Anemia Handout 2014(1)

7/21/2019 Anemia Handout 2014(1)

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Regie A. Layug, MDMedical Pharmacology Program

San Beda College of Medicine

Mendiola, Manila

Session Objectives

At the end of the session, the student-

learners are expected to differentiate the

different agents used in anemia and

hematopoietic growth factors as to:

1. Pharmacokinetic properties

2. Mechanism of action

3. Clinical uses and indications

4.

Adverse effects

Iron Deficiency

! Most common causeof chronic anemia

! Clinical Presentation" Pallor, fatigue,

dizziness, exertional

dyspnea, othergeneralized symptomsof tissue hypoxia

"

Cardiovascularadaptations:!

Tachycardia, increasedcardiac output,vasodilation


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Iron

Forms the nucleus ofiron-porphyrin heme

ring

Together with globin

chains forms

hemoglobin

In its absence, small

RBCs with insufficienthemoglobin

(microcytic

hypochromic anemia)

Clinical Pharmacology of Iron

! Indication" Treatment or prevention of iron deficiency

anemia

! Population with increased iron requirements:1. Infants

2.

Children in rapid growth periods,3. Pregnant and lactating women,

4. CKD patients

! Conditions with inadequate iron absorption:Gastrectomy patients, patients with severesmall bowel disease

! Conditions with blood loss: menstruatingwomen, GI bleeding


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Clinical Pharmacology of Iron

!

Treatment" Oral or parenteral iron preparations

! Oral iron corrects anemia as rapid and

complete as parenteral iron

! Exception: CKD patients undergoing

hemodialysis!parenteral iron is preferred

Oral Iron Therapy

Ferrous salts are used since this is more

efficiently absorbed

Ferrous sulfate

Ferrous gluconate

Ferrous fumarate

200-400 mg elemental iron should begiven daily to correct iron deficiency

anemia continued for 3-6 months

AFTER correction of the iron loss

Oral Iron Therapy

!Adverse Effects

" Nausea, epigastric discomfort, abdominalcramps, constipation and diarrhea

" Usually dose-related

"

Black stools


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Parenteral Iron Therapy

Reserved for patients with: Documented iron deficiency unable to tolerate or

absorb oral iron Patients with extensive chronic blood loss who

cannot be maintained on oral iron alone: s/p Gastrectomy and bowel resection patients Inflammatory bowel disease

Malabsorption syndromes Advanced CKD

Monitor iron storage levels periodically toavoid serious toxicity associated withoverload


! Preparations"

Iron dextran

! Stable complex of ferric hydroxide and LMWdextran containing 50 mg elemental Fe per mLsolution

! Maybe given deep IM or IV but IV route is mostpreferred to eliminate local pain and tissueswelling

!Adverse Effects: headache, light-headedness,fever, arthralgias, nausea and vomiting, back pain,flushing, urticaria, bronchospasm, anaphylaxis(test dose should always be performed prior toadministration)


! Preparations

" Iron-sucrose complex and iron sodiumgluconate complex

! Given via IV route

!

Less likely to cause hypersensitivity reactionscompared to iron dextran


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Clinical Toxicity of Iron

!

Acute Iron Toxicity" Seen almost exclusively children due to

accidental ingestion

"As few as 10 tablets can be lethal in young

children

" Toxic effects: necrotizing gastroenteritis withvomiting, abdominal pain, bloody diarrhea !metabolic acidosis, coma and death


!Acute Iron Toxicity

" Urgent treatment

! Whole body irrigation gastric lavage

! Deferoxamine iron-chelating compound

which may promote excretion of absorbed iron

in the urine and feces

! Supportive therapy for GI bleeding, metabolicacidosis and shock


Chronic Iron Toxicity

Iron overload (Hemochromatosis)

Occurs when excess iron is deposited in the

heart, liver, pancreas, and other organs

May be hereditary ( inherited hemochromatosis)

In patients with chronic red cell transfusions (e.g.

patients with thalassemia major)

In the absence of anemia !treatment is byintermittent phlebotomy

Deferasirox oral iron chelator approved for

treatment of iron overload


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Vitamin B12

Essential cofactor

Deficiency leads toanemia, GI symptomsand neurologicabnormalities

Consists of aporphyrin ring with acentral cobalt atomattached to anucleotide

Vitamin B12

Cyanocobalamin and

hydroxocobalaminfound in food sourcesare converted to theactive forms!deoxyadenosyl-cobalamin andmethylcobalamin

Ultimate source is

from microbialsynthesis

Dietary sources:meat, eggs and diaryproducts

Vitamin B12

Of the 5-30 mcg of vitamin B12taken daily,only 1-5 mcg is absorbed

Trace amounts lost in the urine and stools

Metabolism

Complexes with intrinsic factor and becomesabsorbed in the distal ileum

Once absorbed it becomes transported tovarious cells in the body bound to plasma

transcobalamin II

Excess vitamin is transported to liver for storage


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Vitamin B12

!

Enzymatic reactionsthat require vitaminB12:

1. Conversion of N5-

methyl THF to THF(the precursor to

folate cofactors)

! Depletion ofvitamin lead to

depletion of THFneeded for DNAsynthesis

Vitamin B12

! Enzymatic reactions

that require vitaminB12:

2. Isomerization of

methylmalonyl-CoAto succinyl-CoA

!"#$%&'(&)*%&+,)- '/#(0"

!"#$%&'"(#)%*+#,&*&-.(

Vitamin B12

The most characteristicclinical manifestation ofvitamin B12deficiency ismegaloblastic anemia Clinical findings:

Macrocytic anemiaassociated with mild or

moderate leukopenia orthrombocytopenia,hypercellular bonemarrow withaccumulation ofmegaloblastic erythroidand other precursor cells


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Vitamin B12

!

Neurologic syndrome associated withvitamin B12deficiency

" Paresthesias and weakness in peripheralnerves!spasticity, ataxia, CNSdysfunctions

" Correction of vitamin B12deficiency arrests

the progression of the disease but may notfully reverse symptoms that are present forseveral months

Vitamin B12

Most common causes

of vitamin B12deficiency Pernicious anemia

Defective secretion ofintrinsic factor bygastric mucosal cells

Partial or totalgastrectomy

Conditions that affectthe distal ileum (e.g.malabsorptionsyndromes, IBD, smallbowel resection)

Vitamin B12

! Vitamin B12for parenteral injection isavailable as cyanocobalamin orhydroxocobalamin

" Hydroxocobalamin is preferred because it ismore protein bound and remains longer in

circulation! Initial therapy: 100-1000 mcg vitamin B12IM

daily or every other day for 1-2 weeks toreplenish body stores

! Maintenance: every 1-2 weeks for 6 months!then switch to monthly injections


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Folic Acid

!

Heterocycle (pteridine),p-aminobenzoic acid,and glutamic acid

! May undergo reduction

to give dihydrofolic acid!folate cofactors

Folic Acid

! Of the 500-700 mcgfolic acid taken daily,only 50-200 usuallyis absorbed

! Present in variousplant and animaltissues

! Usual storage is inthe liver

! Excreted in the urineand stools

Enzymatic Reactions that use

Folates


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Folic Acid

!

Folate deficiencyresults to

megaloblastic anemia" Caused by inadequate

dietary intake of folates

and diminished hepatic

storage! Alcoholics

! Patients with liver disease

! Pregnants

! Patients with hemolytic anemia

" Megaloblastic anemia

only develops within 1-6months of stoppage of

folic acid intake

Folic Acid

! Evidence implicates

maternal folic aciddeficiency in theoccurrence of fetal

neural tube defects

Folic Acid

! Other causes of folic acid deficiency

" Patients with malabsorption syndromes

" Renal dialysis patients

! Folates are removed from the plasma

"

Certain drugs! Those which inhibit DHF reductase and result

to deficiency of folate cofactors

" Methotrexate

" Trimethoprim and pyrimethamine

! Long term therapy with phenytoin


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Folic Acid

!

Oral folic acid is well-absorbed makingparenteral folic acid rarely necessary"

A dose of 1 mg folic acid daily is sufficient toreverse megaloblastic anemia and restorefolic acid stores

" Supplementation should be considered in:

! Pregnant patients

!Alcoholics

! Hemolytic anemia patients, liver disease,certain skin diseases and patients on renaldialysis

Hemopoietic Growth Factors

! Glycoprotein hormones that regulate theproliferation and differentiation ofhemopoietic progenitor cells in the bonemarrow"

Erythropoietin

" Granulocyte colony-stimulating factor (G-CSF)

" Granulocyte-macrophage colony-stimulatingfactor (GM-CSF)

" Interleukin 11 (IL-11)

Overview of Hematopoiesis


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Erythropoietin

!

Originally purified from the urine ofpatients with severe anemia

! Serum half-life 4-13 hours in patients

with chronic kidney disease

! Darbepoietin alfa

" Glycosylated form of erythropoietin

" Has 2-3 times longer half life

Erythropoietin

! Stimulates erythroidproliferation and

differentiation byinteracting with

specific erythropoietin

receptors on red cellprogenitors

! Induces the release ofreticulocytes from the

bone marrow

Erythropoietin

! Used for patients with anemia of chronicrenal failure

" Improves hematocrit and hemoglobin levels andusually eliminates the need for transfusions

! May be useful in selected patients for thetreatment of anemia due to primary bone

marrow disorders and secondary anemia

! Sometimes misused by athletes to boostathletic performance


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Myeloid Growth Factors

!

Stimulate proliferation and differentiationby interacting with specific receptorsfound on various myeloid progenitorcells" G-CSF

! Neutrophil lineage

!Activates the phagocytic activity of matureneutrophils and prolongs their survival incirculation

! Mobilizes hemopoietic stem cells in peripheralblood


! Stimulate proliferation and differentiationby interacting with specific receptorsfound on various myeloid progenitorcells"

GM-CSF

! Early and late granulocytic progenitor cells aswell as erythroid and megakaryocyteprogenitors

! Stimulates the function of mature neutrophils

! Stimulate T-cell proliferation

! Mobilizes peripheral blood stem cells


! Uses:

" Treatment of chemotherapy-inducedneutropenia

!Accelerates the rate of neutrophil recovery

after chemotherapy (but does not necessarily

translate to improved survival)

! G-CSF reserved for:

" Patients with prior episodes of febrile neutropenia

after cytotoxic chemotherapy

" Patients receiving dose-intensive chemotherapy

" Patients at high risk for febrile neutropenia


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!

Uses:" Treatment of neutropenia associated with:

! Congenital neutropenia

! Cyclic neutropenia

! Myelodysplasia

! Aplastic anemia

! Toxicity" G-CSF bone pains

"

GM-CSF fever, malaise, arthralgias, myalgias,capillary leak syndrome (peripheral edema withpleural or pericardial effusion)

Megakaryocyte Growth Factors

! Interleukin-11 (IL-11)

" Produced by fibroblasts and stromal cells inthe bone marrow

! Oprelvin recombinant form of IL-11

produced by expression of E. coli

"

Half life 7-8 hours SQ

! Thrombopoietin

" Produced mostly by hepatocytes


! Stimulates the growth of multiple

lymphoid and myeloid cells

!Acts with other growth factors tostimulate the growth of primitive

megakaryocyte progenitors! Increases peripheral platelets and

neutrophils


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!

IL-11" Treatment of thrombocytopenia

" Secondary prevention of thrombocytopeniain patients receiving chemotherapy

! Shown to reduce platelet t ransfusion

! Toxicity

" Fatigue, headache, dizziness and

cardiovascular effects (anemia, dyspnea and

transient arrythmias), hypokalemia

Anemia Handout 2014(1)

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