Pharmacotherapy of Anemias

Dagninet Derebe (B.Pharm., MSc)

11/25/2021 Anemias 1
LEARNING OBJECTIVES
• Identify common causes of anemia
• Common signs and symptoms of anemia
• Diagnostic evaluation required to determine the etiology
of anemia
• Recommend a treatment regimen considering the
underlying cause and patient-specific variables.
1. Compare and contrast oral and parenteral iron
preparations.
2. Explain the optimal use of folic acid and vitamin B12
in patients with macrocytic anemia.
3. Evaluate the proper use of epoetin and darbepoetin
in patients with anemia caused by cancer
chemotherapy or chronic kidney disease.
4. Develop a plan to monitor the outcomes of
pharmacotherapy for the treatment of anemia.
11/25/2021 Anemias 2
 Introduction
• Anemia is a group of diseases characterized by a
decrease in either hemoglobin (Hb) or the volume
of red blood cells (RBCs), resulting in decreased
oxygen-carrying capacity of blood
• WHO criteria for anemia:
– Men with Hb value of <13 g/dl
– Women with Hb value of <12 g/dl
– Pregnant women <11 g/dL
• Almost 1.6 billion people (25% of
the world’s population) are anemic
– Millions of people are unaware they have anemia,
making it one of the most underdiagnosed conditions
11/25/2021 Anemias 3
Pathophysiology
• Anemias can be classified on the basis of
– Pathophysiology, RBC morphology, etiology
Anemia

Impaired RBC Increased RBC Blood loss

production destruction
Reticulocyte (>3%)
1) Inherited hemolytic anemias
• Lack of nutrients - iron, • GI tract lesion (PUD)
• eg, hereditary spherocytosis
B12, or folate • Gynecologic
• sickle cell disease disturbance
• Bone marrow disorders
• thalassemia major • Cancer (colorectal)
• Bone marrow
2) Acquired hemolytic anemias • Infection by intestinal
suppression - eg, Coombs'-positive nematodes feeding
• Low levels of trophic autoimmune hemolytic anemia, on blood such as
hormones which - Rh disase
hookworms, and
- thrombotic thrombocytopenic
• The anemia of chronic purpura, whipworm trichris
disease/inflammation - - hemolytic uremic syndrome, trichiura
- Malaria
11/25/2021 Anemias 4
Pathophysiology
• Morphologic classifications are based on cell size.
– Macrocytic: cells are larger than normal (over 100 fl) and
are associated with deficiencies of vitamin B12 or folate.
• “megaloblastic anemia" or "nonmegaloblastic
macrocytic anemia
– Normocytic: may be associated with recent blood loss or
chronic disease (80–100 fl)
– Microcytic: cells are smaller than normal (less than
80ft) and are associated with iron deficiency
• result of hemoglobin synthesis failure/insufficiency
• Heme synthesis defect= iron deficiency, chronic disease anemia
• Globin synthesis defect = thalassemia
• Lead poisoning, sideroblastic anemia
11/25/2021 Anemias 5
 Lead poisoning

11/25/2021 Anemias 6
• Iron-deficiency anemia can be caused by
– Inadequate dietary intake (children with cow milk, vegan)
– Inadequate GI absorption (Antacid, celiac disease, chrons )
– Increased iron demand (e.g., pregnancy, children)
– Blood loss (menstrual bleeding, donation, GI bleeding
(elderly), Parasitic infestation (hookworms, amebiasis,
schistosomiasis and whipworms)
• Vitamin B12 anemias can be caused by
– Inadequate dietary intake (strict vegan)
– Decreased absorption of vitamin B12
• Drugs (PPIs, H2Rb, metformin)
• GI disease (chorn’s disease, celiac disease, gastic bypass, fish tapeworm)
• Deficiency of IF (i.e., pernicious anemia).

11/25/2021 Anemias 7
• Folate-deficiency anemia can be caused by
– Decrease dietary intake
– Compromised absorption
– hyper-utilization due to pregnancy, hemolytic
anemia, myelofibrosis, malignancy, chronic
inflammatory disorders, long-term dialysis, or
growth spurt.

– Drugs can cause anemia by reducing absorption of

folate (e.g., phenytoin) or by interfering with
corresponding metabolic pathways (e.g.,
methotrexate).

11/25/2021 Anemias 8
11/25/2021 Anemias 9
• Anemia of chronic disease is a hypo-proliferative
anemia associated with chronic infectious or inflammatory
processes, tissue injury, or conditions that release
proinflammatory cytokines.
• Various cytokines, such as interleukin-1, interferon-γ,
interlukin-6, and tumor necrosis factor released during
illness may inhibit the production or action of EPO or the
production of RBCs.
• These cytokines also upregulate hepcidin, which blocks iron
release from storage cells.
• Hepicidin then,
– Increased uptake of iron by hepatocytes;
– reduced iron absorption;
– reduced release of iron from macrophages

11/25/2021 Anemias 10
Cont…

11/25/2021 Anemias 11
Cont…

11/25/2021 Anemias 12
Clinical Presentations
• Factors effecting symptoms of anaemia
– Speed of onset
– Severity of anaemia
– Age
– cardiovascular status of the patient.

• Acute-onset anemia
– characterized by cardio-respiratory symptoms such as tachycardia,
worsening of angina, Heart failure, intermittent claudication
lightheadedness, and Exertional dyspnoea.

• Chronic anemia
– Characterized by weakness, fatigue, headache, vertigo, poor
concentration, faintness, cold sensitivity, pallor (esp, conjunctiva),
and loss of skin tone.
11/25/2021 Anemias 13
 In advanced state (>9g/dl) of IDA
• Angular Cheilitis (fissures at the
corners of the mouth)
• ↓salivary secretion
• koilonychia (spooning of
the fingernails)
• Thin, brittle nails
• Pica (compulsive eating of
nonfood items) and
• Pagophagia (compulsive eating
of ice)
• Atrophic Glossitis
• Aphthous ulcer
• Restless leg syndrome
• Vitamin B12- and folate-deficiency anemias are
characterized by
– Pallor
– Icterus (jaundice) and
– Gastric mucosal atrophy (mouth ulcer)
– Read and smooth tounge

• Vitamin B12 anemia is distinguished by

– neuropsychiatric abnormalities (e.g., numbness,
paresthesias, irritability) which are absent in patients with
folate-deficiency anemia.

11/25/2021 Anemias 15
Diagnosis
• Rapid diagnosis is essential because anemia is often a
sign of underlying pathology.
• Initial evaluation of anemia involves
– A complete blood cell count: looking for
• Hemoglobin and hematocrit levels
• Reticulocyte index
• Number of red blood cells, white blood cells, and
platelets
• Mean corpuscular volume (MCV): clue to identify the
cause
– MCV = Hct / RBC
– Examination of the stool for occult blood
11/25/2021 Anemias 16
Cont…

11/25/2021 Anemias 17
IDA (microcytic hypochromic anemia)
• Serum iron level
– decreased by infection and inflammation (Limitation)
• Serum ferritin: <10 ng/mL in women or <20 ng/mL in men
– The best correlate of the body’s total Fe store
– The earliest and most sensitive laboratory test
– Serum ferritin is an acute phase reactant; so chronic infection
or inflammation can increase its [] independent of iron status
• renal or hepatic disease, malignancies, infection, or inflammatory
• Total iron-binding capacity (TIBC)
– quantifies the iron-binding capacity of transferrin and is
increased in IDA
• Transferrin saturation (serum iron/TIBC) or TSAT
– indicates the amount of transferrin that is bound with iron; it is
lower in IDA
• Absent BM Fe store by staining of a bone marrow biopsy →
gold standard
11/25/2021 Anemias 18
• Macrocytic anemias
– Peripheral blood smear
• Hyper-segmented neutrophil or
polymorphonuclear leukocytes
• (≥ 5 lobes) megaloblastic anemia
• Vitamin B12 (<150 pg/mL) and folate concentrations (RBC folate
concentration (better) (less than 150 ng/mL) or serum folate
concentration (less than 3 ng/mL )
• Homocysteine and Methylmalonic acid
• Schilling Test
– This test used to be the “gold standard” for assessing vitamin B12 absorption.

• Neutrophils < lobes

– Non-megaloblastic anemia (no issue in DNA synthesis)
– Liver disease, alcoholism, hypothyroidism,
– Genetics : down’s syndrome, hereditary spherocytosis,
myelodysplastic syndrome
11/25/2021 Anemias 19
• Normocytic anemia
– Reticulocytes is high
• Acute blood loss
• Hemolysis (lactic dehydrogenase, hemoglobinuria (dark urine), and indirect
bilirubin)
• Splenic sequestration
– Reticulocytes is low (check the WBCs and platelets)
• WBCs and platelets Low
– Bone marrow failure (aplastic anemia, leukemia)
• WBCs and platelets High
– Anemia of acute inflammation
– Anemia of chronic disease
» Serum iron is usually decreased
» Serum ferritin is normal or increased & TIBC is decreased (unlike IDA)
» The bone marrow reveals an abundance of iron
– Malignancy

11/25/2021 Anemias 20
11/25/2021 Anemias 21
Desired Outcome
• The ultimate goals of treatment in the anemic
patient are:
– to alleviate signs and symptoms
– correct the underlying etiology (e.g., restore
substrates needed for RBC production) and
– prevent recurrence of anemia

11/25/2021 Anemias 22
 Treatment
Iron Deficiency Anemia
• Based on severity and cause of iron-deficiency anemia
• Three major therapeutic approaches
1) Red Cell Transfusion
• Hemodynamically unstable due to continued & excessive blood loss
• End organ ischemia
• Hemoglobin level less than 7 g/dl
• 1 unit packed RBC(300ml)-200 mg of iron, raise hct by 3% and Hgb by 1g/dl

2) Oral Iron Therapy

3) Parenteral Iron Therapy

11/25/2021 Anemias 23
Oral iron therapy
• Considered standard because of established safety profile,
low cost, ease of administration
– with soluble ferrous iron salts
– not enteric coated
– not slow- or sustained-release
– Dose- up to 200- 300 mg of elemental iron per day is given
• Usually as three or four iron tablets (each containing 50-65 mg
elemental iron) given over the course of the day
• Diet plays a significant role because
– iron is poorly absorbed from
• vegetables, grain products, dairy products, and eggs
– iron is best absorbed from
• Meat, fish, and poultry
• Administration of iron therapy with a meal decreases absorption by
more than 50% but may be needed to improve tolerability.

11/25/2021 Anemias 24
(metallic taste)
(cheapest)

(tasteless)

11/25/2021 Anemias 25
• Adverse reactions
– GI disturbance: dysphagia, dark discoloration of feces,
constipation (common) or diarrhea (rare), nausea, and
vomiting
Drug interactions
Drugs That Decrease Iron Object Drugs Affected by Iron
Absorption
Al-, Mg-, and Ca+2-containing Levodopa ↓ (chelates with iron)
Antacids Methyldopa ↓ (decreases efficacy of methyldopa)
Tetracycline and doxycycline Levothyroxine ↓ (decreased efficacy of
Histamine2 antagonists levothyroxine)
Proton pump inhibitors Penicillamine ↓(chelates with iron)
Cholestyramine Fluoroquinolones ↓ (forms ferric ionquinolone
complex)
Tetracycline and doxycycline ↓ (when administered
within 2 hours of iron salt)
Mycophenolate ↓ (decreases absorption)

11/25/2021 Anemias 26
• Parenteral iron therapy
– Patient who can not take anything by oral
– Intolerance to oral iron preparation (patients with active IBD)
– Patients who require a dose of iron that would be too large
to take through oral means
• Patients with significant blood loss who refuse transfusions
• Chronic kidney disease (In dialysis patients)
• Cancer patients receiving chemotherapy on erythropoiesis-
stimulating agents
– Iron mal-absorption (gastric bypass/gastric resection) or
– Noncompliance
• Parenteral iron produces more rapid responses and
better repletion of iron stores in several clinical settings
but, until recently, its use was limited by a significant
risk of severe, occasionally fatal, allergic reactions with
the available preparations (especially high molecular
weight iron dextran)
11/25/2021 Anemias 27
• Available parenteral iron preparations have similar
efficacy but different pharmacokinetic and safety
profiles
– Sodium ferric gluconate
better tolerated
– Iron sucrose
– Iron dextran
– Ferumoxytol
– Ferric carboxymaltose
• All parenteral iron preparations carry a risk for
anaphylactic reactions (iron dextran is the most,
especially HMW)
– Test dose is required 25 mg intramuscularly or IV or a 5- to
10-minute infusion of the diluted solution
11/25/2021 Anemias 28
• Doses given by IV administration should not exceed
50 mg of iron per minute (1 mL/min).
11/25/2021 Anemias 29
• Iron Dextran (50 mg iron/mL)
– Complex of ferric hydroxide and dextran
– Patients with documented iron deficiency in whom oral
therapy is unsatisfactory or impossible
– Can be administered IM (not routinely)/IV
– Multiple injection, infusion of diluted (100 mg undiluted at
rate not exceed 50 mg (1 ml) per minute (up to 10 dose)
– ADRs: pain and brown staining at injection site, flushing,
hypotension, fever, chills, myalgia, anaphylaxis (black box
warning)
• When it given orally it requires test dose of 0.5 ml over 5-10
minutes
• Z track technique injection – to avoid staining of skin (IM)

11/25/2021 Anemias 30
• Iron Sucrose (20 mg iron/mL)
– Complex of iron hydroxide in sucrose
– Iron deficiency anemia in CKD
• Those undergoing dialysis and
• Those who do not require dialysis
– It only administered IV
– 100mg into the dialysis line at a rate of 1 ml (20 mg of iron)
undiluted solution per minute (Up to 10 dose)
– ADRs: leg cramps, hypotension, rare anaphylaxis
reaction (black box warning)

11/25/2021 Anemias 31
• Sodium ferric Gluconate (62.5 mg iron/5 mL)
– Ferric oxide hydrate bonded to sucrose chelates with
gluconate in a molar rate of two iron molecules to one
gluconate molecule
– Benzyl alcohol 9mg/5ml (975 mg in 62.5 mg iron) as
preservative
– Iron deficiency anemia in patient undergoing chronic
hemodialysis who are receiving supplemental
erythropoietin therapy
– 125 mg (10 ml) diluted in 100 ml NS, infused over 60
minutes; or as a slow IV injection (rate of 12.5 mg/min)
upto 8 doses
– ADRs: cramps, nausea and vomiting, flushing,
hypotension, rash, pruritus. But no black box warning
11/25/2021 Anemias 32
 Treatment
Vitamin B12 -Deficiency Anemia
Cyanocobalamin and Hydroxocobalamin
• Reversal of hematologic manifestations, replacement of body stores, and
prevention or resolution of neurologic manifestations
• Early treatment is of paramount importance because neurologic damage may be
irreversible if the deficiency is not detected and corrected within months.
• Options include parenteral (IM, SC), oral, sublingual, or intranasal routes
• Oral vitamin B12 supplementation appears to be as effective as parenteral, even
in patients with pernicious anemia, because the alternate vitamin B12 absorption
pathway is independent of intrinsic factor.
• Oral cobalamin is initiated at 1 to 2 mg daily for 1 to 2 weeks, followed by 1 mg
daily.

11/25/2021 Anemias 33
• Parenteral therapy is more rapid acting than oral therapy and
should be used if neurologic symptoms are present.
• A popular regimen is cyanocobalamin 1,000 mcg daily for 1
week, then weekly for 1 month, and then monthly.
• When symptoms resolve, daily oral administration can be
initiated.
• In some cases, neurological symptoms may be irreversible
despite serum vitamin B12 levels returning to normal.
• Adverse events
– rare with vitamin B12 therapy
– Pain at injection site, hyperuricemia and hypokalemia
11/25/2021 Anemias 34
Treatment
Folate Deficiency Anemia
• Oral folate 1 mg daily for 4 months is usually
sufficient for treatment of folate-deficiency anemia,
unless the etiology cannot be corrected.
• If mal-absorption is present, the daily dose should be
increased to 5 mg
• Parenteral folic acid is available but rarely necessary
• Although megaloblastic anemia during pregnancy is
rare, the most common cause is folate deficiency.
• Folic acid supplementation at a dose of 400 mcg daily
is recommended for all women
11/25/2021 Anemias 35
Treatment
Anemia of inflammation
• Resolution of the underlying condition may
prompt recovery from anemia
• ESAs have FDA approval for the use in AI due
– CKD, HIV infection and cancer
– AI due to other underlying
considered causes (off label)
• Iron should not be used in the absence of deficiency
• Iron deficiency can occur in patients treated with ESAs
– Close monitoring is required

• RBC transfusions are effective but should be limited to

episodes of inadequate oxygen transport and Hb is
less than 7g/dl but consider in 8 to 10 g/dL.

11/25/2021 Anemias 36
 Erythropoietin
• Epoetin alfa and darbepoetin alfa
– The initial dosage of
• Epoetin alfa 50 to 100 units/kg three times per weekly
• Darbepoetin alfa 0.45 mcg/kg once weekly
– Iron deficiency can occur in patients treated with ESAs; so
close monitoring of iron levels is necessary
– Ensure the patient’s Hb does not exceed 12 g/dL or
that Hb does not rise >1 g/dL every 2 weeks
• since both of these events have been associated with
increased mortality and cardiovascular events
– Hb should monitored every 2-4 wks and if there is no response
8 wks tt, considered as unresponsive and discontinue
– ADRs: hypertension, nausea, headache, fever, bone pain, and
fatigue.
11/25/2021 Anemias 37
Treatment
Anemia of pediatrics
• Primary prevention of IDA in infants, children, and
adolescents is the most appropriate goal because
delays in mental and motor development are potentially
irreversible.
• In the pediatric population, the daily dose of elemental
iron, administered as iron sulfate, is 3 mg/kg for infants
and 6 mg/kg for older children for 4 weeks.
• If response is seen, iron should be continued for 2 to 3
months to replace storage iron pools.
• The dose and schedule of vitamin B12 should be
titrated according to clinical and laboratory response.
• The daily dose of folate is 1 to 3 mg.
11/25/2021 Anemias 38
Treatment
Hemolytic Anemia
• Treatment of hemolytic anemia should focus on
correcting the underlying cause.

• There is no specific therapy for glucose-6-

phosphate dehydrogenase deficiency, so treatment
consists of avoiding oxidant medications and
chemicals.

• Steroids, other immunosuppressants, and even

splenectomy can be indicated to reduce RBC
destruction.

11/25/2021 Anemias 39
Evaluation of Therapeutic Outcomes
• In iron-deficiency anemia, iron therapy should cause
– Reticulocytosis raise in 5 to 7 days
– Hb raise in 2 to 4 g/dL every 3 weeks
• In megaloblastic anemia
– Signs and symptoms usually improve within a few days
– Neurologic symptoms can take longer to improve or can be irreversible
– Reticulocytosis should occur within 2 to 5 days.
– Hematocrit should rise 2 weeks after starting folate therapy
• In anemia of chronic disease
– Reticulocytosis should occur a few days

11/25/2021 Anemias 40