19 February 08
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
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