AGENTS USED IN CYTOPENIAS; HEMATOPOIETIC GROWTH FACTORS

Subclass Drug Mechanism of Action Indication Kinetics Toxicity

IRON Ferrous sulfate Required for heme biosynthesis Hypochromic, microcytic anemia (IDA) Absorption: Acute
Ferrous gluconate and heme-containing proteins Duodenum and Proximal jejunum - Young children
Ferrous fumarate (myoglobin and hemoglobin) ***Blood loss most common cause of iron Increase 1 2 mg/d in menstruating - Accidental ingestion
deficiency in adults women - Necrotizing gastro-enteritis,
Increase 3 4 mg/d in pregnant women bloody diarrhea, abdominal
pain, lethargy, shock, and
Transport dyspnea
Transferrin B globulin that can bind 2 Fe3+ - Antidote: Whole bowel
Fe3+ transported by DMT1 into cytoplasm irrigation and DEFEROXAMINE
Increased erythropoiesis = increase in Chronic
transferrin receptors = decrease hepatic - Hemochromatosis
hepcidin release - Damage to Heart, Liver, &
Increased serum transferrin = iron Pancreas
depletion and IDA Antidote:
- Deferoxamine (IV)
Storage - Deferasirox (PO)
Site: intestinal mucosal cells
Iron dextran 50 mg of elemental iron per mL of solution FERRITIN in macrophages: Headache
IV eliminates local pain - Liver Lightheadedness
Unable to tolerate oral iron therapy - Speen Fever
Extensive chronic anemia that cannot be - Bone Arthralgias
maintained by oral iron alone. - Parenchymal liver cells N&V
Hepcidin regulation of FERROPORTIN Back pain
activity = controls mobilization of iron from Flushing
macrophages and hepatocytes Uricaria
Low hepcidin = iron release from storage Bronchospasm
sites; high hepcidin = inhibit iron release PAIN
HYPERSENSITIVITY REACTIONS
Elimination
Sodium ferric gluconate Alternative parenteral iron preparations No mechanism of excretion other than cell Ferumoxytol may interfere
complex Ferric carboxymaltose and blood loss with MRI
Iron-sucrose complex - Colloid w/in a CHO polymer Less likely to cause
Ferric carboxymaltose Ferumoxytol hypersensitivity reactions
Ferumoxytol - Supermagnetic iron oxide nano-particle
coated with carbohydrate

IRON Deferoxamine Chelation of excess iron Acute or chronic iron toxicity IV Rapid IV administration-
CHELATORS Preferred route of administration: IM or SC hypotension

Deferasirox Chronic Iron toxicity ORAL Long term use:

Hemochromatosis Neurotoxicity
Increased susceptibility to
certain infections
 AGENTS USED IN CYTOPENIAS; HEMATOPOIETIC GROWTH FACTORS
Subclass Drug Mechanism of Action
VITAMIN B12 Cyanocobalamin COFACTOR required for
Hydroxycobalamin - essential enzymatic reactions
preferred that:
- Form tetrahydrofolate
- Convert homocysteine to
methionine
- Metabolize L-methylmalonyl
CoA
VITAMIN B9 Pletroylglutamic Acid Precursor of an essential donor
FOLIC ACID Folacin of methyl groups used for
synthesis of amino acids,
purines, and deoxynucleotide
ERYTHROPOIETIN Epoetin alfa Agonist of erythropoietin
Darbepoetin alfa receptors stimulating erythroid
MethoxyPEG epoietin proliferation and differentiation
beta and induce release of
reticulocytes from bone marrow
**INVERSE relationship between
hematocrit/hemoglobin and EPO
(except: Chronic Renal Failure)
Indication
MEGALOBLASTIC, (Macrocytic) ANEMIA
Most characteristic clinical manifestation
of deficiency (basis of PERNICEOUS
ANEMIA)
Hypercellular marrow
Accumulation of megaloblastic erythroid
and other precursor cells
Must be determined whether B12 or
Folic Acid Deficiency
Schillings Test: B12 absorption
PERNICIOUS ANEMIA (IV) one of the most
common causes of deficiency
Pernicious deficient B12
Megaloblastic
Defective secretion of intrinsic factor
Schilling Test: diminished absorption
MALABSORPTION SYNDROMES (IV)
Neurologic abnormalities: every 1-2 weeks
for 6 months (maintenance)
Deficiency
Caused by inadequate dietary intake
Manifesting as MEGALOBLASTIC ANEMIA
Dimisnished hepatic storage (liver
disease and alcohol dependence)
Pregnant and Hemolytic Anemia patients
have increased requirement
Renal dialysis: removed from plasma
Drugs: Methotrexate & Trimethoprim
Prevention of Neural Tube Defects
1mg PO daily
Prevention of need for transfusion
Anemia
Chronic Renal Failure
HIV
Cancer
Prematurity
EPO levels:
Nonanemic: < 20 IU/L
Moderately severe: 100 500 IU/L
Severe: Thousands of IU/L
Kinetics Toxicity
PARENTERAL malabsorption syndromes No associated toxicity
Primary storage site: LIVER
Storage pool: 3000 5000 mcg
Normal daily requirements: 2mcg
Total depletion and development of
megaloblastic anemia (5 years)
INTRINSIC FACTOR
- Complexes with B12 (absorption)
- Secreted by: PARIETAL CELLS
- B12 IF complex site of absorption:
DISTAL ILEUM
Deficiency usually from malabsorption
- Lack of intrinsic factor
- Loss or malfunction of absorptive
mechanism in distal ileum
- Nutritional: strict vegetarians (rare)
Absorption binding to specialized
glycoproteins (Cobalamin I, II, and III)
Excess is stored in LIVER
Normal: 5 20 mg stored in tissues Large amounts can mask vitamin
Pregnant women: absorb 300 400 mg B12 deficiency
daily
Excretion: urine and stool
Destroyed by catabolism fall within a few
days in diminished intake
LOW body stores and HIGH requirement =
deficiency and megaloblastic anemia (1 6
months)
Absorption: Proximal jejunum
Intravenous or subcutaneous Hypertension
1 3x per week Thrombotic complications
Darbepoetin long acting glycosylated Pure red cell aplasia (rare)
form administered weekly REDUCE CV EVENTS:
Methoxy PEG epoetin beta long acting Hemoglobin < 12g/dL
administered 1 2x per month
 AGENTS USED IN CYTOPENIAS; HEMATOPOIETIC GROWTH FACTORS
Subclass Drug Mechanism of Action Indication Kinetics Toxicity
MYELOID Filgrastim (rHuG-CSF) Stimulate G-CSF receptors on Cancer chemotherapy-induced neutropenia Pegfilgrastim covalent conjugation Bone pain
GROWTH Sargramostim (rHuGM- mature neutrophils and Congenital neutropenia product of filgrastim; form of PEG with Splenic rupture (rare)
FACTORS CSF) progenitors stimulating Cyclic neutropenia much longer serum half life; can be
Pegfilgrastim proliferation and differentiation Myelodysplasia injected once per myelosuppressive
Lenograstim Aplastic anemia chemotherapy cycle
Secondary prevention of neutropenia Lenograstim glycosylated form of G-CSF
Cytotoxic chemotherapy
Mobilization of peripheral blood cells (stem
cell transplantation)

MEGAKARYOCYTE Thrombopoietin Recombinant from of Romiplostim: Oprelvekin Fatigue

GROWTH IL-11 endogenous cytokine Chronic immune thrombocytopenia Recombinant IL-11 (E. coli) Headache
FACTORS Oprelvekin stimulation of IL-11 receptors (inadequate response to steroids, IVIg, Half life: 7 8 hrs (SC) Dizziness
Romiplostim Splenectomy) Anemia
Eltrombopag Romiplostim (SC) Fluid accumulation in lungs
Eltrombopag Extends the peptides half life Transient atrial arrhythmias
Chronic Immune thrombocytopenia Elimination: reticulo-endothelial
Inadequate response to other therapies system
(corticosteroids, IVIg, Splenectomy) Half life: 3 4 days
Hepatitis C patient with Half life is inverse with serum
thrombocytopenia to allow initiation of platelet count
interferon therapy Longer half life Thrombocytopenia
Shorter half life normal PLT

SECONDARY PREVENTION: Eltrombopag

Thrombocytopenia (Cytotoxic chemotherapy Orally active
in nonmyeloid CA) Small nonpeptide TPO agonist
Peak: 2 6 hrs
Half life: 26 35 hours
Excretion: feces