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Agents Used In
Anemias
HAEMATINICS
By the end of lecture students should be
able to:
Know various types of anemias
 Know aetiology of anemias
 Know drugs used for treatment of anemias
 Explain pharmacokinetics and
pharmacodynamics of Iron
 Know acute and chronic toxicities of iron
 Know the management of overdose of iron
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Haematopoiesis
200 billion new blood cells are produced
per day in normal person
 Process occur in bone marrow in adults
 Essential nutrients: iron, vitamin B12, folic
acid, pyridoxine, ascorbic acid and
riboflavin
 Hematopoietic growth factors
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Erythropoiesis is controlled by a feedback
system in which a sensor in the kidney detects
changes in oxygen delivery to modulate the
erythropoietin secretion
Anemia
Decrease in haemoglobin level below normal
 Deficiency in oxygen-carrying erythrocytes
 Symptoms
Features of tissue hypoxia
Pallor, fatigue, dizziness, exertional dyspnoea
CVS adaptations to anemia (tachycardia, increased
cardiac output, vasodilation)
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ANEMIAS:
Microcytic hypochromic anemia- iron
deficiency most
 Most common cause of chronic anemia is
iron deficiency
 Macrocytic anemias- Vit B12 deficiency
Folic acid deficiency
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Drugs used for the correction of
anemias
Include:
Iron
Folic acid
Vit B12
Hematopoietic growth factors
IRON
Iron forms the nucleus of the ironporphyrin heme ring, which together with
globin chains forms haemoglobin
 Increased iron requirement
Growing children
Pregnancy
Increased losses of iron (menstruating
women)
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Iron containing heme is also an essential
component of
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Myoglobin
Cytochromes
Catalase
Peroxidase
Metalloflavoprotein enzymes
Xanthine oxidase
Mitochondrial enzymes
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Sources:
Natural
Meat, green vegetables, grain
Synthetic
Iron preparations
In body
catalysis of hemoglobin in senescent or
damaged erythrocytes
Pharmacokinetics
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Average diet contain 10-15 mg of elemental iron
daily
Total iron absorption can increase to 3-4 mg/day
in pregnant woman
Iron in meat is absorbed as such (hemoglobin
and myoglobin)
Nonheme iron in foods is reduced by
ferroreductase to ferrous form
A peptide hepcidin produced by liver cells-key
central regulator of the system
Absorption:
Duodenum and Proximal jejunum
as Fe+2
BY:
Active transport by DMT1 (divalent
metal transporter)
Iron complexed with heme
Iron absorption increases when iron stores are
depleted regulated by mucosal iron stores
Absorption…..
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The absorbed iron is actively transported
into the blood across the basolateral
membrane by transporter ferroportin and
oxidized to ferric iron by ferroxidase
hephaestin
DISTRIBUTION
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Bound to Transferrin (β –globulin)
bind two molecules of ferric iron
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The transferrin-iron complex enters maturing
erytthoid cells
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Transferrin receptors, transferrin iron complex is
internalized in erythroid cells by endocytosis
Storage
As ferritin in liver, spleen and bone and in
parenchymal liver cells
Ferroportin is storage protein level is
regulated by hepcidin
 Low hepcidin lead to release of iron from
storage sites
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Ferritin level is checked in serum to
estimate total body iron stores.
Elimination
Small amount lost in faeces by exfoliation
of intestinal mucosal cells
 Trace amounts in bile, urine and sweat
 1 mg of iron is lost from body per day
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Therapeutic uses of Iron
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Iron Deficient Anemia
Treatment and prevention
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Pregnancy
Lactation
Growing children
Premature Babies
Patents with chronic
kidney disease
Blood loss
Inadequate iron absorption
Gastrectomy
Malabsorption Syndrome
 GI Bleeding due to:
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 Ulcers
 Aspirin
 Excess consumption of coffee
 Hookworm infestation
Oral preparations of iron
Oral Iron
 Ferrous Sulphate
 Ferrous Gluconate
 Ferrous Fumarate
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Treatment with oral iron should be continued for 3-6
months after correction of cause of iron loss.
Oral Iron Therapy
Dosage:
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200- 400 mg/ day for 3- 6 months
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Adverse effects:
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nausea, epigastric discomfort,
abdominal cramps, constipation, diarrhea,
black stools
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To overcome adverse effects
 Lower daily dose of iron
 Take iron with food
 Change iron preparation.
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PARENTRAL IRON THERAPY
Indications:
 Patients unable to tolerate oral iron
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Patients with extensive blood loss
Malabsorptive states
 Patients with advanced chronic renal
diseases.
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I/M and I/v use:
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Iron dextran
(ferric oxyhydroxide and dextran
polymers) 50 mg /ml
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I/V only:
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Iron sucrose complex
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Sodium ferric gluconate complex
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Dose calculation
Total iron deficit (TID)
 Body wt (Kg) ˟ (Target Hb-Actual Hb g/dl)
˟ 2.4 + depot iron (mg)
 Total amount of venofer to be
administered in ml = TID mg
200 mg/ml
Ratio of total serum iron concentration and
TIBC
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Adverse Effects
i) Local pain & tissue staining
ii) Headache, giddiness, flushing
iii) Fever, Arthralgia, Backache
iv) Nausea, Vomiting
v) Urticaria
Rarely Anaphylaxis & death.
Test dose of iron dextran is given.
Clinical Toxicity
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Acute Iron Toxicity
Seen in young children, who accidently ingest
Iron tablets.
10 tablets in children
Symptoms:
vomiting, necrotizing gastroenteritis
causing abdominal pain, bloody diarrhea followed
by metabolic acidosis, dyspnea, coma & death
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Rx
i) Gastric Aspiration
Gastric lavage, with carbonate solution to form
insoluble Iron.
whole bowel irrigation
ii) Deferoxamine - potent iron chelating
compound given intravenously
iii) Supportive Therapy
Chronic Iron Toxicity
 Hemochromatosis (excess iron is deposited in
the heart, liver, pancreas, and other organs)
 Cause is inherited hemochromatosis and patient
receiving many blood transfusions
 Rx
– Intermittent Phlebotomy (1 unit of blood is
removed every week)
– Iron. Chelation therapy (Deferoxamine,
deferasirox is oral iron chelator)
Vit B 12
 Cofactor for several essential biochemical
reactions in humans
 Deficiency lead to megaloblastic anemia, GIT
symptoms and neurologic abnormalities
Cyanocobalamine
 Hydroxocobalamine
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Source: microbial synthesis from meat,
eggs and dairy products (microorganisms
grow in soil, sewage, water or in intestinal
lumen of animals)
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Chemistry: porphyrin like ring with a
central cobalt atom attached to nucleotide
Structure…….
Various organic groups may be covalently
bound to cobalt atom forming different
cobalamines
 Deoxyadenosylcobalamine
 Methylcobalamine
active form of vitamins in humans
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Pharmacokinetics
Vitamin B12 is absorbed only after it
complexes with intrinsic factor
(glycoprotein)
 This complex of vit B12 and intrinsic factor
is absorbed in distal ileum
 Transported to various cells by binding
with transcobalamin I, II and III
 Excess is transported to liver for storage.
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Pharmacodynamics
Deficiency of vit B 12 also cause ‘folate
trap’
 Methyltetrahydrofolate is not converted
into other intracellular forms of folic acid
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Clinical uses
 Treat
or prevent deficiency
 Megaloblastic, macrocytic anemia
mild or moderate leukopenia or
thrombocytopenia.
 Neurologic syndrome (paresthesias in
peripheral nerves, weakness.
 Progresses to spasticity, ataxia and CNS
dysfunction.
Mechanism for Peripheral
Neuropathy
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Cobalamin is a cofactor for the enzyme
Methylmalonyl-CoA mutase which converts
methylmalonyl-CoA to succinyl-CoA.
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Succinyl-CoA enters the Krebs cycles and goes
into nerves to make myelin.
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If no Vitamin B12, methylmalonyl-CoA goes on to
form abnormal fatty acids and causes subacute
degeneration of the nerves. Only B12 can
correct this problem.
Diagnosis
Serum levels of vitamins (Vit B12 and Folic
acid)
 Schilling test (measures absorption and
urinary excretion of radioactively labelled
vitamin B12)
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Common causes of vit B12 deficiency
Pernicious anemia
Defective secretion of intrinsic factor
 Partial and total gastrectomy
 Malabsorption syndrome
 Inflammatory bowel disease
 Small bowel resection
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Treatment
If the cause is malabsorption,
 Parenteral injections of vit B12
cyanocobalamine or hydroxocobalamine.
 vitamin B12 can be administered
intranasally as a spray or gel.
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Parenteral therapy
Inj Cyanocobalamin or hydroxcobalamin
 Initial therapy
100 – 1000 µg – I/M-D or on alternate days for
1-2 weeks
Maintenance therapy
100 – 1000 µg – I/M- once a month
Folic Acid
Essential for normal DNA synthesis
 Source
Plant and animal (liver, kidney
& green vegetables.
 Chemistry Pteroylglutamic acid
p-aminobenzoic acid and glutamic acid
Pharmacokinetics of Folic Acid
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Site of absorption:
Proximal jejunum
Polyglutamates
monoglutamate
α- 1 glutamyl transferase (conjugase)
PHARMACODYNAMICS:
Tetrahydrofolate cofactor participate in
one-carbon transfer reactions
dTMP
DNA synthesis
Required for the synthesis of :
Amino acids
purines
DNA
dTMP synthesis cycle
dTMP synthase, dihydrofolate reductase
and serine transhydroxymethylase
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 Synthesis
of methionine from homocystine
 Donate one carbon for synthesis of
essential purines
Folic Acid Deficiency Seen in
i)
ii)
iii)
iv)
v)
vi)
vii)
Inadequate dietary intake of folates
Prolong cooking
In alcholics & in pt with liver diseases
Pregnancy
Hemolytic Anemias
Malabsorption Syndrome
Drugs
Methotrxate
,
trimethoprim
pyrimethamine
and
Treatment of Folic Acid
Deficiency
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parentral administ rarely needed.
Oral therapy:
Dose
1mg/d – continued until cause is
corrected or removed.
Hematopoietic Growth Factors
Glycoproteins hormones
 Erythropoietin
 G-CSF
 GM-CSF
 Interlukin-II
 Romiplostim
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Erythropoietin
Source: Recombinant DNA technology
 I/V administration
 Dose calculated in IU.
 Epoetin alfa and epoetin beta
 Half life is 4-13 hrs
 Darbepoetin alfa is heavily glycosylated
(longer half life)
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Pharmacodynamics
Erythropoietin receptors on red cell
progenitors (JAK/STAT)
 Increased production of RBCs in bone
marrow if
 No nutritional deficiency is present
 No primary bone marrow disorder
 No bone marrow suppression from drugs
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Clinical uses
 Anemia
due to chronic renal disease
After treatment increase in reticulocyte
count is observed in 10 days
Increase in Hb in 2-6 weeks
 Anemia due to zidovudine treatment in
HIV patients
 Reduce the need of transfusions in high
risk patients
Toxicity
Hypertension
 Thrombotic complications
 Allergic reactions are rare
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Erythropoieitin is banned by International
Olympic Committee
Myeloid Growth factors
Filgrastrim
 Sargramostim
 Pegfilgrastim
 Leograstim
used for cancer chemotherapy induced
Neutropenia
Congenital neutropenia
Cyclic neutropenia
Myelodysplasia
Aplastic anemia
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Toxicity
Bone pain
 Fever, malaise, arthralgia, myalgia
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