Pharmacology
Agents Used in Anemias (katzung)
Agents Used in Anemias; Hematopoietic Growth Factors
Hematopoiesis
 The production from undifferentiated stem cells of circulating
erythrocytes, platelets, and leukocytes.
 Resides primarily in the bone marrow in adults
 Requires a constant supply of three essential nutrients –
iron, vitamin B12 and folic acid – as well as the presence of
hematopoietic growth factors, proteins that regulate the
proliferation and differentiation of hematopoietic cells
 Inadequate supplies of either the essential nutrients or the
growth factors result in deficiency of functional blood cells:
Anemia, Thrombocytopenia and Neutropenia.
AGENTS USED IN ANEMIAS
IRON
 Iron deficiency is the most common cause of chronic anemia.
 Leads to pallor, fatigue, dizziness, exertional dyspnea, and
other generalized symptoms of tissue hypoxia.
 The cardiovascular adaptations to chronic anemia-
tachycardia, increased cardiac output, vasodilation-can
worsen the condition of patients with underlying
cardiovascular disease.
 In the absence of adequate iron, small erythrocytes with
insufficient hemoglobin are formed, giving rise to microcytic
hypochromic anemia.
PHARMACOKINETICS
A. Absorption
 Duodenum and proximal jejunum
 Heme iron in meat hemoglobin and myoglobin can be
absorbed intact
 Nonheme iron and iron in inorganic iron salts and
complexes must be reduced to ferrous iron (Fe2+) before
it can be absorbed
 Excess iron can be stored in mucosal cell as ferritin, a
water soluble complex consisting of a core of ferric
hydroxide covered by a shell of a specialized storage
protein called apoferritin.
B. Transport
 Iron is transported in the plasma bound to transferrin, a
β-globulin that specifically binds two molecules of ferrous
iron
C. Storage
 Iron is stored, primarily as ferritin, in intestinal mucosal
cells, macrophages in the liver, spleen, and bone, and in
parenchy mal liver cells
D. Elimination
 ≤1mg/day (feces, bile, sweat, urine)
CLINICAL PHARMACOLOGY
A. Indications for the Use of Iron
 Treatment or prevention of iron deficiency anemia
 Increased iron requirements:
o Infants, especially premature infants; children during
rapid growth periods; pregnant and lactating women;
and patients with chronic kidney disease
 Inadequate iron absorption
o Post-gastrectomy; and severe small bowel disease
Elyu, Brim & Virns
19 February 08
B. Treatment
 Oral Iron Therapy
o Ferrous sulfate, ferrous gluconate, and ferrous
fumarate
o 200-400 mg of elemental iron daily and should be
continued for 3-6 months after correction of iron loss
o ADR: GI sx
 Parenteral Iron Therapy
o Should be reserved for patients with documented iron
deficiency who are unable to tolerate or absorb oral
iron and for patients with extensive chronic blood loss
who cannot be maintained with oral iron alone.
- postgastrectomy conditions and previous small
bowel resection, IBD involving the proximal
small bowel, malabsorption syndromes, and
advanced chronic renal disease including
hemodialysis and treatment with erythropoietin.
o Iron dextran
- A stable complex of ferric hydroxide and low-
molecular-weight dextran containing 50 mg of
elemental iron per mL of solution.
- IM or IV. IV most common.
- ADR: hypersensitivity and anaphylaxis
- A small test dose of iron dextran should always
be given before full IM or IV doses are given
o Iron-sucrose complex and Iron sodium gluconate
complex
- IV
- Less likely to cause hypersensitivity reactions
o Periodically monitor iron storage levels to avoid the
serious toxicity associated with iron overload.
o Iron stores can be estimated on the basis of serum
concentrations of ferritin and the transferrin
saturation, which is the ratio of the total serum iron
concentration to the total iron-binding capacity (TIBC).
CLINICAL TOXICITY
A. Acute Iron Toxicity
 Seen almost exclusively in young children who
accidentally ingest iron tablets
 Necrotizing gastroenteritis, with vomiting, abdominal
pain, and bloody diarrhea followed by shock, lethargy,
and dyspnea.
 Tx: Whole bowel irrigation
 Deferoxamine – a potent iron-chelating compound, can
be given systemically to bind iron that has already been
absorbed and to promote its excretion in urine and feces
B. Chronic Iron Toxicity
 Also known as hemochromatosis
 Results when excess iron is deposited in the heart,
liver, pancreas, and other organs. It
 Most commonly occurs 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
(eg, patients with thalassemia major).
 Chronic iron overload in the absence of anemia is most
efficiently treated by intermittent phlebotomy.
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 Pharmacology – Agents Used in Anemias; Hematopoietic Growth Factors by Katzung
 Deferasirox – an oral iron chelator approved for
treatment of iron overload.
VITAMIN B12
 A cofactor for several essential biochemical reactions in
humans.
 Deficiency leads to anemia, gastrointestinal symptoms, and
neurologic abnormalities.
 Consists of a porphyrin-like ring with a central cobalt atom
attached to a nucleotide
 Deoxyadenosyl cobalamin and methylcobalamin are the
active forms of the vitamin in humans.
 Cyanocobalamin and hydroxocobalamin and other
cobalamins found in food sources are converted to the active
forms.
 The ultimate source of vita min BI2 is from microbially derived
vitamin B12 in meat (especially liver), eggs, and dairy
products.
 Vitamin B12 is sometimes called extrinsic factor.
PHARMACOKINETICS
 Stored primarily in the liver with a total storage pool of 3000-
5000 mcg.
 Only trace amounts are normally lost in urine and stool.
 Normal daily requirements are only about 2 mcg
 Vitamin Bl2 in physiologic amounts is absorbed in the distal
ileum only after it complexes with intrinsic factor
 Vitamin Bl2 deficiency in humans most often results from
malabsorption of vitamin Bl2 due either to lack of intrinsic
factor or to loss or malfunction of the specific absorptive
mechanism in the distal ileum.
 Nutritional deficiency is rare but may be seen in strict
vegetarians after many years without meat, eggs, or dairy
products.
 Once absorbed, vit. BI2 is transported to the various cells of
the body bound to a plasma glycoprotein, transcobalamin II.
PHARMACODYNAMICS
• Two essential enzymatic reactions in humans require vitamin
Bl2 :
1. Methylcobalamin serves as an intermediate in the
transfer of a methyl group from N5
-methyltetrahydrofolate to homocysteine, forming
methionine.
- Without vitamin Bl2 conversion of the major dietary
and storage folate, N5-methyltetrahydro folate, to
tetrahydrofolate, the precursor of folate cofactors,
cannot occur.
- The depletion of tetrahydrofolate prevents synthesis
of adequate supplies of the deoxythymidylate
(dTMP) and purines required for DNA synthesis in
rapidly dividing cells.
- The accumulation of folate as N5-methyltetrahydro
folate and the associated depletion of
tetrahydrofolate cofactors in vitamin Bl2 deficiency
have been referred to as the "methylfolate trap."
2. Isomerization of methylmalonyl-CoA to succinyl CoA by
the enzyme methylmalonyl-CoA mutase
- In vitamin BI2 deficiency, this conversion cannot take
place, and the substrate, methylmalonyl. CoA,
accumulates.
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CLINICAL PHARMACOLOGY
 Vitamin Bl2 is used to treat or prevent deficiency
 Megaloblastic Anemia
o The most characteristic clinical manifestation of vitamin
Bl2 deficiency
o Clinical findings: macrocytic anemia, often with
associated mild or moderate leukopenia or
thrombocytopenia (or both), and a characteristic
hypercellular bone marrow with an accumulation of
megaloblastic erythroid and other precursor cells
o The neurologic syndrome associated with vitamin B12
deficiency usually begins with paresthesias and
weakness in peripheral nerves and progresses to
spasticity, ataxia, and other central nervous system
dysfunctions.
 Schilling test, which measures absorption and urinary
excretion of radioactively labeled vitamin B12 can be used to
further define the mechanism of vitamin B12 malabsorption
when this is found to be the cause of the megaloblastic
anemia.
 Most common causes of vitamin B12 deficiency: pernicious
anemia, partial or total gastrectomy, and conditions that affect
the distal ileum, such as malabsorption syndromes,
inflammatory bowel disease, or small bowel resection.
 Pernicious anemia results from defective secretion of
intrinsic factor by the gastric mucosal cells. Patients with
pernicious anemia have gastric atrophy and fail to secrete
intrinsic factor (as well as hydrochloric acid).
 Other rare causes of vitamin Bl2 deficiency include bacterial
over growth of the small bowel, chronic pancreatitis, and
thyroid disease.
 Rare cases of vitamin Bl2 deficiency in children have been
found to be secondary to congenital deficiency of intrinsic
factor and congenital selective vitamin Bl2 malabsorption due
to defects of the receptor sites in the distal ileum.
TREATMENT
 Parenteral injections of Vitamin B12
 The underlying disease should be treated after initial
treatment
 Vitamin Bl2 for parenteral injection is available as
cyanocobalamin or hydroxocobalamin.
o Hydroxocobalamin is preferred because it is more
highly protein-bound and therefore remains longer in the
circulation.
 Initial therapy should consist of 100-1000 mcg of vitamin B12
intramuscularly daily or every other day for 1-2 weeks to
replenish body stores.
 Maintenance therapy consists of 100-1000 mcg
intramuscularly once a month for life.
 If neurologic abnormalities are present, maintenance therapy
injections should be given every 1-2 weeks for 6 months
before switching to monthly injections.
 Oral doses of 1000 mcg of vitamin B 12 daily are usually
sufficient to treat patients with pernicious anemia who
refuse or cannot tolerate the injections.
o After pernicious anemia is in remission following
parenteral vitamin B12 therapy, the vitamin can be
administered intranasally as a spray or gel.
 Pharmacology – Agents Used in Anemias; Hematopoietic Growth Factors by Katzung Page 3 of 4

o Granulocyte-macrophage colony stimulating factor

● Megakaryocyte Growth Factors
o Iinterleukin-11

FOLIC ACID
● Reduced forms are required for essential biochemical
reaction ERYTHROPOIETIN
● Provides precursor for the synthesis of amino acids, purines ● The first human hematopoietic growth factor
& DNA ● Serum half life: 4 – 13 hrs in pts w/ chronic renal failure
● Folate deficiency is common ● Not cleared by dialysis
● Darbepoietin alfa
CHEMISTRY o Glycosylated form of erythropoietin
● Heterocycle (pteridine) + p-aminobenzoic acid + glutamic o Twofold to threefold longer half-life
acid = Folic acid (pteroylglutamic acid)
● It can undergo reduction through dihydrofolate reductase PHARMACODYNAMICS
(“folate reductase”) ● It stimulates erythroid proliferation and differentiation
● Erythropoietin receptor
PHARMACOKINETICS o Member of JAK/STAT superfamily
● Average diet : 500 – 700 mcg ● It also induces release of reticulocytes from the bone
● Absorbed : 50 – 200 mcg marrow
● Pregnant (absorption) : 300 – 400 mcg ● Kidney produces endogenous erythropoietin
● Folate stored in the liver and tissues : 5 – 20 mg ● Erythropoietin production
● Sources : yeast, liver, kidney, green veggies o Direct relationship w/ hypoxia
● Excretion : Urine and stool o Inverse relationship w/ hematocrit level
● Absorption : Proximal jejunum o Inverse relationship w/ hemoglobin level
o Exception in inverse relationship: anemia of CRF
PHARMACODYNAMICS
● Tetrahydrofolate cofactors participate in one-carbon transfer CLINICAL PHARMACOLOGY
reaction which produces the dTMP needed for DNA synthesis ● Useful in the treatment of anemia due to:
● Other cofactors is required for the vitamin B12-dependent o Chronic renal failure
reaction that generates methionine from homocysteine
o Primary bone marrow disorders
● Other cofactors donate 1-carbon units in de novo synthesis
 e.g. aplastic anemia
of essential purines
o Secondary anemia
CLINICAL PHARMACOLOGY o Zidovudine induced (in HIV)
● Folate deficiency ● It is also useful to accelerate erythropoiesis after
o Causes: phlebotomies
 Inadequate dietary intake (most common) ● Effective for the treatment of iron overload
(hemochromatosis)
 Alcohol dependence
● One of the drugs banned by the international olympic
 Liver disease
committee
 Pregnancy
− Causes neural tube defects (e.g. spina bifida)
 Pts w/ hemolytic anemia
MYELOID GROWTH FACTORS
 Pts w/ malabsorption syndromes
● Recombinant human G-CSF (rHuG-CSF; filgrastim)
 Pts undergoing renal dialysis
o Produced in bacterial expression system
 Drug(methotrexate, trimethoprim, pyrimethamine,
● Recombinant human GM-CSF (rHuGM-CSF; sargramostim)
phenytoin)
o Produced in yeast expression system
o Results in megaloblastic anemia
● Pegfilgrastim
o Does not cause neurologic syndrome (seen in vit B12
o A covalent conjugation product of filgrastim and a form
deficiency)
of polyethylene glycol
o 1 mg oral dose daily is sufficient to treat effects of
o Has a much longer half-life than recombinant G-CSF
folate deficiency
● RBC folate level are of greater diagnostic value than serum
PHARMACODYNAMICS
levels
● Myeloid growthfactors stimulates proliferation and
differentiation
● Receptors are members of JAK/STAT superfamily
HEMATOPOIETIC GROWTH FACTORS
● G-CSF
● Glycoprotein hormones
o It also activates phagocytic activity of mature
● Regulates the proliferation and differentiation of
neutrophils and prolongs their survival
hematopoietic progenitor cells in the bone marrow
o It also mobilizes stem cells
● Colony-stimulating factors
● GM-CSF
o 1st growth factors to be identified o has a broader biologic actions than G-CSF
o Stimulates the growth of colonies of progenitor cells in o Stimulates proliferation and differentiation of early and
vitro late granulocytic progenitor cells
o It also stimulates the function of mature neutrophils
CLINICALLY USED HEMATOPOIETIC GROWTH FACTORS
o Stimulates T-celll proliferation together with IL-2
● Erythropoietin
o A local active factor at the site of inflammation
● Myeloid Growth Factors
o Granulocyte colony-stimulating factor o It mobilizes peripheral blood stem cells
 Pharmacology – Agents Used in Anemias; Hematopoietic Growth Factors by Katzung Page 4 of 4

“Rivers know this: there is no hurry. We shall get there some day.”
CLINICAL PHARMACOLOGY
Cancer Chemotherapy-Induced Neutropenia
● G-CSF
o Used as treatment of chemotherapy-induced
neutropenia
o Used for febrile neutropenia
o Pegfilgrastim can used as an alternative treatment for
G-CSF for the prevention of febrile neutropenia
● GM-CSF
o Used as treatment of chemotherapy-induced
neutropenia
o Can not be used for febrile neutropenia because it can
induce fever
● Both G-CSF and GM-CSF can be used for the treatment of
pts with AML

Other Applications
● Both are effective in treating neutropenia associated with
congenital neutropenia, cyclic neuropenia, myelodysplasia,
and aplastic anemia
● Both plays an important role in autologous stem cell
transplantation
● The most important role of myeloid growth factors in
transplantation is for the mobilization of peripheral blood
stem cells (PBCs)

TOXICITY
● G-CSF can cause bone pain
● GM-CSF can cause more severe side effects
o Fever, malaise, arthralgias, myalgias, capillary leak
sundrome (peripheral edema and pleural or pericardial
effusion)
● Allergic rxnx may occur
● Splenic rupture is rare but can be a serious complication of
G-CSF

MEGAKARYOCYTE GROWTH FACTORS

CHEMISTRY AND PHARMACOKINETICS
● Il-11
o PRODUCED BY FIBROBLASTS AND STROMAL CELLS IN
THE BONE MARROW
● Oprelvekin
o Recombinant form of Il-11
● Thrombopoietin
o Hepatocytes are the major source of human
thrombopoietin

PHARMACOKINETICS
● Il-11 acts through specific cell surface cytokine receptor
● Stimulates the growth of multiple lymphoid and myeloid
cells
● It increases the number of peripheral platelets and
neutrophils
● Stimulates the growth of primitive megakaryocytic
progenitors
● Stimulates mature megakaryocytes

CLINICAL PHARMACOLOGY
● Used as treatment of thrombocytopenia

TOXICITY
● Most common adverse effects: fatigue, headache, dizziness,
cardiovascular effect (anemia due to hemodilution, dyspnea
due to fluid accumulation in the lungs & transient atrial
arrhythmias), and hypokalemia – all reversible