IRON

ANAEMI
A
Reduced oxygen carrying capacity of the blood due to various
reasons including reduced Hb content or reduced number of RBCs
or abnormal RBCs..

 Can be due to:

i. Decrease RBC production

ii. Increase RBC destruction

iii. Blood loss

 IRON

 Iron forms the nucleus of the iron-porphyrin heme ring.

 Four iron-porphyrin heme ring + globin chains 

Hemoglobin

 Iron deficiency: Microcytic Hypochromic Anemia.

 IRON DEFICIENCY
 Peptic ulcer

 Hookworm infestation

 Menstrual loss

 Poor absorption  Malabsorption, Post gastrectomy

 Increased requirement  Premature infants, Growing children,

During pregnancy

& Lactation..
 ROLE OF IRON
 Haemopoiesis / erythropoiesis

 Myoglobin

 Cytochrome

 Catalase

 Peroxidase

 Metaloflavoproteins (including xanthine oxidase)

 Mitochondrial enzyme (alpha glycerophosphate oxidase)

 Also important for brain functions….

 SOURCE OF IRON

Animal • Meat, Liver,

• Chicken, Fish,
• Egg yolk, Oyster…
sources

• Wheat germs, Dry

Plant fruits,
sources • Spinach, Dried beans,
Apple, Banana, Jaggery,
• Milk & Milk products..

MEAT IRON IS HEME IRON AND EASILY ABSORBED

 DISTRIBUTION OF IRON IN THE BODY
Distribution of iron in the body
Hb 66 %
Ferritin,
25%
ADULT 2.5 - 5 g
Haemosiderin
MEN 50 mg/kg Myoglobin
WOMEN 38 03%
mg/kg
(in muscle)
Enzymes
(Cytochromes 06%
, etc.)

Apoferritin + Haemosiderin
Fe3+
Ferritin (not reutilized)
DAILY REQUIREMENT OF IRON IN THE BODY

Daily requirement of iron

Infant 0.06 mg/ kg
Children 0.025 mg/ kg
Adult male 0.5 - 01 mg
Adult female 01 - 02 mg
Pregnancy &
03 - 05 mg
lactation
 BODY IRON REGULATION BY HEPCIDIN
Iron Deficiency 1
Hepcidin
Body iron decrease
1
lowers hepcidin
synthesis in the liver

2 Hepcidin deficiency
2
targets the
duodenum and
spleen

3 Duodenal absorption of iron

increases

4 Splenic iron is released into

the circulation
Iron
Iron concentration in plasma
4
5 5
increases, leading to
restoration of iron balance
3

Ganz T, et al. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.

 Down-regulation of liver hepcidin synthesis,
Induction of liver hepcidin synthesis, decreases iron
increases iron export from absorptive cells
export from absorptive cells (enterocytes) recycling
cells (macrophages) and storage cells (hepatocytes).
(enterocytes) recycling cells (macrophages) and
storage cells (hepatocytes).

The box labelled ‘HFE- and Non-HFE haemochromatosis.(not FP disease)’ refers to HFE- and non-HFE
haemochromatosis with the sole exception of ferroportin disease.
FACTORS THAT INFLUENCE IRON ABSORPTION
INCREASE ABSORPTION DECREASE ABSORPTION

Ascorbic acid Antacids

Amino acids Phosphates (egg yolk)

Meat Phytates (phytic acid),

Tannins
Increase gastric acidity Tetracyclines,
Presence of food in stomach
IRON METABOLISM
 PHARMACOKINETICS OF IRON
 No metabolism to excrete excess iron
 Controlled by regulating absorption according to need
 Daily requirement – 1 mg / day
 Dietary requirement – 10 to 20 mg / day (as only 5 – 10% is absorbed)
 Absorption – Duodenum & Upper (proximal) jejunum
 Absorption increased in iron deficiency
 Transport – Transferrin
 Storage – Ferritin (non toxic)
Hemosiderin (aggregated ferritin, toxic)
 IRON THERAPY
 Oral or Parenteral iron preparations.

REMEMBER!!!

Oral iron corrects the anemia just as rapidly and completely

as parenteral iron.
Elemental iron content, but not the quantity of iron compound per
dose is taken into consideration.

 Sustained release formulations not rational…

 WHEN TO USE IRON ???
1. Treatment or prevention of iron deficiency anemia.

2. Premature infants & children

3. Pregnant & lactating women

4. Patients with chronic kidney disease (CKD)

5. Gastrectomy & severe small bowel disease

6. Blood loss

7. Megaloblastic anemia
AIM OF TREATMENT OF IRON DEFICIENCY ANAEMAI

 Correction of Hb

 Correction of the underlying cause

 Building up body iron stores

TYPES OF IRON PREPARATIONS

IRON PREPARATIONS

ORAL PARENTERAL

FERROUS SULPHATE, IRON DEXTRAN,IRON

FERROUS FUMARATE, SORBITOL CITRIC ACID
FERROUS GLUCONATE, COMP., IRON SUCROSE &
COLLOIDAL FERRIC SOD. FERRIC GLUCONATE,
HYDROXIDE, FERRIC CARBOXYMALTOSE
CARBONYL IRON & FERUMOXYTOL
 ORAL IRON
 Preparation of choice due to efficacy, safety, low cost
Dose/Tab Ele.Fe Daily dose
Fe. sulphate 325 mg 65 mg 2 - 4 tab
Fe. gluconate 325 mg 36 mg 3 - 4 tab
Fe. fumarate 325 mg 106 mg 2 - 3 tab
Colloidal ferric hydroxide 50 mg/ml drops.
Carbonyl iron: highly purity metallic iron prepared
by decomposition of iron pentacarbonyl  a highly toxic
compound.

 Ferrous sulphate – most effective, low cost & better absorption...

OTHER FORMS OF IRON PRESENT IN ORAL FORMULATIONS

 Ferrous succinate (35% iron)

 Iron choline citrate

 Iron calcium complex (5% iron)

 Ferric ammonium citrate (20% iron)

 Ferrous aminoate (10% iron)

 Ferric glycerophosphate

 Ferric hydroxyl polymaltose

Better absorption, less bowel upset, lower iron content – more expensive
 ORAL IRON

 Ferrous (Fe2+) form readily absorbed than ferric (Fe3+) form..

Ascorbic acid increases absorption, but therapeutically not useful

Caution:
Many FDC containing Iron & Vit. C are available.

They are costly and not advantageous.

 ORAL IRON
 Food impairs absorption, but still given with or after meals
Reason:
Causes less GI upset, as less is absorbed  Hence improves compliance.

 Absorbed in duodenum and upper jejunum.

Clinical implication:
Delayed / modified release preparations release iron in lower part of small
intestine their iron content lower down…
So no therapeutic advantage.
 ORAL IRON
 Phytates, tannins – impair absorption

Clinical implication:

Advice patient not to take tablet along with tea.

 Drugs can also impair absorption, e.g.

Tetracyclines,
Fluoroquinolones,
Levodopa,
Penicillamine…
 DOSE OF ORAL IRON
 Therapeutic:

200 mg/day in 3 divided doses with or after meals.

 Prophylaxis:

Pregnancy: 100 mg elemental iron daily from 2nd trimester.

Continue throughout lactation.

Professional Blood donors: 300 mg ferrrous sulphate for 1 month after donating 500 ml.
 RESPONSE TO THERAPY

 Early  increase in appetite & well being  2 days

 reticulocyte count  5 to 7 days…

 Evidence of adequate response

– Rise of Hb by 2 g/dl after 3 weeks of therapy..
 ORAL IRON ADRs
Most common – GI disturbance,
heartburn,
nausea, vomiting,
bloating, colic.
 Constipation,
blackens the
faeces
 Metallic taste
 Liquid
formulation can
stain the teeth
 ORAL IRON PRECAUTIONS
 Keep out of reach of children.

Reason:

 Children are very sensitive to iron toxicity (necrotizing gastroenteritis),

bloody diarrhea & later produce shock…

 Even 1 g of ferrous sulphate can be fatal.

Contraindications:

 Hemolytic anemia

 Ulcerative colitis
 PARENTERAL IRON
 Does NOT hasten Hb response
 So indicated only in
-Malabsorption from gut (inflammatory bowel disease,
chronic inflammation…)
-Intolerable adverse effect
-Cannot be relied on to take tablets
-Presence of severe deficiency with chronic bleeding

Iron requirement (mg) = 4.4 x bw (kg) x Hb deficit (g/dl)

IRON DEXTRAN
 Complex of hydroxide
ferric with
 dextran.
High molecular
weight IM. & given by IV &
 IM in gluteal region by ‘Z’ track
technique.
 Reaches RE cells via lymphatics.
 Need 25 % extra than calculated
dose.
 Not excreted in urine & bile.
 Not preferred now a days because of high
incidence of fatal anaphylaxis.
 IRON DEXTRAN Cont…

Intramuscular:
2 ml (100 mg) daily or alternate days

Intravenous:
Test dose 0.5 ml over 5-10 min.

2 ml/ day over 10 min.

Total dose i. v. infusion

Dilute total calculated dose in 500 ml of 5% glucose/ Saline infuse
i.v. @ 10 drops /min. & ↑ to 30-40 drops/ min over 6-8 hrs.
 IRON – SORBITOL CITRIC ACID COMPLEX

 Low molecular weight complex

 Only IM

 Enters RE cells from blood

 30 % excreted in urine

 CI in Kidney disease
 IRON SODIUM GLUCONATE
Preferred agent for parenteral (i.v) therapy, 80% delivered
to transferrin within 24 hrs.

 FERROUS (IRON) SUCROSE

Complex of ferric hydroxide with sucrose. Given by slow i.v. inj. /
infusion  cause severe may occur drugs for resuscitation
& anaphylaxis.

Do not give oral Fe concurrently & up to 5 days…..

 IRON SUCROSE
Not preferred by intramuscular route

Reason:
Can cause soft tissue sarcomas

Most likely among all iron preparations to cause renal tubular injury

Reason:
Has a high renal uptake
 FERUMOXYTOL

 Carbohydrate – coated, superparamagnetic

iron oxide nanoparticle (little free iron is present in the

preparation)
 Administered intravenously

 In 2009, FDA was approved by this drug for i,.v.

 Mainly in treatment of anaemia of chronic kidney

disease (CKD).

 It interfere with MRI study.

 FERRIC CARBOXYMALTOSE (FCM)

 Colloidaliron preparation embedded within a carbohydrate

polymer.

 Administered intravenously

 In 2013, FDA was approved by this drug for i,.v.

 Mainly in treatment of anaemia of chronic kidney disease

(CKD).
 PARENTERAL IRON- ADRs
 Most common – headache, vomiting, pain at site of injection,

pigmentation

 Most serious – anaphylaxis

 Others – hypotension
Precautions
 Always administer test dose

 Observe the vital signs during infusion

 Be ready with measures for resuscitation

 ACUTE IRON POISONING
 Mainly Children and infants

 Ferrous sulphate > 1g

Vomiting, Diarrhoea, Abdominal pain, Dehydration,

Acidosis, Lethargy, Convulsion, Collapse, Death (6-48 hours)

Haemorrhage & inflammation in the gut, liver necrosis,

brain damage..
 ACUTE IRON POISONING

To prevent further absorption of iron from

gut:
Gastric lavage with sodium bicarbonate solution

Egg yolk & milk  orally to complex iron.

Activated charcoal does not absorb iron molecules.

 ACUTE IRON POISONING

 To bind & remove iron already absorbed:

 Overdose of iron  oral & parenteral Desferrioxamine  a potent iron chelating agents.

 50 mg /kg, IM; repeat 4-12 hrs…

 If shock : 10-15 mg/kg/ hr  max 75 mg/kg in a day till serum iron falls below 300
μg /dl

 Calcium edetate

 BAL is contraindicated  its iron chelate is also toxic

 Supportive measures:

 Maintain electrolyte balance  IVF & Diazepam - i.v. used to control convulsion
..
MISCELLANEOUS / ADJUVANT HAEMATINICS

 Copper

 Pyridoxine (Vit B6)

 Riboflavin (Vit B2)

 VITAMIN B12

 Dietary  essential for DNA synthesis & cell

constituents
proliferation.
 Deficiency affects tissues with rapid cell
proliferation.

 Megaloblastic haemopoiesis – disorders of erythroblast

proliferation & defective erythropoiesis…

 Leukopenia and thrombocytopenia…

Cobalamin Methylcobalamine

Methionine synthase
 VITAMIN B12
Daily req.: 1– 3 μg, 3 - 5 μg in pregnancy & lactation.
Source:
Meat, eggs, dairy products, legumes (pulses)
Microbial synthesis (not useful), Streptomyces
griseus

Deficiency:
Anaemia, GI symptoms & neurological
abnormalities…

Causes:
↓ absorption (lack of intrinsic factor)
Factors affecting absorption in
 STRUCTURE & TYPES
Porphyrin like ring, central cobalt atom attached to a nucleotide.

Active forms : Deoxyadenosyl-cobalamin (DAB12)

Methyl-cobalamin (methyl B12)
Therapeutic use : Cyanocobalamin
(Food) Hydroxocobalamin
 PHARMACOKINETICS
Absorption:
Forms a complex with intrinsic factor
Distal ileum by specific receptor mediated
transport

Transport:
Bound to transcobalamin II (TC II)
Storage:
Liver, 1 – 10 mg store in adults.
Undergoes enterohepatic circulation
Stored in a healthy person is about 3 -5
g
(sufficient for about 3 -5 years)
 PHARMACODYNAMIC
1. Methylcobalamine :
S
Intermediate in transfer of a methyl group from N5 methyl tetra
hydrofolate (methyl THF) to methionine while forming
tetrahydrofolate (THF) (precursor of folate cofactors).
Large amounts of folic acid can correct megaloblastic anaemia
of B12 deficiency..

2. Isomerisation of methylmalonyl-CoA to succinyl-CoA

Deficiency : Neurological manifestations.

 VIT B12 DEFICIENCY
 Results from Malabsorption of vitamin B12 due to

 lack of IF

 loss or malfunction of the specific absorptive mechanism in the distal ileum

 Nutritional deficiency rare

 Inflammatory bowel disease (IBD)

 High consumption due to intestine flora or fish tape worm

 Increased demand : Pregnancy & infancy

 VIT B12 DEFICIENCY - CLINICAL FEATURES

 Megaloblastic anaemia

 Leucopenia

 Thrombocytopenia

 Neurologic syndrome
What will happen when folic acid is given
in the presence of Vit B12 deficiency ?

Anaemia may get corrected but not the

neurological manifestations…….
 VIT B12 PREPARATIONS

 Cyanocobalamin

 Hydroxocobalamin

 Methylcobalamin
 VIT B12 USES
 Pernicious anaemia

 Partial / Total gastrectomy

 Distal ileal diseases – IBD, malabsorption syndrome,

 Chronic pancreatitis, thyroid disease

 Bacterial overgrowth of small bowel

 TREATMENT

Parenteral injections of B12

Initial treatment : 100 - 1000μg IM/ SC daily / alternate day for 1-2

wk. Maintenance : 100 - 1000 μg IM / SC once a

month…

Neurological abnormality: every 1 - 2 wks for 6 months then switch

to monthly injection.
Prophylaxis:

3-10 µg/day orally Cyanocobalamine

Neurological defects in diabetic, alcoholic & other peripheral neuropathy

Methylcobalamine: 1.5 mg/ day orally.

Tobacco amblyopia: Hydroxocobalamin

 AD
R
- Large doses are quite safe

- Some time allergic reactions occurred on injection

- Anaphylactic reactions occurred on i. v. injection  due

to contamination / contain sulfite in preparation…

 FOLIC ACID
(WILLS FACTOR/ VIT. M)

Pteroyl glutamic acid (PGA)  pteridine + PABA + glutamic acid

Req. : 0.2 mg / day, 0.8 mg / day (Pregnancy, lactation)

Source : Yeast, liver, meat, green vegetables (spinach),

Dietary folates (poly glutamates),
Synthesized by gut flora unavailable

for absorption..
Absorption : Proximal jejunum
Dietary folates (poly glutamates)

Mono glutamates

Active & passive

absorption
 PHARMACOKINETICS
 50–200 µg absorbed in proximal jejunum

 Absorption increases in pregnancy

 5–20 mg of folates are stored in the liver and other tissues.

 Excreted in the urine and stool & are also destroyed by catabolism..
 Because body stores of folates are relatively low & daily requirements high,

Folic acid deficiency & Megaloblastic anemia can develop within 1–6 months

after the intake of folic acid stops,

depending on the patient's nutritional status & the rate of folate utilization.
 PURINE SYNTHESIS
dUMP
N5, N10 - METHYLENE 2
THYMIDYLATE
TETRAHYDROFOLATE SYNTHASE
GLYCINE
dTMP DNA SYNTHESIS
SERINE TRANS
HYDROXYMETHYLASE

Enzymatic reactions that use folates

SERINE
3
FOLATE FOLATE
REDUCTAS REDUCTAS
TETRAHYDROFOLATE E DIHYDROFOLATE E FOLIC ACID

METHYLCOBALAMIN
HOMOCYSTEINE
1
COBALAMIN METHIONINE

N5 - METHYL
TETRAHYDROFOLATE 1. Vit B12 dependent reaction  THF
2. dTMP cycle
3. Folic acid enters the THF cofactor pool
DIETARY FOLATES
 USES OF FOLIC
 Dietary inadequacy ACID
 Alcoholics, liver disease

 Megaloblastic anaemia (1-5 mg/ day)

 Prophylaxis – in pregnancy (1-4 mg)

 Methotrexate toxicity

 Citrovorum factor rescue (within ½ - 1 hr )

 To enhance anticancer efficacy of 5-FU

 USES OF FOLIC ACID cont..

 Malabsorption syndrome

 Cancer, leukemia, myeloproliferative diseases, chronic debilitating

diseases

 Patients on renal dialysis

 Drug induced deficiency of folic acid

 DRUGS CAUSING FOLATE DEFICIENCY
 Methotrexate

 Trimethoprim

 Pyrimethamine

 Phenytoin

 Phenobarbitone

 Oral contraceptives
 TREATMENT OF FOLIC ACID DEFICIENCY

 2 - 5 mg folic acid orally daily.

 Therapy continued until the underlying cause of the deficiency is

removed or corrected.

Folic acid prophylaxis: 1 mg/day.

 FOLINIC ACID IN METHOTREXATE TOXICITY

 MTx is a DHFRase inhibitor

 Folinic acid (Citrovorum factor/ Leucovorin calcium):
-Active coenzyme of folic acid
-Does not need to be reduced by DHFRase
What is Citrovorum factor rescue?
 High dose MTx  i.v.
 1-3 mg folinic acid  i.v. after ½ - 1 hrs.
HAEMATOPOIETIC GROWTH FACTORS / AGENTS
 ERYTHROPOIETI
N
 Sialo glycoprotein hormone ( MW 34000)

EPO produced by peritubular cells of kidneys from

here to its goes to bone marrow cells..

oStimulate proliferation of erythroid series cells

oInduce Hb formation & erythroblast maturation

oRelease reticulocyte in the circulation

 Binds to EPO receptor (JAK-STAT)  intracellular
protein  to regulate gene expression…
 ERYTHROPOIETIN IN ANAEMIA
 Chronic renal failure

 In anaemia of chronic disease (ACD)

 Anaemia in AIDS patients treated with Zidovudine

 Cancer chemotherapy induced anaemia

 Autologous blood transfusion

 Anaemia in premature infants

Symptomatic anaemia with Hb < 8

g/dl
 RECOMBINANT HUMAN EPO
Epoetin α & β:

 Epoetin α  mammalian cell line (Chinese hamster ovary cell)

 It is closely similar to endogenous erythropoietin it is used for all

the conditions

Dose:

25-100 U / kg  IV / SC  3 times a week (max. 600 U / kg / week).

Half life : 6 -10 hr but action lasts several days..

Darbepoietin:

 Similar action of epoetin,

 Hyperglycosylated form of epoetin alfa with longer plasma half life 

thus less frequent administration (once a week)  very convenient..

Peginesatide:

 Pegylated erythropoiesis stimulation agent (ESA) a functional analogue of EPO.

 Chronic renal failure in adult patients on dialysis.

 Serious hypersensitivity reactions anaphylaxis may occur.

 ADVERSE EFFECTS

 Increase clot formation in A-V shunt

 Hypertensive episodes

 Seizures

 Flu like symptoms

 MYELOID GROWTH FACTORS

 Granulocyte colony stimulating factors (G-CSF):

Filgrastim, Pegfilgrastim, Lenograstim

 Granulocyte monocyte colony stimulating factors (GM-CSF):

Sargramostim, Molgramostim, Regramostim

 Megakarycocyte growth

factors: Interleukin – 11,

Thrombopoietin
 Growth factors Examples Blood cells Preferred use
affected
EPO Epoietin, Anaemia in CRF & due to BM
Darbepoietin RBC depression , e.g.:
Zidovudine, anticancer drugs
Peginesatide
G-CSF Filgrastim, Neutropaenia including drug
Pegfilgrastim, induced e.g.: Cytotoxic drugs
Lenograstim
WBC
GM-CSF Sargramostim, Bone marrow & stem cell
Molgramostim, transplantation
Regramostim

Interleukin – 11 Oprelvekin Thrombocytopaenia due to

anticancer drugs
Platelets
Thrombopoietin Romiplostim, Idiopathic thrombocytopenia (ITP)