Agents used in Anemias and Hematopoietic Growth Factors Flashcards
Condition caused by a lack of RBCs which supply oxygen to different parts of the body
Anemia
Possible causes of Anemia
- low iron
- low folic acid & vit. B12
Essential component of hemoglobin
Iron
Essential for the maturation of cells
Folic acid & Vitamin B12
Formation of blood cells
Hematopoiesis
Drugs involved in the formation of blood cells
Hematopoietic drugs
Need growth factors or stimulating factors
Hematopoietic Stem Cells (HSC)
Other term for HSC
Hemocytoblasts
Capable of producing different types of cells which are pluripotent
Hematopoietic Stem Cells (HSC)
Refers to the ability of HSCs to renew on its own
Pluripotent
Cells that arise from HSC
- Lymphoid progenitor
- Myeloid progenitor
Arise from lymphoid progenitor
Lymphoblasts
Arise from lymphoblasts
- T-lymphocytes
- B-lymphocytes
- Natural killer cells
Cells that arise from myeloid progenitor
- Erythrocyte
- Megakaryocyte
- Myeloblast
Arise from myeloblast
- Monocyte
- Neutrophil
- Basophil
- Eosinophil
Gives rise to Macrophage
Monocyte
Fights bacterial infection
Neutrophil
Carries oxygen
Erythrocyte
Fights helminthic infection
Eosinophil
Gives rise to platelets
Megakaryocyte
Forms clots to stop bleeding
Platelets
Release in response to worms and environmental threats
Basophil
Deficiency in erythrocytes
Anemia
Deficiency in platelet
Thrombocytopenia
Deficiency in neutrophil
Neutropenia
Normal color of RBCs
Normochromic
Paler than normal RBCs
Hypochromic
Normal sized RBCs
Normocytic
Smaller sized RBCs
Microcytic
Larger size RBCs
Macrocytic
Large and immature cells
Megaloblastic
Rate of cell destruction
Hemolysis
Normal range of WBCs
3,500-11,000 cells/mcL
Normal range of hematocrit for women
34.9%-44.5%
Normal range of hematocrit for men
38.8%-50.0%
Normal range of platelets count
150,000-450,000/mcL
Normal range of RBCs in women
3.9-5.1 million cells/mcL
Normal range of RBCs in men
4.3-5.7 million cells/mcL
Normal range of hemoglobin in men
13-17 g/dL
Normal range of hemoglobin in women
11.5-15.5 g/dL
5 Types of Anemia
- Sickle cell
- Iron deficiency
- Aplastic
- Thalassemia
- Vitamin Deficiency
Genetic disorder wherein the erythrocytes is shaped like crescent moon
Sickle cell
Most common type of anemia
Iron deficiency
Occurs when the body stops producing enough new blood
Aplastic
Inherited blood disorder that causes the blood to have less hemoglobin
Thalassemia
Lack of healthy blood cell caused by a deficiency in Vitamin B12 and folate
Vitamin Deficiency
3 Possible causes of Anemia
- malabsorption of RBCs
- hemolysis of RBCs
- increased demand for RBCs
Forms the nucleus of iron-porphyrin heme which together with globulin chains form hemoglobin
Iron
How is hemoglobin formed?
Fe-porphyrin heme + protein (globulin)
Indicated for the tx or prevention of IDA
Iron
Manifest as hypochromic, microcytic anemia
Iron Deficiency Anemia (IDA)
Commonly seen in infants, children during rapid growth, pregnant and lactating women and CKD patients undergoing dialysis
IDA
more absorbable source of iron in animals
heme
source of iron in plants
non-heme
Site of blood formation
bone marrow
produce the erythropoietin hormone needed for the formation of RBCs
kidneys
transported by heme carrier protein (HCP)
Heme
transported by divalent metal transporter (DMT)
Non-heme
Heme carrier protein (HCP) → Ferroportin (FP) → bloodstream
Heme Pathway
Divalent metal transporter (DMT) → Apoferritin (AF) will complex with ferrous → FP → bloodstream
Non-Heme Pathway
attach to the receptor in the bone marrow
Transferrin (Tf)
The following process occurs where?
Tf → release ferrous → mix to form hemoglobin
Bloodstream
stored in the liver
Ferritin
most efficiently absorbed iron in oral iron therapy
Ferrous (II) iron
Other types of oral iron therapy for anemia
Ferrous sulfate, Ferrous gluconate and Ferrous fumarate
About _____________________ given as ferrous salt can be absorbed
25% of oral iron
About 25% of oral iron given as ______________ can be absorbed
ferrous salt
Common ADRs of oral iron therapy
- Nausea
- Epigastric discomfort
- Abdominal cramps
- Constipation
- Diarrhea
Major side effect of iron
Gastric toxicity
Patients unable to tolerate large amount of iron may be given _______________________
lower daily dose of iron
Absorbed iron
Elemental iron
Elemental iron content of Ferrous sulfate, hydrated
65 mg
Elemental iron content of Ferrous sulfate, desiccated
65 mg
Elemental iron content of Ferrous gluconate
36 mg
Elemental iron content of Ferrous fumarate
106 mg
Tablet size of commonly used oral iron preparations (ferrous sulfate, ferrous gluconate, & ferrous fumarate)
325 mg
Usual adult dose of tx using ferrous sulfate hydrated & desiccated
2-4 tablets per day
Usual adult dose of tx using ferrous gluconate
3-4 tablets per day
Usual adult dose of tx using ferrous fumarate
2-3 tablets per day
Reserved for patients with iron deficiency who can not tolerate oral iron
Parenteral Iron
Reserved for patients with advance CKD requiring hemodialysis & treatment with erythropoietin
Parenteral iron
Reserved for patients with various post gastrectomy condition and previous small bowel resection, inflammatory bowel disease
Parenteral iron
Can produce serious dose dependent toxicity
Parenteral iron
Types of Parenteral iron
Iron Dextran, Sodium Ferric Gluconate Complex, Iron Sucrose Complex
Stable complex or ferric oxyhydroxide and dextran polymer containing 50mg elemental iron/mL of solution
Iron dextran
Iron dose is also known as _________
Elemental iron
Iron dextran is composed of?
ferric oxyhydroxide and dextran polymer
Given by deep IM or IV infusion
Iron dextran
Colloidal Iron preparation with carbohydrate polymer
Ferric carboxymaltose
Superparamagnetic iron oxide nanoparticle coated with carbohydrate that may interfere with MRI
Ferumoxytol
Only given by IV route
Sodium Ferric Gluconate Complex and Iron Sucrose Complex
Monitoring iron storage level to avoid serious toxicity is done for _____________________
patients treated chronically parenteral iron
What must be done for patients treated with chronically parenteral iron?
Monitor iron storage level
Why must iron storage level be monitored for patients treated with chronically parenteral iron?
To avoid serious toxicity
Almost exclusive in young children
Acute Iron Toxicity
10 tablets can be lethal in young children
Acute Iron Toxicity
Children poisoned with oral iron may experience
Necrotizing gastroenteritis with vomiting, abdominal pain, bloody diarrhea
Flush unabsorbed pills
Whole bowel Irrigation
Antidote for iron toxicity
Deferoxamine
Potent chelating agent in which excess iron will combine with this drug and is excreted through urine
Deferoxamine
Hemochromatosis
Chronic Iron Toxicity
Excess iron may be deposited in the heart, liver, pancreas and other organs
Chronic Iron Toxicity
Most commonly occur in patients with inherited hemochromatosis
Chronic Iron Toxicity
Iron chelating therapy with parenteral deferoxamine or oral iron chelator is less efficient
Chronic Iron Toxicity
Antidote for Chronic Iron Toxicity
Phlebotomy
serves as a cofactor for several essential biochemical reaction
Cobalamin or Vit. B12
Vit. B12 deficiency leads to
- Megaloblastic anemia
- Gastrointestinal symptoms
- Neurologic abnormalities
abnormal sensation, cause ataxia, weakness and spasticity
Paresthesia
disorder that affect coordination and balance
Ataxia
Active forms of the vitamin B12 in humans
Deoxyadenosylcobalamin and Methylcobalamin
Naturally-occuring forms of vitamin B12
Deoxyadenosylcobalamin and Methylcobalamin
Available for therapeutic use
Cyanocobalamin and Hydroxycobalamin
Synthetic forms of vitamin B12
Cyanocobalamin and Hydroxycobalamin
Stable and most effective form of vit. B12 but must be converted to the active form
Cyanocobalamin
Ultimate source of Vit. B12
microbial synthesis
needs to bind with intrinsic factor (secreted by GI) to be absorbed
Extrinsic factor
Average American Diet of Vit. B12
5-30 mcg of Vit. B12
Absorbed Vit. B12
1-5 mcg
Recommended daily allowance of Vit. B12
2-2.4 mcg
released by salivary glands to separate vit. B12 and dietary protein
Haptocorrin
a protein released by the stomach to bind with vit. B12, aiding its absorption
Intrinsic factor
Illium contains this receptor which specializes in the absorption of vit. B12 resulting in the separation of vit. B12 and IF
Cubam receptor
Transport vit. B12 to bloodstream of the cell
Transcobalamin
2 essential enzymatic reaction in humans associated with vit. B12
- Methyltransfer from N5-methyltetrahydrofolate
to homocysteine - Isomerization of L-Methylmalonyl CoA
precursor of different biochemical reactions
Methyltransfer from N5-methyltetrahydrofolate
to homocysteine
Manifestation of Vit B12 deficiency
- Megaloblastic, macrocytic anemia
- Often associated mild or moderate leukopenia or thrombocytopenia
- Neurological syndrome
low leukocytes
leukopenia
Correction of vit. B12 deficiency _________________________ of neurologic disease it may not fully reverse neurologic symptoms
arrest the progression
Correction of vit. B12 deficiency arrest the progression of neurologic disease it ____________________________ neurologic symptoms
may not fully reverse
measures the absorption & urinary excretion of radioactively labeled vit. B12
Schilling test
Defective secretion of intrinsic factor by the gastric mucosal cell
Pernicious anemia
available as cyanocobalamin or hydroxycyanocobalamin
Vitamin B12 parenteral injection
Initial dose of Vitamin B12 parenteral injection
100 – 1000mcg vit B12 IM daily or every other day for 1 – 2 weeks
Maintenance dose of Vitamin B12 parenteral injection
100 – 1000mcg IM once a month for life
Very important for pregnancy as it is needed for the baby’s brain and spinal cord development
Folic acid
result of inadequate folic acid during pregnancy
Neural tube defect
required for essential biochemical reaction that provides precursors for the synthesis of amino acid, purine and DNA
reduced form of folic acid
cause of congenital malformation in newborns
Folate deficiency
Play an important role in vascular disease
Folic acid
undergoes reduction, catalyzed by the enzyme dihydrofolate reductase to give dihydrofolic acid
Folic acid
Enzyme that catalyzes folic acid, giving rise to dihydrofolic acid
dihydrofolate reductase
Average American Folic Acid diet
500-700 mcg folate daily
Folate absorbed
50-200 mcg
Folate absorbed by pregnant women
300-400 mcg daily
excreted in urine and stool
Folic acid
readily and completely absorbed in the proximal jejunum
Unaltered folic acid
Folate deficiency results in
Megaloblastic anemia
Patients with alcohol dependence and patients with liver disease can develop
folic acid deficiency
Folic acid deficiency can develop in pregnant women and patients with ________________________
hemolytic anemia
Folic acid deficiency can also develop in patients who require __________________
renal dialysis
Dose and frequency sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients
1 mg folic acid orally daily
Glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow
Hematopoietic Growth Factor
Stimulate the growth of colonies of various bone marrow progenitor cells in vitro
Colony Stimulating Factor (CSF)
for neutrophil, basophil, and eosinophil
Granulocyte colony stimulating factor (G-CSF)
typically given for neutrophil deficiency
Granulocyte colony stimulating factor (G-CSF)
First human hematopoietic growth factor to be isolated
Erythropoietin
Originally purified from the urine of patients with severe anemia
Erythropoietin
Produced in a mammalian cell expression system
Recombinant human erythropoietin (rHuEPO, Epoetin Alpha)
Half-life after IV admin of rHuEPO in px with chronic kidney failure
4-13 hours
Not cleared by dialysis
Recombinant human erythropoietin (rHuEPO, Epoetin Alpha)
Administered thrice a week
Recombinant human erythropoietin (rHuEPO, Epoetin Alpha)
Given once a week
Darbepoetin alpha
Modified form of erythropoietin that is more heavily glycosylated as a result of changes in amino acid
Darbepoetin alpha
Has two-fold to three-fold longer half-life than epoetin alpha
Darbepoetin alpha
Isoform of erythropoietin covalently attached to a longer polyethylene glycol polymer
Methoxy polyethylene glycol – epoetin
Long lived recombinant product is administered as a single intravenous or subcutaneous dose at 2 week or monthly intervals
Methoxy polyethylene glycol – epoetin
Stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptor on the RBC progenitor
Erythropoietin
Induces the release of reticulocyte from the bone marrow
Erythropoietin
Immature RBC from the bone marrow
reticulocyte
primarily produced in the kidney
Endogenous erythropoietin
In response to _______________, more erythropoietin is produced through an increased rate of transcription of the erythropoietin gene
tissue hypoxia
Low hematocrit, low hemoglobin, and high erythropoietic results in
Anemia
consistently improve the hematocrit and hemoglobin level, often the need for transfusion
Erythropoiesis – stimulating agents (ESA)
Used routinely in patients with anemia secondary to CKD
Erythropoietin-Stimulating agent
T/F: Erythropoietin-Stimulating agent dose should not exceed 10-12 g/dL
True
T/F: Erythropoietin-Stimulating agent increase the need for RBC transfusion in px undergoing myelosuppressive cancer chemotherapy who have hemoglobin of less than 5g/dL.
False; reduce the need…hemoglobin of less than 10g/dL
Most commonly observed HTN and thrombic complication
Erythropoietin-Stimulating agent toxicity
Myeloid Growth Factor drugs
- Recombinant Human G-CSF (rHuG-CSF; Filgrastim)
- Recombinant human GM-CSF (rHuGM-CSF; Sargramostim)
- Pegfilgrastim
- Lenograstim
used for patients with neutropenia
Recombinant Human G-CSF (rHuG-CSF; Filgrastim)
Produced by bacterial expression system
Recombinant Human G-CSF (rHuG-CSF; Filgrastim)
Non-glycosylated peptide of 175 amino acid with a molecular weight of 18KDa
Recombinant Human G-CSF (rHuG-CSF; Filgrastim)
Stimulates the proliferation and differentiation of progenitor already committed to the neutrophil lineage
Recombinant Human G-CSF (rHuG-CSF; Filgrastim)
Activates the phagocytic activity of mature neutrophil and prolongs their survival in the circulation
Recombinant Human G-CSF (rHuG-CSF; Filgrastim)
Recombinant Human G-CSF (rHuG-CSF; Filgrastim) Dose
5 mcg/kg/day
Recombinant Human G-CSF (rHuG-CSF; Filgrastim) toxicity
Minimal but may cause bone pain
Given for cancer related disease(s) before chemotherapy
Recombinant Human G-CSF (rHuG-CSF; Filgrastim)
Recombinant human GM-CSF (rHuGM-CSF; Sargramostim) Half-life of IV or SC
2-7 hours
Has broader biological activity that G-CSF
Recombinant human GM-CSF (rHuGM-CSF; Sargramostim)
Stimulates the function of mature neutrophils
Recombinant human GM-CSF (rHuGM-CSF; Sargramostim)
Less efficacious and more toxic than G-CSF
Recombinant human GM-CSF (rHuGM-CSF; Sargramostim)
Reduces the duration of neutropenia after cytotoxic chemotherapy
Recombinant human GM-CSF (rHuGM-CSF; Sargramostim)
Recombinant human GM-CSF (rHuGM-CSF; Sargramostim) Dose
250 mcg/m2/day
May cause anaphylactic shock, arthralgias and capillary leak (causing peripheral edema)
Recombinant human GM-CSF (rHuGM-CSF; Sargramostim)
Recombinant human GM-CSF (rHuGM-CSF; Sargramostim) at high doses
Severe effect
Covalent conjunction product of filgrastim and a form of polyethylene glycol
Pegfilgrastim
longer serum half-life than recombinant G-CSF
Pegfilgrastim
Can be injected once per myelosuppressive chemotherapy cycle instead of daily for several days
Pegfilgrastim
Alternative for G-CSF
Pegfilgrastim
for prevention of chemo induced febrile neutropenia
Pegfilgrastim
May shorten the period of severe neutropenia slightly more than G-CSF
Pegfilgrastim
Pegfilgrastim Dose
Single dose of 6 mg
Glycosylated form of recombinant G-CSF
Lenograstim
For patients with thrombocytopenia
Megakaryocyte Growth Factor
Commonly used to treat thrombocytopenia
Platelet transfusion
Thrombopoietin (TPO) and Interleukin-11
Megakaryocyte Growth Factor
Produced fibroblast and stromal cell of the bone marrow
Interleukin - 11
Acts through a specific cell surface cytokine receptor to stimulate the growth of multiple lymphoid and myeloid cell
Interleukin - 11
Acts synergistically with other growth factors to stimulate growth and proliferation of primitive megakaryocyte progenitor
Interleukin - 11
Half-life of Interleukin - 11 when administered SQ
7-8 hours
for secondary prevention of thrombocytopenia
Interleukin - 11
Reduces the number of platelet transfusion required
Interleukin - 11
Interleukin - 11 Dose
50 mcg/kg/day
Starts 6-24 hours after completion of chemo & continued for 14-21 days
Interleukin - 11
Recombinant form of IL-11
Oprelvekin
Produced by expression of E. coli
Oprelvekin
Recombinant thrombopoietin
Romiplostim
Peptide covalently linked to antibody fragment which extends the peptides T1/2
Romiplostim
After SQ, Romiplostim is eliminated by ___________________
reticuloendothelial system
Average half-life of Romiplostim SQ
3-4 days
Relationship of Romiplostim half-life and serum platelet count
inversely related
In patients with thrombocytopenia, Romiplostim has a _____________ (longer/shorter) half-life
longer
only oral preparation of Megakaryocyte Growth Factor
Eltrombopag
For chronic immune thrombocytopenia and thrombocytopenia in patients with Hepa C
Eltrombopag
Eltrombopag mode of administration
Oral
Eltrombopag half-life
26-35 hours
Eltrombopag peaks
2-6 hours
Potentially hepatotoxic
Eltrombopag
Increases the blast count and risk of progression to acute myeloid leukemia
Romiplostim
Increase risk of clot formation
Romiplostim
Recombinant G-CSF
Filgrastim
Recombinant GM-CSF
Sargramostim
Recombinant thrombopoietin
Romiplostim
Thrombopoietin Agonist
Eltrombopag
Recombinant human Erythropoietin
Epoeitin alpha
Epoeitin alpha Route of Admin
IV
Eltrombopag Route of Admin
Oral
Sargramostim Route of Admin
IV or SC
Filgrastim Route of Admin
IV or SC
Romiplostim Route of Admin
SC
Epoetin alpha Use
Anemia
Eltrombopag Use
Thrombocytopenia
Sargramostim Use
Neutropenia
Filgrastim Use
Neutropenia
Romiplostim
Thrombocytopenia
