Pharmacotherapy of anaemia dr jayesh vaghela

2. Pharmacotherapy
of
Anaemia
Dr. JayeshVaghela

3. Oral
preparations
Parenteral
Preparations
Take-Home
message
Acute Iron
Poisoning
Therapeutic
consideration
Iron
Chelators

4. Iron preparations

5. Oral
Iron
Preparations
• Ferrous sulfate
• Ferrous gluconate
• Ferrous fumarate
• Colloidal ferric hydroxide
• Carbonyl iron

6. Ferrous
sulfate
ferrous
sulfate
(exsiccated)
Ferrous
gluconate
Ferrous
fumarate
Polysaccharide
iron complex
Carbonyl
iron
Elemental
iron (%)
20 30 12 33 100 100
Elemental
iron
provided
• 60–65
mg/324–
325 mg
tablet
• 18 mg
iron/5 mL
syrup
• 44 mg
iron/5 mL
elixir
• 15 mg
iron/0.6
mL drop
• 65 mg/200
mg tablet
• 60 mg/187
mg tablet
• 50 mg/160
mg tablet
• 36 mg/325
mg tablet
• 27 mg/240
mg tablet
• 33 mg/100
mg tablet
• 63–66
mg/200 mg
tablet
• 106
mg/324–
325 mg
tablet
• 15 mg/0.6
mL drop
• 33 mg/5 mL
suspension
• 150 mg capsule
• 50 mg tablet
• 100 mg/5 mL
elixir
• 50 mg
caplet
Ferrous salts available in the market

7. • Oral preparations – strong protein precipitating action – can not be
injected
• Variations in the ferrous salts have relatively little effect on the
bioavailability.
• Sulfate, fumarate, and gluconate salts are absorbed approximately same
extent.
• Addition of cobalt, copper, or other substances only adds in expense
without significant benefit.
• Iron is best absorbed in ferrous (Fe2+) reduced form
• Maximum absorption in duodenum (∵ acidic nature of stomach)
• Only 10 – 20 % of administered dose is absorbed from G.I.T.

8. • Slow-release or sustained release iron preparations
do not undergo sufficient dissolution until they
reach the small intestine
⇓
In the alkaline environment of the small intestine
⇓
iron tends to form insoluble complexes
⇓
significantly reduces absorption

9. • Many oral formulations available in India contain iron compounds along
with many vitamins, yeast, amino acids and other minerals.
• But they are considered irrational.
• Technical advisory board (India) has recommended that even B complex
vitamins and zinc should not be added to iron preparations.
• Combination of iron with strychnine, arsenic and yohimbine and all fixed
dose combination of haemoglobin in any form are banned in India.

10. Treatment strategy
 Elemental iron content is to be taken into account, not the total iron
compound
• Recommended – 200 mg elemental iron daily in 2 – 3 divided doses
⇛ Maximum haematopoietic effect
• If not tolerated ⇛ - small amounts
- e.g.Tab. Fe sulfate 325 mg ⇛ 65 mg (20%)
• Generally, start with low dose ⇛ escalation gradually to full dose

11.  Administration:
• 1 hour before meal (food interferes with absorption), but side effects are
more
• some prefer giving larger amounts after meals, while others like to give
smaller doses in between meals
• Liquid preparations stain the teeth; should be put on back of tongue.
• Less satisfactory in general.

12. Adverse Drug Reactions
• Epigastric pain,
• Heartburn,
• Nausea, vomiting,
• Bloating,
• Staining of teeth, metallic taste,
• Colic
• Constipation (astringent action of iron) is more common than diarrhoea
(irritant action)

13. Common Preparations of oral iron
oFerrous sulfate:
• The cheapest; preferred; Leaves metallic taste
oFerrous fumarate:
• Less water soluble than ferrous sulfate; tasteless
oCarbonyl iron:
• High purity metallic iron in very fine powder form (particle size < 5 μM)
• Absorbed from intestines over a long time, better gastric tolerance
• Bioavailability is about 3/4th that of ferrous sulfate

14. Ferric hydroxy polymaltose:
• Vigorously promoted for its high iron content, no metallic
taste, good g.i. tolerability and direct absorption from the
intestines
• Because the complex releases little free iron in the gut lumen
— g.i. irritation is minimal
• High bioavailability observed in rats has not been found in
humans.
• Reports of its poor efficacy in treating iron deficiency anaemia
have appeared
• Therapeutic efficacy is questionable.

15. Daily Dose of Iron and Improvement in Hb level
• Suppose Ferrous sulphate (hydrated - 7H2O) is administered 300 mg tid  total daily
FeSO4 = 900 mg
• 20 % of elemental iron = per day 180 mg (20 % of 900 mg) elemental iron is given
• Presuming that 10 % of this gets absorbed  18 mg available for Hb synthesis
• This increases Hb by about 0.16 g/dl, means correction of Hb deficit is by 1 % per day
• If Hb is deficient by more than 3 g/dl, an average increment of 0.1 - 0.2 g/dl/day is
observed with usual therapeutic doses

16. How long the therapy will be needed?
• Considering daily rate of about 0.2 g/dl rise in Hb and normal level of 14.8
g/dl,
• if Hb level in an anaemic patient is 5 g/dl it may take about 50 days
(approx. 2 months) to reach normal level
• As the anaemic status improves, rate of absorption decreases
• Iron stores (total 40-50 mg/kg) may increase at a rate not more than 100
mg per month
• Hence, therapy should be continued for a 2-4 months after Hb level
becomes normal.

17. DrugsThat Decrease
Iron Absorption
Object Drugs Affected by Iron
Al-, Mg-, and Ca +2 -containing antacids Levodopa ↓ (chelates with iron)
Tetracycline and doxycycline Methyldopa ↓ (decreases efficacy
of methyldopa)
Histamine2 antagonists Levothyroxine ↓ (decreased efficacy
of levothyroxine)
Proton pump inhibitors Penicillamine ↓ (chelates with iron)
Cholestyramine Fluoroquinolones ↓ (forms ferric
ionquinolone complex)
Tetracycline and doxycycline ↓ (when
administered within 2 hours of iron salt)
Mycophenolate ↓ (decreases
absorption)
Drug interactions of iron

18. Failure to respond to therapy
• Poor patient adherence, inability to absorb iron, incorrect diagnosis, continued
bleeding
o Iron test: (To rule out malabsorption)
Administration of 50 mg of elemental iron as liquid Fe2+ sulfate
⇓
Plasma iron levels are determined at half-hour intervals for 2 hours
⇓
If plasma iron levels increase by >50 mcg/dL during this time
⇓
Absorption is satisfactory

19. Parenteral
Iron
Preparations
• Iron-dextran
• Iron-sorbitol-citric acid
• Ferrous-sucrose
• Ferric carboxymaltose
• Sodium ferric gluconate
• Ferumoxytol

20. Indications of Parenteral Therapy
• Oral iron not tolerated
• Oral iron not absorbed
• Non-compliance to oral iron
• Severe deficiency with chronic bleeding
• Along with erythropoietin
 Iron requirement (mg) = 4.4 × body weight (kg) × Hb deficit (g/dl)

21. • High molecular weight colloidal solution
The only preparation which can be used
i.m. & i.v.
• i.m. injection
⇓
Absorbed through lymphatics
⇓
Circulates without binding to transferrin
⇓
Engulfed by RE cells
⇓
Iron dissociates & available for haeme
synthesis
• Low MW complex
• Binds with transferrin
⇓
Saturates it if in large quantity
⇓
Remaining free iron is highly toxic
⇓
Not suitable for i.v.
Only i.m. is safe
• Direct absorption into
circulation, not lymphatics
Iron dextran Iron-Sorbitol-Citrate

22. • No local binding in muscles
• But, 30% dose excreted in urine
⇓
Dose needs to be increased
accordingly
ADRs:
• V-Tach, hypotension, A-V block,
flushing
• C/I in Kidney disease
Iron dextran Iron-Sorbitol-Citrate
• 10–30% of the dose remains
locally bound in muscles
⇓
• Unavailable for utilization for
several weeks
⇓
• 25% extra needs to be added to
the calculated dose
ADRs:
• Anaphylactic reaction (dextran)

23. Therapeutic concerns about iron dextran
Intramuscular injection Intravenous injection
• Deeply in the gluteal region using Z –
track technique
 Preparation:
• iron dextran 100 mg in 2 ml
 Administration:
• 2 ml daily, or on alternate days,
Or
• 5 ml each side on the same day
 Problems:
• Discomfort, tissue necrosis, atrophy
Test dose: (Black box warning)
• 0.5 ml iron dextran injected i.v. over
5–10 min
• Observe for 1 hour
• If untoward reaction ⇛ Give
epinephrine, diphenhydramine or
corticoids
• Administration:
• Method 1:
• 2 ml (100 mg) can be injected per day
taking 10 min for the injection.

24. Therapeutic concerns about iron dextran
Intravenous injection
• Method 2: (Total Dose Infusion)
• Total calculated dose is diluted in 500
ml of glucose/saline solution
⇓
infused i.v. over 6–8 hours under
constant observation.
• Higher risk of ADRs
• More risk in pre-existing immune-
mediated disease
 Stop infusion if giddiness,
paraesthesia, tightness in chest

25. Adverse Drug Reactions of iron dextran
Local :
• Pain at site of i.m. injection, pigmentation of skin.
• Sterile abscess — especially in old and debilitated patient.
Systemic:
• Fever, headache, joint pains, flushing, palpitation, chest pain, dyspnoea, lymph
node enlargement.
• Rarely, An anaphylactoid reaction resulting in vascular collapse, death
 Precaution:
• i.m. dose should not be >25 mg in 5 kg patient, >50 mg in 10 kg, and >100 mg for all
other patients

26. Ferrous sucrose
• Newer high MW compound complex of iron hydroxide with sucrose
• i.v. injection ⇛ taken up by RE cells ⇛ iron dissociates ⇛ Utilized
Administration:
• 100 mg / 5 ml single-dose vials
• 100 mg (max 200 mg/day) once a day to once a week can be given over 5 min
• Only i.v.
• Not to be given i.m. / s.c. (∵ solution is highly alkaline)

27.  Indication:
• Anaemia in chronic kidney diseases
 Precaution:
• Total dose infusion is not possible
• Oral iron therapy should not be given concurrently and till 5 days after the
last injection (∵ it decrease absorption of oral iron)

28. Ferric carboxymaltose
• Ferric hydroxide core is stabilized by CH shell
• i.v. injection ⇛ macromolecule is taken up by RE cells (mainly by bone marrow, 80
% and also liver, spleen)
 Preparation:
• 50 mg / ml, such 2 ml & 10 ml vials
 Administration:
• Method – 1: - Daily 100 mg i.v. injection,
• Method – 2: - Up to 1000 mg diluted in 100 ml saline & infused over 15 min or more

29.  Advantage:
• In clinical trials, it has caused rapid increase in haemoglobin level and replenished
stores
• very low incidence of acute reaction, rare anaphylaxis
 ADRs:
• Mild Headache, nausea, abdominal pain
 Caution:
• Due to lack of safety data, it is not recommended for children < 14 years.

30. Sodium Ferric Gluconate
• High MW Iron complex bound to 1 gluconate & 4 sucrose molecules
• i.v. injection of aqueous solution ⇛ complex taken up by phagocytes ⇛
iron is released ⇛ utilized.
 Preparation:
• 62.5 mg in 5 ml vials
 Administration: (Only i.v.)
• Method – 2: - 125 mg diluted in 100 ml NS ⇛ infused over 60 min
• Method – 2: - slow i.v. injection @ 12.5 mg / min

31. Ferumoxytol
• Approved by USFDA in June – 2009
• i.v. injection ⇛ complex taken up by macrophages in liver, spleen, bone
marrow ⇛ iron is released ⇛ - Enters storage pool as ferritin, or
-Transported by Tf to haeme synthesis
 Preparation:
• 30 mg / ml elemental iron
 Administration:
• Initial 510 mg dose i.v. ⇛ second dose of 510 mg after 3 – 8 days

32. • Advantage:
• Can be administered at a higher rate than any other iron preparations
• i.e. @ 30 mg / sec
• No anaphylaxis, but should be observed for at least 30 min
• Less g.i. upset, & peripheral oedema
• Caution:
• Higher incidence of hypotension, dizziness

33. Ferumoxytol Sodium Ferric Gluconate Iron Dextran Iron Sucrose
Amount of
elemental
iron
30 mg/mL 62.5 mg iron/5 mL 50 mg iron/mL 20 mg iron/mL
Composition
Superparamagnetic
iron
oxide that is coated
with
a carbohydrate shell
Ferric oxide hydrate
bonded
to sucrose chelates with
gluconate in a molar rate
of
2 iron molecules to 1
gluconate
molecule
Complex of ferric
hydroxide and
dextran
Complex of polynuclear
iron
hydroxide in sucrose
Indication
Treatment of iron
deficiency
anemia for adult
patients
with chronic kidney
disease
(CKD)
Treatment of iron-
deficiency
anemia for patients
undergoing
chronic hemodialysis
who
are receiving
supplemental
erythropoietin therapy
Treatment of
patients with
documented iron
deficiency
in whom oral
therapy is
unsatisfactory or
impossible
Treatment of iron-
deficiency
anemia for patients
undergoing chronic
hemodialysis who are
receiving supplemental
epoetin alfa therapy

34. Ferumoxytol
Sodium Ferric
Gluconate
Iron Dextran Iron Sucrose
Usual
dose
• Initial 510 mg
intravenous
Injection
⇓
• second 510 mg
intravenous injection
3 to 8 days later
(rate 30 mg/s)
• 125 mg (10 mL)
diluted in 100 mL
normal saline, infused
over 60 minutes;
• Also slow IV injection
(rate of 12.5 mg/min).
• 100 mg undiluted
at a rate not to
exceed 50 mg (1
mL) per Minute
• 100 mg into the
dialysis line at a
rate of 1 mL (20
mg of iron)
undiluted solution
per Minute
Treatment
2 doses × 510 mg =
1,020 mg
8 doses × 125 mg = 1,000
mg
10 doses × 100 mg =
1,000 mg
Up to 10 doses × 100
mg =
1,000 mg
Common
adverse
effects
Diarrhea, constipation,
nausea,
dizziness, hypotension,
peripheral edema
Cramps, nausea and
vomiting,
flushing, hypotension,
rash,
pruritus
Pain and brown
staining at
injection site,
flushing,
hypotension, fever,
chills,
Leg cramps,
hypotension

35. Erythropoietin (EPO)
• Sialoglycoprotein hormone (MW 34000) produced by peritubular cells of
the kidney
• Essential for normal erythropoiesis
 M/A:
• EPO binds to specific receptors on the surface of its target cells
• Alters phosphorylation of intracellular proteins and activates transcription
factors to regulate gene expression
• induces erythropoiesis in a dose dependent manner, but has no effect on
RBC lifespan.

36.  Use:
• Anaemia due to chronic renal failure
• Only symptomatic patients with Hb ≤ 8 g/dl should be considered for EPO
therapy
• Epoetin 25–100 U/kg s.c. or i.v. 3 times a week (max. 600 U/kg/week) raises
haematocrit and haemoglobin
• Start with a low dose and titrate upwards to keep –
- Haematocrit between 30–36%, and
- Hb 10–11 g (max 12 g) per dl

37.  ADRs:
• Related to sudden increase in haematocrit, blood viscosity and peripheral
vascular resistance (due to correction of anaemia)
• Increased clot formation in the A-V shunts (most patients are on dialysis),
• Hypertensive episodes, serious thromboembolic events,
• Seizures
• Flu like symptoms lasting 2–4 hr occur in some patients

38. Darbepoetin
• Recently introduced
• Hyperglycosylated modified EPO
 Advantages:
• t½ >24 hours,
• Longer acting
• Can be administered once every 2–4 weeks

39. Acute
Iron
Poisoning

40. • General
• Gastrointestinal symptoms shortly after ingestion with possible rapid
progression to shock and coma
• Symptoms
• Vomiting, abdominal pain, and diarrhea within 1 to 6 hours
• Lethargy, coma, seizures, bloody vomiting, bloody diarrhea, and shock within 6
to 24 hours
• Signs
• Hypotension and tachycardia within 6 to 24 hours
• Liver dysfunction and failure possible in 2 to 5 days

41. Management
oTo prevent further absorption of iron from gut:
• (a) Induce vomiting or perform gastric lavage with sodium bicarbonate solution—
to render iron insoluble.
• (b) Give egg yolk and milk orally: to complex iron. Activated charcoal does not
adsorb iron.
oTo bind and remove iron already absorbed:
• Desferrioxamine (an iron chelating agent) — is the drug of choice.
• 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/hour; max 75 mg/kg in a day till serum iron
falls below 300 μg/dl.

42. Desferrioxamine
• Ferrioxamine is a long chain iron containing complex obtained from an
actinomycete
• Chemical removal of iron from it yields desferrioxamine which has very
high affinity for iron
• 1 g is capable of chelating 85 mg of elemental iron.
• Straight chain desferrioxamine molecule winds round ferric iron and
forms a stable nontoxic complex ⇛ excreted in urine
oAdvantage:
• It removes loosely bound iron as well as that from haemosiderin and
ferritin, but
• Not from haemoglobin or cytochrome

43. oUses:
Acute iron poisoning:
Transfusion siderosis:
• occurs in thalassemia patients who receive repeated blood transfusion
oADRs:
• Histamine release → fall in BP, flushing, itching, urticaria, rashes
oPreparation:
• 0.5 gm / vial

44. Deferiprone
• Orally active iron chelator
• Specially indicated for the treatment of transfusion
siderosis in thalassemia patients
• Less effective alternative to injected desferrioxamine
• Other uses:
• Acute iron poisoning
• Iron load in Liver cirrhosis
• Dose: 50–100 mg/kg daily in 2–4 divided doses.

45. Therapeutic
Considerations
To start
Iron Therapy . . .

46.  Role of iron for therapeutic or prophylactic is considered only when –
- Iron deficiency has already been established, or
-To prevent further depletion of stores.
 Initial approach to treatment depends upon the severity and cause of IDA.
 However, the response of iron deficiency anemia to iron is influenced by several
factors like –
- Ability of patient to tolerate and absorb medicinal iron,
- Presence of other complicating illness,
- Severity of the anemia.

47. Take – Home Message
 The advantages and disadvantages of the
various preparations and routes of
administration should be fully weighed before
selecting the form of therapy.
 In the first instance, Under normal
circumstances, oral iron is the treatment of
choice since it is simple, effective, safe and
cheap.
 However, the ultimate decision depends on
patient’s condition & compliance.

48. Thank You . . .