hematinics and epo

8/6/2019 Hematinics and EPO

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Laura M. Aguirre-Aguinaldo,MD,DPPS



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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ERYTHROPOETIN



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




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




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




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




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




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



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



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



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



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)



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.



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



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



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



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



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,



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



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



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



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



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.



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.




� 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).



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.



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




�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.



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




� 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.




� 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.




� 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




� 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)



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



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



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



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




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.




� 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



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



IRON

� To compute for elemental iron:

Elemental Fe=

No of tabs x (mg of FeSO4/tab) (% elemental iron)

weight of the patient (kg)



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.



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).



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



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



IRON

Iron Overdose

High levels of freecirculating iron

Cellular Toxicity



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



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



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.




� 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




� 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.




� 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.




�

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.



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



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



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.



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



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




� 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




� Riboflavin deficiency:

± Associated with infection and protein deficiency

±

Gross, generalized malnutrition ± Hypoproliferative anemia or pure red-cell aplasia

hematinics and epo

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