Hematinics

Madan Sigdel
Lecturer
Department of Pharmacology
Gandaki Medical College
 Hematinics: Hematinics are the substances
used in the prevention and treatment of
anemia.

 Anemia: Reduced oxygen carrying capacity

of blood due to various reasons including
reduced Hb content or reduced number of
RBCs or abnormal RBCs.
 Measurements of Anemia
 Hemoglobin = grams of hemoglobin per 100 mL of whole
blood (g/dL)

 Hematocrit = percent of a sample of whole blood occupied

by intact red blood cells

 RBC = millions of red blood cells per microL of whole

blood

 MCV = Mean corpuscular volume

 If > 100 → Macrocytic anemia
 If 80 – 100 → Normocytic anemia
 If < 80 → Microcytic anemia
 The mean corpuscular hemoglobin (MCH), or
"mean cell hemoglobin" (MCH), is the
average mass of hemoglobin per red blood
cell in a sample of blood. The normal MCH
level is between 26 and 33 picograms of
hemoglobin per red blood cell.
Causes of Anaemia
1. Deficiency of substance
a. Exogenous substances
b. Endogenous substances
2. Reduced (hypoplastic) or absent synthesis (aplastic)
including disease and drug induced.
3. Excess destruction (haemolysis) including disease and drug
induced.
4. Genetic abnormalities
5. Excess loss of blood
6. Drug induced
7. Other causes
Iron in diet and body
 The normal daily diet contains about 10 to 20 mg
of iron, mostly in the form of heme.
 About 20% of heme iron and only 1% to 2% of
non heme iron) is absorbable.
 The total body iron content is normally about 2
gm in women and as high as 6 gm in men divided
into functional and storage pools.
 About 75% of the functional iron is found in
hemoglobin; myoglobin and iron-containing
enzymes such as catalase and the cytochromes
contain the rest.
 The storage pool (hemosiderin and ferritin)
contains about 25% of total body iron.
iron requirements are:
Adult male 0.5-1 mg (13 µg/kg)
Adult female 1-2 mg (21 µg/kg)
(menstruating)
Infants 60 pg/kg
Children 25 pg/kg
Pregnancy 3-5 mg (80 pg/kg)
(last 2 trimesters)
Dietary sources of iron
Rich : Liver, egg yolk, dry beans dry fruits, wheat germ, yeast.
Medium : Meat, chicken, fish, spinach, banana, apple.
Poor : Milk and its products, root vegetables
Iron Distribution in Healthy Young Adults
(mg)
Pool Men Women
Total 3450 2450
Functional
Hemoglobin 2100 1750
Myoglobin 300 250
Enzymes 50 50
Storage
Ferritin, hemosiderin 1000 400
Iron Absorption
• Diet – 10 to 20 mg – absorbed from all over
the Intestine (more from upper part)
• 2 forms – haeme and Inorganic
• Factors increasing absorption –
• Factors impending absorption –

• Mucosal block: from ferritin the iron is very

slowly released into the plasma. So iron (as
ferritin) will be in the mucosal cell for a long
time
Iron – Transport, storage etc.
• In plasma immediately converted to Fe3+ form –
complexed with transferrin (Tf) –
• Transported to RBCs by transferrin receptors (TfRs) –
endocytosis – Iron dissociates from TfR in acidic pH of
vesicles
• Iron utilized for Hb synthesis – TfRs return to surface
• In Iron deficiency – TfRs increase
• Storage – RE cells in Liver, spleen, bone and muscles
as ferritin and haemsiderin
• Excretion – 0.5 to 1 mg/day – exfoliation in GI mucosal
cells, RBCs and in Bile …. Also in skin, urine and sweat
Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2008
 Preparation
 Oral Preparations
 ferrous sulfate, contains 20 % ( hydrated salt) and 32
% elemental iron. It is the oldest and cheapest iron
preparations.
 Ferrous gluconate: contains 12 % elemental iron and is
less gastric irritant.
 Ferrous fumarate contains 33 % elemental iron.
 Other preparations are ferrous choline citrate, ferric
ammonium citrate

 SE: GIT upset, blackened stool, teeth stain

 Form: tablet, liquid, sustained-release
Parenteral preparations
 Iron sorbitol citric acid complex: given i.m.
 Iron dextran : commonly used parenteral
preparations and can be administered i.v.
and i.m.
 Sodium ferric gluconate: recently approved
preparation for i.v. use, has a much lower risk
of anaphylactic reaction than iron dextran.
 Interactions
 Iron chelates in the gut with tetracyclines,
penicillamine, methyldopa, levodopa, carbidopa,
ciprofloxacin, norfloxacin and ofloxacin;
 it also forms stable complexes with thyroxine,
captopril and biphosphonates.
 Ingestion should be separated by 3 hours.
 ↑absorption: vit C
 ↓absorption: desferrioxamine, tea (tannins) , Zn,
and bran
 Unwanted effects of iron
 Dose related, include nausea, abdominal cramps and
diarrhoea.
 overcome : ↓dose or by taking the tablets after or with meals
 Acute iron toxicity
 Ingestion of large quantities of iron salts.

 Result: severe necrotising gastritis with vomiting,

haemorrhage and diarrhoea  collapse
  Treatment : gastric lavage with NaHCO3, iron chelating
agent, and treatment of causes.
 Chronic iron toxicity

 Caused by conditions other than ingestion of iron salts,

 Cause pancreatic damage and leading to diabetes.

 Iron chelators

 Used for treatment of iron toxicity

 Desferrioxamine(Desferal) (t1/2 6 h)

 Injected i.m. (preferably) 0.5-1 g (50 mg/kg) repeated 4-12

hourly as required, or i.v. (if shock is present). 10-15
mg /kg/hr, max 75 mg/kg in a day till serum iron falls
below 300 ϥg /dl.
 In severe poisoning: slow IV too fast: hypotension

 forms a complex with ferric iron, excreted in the urine.

 Iron Summary
 Present as haemoglobin; myoglobin, cytochromes and other enzymes.
 Absorption: Ferric iron (Fe3+)  ferrous iron (Fe2+)
 active transport into mucosal cells in jejunum and upper ileum
transported into plasma and/or stored intracellularly as ferritin.
 Iron loss occurs mainly by sloughing of ferritin-containing mucosal
cells; iron is not excreted in the urine.
 Iron in plasma is bound to transferrin, and most is used for
erythropoiesis. Some is stored as ferritin in other tissues. Iron from time-
expired erythrocytes enters the plasma for re-use.
 The main therapeutic preparation is ferrous sulfate
 Unwanted effects include gastrointestinal disturbances. Severe toxic
effects occur if large doses are ingested; these can be countered by
desferrioxamine, an iron chelator.
MEGALOBLASTIC
ANAEMIAS
What is Megaloblastic anemia?
 Megaloblastic anemias are characterized by
the presence of abnormally large developing
red cells in the bone marrow.
 Anemia is based on ineffective
erythropoiesis.
 These red cells are large in shape
 Vit B12 deficiency causes damage to myelin in
the peripheral nerves, spinal cord & brain
 Folate deficiency: weight loss, nervous instability
but damage to myelin is doubtful
 Other causes of macrocytic anemias: Liver
disease, myxedema, Leukemia & certain
hemolytic states
Diet of Megaloblastic
Anaemia
 Sources of B-12: Animal products: Meat, eggs,
milk , Vitamin supplements

 Sources of folic acid:

Legumes, nuts, whole grain cereals, yeast Green
vegetables, broccoli, asparagus, okra, cauliflower,
and brussel sprouts. Oranges, carrots.
Vit B12
 Vit B12 acts as a coenzyme in certain
metabolic pathway.
 Methyl cobalamin (methyl B12)
 5’ deoxyadenosylcobalamin (DAB12)

 Homocysteine methyl B12 methionine

 Methylmalonyl CoA DAB12 Succinyl CoA

VITAMIN B12....
Essential in two reactions:
1. Conversion of methylmalonyl-coenzyme A to
Succinyl-CoA
2. Conversion of Homocysteine to Methionine

The second reaction is linked to folic acid

metabolism and synthesis of deoxythymidylate
(dTMP)

dTMP is a precursor for DNA synthesis

Vitamin B12 binds to Intrinsic factor (secreted by gastric
parietal cells)
It prevents digestion of B12
In bound state ,it binds to receptors on brush border of mucosa
These receptors are located in ileum

Bound intrinsic factor and B12 are absorbed with pinocytosis

DISTRIBUTION:
Vitamin B12 is distributed to various cells bound to a plasma glycoprotein,Transcobalamin II
STORAGE:
Excess vitamin B12 (upto 300-500 microgram) is
stored in liver
Absorption
Storage sites
 Total amount of vitamin in body is 2-5 mg
( adequate for 3 years )
 Major site : liver
 Excreted through the bile and shedding of
intestinal epithelial cells
 Most of the excreted vitamin B12 is again
absorbed in the intestine (enterohepatic
circulation)
SCHILLING TEST
 For evaluation of absorption of vitamin B12 in the
GIT

 Performed in 2 parts – part 1 and part 2

 Part 1 :
 0.5 to 1 µg of radiolabelled vitamin B12 is given orally
 After 2 hrs IM dose (1000 µg) of unlabelled vitamin B12
is given [ saturates binding sites of TC I and TC II and
displaces any bound radiolabelled vitamin B 12 (thus
permitting urinary excretion of absorbed radiolabelled
vitamin B12 )
 Radioactivity is measured in subsequently
collected 24 hr urine sample and expressed as a
% of total oral dose

 In normal persons, > 7% of the oral dose of

vitamin B12 is excreted in urine
 If excretion is less than normal it indicates impaired
absorption, which may be due to either lack of IF or
small intestinal malabsorption

 Part 2 performed if part 1 of test is abnormal

 Part 2 : patient is orally administered
radiolabelled vitamin B12 along with IF while
remainder of test is carried out out as in part
1

 Excretion becomes normal – lack of IF

 Excretion remains below normal – defective
absorption in small intestine
preparations
 Cyanocobalamin, hydroxycobalamin and methylcobalamin.

 Cyanacobalamin is the preparation of choice and is given

through i.m. or s.c. route. The dose of cobalamin is 100 mcg
i.m. once a week for 8 weeks followed by 1000 mcg i.m. every
month life long.
 Oral methylcobalamin has been used in the treatment of
trigeminal neuralgia, multiple sclerosis and other
neuropathies.
 In alcohol and tobacco amblyopia weekly injections of
hydroxycobalamin is given for 10 weeks
Folic acid: (Pteroyl Monoglutamic acid)
 FOLIC ACID.....
ABOSRPTION:
Form:
Dietary folates in polyglutamate forms; first undergo
hydrolysis by conjugase (present in brush border of
intestinal mucosa) and form monoglutamate
Site:
Proximal jejunum

Only modest amounts of folic acid are stored in

body, therefore a decrease in diet will lead to
anemia in few months
Folic acid
Distribution:
Widely distributed through out the body via
blood stream

Storage:
Normally, 5-20 mg is stored in liver and other
tissues

Elimination:
Excreted in urine and stool, and also destroyed
by catabolism
 Transport storage and fate:
 Orally given folic acid appears in 30 min as
circulation it circulates as N5 Methyl THF
 Majority is loosely bound to albumin from
where it is easily taken up by cells
 Inside the cells converted to THF by
cobalamine dependent enzyme methionne
synthetase
 Vit C protects THF from destruction
 Total folate in body = 5 to 20 mg (1/3 in liver
as methyl folate)
 Metabolic functions
 Folic acid DHFA THFA (Active
form)
folate DHF
reductase reductase
 THFA mediates number of one Carbon tranfer
reactions
 Conversion of homocysteine to methionine
 Generation of thymidylate
 Conversion of serine to glycine
 Purine synthesis
 Histidine metabolism
Deficiency :
1. Inadequate dietary intake

2. Malabsorption : coeliac disease, tropical sprue ,

regional ileitus
3. Biliary fistula: no recirculation

4. Chronic alcoholism

5. Increased demand : Pregnancy , lactation

6. Drugs: Phenytoin, phenobarbitone, primidone

 Preparations and dose:
 Folic acid tab 5 mg ; dose = 5 to 20 mg

 Prophylaxis 0.5 mg/day

 Parenteral form available in combination only

 Folinic acid: N5 Formyl THFolinic acid

(Citrovorum factor) 3 mg/mL Inj
 Uses:
1. Megaloblastic anemia

2. Prophylaxis

3. Methotrexate toxicity: Folinic acid used as it is

an active no need to reduced by DHFR before it
can act, Methotrexate is DHFR inhibitor, its
toxicity not reversed by folic acid
4. Citrovorum factor rescue: Methotrexate high
dose IV then half to 2 hr later 1-3 mg folinic acid
IV to rescue normal cells
Adverse events:
 CLINICAL USES OF VIT B12 AND
FOLIC ACID
These are used in anemia (megaloblastic). 1-5 mg daily and
continued for about 3-4 months.

Pernicious anemia ( Vitamin B12, basically IF)

Prophylaxis for neural tube defects (folic acid

0.5 mg/ day is given from the 1st trimester)

Neuropathy (Vitamin B12)

Cancer chemotherapy
Certain drug therapies lead to deficiency of folic
acid so replacement is required