Haematopoetic agents

1. Dr Shinde Viraj Ashok
Jr 2 Dept of Pharmacology
GMC Nagpur

2. overview
• Iron
• Folic acid
• Vitamin B12
Haematinics
• Erythropoeisis stimulating
agents
• Myeloid growth factors
• Megakaryocytic growth factors
Haematopoietic
growth factors

3. haemtopoeisis
• Production of all types of blood cells including
formation , development & differentiation of
blood cells.
Definition
• Haematinics – substances required in
formation of blood and are used for
treatment of anemia.
• Haematopoietic growth factors - proteins
that regulate proliferation and
differentiation of hematopoietic cells.

4. • Iron deficiency - most common cause of
chronic anemia.
Daily iron requirement
▫ Adult male – 0.5 - 1 mg
▫ Mensturating female – 1- 2mg
▫ Pregnant female – 3- 5mg
▫ Children – 25 micro gram /kg
IRON

5. • Good source of iron - Liver , egg yolk , beans
,dry fruits.
• Poor sources of iron - Milk & its products.
• Reducing substances like ascorbic acid &
gastric acid - ↑ Absorption
• Alkalies , phosphates , phytates ,
tetracyclines - ↓ Absorption

7. • Iron – prophylaxis or treatment of iron
deficiency anemia ( microcytic hypochromic
anemia)
• Parenteral route indicated -
▫ Oral iron not tolerated
▫ Oral iron not absorbed
▫ Non compliance to oral iron
▫ Severe iron deficieny with chronic bleeding
▫ Along with erythropoietin

8. Oral preparations
• Ferrous sulphate – 20% elemental iron
• Ferrous gluconate – 12% elemental iron
• Ferrous succinate -35% elemental iron
• Reticulocyte count - ↑ in 2 weeks & peak in 4
weeks
• Rise of haemoglobin - 0.5- 1 gm /dl per week
considered adequate

9. • Major adverse effects of oral iron
preparations - Poor compliance
1. Epigastric pain
2. Nausea
3. Vomiting
4. Metallic taste
Elemental iron content in preparation

10. Parenteral iron preparations
Iron dextran Iron sorbitol citrate
Can be given IV or IM Only IM
Not excreted in urine Excreted 30% in urine
Absorbed through
lymphatics
Absorbed directly in
circulation
Not bound to transferrin Bound to transferrin
Adverse effects – Pain at
injection site ,fever,
palpitation
Adverse effects – Incidence
of immediate reaction ,
ventricular tachycardia, A- V
block , hypotension - Higher

11. Ferrous sucrose
▫ High molecular weight complex of iron hydroxide
with sucrose
▫ IV injection
▫ Safer than older formulations
▫ Incidence of hypersensitivity reaction very low
Indicated for anaemia in kidney disease but
reports of kidney damage are on record

12. Ferric carboxymaltose
▫ Ferric hydroxide core is stabilised by a
carbohydrate shell
▫ Injected IV
▫ In clinical trials it has caused rapid increase in
haemoglobin level in anaemia patients &
replenished stores.
▫ Acute reaction - Low

13. • To avoid the serious toxicity associated with
iron overload – chronic parenteral iron
therapy
• Iron stores estimated - basis of
▫ Serum concentrations of ferritin and
▫ Transferrin saturation(ratio of the total serum
iron concentration to the total iron-binding
capacity (TIBC)
Important to monitor iron storage levels

14. • Total iron requirement

15. Clinical Toxicity
• Acute iron toxicity – exclusively seen in
young children – accidentally ingest iron
tablets.
• Adult patients taking oral iron preparations
should be instructed
Store tablets in child-proof containers out of the
reach of children

16. • Children poisoned with oral iron experience
necrotizing gastroenteritis, severe metabolic
acidosis, coma, and death.
• Urgent treatment - Necessary.
• Whole bowel irrigation - To flush out unabsorbed
pills.
• Gastric lavage with sodium bicarbonate – To render
iron insoluble
• Desferrioxamine - Potent iron-chelating compound,
can be given intravenously to bind iron that has
already been absorbed & to Promote its excretion in
urine and feces

17. • Iron overload - Hemochromatosis
• Most commonly occurs in patients
▫ Inherited hemochromatosis, a disorder
characterized by excessive iron absorption
▫ Patients - receive many red cell transfusions
over a long period of time (eg individuals with ß-
thalassemia).

18. • Chronic iron overload in absence of anemia -most
efficiently treated by intermittent phlebotomy.
• One unit of blood - removed every week or so until all
of the excess iron is removed.
• Iron chelation therapy using
▫ Parenteral desferrioxamine or
▫ Oral iron chelator deferasirox is
Less efficient more complicated, expensive, and hazardous.
Used for iron overload cannot be managed by phlebotomy
(Inherited and acquired causes of refractory anemia such as
thalassemia major, sickle cell anemia, aplastic anemia etc.)

19. Folic acid
• Consist pteridine, para amino benzoic acid,
glutamic acid
• Dietary folic acid – polyglutamates- cleaved of in
intestine - Maximum absorption – jejunum
• Folic acid is transported in blood -Methyl tetra
hydrofolate.
• THFA participates in many one carbon transfer
reaction

20. Metabolic functions
 Conversion of homocysteine to methionine
Methyl THFA B12 methionine
THFA methyl B12 homocysteine
 Generation of thymidylate – essential constituent of DNA
 Conversion of serine to glycine requires THFA → results in
formation of methylene THFA - utilised in thymidylate
synthesis.
 Purine synthesis & Generation & utilisation of formate pool.
 Histidine metabolism – mediating formimino group transfer.

21. Main uses –
• Treatment of megaloblastic anemia.
• Indicated in pregnancy – To prevent neural
tube defects.
• Leucovorin – Used to prevent toxicity of
methotrexate.

22. Vitamin B12
• Contains cobalt
• Forms present in diet – Cyanocobalamin &
hydroxycobalamin
• Present – Animal foods
• Vegetable source – Legumes
• Vitamin B12 + intrinsic factor – Absorbed in terminal ileum
Deficiency of Vitamin B12 –
1) Megaloblastic anemia
2) Sub acute combined degeneration of cord

23. Metabolic functions
1. Conversion of homocysteine to methionine –methionine is
needed as methyl group donor in many metabolic
reactions and protein synthesis.
2. Purine & pyrimidine affected – defective one carbon
transfer.
3. Conversion of malonic acid to succinic acid- important
step in propionic acid metabolism & links carbohydrate
metabolism with lipid metabolism.
4. Conversion methionine to S adenosyl methionine – SAM
is needed in synthesis of phoshpholipids & myelin.
5. Essential for cell growth & multiplication

24. Uses
1. Megaloblastic anemia
2. Pernicious anemia
3. Correcting neurological abnormalities of
diabetes, alcoholic & other peripheral
neuropathy – methylcobalamin
4. Tobacco amblyopia – hydroxycobalamin

25. Erythropoiesis Stimulating Agents
Pharmacological substance stimulates red blood cell
production.
• Recombinant human erythropoietin (rHuEPO,
epoetin alfa) –
▫ Produced in a mammalian cell expression system.
▫ Half -life - 4 -13 hours in patients with chronic
renal failure.
▫ Epoetin alfa is generally administered three times
a week.

26. Erythropoetin
Darbepoetin alfa
▫ Modified form of erythropoietin more heavily
glycosylated as a result of changes in amino acids.
▫ 2 to 3 fold longer half-life than epoetin alfa.
▫ Darbepoetin is administered weekly.

27. Methoxy polyethylene
glycol epoetin beta
▫ Isoform of erythropoietin covalently attached
to a long polyethylene glycol polymer.
▫ Single IV or SC dose at 2-week or monthly
intervals.
▫ Methoxy polyethylene glycol-epoetin beta should
not be used for treatment of anemia caused by
cancer chemotherapy
Clinical trial found significantly more deaths among
patients receiving this form of erythropoietin.

28. Pharmacodynamics
• Stimulates erythroid proliferation and
differentiation by interacting with
erythropoietin receptors on red cell
progenitors.
• Erythropoietin receptor is member of the
JAK/STAT superfamily of cytokine
receptors.
• Inverse relationship exists between the
hematocrit or hemoglobin level & serum
erythropoietin level.

29. • Endogenous Erythropoietin levels are low - Renal
disease
• Endogenous erythropoietin levels are high
 Primary bone marrow disorders (aplastic anemia,
leukemias, myeloproliferative and myelodysplastic
disorders etc) and
 Most nutritional and
 Secondary anemias
Less likelihood of a response to exogenous
erythropoietin
Most likely to respond to treatment with exogenous
erythropoietin

30. Clinical Pharmacology
• Availability of erythropoiesis-stimulating
agents (ESAs) significant positive impact for
patients with several types of anemia.
• Dosages of ESAs - Maintain a target
hemoglobin up to, but not exceeding, 10-12
g/dL.
• Oral or parenteral iron supplementation - To
support increased erythropoiesis

31. Indications
A. Patients with chronic renal failure.
B. HIV-infected patients treated with zidovudine.
C. Cancer patients treated with myelosuppressive
cancer chemotherapy.
D. Patients scheduled for elective, non cardiac ,non
vascular surgery.

32. • ESAs improve -
• Reticulocyte count - 10 days
• Hematocrit & hemoglobin level - 2 weeks
• Often eliminate the need for transfusions
• Improve quality of life

33. Toxicity
• Most common adverse effects of erythropoietin are
▫ Hypertension and
▫ Thrombotic complications.
• In March 2007, FDA issued a warning that patients
with chronic renal failure or cancer whose serum
hemoglobin is raised to more than 12 g/dL with an
ESA
Face a greater risk of a thrombotic event
or with advanced head and neck cancers - faster tumor
growth.

34. MYELOID GROWTH FACTORS
Chemistry & Pharmacokinetics
Recombinant human G-CSF ( rHuG-CSF- filgrastim)
▫ Produced in a bacterial expression system
▫ Nonglycosylated peptide of 175 amino acids, with a
molecular weight of 18 kDa
Recombinant human GM-CSF( rHuGM-CSF- sargramostim)
▫ Produced in a yeast expression system
▫ Partially glycosylated peptide of 127 amino acids with three
molecular species with molecular weights of 15,500; 15,800;
and 19,500.
▫ Serum half-lives of 2 hours after IV or SC administration.

35. Pharmacodynamics
• Myeloid growth factors stimulate
▫ Proliferation &
▫ Differentiation by interacting with specific
receptors (members of JAK/STAT superfamily)
found on myeloid progenitor cells.
• G-CSF - Remarkable ability to mobilize
hematopoietic stem cells, i.e, to increase their
concentration in peripheral blood.
• Peripheral blood stem cells (pbscs) are used for
autologous & allogeneic hematopoietic stem cell
transplantation.

36. GM-CSF
• Broader biologic actions than G-CSF.
• Multipotential hematopoietic growth factor that
stimulates
▫ Proliferation and
▫ Differentiation of early and late granulocytic
progenitor cells as well as erythroid and
megakaryocyte progenitors.
• GM-CSF acts together with interleukin-2 to stimulate
T-cell proliferation.

37. Clinical Pharmacology
A. Cancer Chemotherapy-Induced Neutropenia
• Growth factor accelerates the rate of neutrophil
recovery after dose-intensive myelosuppressive
chemotherapy.
• Reduces the duration of neutropenia and raises the
nadir count (lowest neutrophil count seen following a
cycle of chemotherapy.)

38. Clinical guidelines recommend G-CSF for
patients at high risk for
Febrile neutropenia based on age, medical history & disease
characteristics
Patients receiving dose-intensive chemotherapy regimens that
carry a greater than 40% risk of causing febrile neutropenia
Prior episode of febrile neutropenia after cytotoxic
chemotherapy
At high risk for febrile neutropenia
Patients who are unlikely to survive an episode of febrile
neutropenia

39. • GM-CSF reduces the duration of neutropenia
after cytotoxic chemotherapy.
• Growth factors accelerate neutrophil
recovery and reduce infection rates and days
of hospitalization.
• G-CSF and GM-CSF have FDA approval for
treatment of patients with AML.

40. Pegfilgrastim
▫ Covalent conjugation product of filgrastim and a form of
polyethylene glycol
▫ Longer serum half-life than recombinant G-CSF -
▫ Alternative to G-CSF for prevention of chemotherapy-
induced febrile neutropenia.
▫ Shorten the period of severe neutropenia slightly more
than G-CSF.
Injected once per myelosuppressive chemotherapy
cycle instead of daily for several days

41. Lenograstim
▫ Glycosylated form of recombinant G-CSF

42. B. Other Applications
• G-CSF and GM-CSF - proved to be effective
neutropenia associated with
 Congenital neutropenia
 Cyclic neutropenia
 Myelodysplasia and
 Aplastic anemia.
• Myeloid growth factors play an important role
in autologous stem cell transplantation for
patients undergoing high-dose chemotherapy.

43. • Allogeneic bone marrow transplantation for
treatment of hematologic malignancies or bone
marrow failure states.
• G-CSF is most commonly used for PBSC mobilization
because of its increased efficacy and reduced
toxicity compared with GM-CSF.
• Dose - 5- 10mcg/kg/d subcutaneously for 4 days.
• On the fifth day they undergo leukapheresis.
• Goal is to infuse at least 5 × 10 6 CD34 cells/kg

44. Plerixafor
Plerixafor can be added to G-CSF for patients with
multiple myeloma or non-hodgkin’s lymphoma who
respond suboptimally to G-CSF alone, the novel
hematopoietic stem cell mobilizer.

45. Toxicity
• G- CSF & pegfilgrastim can cause bone pain –
Reversible
• GM-CSF - more severe side effects- at higher doses.
▫ Fever
▫ Malaise
▫ Arthralgias
▫ Myalgias and
▫ Capillary leak syndrome (peripheral edema and pleural or
pericardial effusions)
• Splenic rupture - rare but serious complication of
the use of G-CSF for PBSC

46. MEGAKARYOCYTE GROWTH
FACTORS
• Patients with thrombocytopenia have a high risk of
hemorrhage.
• Recombinant form of IL-11 was the first agent to
gain FDA approval for treatment of
thrombocytopenia.
• Romiplostim was approved by the FDA for idiopathic
thrombocytopenic purpura in 2008.

47. Chemistry & Pharmacokinetics
• Oprelvekin - Recombinant form of IL-11 is
produced by expression in Escherichia coli.
• Half-life - 7- 8hours when the drug is
injected subcutaneously.

48. • Romiplostim (AMG 531) is a member of new
class of therapeutics called peptibodies.
• Half -life is inversely related to the serum
platelet count
Romiplastim has longer half-life in patients with
thrombocytopenia and a shorter half-life in patients
whose platelet counts have recovered to normal levels

49. Eltrombopag
• Orally active small molecule agonist at
thrombopoietin receptor.
• Licensed in 2008 for use in patients with severe
idiopathic thrombocytopenia {have failed to
respond adequately to first-line treatments.}
• Because of concerns about hepatotoxicity and
hemorrhage, eltrombopag is restricted to use by
registered physicians and patients and its use
requires close monitoring of liver enzymes.

50. Pharmacodynamics
• Interleukin-11 acts - Specific cell surface cytokine
receptor to stimulate the growth of multiple lymphoid
and myeloid cells.
• Acts synergistically with other growth factors to
stimulate the growth of
▫ Primitive megakaryocytic progenitors
▫ Increases the number of peripheral platelets and
neutrophils
• Romiplostim - high affinity for the human Mpl
receptor. It causes a dose-dependent increase in
platelet count that begins on day 5 after subcutaneous
administration and peaks at 12-15 days.

51. Clinical Pharmacology
• Oprelevkin - Secondary prevention of
thrombocytopenia in patients receiving
Cytotoxic chemotherapy for Treatment of
nonmyeloid cancers.
• Clinical trials show that it reduces the
number of platelet transfusions required by
patients who experience severe
thrombocytopenia after a previous cycle of
chemotherapy.

52. • Oprelevkin is given by subcutaneous injection
at a dose of 50 mcg/kg/d.
• It is started 6-4 hours after completion of
chemotherapy and continued for 14 -21 days
or until the platelet count passes the nadir
and rises to more than 50,000 cells/L.

53. Toxicity
• Most common adverse effects of oprelevkin are
fatigue, headache, dizziness, and cardiovascular
effects. (reversible)
• Cardiovascular effects include
▫ Anemia (due to hemodilution),
▫ Dyspnea (due to fluid accumulation in the lungs), and
▫ Transient atrial arrhythmias.
▫ Hypokalemia.
• Romiplostim - Well tolerated
- Potential long-term concern treated
with romiplostim - ↑ in bone marrow reticulin, (marker
of myelodysplastic or myeloproliferative processes)

54. summary
Mechanism of action Clinical application
Iron Required for biosynthesis of heme
& heme-containing proteins,
hemoglobin
& myoglobin
Microcytic hypochromic
anemia
Vitamin B12 Cofactor required for essential
enzymatic reactions
Megaloblastic
anemia ,
pernicious anemia
Folic acid Precursor of an essential
donor of methyl groups
used for synthesis of
amino acids, purines, and
deoxynucleotide
Megaloblastic anemia &
Prevention of
congenital neural tube
defects

55. Growth factor Drug Mechanism of
action
Clinical applications
Erythropoietin Epoietin α
Darbopoietin α
Methoxy
polyethylene
glycol epoetin
beta
Agonist of
erythropoietin
receptors
expressed by
red cell
progenitors
Anemia in CRF,
Myelosuppressive drug use
G-CSF
GM- CSF
Filgrastim
Pegfilgrastim
Lenograstim
Sargromostim
Proliferation &
differentiation
of myeloid
growth factors
Neutropenia due to
anticancer drugs ,severe
chronic neutropenia stem
cell transplantation ,
mobilisation of PBSC
IL 11
Thrombopoietin
Oprelevkin
Romiplastin
Eltrombopag
Activates IL-11
receptors
Activate
thrombopoietin
receptor
Thrombocytopenia due to
anticancer drugs,
ITP

56. References
• The pharmacological basis of therapeutics -
Goodman and gillman (12th edition)
• Basic and clinical pharmacology – Bertram
Katzung (12th edition)
• Principles of pharmacology- H.L. Sharma(2nd
edition)

60. • Erythropoietin has been used successfully to
offset the
▫ Anemia produced by zidovudine treatment in
patients with HIV infection and
▫ Treatment of the anemia of prematurity.
• It can also be used to reduce the need for
transfusion in high-risk patients undergoing
elective, non-cardiac, nonvascular surgery.

62. • Plerixafor is eliminated primarily by the renal
route and dose must be adjusted for patients
with renal impairment.
• Drug is well tolerated.
• Most common adverse effects associated with its
use are
1. Injection site reactions
2. GI disturbances
3. Dizziness
4. Fatigue &
5. Headache.