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HEME PHARM > Anemias > Flashcards

Anemias Flashcards

1
Q

Recall major symptoms of iron deficiency (and how they occur)

A 
Pallor
Fatigue
dizziness
Exertional dyspnea
Generalized symptoms of tissue hypoxia
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2
Q

Major symptoms of vitamin B12 deficiency (and how they occur)

A

Megaloblastic macrocytic anemia
GI symptoms
neurologic abnormalities

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3
Q

Major symptoms of folate deficiency (and how they occur)

A

megaloblastic macrocytic anemia

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4
Q

Drugs used to treat iron/vitamin/folate deficiencies

A 
ferrous salts
--ferrous sulfate
--ferous gluconate
--ferous fumarate
Cyanocobalamin
Hydroxocobalamin
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5
Q

Hematopoietics

A 
Clinical effects:
--
Major Toxicities:
--
Clinical utilities:
--
Adverse effects of concurrent drug therapy:
--
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6
Q

G-CSF

A

Clinical effects:

  • -Stimulates G-CSF receptors expressed on mature neutrophils and their progenitors
  • -Stimulates prolif and differentiation of neutrophil progenitors
  • -activates phagocytic activity of mature neutrophils and extends their survival
  • -mobilizes hematopoietic stem cells

Major Toxicities:

  • -Bone pain
  • -Rarely, splenic rupture

Clinical utilities:

  • -Neutropenia associated w/ congenital neutropenia, cyclic neutropenia, myelodysplasia, aplastic anemia
  • -secondary prevention of neutropenia in pts undergoing cytotoxic chemo
  • -mobilization of peripheral blood cells in preparation for autologous and allogenic stem cell transplantation

Administration
–Daily subQ

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7
Q

GM-CSF

A 
Clinical effects:
--
Major Toxicities:
--
Clinical utilities:
--
Adverse effects of concurrent drug therapy:
--
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8
Q

Oprelvekin/Romiplostim

A 
Clinical effects:
--
Major Toxicities:
--
Clinical utilities:
--
Adverse effects of concurrent drug therapy:
--
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9
Q

Iron Deficiency

A

Most common cause of chronic anemia

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10
Q

Cardiovascular adaptations to chronic anemia

A
  • -tachycardia
  • -increased CO
  • -vasodilation
  • -(can worsen condition of pts w/ underlying CV disease)
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11
Q

ORAL iron therapy

A
  • -ferrous most efficiently absorbed…ferrous salts!
  • -ferrous sulfate, ferrous gluconate, ferrous fumarate
  • -treatment should be continued for 3-6 months after correction of cause of iron loss (corrects AND replenishes)
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12
Q

Amount of iron incorporated into hemoglobin daily

A

50-100mg

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13
Q

percentage of oral iron given as ferrous salt that can be absorbed

A

25%

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14
Q

Amount of elemental iron that should be given daily to correct iron deficiency MOST RAPIDLY

A

200-400mg

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15
Q

If Patients unable to tolerate large doses of iron…

A

lower daily doses of iron..slower but still complete correction of iron deficiency

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16
Q

Toxic effects of ORAL iron therapy

A
  • -Nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea
  • -usually dose-related and can be overcome by lowering daily dose/ by taking tablets immediately after or w/ meals
  • -one iron salt may affect pt. more than another
  • -black stools (may obscure diagnosis of continued GI blood loss!!!)
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17
Q

When to use PARENTERAL iron therapy

A

–pt can’t tolerate oral dosing
–pt w/ extensive chronic anemia, oral iron alone is not enough…
…..Advanced chronic renal disease requiring hemodialysis and treatment w/ EPO
…..Various postgastrecotomy conditions
…..Previous small bowel resection
…..Inflammatory bowel disease involving proximal small bowel
…..Malabsorption syndromes

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18
Q

PARENTERAL iron treatment challenges

A

inorganic free ferric iron produces serious dose-dependent toxicity
–severely limits dose that can be administered

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19
Q

PARENTERAL iron treatment solutions to the treatment challenges

A
  • -Colloidal formulations (carb surrounding core of iron oxyhydroxide)
  • -Iron dextran (IV & IM)–sodium ferric gluconate complex (IV) - iron sucrose (IV)
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20
Q

Toxic effects of PARENTERAL iron therapy

A

IV Iron dextran therapy

  • -Headache, light-headedness, fever, arthralgias, nausea, vomiting
  • -Back pain, flushing urticaria, bronchospasm,
  • -RARELY anaphylaxis and death (small test dose should always be given; Hx of allergy and previous exposure are additional risk factors)

Other preps less likely to cause hypersensitivity rxns

Pts should be monitored for iron overload (b/c perenteral bypasses absorptive regulatory processes of oral..)

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21
Q

How can iron stores be estimated?

A

based on serum concentrations of ferritin and transferrin saturation
(Ratio of total serum iron concentration to TIBC)

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22
Q

TIBC

A

total iron binding capacity (essentially, how much transferrin?)

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23
Q

Acute iron toxicity in young children

A

as few as 10 tablets can be fatal to child
necrotizing gastroenteritis
–vomiting, abdominal pain
–bloody diarrhea
–shock, lethargy and dyspnea
–initial improvement followed by metabolic acidosis, coma, death

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24
Q

Detoxification (of iron toxicity)

A

whole bowel irrigation
–activated characoal does NOT bind-(ineffective)

Deferoxamine (Desferal), a potent iron-chelating compound given IV

  • -doesn’t chelate other important trace metals
  • -excreted in urine and bile…urine red
  • -tachycardia, hypotension, shock
  • -could add to the CV collapse caused by iron toxicity
  • -abdominal discomfort, N/V, diarrhea…may add to symptoms of acute iron toxicity
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25
Q

Chronic Iron toxicity

A
  • -Hemochromatosis
  • -Deferasirox (Exjade) can be given orally in OJ
  • -Chronic iron overload in absence of anemia can be treated by intermittent phlebotomy (one unit of blood removed/week)
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26
Q

Hemochromatosis

A

Excess iron deposited in heart, liver, pancreas, etc.
–can lead to organ failure and death
Most commonly occurs in pts w/ inherited hemochromatosis
–Excessive iron absorption
Pts who receive many RBC transfustions over long period of time (i.e. thalassemia major)

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27
Q

Deferasirox (Exjade) given orally in OJ…

A

–to treat chronic iron overload due to multiple blood transfusions
(also used for iron ingestion)
–Diarrhea, nausea, abdominal pain, headache, pyrexia, cough
–increased serum creatinine and hepatic enzyme levels
–auditory and visual disturbances

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28
Q

Macrocytic anemia due to B12 deficiency

A

associated mild or moderate leukopenia and/or thrombocytopenia
Characteristic hypercellular bone marrow w/ accumulation of megaloblastic erythroid and other precursor cells

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29
Q

Neurologic syndrome of B12 deficiency

A
  • -Parethesias in peripheral nerves and weakness and progresses to spasticity, ataxia, other CNS dysfunctions
  • -Correction of vitamin B12 deficiency arrest progression of neurologic disease, but may not fully reverse
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30
Q

Common causes of B12 deficiency

A 
perniscious anemia
partial/total gastrectomy
--conditions that affect distal ileum:
1. Malabsorption syndromes
2. inflammatory bowel disease
3. Small bowel resection
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31
Q

Rare causes of B12 deficiency

A
  • -Bacterial overgrowth of small bowel
  • -Chronic pancreatitis
  • -Thyroid disease
  • -In children: secondary to congenital deficiency of IF or to defects of receptor sites for vitamin B12-intrinsic factor complex located in distal ileum
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32
Q

Parenteral Therapy (IM) for B12 deficiency

A

(since almost all cases of B12 deficiency caused by malabsorption…parenteral therapy!)

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33
Q

Vitamin B12

A

Available as cyanocobalamin or hydroxocobalamin
(Hydroxocobalamin is preferred…b/c:
–more highly protein-bound
–Remains longer in the circulation)

34
Q

Folic acid

A

Reduced forms needed for biochem rxns
precursors for synthesis of aa, purines, DNA
Deficiency not uncommon (easily corrected by administration of folic acid)

35
Q

Folic acid deficiency most common in…

A

–alcoholics
–liver disease
(b/c poor diet and bad hepatic storage of folates)
–Pregnant women
–pts w/ hemolytic anemia
–pts w/ malabsorption syndromes
–pts doing renal dialysis (b/c dialysis removes folate from plasma)

36
Q

ORAL therapy for folate deficiency

A
  • -Absorption high, even in pts w/ malabsorption syndrome
  • -1 mg folic acid daily=usually enough to reverse megaloblastic anemia, restore serum folate levels, replenish stores
  • -Continue therapy until underlying cause of deficiency removed or corrected
  • -Continue indefinitely for pts w/ malabsorption or dietary inadequacy
  • -supplementation for high-risk pts
37
Q

Drug-induced folic acid deficiencies

A

**Methotrexate
Trimethoprim (to lesser extent)
Pyrimethamine (to lesser extent)

Phenytoin (causes by inhibiting intestinal uptake process…NOT by interfering w/ dihydrofolate reductase activity like others)

38
Q

? Leucovorin ?

A

Reduced folate
rescues cells from effects of folate antagonists
modulates effect of fluorouracil, 5-FU
–does not itself function as cyotoxic chemo agent

39
Q

Folate and depression

A

see section in handout

40
Q

Levomofolate

A

the biologically active form of folate found in ciruculation

  • -both folic acid and dihydrofolate must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to levomefolate
  • -Levomefolate then transported across cell membranes by receptor-mediated endocytosis

Levomefolate readily crosses blood brain barrier where it modulates formation of monoamines serotonin, norepinephrine, dopamine

41
Q

Recombinant mammalian human erythropoietin (rHuEPO)

A

Epoetin alfa
Darbepoetin alfa
methoxy polyethylene glycol-epoetin beta

42
Q

Epoetin alfa MOA

A

agonist of EPO receptors expressed by red cell progenitors

  • -stimulates erythroid prolif and differentiation
  • -induces release of reticulocytes from bm
43
Q

Epoetin alfa utility

A

treatment of anemia, esp. associate w/:

  • -chronic renal failure
  • -HIV infection
  • -cancer
  • -prematurity

prevention of need for transfusion in pts undergoing certain electivesurgery

44
Q

Epoetin alfa administration

A

IV or SC 1-3 times per week

45
Q

Epoetin alfa Toxicity

A

Hypertension
throbotic complications
rarely, pure red cell aplasia
(to reduce risk of serious CV events, hemoglobin levels hould be maintained less than 12 g/dL)

46
Q

Darbepoetin alfa

A

Long-acting glycosylated form administered 1-2 times per month

47
Q

Methoxy polyethylene glycol-epoetin beta

A

Long-acting form administered 1-2 times per month

*Should NOT be used for treatment of anemia caused by cancer chemo (trial found significantly more deaths among pts receiving this form of EPO)

48
Q

Drugs w/ PEG prefix

i.e. pegasparaginase, pegfilgrastim, perinterferon

A

indicates original drug has been reformulated w/ addition of polyethylene glycol moieties to extend PKs of drug and reduce need for so frequent re-dosing

49
Q

Hematopoietic growth factors

A

glycoprotein hormones that regulate proliferation and differentiation of hematopoietic progenitor cells in bone marrow

50
Q

EPO and its receptor

A

receptor= member of JAK/STAT supperfamily of cytokine receptors

51
Q

Normal serum levels of EPO

A

non-anemic…<20 IU/L
Moderately severe anemia…100-500 IU/L
Severe anemia…thousands of IU/L

52
Q

Different Responses to EPO in renal failure

A

renal disease
–EPO usually low
–most likely will respond to exogenous EPO
Primary bm disorders and nutritional and secondary anemias
–EPO levels usually high
–less likely to respond to exogenous EPO

Folate and/or iron supplementation may be necessary

53
Q

ESA

A

erythropoisis stimulating agents

54
Q

Black box Warnings for ESAs

CKD pts

A

greater risk for death, serious CV rxns, stroke when ESA administered w/ target Hb level greater than 11 g/dL

No identified target Hb level that doesn’t increase these risks

Use the lowest dose sufficient to reduce need for RBC transfusions

55
Q

Black Box Warnings for ESAs

Cancer pts

A

shortened overall survival/ increased risk for tumor progression in pts w/…
breast, head, neck, lymphoid, non-small cell lung, and cervical cancers

prescribers and hospitals must enroll in and comply w/ ESA APPRISE Oncolgy Program to prescribe and/or dispense ESAs to cancer pts

Use lowest dose to avoid RBC transfusions

Use ESAs only for anemia from myelosuppressive chemo

ESAs not indicated for pts receiving myelosuppressive chemo when anticipated outcome is cure

Discontinue following completion of chemo course perisurgery

56
Q

Due to increased risk of DVT during ESA treatment…

A

DVT prophylaxis is recommended

57
Q

Non-Life-threatening adverse effects of ESAs

Most commonly (in order of frequency)…

A

Hypertension
Headache
Arthralgias
Nausea

58
Q

Non-Life-threatening adverse effects of ESAs

Less commonly (<10%)…

A

Edema, fatigue, diarrhea, vomiting, asthenia, chest pain, dizziness, skin rxn @ injection site, seizures

59
Q

EPO used successfully to…

A

Offset anemia produced by zidovudine (Retrovir; ZDV) treatment in pts w/ HIV

in the treatment of anemia of prematurity

60
Q

Clinical effects of G-CSF

A
  • -Stimulates G-CSF receptors expressed on mature neutrophils and their progenitors
  • -Stimulates prolif and differentiation of neutrophil progenitors
  • -activates phagocytic activity of mature neutrophils and extends their survival
  • -mobilizes hematopoietic stem cells
61
Q

Toxicities of G-CSF

A
  • -Bone pain

- -Rarely, splenic rupture

62
Q

Clinical Utilities of G-CSF 1

A
  • -Neutropenia associated w/ congenital neutropenia, cyclic neutropenia, myelodysplasia, aplastic anemia
  • -secondary prevention of neutropenia in pts undergoing cytotoxic chemo
  • -mobilization of peripheral blood cells in preparation for autologous and allogenic stem cell transplantation
63
Q

Administration of G-CSF

A

Administration

–Daily subQ

64
Q

G-CSF:

Adverse effects of concurrent drug therapy

A

…

65
Q

Pegfilgrastim

A

Long-acting form of filgrastim that is covelently liked to a type of polyethylene glycol

66
Q

G-CSF

A

Filgrastim

67
Q

GM-CSF (sargramostim)

A

myeloid growth factor that acts through GM-CSF receptor to stimulate prolif and differentiation of early and late granulocytic progenitor cells, and erythroid and megakaryocyte progenitors

clinical uses similar to G-CSF, but more likely than G-CSF to cause:

  • -fever
  • -arthraalgia
  • -myalgia
  • -capillary leak syndrome
68
Q

G-CSF mobilization of hematopoietic stem cells i.e to increase their conc. in peripheral blood…

A

permits use of peripheral blood stem cells (PBSCs) rather than bone marrow stem cells for autologous and allogeneic hematopoietic stem cell translplantation

69
Q

GM-CSF activity

A

broader biologic actions than G-CSF
–multipotential hematopoietic GF
(stimulates prolif and differentiation of early and late granulocytic progenitor cells; erythroid and megakaryocyte progenitors)

stimulates function of mature neutrophils

acts together w/ IL-2 to stimulate T-cell prolif

appears to be locally active factor at site of inflammation

mobilizes peripheral blood stem cells, but LESS effectively than G-CSF

70
Q

Clinical Utilities of G-CSF 2

A

accelerates rate of neutrophil recovery after dose-intensive myelosuppressive chemo
–reduces episodes of febrile neutropenia, requirements for broad-spectrum antibiotics, infections, days of hospitalization BUT has NO effect on pt survival!
(Pegfilgrastim can be administered less frequently…may shorten period of severe neutropenia slightly more than G-CSF)

71
Q

Clinical Utilities of G-CSF 3

A

In autologous stem cell transplantation for pts undergoing high-dose chemo

  • -high doses chemo necessitated by the resistance of tumor cell population
  • -Myelosuppression is then counteracted by reinfusion of pts own hematopoietic stem cells collected prior to chemo

Mobilization of PBSCs
–PBSCs have largely replaced bm as hematopoietic prep used for autologous transplantation

72
Q

G-CSF, pegfilgrastim, GM-CSF

A

have similar effects on neutrophil counts
–G-CSF and pegfigrastim are better tolerated
(but w/ bone pain upon discontinuation)
–G-CSF and pegfigrastim are used more frequently

73
Q

GM-CSF has more severe side effects than G-CSF and pegfilgrastim…

A

fever, malaise, arthralgias, myalgias, capillary leak syndrome (characterized by peripheral edema and pleural or pericardial effusions)
Allergic rxn may occur (but infrequent)

*Splenic rupture is rare but serious complication of use of G-CSF for PBSC

74
Q

Oprelvekin

IL-11

A

Recombinant form of endogenous cytokine

activates IL-11 receptors

75
Q

Oprelvekin MOA

A

stimulates growth of multiple lymphoid and myeloid cells, including megakaryocyte progenitors

increases number of circulating platelets and neutrophils

76
Q

Oprelvekin clinical utility

A

Secondary prevention of thrombocytopenia in pts undergoing cytotoxic chemo for nonmyeloid cancers

77
Q

Oprelvekin administration

A

daily by SC injection

(to increase platelet count to more than 50,000 cells/uL

78
Q

Oprelvekin toxicity

A 
fatigue
headache
dizziness
CV effects
--anemia (due to hemodilution)
--Dyspnea (due to fluid accumulation in lungs)
--transient atrial arrythmias
Hypokalemia occasionally
All adverse effects seem to be reversible!
79
Q

Romiplostim (Nplate)
(recombinant DNA technology in E. coli)
NC#1

A

genetically engineered protein in which Fc component of human antibody is fused to two copies of peptide that stimulates thrombopoietin receptors

approved for treatment of idiopathic thrombocytopenic purpura

80
Q

Oprelvekin (Neumega)

A

rh-IL-11 from E. Coli

stimulates megakaryocytopoiesis and thrombopoiesis

  • -binds to IL-11Ralpha on megakaryocytes and megakaryocyte progenitor cells
  • -Induces megakaryocyte maturation…inc platelet production (morphologically and functionally normal w/ normal life-span)
81
Q

IL-11 Ralpha

A

IL-11 receptor

belongs to family of cytokine receptors able to interact w/ signal transducing receptor gp130

82
Q

Romiplostim (Nplate)
(recombinant DNA technology in E. coli)
NC#2

A

Thrombopoietin-mimetic Fc-peptide fusion protein (peptibody)
Contains two identical single-chain subunits, each consisting of human IgG1 Fc domain, covalently linked at C-terminus to 2 identical peptide sequences that each bind and activate TPO receptor

Fc component of romiplostim peptibody extends half-life

  • -remains active in circulation much longer than endogenous TPO
  • -eventually removed by reticuloendothelial system

HEME PHARM (10 decks)

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