anemia handout 2014(1)
TRANSCRIPT
-
7/21/2019 Anemia Handout 2014(1)
1/15
9/5/14
1
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
-
7/21/2019 Anemia Handout 2014(1)
2/15
9/5/14
2
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
-
7/21/2019 Anemia Handout 2014(1)
3/15
9/5/14
3
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
-
7/21/2019 Anemia Handout 2014(1)
4/15
9/5/14
4
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
Parenteral Iron Therapy
! 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)
Parenteral Iron Therapy
! Preparations
" Iron-sucrose complex and iron sodiumgluconate complex
! Given via IV route
!
Less likely to cause hypersensitivity reactionscompared to iron dextran
-
7/21/2019 Anemia Handout 2014(1)
5/15
9/5/14
5
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
Clinical Toxicity of Iron
!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
Clinical Toxicity of Iron
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
-
7/21/2019 Anemia Handout 2014(1)
6/15
9/5/14
6
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
-
7/21/2019 Anemia Handout 2014(1)
7/15
9/5/14
7
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
-
7/21/2019 Anemia Handout 2014(1)
8/15
9/5/14
8
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
-
7/21/2019 Anemia Handout 2014(1)
9/15
9/5/14
9
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
-
7/21/2019 Anemia Handout 2014(1)
10/15
9/5/14
10
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
-
7/21/2019 Anemia Handout 2014(1)
11/15
9/5/14
11
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
-
7/21/2019 Anemia Handout 2014(1)
12/15
9/5/14
12
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
-
7/21/2019 Anemia Handout 2014(1)
13/15
9/5/14
13
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
Myeloid Growth Factors
! 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
Myeloid Growth Factors
! 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
-
7/21/2019 Anemia Handout 2014(1)
14/15
9/5/14
14
Myeloid Growth Factors
!
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
Megakaryocyte Growth Factors
! 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
-
7/21/2019 Anemia Handout 2014(1)
15/15
9/5/14
15
Megakaryocyte Growth Factors
!
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