Download L08 Anemia-Edited

Anemias
Pharmacotherapy 4 for PharmD students
Prof. Nayla Younes
Background
According to WHO:
 30% of world’s population are anemic
 Many people can be unaware that they have anemia
 It is one of the most under-diagnosed conditions worldwide
 The highest prevalence of anemia is seen in women, elderly &
low income persons.
 Prevalence of anemia in the surgical population is 75%
 Importance of anemia is often overlooked & untreated.
 It can affect both length & quality of life.
Homework
 Comparison between once weekly, twice weekly, and
daily oral iron therapy in Jordanian children
suffering from iron deficiency anemia
 doi: 10.1007/s10995-012-0981-3
 What do you conclude?
Homework
 What id the prevalence of anemia among Bedouin
schoolchildren ?
 doi: 10.1159/000258632
 What do you concluse?
Homework
 What is the prevalence of glucose-6-phosphate
dehydrogenase (G6PD) deficiency in Jordan ?
 doi: 10.1159/000339505
 What do you concluse?
Homework
 What is the prevalence of folate deficiency anemia
among women in Jordan ?
 doi: 10.1038/ejcn.2014.100
 What do you concluse?
Homeworks
 Enlist all Fe supplements with their doses, salts and dosage forms
 Enlist all folate supplements with their doses, salts and dosage
forms
 Enlist all B12 supplements with their doses, salts and dosage forms
Definition
 Anemias: group of diseases characterized by ↓ in red cell mass:
 ↓ in number of (RBC)/(mm3) /or
 ↓ in Hb concentration in blood to level below normal
physiologic requirement for adequate tissue oxygenation.
 WHO definition:<13 g/dL in men & <12 in women
 Term anemia is not diagnosis, but rather objective sign of
disease.
 Exact diagnosis is important to understanding of problem & to
implement specific therapy to correct anemia.
 Anemias associated with acute blood loss, those that are iron
related, & those caused by chronic disease comprise most of all
anemias.
Classification of anemia
 Morphology
 Micro/normo/macro-cytic
 Hypo/normo chromic
 Etiology
 Deficiency
 Peripheral
 Central
 Pathophysiological
 Loss
 Production
 destruction
 Functional
 Proliferative
 Loss
 Maturation
Morphologic Classification of Anemia
Macrocytic
•Defective maturation with decreased production
•Megaloblastic: pernicious (vitamin B12 deficiency), folic acid deficiency
Normochromic, normocytic
•Recent blood loss
•Hemolysis
•Chronic disease
•Renal failure
•Autoimmune
•Endocrine
Microcytic, hypochromic (provide evidence of impaired Hb synthesis)
•Iron deficiency
•Genetic abnormalities: sickle cell, thalassemia
Etiologic Classification of Anemia
Deficiency
• Iron
• Vitamin B12
• Folic acid
• Pyridoxine
Central, caused by impaired bone marrow function
•
•
•
Anemia of chronic disease
Anemia of the elderly
Malignant bone marrow disorders
Peripheral
• Bleeding (hemorrhage)
• Hemolysis (hemolytic anemias
Pathophysiologic Classification of Anemia
Blood Loss
•Acute: trauma, ulcer, hemorrhoids, recent hemorrhage
•Chronic: ulcer, vaginal bleeding, aspirin ingestion
Inadequate Red Blood Cell Production
•Nutritional deficiency: B12, folic acid, iron
•Erythroblast deficiency: bone marrow failure (aplastic anemia, irradiation,
chemotherapy, folic acid antagonists) or bone marrow infiltration (leukemia,
lymphoma, myeloma, metastatic solid tumors, myelofibrosis)
•Endocrine deficiency: pituitary, adrenal, thyroid, testicular
•Chronic disease: renal, liver, infection, granulomatous, collagen vascular
Excessive Red Blood Cell Destruction
•Intrinsic factors: hereditary (G6PD), abnormal hemoglobin synthesis
•Extrinsic factors: autoimmune reactions, drug reactions, infection (endotoxin),
physical trauma to RBC
Functional classification of anemia
Maturation & development of RBCs
 In adults, RBCs are formed in

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marrow of vertebrae, ribs,
sternum, clavicle, pelvic (iliac)
crest & proximal epiphyses of
long bones.
In children, most bone marrow
space is hematopoietically active
to meet ↑ RBC requirements.
Figure: normal RBC formation.
Circulating erythrocyte is
nonnucleated, nondividing cell.
> 90% of protein content of
erythrocyte consists of oxygencarrying molecule Hb.
Erythrocytes compose 40-50%
of total blood volume & have
normal survival time 120 days.
Stimulation of erythropoiesis
 Hormone EPO, 90% of which
is produced by kidneys, initiates
& stimulates production of
RBCs.
 Erythropoiesis is regulated by
feedback loop.
 Main mechanism of action of
EPO is preventing apoptosis, or
programmed cell death, of
erythroid precursor cells &
allowing their proliferation &
subsequent maturation.
Body iron
 normal iron content of body is ~3-4 g.
 significant amount of iron is stored as ferritin or aggregated ferritin
(hemosiderin) in reticuloendothelial cells of liver, spleen, & bone marrow
& by hepatocytes.
 ferritin circulates at concentrations that reflect total iron body stores.
 only small fraction of iron is found in plasma (100-150 mcg/dL), & most
is bound to transferrin, transport protein.
70 kg man
60 kg woman
Iron stores - transferrin,
ferritin, hemosiderin
0.7 g
0.3 g* (average)
Hemoglobin
2.5 g
1.9 g
Myoglobin
0.14 g
0.13 g
Heme enzymes (cytochromes) 0.01 g
0.01 g
TOTAL
2.34 g
3.35 g
Iron homeostasis
Hepcidin is a regulator of intestinal iron
absorption, iron recycling and iron
mobilization from hepatic stores.
Iron absorption
 Iron, which is absorbed from duodenum & upper jejunum by
active transport mechanism, is enhanced in presence of acidic
gastric environment.
 Dietary iron, which is primarily in ferric state, is
converted to more readily absorbed ferrous form in acid
environment of stomach. Ferrous form binds to
transferrin for its journey to bone marrow, where it is
incorporated into Hgb of mature erythrocytes.
 GI absorption of iron is ↑ from usual 10% to 3-5-fold in iron
deficiency states or when erythropoiesis occurs more rapidly.
 Animal sources of iron (heme iron) are better absorbed than
plant sources (nonheme iron).
 Certain foods & drugs can complex with iron →↓absorption.
Q1
 Dietary iron requirements
 Age
 Milk formula
 Gender
 Post menopausal
 Pregnancy status
 Lactation status
 Diet type
Dietary reference intakes (DRI) for iron
AGE
mg iron
mg iron
Females
Infants and Children
0 – 6 months
AGE
0.27
9 – 13 years
8
14 – 18 years
15
19 - 50 years
18
8
7 – 12 months
11
1 – 3 years
7
51 + years
4 – 8 years
10
Pregnancy
Males
<18 years
27
>18 years
27
9 – 13 years
8
14 – 18 years
11
< 18 years
10
19 + years
8
> 18 years
9
 Vegetarians
16 mg/day
Lactation
Dietary iron sources
 Heme iron, which is found in
meat, fish, & poultry is ~3
times more absorbable than
nonheme iron found in
vegetables, fruits, dried
beans, nuts, grain products &
dietary supplements.
 40% percent of iron from
animal sources is in heme
form.
 Heme & nonheme iron are
absorbed by different
receptors on intestinal
mucosa.
Food
Serving
Size
Amount
(mg)
Total cereal
1 cup
18
Grape-Nuts cereal
1 cup
18
Instant Cream of
Wheat
1 cup
8.2
Instant plain
oatmeal
1 cup
6.7
Wheat germ
1 oz.
2.6
Broccoli
1 medium
stalk
2.1
Baked potato
1 medium
2.7
Raw tofu
1/2 cup
4
Lentils
1/2 cup
3.3
Beef chuck
3 ounces
3.2
Factors influencing absorption of dietary iron
Absorption of heme iron
Absorption of nonheme iron
Amount of heme iron, especially in Iron status
meat
Content of calcium in meal
(inhibit)
Amount of potentially available
nonheme iron
Food preparation (time,
temperature)
Balance between +ve & -ve factors
Positive factors (enhance absorption)
Ascorbic acid
Meat or fish
Negative factors (inhibit absorption)
Phytate (in bran, oats, rye fiber)
Polyphenols (in tea, some vegetables &
cereals)
Dietary calcium
Soy protein
Incorporation of Iron into Heme
 Specific plasma transport protein transferrin delivers iron to
bone marrow for incorporation into Hb molecule.
 Transferrin enters cells by binding to transferrin receptors,
which circulate & then attach to cells needing iron.
 There are <transferrin receptors on surface of cells that do not
need iron.
 Circulating transferrin normally is ~30% saturated with iron.
 Transferrin delivers extra iron to other body storage sites, such
as liver, marrow, & spleen, for later use. This iron is stored
within macrophages as ferritin or hemosiderin.
Normal Destruction of RBCs
 Phagocytic breakdown destroys
older blood cells, primarily in
spleen, but also in marrow.
 Fate of:
 Globin chains (amino acids)
 Porphyrin heme (heme
oxygenase)
Diagnosis of Anemia: History
 Onset of symptoms (& surrounding events)
 Because longstanding anemias can indicate hereditary
disorders, family history should be noted.
 Past Hgb or hematocrit (Hct) determinations, transfusion
history, as well as occupational, environmental, & social
histories may be valuable.
 Medication history can help eliminate drug reactions or
interactions as cause of anemia.
Ds: Physical Examination
 Pallor is most easily observed in the conjunctiva, mucous


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
membranes, nail beds, and palmar creases of the hand.
Postural hypotension and tachycardia can be seen when
hypovolemia (acute blood loss) is the primary cause of anemia.
Patients with B12 deficiency may exhibit neurologic findings,
which include changes in deep tendon reflexes, ataxia, and loss of
vibration and position sense; all are consistent with nerve fiber
demyelination.
Patients with anemia from hemolysis may be slightly jaundiced
from bilirubin release.
Manifestations of hemorrhage can include petechiae,
ecchymoses, hematomas, epistaxis, bleeding gums, and blood in the
urine or the stool.
Signs and Symptoms
 General
 Patients may be asymptomatic or have vague complaints
 Patients with vitamin B12 deficiency may develop neurologic consequences
 In ACD, S&S of underlying disorder often overshadow those of anemia
 Symptoms
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
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Decreased exercise tolerance
Fatigue
Dizziness
Irritability
Weakness
Palpitations
Vertigo
Shortness of breath
Chest pain
Neurologic symptoms in vitamin
B12 deficiency (WHY?)
 Signs
 Tachycardia
 Pale appearance (most prominent
in conjunctivae)
 Decreased mental acuity
 Increased intensity of some cardiac
valvular murmurs
 Diminished vibratory sense or gait
abnormality in vitamin B12
deficiency
Note:
 Presenting S&S of anemias depend on:
 rate of development (acute vs. slowly developing)
 age of patient (young vs. elderly)
 cardiovascular status of patient (healthy myocardium vs.
heart disease)
 Severity of symptoms does not always correlate with degree of
anemia.
Laboratory Evaluation
 Full laboratory evaluation is necessary to:
 confirm diagnosis (together with information gained from history &
physical examination),
 establish its severity,
 determine its cause.
 Cornerstone of this evaluation is CBC.
 Morphologic appearance of RBC provides useful information about
nature of anemia.
 Microscopic evaluation of peripheral blood smear can detect:
 macrocytic (large) RBC, which usually are present when anemia results
from vitamin B12 or folic acid deficiency;
 microcytic (small) RBC usually are associated with iron deficiency
anemia.
 Acute blood loss generally is associated with normocytic cells.
Routine Laboratory Evaluation for Anemia Workup
Complete blood count (CBC): Hgb, Hct, RBC count, red cell indices (MCV,
MCH, MCHC), WBC count (& differential)
Platelet count
Red cell morphology
Reticulocyte count
Bilirubin & LDH
Serum iron, TIBC, serum ferritin, transferrin saturation
Peripheral blood smear examination
Stool examination for occult blood
Bone marrow aspiration & biopsya
Hct, hematocrit; Hgb, hemoglobin; LDH, lactic dehydrogenase; MCV, mean corpuscular volume;
MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RBC,
red blood cell; TIBC, total iron-binding capacity; WBC, white blood cell.
Laboratory tests in the evaluation of anemia
Homework
 If MCV= 100 fL
 If Hct=50%
 Then how many RBCs in 1 ml?
Other Diagnostic Tests
 Schilling test may help
uncover intrinsic factor
deficiency (done in four
stages)
 Bone marrow testing with
iron staining can indicate low
iron levels in IDA and adequate
stores in ACD
IDA vs. ACD
Summary: Lab tests
 Hb, hematocrit (Hct), & RBC indices may remain normal early in disease

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& then decrease as anemia progresses
Serum iron is low in IDA & ACD
Ferritin levels are low in IDA & normal to increased in ACD
TIBC is high in IDA & is low or normal in ACD
Mean cell volume is elevated in vitamin B12 deficiency & folate
deficiency
Vitamin B12 & folate levels are low in their respective types of anemia
Homocysteine is elevated in vitamin B12 deficiency & folate deficiency
Methylmalonic acid is elevated in vitamin B12 deficiency
HW: Coombs’ test?
Treatment of Anemia
Desired Outcomes
 Goal: to increase hemoglobin level, which will improve red
cell oxygen-carrying capacity, alleviate symptoms, & prevent
anemia complications.
 Patients who experience resolution in their symptoms such as
shortness of breath, tachycardia, fatigue, dizziness, & edema
may not require aggressive therapy to maintain their
hemoglobin values within normal limits.
 Prevention of complications owing to anemia such as
hypoxia & cardiovascular sequelae can be avoided if
hemoglobin levels are > 7 g/dL.
General Approach to Anemic Patient
 Underlying cause of anemia (e.g., blood loss; iron, folic acid,
or vitamin B12 deficiency; or chronic disease) must be
determined & used to guide therapy.
 Patients should be evaluated initially based on laboratory
parameters to determine etiology of anemia.
 Appropriate pharmacologic treatment should be initiated
based on cause of anemia.
Iron Deficiency Anemia (IDA)
Iron deficiency is state of negative iron balance in which
daily iron intake & stores are unable to meet RBC & other
body tissue needs.
Signs, Symptoms, & Laboratory Tests
 The most important S&S of IDA are related to cardiovascular
system & are reflection of imbalance between ongoing demands for
oxygen against diminishing oxygen supply.
 low serum iron, low serum ferritin, & elevated TIBC are typical
laboratory findings associated with IDA.
 Serum transferrin receptor levels, which reflect amount of RBC
precursors available for active proliferation, are increased in iron
deficiency.
 In severe iron deficiency, RBC become hypochromic (low MCHC) &
microcytic (low MCV) – when Hgb concentration falls to <12
g/dL in male patients or <10 g/dL in female patients.
Laboratory tests in iron deficiency of increasing severity
Normal
Fe deficiency Fe deficiency
without
with mild
anemia
anemia
Severe Fe
deficiency with
severe anemia
Marrow reticulo- endothelial
iron
2+ to 3+
None
None
None
Serum iron, µg/dL
60 to 150
60 to 150
<60
<40
Iron binding capacity
(transferrin), µg/dL
300 to 360
300 to 390
350 to 400
>410
Saturation (SI/TIBC), percent 20 to 50
30
<15
<10
Hemoglobin, g/dL
Normal
Normal
9 to 12
6 to 7
Red cell morphology
Normal
Normal
Normal or slight Hypochromia and
hypochromia
microcytosis
Plasma or serum ferritin,
ng/mL
40 to 200
<40
<20
<10
Erythrocyte protoporphyrin,
ng/mL RBC
30 to 70
30 to 70
>100
100 to 200
Other tissue changes
None
None
None
Nail and epithelial
changes
Peripheral blood smear
Normal peripheral blood smear
Several platelets (black arrows) & normal
lymphocyte (blue arrow) can also be seen.
Red cells are of relatively uniform size &
shape. Diameter of normal red cell should
approximate that of nucleus of small
lymphocyte; central pallor (red arrow)
should equal 1/3 of its diameter.
Microcytic hypochromic red cells
Iron deficiency: pale small red cells with
just scant rim of pink hemoglobin;
occasional "pencil" shaped cells. Normal
red cells are similar in size to nucleus of
small lymphocyte (arrow); thus, many
microcytic cells are present in this smear.
Thalassemia can produce similar findings.
Predisposing Factors
Iron Deficiency Anemia
nutritional deficiency
Causes
worldwide.
Blood Loss
 Blood loss is considered one Menstruation, gastrointestinal
of the more common causes.
(e.g., peptic ulcer), trauma
 Common causes of chronic
Decreased Absorption
blood loss include peptic
ulcer disease, hemorrhoids, Medications, gastrectomy,
ingestion of GI irritants,
regional enteritis
menstruation, multiple
Increased Requirement
pregnancies, & multiple blood
Infancy, pregnant/lactating
donations.
women
Impaired Utilization
Hereditary, Iron use
 IDA is the most common
Treatment: IDA
 Severity & cause of IDA determine approach to treatment.
 Because iron deficiency can be early sign of other illnesses,
treatment of underlying disease may aid in correction of
iron deficiency.
 Treatment is focused on replenishing iron stores.
 Dietary iron intake should be analyzed & modified.
Dietary Supplementation & Therapeutic Iron Preparations
 Treatment of IDA usually consists of dietary
supplementation & administration of therapeutic
iron preparations.
 Iron is poorly absorbed from vegetables, grain products, dairy
products, & eggs; it is best absorbed from meat, fish, &
poultry. Beverages have been shown to affect iron absorption.
Meat, orange juice, and other ascorbic acid–rich foods should
be included with meals, whereas milk & tea should be
consumed in moderation between meals.
 In most cases of IDA, oral administration of iron therapy with
soluble Fe2+ iron salts is appropriate.
 Iron supplementation resolves anemia by replacing iron stores
in body that are necessary for RBC production & maturation.
Goals of iron therapy
 to normalize Hgb & Hct concentrations
 to replete iron stores.
 Initially, if doses of iron are adequate, reticulocyte count
will begin to increase by 3rd-4th day & peak by 7th-10th day of
therapy. By the end of 2nd week of iron therapy, reticulocyte
count will fall back to normal.
 Hgb response is convenient index to monitor in outpatients.
 Hematologic response is usually seen in 2-3 weeks with 1
g/dL increase in Hb & 6% increase in hematocrit.
 Iron therapy should be continued for 3-6 months after Hb is
normalized to replete iron stores.
Iron Therapy
 Initial treatment of IDA is oral iron: 200 mg of elemental
iron daily for those who are able to tolerate oral route.
 Why 200 mg/day?
 Many different iron products & salt forms are available
(Table)
 Dosing for iron should be divided equally into 2-3 doses
daily.
 Empty stomach (1 hr before or 2 hrs after meal) is preferred
for maximal absorption.
 If treated properly, response (via presence of reticulocytosis)
should be seen in 7-10 days, & Hb should rise by ~1 g/dL per
week.
 Patients should be reassessed if Hb does not increase by 2 g/dL
in 3 weeks.
Iron Therapy - doses
 Usual adult dose of ferrous sulfate is 325 mg (one tablet)
administered three times daily, between meals.
 If no iron is being lost through bleeding, required daily dose of
elemental iron can be calculated using formula that assumes that
0.25 g/dL/day is maximal rate of Hb regeneration.
Differences between iron products
 Ferrous form of
iron is absorbed 3
times > readily
than ferric form.
 Although ferrous
sulfate, ferrous
gluconate &
ferrous fumarate
are absorbed
almost equally,
each contains
different amount
of elemental iron.
Product Formulation
 Product formulation is of considerable importance in product selection.
 Some believe that more expensive, sustained-release (SR) iron preparations
are inherently better. SR preparations fall into three groups:
(a) those claimed to increase GI tolerance or decrease side effects??
(b) those formulated to increase bioavailability,
(c) those with adjuvants claimed to enhance absorption (e.g. ascorbic acid) or
decrease side effects (e.g. stool softener)
 Because these products can be given once daily, increased compliance is an
additional claim.
Drug
Ferro-Grad 500 (Filmtabs)
Vitron C
Ferro DSS/Ferro-Sequel
DOSS (mg)
0
0
100
Vitamin C (mg)
500
125
0
DOSS, dioctyl sodium sulfosuccinate; docusate sodium; Fe, iron.
Fe++ Content (mg)
105
66
50
Causes for failure to respond to oral iron therapy
Patient is not taking the medication
Medication is being taken but is not being absorbed
Diagnosis is incorrect
Coexisting disease interfering with marrow response
Continued blood loss or need in excess of iron dose
Causes for failure to respond to oral iron therapy
Coexisting disease interfering with marrow response
Infection
Inflammatory disorder (eg, rheumatoid arthritis)
Concomitant malignancy
Coexisting folic acid &/or vitamin B12 deficiency
Bone marrow suppression from another cause
Diagnosis is incorrect, possible correct diagnoses include
Thalassemia
Lead poisoning
Anemia of chronic disease (anemia of chronic inflammation)
Copper deficiency (zinc toxicity)
Myelodysplastic syndrome/refractory sideroblastic anemia
Patient is not taking the medication
Prescription has not been filled
Prescription has been filled but patient is no longer taking the medication
Causes for failure to respond to oral iron therapy
Medication is being taken but is not being absorbed
Rapid intestinal transport bypasses area of maximum absorption
Enteric coated product: coating is not dissolving
Patient has malabsorption for iron (eg, sprue, atrophic gastritis)
Medication taken in association with an agent interfering with absorption (eg, antacids,
tetracycline, tea)
Continued blood loss or need in excess of iron dose ingested
Cause of blood loss treatable (eg, bleeding peptic ulcer)
Initiate appropriate treatment
Cause of blood loss not treatable
(eg, Osler Weber Rendu disease) or need cannot be met by oral iron preparation (eg,
renal failure responding to erythropoietin)
Switch patient to parenteral iron product
Patient information
 Iron should be dispensed in childproof container.
 Oral iron therapy produces dark stools.
 Take iron on empty stomach because food, especially dairy
products, decreases absorption by 40-50%.
 Gastric side effects occur in 5-20% of patients & include
nausea, epigastric pain, constipation, abdominal cramps, &
diarrhea.
 To minimize gastric intolerance, oral iron therapy can be
initiated with single tablet of ferrous sulfate 325 mg/day; dose
is increased by increments of 1 tablet per day Q 2-3 days until
full therapeutic dose of ferrous sulfate, 325 mg TID daily, can
be administered.
 Patients should be educated about potential drug
interactions that can occur with iron therapy.
Iron-drug interactions
Parenteral Iron Therapy
 Parenteral iron therapy may be appropriate in:
 cases where patients are unable to tolerate oral formulation
because of toxicities or compliance.
 those who have documented iron-deficiency anemia & have
not responded to oral iron therapy (e.g., because of
malabsorption)
 Iron can be given parenterally as:
 ferric gluconate (Ferrlecit),
 iron dextran (INFeD and Dexferrum),
 iron sucrose (Venofer).
Iron dextran
 Can be administered undiluted IM or by very slow IV injection.
 Is commonly diluted in 250-1,000 mL 0.9% NaCl & administered by IV
infusion.
 IV administration is preferred to IM administration when:
 muscle mass available for IM injection is limited;
 absorption from muscle is impaired (e.g., stasis, edema);
 uncontrolled bleeding is risk (e.g., secondary to hemophilia,
thrombocytopenia, anticoagulation therapy);
 large doses are indicated for therapy.
 In few instances, IM iron dextran is preferred treatment (e.g., patients
with limited IV access).
 Upper limit of each daily dose is based on patient's weight & should not
be >100 mg/day.
Iron dextran
 Z-track technique
 Avoid staining the skin
 IM iron dextran is absorbed in two phases
 1st 72 hours, 60% of the dose is absorbed
 Remaining drug is absorbed over weeks to months.
 The response time is similar to that of oral iron therapy,
 Infusion rates of undiluted IV iron dextran
 Not exceed 50 mg (i.e., 1 mL) per minute.
 Infusions generally are given over 1 to 6 hours
Ferric gluconate & iron sucrose
 Are FDA approved for treatment of IDA in patients undergoing
chronic hemodialysis & receiving supplemental EPO.
 Iron requirements in these patients typically exceed 1-2 g →
multiple doses of ferric gluconate & iron sucrose are needed
to achieve total dose of iron.
 Ferric gluconate can be administered undiluted as slow IV
injection (rate < 12.5 mg/minute) or as IV infusion (125 mg
ferric gluconate in 100 mL 0.9% NaCl over 1 hour).
 Iron sucrose can be administered undiluted as slow IV
injection (rate not to exceed 20 mg/minute) or as IV infusion
(dilute in maximum of 100 mL 0.9% NaCl & infuse at rate of
100 mg over 15 minute).
Calculation of parenteral iron dose
Required information:
Body weight (kilograms) = BW
Hemoglobin concentration (g/dL) = Hgb
Concentration of elemental iron in the parenteral product (mg/mL) = C*
C* = Iron dextran: 50 mg/mL Iron sucrose: 20 mg/mL Ferric gluconate: 12.5 mg/mL
Assumptions:
Blood volume is 65 mL per kilogram
Hemoglobin concentration to be corrected to 14.0 g/dL
No additional iron to be given for repletion of body stores
Intermediate calculations:
Blood volume (dL) = 65 (mL/kg) x body weight (kg) ÷ 100 (mL/dL)
Hemoglobin deficit (g/dL) = 14.0 - patient hemoglobin concentration
Hemoglobin deficit (g) = hemoglobin deficit (g/dL) x blood volume (dL)
Iron deficit (mg) = hemoglobin deficit (g) x 3.3 (mg Fe/g Hgb)
Volume of parenteral iron product required (mL) = Iron deficit (mg) ÷ C(mg/mL)
Final calculations:
Hemoglobin iron deficit (mg) = BW x (14 - Hgb) x (2.145)
Volume of product required (mL) = BW x (14 - Hgb) x (2.145) ÷ C
Example:
 60 kg woman with a hemoglobin concentration of 8 g/dL.
 Parenteral iron product is iron sucrose (C = 20 mg elemental iron/mL)
 Hemoglobin iron deficit = 60 x (14 - 8) x (2.145) = 772 mg iron
 Volume of iron sucrose needed = 60 x (14 - 8) x (2.145) ÷ 20 = 38.6 mL
For
iron dextran
Side effects
 Anaphylactoid reactions can occur in <1% of patients treated with
parenteral iron therapy.This reaction is more commonly associated with
iron dextran than with ferric gluconate & iron sucrose.
 → 25-mg test dose of iron dextran should be given IM or by IV
infusion over 5-10 minutes. If headache, chest pain, anxiety, or signs
of hypotension are not experienced, remainder of dose can be
administered parenterally.
 Nevertheless, delayed reactions (e.g., fever, urticaria, arthralgias, &
lymphadenopathy) have occurred 24-48 hours after large doses of
IV iron dextran & have lasted 3-7 days in 1-2% of patients.
 Test dose is not indicated for ferric gluconate & iron sucrose because of
lower incidence of serious anaphylactoid reactions.
 Other side effects seen with parenteral iron agents include:
hypotension, N&V, cramps, & diarrhea.
 Parenteral iron medications should not be mixed with (or added to)
other medications or parenteral nutrition solutions for IV infusion.
Transfusions
 Another form of treatment involves blood transfusions.
 The decision to manage anemia with blood transfusions is based on
evaluation of risks & benefits.
 Transfusion of allogeneic blood is indicated in
 Acute situations of blood loss
 When hemodynamic support is needed.
 Blood transfusion in chronic anemia
 Can elevate Hb concentration in short term but does not address underlying disorder.
 In critically ill patients,
 risk of infection, length of stay, & economic cost increase with each unit of transfused
packed RBCs.
 Guidelines for transfusion in perisurgical anemias suggest
 6-8 g/dL of Hb as a threshold for treatment,
 with no benefit at levels >10 g/dL.
Vitamin B12 & Folic Acid anemia
Anemia from vitamin B12 or folic acid deficiency is treated
effectively by replacing missing nutrient.
Both folic acid & vitamin B12 are essential for erythrocyte
production & maturation. Replacing these factors allows
for normal DNA synthesis &, consequently, normal
erythropoiesis.
Role of Vitamin B12 and Folic Acid
DHF, dihydrofolate; THF, tetrahydrofolate; 5-MTHF, 5-methyl-tetrahydrofolate;
5,10-MTHF, 5,10-methyl-tetrahydrofolate THF;
Peripheral blood smear
Peripheral smear shows marked
macroovalocytosis in patient with
vitamin B12 deficiency.
Peripheral blood smear showing
hypersegmented neutrophil (7 lobes) &
macroovalocytes - pattern that can be
seen with cobalamin or folate
deficiency.
Diagnosis
 As a first step, serum for determination of BOTH
Cbl & folate concentrations should be obtained.
 If serum folate & Cbl concentrations are >4 ng/mL
& >300 pg/mL, respectively, deficiencies of 2
vitamins are unlikely, & additional testing is not
required.
 If above 2 tests are not in the ranges, next step should be evaluation
of metabolites methylmalonate (MMA) & total
homocysteine:
 If both test results are within normal range (ie, MMA 70-
270 nmol/L & total homocysteine 5-14 micromol/L), deficiency of
both vitamins is ruled out.
 If concentrations of both metabolites are ↑, Cbl deficiency is
confirmed, with sensitivity & specificity of 94 & 99 %, respectively.
 If MMA is normal & total homocysteine is ↑, folate
deficiency is likely, with sensitivity & specificity of 86 & 99%,
respectively.
 If diagnosis of Cbl &/or folate deficiency has been
established, it is reasonable to determine, if
possible, cause for deficiency in order to not
overlook potentially treatable underlying condition
 Sprue,
 IBD,
 Pancreatic insufficiency,
 Medication
Causes of vitamin B12 deficiency
 3 major causes of vitamin B12 deficiency
are:
Inadequate intake,
Malabsorption syndromes
Inadequate utilization
Gastric abnormalities
Pernicious anemia
Gastrectomy/Bariatric surgery
Gastritis
Autoimmune metaplastic atrophic
gastritis
Pancreatitis
Pancreatic insufficiency
Small bowel disease
Malabsorption syndrome
Ileal resection or bypass
Crohn's disease
Blind loops
Agents that block absorption
Neomycin
Biguanides (eg, metformin)
PPIs (eg, omeprazole)
N2O inhibits methionine synthase
Inherited transcobalamin II
deficiency
Diet
Strict vegans
Vegetarian diet in pregnancy
HW:
 Medications that cause false decrease in vit. B12 level?
 use of oral contraceptives,
 folate deficiency,
 pregnancy,
 congenital deficiency of serum haptocorrins and multiple myeloma
Schilling test – how is it done?
 4 different stages to find cause of low vitamin B12 levels.
 Stage I: 2 doses of vitamin B12 (cobalamin) are given: small,
first dose (a radioactive form of B12) by mouth → second,
larger dose by shot 1 hour later →urine is collected over the
next 24 hours → urine is checked to see if vitamin B12 is
absorbing normally.
 If Stage I is abnormal, Stage II may be done 3 - 7
days later.
Schilling test – how is it done?
 Stage II:
 Radioactive B12 is given along with intrinsic factor
 Stage II can tell whether low vitamin B12 levels are
caused by problems in the stomach that prevent it
from producing intrinsic factor.
 If Stage II test is abnormal, Stage III test is
performed.
Schilling test – how is it done?
 Stage III: Is done after taking antibiotics for 2
weeks. It can tell whether abnormal bacterial growth
has caused low vitamin B12 levels.
 Stage IV: Determines whether low vitamin B12 levels
are caused by problems with pancreas. Pancreatic
enzymes are taken for three days, followed by a
radioactive dose of vitamin B12.
The test can be repeated with addition of missing factors (eg, intrinsic factor,
pancreatic extract), or following the use of nonabsorbable antibiotics (blind loops &/or
bacterial overgrowth present), or gluten-free diet (celiac disease).
4: One hour after the test dose, a 1000
µg "flushing" dose of non-radioactive
B12 is given to saturate B12 binders
(transcobalamines).
5: If present, bacteria in
"blind loops" in the
duodenum or jejunum
preferentially utilize
vitamin B12, allowing
none to be available at
the site of absorption.
1: One µg of
radioactive crystalline
B12 is taken orally.
2: Gastric acid and pepsin
free vitamin B12 from food
proteins (not required for
crystalline form). B12
attaches to "R" binders (R).
3: Pancreatic proteases
degrade the "R" binders,
allowing formation of the
B12-IF complex, the
specific form absorbed by
the terminal ileum.
B12 is excreted in the urine
B12/IF complex is absorbed by the terminal ileum
Schilling test in various diseases
Test
Gastrectomy,
pernicious
anemia
Celiac
disease*
Ileal
Bacterial
resection
overgrowth or disease
#
Vitamin B12
Low
Low
Low
Low/normal Low
Vitamin B12
+ intrinsic
factor
Normal
Low
Low
Low/normal Low
Vitamin B12
+ antibiotics
n/a
Low
Normal
Low/normal Low
Vitamin B12
+ gluten-free
diet
n/a
Normal
n/a
Low/normal Low
Vitamin B12
+ pancreatic
enzymes
n/a
n/a
n/a
n/a
Pancreatic
insufficienc
y
Normal
* The Schilling test may be normal in patients with celiac disease because the terminal ileum is frequently
spared. n/a, these stages of the Schilling test are not needed for the disorder.
# Results depend upon the length of resection or the extent of disease. Values will not normalize with >100
cm of resection. Values may normalize after treatment of active Crohn's disease.
Vitamin B12
 Vitamin B12
 works closely with folate in synthesis of building blocks for DNA




& RNA,
 is essential in maintaining integrity of neurologic system,
 plays role in fatty acid biosynthesis & energy production.
It is water-soluble vitamin obtained exogenously by ingestion of
meat, fish, poultry, dairy products & fortified cereals.
Body stores range: 2-5 mg, of which ~half is in liver.
Recommended daily allowance is 2 mcg in adults & 2.6 mcg in
pregnant or breast-feeding women.
Vitamin B12 deficiency takes several years to develop following
vitamin deprivation because of efficient enterohepatic
circulation of vitamin.
Sources of Vitamin B12
Food
Serving Size
Amount (mcg)
Beef liver, cooked
3 oz
60
Breakfast cereal, fortified (100%)
3/4 cup
6
Rainbow trout, cooked
3 oz
5.3
Sockeye salmon, cooked
3 oz
4.9
Beef, cooked
3 oz
2.1
Breakfast cereal, fortified (25%)
3/4 cup
1.5
Haddock, cooked
3 oz
1.2
Clams, breaded and fried
3/4 cup
1.1
Oysters, breaded and fried
6 pieces
1
Tuna, canned in water
3 oz
0.9
Milk
1 cup
0.9
Yogurt
8 oz
0.9
Vitamin B12
 Parenteral vs. Oral
 use of parenteral cyanacobalamin is the most common
method of vitamin B12 replacement because it may be more
reliable & practical.
 Subcutaneous or intramuscular administration is appropriate.
 Vitamin B12 is absorbed completely following parenteral administration,
 whereas oral vitamin B12 is absorbed poorly via GI tract.
 use of parenteral vitamin B12 to treat megaloblastic anemia
may circumvent need to perform Schilling test to diagnose
lack of intrinsic factor.
 Nasal preparation?
 Nascobal: 500 mcg in one nostril once weekly
Cyanocobalmin dosing regimen
 Typical cyanocobalmin dosing regimen is:
 800-1000 mcg/day for 1-2 weeks, /followed by
 100-1000 mcg/day every week until Hgb/Hct
normalizes
 maintenance of 100-1000 mcg monthly for life.
 A number of dosing regimens exist.
 A number of oral vitamin B12 preparations are
available, including many over-the-counter
formulations.
Cyanocobalmin dosing regimen
 A common oral dosing regimen is 1000-2000 mcg/day.
 If parenteral cyanocobalmin is used initially, oral vitamin B12
can be useful as maintenance therapy.
 Typically, response to therapy is quick.
 Neurologic symptoms & megaloblastic cells disappear
 within few days, &
 Hb levels ↑
 after week of therapy.
Cyanocobalmin dosing regimen
 Vitamin B12 generally is well tolerated & exhibits minimal
adverse effects.
 Injection-site pain, pruritus, rash, &
 diarrhea have been reported.
 Drug interactions have been observed with omeprazole
& ascorbic acid that ↓ oral absorption.
 N.B. Lexi: reveals no such interactions
Causes of folic acid deficiency
 Nutritional deficiency
 Poor dietary intake
 Malabsorption
 Increased requirements
 Drugs (various mechanisms)
Causes of folic acid deficiency
Nutritional deficiency
Substance abuse
Alcoholism
Poor dietary intake
Overcooked foods
Depressed patients
Nursing homes
Malabsorption
Celiac disease (sprue)
Inflammatory bowel disease
Infiltrative bowel disease
Short bowel syndrome
Drugs (various mechanisms)
Methotrexate
Trimethoprim
Ethanol
Phenytoin (folate decr conc of
phenytoin)
Increased requirements
Pregnancy, lactation
Chronic hemolysis
Exfoliative dermatitis
Good sources of folate
Food
Serving
Amount (mcg)
Chicken liver
3.5 oz
770
Cereal
1/2 to 1 1/2 cups
100–400
Lentils, cooked
1/2 cup
180
Chickpeas
1/2 cup
141
Asparagus
1/2 cup
132
Spinach, cooked
1/2 cup
131
Black beans
1/2 cup
128
Pasta
2 oz
100–120
Kidney beans
1/2 cup
115
Lima beans
1/2 cup
78
White rice, cooked
3/4 cup
60
Tomato juice
1 cup
48
Brussels sprouts
1/2 cup
47
Orange
1 medium
47
Folic Acid
 When treating folic acid deficiency, initial daily dose of 1 mg/day
by mouth typically is effective.
 Absorption of folic acid
 Generally is rapid & complete.
 However, patients with malabsorption syndromes may require larger
doses (up to 5 mg/day).
 Onset of action
 Resolution of symptoms & reticulocytosis is prompt,
 occurring within days of commencing therapy.
 Hgb will start to rise after 2 weeks of therapy & may take 2 -4 months
to resolve deficiency completely.
Folic Acid
 If underlying deficiency is corrected, folic acid replacement can be
discontinued.
 In cases where folic acid is consumed rapidly or absorbed poorly, chronic
replacement may be required.
 Some nonspecific ADEs:




allergic reactions,
flushing,
malaise, &
rash.
 Folic acid has been reported to decrease phenytoin levels by inducing
its metabolism.
Anemia of Chronic Disease
These chronic diseases can include
cancer,
chronic kidney diseases, &
chronic inflammatory disorders.
IDA vs. ACD
ACD treatment
 In patients with anemia owing to cancer & chronic kidney disease,
therapy with epoetin or darbepoetin can:
 decrease transfusion increase hemoglobin,
 improve quality of life.
Old, now 10
Old, now
no increase after 8-9
 Management according to cause of anemia:If the cause of anemia is
identified during evaluation, treat the underlying cause as indicated.
 If the likely cause of anemia is cancer-related inflammation and/or
myelosuppressive chemotherapy:
 offer red blood cell transfusion to symptomatic patients (for example,
sustained tachycardia)
 consider red blood cell transfusion for patients at high risk (with
rapidly declining Hb due to recent chemotherapy or radiation) or those
who are asymptomatic but with comorbidities (for example, cardiac
disease) (Weak recommendation)
 consider an erythropoiesis-stimulating agent (ESA) in patients with
non-myeloid malignancies receiving myelosuppressive therapy for
noncurative intent (Weak recommendation)
 consider intravenous iron in patients with evidence of functional
 Red blood cell (RBC) transfusion
 consider a RBC transfusion for patients with cancer- and
chemotherapy-induced anemia who are at high risk (for
example, progressive decline in hemoglobin [Hb] with
recent intensive chemotherapy or radiation) or
asymptomatic with cardiac disease, chronic pulmonary
disease or cerebrovascular disease (Weak recommendation)
 give a RBC transfusion to symptomatic patients with
sustained tachycardia, tachypnea, chest pain, dyspnea on
exertion, lightheadedness, syncope, or severe fatigue
(Strong recommendation)
http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations
 Erythropoiesis-stimulating agent (ESA):
 while ESAs have been reported to increase hemoglobin and
reduce transfusion requirements in many patients with
chemotherapy-associated anemia, they are associated with
increased risk of thromboembolism, tumor progression and
mortality; thus their use has been significantly reduced
 consider in patients (Weak recommendation):
 with Hb < 10 g/dL receiving myelosuppressive therapy for
noncurative intent without other identifiable causes of anemia,
depending on patient preferences
 undergoing palliative treatment, depending on patient preferences
who refuse blood transfusions
http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations
 Erythropoiesis-stimulating agent (ESA):
 contraindications include patients (Weak recommendation):
 with cancer not receiving therapy (an exception is patients with low-risk
myelodysplastic syndrome)
 receiving nonmyelosuppressive therapy
 receiving myelosuppressive chemotherapy with curative intent
 ESAs should be administered following Risk Evaluation and Mitigation
Strategy guidelines and include informed consent of patient.
 target Hb is uncertain, but consider using lowest possible dose
needed to avoid transfusions.
 epoetin and darbepoetin are considered comparable in efficacy and
safety profile.
http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations
Package Insert Dosing Schedule for ESAs and FDA
Recommendations for Dose Modifications
http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations
Package Insert Dosing Schedule for ESAs and FDA
Recommendations for Dose Modifications
http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations
Package Insert Dosing Schedule for ESAs and FDA
Recommendations for Dose Modifications
 alternative ESA dosing regimens may also be considered
 discontinue ESA therapy if after 8-9 weeks of therapy, there is no
response (measured by Hb levels or need for transfusion), or when
chemotherapy is discontinued
 Guidance from professional organizations regarding use of IV
iron is conflicting, but consider in patients who are taking
erythropoiesis stimulating agents (ESAs) with evidence of functional
iron deficiency (Weak recommendation).
http://www.dynamed.com/topics/dmp~AN~T909257/Anemia-of-cancer#sec-Overview-and-Recommendations
Anemia of Critical Illness
•Patients with anemia of critical illness require necessary substrates
of iron, folic acid, &vitamin B12 for RBC production.
•Parenteral iron is generally preferred in this population because
•EPO
•RBC transfusions
Anemia of Critical Illness
•Patients with anemia of critical illness require necessary substrates
of iron, folic acid, &vitamin B12 for RBC production.
•Because iron stores usually are insufficient to meet physiologic
demands, administration of supplemental iron is necessary to
support erythropoiesis.
•Parenteral iron is generally preferred in this population because
• patients often are undergoing enteral therapy or
• because of concerns regarding inadequate iron absorption.
•Pharmacologic doses of EPO have been used to treat anemia of
critical illness.
•Many critically ill patients receive RBC transfusions despite inherent
risks associated with transfusions.
Anemia in Elderly
•Although incidence of anemia is high in elderly, anemia should not
be regarded as inevitable outcome of aging because underlying cause
can be identified in ~2/3 of patients.
•Undiagnosed & untreated anemia can have severe ramifications.
•Depending on cause of the anemia, treatment in elderly is same as
that described for each type of anemia.
Anemia in Pediatric Population
•IDA is leading cause of infant morbidity & mortality around the world.
•Primary prevention of IDA in infants, children, & adolescents is the
most appropriate goal because delays in mental & motor development are
potentially irreversible.
•Interventions likely to prevent anemia include diverse foods with
bioavailable forms of iron, food fortification for infants & children, &
individual supplementation.
•Anemia of prematurity is frequently treated with RBC transfusions.
EPO may be used to treat anemia of prematurity, but it is important to
note that EPO pharmacokinetics differs depending on developmental age
of infant. Use of EPO is controversial because it has not been shown to
clearly reduce transfusion requirements
TC: transcobalamine; Cbl: cobalamine; MeCbl:methcobalamine; Ado-Cbl: Adenosine cobalamine