Download Hematopoietic drugs

HEMATOPOIETIC DRUGS
Diana Pendicheva1, Galya Stavreva1, Ivan Lambev2
1Faculty of Medicine, Medical University – Pleven
2Faculty of Medicine, Medical University – Sofia
Introduction
Hematopoiesis (formation of blood) is a complex process of proliferation, differentiation, and
maturation of cellular components of blood (erythrocytes, leucocytes and platelets) from the bone
marrow stem cells. It is regulated by balanced interaction between endogenously derived
hematopoietic growth factors and exogenously supplied essential nutrients (hematinics). Inadequate
supply of either the growth factors or the hematinics results in deficiency of normal blood cells
which is manifested as anemia, thrombocytopenia or neutropenia.
 Hematopoietic growth factors are glycoproteins that control and maintain the production
of various blood cell lineages
from
pluripotent
hematopoietic stem cells and
multipotent progenitors. A
number of these factors (also
called cytokines) have been
cloned and produced for
clinical use: Erythropoietin;
Myeloid Growth Factors
(Colony Stimulating Factors)
–
Granulocyte-Macrophage
Colony Stimulating Factor
(GM-CSF) and Granulocyte
Colony Stimulating Factor
(G-CSF); and Megacariocyte
(Thrombopoietic)
Growth
factors – Interleukin-11 and
Trombopoietin.
 Hematincs (iron, vitamin B12
and folic acid) and accessory
hematinics
(vitamin
C,
riboflavin, pyridoxine and
certain minerals like Cu, Co
and Mn) are also necessary
for blood cell maturation and physiological turnover under basal conditions and on demand.
 Anaemia is the most common objective sign of a deficiency in oxygen-carrying
erythrocytes. It is classified according to the size of erythrocytes (microcytic and macrocytic
or megaloblastic) and their haemoglobin content (hypochromic or hyperchromic) or to the
cause of the condition: haemorrhagic anaemia (due to acute or chronic blood loss),
haemolytic anaemia (due to damaged red cell membranes and destruction of erythrocytes),
aplastic and hypoplastic anaemia (caused by bone marrow damage), deficiency of essential
nutrients (iron deficiency anemia, megaloblastic anemias) and genetic alteration in the
hemoglobin molecule (hemoglobin-S in Sickle cell anemia).
 Thrombocytopenia and neutropenia are not rare and CSF therapy is used for their
prevention and treatment in patients with immune deficiency, being on radiotherapy or
receiving myelosuppressive chemotherapy.
Classification of hematopoietic drugs
A. Drugs for Anemia
1. Drugs for treatment of iron deficiency (microcytic, hypochromic) anemia
1.1. Oral preparations of iron (Fe2+)
 Ferrous sulfate: Ferro-gradumet, Hemofer prolongatum (film-tabl. 325 mg, 105
mg Fe2+; 1 tab. b.i.d. after meals), Tardyferon depot (80 mg Fe2+ included in
mucoprotein obtained from intestinal mucosa of sheep; absorption continues 7 h; 1-2
tab. q.d.)
 Ferrous glutamate: Glubifer
 Ferrous aspartate: Ferrospartin (tab. 350 mg, 50 mg Fe2+)
 Ferrous fumarate: Ferronat
 Ferrous gluconate: TOTHEMA® (amp. Fe2+ gluconate 50 mg; Mn2+ gluconate; Cu2+
gluconate)
 Ferric hydroxide polymaltose complex: Maltofer (1 ml sol. contains 50 mg
unionized Fe3+ hydroxide polymaltose complex)
1.2. Parenteral preparations of iron (Fe3+)
 Iron sucrose complex:, Venofer
 Iron isomaltoside: Monofer
 Iron dextran: Dexferrum®*
 Sodium ferric gluconate complex: Ferrlecit®
2. Drugs for treatment of megaloblastic (macrocytic, hyperchromic) anemias
 Vitamin B12 (Cyanocobalamin) – amp. 250 mcg/1 ml i.m.
 Folic acid
Iron chelators: Deferoxamine (Desferal), Deferasirox (Exjade)
B. Hematopoietic Growth Factors
1. Erythropoietins
 Erythropoietin: Epoetin alfa (Eprex), Epoetin beta (Recormon)
 Darbepoetin alfa (Aranesp)
 Methoxy polyethylene glycol-epoetin beta (long-acting erythropoietin receptor
activator): Mircera
2. Myeloid growth factors
 Granulocyte Colony Stimulating Factor (G-CSF): Filgrastim (Neupogen),
Lenograstim (Granocyte)
 Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF): Molgramostim
(Leucomax), Sargramostim (Leukine)
3. Megakaryocyte (Thrombopoietic) Growth Factors
 Oprelvekin (IL-11): Newmega
 Thrombopoietin
Mechanisms of action and pharmacological effects
1. Drugs for treatment of iron deficiency
Iron deficiency anemia is microcytic hypochromic anemia, caused by insufficient supply of iron. It
is the most common type of anemia. Iron deficiency in normal conditions may occur more often in
women (with menstrual blood loss or pregnancy), in adolescents (increased demand) and in
vegetarians or persons with malnutrition (inadequate dietary iron intake).
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Pharmacokinetics of iron: Haemoglobin is a protoporphyrin and each molecule has 4 iron-haeme
residues. Haeme is responsible for the bulk of oxygen transport in the blood and iron is the essential
metallic component of it. The total body iron is about 3.5–4 g in men and 2.5 g in women, and over
70% of it circulates in the blood as haemoglobin. About 15-18% is stored in the liver, spleen and
bone marrow mainly as ferritin and haemosiderin. Maximum iron absorption occurs by active
transport in the duodenum and proximal jejunum. Absorption rate depends on the ratio of apoferitin
(a protein) to feritin (apoferitine-iron complex) in the intestinal mucosa. The so called “mucosal
block” is a mechanism that prevents the entry of excess iron in the body. Ascorbic acid and SHgroup containing amino acids (in gastric juice) facilitate Fe3+ to Fe2+ conversion and promote its
absorption. Iron absorption is hindered by coffee, tea, antacid agents, phosphates (rich in egg
yolks), tetracyclines, etc. In the body iron is distributed into: haemoglobin (Hb) – 66%; iron
storages (ferritin and haemosiderin) – 25%, myoglobin in muscles – 3%, and parenchimal iron (as
prostetic group in cytochrome, peroxidases, catalases, xanthine oxidases and other cellular
enzymes) – 6%. Haemoglobin contains 0.33% iron and 50 mg elemental iron is averagely lost with
the loss of 100 ml blood (15 g Hb).
Iron preparations: Treatment or prevention of iron deficiency anemia is the only clinical
indication for the use of iron preparations.
 The preferred route of iron administration is oral. Elemental iron quantity per dose should be
taken into consideration. Oral preparations contain ferrous (Fe2+) salts (sulfate, glutamate,
aspartate, fumarate, gluconate, succinate, etc.). Ferric (Fe3+) salts are also available (Ferric
hydroxide polymaltose complex, Iron polysaccharide, etc.), but ferrous (Fe2+) salts are
supposed to be better absorbed. A number of iron combinations (with vitamins, minerals,
amino acids, etc.) are marketed, but should be considered irrational due to lower iron
content.
 About 50–100 mg of iron can be incorporated into hemoglobin daily, and about 25% of oral
iron can be absorbed. Full haemopoetic response in adults is usually achieved with
administration of 200 mg elemental iron daily p.o. in 2 or 3 divided doses after or in
between meals. Absorption of iron is much better when taken in empty stomach, but side
effects may limit patient compliance. For prophylactic use, a daily dose of 30 mg elemental
iron is sufficient.
 Parenteral iron preparations are indicated only in case of: severe deficiency with chronic
bleeding; intolerance to oral iron; malabsorption or inflammatory bowel disease;
erythropoietin therapy (to meet the increased needs of induced erythropoiesis). Parenteral
forms contain organically complexed salts of unionized iron: Iron dextran, Iron sucrose
complex, etc. (See Classification). A sensitivity test with a small test dose must be
performed before parenteral administration of iron to avoid any risk of hypersensitivity
reactions.
 In severe anemia, treatment with oral iron should be continued for at least 3 months after
correction to replenish iron stores.
 Desferrioxamine (Deferoxamine), an iron chelator, is a specific antidote that is given
systematically to remove iron.
2. Drugs for treatment of megaloblastic anemias
Megaloblastic anemia is clinically manifested with a deficiency in serum hemoglobin and
erythrocytes in which the erythrocytes are hyperchromic, fragile and abnormally large. It results
from either folate or vitamin B12 deficiency. Pernicious anemia is a form of megaloblastic anemia
resulting from reduced intestinal absorption of vitamin B12 (extrinsic factor) due to deficiency of
intrinsic factor (a protein produced by parietal cells of the gastric mucosa). Parenteral injections of
vitamin B12, but not oral preparations, are effective for treatment of pernicious anemia.
Vitamin B12
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
Cyanocobalamin (vitamin B12 – amp. 250 mcg/1 ml i.m.). Cyanocobalamin and
hydroxocobalamin are complex cobalt-containing compound present in diet and referred to
as vitamin B12. Vitamin B12 is essential for cell growth and multiplication. Along with folic
acid, it is involved in the DNA synthesis as a cofactor in the transfer of 1-carbon units.
 Two biochemical reactions require vitamin B12: conversion of methylmalonyl-coenzyme A
(CoA) to succinyl-CoA and conversion of homocysteine to methionine. Methylcobalamin
and deoxyadenosylcobalamin are the active forms of the vitamin.
 Conversion of homocysteine to H4 folate and methionine is conjugated with the conversion
of cobalamin to methylcobalamin. Vitamin B12 deficiency results in deficiency of folate
cofactors for DNA synthesis and megaloblastic anemia occurs first. This biochemical
interaction explains why high doses of folic acid can improve the anemia, caused by
insufficient supply of vitamin B12.
 Conversion of methylmalonyl-CoA to succinyl-CoA requires desoxycobalamin. Vitamin B12
deficiency results in accumulation of methylmalonyl-CoA, synthesis of abnormal fatty acids
and neurologic defects, which may become irreversible if not treated promptly. The
disruption of methionin synthesis is also supposed to be involved in the neuronal damage.
 Vitamin B12 deficiency is manifested by megaloblastic anaemia, glossitis, peripheral neuritis,
paresthesias, poor memory, mood changes, hallucinations, etc. It is clinically used for
treatment of megaloblastic anaemia, tobacco amblyopia, neuropathies and psychiatric
disorders.
 Hydroxocobalamin is highly protein-bound and longer acting, but is associated with the
development of antibodies (hence lesser in use).
Folic acid
 Humans do not synthesize folic acid and meet theirs requirements from green leafy
vegetables, fruit, mushrooms, liver, meat, kidney, eggs, milk and yeast. In the intestinal
mucosa of jejunum folic acid is reduced by dihydrofolate reductase to tetrahydrofolic acid.
Tetrahydrofolic acid through 1-C carbon transfer reactions is involved in the synthesis of
purines and pyrimidines which are essential for DNA synthesis.
 Deficiency of folic acid leads to megaloblastic anaemia and teratogenic effects (spina bifida,
etc.). Vitamin B9 prophylactically can be used during pregnancy and lactation – 0.4 mg p.o.
daily)
3. Haematopoetic Growth Factors



Erythropoetin: Epoetin alfa and Epoetin beta (Recormon). Erythropoietin stimulates
erythrocyte proliferation and differentiation by acting on specific receptors present on red
cell progenitors and promotes the release of reticulocytes. It is used to treat anemia in
chronic renal failure or anemias secondary to cancer chemotherapy or HIV treatment, bone
marrow transplantation, AIDS, cancer.
Myeloid Growth Factors (Colony Stimulating Factors – CSFs). Granulocyte (G) and
Granulocyte-Macrophages (GM) CSFs are cytokines. They accelerate the formation of
matured leucocytes by acting on many progenitor cells. Filgrastim (recombinant G-CSF),
Lenograstim (rG-CSF), Molgramostim (rGM-CSF) and Sargramostim (rGM-CSF) are used:
to reduce the severity and duration of neutropenia induced by cytotoxic chemotherapy,
radiotherapy or following bone marrow transplant; to treat congenital neutropenia, cyclic
neutropenia and neutropenia associated with aplastic anaemia. Pegfilgrastim is a PEGilated
(covalently conjugated to PolyEthylene Glycol polymer chain) form of filgrastim with a
much longer t1/2 than the recombinant G-CSF.
Megakaryocythe Growth Factors. Oprelvekin (IL-11) and Thrombopoietin stimulate the
growth of megakaryocytic progenitors and increase the number of peripheral platelets. They
are used to treat thrombocytopenia following cancer chemotherapy.
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Table 1: Pharmacokinetic parameters
Drug
Iron preparations
Ferrous sulfate
Rout of application t1/2; Tmax; Cmax
Methabolism
Orally (20-30%
absorption);
sustained release
tablets
Bound to transferrin;
endogenous system for
storage and transport;
elimination with cell loss
(skin, hair, nails), in feces,
perspiration, breast milk,
blood loss, urine.
About 5% excreted in urine
in 24 hours
t1/2=6 h
Tmax is 2 h
Mean Cmax is 203 mcg/dL
t1/2 values do not represent
clearance of iron from the
body
Iron sucrose
intravenously
complex
Vitamin B12 and Folic acid
Vitamin B12
orally, rapidly
(Cyanocobalamin) absorbed;
intranasally,
intramuscularly;
should not be
administered i.v.
t1/2=6 h, T max is 10 min,
Cmax is 538 μmol/l
Folic acid
t1/2=24 (15-60) h
Tmax is 1 h (oral)
Cmax is 273. 3 ng/mL
orally, rapidly
absorbed; (rarely
intravenously,
subcutaneously,
intramuscularly)
t1/2=1.5-2 h
Tmax is 1.25±1.9h
(intranasal); 1 h (i.m.).
Cmax is 757.96 pg/mL
Hematopoietic growth factors
Erythropoietin
intravenously,
t1/2=4-13 h (i.v.) to 24 h
Alfa (Epoetin alfa) subcutaneously
(s.c.) in chronic renal
(1-3 times a week) failure
Tmax is 12-18 h (s.c.)
Cmax is 861 mIU/mL
G-CSF
Filgrastim
intravenously,
subcutaneously
t1/2= 3.5 h
Tmax is 2 (8) h
Cmax is 49 (150) ng/mL
Oprelvekin
(IL-11)
subcutaneously
t1/2= 6.2 h
Tmax is 3.2 h
Bound to intrinsic factor
during transit through the
stomach; bound to
transcobalamin for
transport; main storage in
the liver; secretion in the
bile (3-8 mcg) and
enterohepatic circulation;
unbound vitamin is rapidly
eliminated in the urine (50
to 98% within 48 h after
i.m. injection).
Intracellular demethylation
of methyltetrahydrofolate to
tetrahydrofolate (reaction
requires vitamin B12);
tetrahydrofolic acid is the
active metabolite;
methyltetrahydrofolic acid
is the form for transport and
storage; excreted mainly in
the urine (traces in feces),
breast milk.
Metabolism is unknown,
some degradation occurs;
majority of excretion is
found in feces with 10%
unchanged in urine. It is not
cleared by dialysis.
Elimination route is not
known. Level of circulating
neutrophils may affect
filgrastim clearance, with
clearance increasing as
neutrophil counts increase.
Excreted through the
kidney.
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Cmax is 17.4 ng/mL
Iron helators
Desferrioxamine
(Deferoxamine)
intramuscularly,
subcutaneously
t1/2=6.4 min
Tmax is 0.5 h
Cmax is 8.7 µg/ml
Liver, transamination,
oxidation, beta-oxydation,
decarboxylation and Nhydroxylation yielding
neutral metabolites;
excreted in the urine
Side effects and toxicity
Iron

Iron salts can cause constipation, diarrhea (rarely), epigastric pain, heart burns, nausea,
vomiting, metallic taste, and staining of teeth (mainly with oral liquid or chewable
preparation).
 Local reactions: Pain at the site of action, skin pigmentation, sterile abscess.
 Systemic side effects: Fever, headache, joint pain, urticaria, lymphadenopathia;
anaphylactoid reaction (palpitation, chest pain, dyspnoea, cardiovascular collapse) may
occur with iron-sorbitol preparations, but rarely with other preparations).
 Acute iron toxicity occurs mostly in young children after accidental ingestion of iron tablets.
Severe intoxication is clinically presented with necrotizing gastroenteritis, shock and
metabolic acidosis. Coma and death may result. Unfortunately, activated charcoal, does not
work here. Deferoxamine is used as a specific antidote.
 Chronic iron toxicity (hemochromatosis) occurs in persons with an inherited abnormality of
iron absorption or with frequent transfusions (eg, thalassemia major). Iron chelators
(deferoxamine or the oral agent deferasirox) are used in the treatment of chronic iron
overload.
Vitamin B12 and folic acid
 Both substancies are well tolerated and neither their form has significant toxicity.
Hematopoietic growth factors
 Erythropoietin can provoke an increase in hematocrit, blood viscosity and peripheral
vascular resistance. Hypertension, thrombotic complications and flu-like symptoms (rare)
may occur. For prevention of CV complications, it is recommended to maintain hemoglobin
levels < 12 g/dL.
 Myeloid Growth Factors: G-CSF is better tolerated than GM-CSF. It may cause fever, bone
pain (10-15%), myalgia, and vasculitis. GM-CSF is more likely to provoke fever, arthralgia,
myalgia and skin rash.
Megakaryocythe Growth Factors
 IL-11 treatment is associated with dizziness, headache and fatigue. Recombinant human
trombopoietin is supposed to be better tolerated.
OUESTIONS1
1. All of the following drugs are used for iron deficiency anemia, except: A) Ferrous sulphate;
B) Folic acid; C) Ferrous glutamate; D) Ferrous fumarate.
2. The recommended dose of elemental iron for oral supplementation is: A) 50 mg daily; B)
100 mg daily; C) 150 mg daily; D) 200 mg daily.
3. An adverse effect of oral iron therapy is: A) Anemia; B) Thrombocytopenia; C)
Constipation; D) Headache.
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Answers: 1B; 2D; 3C; 4B, C; 5D; 6D; 7C; 8A, B; 9A; 10A, C, D; 11C.
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4. Iron preparations for parenteral use are: A) Ferrous aspartate; B) Iron dextran; C) Iron
isomaltoside; D) Ferric hydroxide polymaltose complex.
5. Iron sucrose complex can be administered: A) Orally; B) Subcutaneously; C)
Intramuscularly; D) Intravenously.
6. Which of the following is used for treatment of pernicious anemia? A) Erythropoetin B)
Oral Vitamin B12; C) Iron; D) Parenteral Vitamin B12.
7. Which of the following statements about Folic acid is correct? A) It is used for treatment of
trombocytopenia; B) It is contraindicated in pregnancy; C) It is used for treatment of
megaloblastic anemias; D) Its clinical use is limited by serious side effects.
8. Select the correct statements about Desferrioxamine: A) It is specific antidote in acute iron
overdose; B) It is an iron chelator; C) It is a drug of choice for treatment of iron deficiency;
D) Both B and C are correct.
9. Erythropetin is used for: A) Treatment of anemia associated with chronic renal failure; B)
Treatment of neutropenia associated with radiotherapy; C) Treatment of thrombocytopenia
associated with cancer chemotherapy; D) Prevention of congenital neural tube defects.
10. Which of the following drugs influence leucopoiesis? A) Filgrastim; B) Erythropoetin; C)
Doxorubicin; D) Sargramostim.
11. This drug is used for treatment of thrombocytopenia following cancer chemotherapy: A)
Vitamin B12; B) Filgrastim; C) Oprelvekin; D) Molgramostim.
Conclusions:









Hemopoiesis is regulated by balanced interaction between endogenously derived hematopoietic
growth factors and exogenously supplied essential nutrients (hematinics).
Hematopoietic growth factors in clinical use are: Erythropoietins (Epoetin alfa, Epoetin beta); GCSF (Filgrastim, Lenograstim), GM-CSF (Sargramostim, Molgramostim); Oprelvekin (IL 11) and
Trombopoietin.
Hematinics in clinical use are: Iron salts, Vitamin B12 and Folic acid.
Treatment or prevention of iron deficiency anemia is the only clinical indication for the use of iron
preparations. The main therapeutic preparation is Ferrous sulfate.
Vitamin B12 and Folic acid are used for the treatment of megaloblastic anemias.
Parenteral Vitamin B12 is required for treatment of pernicious anemia.
Erythropoietin stimulates the production of erythrocytes and increases their release from the bone
marrow. It is used to treat anemia in chronic renal failure and anemias secondary to inflammation,
cancer or cytotoxic therapy.
Myeloid Growth Factors are used to treat neutropenia after myelosuppressive therapy.
Oprelvekin (IL-11) and Thrombopoietin are used to treat thrombocytopenia following cancer
chemotherapy.
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