hematinics and epo
TRANSCRIPT
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Laura M. Aguirre-Aguinaldo,MD,DPPS
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1. To briefly review the process of hematopoiesis.
2. To discuss the PK/PD properties of the
different hematopoietic agents available.3. To describe their indications for use.
4. To discuss the adverse effects which are
related to the use of these substances.4. To know specific precautions which should beemployed when administering/using thesemedications if any.
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H
E
M
A
T
O
P
O
I
E
S
I
S
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ERYTHROPOETIN
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Hematopoietic Growth Factors
� Together with cytokines, are involved in theregulation and differentiation of the bloodcells.
� They include the following:
± Factors regulating specific cell lineage
± Factors regulating multiple cell lineage
±
Factors indirectly regulating hematopoiesis byinducing gene expression of growth factors andcytokines
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Hematopoietic Growth Factors
ERYTHROPOIETIN (EPO)
Stimulates proliferation and maturation of committed erythroid
progenitors to increase red cell production
STEM CELL FACTOR (SCF, c-kit ligand, Steel factor) and FLT-3LIGAND (FL)
Act synergistically with a wide range of other colony-stimulating
factors and interleukins to stimulate pluripotent and committed
stem cells
FL also stimulates both dendritic and NK cells (anti-tumor
response)
SCF also stimulates mast cells and melanocytes
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Hematopoietic Growth Factors
INTERLEUKINS
IL-1, IL-3, IL-5, IL-6, IL-9, and IL-11
Act synergistically with each other and SCF, GM-CSF, G-CSF, and EPO to
stimulate BFU-E, CFU-GEMM, CFU-GM, CFU-E, and CFU-Meg growth
Numerous immunologic roles, including stimulation of B cell and T cell growth
IL-5
Controls eosinophil survival and differentiation
IL-6
IL-6 stimulates human myeloma cells to proliferate
IL-6 and IL-11 stimulate BFU-Meg to increase platelet production
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Hematopoietic Growth Factors
INTERLEUKINS
IL-1, IL-2, IL-4, IL-7, and IL-12
Stimulate growth and function of T cells, B cells, NK cells, and
monocytes
Co-stimulate B, T, and LAK cells
IL-8 and IL-10
Numerous immunological activities involving B and T cell
functions
IL-8 acts as a chemotactic factor for basophils and neutrophils
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Hematopoietic Growth Factors
GRANULOCYTE-MACROPHAGE COLONYSTIMULATING FACTOR (GM-CSF)
Acts synergistically with SCF, IL-1, IL-3, and IL-6 to stimulate CFU-GM, and CFU-
Meg to increase neutrophil and monocyte production
With EPO may promote BFU-E formation
Enhances migration, phagocytosis, superoxide production, and antibody-
dependent cell-mediated toxicity of neutrophils, monocytes, and eosinophils
Prevents alveolar proteinosisGRANULOCYTE COLONYSTIMULATING FACTOR (G-CSF)
Stimulates CFU-G to increase neutrophil production
Enhances phagocytic and cytotoxic activities of neutrophils
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Hematopoietic Growth Factors
MONOCYTE/MACROPHAGE COLONYSTIMULATING FACTOR (M-CSF, CSF-1)
Stimulates CFU-M to increase monocyte precursors
Activates and enhances function of monocyte/macrophages
MACROPHAGE COLONYSTIMULATING FACTOR (M-CSF)
Stimulates CFU-M to increase monocyte/macrophage precursors
Acts in concert with tissues and other growth factors to determine the proliferation,
differentiation, and survival of a range of cells of the mononuclear phagocyte system
THROMBOPOIETIN (TPO, Mpl ligand)Stimulates the self-renewal and expansion of hematopoietic stem cells
Stimulates stem cell differentiation into megakaryocyte progenitors
Selectively stimulates megakaryocytopoiesis to increase platelet production
Acts synergistically with other growth factors, especially IL-6 and IL-11
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TERMS
Anemia below normal concentration of
circulatory hemoglobin or Hct concentration
less than 40% in men and 37% in women.
Sym ptoms are due to the reduced Hgb carrying
capacity of the RBCs.
* pallor, shortness of breat h , fatigue,
d ecreased mental alertness , apat hy ,
head ac hes
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TERMS
Two categories of Anemia:
Hypoproliferative: bone marrow production of
RBC is inadequate; low Rct count
Hyperproliferative: high Rct count, increased
destruction of RBC despite increased
production of the bone marrow
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Causes of Anemia
� Hypoproliferative ± Microcytic anemi a: iron
deficiency, anemia of chronic
dse,sideroblastic anemia
± Nor mocytic: anemia of chronicdse, endocrine anemia, bone
marrow failure
± Macrocytic: Vit. B12
deficiency, folic aciddeficiency,myelodysplastic
syndrome
� Hyperproliferative
± Hemolytic:
Hemoglobinopathies,
autoimmune,
membrane disorder,drug-induced,
metabolic
abnormalities, G6PD
deficiency, infections
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Erythropoiesis Stimulating Agents
(ESA)
� ESA connotes substances used for stimulation
of erythrocyte production
� Erythropoietin� The most important regulator of committed
erythrocyte progenitors (CFU-E)
� Severe anemia is a consequence of its absence( seen in patients with CRD)
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Erythropoiesis Stimulating Agents (ESA)
� Erythropoietin and renal disease
� Recombinant human erythropoietin (epoetin
alfa) and blood doping� Available preparations of epoetin alfa include
EPOGEN, PROCRIT, and EPREX, supplied in
single-use vials containing 2000-40,000units/mL for IV or SC administration.
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Erythropoiesis Stimulating Agents (ESA)
� When injected IV, epoetin alfa is cleared from
plasma with a t1/2 of 4-8 hours.
� Once-weekly dosing can be sufficient to achieve
an adequate response since the effect on
marrow progenitors lasts much longer.
� Although allergic reactions have been reported,
no consistent pattern of significant allergicreactions has emerged
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Erythropoiesis Stimulating Agents
(ESA)
� Darbepoetin alfa (ARANESP) recently
approved, a novel erythropoiesis-stimulatingprotein
� Approved for clinical use in patients with
indications similar to those for epoetin alfa
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Therapeutic uses, monitoring and
adverse effects
� There is a clear dose-response relationship
between erythropoietin and rise of hematocrit
values
� Indications: Treatment of anemias due to
surgery, AIDS, cancer chemotherapy and
chronic inflammatory conditions
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Therapeutic uses, monitoring and
adverse effects
� Possible complications:
± development of functional iron deficiency (
normal ferritin levels, low transferrin saturation)
± Monitor hemoglobin (hgb) and hematocrit (hct)
levels. Decrease dose if there is > 4 point increase
in hct or increase in hgb by > 1g/dL in two weeks
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Therapeutic uses, monitoring and adverse
effects
� Possible complications:
± Development of thromboembolic events duringhemodialysis. Targeting ideal hemoglobin/hematocritlevels may contribute to risk
± Increased risk of cancer recurrence and decreasedsurvival
± Hypertension
± Resistance to treatment
± Pure red cell aplasia
± Headache, nausea, vomiting, flu-like symptoms,diarrhea, edema, tachycardia, shortness of breath,stinging at injection site,
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Specific Indications
� Anemia of chronic renal failure
± SC route preferred
± 2-4 months of treatment until targethgb/hct is reached
± Starting dose 80-120 u/kg 3x/week, average
75 u/kg 3x/week ±Children usually require higher doses
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Specific Indications
� Cancer related Anemias:
± 150 u/kg 3x/week or 450-600 u/kg 1x a week can
reduce transfusion requirements
± Recommended once hgb levels 10 g/dL ± May have a cytoprotectant effect
± May stimulate growth of tumor cells
�
Anemia in AIDS ± In patients on zidovudine therapy
± Doses given at 100-300 u/kg 3x/week SC
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Granulocyte-Macrophage Colony-
Stimulating Factor
� Recombinant human GM-CSF (sargramostim) is a127 amino acid glycoprotein produced in yeast
� Its primary therapeutic effect is to stimulate
myelopoiesis� Initially given to patients undergoing autologous
bone marrow transplantation.
� The shortened duration of neutropeniasignificantly reduced transplant morbidity withouta change in long-term survival or risk of inducingan early relapse of the malignant process
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Granulocyte-Macrophage Colony-
Stimulating Factor
� Sargramostim (LEUKINE) is administered by SC injection or slow IV infusion at doses of 125-500g/m2 per day.
�
Plasma levels of GM-CS
F rise rapidly afterSC
injection and then decline with a t1/2 of 2-3 hours.When given IV, infusions should be maintainedover 3-6 hours.
� A transient decrease in the absolute leukocytecount secondary to margination and sequestrationin the lungs is noted during initial treatmentfollowed by a dose-dependent, biphasic increasein leukocyte counts over the next 7-10 days
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Granulocyte-Macrophage Colony-Stimulating
Factor
� The dose may be increased if the patient fails torespond after 7-14 days of therapy.
� However, higher doses are associated with morepronounced side effects, including bone pain,
malaise, flu-like symptoms, fever, diarrhea,dyspnea, and rash.
� Capillary leak syndrome may develop in somepatients with prolonged use with peripheral edema
and pleural and pericardial effusions.� Other serious side effects: transient
supraventricular arrhythmia, elevation of serumcreatinine, bilirubin, and hepatic enzymes anddyspnea.
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Granulocyte Colony-Stimulating Factor
� Recombinant human G-CSF filgrastim
(NEUPOGEN) is a 175 amino acid glycoprotein
produced in Escherichia coli
� Acts mainly to stimulate CFU-G to increase
neutrophil production. It also enhances the
phagocytic and cytotoxic functions of neutrophils.
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Granulocyte Colony-Stimulating Factor
� Indications: used in the treatment of severe neutropenia afterautologous hematopoietic stem cell transplantation and high-
dose cancer chemotherapy.
� Filgrastim shortens the period of severe neutropenia and
reduces morbidity secondary to bacterial and fungal infections.
� also is effective in the treatment of severe congenital
neutropenias.
� In patients with cyclic neutropenia, G-CSF therapy will increase
the level of neutrophils and shorten the length of the cycle
sufficiently to prevent recurrent bacterial infections.
� can improve neutrophil counts in some patients with
myelodysplasia or marrow damage (moderately severe aplastic
anemia or tumor infiltration of the marrow).
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Granulocyte Colony-Stimulating
Factor� The neutropenia of AIDS patients receiving
zidovudine also can be partially or completelyreversed.
� Routinely used in patients undergoing peripheralblood stem cell (PBSC) collection for stem celltransplantation.
�
G-CS
F
induced mobilization of stem cells into thecirculation has been promoted as a way toenhance repair of other damaged organs in whichPBSC might play a role.
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Granulocyte Colony-Stimulating
Factor� Filgrastim is administered by SC injection or IV
infusion over at least 30 minutes at doses of 1-
20 g/kg per day. The usual starting dose in a
patient receiving myelosuppressive
chemotherapy is 5 g/kg per day.
� The distribution and clearance rate from
plasma (t1/2 of 3.5 hours) are similar for bothroutes of administration
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Granulocyte Colony-Stimulating Factor
�Adverse reactions to filgrastim include: mild tomoderate bone pain in patients receiving highdoses over a protracted period
� Local skin reactions following SC injection, and rare
cutaneous necrotizing vasculitis.� Patients with a history of hypersensitivity to
proteins produced by E. coli should not receive thedrug.
� Marked granulocytosis, with counts >100,000/L,can occur in patients receiving filgrastim over aprolonged period of time.
� Mild to moderate splenomegaly has beenobserved in patients on long-term therapy.
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Thrombopoietic Growth Factors
� Oprelvekin (interleukin-11): the first growth factorapproved by the US FDA for the treatment of secondary thrombocytopenia in cancer patientsreceiving chemotherapy
� Recombinant human IL-11 oprelvekin (NEUMEGA)is a bacterially derived 19,000-Da polypeptide of 177 amino acids
� Stimulates the production of megakaryocytes andthrombocytes by activation IL-11 receptors on theprogenitor cells of platelets
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Thrombopoietic Growth Factors
� t1/2: 7-hour after SC injection.
� In normal subjects, daily administration of
Oprelvekin leads to a thrombopoietic response
in 5-9 days.
� The drug is available in single-use vials
containing 5 mg and is administered to patients
at 25-50 g/kg per day SC.
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Thrombopoietic Growth Factors
� Approved for use in patients undergoing
chemotherapy for nonmyeloid malignancies
that displayed severe thrombocytopenia
(platelet count <20,000/L) on a prior cycle of the same chemotherapy, and it is administered
until the platelet count returns to >100,000/L.
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Thrombopoietic Growth Factors
� Major complications: fluid retention andassociated cardiac symptoms .
� Fluid retention reverses upon drug
discontinuation, but volume status should becarefully monitored in elderly patients, those
with a history of heart failure, or those with
preexisting fluid collections in the pleura,
pericardium, or peritoneal cavity.
� Other effects: blurred vision, paresthesias and
rash or erythema at injection site
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Thrombopoietic Growth Factors
� Others:
� Recombinant thrombopoietin
± recombinant human megakaryocyte growth and
development factor (rHuMGDF); produced inbacteria
± recombinant human thrombopoietin (rHuTPO),
produced in mammalian cells
� Romiplostim (NPLATE)
� Eltrombopag ( PROMACTA)
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IRON
� The average adult body contains 3-5g of iron
± 70% in ferrous (Fe+2) state in Hgb & myoglobn
± 25% as ferric (Fe+3 ) in the form of ferritin and
stored as hemosiderin
± 5% found attached to transferrin or in heme and
flavin enzymes
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IRON
� Dietary iron is mainly absorbed in the ferrous
form ( duodenum and upper jejenum)
�
Plasma iron is bound to transferrin in theferric state
± Transferrin is a protein carrier that transports
either dietary or storage iron entering the plasma
for redistribution and utilization
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IRON
� Majority of the iron is transported to the
reticuloendothelial system and hepatocytes
± Stored w/in the protein ferritin
� Elimination is primarily thru exfoliation of GI
mucosal cells
± 1mg/day in adult males
± 2mg/ day (menstrual loss) in females
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Treatment of Iron Deficiency:
� Clinically, the effectiveness of iron therapy is bestevaluated by tracking the reticulocyte response and therise in the hemoglobin or the hematocrit. Hematocrit isobserved for at least 4-7 days after beginning therapy. Ameasurable increase in the hemoglobin level takes even
longer.� A decision as to the effectiveness of treatment should
not be made for 3-4 weeks after the start of treatment.An increase of 20 g/L in the concentration of hemoglobin by that time should be considered a
positive response, assuming that no other change in thepatient's clinical status can account for theimprovement and that the patient has not beentransfused
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Treatment of Iron Deficiency:
Oral administration of ferrous sulfate is the best
standard therapy for iron deficiency.
Best absorbed taken on an empty stomach withascorbic acid ( >200mg) which binds to it and
facilitates transport to intestinal cells
Absorption is impaired by antacids and other
medications that reduce stomach acid
production.
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Treatment of Iron Deficiency:
� Dose: 150-300 mg of elemental iron per day,average 200mg ( 2-3mg/kg) divided into 3-4doses
� Children can tolerate higher doses: 5mg/kg
� Duration of treatment: months, variable
� Common adverse effects: upper GI discomfort,constipation, heartburn, nausea,diarrhea,
transient staining of teeth� Food sources: organ meats, brewers yeast,
wheatgerm, egg yolks, oysters, certain driedbeans and fruit
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Commonly used oral preparationsPreparation Tablet size
(mg)
Elemental iron
per tablet (%)
Elemental iron
per tablet
(mg)
Dosage
(tablets/day)
Ferrous
sulfate,
hydrated
325 20% 65 3-4
Ferroussulfate,
dessicated
200 30% 60- 65 3-4
Ferrous
gluconate
325 12% 36 -39 3-4
Ferrous
fumarate
100 33 6-8
325 33% 106 -107 2-3
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IRON
� To compute for elemental iron:
Elemental Fe=
No of tabs x (mg of FeSO4/tab) (% elemental iron)
weight of the patient (kg)
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Parenteral Iron
� Common indications are iron malabsorption(e.g., sprue, short bowel syndrome), severeoral iron intolerance, as a routine supplement
to total parenteral nutrition, and in patientswho are receiving erythropoietin
� Parenteral iron also has been given to iron-deficient patients and pregnant women tocreate iron stores, something that would takemonths to achieve by the oral route.
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Parenteral Iron
� Parenteral iron therapy should be used only whenclearly indicated because acute hypersensitivity,including anaphylactic and anaphylactoidreactions, can occur in 0.2-3% of patients.
� Other reactions to intravenous iron includeheadache, malaise, fever, generalizedlymphadenopathy, arthralgias, urticaria andexacerbation of rheumatoid arthritis.
� Four iron formulations are available in the U.S.These are iron dextran (DEXFERRUM or INFED),sodium ferric gluconate (FERRLECIT), ferumoxytol(FERAHEME), and iron sucrose (VENOFER).
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IRON POISONING
� Free iron is toxic to many cellular processes
� Children may be more at risk
�
Defense mechanisms to prevent toxicity: ± Once absorbed, either stored w/in ferritin
± or prepared for release to transferrin;
± Constant sloughing of intestinal cells
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IRON POISONING
� The body is poorly equipped to handle
excessive amounts of iron
� In excessive doses, absorption continues
towards a concentration gradient
� Intestinal mucosal injury promotes further
absorption
� Normal protective mechanisms (transport and
storage proteins) become saturated
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IRON
Iron Overdose
High levels of freecirculating iron
Cellular Toxicity
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VITAMIN B12
� Cyanocobalamin/ Hydroxocobalamin
� MOA: a co factor required for essential
enzymatic reactions that form
tetrahydrofolate, convert homocysteine to
methionine and metabolize L-methylmalonyl-
CoA
� Effects: essential for amino and fatty acid
metabolism and in DNA synthesis
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VITAMIN B12
� Indication: Treatment of vitamin B12deficiency which manifests as megaloblasticanemia and is the basis of pernicious anemia
� Vitamin B12 deficiency can irreversiblydamage the nervous system. Progressive
swelling of myelinated neurons,demyelination, and neuronal cell death areseen in the spinal column and cerebral cortex
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Vitamin B12 Deficiency
� Cobalamin, source is dietary animal proteins.Humans depend on exogenous sources of vitaminB12.
� In nature, the primary sources are certain
microorganisms that grow in soil, sewage, water, orthe intestinal lumen of animals that synthesize thevitamin. Vegetable products are free of vitamin B12unless they are contaminated with such
microorganisms� Deficiency states are rare except in vegetarians and
infants of vegetarian mothers.
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Vitamin B12 Deficiency
� Disease states: ± Achlorhydria secondary to gastric atrophy or gastric
surgery
±
Pancreatic disorders ± Bacterial overgrowth
± Intestinal parasites
± Sprue
± Localized damage to ileal mucosal cells
± Children with methylmalonic aciduria and
homocystinuria
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Vitamin B12 Deficiency
� Causes a wide range of neurological signs andsymptoms, including paresthesias of the handsand feet, decreased vibration and position senseswith resultant unsteadiness, decreased deeptendon reflexes, and in the later stages, confusion,moodiness, loss of memory, and even a loss of central vision.
� The patient may exhibit delusions, hallucinations,or even overt psychosis.
� Vitamin B12 deficiency must be considered inelderly patients with dementia or psychiatricdisorders, even if they are not anemic.
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Vitamin B12 Deficiency
� Diagnosis is based on low serum levels of Vit.B12 or increase serum and urine concentrations
of methylmalonic acid
�
Treatment: Initially parenteral administration of Vit. B12 (cyanocobalamin or hydroxocobalamin)
� IM or SC never IV
�
Dose:C
yanocobalamin at 0.1-1.0 mg IM dailyfor 1-2 weeks.
± For pernicious anemia, lifelong monthly injections
with cyanocobalamin 1 mg.
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Vitamin B12 Deficiency
�
Hydroxocobalamin given in doses of 100 µgintramuscularly has been reported to have a moresustained effect than cyanocobalamin, with a singledose maintaining plasma vitamin B12concentrations in the normal range for up to 3
months.� However, some patients show reductions of the
concentration of vitamin B12 in plasma within 30days, similar to that seen after cyanocobalamin.
� Furthermore, the administration of hydroxocobalamin has resulted in the formation of antibodies to the transcobalamin II vitamin B12complex.
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FOLIC ACID
� Folacin (pteroylglutamic acid)� MOA: a precursor of an essential donor of
methyl groups used for synthesis of amino
acids, purines and deoxynucleotide
� Effects: adequate supplies are required for
essential biochemical reactions involving
amino acid metabolism, and purine and
DNA synthesis
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FOLIC ACID
� Indication: treatment of megaloblastic anemiaand prevention of congenital neural tube
defects.
�Mainly absorbed in the proximal portion of the jejenum
� Well absorbed orally
�
Not toxic in overdose� Use with caution in patients who might also be
deficient in Vit. B12
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FOLIC ACID
� Many food sources are rich in folates, especially
fresh green vegetables, liver, yeast, and some
fruits. However, lengthy cooking can destroy up
to 90% of the folate content� Normal daily requirement is 100g
� It is especially recommended for pregnant
women to take folate supplements sincedeficiency is linked to development of
congenital neural tube defects.
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Folic Acid Deficiency
� May result because of disease states, use of
drugs such as methotrexate, trimethoprim ,
oral contraceptives and some anticonvulsants
� Treatment: Initially give 1-5 mg IM then perorem 1-2mg daily for two weeks.
� Severe Vit. C deficiency may be a barrier to
effective treatment
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Deficiency of Other Nutrients
� Copper deficiency:
± Extremely rare; copper supplied in the diet
is usually sufficient
± May interfere with iron absorption and
release from reticuloendothelial cells
± May affect mitochondrial production of heme
± Microcytic anemia
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Deficiency of Other Nutrients
� Pyridoxine deficiency:
± may have a role in the treatment of acquired or
hereditary sideroblastic anemia
± Anti-TB drugs isoniazid and pyrazinamide and the
anti-Parkinsons drug levodopa can cause
sideroblastic anemia
±
Not beneficial if the defect is due tochloramphenicol or lead
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Deficiency of Other Nutrients
� Riboflavin deficiency:
± Associated with infection and protein deficiency
±
Gross, generalized malnutrition ± Hypoproliferative anemia or pure red-cell aplasia