Pharmacology of Anemia lecture

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2. Objectives
At the end of the lesson, the student should be able to
 Define anemia
 Differentiate the different types of anemia
 Describe the clinical presentations of anemia
 Describe the pharmacotherapeutics basis of managing
anemia
 Describe the pharmacokinetic and pharmacodynamic effect
of antianemic drugs
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3. Introduction to Hematopoietic
• Hematopoietic machinery resides primarily in the bone
marrow in adults
• The process requires a constant supply of three essential
nutrients—iron, vitamin B12, and folic acid
– Also the presence of hematopoietic growth factor proteins
 regulate the proliferation and differentiation of hematopoietic cells.
• Inadequate supplies of the essential nutrients and the growth
factors  result in deficiency of functional blood cells.
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4. Anemia
• Anemia is a group of diseases characterized by a decrease
in either Hb or RBCs
 Resulting in reduced oxygen carrying capacity of the
blood.
• Anemias can result from :
Inadequate RBC production
Increased RBC destruction, or
Blood loss
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5. Classification of Anemia
Based on RBC size (Morphology)
3. Microcytic
• Iron-deficiency anemia
• Genetic anomaly
Sickle cell anemia
Thalassemia
2. Normocytic
• Recent blood loss
• Chronic disease i.e CKD
1. Macrocytic
• Megaloblastic (B12 and folate
Deficiency)
• Nonmegaloblastic May be due to
liver disease, hypothyroidism,
hemolytic anemia, alcoholism
Anemia
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6. Based on etiology
1. Deficiency Anemia
 Iron
 Vitamin B12
 Folic acid
3. Peripheral
Bleeding(hemorrhage)
Hemolysis (hemolytic anemia)
2 Central -- caused by impaired bone marrow function
 Anemia of chronic diseases
 Anemia of elderly
 Malignant bone marrow disorder
Anemia
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Classification of Anemia…..

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8. Iron Deficiency/Microcytic anemia
• In the absence of adequate iron  small erythrocytes
with insufficient hemoglobin are formed
 Giving rise to microcytic hypochromic anemia.
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9. Symptoms of IDA
Iron deficiency anaemia leads to
• Pallor
• Fatigue
• Dizziness
• Exertional dyspnea
• Tissue hypoxia
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10. Pharmacologic management
Iron
• Iron is stored as ferritin (an iron–protein complex) until needed by the
body.
 Intestinal mucosal cells
 Liver
 Spleen
 Bone marrow
• Iron is delivered to the marrow for hemoglobin production by
transferrin proteins
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11. Drug therapy of IDA
Iron formulation Elemental Iron (%)
Ferrous sulfate 20
Ferrous gluconate 12
Ferric ammonium citrate 18
Ferrous fumarate 33
Carbonyl iron 100
Polysaccharide-iron complex 100
Elemental iron content
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12. Pharmacokinetics of iron
Iron absorption
• Iron is absorbed after oral administration.
• Orally taken Ferrouse (Fe+3) is converted to ferric Fe+2 to be
absorbed (feroreductse enzyme-DCYTb) -- Fe+3 DCYTb Fe+2
• Iron crosses the luminal membrane of the intestinal mucosal
cell by two mechanisms:
1. Active transport of ferrous iron (Fe+2) by the divalent
metal transporter DMT1
2. Absorption of iron complexed with heme
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13. Pharmacokinetics ….
• Free inorganic iron is extremely toxic, but iron is required for
essential proteins such as hemoglobin;
• Acidic conditions in the stomach keep iron in the reduced ferrous
form which is the more soluble form.
• The amount absorbed depends on the current body stores of iron.
• The relative percentage of iron absorbed decreases with increasing
doses.
– For this reason, it is recommended that most people take the
prescribed daily iron intake in two or three divided doses.
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14. Pharmacokinetics ….
• The absorbed iron can be actively transported into the
blood across by a transporter called ferroportin and
oxidized to ferric iron (Fe3+) by the ferroxidase
hephaestin.
• Then Iron (Fe+3) is transported in the plasma bound
to transferrin
Fe+2 Fe+3
Hephaestin
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16. Drug Interactions
• Antacids reduce the absorption of iron
• Co-administration of iron with tetracyclines decreases
absorption of both
• Ascorbic acid (vitamin C) promotes iron absorption but
also increases its adverse effects.
• Al3+, Mg2+, and Ca2+-containing antacids
• Levodopa (chelates with iron)
• Levothyroxine (decreased efficacy of levothyroxine)
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17. Side effect
GI related in side effects
• Dark discoloration of feces
• Constipation or diarrhea
• Nausea, and vomiting
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18. Parenteral formulations
• Parenteral formulations of iron
 Iron dextran
 Sodium ferric gluconate complex
 Iron sucrose
Iron-dextran
• It is a high molecular weight colloidal solution containing 50
mg elemental iron/ml
• The preparation that can be injected I.M/I.V.
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19. Indication of Parenteral iron
Iron therapy by injection is indicated only when:
1. Oral iron is not tolerated
2. Failure to absorb oral iron: mal-absorption; inflammatory
bowel disease.
3. Non-compliance to oral iron.
4. In presence of severe deficiency with chronic bleeding
5. Along with erythropoietin: oral ion may not be absorbed at
sufficient rate to meet the demands of induced rapid
erythropoiesis.
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20. Acute Iron Toxicity
• Seen almost exclusively in young children
• Symptoms of oral iron poison shows necrotizing gastroenteritis
with
– Vomiting, abdominal pain, and bloody diarrhea followed by
shock, lethargy, and dyspnea.
• Whole bowel irrigation  to flush out unabsorbed pills.
• Deferoxamine  a potent iron-chelating compound, can be given
intravenously to bind absorbed iron
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21. Chronic iron toxicity
• Also known as hemochromatosis
• Results when excess iron is deposited in the heart, liver,
pancreas, and other organs.
• It can lead to organ failure and death
• Most commonly occurs in patients
With inherited hemochromatosis (disorder with excessive iron
absorption)
During long term & many red cell transfusions
• Most efficiently treated by intermittent phlebotomy. 21

22. Vitamin B-12/ Cobalamin
Deficiency
Vitamin B-9/ Folic
Acid Deficiency
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23. Vitamin B12 (cobalamin)
• Serves as a cofactor for several essential biochemical reactions in
humans.
• Deficiency leads to
Megaloblastic anemia
Gastrointestinal symptoms
Neurologic abnormalities
• Vitamin B12 is important for myelination of neurons, primarily in
the spinal cord and brain.
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24. Function of Vit B12
• Vitamin B12 is essential for synthesis of DNA
– Hence is required for the growth and division of all
cells. HOW?
• Vitamin B12 helps catalyze the conversion of folic
acid to its active form
• Active folic acid then essential for DNA synthesis
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25. Folic acid
(Inactive)
Folic acid
(Active)
DNA
Synthesis
Regeneration of new
Erythrocytes and
other cells
Folic acid
(Inactive)
1. Common path
Vit B12
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26. Cont…
• Deficiency of vit B12 due to inadequate supply is unusual
• But deficiency of vit B12 in elderly patients due to
inadequate absorption of dietary vit B12 is a relatively
common
 Lack of intrinsic factor
• Nutritional deficiency is rare but may be seen in strict
vegetarians
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27. Sources of Vit B12
• Ultimate source of vitamin B12 is from microbial synthesis
– Microbially derived from meat (especially liver), eggs, and
dairy products
• Only trace amounts of vit B12 are normally lost in urine and stool.
– Because the normal daily requirements of vitamin B12 are
only about 2 mcg  it would take ~5 years for all of the stored
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28. Absorption of Vit B12
• Vitamin B12 is absorbed after it complexes with intrinsic
factor, a glycoprotein secreted by the parietal cells of the
gastric mucosa.
• Following absorption
 The vitamin B12–intrinsic factor complex dissociates.
 Free B12 then binds to transcobalamin II for transport to
tissues.
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29. Symptoms of Vit B12 deficiency
• Tingling (pins and needles) in the hands and feet
• Difficulty walking
• Dementia
• In extreme cases, hallucinations, paranoia, or
schizophrenia
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30. Pharmacodynamics
• Two essential enzymatic reactions in humans require vitamin B12
1. Methylcobalamin serves as an intermediate in the transfer of a methyl group
from N 5-methyltetrahydrofolate to homocysteine, to form methionine
 Without vitamin B12, conversion of the major dietary and storage folate
N 5-methyltetrahydrofolate to tetrahydrofolate, the precursor of folate
cofactors, cannot occur.
 As a result, vitamin B12 deficiency leads to deficiency of folate
cofactors
2. Isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme
methylmalonyl-CoA mutase
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32. • Methylcobalamin is active coenzyme for synthesis of
methionine and S-adenosylmethionine
– That is needed for integrity of myelin
– For correcting the neurological defects
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33. Cont..
• Folic acid administration alone reverses the hematologic
abnormality
Thus, masks the vitamin B12 deficiency, which can then
proceed to severe neurologic dysfunction and disease.
• Therefore, megaloblastic anemia should not be treated with
folic acid alone but combination
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34. Preparations of cobalamin
• Cyanocobalamin
• Hydroxocobalamin
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(PO, SC, & IM)
But not IV

35. Vitamin B9 (folic acid)
• Reduced forms of folic acid are required for essential biochemical
reactions
– i.e. synthesis of amino acids, purines, and DNA
• Folate deficiency is relatively common
– Caused by inadequate dietary intake of folates.
• The richest sources are yeast, liver, kidney, and green vegetables.
• The excess Folate is stored in the liver
– Patients with alcohol dependence and with liver disease
develop Folate deficiency
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36. Cont…
• The result of folic acid deficiency is megaloblastic
anemia (large-sized red blood cells),
– Which is caused by diminished synthesis of purines
and pyrimidines
– This leads to an inability of erythropoietic tissue to
make DNA
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37. Folic acid supplementation
• Prevent folic acid deficiency should be considered in high-risk
patients
 Pregnant women – prevents neural tube defects (spina bifida)
 Alcoholic patients
 Hemolytic anemia
 Liver disease
Currently the reduced or active form of the vitamin (folinic acid—
also known as leucovorin calcium available as oral and parenteral
formulations) is used for treatment.
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38. Drug interaction
• The effect of folic acid can be affected by drugs.
 Drug induced folic acid deficiency anemia
 Methotrexate
 Trimethoprim and pyrimethamine
 Phenytoin  reduce absorption of Folic acid
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Folic Acid
DHF
THF
DHFR
Thymidylate synthase
5,10, methyl THF
Co-enzyme
dUMP
dTMP
dTDP
dTTP
Nucleotide
cell division
DNA
mRNA
Methotrexate
Protein
synthesis

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