Drugs affecting

haemopoietic system
Dr. Sulafa Ahmed
Faculty of Pharmacy-UST
 Anaemia
• Defined as haemoglubin (Hb) level <12g/dl in females and
<14g/dl in males
• Classified by

 Cytometric scheme ( depends on cell size & Hb content )

 Erythrokinetic scheme (takes into account rate of RBC

production &destruction)
 Biochemical /molecular scheme (consider etiology of
anaemia at molecular level)
Cytometric classification
Normochromic normocytic anemia includes
Anemia of chronic diseases
Hemolytic anemias
Aplastic anemia
Anemia of acute hemorrhage
Hypochromic microcytic anemia
Iron deficiency anemia
Normochromic macrocytic anemia
Vitamin B deficiency anemia
Folic acid deficiency anemia
Haematinics agents
 Iron

• Requirements vary in different periods of life in association with

the demands of growth, menstruation or pregnancy
• The normal daily requirement for an adult man is 5-10 mg

• Normally 5-10 % of the iron in the food is absorbed

• Duodenum & upper jejunum are site of iron absorption

• Absorption occurs through an active transport process

• Hydrochloric acid increases the reduction of ferric iron to
ferrous
• Ascorbic acid, fructose & various amino acids stimulate iron
absorption
• Antacid, tetracyclines, phosphate& tannate inhibit absorption of
iron
• Iron stores mainly in the liver, spleen & bone marrow

• Storage takes place in the form of ferritin & haemosiderin

 Iron preparation & administration

• Usually given orally

• May be given parenterally
• Available as
 Ferrous sulfate
 Ferrous succinate
 Ferrous gluconate
 Ferrous fumarate
• Parenteral iron is indicated only in emergency or when oral
therapy is impractical due to malabsorption syndrome or
inflammation
• The preparations used are iron dextran (I.M & I.V) and iron
sorbitol (I.M only)
 Clinical uses

• Treatment or prevention of iron deficiency anaemia due to

 Chronic blood loss

 Increase demand e.g. in pregnancy & early infancy

 Inadequate dietary intake or absorption

 Side effects & toxicity
• Nausea, abdominal cramps & constipation

Acute iron toxicity: characterized by

abdominal pain, nausea, vomiting, haemorrhage & diarrhea.

• Treated by iron chelating agent

• Desferrioxamine given by

 Gastric tube

 intramuscular or intravenous injection

 Folic acid

• The daily requirement about 200 μg

• Metabolic functions include

 Conversion of homocysteine to methionine

 Conversion of serine to glycine

 Synthesis of thymidylate

 Histidine metabolism
 Folic Acid metabolism

• Dietary folate present in form of poyglutamates

• Dietary folate should be hydrolyzed before absorption
• Ployglutamates are converted to monoglutamates before
absorption
• Monoglutamates are converted back to polyglutamates in
tissues
• Most absorption occurs in the proximal small intestine
• Folic acid is not active but reduced to tetrahydrofolate (FH4 ) &
dihydrofolate (FH2 ) by an action of an enzyme
 Dihydrofolate reductase
 Folate Deficiency
• Common complication of small intestine diseases
• Acute or chronic alcoholism
• Disease states characterized by high rate of cell turnover
 Cancer
 Chronic haemolysis
• Drugs that inhibit dihydrofolate reductase
 Trimethprim
 Methotrexate
• Folate deficiency implicated in neural tube defects including
 Spina bifida
 Encephaloceles
 Clinical uses of folic acid

A)Treatment of megablastic anaemia caused by

Insufficient diet
Drugs (Phenytion)
Malabsorption syndrome
B) Treatment or prevention of toxicity from methotrexate

C) Prophylactic measures in individuals at hazard from developing

folate deficiency
Pregnancy
Premature infants
Patients with severe chronic haemolytic anaemias
 Vitamin B12
• Intracellular vitamin B12 is maintained as two active coenzymes
 Methylcobalamin
 Deoxyadenosylcobalamin
• Deoxyadenosylcobalamin cofactor for mitochondrial mutase
enzyme
• Mutase enzyme catalyzes isomerization of L-methylmalonyl
CoA to succinylCoA
• Methylcobalamin supports methionine synthetase reaction
• Methionine synthetase reaction is essential for normal
metabolism of folate
• Methionine synthetase reaction is largely responsible for
 Control of folate recycling
 Maintenance of intracellular concentrations of polyglutamates
 Maintenance of number of methylation reactions
• Absorption requires intrinsic factor which forms one -one
complex with Vit B12
• Dietary vitamin B12 is released from food & bound to gastric
intrinsic factor in presence of
 Gastric acid
 Pancreatic proteases
• Ileal transport of vitamin B12 require

 Adequate intrinsic factor , bile & sodium bicarbonate

 Vit B12 is carried in the plasma by binding β-globulin

Transcobalamin II (TcII)
 The vitamin is stored mainly in the liver as active cofactor

• Recommended daily intake of the vitamin in adults is 2.4 μg

Deficiency
• Common cause of vitamin B12 deficiency in adults

Achlorhydria

Decreased secretion of intrinsic factor by parietal cells

secondary to gastric atrophy or gastric surgery
• Antibodies to parietal cells or intrinsic factor complex also can
play prominent role
• Intestinal diseases can interfere with absorption
• Vitamin B12 deficiency is recognized by its impact on

 Hematopoietic & nervous system

• Vitamin B12 deficiency can irreversibly damage nervous

system
• Progressive swelling of myelinated neurons, demyelination &
neuronal cell death seen in
 Spinal column

 Cerebral cortex
 Preparations

• Available for injection or oral administration

• Oral administration is of limited value
• Combinations with other vitamins & minerals also can be
given orally or parenterally
• Treatment of choice for vitamin B12–deficiency
 Cyanocobalamin
• Cyanocobalamin given
 S.C
 I.M
 Drugs induce macrocytic anemia
 Alcohol
Causes bone marrow toxicity & interference with folate
metabolism

 Antineoplastic drugs
 Zidovudine
Cause bone marrow toxicity

 Phenytion
Altered folate absorption
 Methotrexate
 Oral contraceptives
 Trimethoprim
Altered folate absorption

 Proton pump inhibitors

 Metformin
Cause vitamin B malabsorption
Haemopoietic Growth Factors
• Maintenance of haemopoiesis requires balance between

 Self-renewal

 Differentiation into various types of blood cells

• Maintenance is controlled by haemopoietic growth factors

 Erythropoietin

 Colony-Stimulating factors (CSFs)

 Erythropoietin
• Most important regulator of proliferation of committed progenitors
• Expressed primarily in peritubular interstitial cells of kidney
• Following secretion it binds to
 Membrane receptor on committed erythroid progenitors in
marrow
• Recombinant human erythropoietin nearly identical to
endogenous hormone
 Epoetin

 Given I.V I.M & S.C

 Therapeutic uses
• Recombinant erythropoietin therapy in conjunction with
adequate iron intake can be highly effective in number of
anemias especially those associated with poor erythropoietic
response
• Effective in management of
 Anaemia of chronic renal failure
 Anaemia during chemotherapy
 Prevention of anaemia occurs in premature infants
 Anaemia for AIDS
 Anaemia of chronic inflammatory conditions
 To increase autologous blood before blood donation
 Adverse effects & Monitoring
• Absolute or functional iron deficiency may develop
• Transient flu-like symptoms
• Hypertension
• During initial therapy & after any dosage adjustment
 Hematocrit is determined once/week in HIV-infected
 Hematocrit is determined twice/week in renal failure patients
 Hematocrit monitored at regular intervals after stabilization in
target range
•In case hematocrit increases by more than 4 points in any 2-
week period dose should be decreased
• During hemodialysis patients receiving epoetin may require
increased anticoagulation
•Erythropoietin's should be withheld in patients with pre-existing
uncontrolled hypertension
• Patients may require
Initiation antihypertensive therapy
 Increases in antihypertensive therapy
 Colony-stimulating factors (CSFs)
• Stimulate proliferation& differentiation of
 Neutrophils
 Monocytes
 Macrophages
• Involved in mature cell function
• Stem cell differentiation involves series of steps that produce
 Burst-forming units (BFU)
 Colony-forming units (CFU)
• CSFs in clinical use
 Granulocyte/ macrophage CSF (GM-CSF)
 Granulocyte CSF (G-CSF)
 Granulocyte (G-CSF)

 Filgrastim

 Lengograstim

 Pegfilgrastim
Filgrastim
• Recombinant human G-CSF
• Stimulates CFU-G to increase neutrophil production
• Enhances phagocytic & cytotoxic functions of neutrophils
• Administered
 S.C
 I.V infusion over at least 30 minutes at doses of 1–20
mg/kg/day
• 5 mg/kg/day usual starting dose in patient receiving
myelosuppressive chemotherapy
• t1/2 ~3.5 hours
 Clinical uses

• Effective in t treatment of severe neutropenia after autologous

• hematopoietic stem cell transplantation & high-dose cancer

chemotherapy
• Effective in treatment of severe congenital neutropenias
• Shortens period of severe neutropenia & reduces morbidity
secondary to bacterial & fungal infections
• Decrease frequency of hospitalization for febrile neutropenia

& interruptions in chemotherapy protocol

• Improves neutrophil counts in some patients with

myelodysplasia

• Positive impact on survival has not been demonstrated

 Adverse effects
• Mild -moderate bone pain in patients receiving high doses o

protracted period
• Local skin reactions following S.C injection
• Rare cutaneous necrotizing vasculitis
• Marked granulocytosis with counts >100,000/ml can occur in
patients receiving filgrastim over prolonged period of time
• Mild-moderate splenomegaly has been observed in patients on
long-term therapy
 Thrombopoietic Growth Factors

Interleukin-11
•Stimulates hematopoiesis

• Intestinal epithelial cell growth

•Osteoclastogenesis

•Inhibits adipogenesis

•Enhances megakaryocyte maturation

Oprelvekin
• Recombinant human interleukin-11
• Approved for use in
Patients undergoing chemotherapy for nonmyeloid malignancies
with severe thrombocytopenia

• Administered at 25–50 mg/kg/day S.C

•The major complications of therapy
Fluid retention & associated cardiac symptoms
 Injection-site rash or erythema & paresthesias are reported
•Fluid retention reverses upon drug discontinuation
• Pregnancy category C
• Excretion in breast milk unknown
• Contraindicated in
 Patients with hypersensitivity to oprelvekin or any
component of formulation

• May increase risk of hypokalaemia in patients receiving chronic

diuretic therapy
• Safety & efficacy not established in children younger than
12 years of age
• Monitoring is essential
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