AGENTS USED IN ANEMIAS HEMATOPOITIC GROWTH

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					  AGENTS USED IN            ANEMIAS & HEMATOPOITIC
  GROWTH FACTORS


 LEARNING OBJECTIVE
 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 sites of action of erythropoietin.
 Explain the approved indications for treatment of anemia by
    erythropoietin, iron, folic 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 (IL-
    11), filgrastim (G-CSF), iron preparations (ferrous sulfate, iron
    dextran, iron sucrose, ferric gluconate), iron overdose
    preparations (deferoxamine, deferasirox), folic acid, Vitamin
    B12

 ANEMIA
 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
 Hemoglobin concentration (Hg)
             F: 7,2 –10; M: 7,8-11,3 mmol Fe/l (12-18 g/dl)
 Erythrocytes count (RBC)
          F: 4-5,5; M: 4,5-6 x1012/l (4-6 x106 /l)
 Hematocrit (Hct)
          F: 37-47; M: 40-54; (37-54%)
 Platelet count (Plt)
          150 – 450 x 103/l (150-450 x 109/l)
 Leukocytes count (WBC)
          4-10 x 109/l (4-10 x 103/ l)
 Erythrocytes parameters
    Mean corpuscular volume (MCV)
              N: 80-100 fl
    Mean corpuscular hemoglobin (MCH)
              N: 27-34 pg
    Mean corpuscular hemoglobin concentration (MCHC)
              N: 310 – 370 g/lRBC (31-37 g/dl)
 Causes of Anemia
 A: Blood Loss
     1:Acute eg: trauma
     2:Chronic eg: GIT lesions
 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
 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
 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
 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
       Gross overload ,in parenchymal cells of the skin, heart and
                                                       other organs.
                   Apoferritin level is regulated by free iron levels

 Elimination
 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
 Iron Deficient Anemia
 Pregnancy
 Premature Babies
 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
 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.


 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

     i)   Gastric Aspiration           Gastric lavage, with
     carbonate solution to form insoluble Iron.
  ii)  Deferoxamine - potent iron chelating compound
  iii) 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
 Essential for normal DNA synthesis
Pharmacokinetics of Folic Acid
 Daily requirment 500-700 mcg
 50-200mcg daily absorbs
 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
 Inadequate dietary intake of folates
 Prolong cooking
 In alcaholics & in pt with liver diseases
 Pregnancy
 Hemolytic Anemias
 Malabsorption Syndrome
 Occasionally associated with cancers, Leukemias., in certain
       skin disorders, in chronic debiliating disease
   Pt. on Renal dialysis.
   Drugs interferring folate absorption or metabolism
      e.g Phenytoin, Anti-convulsants, Oral contraceptives,
      Isoniazid & others.

 Treatment of Folic Acid Deficiency
 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
 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

 Erythropoietin
 Myeloid growth factors
 Megakaryocytic growth factors
 Erythropoietin
 Produced by the kidney
 Reduction in synthesis responsible for the anemia of renal
   faliure
  Pharmacological effect
  Stimulates the production and release of red cells ,by
   activating the receptors on erythroid progenitors in the bone
   marrow
 Erythropoietin (T/U)
 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
 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

      GM-CSF acts together with interleukin-2 to stimulate T-cell
        proliferation
     locally active factor at site of inflamation
     THERAPEUTIC USES
      Congenital neutropenia
      Cyclic neutropenia
      Myelodysplasia
      Aplastic anemia
5.     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
 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
 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




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