1. Hematinics

2. • Hematinics are the agents used
a) Treatment of anemia
b) Increase the number of RBC or hemoglobin
content of RBC or both when there is
deficiency

3. Normal erythropoiesis
Pluripotent stem cell
Erythroid burst forming unit
Erythroid colony forming unit Within BM
Erythroblast
Reticulocyte
Mature red cell
Peripheral
blood

4. Normal erythropoiesis
• Erythropoietin production is impaired in
conditions such as RA, cancer and Sickle cell
anemia
• Normally survive for 120 days

5. Normal erythropoiesis
• Destroyed by reticuloendothelial system found
in spleen and BM
• Iron is removed from haem component of Hb
and transported back into bone marrow for
reuse

6. Normal erythropoiesis
• Pyrole ring from globin is excreted as
conjugated bilirubin by the liver and the
polypeptide portion enters the body’s protein
pool

7. Anemia

8. Introduction
• Not a single disease
• Results from a number of different pathologies
• Defined as a reduction from the normal quantity of
Hb in blood
• WHO defines anemia as Hb levels less than 13 g/dl
for males and less than 12 g/dl for females
• Low Hb levels results in decreased oxygen carrying
capacity of blood

9. Epidemiology
• Most common condition resulting in significant
morbidity and mortality
• Worldwide: Over 50% of pregnant women and 40 %
of infants are anemic

10. Aetiology
Two different mechanisms:
1. Reduced Hb synthesis (due to lack of nutrient
or bone marrow failure)
Reduced proliferation of precursors or
defective maturation of precursors or both

11. Aetiology
• Increased Hb loss due to haemorrhage (red cell
loss) or hemolysis (red cell destruction)
(More than one cause can be found in a patient)

12. Classification of anemia:
A) Morphological classification:
1) normocytic normochromic anemia
-acute blood loss
-marrow failure ( aplastic anemia)
- chronic renal failure
- anemia of chronic disease
2) Microcytic hypochromic anemia
- iron deficiency anemia
- thalessemia
3) Macrocytic Anemia :
- Vitamin B-12 deficiency
- folic acid deficiency

13. B) Patho-physiological classification:
1) Hemorrhagic or blood loss anemia
- acute blood loss
- chronic blood loss
2) Impaired RBC production
a) Nutritional deficiency anemia :
- iron deficiency anemia
- Vitamin deficiency anemia
- Protein – energy malnutrition
b) Aplastic Anemia
- leukemia
- lymphoma
- myeloproliferative diseases
c) Chronic Renal Failure
d) Anemia of chronic Disease
3) Hemolytic Anemia

14. Symptoms and signs of anemia
Symptoms
• Fatigue
• Faintness
• Headache
• Palpitations
• Angina of effort
• Breathlessness
Signs
• Pallor
• Tachycardia
• Systolic flow murmur
• Cardiac failure
• Koilonychia
• Jaundice

15. Classification of hematinics
1) Drugs used in anemias :
2) Hematopoietic growth factors
a) Drugs used in iron
deficiency anemia:
i) iron preparations
ii) copper
iii) cobalt
iv) pyridoxin
v) riboflavin
b) drugs used in
megaloblastic anemias :
i) Vit B-12
ii) Folic acid
iii) Vitamin –C
a) erythropoetin
b) myeloid growth factors :
- G-CSF ( filgrastim)
- GM-CSF ( sargramostim)
- pegfilgrastim
c) megakaryocyte growth
factors:
- interleukin -11 (oprelvekin)
- thrombopoetin

16. IRON

17. Iron
Absorption , transport and strorage of iron

18. Iron distribution

19. Pharmacokinetics
ABSORPTION
• absorbs 5–10% of iron ingested or about 0.5–1 mg daily.
• normally absorbed in the duodenum and proximal jejunum.
• absorption increases in response to low iron stores or increased
iron requirements.
• abundant in meat. heme iron in meat hemoglobin and myoglobin
can be absorbed intact without first dissociated into elemental iron
. Nonheme iron in foods and iron in inorganic iron salts and
complexes must be reduced to ferrous iron (Fe2+) before it can be
absorbed by intestinal mucosal cells.
two mechanisms:
i) active transport of ferrous iron and
ii) absorption of iron complexed with heme
• divalent metal transporter, DMT1,.
• actively transported into the blood across the basolateral
membrane, probably by the transporter IREG1, also known as
ferroportin1.
• Excess iron can be stored in the mucosal cell as ferritin, a watersoluble complex consisting of a core of ferric hydroxide covered by a
shell of a specialized storage protein called apoferritin.

20. TRANSPORT
• transported in the plasma bound to transferrin, a -globulin that
specifically binds two molecules of ferrous iron The transferrin-iron
complex enters maturing erythroid cells by a specific receptor
mechanism. Transferrin receptors internalize the transferrin-iron
complex through the process of receptor-mediated endocytosis.
• Increased erythropoiesis is associated with an increase in the number
of transferrin receptors on developing erythroid cells. Iron store
depletion and iron deficiency anemia are associated with an increased
concentration of serum transferrin.
STORAGE
• primarily as ferritin, in macrophages in the liver, spleen, and bone, and
in parenchymal liver cells. Apoferritin synthesis is regulated by the
levels of free iron.
• Ferritin is detectable in serum. Since the ferritin present in serum is in
equilibrium with storage ferritin in reticuloendothelial tissues, the
serum ferritin level can be used to estimate total body iron stores.
ELIMINATION
• Small amounts are lost in the feces by exfoliation of intestinal mucosal
cells, and trace amounts are excreted in bile, urine, and sweat.

21. Indications of oral iron therapy
Prophylactic use :
1) pregnancy- from 4th month
to lactation.
2) Menstruation
3) Infancy and childhood
4) Premature babies and
babies weaned late
5) Professional blood donors
Therapeutic use :
1) Iron deficiency anemia
2) Iron deficiency anemia due
to:
- menorrhagia
- peptic ulcer
- piles
- hook worm infestation
3) Malabsorption syndrome
4) Anemia of pregnancy
5) Treatment of severe pernicious
anemia

23. Adverse effects of oral iron therapy
1) Gastrointestinal upset
- nausea
- heart burn
- upper abdominal discomfort
- constipation or diarrhoea
- abdominal cramps
2) Hemochromatosis
3) Obscure the diagnosis of git bleeding due to
balckening of stools ( melena )

24. Parenteral iron preparations:
• Iron dextran is a stable complex of ferric hydroxide and
low-molecular-weight dextran containing 50 mg of
elemental iron per milliliter of solution. It can be given by
deep intramuscular injection or by intravenous infusion,
although the intravenous route is used most commonly
– headache, light-headedness, fever, arthralgias, nausea and
vomiting, back pain, flushing, urticaria, bronchospasm, and,
rarely, anaphylaxis and death.
– hypersensitivity reaction to the dextran component.
Hypersensitivity reactions may be delayed for 48–72 hours after
administration.
– Anaphylactic reactions
• Iron-sucrose complex and iron sodium gluconate complex
only by the intravenous route.

25. Indications of parenteral iron therapy
• unable to tolerate ( GIT upset)
• unable to absorb oral iron ( malabsorption syndrome,
ulcerative colitis , achlorhydria, surgical resection of
gut)
• patients unreliable in taking drug( extreme old age and
mentally ill patients )
• patients with extensive chronic blood loss who cannot
be maintained with oral iron alone.
• Immediate iron therapy need :premature birth,
pregnancy , infancy
• Blood loss from hemorrhoids , worm infection

26. • Total iron requirement (mg)
= 4.4* body weight (kg)* Hb
deficit ( g/dL)
Adverse effects of parenteral iron
• Local discomfort
• Discoloration of skin
• Headache ,fever , arthralgia
• Anaphylactic reaction
• Respiratory distress
• Circulatory collapse
• Severe chest pain
• Hemolysis
• tachycardia
• Bronchospasm
Contraindications :
• History of asthma
• Acute phase of kidney
disease
• History of allergy

27. Acute iron poisoning
Fatal dose : 2-10 grams ( 10
tablets for children)
Clinical course of acute iron
poisoning :
1) First phase: 0.5-1 hrs after
ingestion
•
•
•
•
Abdominal pain , nausea , vomiting
, diarrhoea , with black or bloody
stool ( children)
Constipation with black stool (
adults )
Drowsiness , cardiovascular
collapse
Coma
2) Second phase :8-16 hrs after
ingestion
•
Period of improvement or pass
onto third phase
3) Third phase : 24 hrs after
ingestion
• Cardiovascular collapse
• Convulsion, coma
• Liver damage
4) Fourth phase : 1-2 months
after ingestion
• Recovery with pyloric
stenosis due to scarring

28. Treatment
1) Prevent further absorption:
• induce vomiting or gastric lavage by 1% NaHCO3
• give egg yolk or milk orally
• Desferroxamine (5-10g in 100 ml saline )
2) Specific antidote :
• Desferroxamine : 1-2 g i/v or i/m
3) Supportive measures :
• maintenance of fluid , electrolytes and acid base balance
• Diazepam or phenobarbitone i/v
• Cardiopulmonary support

29. Chronic iron poisoning
– Excess iron deposited in heart ,
liver , pancreas and other organs
leading to organ failure and death.
Results from:
– Excessive parenteral therapy
– Repeated blood transfusion to
treat hemolytic anemia
– Inherited disorder
•
Hemosiderosis
– Excess accumulation of
hemosiderin in liver
• Hemochromatosis :
– Inherited disorder , excessive iron
absorption
– Brown pigmentation of skin
– Pancreatic damage leading to
diabetes
– Cirrhosis of liver with ascites
– Hepatic coma
– Gonadal atrophy
Treatment:
1) Intermittent
phlebotomy
(Removal of one
unit of blood per
week )
2) Iron chelation
therapy –
desferoxamine,
deferasirox (oral)
3)
High intake of tea

30. Desferroxamine
• Isolated from Streptomyces
pilosus
• Has high affinity for ferric iron.
Competes with iron of ferritin and
hemosiderin .
• Iron+desferroxamine =
ferrioxamine( nonabsorbable)
and is excreted in bile and faeces
• Oral absorption poor , so given
parenterally.
• Therapeutically used in acute iron
poisoning and diagnosis and
treatment of chronic iron
poisoning.
• 100 mg chelates 8.5 mg of iron
• Adverse effects:
–
–
–
–
–
–
–
–
–
–
–
–
Hypotension
Pruritus
Wheals
Rash
Anaphylaxis
Dysuria
Abdominal discomfort
Fever
Leg cramps
Tachycardia
Neurotoxicity
Visual and auditory changes

31. Folic acid
• Structure
3 building blocks
a) pteridine group
b) para – amino benzoic
acid ( PABA)
c) glutamic acid
• Not present in nature
but parent compound
of folates

32. • Sources :
yeast , liver , green vegetables
Fruits , nuts and cereals
Daily requirements :
Adult: 50 mcg / day
Pregnant women : 100-200 mcg / day
Lactating women : 100-200 mcg / day

33. Pharmacokinetics :
•
•
•
•
Route : oral , parenteral
Absorption: from proximal jejunum
Distribution: widely distributed
Folates are excreted in the urine and stool and are also
destroyed by catabolism
• folic acid deficiency and megaloblastic anemia can develop
within 1–6 months after the intake of folic acid stops
• Dietary folates consist primarily of polyglutamate forms of
N5-methyltetrahydrofolate. Before absorption, all but one
of the glutamyl residues of the polyglutamates must be
hydrolyzed by the enzyme -1-glutamyl transferase
("conjugase")

34. Pharmacodynamics
• Functions :
Tetrahydrofolate cofactors participate in one-carbon
transfer reactions
1) DNA synthesis : cofactors for the synthesis of
purines and pyrimidines
2) Synthesis of thymidylic acid :
enzyme thymidylate synthase catalyzes the
transfer of the one-carbon unit of N5,N10methylenetetrahydrofolate to deoxyuridine
monophosphate (dUMP) to form dTMP

35. Causes of folate deficiency
A) Nutritional ( major
causes)
1) poor intake due to
•
old age
•
Starvation
•
Anorexia
•
•
•
2) gastrointestinal disease
Partial gastrectomy
Coeliac disease
Crohn’s disease
B) Poor Utilisation:
1) Physiological
•
pregnancy
•
starvation
•
prematurity
2) Pathological
• hemolytic disease with
excess RBC formation
• malignant disease with
increased cell turnover
• inflammatory disease

36. C) Malabsorption syndrome
D) Antifolate drugs :
– anticonvulsants ( phenytoin , primidone )
– methotrexate
– Pyrimethamine
– Trimethoprim
– Sulfonamides

37. Effects of folate deficiency
• Megaloblastic anemia
• Neural tube defect ( spina bifida ) in the foetus
High-risk patients:
• pregnant women
• patients with alcohol dependence,
• hemolytic anemia
• liver disease
• certain skin diseases
• patients on renal dialysis

38. Indications of folic acid
1) Treat magaloblastic anemia due to folate
deficiency
2) Pregnant women
3) Premature infants
4) Patients with hemolytic anemia
5) Liver disease
6) Chronic skin disease
7) Renal dialysis
8) With anti convulsant drugs

39. • Folinic acid (leucovorin calcium, citrovorum
factor) is the 5-formyl derivative of
tetrahydrofolic acid used in methotrexate
therapy
• Folic acid in large amounts may counteract
the antiepileptic effect of phenobarbital,
phenytoin, and primidone, and increase the
frequency of seizures in susceptible children

40. Preparations and doses of folic acid :
Liquid oral preparations and injectables in
combination form
Given im
Dose
Therapeutic : 2-5 mg / day
Prophylactic : 0.5 mg / day

41. Vit B12
• consists of a porphyrin-like
ring with a central cobalt
atom attached to a
nucleotide.
• Deoxyadenosylcobalamin
and methylcobalamin are
the active forms
• The chief dietary source of
vitamin B12 is microbially
derived vitamin B12 in meat
(especially liver), eggs, and
dairy products
• extrinsic factor

42. Pharmacokinetics
• stored, primarily in the liver, with an average adult having a total
vitamin B12 storage pool of 3000–5000 mcg
• normal daily requirements of vitamin B12 are only about 2 mcg
• is absorbed only after it complexes with intrinsic factor, a
glycoprotein secreted by the parietal cells of the gastric mucosa
• the intrinsic factor-vitamin B12 complex is subsequently absorbed in
the distal ileum by a highly specific receptor-mediated transport
system.
• Nutritional deficiency is rare but may be seen in strict vegetarians
after many years without meat, eggs, or dairy products.
• vitamin B12 is transported to the various cells of the body bound to
a plasma glycoprotein, transcobalamin II
• Stored in liver
• Excreted through urine

43. Pharmacodynamics
1) transfer of a methyl group from N5methyltetrahydrofolate to homocysteine, forming
methionine
• conversion of the major dietary and storage
folate, N5-methyltetrahydrofolate, to
tetrahydrofolate necessary for transfer of onecarbon groups.
2) isomerization of methylmalonyl-CoA to succinylCoA by the enzyme methylmalonyl-CoA mutase

46. Indications of Vit B12
a)
b)
c)
Megaloblastic anemia
Neurologic syndrome associated with cobalamin deficiency
Pernicious anemia
•
Vitamin B12 for parenteral injection is available as cyanocobalamin
or hydroxocobalamin
Administered im
Initial therapy should consist of 100–1000 mcg of vitamin B12
Maintenance therapy consists of 100–1000 mcg intramuscularly
once a month for life
neurologic abnormalities are present, maintenance therapy
injections should be given every 1–2 weeks for 6 months before
switching to monthly injections
oral doses of 1000 mcg of vitamin B12 daily are usually sufficient to
treat patients with pernicious anemia
•
•
•
•
•

47. Erythropoetin
• most important regulator of the proliferation of
committed progenitors (CFU-E) and their
immediate progeny
• cytokine receptors that use protein
phosphorylation and transcription factor
activation to regulate cellular function
• induces release of reticulocytes from the bone
marrow
• Hypoxia-inducible factor (HIF-1)--a sensor in the
kidney detects changes in oxygen delivery to
modulate the erythropoietin secretion

48. • Recombinant human erythropoietin (epoetin alfa), produced using
engineered Chinese hamster ovary cells
• supplied in single-use vials of from 2000 to 40,000 units/ml for
intravenous or subcutaneous administration, three times a week
• epoetin alfa is cleared from plasma with a half-life of 4 to 8 hours.
• erythropoiesis-stimulating protein or darbapoetin alfa
• Epoetin alfa is effective in the treatment of anemias associated
with surgery, AIDS, cancer chemotherapy, prematurity, and certain
chronic inflammatory conditions
• rapid increase in hematocrit and hemoglobin and include
hypertension and thrombotic complications
• absolute or functional iron deficiency may develop
• Serious thromboembolic events have been reported, including
migratory thrombophlebitis, microvascular thrombosis, pulmonary
embolism, and thrombosis of the retinal artery