Semester V – WEEK 1
HEMATOLOGY MODULE
PHARMACOLOGY
IRON,B12 TREATMENT
LEARNING OBJECTIVES:
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Sites of action of erythropoietin.
Explain the approved indications for treatment of anemia by
erythropoietin, iron, folic By the end of this lecture the student
should be able to
Describe the causes of different anemias.
Explain the type of anemia expected as a result of
deficiencies of iron, erythropoietin, Vitamin B12 and folic acid.
Describe the primary acid and Vitamin B12.
Describe the absorption of iron by the intestines.
Explain the treatment for iron toxicity or overdose.
DRUG LIST:
Erythropoietin, darbopoietin, thrombopoietin, oprelvekin (IL11), filgrastim (G-CSF), iron preparations (ferrous sulfate, iron
dextran, iron sucrose, ferric gluconate), iron overdose
preparations (deferoxamine, deferasirox), folic acid, Vitamin B12
ANEMIA:
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Definition
Anemia; from Ancient Greek word,meaning lack of blood,
is a decrease in number of red blood cells (RBCs) or less than
the normal quantity of hemoglobin in the blood,or decreased
oxygen-binding ability
BLOOD PARAMETERS
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Hemoglobin concentration (Hg)
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F: 7,2 –10; M: 7,8-11,3 mmol Fe/l (12-18 g/dl)
Erythrocytes count (RBC)
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F: 4-5,5; M: 4,5-6 x1012/l (4-6 x106 /l)
Hematocrit (Hct)
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F: 37-47; M: 40-54; (37-54%)
Platelet count (Plt)
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150 – 450 x 103/l (150-450 x 109/l)
Leukocytes count (WBC)
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4-10 x 109/l (4-10 x 103/ l)
ERYTHROCYTES PARAMETERS
– Mean corpuscular volume (MCV)
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N: 80-100 fl
– Mean corpuscular hemoglobin (MCH)
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N: 27-34 pg
– Mean corpuscular hemoglobin concentration (MCHC)
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N: 310 – 370 g/lRBC (31-37 g/dl)
CAUSES OF ANEMIA
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A: Blood Loss
1:Acute eg: trauma
2:Chronic eg: GIT lesions
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B: Inadequate RBCs Production
1:Deficiency of essencial factors
a:Iron deficiency anemia
b:Intrinsic factor deficiency
c:Vit.B12 or Folic acid deficiency
2:Endocrine deficiency
e.g.: dec erythropoietin production
3:Bone marrow invasion
e.g.: a: leukemia
b: secondary carcinoma
4:Stem cells failure
e.g.: aplastic anemia
5:Drugs
e.g.: cholramphenicol
thiouracil
C: Increased RBCs Desrtuction
1: Intra-erythrocytic defects
a:Hereditary spherocytosis
b:Thalassemia
2: Extra-erythrocytic abnormalities
a: Erythroblastosis fetalis
b: Transfusion reactions
c: Malaria
BASIC PHARMACOLOGY
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Most common cause of chronic anemia
Iron forms the nucleus of the iron–porphyrin heme ring
Heme together with globin forms hemoglobin
Hemoglobin reversibly binds with oxygen and carry it from
lungs to other tissues.
PHARMACOKINETICS
MECHANISM OF IRON ABSORPTION
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Absorption:
Daily requirement 10-15mg
0.5 -1 mg daily absorbs
Site: duodenum and proximal jejunum
Absorption increases: low iron stores or increase iron
requirements
Mensturating women 1-2 mg/d
Pregnant women 3-4 mg/d
IRON CROSSES THE INTESTINAL MUCOSAL CELL BY
1:active transport of ferrous iron
2:absorption of iron complexed with heme
DMT1 divalent metal transporter, transports ferrous iron across
the luminal membrane. Dietary iron in the form of heme and
the ferrous ion (Fe2+)are taken up by specialized transporters
ferroreductase in intestinal epithelial cells and oxidized in the
mucosal cell to the ferric(Fe3+)form by ferroxidase.
TRANSPORT
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Iron bound to transferrin to transport in the plasma
Ferric iron is released ,reduce ferrous iron and transported by
DMT1 into the cell .
Transferrin-transferrin complex is recycled to the plasma, here
trasfferin dissociate and return to plasma
STORAGE:
• Stored in the mucosa (bound to ferritin),
• Carried elsewhere in the body (bound to transferrin)
• Excess iron stored in the protein –bound form in
macrophages and hepatocytes
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Gross overload ,in parenchymal cells of the skin, heart and
other organs.
Apoferritin level is regulated by free iron levels
ELIMINATION
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No mechanism for excretion
Small amounts are lost in the feces no more than 1mg per
day
Traces excreted in bile. sweat and urine
M.O.A
Fe combines with protoporphyrin IX & forms heme→4-heme
combine with polypeptide (gobin) to form hemoglobin (α or β)
IRON DEFICIENCY ANEMIA
• GENERAL SYMPTOMS:
– FATIGABILITY
– DIZZENES
– HEADACHE
– IRRITABILITY
– ROARING
– PALPITATION
THERAPEUTIC USES OF IRON
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Iron Deficient Anemia
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Pregnancy
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Premature Babies
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B l ood l os s
Hookworn infestation
Malabsorption Syndrome
GI Bleeding due to:
• Ulcers
• Aspirin
• Excess consumption of coffee
Preparation of Iron
i)Oral Iron
ii)
Parenteral Iron
Oral Iron
• Ferrous Sulphate
• Ferrous Gluconate
• Ferrous Fumarate
• Dose: 200 - 400mg daily and continue for 3-6 months in iron
deficiency anaemia
Adverse Effects: nausea, epigastric discomfort, abd.cramps,
constipation and diarrhea
• Parenteral Iron
INDICATION FOR USE
in pts unable to tolerate or absorb oral iron
in pts with chronic blood loss.
PREPARATION AVAILABLE
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Iron – Dextran. (imferon)
Sodium ferric gluconate complex
Iron – Sucrose (Jectofer)
Iron – Dextran. (imferon):
complex of ferric oxyhydroxide and dextran
50 mg of elemental iron/ml of solution
Deep I/M inj or I/V infusion.
ADVERSE EFFECTS:
Local pain & tissue staining
Headache, giddiness, flushing
Fever, Arthralgia, Backache
Nausea, Vomiting
Urticaria
Rarely Anaphylaxis & death.
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Sodium ferric gluconate complex and
Iron – Sucrose (Jectofer
Only given through I/V
Hypersensitivity reaction is less than dextran.
TOXICITY
Acute Iron Toxicity
• Symptoms: necrotizing gastroenteritis, abd pain, bloody
diarrhoea followed by metabolic acidosis, dyspnea, coma &
death
Rx
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i)Gastric Aspiration
Gastric lavage, with carbonate
solution to form insoluble Iron.
ii)
Deferoxamine - potent iron chelating compound
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Supportive Therapy
Chronic Iron Toxicity
• Seen in pt with hemochromatosis, and who received many
red cell transfusion
• Lead to organ failure or death
• Rx
– Intermittent Phlebotomy
– Oral iron chelator deferasirox
FOLIC ACID
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Essential for normal DNA synthesis
PHARMACOKINETICS OF FOLIC ACID
• Daily requirment 500-700 mcg
• 50-200mcg daily absorbs
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Pregnant women 300 400mcg
Richest source:yeast, liver, kidney, green vegetables
Store in liver and other tissues 5-20mg of folates
Excreted in urine and stool and also destroy by catabolism
Dietary folate Polyglutame of N5 –methyltetrahydrofolate
After absorption hydrolyed by the enzyme alpha-1-glutamyl
transferase
Transported into the blood stream by active and passive
transport and then distributed.
FOLIC DEFICIENCY SEEN IN
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Inadequate dietary intake of folates
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Prolong cooking
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In alcaholics & in pt with liver diseases
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Pregnancy
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Hemolytic Anemias
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Malabsorption Syndrome
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Occasionally associated with cancers, Leukemias., in
certain skin disorders, in chronic debiliating disease
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Pt. on Renal dialysis.
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Drugs interferring folate absorption or metabolism
e.g Phenytoin, Anti-convulsants, Oral contraceptives,
Isoniazid & others.
TREATMENT OF FOLIC ACID DEFICIENCY
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parentral administration rarely needed.
Oral therapy
Dose-1mg/d – continued until cause is corrected or removed.
Folic Acid supplementation, in high risk pts.
Clinical Toxicity of Vit B12 & Folic acid
not usually seen.
Vit B12 deficiency seen in
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Deficiency of intrinsic factor
Defect in absorption of Vit B12
Pernicious Anemia
Partial or total gastrectomy
Diseases affecting distal ileum.
Strict vegetarians
TREATMENT
Treatment of underlying disease
Parenteral therapy with
Inj Cyanocobalamin or hydroxocobalamin
• Initial therapy
100 – 1000 µg – I/M daily or on alternate days for 1-2weeks
Maintenance therapy
100 – 1000 µg – I/M- once a month
For Pernicious Anemia
1000 µg Orally of vitamin B12/daily
HEMATOPOIETIC GROWTH FACTORS
Proteins that regulate the proliferation and differentiation of
hematopoietic cells i.e. erythrocytes, platelets and leukocytes
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Erythropoietin
Myeloid growth factors
Megakaryocytic growth factors
Erythropoietin
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Produced by the kidney
Reduction in synthesis responsible for the anemia of renal
failure.
PHARMACOLOGICAL EFFECT
Stimulates the production and release of red cells ,by
activating the receptors on erythroid progenitors in the bone
marrow.
ERYTHROPOIETIN (T/U)
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Anemia of chronic renal disease
Primary bone marrow disorders
Anemia associated with malignancy & chemotherapy
Anemia of chronic diseases
HIV treatment
Bone marrow transplantation
Erythropoietin A/E
Thrombosis and hypertension
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Myeloid Growth Factors
CHEMISTRY
• G-CSF (granulocyte colony stimulating factor)
• GM-CSF (granulocyte macrophage colony stimulating factor)
Originally purified from cultured human cell lines
1: filgrastin (G-CSF)
Produced in a bacterial expression system
Non –glycosylated peptide of 175 amino acids
M.W 18kDa
2: sargramostin (GM-CSF)
produced in yeast expression system
Glycosylated peptide of 127 amino acids
3 molecular species 15,500; 15,800; 15,900
Half life 2-7 hours
PHARMACODYNAMICS
Stimulate proliferation and differentiation by interacting with
specific receptors found on myeloid progenitor cells
Stimulate the production and function of neutrophils after cancer
chemotherapy
It activates the phagocytic activity of mature neutrophils and
prolong their survival in the circulation
G-CSF has remarkably ability to mobilize hematopoietic stem
cells
Helps in major advance in transplantation
The use of peripheral blood stem cells(PBSCs) rather than bone
marrow stem cells for transplantation
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GM-CSF acts together with interleukin-2 to stimulate T-cell
proliferation
locally active factor at site of inflammation.
THERAPEUTIC USES
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Congenital neutropenia
Cyclic neutropenia
Myelodysplasia
Aplastic anemia
stem cell transplantation.
SIDE EFFECTS
Fever
Malaise
Arthralgias
Myalgias
Capillary leak syndrome (peripheral edema and pleural or
pericardial effusion)
TOXICITY
Bone pain.
MEGAKARYOCYTE GROWTH FACTORS
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Chemistry & Pharmacokinetics
thrombopoietin and interleukin-11 are the key endogenous
regulators of platelets production
1:Recombinant form of IL-11(OPRELVEKIN) was the first agent
for the treatment of thrombocytopenia
Interleukin-11 is 65-85kDa protein produced by fibroblast and
stromal cells in the bone marrow
Half life:7-8hours
ROA: subcutaneously
2:Romiplostin
Half life:3-4 days (inversely related to serum platelet count)
ROA: subcutaneously
 3:Eltrombopag
new orally small molecule agonist at thrombopoietin receptor
Use in idiopathic thrombocytopenia.
PHARMACODYNAMICS
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Stimulates the growth of multiple lymphoid and myeloid cell by
acting on cytokine receptors
Increases the number of peripheral platelets and neutrophils
Therapeutic uses
Secondary thrombocytopenia
Idiopathic thrombocytopenia
ADVERSE EFFECTS:
fatigue
Headache
Dizziness
Anemia
Dysnea
Atrial arraythmia
REFERENCES:
• BASIC AND CLINICAL PHARMACOLOGY,KATZUNG,
11th EDITION.
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