Anemias Flashcards
Recall major symptoms of iron deficiency (and how they occur)
Pallor Fatigue dizziness Exertional dyspnea Generalized symptoms of tissue hypoxia
Major symptoms of vitamin B12 deficiency (and how they occur)
Megaloblastic macrocytic anemia
GI symptoms
neurologic abnormalities
Major symptoms of folate deficiency (and how they occur)
megaloblastic macrocytic anemia
Drugs used to treat iron/vitamin/folate deficiencies
ferrous salts --ferrous sulfate --ferous gluconate --ferous fumarate Cyanocobalamin Hydroxocobalamin
Hematopoietics
Clinical effects: -- Major Toxicities: -- Clinical utilities: -- Adverse effects of concurrent drug therapy: --
G-CSF
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
GM-CSF
Clinical effects: -- Major Toxicities: -- Clinical utilities: -- Adverse effects of concurrent drug therapy: --
Oprelvekin/Romiplostim
Clinical effects: -- Major Toxicities: -- Clinical utilities: -- Adverse effects of concurrent drug therapy: --
Iron Deficiency
Most common cause of chronic anemia
Cardiovascular adaptations to chronic anemia
- -tachycardia
- -increased CO
- -vasodilation
- -(can worsen condition of pts w/ underlying CV disease)
ORAL iron therapy
- -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)
Amount of iron incorporated into hemoglobin daily
50-100mg
percentage of oral iron given as ferrous salt that can be absorbed
25%
Amount of elemental iron that should be given daily to correct iron deficiency MOST RAPIDLY
200-400mg
If Patients unable to tolerate large doses of iron…
lower daily doses of iron..slower but still complete correction of iron deficiency
Toxic effects of ORAL iron therapy
- -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!!!)
When to use PARENTERAL iron therapy
–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
PARENTERAL iron treatment challenges
inorganic free ferric iron produces serious dose-dependent toxicity
–severely limits dose that can be administered
PARENTERAL iron treatment solutions to the treatment challenges
- -Colloidal formulations (carb surrounding core of iron oxyhydroxide)
- -Iron dextran (IV & IM)–sodium ferric gluconate complex (IV) - iron sucrose (IV)
Toxic effects of PARENTERAL iron therapy
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..)
How can iron stores be estimated?
based on serum concentrations of ferritin and transferrin saturation
(Ratio of total serum iron concentration to TIBC)
TIBC
total iron binding capacity (essentially, how much transferrin?)
Acute iron toxicity in young children
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
Detoxification (of iron toxicity)
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
Chronic Iron toxicity
- -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)
Hemochromatosis
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)
Deferasirox (Exjade) given orally in OJ…
–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
Macrocytic anemia due to B12 deficiency
associated mild or moderate leukopenia and/or thrombocytopenia
Characteristic hypercellular bone marrow w/ accumulation of megaloblastic erythroid and other precursor cells
Neurologic syndrome of B12 deficiency
- -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
Common causes of B12 deficiency
perniscious anemia partial/total gastrectomy --conditions that affect distal ileum: 1. Malabsorption syndromes 2. inflammatory bowel disease 3. Small bowel resection
Rare causes of B12 deficiency
- -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
Parenteral Therapy (IM) for B12 deficiency
(since almost all cases of B12 deficiency caused by malabsorption…parenteral therapy!)
Vitamin B12
Available as cyanocobalamin or hydroxocobalamin
(Hydroxocobalamin is preferred…b/c:
–more highly protein-bound
–Remains longer in the circulation)
Folic acid
Reduced forms needed for biochem rxns
precursors for synthesis of aa, purines, DNA
Deficiency not uncommon (easily corrected by administration of folic acid)
Folic acid deficiency most common in…
–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)
ORAL therapy for folate deficiency
- -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
Drug-induced folic acid deficiencies
**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)
? Leucovorin ?
Reduced folate
rescues cells from effects of folate antagonists
modulates effect of fluorouracil, 5-FU
–does not itself function as cyotoxic chemo agent
Folate and depression
see section in handout
Levomofolate
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
Recombinant mammalian human erythropoietin (rHuEPO)
Epoetin alfa
Darbepoetin alfa
methoxy polyethylene glycol-epoetin beta
Epoetin alfa MOA
agonist of EPO receptors expressed by red cell progenitors
- -stimulates erythroid prolif and differentiation
- -induces release of reticulocytes from bm
Epoetin alfa utility
treatment of anemia, esp. associate w/:
- -chronic renal failure
- -HIV infection
- -cancer
- -prematurity
prevention of need for transfusion in pts undergoing certain electivesurgery
Epoetin alfa administration
IV or SC 1-3 times per week
Epoetin alfa Toxicity
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)
Darbepoetin alfa
Long-acting glycosylated form administered 1-2 times per month
Methoxy polyethylene glycol-epoetin beta
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)
Drugs w/ PEG prefix
i.e. pegasparaginase, pegfilgrastim, perinterferon
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
Hematopoietic growth factors
glycoprotein hormones that regulate proliferation and differentiation of hematopoietic progenitor cells in bone marrow
EPO and its receptor
receptor= member of JAK/STAT supperfamily of cytokine receptors
Normal serum levels of EPO
non-anemic…<20 IU/L
Moderately severe anemia…100-500 IU/L
Severe anemia…thousands of IU/L
Different Responses to EPO in renal failure
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
ESA
erythropoisis stimulating agents
Black box Warnings for ESAs
CKD pts
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
Black Box Warnings for ESAs
Cancer pts
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
Due to increased risk of DVT during ESA treatment…
DVT prophylaxis is recommended
Non-Life-threatening adverse effects of ESAs
Most commonly (in order of frequency)…
Hypertension
Headache
Arthralgias
Nausea
Non-Life-threatening adverse effects of ESAs
Less commonly (<10%)…
Edema, fatigue, diarrhea, vomiting, asthenia, chest pain, dizziness, skin rxn @ injection site, seizures
EPO used successfully to…
Offset anemia produced by zidovudine (Retrovir; ZDV) treatment in pts w/ HIV
in the treatment of anemia of prematurity
Clinical effects of G-CSF
- -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
Toxicities of G-CSF
- -Bone pain
- -Rarely, splenic rupture
Clinical Utilities of G-CSF 1
- -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 of G-CSF
Administration
–Daily subQ
G-CSF:
Adverse effects of concurrent drug therapy
…
Pegfilgrastim
Long-acting form of filgrastim that is covelently liked to a type of polyethylene glycol
G-CSF
Filgrastim
GM-CSF (sargramostim)
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
G-CSF mobilization of hematopoietic stem cells i.e to increase their conc. in peripheral blood…
permits use of peripheral blood stem cells (PBSCs) rather than bone marrow stem cells for autologous and allogeneic hematopoietic stem cell translplantation
GM-CSF activity
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
Clinical Utilities of G-CSF 2
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)
Clinical Utilities of G-CSF 3
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
G-CSF, pegfilgrastim, GM-CSF
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
GM-CSF has more severe side effects than G-CSF and pegfilgrastim…
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
Oprelvekin
IL-11
Recombinant form of endogenous cytokine
activates IL-11 receptors
Oprelvekin MOA
stimulates growth of multiple lymphoid and myeloid cells, including megakaryocyte progenitors
increases number of circulating platelets and neutrophils
Oprelvekin clinical utility
Secondary prevention of thrombocytopenia in pts undergoing cytotoxic chemo for nonmyeloid cancers
Oprelvekin administration
daily by SC injection
(to increase platelet count to more than 50,000 cells/uL
Oprelvekin toxicity
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!
Romiplostim (Nplate)
(recombinant DNA technology in E. coli)
NC#1
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
Oprelvekin (Neumega)
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)
IL-11 Ralpha
IL-11 receptor
belongs to family of cytokine receptors able to interact w/ signal transducing receptor gp130
Romiplostim (Nplate)
(recombinant DNA technology in E. coli)
NC#2
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
