romiplostim
A
megakaryocyte growth factor
3
Q
Sargramostim
A
granulocyte-macrophage colony stimulating factor (GM-CSF)
4
Q
pegfilgrastim
A
granulocyte colony stimulating factor (G-CSF)
5
Q
filgrastim (neupogen)
A
granulocyte colony stimulating factor (G-CSF)
6
Q
epoeitin alpha (Epogen, Procrit)
A
Erythrocyte stimulating agent
7
Q
Darbepoietin alpha
A
Erythrocyte stimulating agent
8
Q
cyanocobalamin
hydroxocobalamin
A
Vitamin B12 prep
9
Q
deferoxamine
A
iron chelator
10
Q
deferasirox
A
iron chelator
11
Q
iron dextran
A
parenteral iron
12
Q
iron sucrose complex
A
parenteral iron
13
Q
sodium ferric gluconate complex
A
perenteral iron
14
Q
ferrous sulfate
ferrous gluconate
ferrous fumarate
A
oral iron
15
Q
what re the causes of iron deficiency
A
nutrition
iron malabsorption- after gastrectomy, severe small bowel disease
blood loss
increased iron requirement –> pregnant, lactating, growing children, infants, premature infants, pt’ with chronic kidney disease
16
Q
what are the common signs of anemia
A
pallor, fatigue, dizziness
exertional dyspnea
tachycardia
increased CO
vasodilation
17
Q
what happens to erythrocytes in the absence of iron
A
small erythrocytes form with insufficient hemoglobin
microcytic hypochromic anemia
18
Q
where does iron absorption occur
when does iron absorption increase
A
duodenum and proximal jejunum
increases –> low iron stores or increased iron requirements
19
Q
non heme iron vs heme iron and absorption?
A
(4) Heme iron in hemoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron (e.g., iron in meat protein)
(5) Nonheme iron must be reduced by ferroreductase to ferrous iron (Fe2+) before absorption can occur
20
Q
what happens when iron stores are high/ or iron requirements are low
what happens when iron stores are low/ or iron requirements are high
A
(6) When iron stores are high and/or iron requirements are low, absorbed iron is diverted into ferritin in the intestinal epithelial mucosal cells for storage
(7) When iron stores are low and/or iron requirements are high, absorbed iron is immediately transported from the mucosal cells to the bone marrow to support hemoglobin production
21
Q
how is inorganic (non heme iron) absorbed by intestinal epithelial cells
A
via the divalent metal transporter (DMT1)
22
Q
how is (heme iron) absorbed by intestinal epithelial cells
A
HCP1
23
Q
what transport iron that is absorbed into the blood
A
ferroportin or complexes with apoferritin and stored as ferritin
24
Q
in the blood how is iron transported and where does it go
A
transferrin
goes to erythroid precursors in the bone marrow for synthesis of hemoglobin
or to the hepatocytes for storage as ferritin
The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized.
25
transferrin
a β-globulin that binds two molecules of ferric iron (Fe3+) and transports iron in the plasma
increased concentration when there is iron store depletion and iron deficiency anemia
26
where is iron stored
(2) Iron is stored in intestinal mucosal cells, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells
27
what is the only clinical indication for the use of iron preparations
treatment or prevention of iron deficiency anemia
28
what are the adverse effects of oral iron supplements
```
nausea
epigastric discomfort
abdominal cramps
constipation **
black stools
diarrhea
```
can be reduced if taken with or immediately after food
switching to a different ferrous salt prep may reduce GI problems
be careful of poisoning!!! make sure its in a childproof container
29
what type of patients shoulder be given parenteral iron
(a) Reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron and for patients with extensive chronic anemia who cannot be maintained with oral iron alone
(e. g., patients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoietin, small bowel resection, inflammatory bowel disease involving the proximal small bowel, or malabsorption syndromes)
30
how are parenteral iron therapies made so that the iron is released slowly
(b) All parenteral forms of iron are formulated as colloid containing particles with a core of iron oxyhydroxide surrounded by a core of carbohydrate so that iron is released slowly from the stable colloid particle after infusion (avoids the severe toxicity of free ferric iron upon administration)
31
why should monitoring of iron storage levels be done with parenteral iron supplements
(c) Parenteral administration bypasses iron storage regulatory mechanisms of the intestine and can deliver more iron than can safely be stored; monitoring iron storage levels helps to avoid serious toxicity of iron overload
32
what are the adverse effects of iron dextran
```
headache
light-headed
fever
arthralgias
nausea/vomiting
back pain
flushing
urticaria
bronchospasm
anaphylaxis -- death (rare)
```
give IM-local pain and tissue staining
most given IV
33
what should usually be done before giving iron dextran
a small test dose to test for hypersensitivity rx
34
how do you administer sodium ferric gluconate
IV only
and it is less likely to cause hypersensitivity
35
how do you administer iron sucrose complex
IV
less likely to cause hypersensitivity
36
when is acute iron toxicity most often seen
(1) Seen almost exclusively in young children who accidentally ingest iron tablets (as few as 10 tablets of common iron preparations can be lethal)
37
what are the symptoms of acute iron toxicity
necrotizing gastroenteritis, accompanied by vomiting and abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea
improvement may be noted and followed by severe metabolic acidosis, coma and death
38
what is the treatment for acute iron toxicity
whole bowel irrigation
parenteral deferoxamine (iron chelator that promotes excretion in the feces and urine)
39
chronic iron toxicity is common in what pt's
(2) Toxicity is most common in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time
(1) Excess iron deposits in the heart, liver, pancreas, and other organs can lead to organ failure and death
40
how do you treat chronic iron toxicity
(3) Efficiently treated with intermittent phlebotomy (deferoxamine is less efficient and potentially hazardous but may be only option for iron overload unsuccessfully managed by phlebotomy)
oral iron deferasirox reduces liver iron concentrations but is not sure about how well it removes iron from the heart
41
what can a vitamin B12 deficiency lead to
deficiency can lead to megaloblastic anemia, gastrointestinal symptoms, and neurologic abnormalities
42
what are the 2 Vitamin B12 preps available for clinical use
cyanocobalamin and hydroxocobalamin
43
what is the ultimate source of vit b12
microbial synthesis
chief dietary source is derived from B12 in meats, eggs, dairy products
44
where is vit b12 stored
liver
45
how long would it take for effects of b12 deficiency to occur if a patient stopped taking in vit B12 completelet
5 years to develop megaloblastic anemia
46
how is B12 absorbed
only absorbed after complexing with intrinsic factor --> a glycoprotein secreted by the parietal cells of the gastric mucosa
47
where does vitamin b12 absorption occur
distal ileum by highly selective receptor mediated transport system
48
how does B12 deficiency occur
most often from malabsorption due to lack of IF or to loss or malfunction of the absorptive mechanism in the distal ileum
(IBS)
vegans- diet
pernicocious anemia
partial or total gastrectomy
49
what 2 enzymatic rxns in humans require B12
synthesis of amino acid methionine
synthesis of succinyl-CoA
50
explain the synthesis of methionine
```
job of:
methylcobalamin
N5-methyltetrahydrofolate
homocysteine
tetrahydrofolate ***
```
how can a B12 deficiency be partially corrected
what is a diagnostic marker for Viramin B12 deficiency
(1) Methylcobalamin serves as an intermediate in the transfer of a methyl group from N5-methyltetrahydrofolate to homocysteine, forming methionine
(2) During the methyl transfer, N5-methyltetrahydrofolate is converted to tetrahydrofolate, the precursor of folate cofactors that leads to the synthesis of deoxythymidylate and purines required for DNA synthesis
(3) B12 deficiency causes the accumulation of N5-methyltetrahydrofolate and depletion of tetrahydrofolate (link between B12 and folic acid metabolism; B12 deficiency can be partially corrected by ingestion of large amounts of folic acid, which largely corrects the anemia caused by B12 deficiency; folic acid does not prevent neurologic manifestations of B12 deficiency, which are thought to be caused by loss of methionine synthesis; see Figure 33-3 below)
(4) B12 deficiency causes the accumulation of homocysteine due to the reduced formation of methylcobalamin; increased serum levels are diagnostic of B12 deficiency
51
what is the role of Vitamin B12 in the synthesis of succinyl -CoA
what is a diagnostic marker that can accumulate from this rxn that helps diagnose Vit B12 deficiency
iii) Synthesis of succinyl-CoA
(1) Deoxyadenosylcobalamin is required for the isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase
(2) In patients deficient in B12, methylmalonic acid and methylmalonyl-CoA accumulate (serum and urine levels of methylmalonic acid are diagnostic for B12 deficiency)
52
what are some common clinical characteristics of Vitamin B12 deficiency
megaloblastic macrocytic anemia
mild or moderate leukopenia or thrombocytopenia
hypercellular bone marrow
iv) Neurologic syndrome associated with B12 deficiency usually begins with paresthesias in peripheral nerves and weakness and progresses to spasticity, ataxia, and other CNS dysfunctions (B12 treatment stops the progression of neurologic disease but may not fully reverse neurologic symptoms)
53
what is the treatment of vit B12 deficiency
v) Almost all cases of B12 deficiency are due to malabsorption; therefore parenteral injections are required for therapy (often lifelong if syndrome causing deficiency is incurable)
vi) Parenteral injections are available as cyanocobalamin and hydroxocobalamin forms of B12
vii) Initial therapy: 100-1000 mcg B12 IM daily or every other day for 1-2 weeks to replenish body stores
viii) Maintenance therapy: 100-1000 mcg B12 IM once a month for life
54
if neuro symptoms are present,, how should vitamin b12 deficiency treatment be adjusted
maintenance therapy should be given every 1-2 weeks for 6 months before switching to monthly injections
55
what is folic acid required for
synthesis of amino acids, purines and DNA
56
what are the richest dietary sources of folic acid
yeast
liver
kidney
green vegetables
57
how long does it take for folate levels to fall after you stop taking it
few days
due to low body stores and high daily requirements, folic acid deficiency and megaloblastic anemia may develop within 1-6 months after the inatke of folic acid stops
58
where is folic acid absorbed
proximal jejunum
59
once inside the cell, folate (N5-methyltetrahydrofolate) is converted what? what does this require
converted to tetrahydrofolate requiring vitamin B12
60
does folate deficiency result in neuro symptoms like vitamin b12 deficiency?
no
61
in what patients is risk for folate deficiency high
```
alocholics
pregnant women
pt's with hemolytic anemia
pt's with malabsorption syndromes
pt's undergoing renal dialysis
```
62
what drugs can cause folic acid deficiency
methotrexate
trimethoprim
pyrimethamine
phenytoin
63
WHERE IS erythropoietin normally expressed
what triggers its production
peritubular interstitial cells of the kidney
production is triggered by anemia or hypoxemia
64
what suppresses erythropoietin
inflammatory cytokines
65
what is the MOA of erythrocyte stimulating drugs:
epoetin alpha
darbepoitein alpha
and what is the result after administration of these drugs
i) MOA: induces erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells; induces the release of reticulocytes from the bone marrow into the bloodstream, where they mature to erythrocytes (agonist at erythropoietin receptors on red cell progenitors)
ii) Results in an increase in reticulocyte counts (10 days) followed by a rise in hematocrit and hemoglobin levels (2-6 weeks)
66
what are the clinical uses of erythropoiesis stimulating agents
-used to decrease the need for RBC transfusions in pt's with anemia secondary to chronic kidney disease
(usually always couple with oral or parenteral iron supplementation)
- anemia due to myelosuppressive chemotherapy in pt's with cancer of nonmyeloid malignancy for palliative care
- treat anemia associated with HIV therapy (zidovudine)
(3) Reduction of allogenic RBC transfusion for elective, noncardiac, nonvascular surgery when perioperative Hgb is 10-13 g/dL and there is a high risk for blood loss
67
in what pt's are erythropoiesis stimulating drugs NOT indicated
(1) Cancer patients receiving hormonal therapy, therapeutic biologic products, or radiation therapy unless also receiving concurrent myelosuppressive chemotherapy
(2) Cancer patients receiving myelosuppressive chemotherapy when the expected outcome is curative***
(3) Surgery patients who are willing to donate autologous blood
(4) Surgery patients undergoing cardiac or vascular surgery
(5) As a substitute for RBC transfusion in patients requiring immediate correction of anemia
68
what are the adverse effects of erythropoietin stimulating drugs
HTN
thrombotic complications
aggressive used in chemotherapy pt's or those with chronic renal failure has been linked to increased mortality and CV events
69
what do myeloid growth factors do?
i) Myeloid growth factors stimulate proliferation and differentiation of one or more myeloid cell lines and enhance the function of mature granulocytes and monocytes
70
what are the specific functions of G-CSF
(1) Stimulates proliferation and differentiation of progenitors already committed to the neutrophil lineage
(2) Activates the phagocytic activity of mature neutrophils and prolongs survival
(3) Increases concentration of hematopoietic stem cells in peripheral blood (major advance in transplantation because peripheral blood stem cells (PBSCs) may be used rather than bone marrow stem cells)
71
what are the specific actions of GM-CSF
effect on myeloid cells
effect on T cells?
(1) Broader biologic actions than G-CSF
(2) Primary therapeutic effect is to stimulate myelopoiesis ***
(a) Stimulates the proliferation and differentiation of early and late granulocytic progenitor cells as well as erythroid and megakaryocyte progenitors
(b) Stimulates the function of mature neutrophils
(c) Stimulates T-cell proliferation together with interleukin-2
(3) Increases concentration of peripheral blood stem cells to a lesser extent than G-CSF
72
what are the clnical uses of GM-CSF and G-CSF
cancer chemotherapy induce neutropenia
-G-CSF--> accelerate neutrophil recovery after chemo, reduce requirements for broad-spectrum antibiotics, infections and days of hospitalizations
doesn't improve survival in cancer pt's
treat neutropenia associated with congenital neutropenia, myelodysplasia and aplastic anemia
combine with other growth factors to treat pancytopenia
autologous stem cell transplants in pt's undergoing high dose chemo
73
filgrastim and pegfilgrastim are used more frequently than GM-CSF b/c they are better tolerated
but what are the adverse effects of these drugs...
bone pain
74
what are the adverse effects of GM-CSF
```
fever
malaise
arthralgias
myalgias
capillary leak syndrome- peripheral edema, pleural or pericardial effusions
```
75
what are the endogenous regulators of platelet production
thrombopoietin and IL-11
c) Recombinant thrombopoietin cannot be used clinically due to production of autoantibodies that result in development of thrombocytopenia
76
what is the mOA of oprelvekin (IL-11)
activates specific cell surface cytokine receptors to stimulate the growth of multiple lymphoid and myeloid cells; acts synergistically with other growth factors to stimulate the growth of primitive megakaryocytic progenitors; increases the number of peripheral platelets and neutrophils
77
what is romiplostim
MOA
when do its actions start to take place
peptide agonist of the thrombopoietin receptor MpI
it is a megakaryocyte growth factor
(1) Member of a new class of therapeutics called peptibodies, which are peptides with key biologic activities covalently linked to antibody fragments that serve to extend the peptide’s half-life
activates Mpl thrombopoietin receptor to cause a dose-dependent increase in platelet count that begins 5 days after SubQ injection and peaks at 12-15 days
78
what is the clinical use of oprelvekin (IL-11)
prevention of thrombocytopenia in pt's receiving cytotoxic chemo for nonmyeloid cancer
reduces the number of platelet transfusions
79
what is the clinical use of romipolstim
treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia purpura (ITP) who have had insufficient response to corticosteroids, immune globulin, or splenectomy
80
what is the toxicity effects of IL-11
fatigue
headache
dizziness
CV--> anemia, dyspnea, atrial arrythmias
hypokalemia
all adverse effects are reversible
81
what are the adverse effects of romiplostim
(1) Well tolerated except for a mild headache on the day of administration
