its a update of recent drugs( haematinics)2014 explains anemia,treatment,newer drugs

1. Dr.vishnu priya NMCH
1

2. DEFINITION
These are substances required in blood formation are used as
adjuvants in treatment of anemia
• Iron
• vitamin B12
• Folic acid
• Growth factors
2

3. • Decrease in circulating RBC mass ,the criteria in
which Hb <12g/dl in women and <14g/dl in men
ETIOLOGY
A complex interaction of socio-economic conditions,
nutritional deficiencies and co-existing disease (malaria, HIV) are
key contributors to anemia in developing nations.
3

4. CLASSIFICATION OF ANEMIA
According to morphology
• Hypochromic microcytic anemia
• Macrocytic anaemia/megaloblastic anemia
• Normochromic normocytic anemia
According to underlying mechanism :
• Blood loss (acute/chronic)
• Decreased RBC production
• Increased RBC destruction (haemolysis)
4

5. Adult Reference Ranges for Red Cells
source:Robbins and Cotran pathologic basis of diseases,8edtn
5

6. HISTORY:
IRON DEFECIENCY ANEMIA
• 1713 iron was shown to be present in blood
• 19th century Blaud developed Blaud’s pill consists of ferrous
sulfate and potassium carbonate for anemia.
IRON DEFICIENCY ANEMIA
• Iron defeciency is most Common and seen in developing and
developed countries as well.
• particularly in toddlers, adolescent girls, and women of
childbearing age
6

7. CAUSES OF IRON DEFICIENCY ANAEMIA
 Dietary lack,
 impaired absorption,
 increased requirement, or (most importantly)
 chronic blood loss.
7

8. IRON LOSS
• Each Hb molecule has 33% iron for loss of 100ml of blood
there will be loss of 50mg of elemental iron
Normal iron requirement
Adult male – 0.5-1mg
• Adult female (mensurating) - 1-2mg
• Infants - 60μg/kg
• Children - 25μg/kg
• Pregnancy -3-5mg
8

9. Requirement and availability of iron
9

10. Iron deficiency anemia cont…
• IRON DISTRIBUTION
Iron content in mg
Male Female
Haemoglobin – 2500 1700
Myoglobin/enzymes – 500 300
Transferrin iron – 3 3
Iron stores - 600-1000 0-300
Total body iron in adult is 2.5-5g, more in men than women
10

11. Iron metabolism
11

12. Transport of iron
12

13. TREATMENT OF IRON DEFICIENCY ANEMIA
Indication:
only clinical indication of iron in iron deficiency anemia with
MCV < 80 fL and MCHC < 30%
lab parameter:
Low SI < 30 mcg/dL with increased TIBC,
% saturation (SI/TIBC) of < 10%;
low serum ferritin level (< 20 mcg/L)
PREPARATIONS:
• Oral
• parentral
13

14. ORAL IRON PREPARATIONS
• Ferrous sulphate(32% iron): cheap, metallic taste is
present 200mg tab
• Ferrous gluconate (12% iron) 300mg,400mg/15ml elixer
• Ferrous fumarate (33% iron) 200mg tab
• Colloidal ferric hydroxide (50% iron) 50mg/ml drops
• Carbonyl iron highly pure fine powder prepared by
decomposition of iron pentacarbonyl ,toxic compound
• Ferrous salts are cheap, high iron content, better absorbed than ferric
salts
• All have same degree of gastric tolerance
14

15. • For full haematopoietic effect –
• adult total dose of 200mg of elemental iron given daily in 2 or 3
divided doses in empty stomach.
• Child- 3-5mg/kg in 3 divided doses
prophylaxis:
• 30mg elemental iron/day is sufficient
Other preparations :
• Ferrous succinate (35%iron)
• Iron choline citrate
• Iron calcium complex(5% iron)
• Ferric ammonium citrate (20% iron)
• Ferrous aminoate (10% iron) 15

16. Oral iron preparation cont..
• Ferric glycerophosphate
• Ferric hydroxy polymaltose
These are better absorbed or less side effects but has lower iron
content and expensive
• Iron solutions given in some patients with gastric disease or prior
gastric surgery
• The reticulocyte count should begin to increase within 4–7 days
after initiation of therapy and peak at 1–11/2 weeks.
16

17. Adverse drug reactions of oral therapy
 Constipation due to astringent effect is common than diarrhoea
 Epigastric pain
 Heartburn
 Nausea
 Vomiting, bloating,
 Teeth staining
 Metallic taste,
 Start with low dose then increase the dose higher
17

18. Parentral preparations
Indications :
 Oral iron not tolerated,
 Failure to absorb oral iron
 Non compliance
 Severe deficiency – chronic bleeding
 Along with erythropoietin oral iron may not be absorbed at sufficient
rate to meet demands
For replinishment of iron stores this formula is been used
Iron requirement (mg) = 4.4 × body weight (kg) × Hb deficit (g/dl)
18

19. Organic preparations
• Iron dextran & iron sorbitol - citric acid (i.m)
• Ferrous sucrose & ferric carboxymaltose
Iron dextran: i.v/i.m
• Colloidal preparation of ferric oxyhydroxide complexed with
polymerized dextran
• High molecular weight >6000,dark brown viscous liquid
• 50mg of elemental iron is present in one ml
19

20. IRON DEXTRAN I.M cont…..
On i.m:
• 30% binds locally with muscles taken up by macrophages
• Since its antigenic anaphylactic reactions more common
• Given deep in gluteal region using Z track technique
• Dose:
2ml daily or alternative days or 5ml each side on same day (local pain
lasting weeks may occur at higher days)
20

21. On i.v administration:
• After test dose injected I.V over 5-10mins, 2ml injected/day
10mins
• Alternatively total calculated dose is diluted in 500ml of
glucose/saline solution infused i.v over 6-8hrs under constant
observation
• If any complaints of giddiness, paresthesia, chest tightness
present should be terminated
To avoid risk of hypersensitivity 0.25-0.5ml inj i.v over to ½-1hr
reactions perform sensitivity test with small test dose before
i.v/i.m
21

22. ADVERSE DRUG REACTIONS
Local:
Pain at inj site, pigmentation, sterile abscess- old deblitated pts
Systemic:
Fever, headache, joint pain, flushing, palpitation, chest pain,
dyspnoea, lymph node enlargement
Rare:
Anaphylactoid reaction vascular collapse and death
IRON SORBITOL CITRIC ACID COMPLEX:
• Low mol wt, by i.m route does not bind locally in muscular tissues
directly available for haemopoiesis
• Cannot be used by i.v route, binds with transferrin may saturate it
22

23. • 30% iron unbound is excreted in urine imparting black colour to
urine due to formation of iron sulphide
Adverse drug reaction
Ventricular tachycardia, A-V block, other irregularities, hypotension,
flushing is higher.
It is contraindicated in patient with kidney disease
Dose:75mg i.m max 100mg daily or alternative days
FERROUS SUCROSE:
Newer formulation high molecular weight complex of iron hydroxide
with sucrose that on i.v is taken by RE cells
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24. Safer
Dose:
• 100mg iv taking 5mins once daily to once weekly till total
calculated dose is administered
• Hypersensitivity lower
FERRIC CARBOXYMALTOSE
Latest drug ,ferric hydroxide core is stabilized by carbohydrate shell
Macromolecule taken by RE Cells primarily in bone marrow, liver
and spleen
Dose:100mg i.v injection or upto 1000mg is diluted with 100ml
saline infused i.v takin 15min or more,repeated after week
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25. Adverse drug reactions
Mild:
• Headache, nausea, abdominal pain.
• Pain at injection site, rash, anaphylaxis rare
• Hypotension, flushing, chest pain infrequent
• Not recommended for children <14yrs
Iron poisoning
In Infants and children 10-20 tab or equivalent liquid preparation
cause serious toxicity
Manifestations are:
Vomiting,Abdominalpain,Haematemisis,diarrhoea,lethargy,cyano
sis,dehydration,acidosis,convulsion,shock,cardiovascular collapse
and death
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26. • Haemorrhage and inflammation of gut will be present
• Hepatic necrosis and brain damage present.
Treatment of poisoning
Supportive measures
fluid and electrolyte balance
vitals monitoring
Diazepam i.v – convulsions
Prevent absorption from gut:
• induce vomiting & gastric lavage with sodium bicarbonate solution
• Egg yolk and milk orally it causes complex of iron
26

27. Treatment of poisoning cont…
Bind and remove iron already absorbed:
Desferrioxamine :
• iron chelator is D.O.C
• Obtained from streptomyces pilosus potent and specific
• Readily binds ferric iron to form ferrioxamine
• Well tolerated
• rapid iv causes hypotension, tachycardia, anaphylactoid reaction &
urticaria,
Dose: I.M 0.5-1g (50mg/kg) repeatedly 4-12hrs required or
I.V in case of shock 10-15mg/kg/hr, max 75mg/kg in a day till serum
iron falls below 300μg/dl
calcium edetate can be used.
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28. contraindication for treatment :
• Severe renal disease
• Pregnant women
• Available in lyophilized powder 500mg ,i.v,i.m.
Hemochromatosis:
• Desferrioxamine useful in prevention and treatment of iron
overload in chronic anemia in thalassemia major with multiple
transfusions,
• given continuous infusion 2g for 12hrs OD,but phlebectomy is
treatment of choice
• Deferiprone, Deferasirox are alternative choice who cannot tolerate
the above drug
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29. ADJUVANTS TO IRON THERAPY
Vitamin c, cobalt, copper, zinc & manganese
Vitamin B12(extrinsic factor)
History
• 1820 Combe and Addison described megaloblastic anemia
• 1860- Austin flint described in certain patient with treatment
failure with iron found it was related with atrophy of gastric
mucosal cells.
• 1926- Minot and murphy received noble prize demonstrated
correction of pernicious anemia by feeding liver
• 1929-Castle extrinsic factor in diet and intrinsic factor in parietal
cells both important of hematopoietic effect
• Vitamin B12 isolated in 1948
• Dorothy Hodgkin determined structure of vitamin B12 received
noble prize for this work 29

30. Structure of vitamin B12:
Porphyrin like rings with cobalt in centre with various organic groups
attached by covalent bond.
Congeners:
Cyanocobalamin and Hydroxycobalamin (therapeutically used)
Methylcobalamin and deoxyadenosylcobalamin
Source and requirements:
Synthesized by normal gut flora in human beings
Diet source : non vegetarian food,legimunous plants,milk and milk
products
Requirement:2-3μg in normal adults
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31. Pharmacokinetics:
• Vit B12 (diet) + protein → acidic environment + intrisic factor of
castle (glycoprotein)
Extrinsic factor
+ receptors (gastric mucosal cells)
Intrinsic factor
Absorbed (carrier mediated active
transport)
• If high dose consumed transported by ß globulin to various tissues
excess transported to liver for storage.
• Undergoes enterohepatic circulation affected in presence of
malabsorption worsens if deficiency present
• Storage: total amount stored in body 3-5g lasts for 3-5yrs
31

32. Functions:
Methylation Occurs simultaneously using homocysteine methionine
methyltransferase
1.Methyltetrahydrofolate Tetrahydrofolate
(methyl donar) cobalamin
Homocysteine
Methionine
In this reaction inactive methyl FH4 is converted to active FH4 at
same time homocysteine converted to methionine,
in case of deficiency it prevents activation of methyl FH4 called
‘methylfolate trap’.
32

33. • Isomerization of methylmalonyl-CoA to succinyl-CoA
Deficiency of B12
Causes:
• Deficiency in diet,
• Intrinsic factor of castle,
• Transcobalamin II genetic deficiency,
• Diseases,
• worm infestation with D.latum,
• Drug induced
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34. Treatment-pernicious Anaemia
Oral B12
Parentral B12
Dosage:
1)Initially 100 microg -1000 microg IM(daily or alternate days for
1-2 weeks to replenish the body store)
2)Maintenance therapy:
Without neurological manifestation –
100 microg – 1000microg ,once a month for lifetime
With neurological manifestation-once
a week or once every 2 weeks for 6 months, followed by
once a month lifelong
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35. In Megaloblastic anemia
Dose:
parentral (IM/SC) -100 to 1000 microgram of cyanocobalamin
is given
FOLIC ACID
History:
• Wills identified crude liver extract that correct macrocytic
anemia and is called wills factor later as folic acid.
• 1941 Mitchell named Folic acid
Requirement: 100 micro gram(Normal Adult)
500 – 600 microgram( Pregnancy, Lactation)
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36. Pharmacokinetics of folic acid:
• Absorption primarily – proximal jejunum
• conjugates hydrolyse dietary pteroylmonoglutamic by
conjugases
• Folic acid reduced by dihydrofolate reductase to THFA
• Methylated to 5-MeTHFA THFA→ folate
polyglutamate Methionine synthase
• Rest 5-20mg stored in liver undergoes enterohepatic
circulation
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37. Functions of folic acid
THFA Folate cofactors
Synthesis of purine and pyrimidine
Deficiency folic acid:
Diet lack, malabsorption syndrome, excessive demands in
Pregnancy & anemia, liver disease & renal dialysis, drug
induced, megaloblastic anemia and teratogenic effects
Doses:
• Daily requirement of folic acid 50μg
• Pregnancy & lactation :↑200-300μg/day
• Therapeutic doses :1-5mg/day
• Folinic acid - prevention or in treatment of toxicity from
Methotrexate
37

38. • Folic acid - treat folate deficiency by phenytoin or
phenobarbitone
• Prophylactically given during pregnancy, lactation or using
oral contraceptive
• Given along with vitB12 treat megaloblastic anemia
HEMATOPOIETIC GROWTH FACTORS
• Maintains balance between proliferation and differentiation of
various blood cells
• Known as cytokine growth factor glycoproteins responds to
any stimulation anemia & hypoxia
• Regulates host defense system to inflammation.
• These are erythropoietin, CSF, IL-11
38

39. Hematopoietic Growth factors
39

40. ERYTHROPOIESIS STIMULATING AGENTS
Important regulator of the proliferation CFU-E and their progeny.
• During states of hypoxia, the prolyl hydroxylase is inactive,
accumulates of HIF-1 activates erythropoietin expression,
stimulates rapid expansion of erythroid progenitors.
ERYTHROPOIETIN
• Encoded by a single copy gene on human chromosome 7 that is
expressed primarily in peri-tubular interstitial cells of the kidney.
• Binds to a receptor on the surface of committed erythroid
progenitors in the marrow
40

41. EPOETIN ALFA:
• Produced using recombinant DNA technology EPOETIN ALFA
using mammalian cell lines
• Used to identify in athlete “blood doping”.
• Kidney disease, bone marrow damage, iron deficiency leads to
improper secretion in case of anemia or hypoxia
• inflammatory cytokines also ↓ secretion –infection and
inflammation
Pharmacokinetics:
• Comes in single-use vials having 2000-40,000 units/mL i.v/s.c
• On iv it clears from plasma with t1/2 of 4-8 hours
41

42. Darbopoietin
Genetically modified, four amino acids have been mutated with
carbohydrate side chains thus increases the action drug to 24-26
hours in body.
• Stimulates erythrocyte proliferation and differentiation causes
release of reticulocytes
USES: EPOETIN ALPHA:
 Anemia of chronic renal failure –
• Before starting therapy plasma ferritin >400μg/l should be
present.
• Gradual ↑ in 2-4mths hematocrit levels >36% is not
recommended ,hematocrit >40% causes myocardial infarction
and death.
Dose: 80-120 units/kg given subcutaneously, thrice a week.
Maintenance dose :10-300u/kg (average 75u/kg)
42

43. • Drug resistance due to occult blood loss, folic acid deficiency,
inadequate dialysis, aluminum toxicity, and osteitis fibrosa cystica
secondary to hyperparathyroidism
 HIV-infected patients: on zidovudine therapy
Dose :100-300 units/kg, given s.c three times a week
 Cancer-Related Anemias: multiple myeloma
Dose: 150 units/kg three times a week or 450-600 units/kg once a
week, can reduce the transfusion requirement in cancer patients
undergoing chemotherapy
43

44.  Surgery:
Perioperatively orthopedic and cardiac procedures treat anemia
and reduce the need for erythrocyte transfusion
Dose:150-300 units/kg OD for the 10 days before surgery,on the
day of surgery, and for 4 days after surgery
Other Uses
Orphan drug status from the FDA for the treatment of the anemia
of prematurity, HIV infection, and myelodysplasia.
44

45. • Darbopoietin alfa
uses
• approved in anemia associated with chronic kidney disease and
is under review for several other indications
• tested in cancer patients undergoing chemotherapy and in
preliminary studies
Dose:
• 0.45 g/kg intravenously or subcutaneously once weekly, with
dose adjustments depending on the response
• Iron & folic acid supplements given were increased demand is
present during therapy
45

46. Adverse drug reactions of Epoetin and
Darbopoietin
• Flu like symptoms
• Mild hypertension,
• Encephalopathy with headache,
• Disorientation,
• Convulsions
• Thrombosis during hemodialysis
46

47. Myeloid Growth Factors
• Glycoproteins stimulate the proliferation and differentiation of
one or more myeloid cell lines.
• Enhance the function of mature granulocytes and monocytes
• By Recombinant technology:
 G-CSFs
 GM-CSFs cytokines, stimulates (CFU-GEMM) enhance cell
production, neutrophil, monocyte & eosinophil
 IL-11,CSF-1 SCF & Thrombopoietin been produced.
47

48. G-CSF:
• Used in treatment & prevention of neutropenia
• stimulates proliferation and differentiation of neutrophil
progenitor cells,
• activates phagocytic activity of mature neutrophil
 FILGASTRIM:
• Recombinant human G-CSF is produced in E.coli,
nonglycosylated glycoprotein
 LENOGRASTIM –
similar to Filgastrim but glycosylated, given 5μg/kg/day s.c/i.v
started within 24-72h after cytotoxic chemotherapy completion
continued till neutrophil count reaches >10,000cells/μl
48

49. PEGFILGASTRIM: S.C given
• Pegylation increases molecular size so plasma t1/2 ↑ 10-12
times
• Longer acting given Once per chemotherapy cycle till
chemotherapy lasts, shortens period of neutropenia
• mobilize haematopoietic stem cells increases their
concentration in peripheral blood
• Used in autologous haematopoietic stem cell transplant
Dose:
• 6mg s.c OD single dose during each cycle of cytotoxic
chemotherapy
• Side effects: fever, bone pain, myalgia, rashes & GI effects
49

50. GMCSF:
 Stimulates development of progenitor cells & multipotent
haematopoietic growth factor
 By acting along with IL2 & 3 causes Proliferation and
differentiation of T cells
SARGRAMOSTIM:
 Recombinant human GM-CSF produced in yeast cell similar
to endogenous GMCSF
 Used in neutropenia due to cytotoxic drugs, lymphoma,
leukaemia, Hodgkin disease & bone marrow transplantation,
intermittent cancer chemotherapy & AIDS
 doses of 125-500 g/m2 per day. Plasma levels of GM-CSF rise
rapidly after subcutaneous injection and then decline with a t1/2
of 2-3 hours.
given intravenously, infusions should be maintained over 3-6
hours.
50

51. In clinical trials
MOLGRAMOSTIM(bacterially derived,
REGRAMOSTIM(Mammalian derived
Adverse effects of GM-CSF:
 Fever,
 skin rash,
 muscle pain and lethargy,
 pain and redness at injection site,
 flushing, fall in Bp,
 tachycardia,
 breathlessness,
 nausea & vomiting
51

52. MEGAKARYOCYTE GROWTH FACTORS
Used in treatment of thrombocytopenia due to cancer
chemotherapy& bone marrow transplantation
IL-11:
Endogenous megakaryocyte growth factor
Its Cytokine, produced by fibroblasts and bone marrow stromal
cells
THROMBOPOIETIN:
Glycoprotein produced by hepatocytes, bone marrow stromal
cells and other organs, level is ↓ cases of thrombocytopenia &
cirrhosis of liver
↑platelets and neutrophils
OPRELVEKIN:
• Recombinant form IL-11 produced by expression of ecoli
• t1/2:7-8hr 52

53. Function:
Stimulates growth of myeloid and lymphoid cells.
Dose:
50μg/kg/day S.C until 2-3 weeks or Until platelet count reaches
>50000 cells/μL
6-24h after completion of cancer chemotherapy
Uses
• Thrombocytopenia, secondary prevention of thrombocytopenia
following cancer chemotherapy
• IL11 reduces platelet transfusion in cancer chemotherapy for
non myeloid cancers
Adverse effects:
• Dizziness, headache, fatigue, anemia, dyspnoea & hypokalemia.
53

54. Recombinant thrombopoietin:
Two types :
Recombinant human megakaryocyte growth and
development factor(rHuMGDF):
Pegylated covalently ↑ plasma t1/2 so the duration of action
Recombinant human thrombopoietin (rHuTPO):
Polypeptide with full length
Trials shows reduction in platelet transfusion & duration of
severe thrombocytopenia in patient receiving cancer
chemotherapy.
Results were not encouraging in leukaemia patients
54

55. Newer drugs for ITP
ROMIPLOSTIM:
Peptibodies,
Non immunogenic,
t1/2- 3to4days,
S.C route is used
ELTROMBOPAG:
Orally effective agonist at thrombopoietin receptor,
restricted use due to toxicity.
55

56. REFERENCES
• Principles of pharmacology – HL Sharma & KK
Sharma.
• Pharmacology – Rang & Dale 5th Edition.
• Text book of pharmacology – K. D. Tripathi.7th
Edition.
• Basics & clinical pharmacology – Katzung 11th
edition.
• Pharmacology & Pharmacotherapeutics -
Satoskar-21st edition.
• Pharmacological basis of Therapeutics –
Goodman & Gilman 12th Edition.
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