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Pharmacotherapyof
AnaemiaDr. Jayesh Vaghela
Oralpreparations
ParenteralPreparations
Take-Homemessage
Acute IronPoisoning
Therapeuticconsideration
IronChelators
Iron preparations
OralIron
Preparations• Ferrous sulfate• Ferrous gluconate• Ferrous fumarate• Colloidal ferric
hydroxide• Carbonyl iron
Ferrous sulfate
ferrous sulfate
(exsiccated)
Ferrous glucona
te Ferrous
fumarate Polysaccha
ride 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
• 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.
• 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
• 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.
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
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.
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)
Common Preparations of oral ironoFerrous 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
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.
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
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.
Drugs That DecreaseIron Absorption Object Drugs Affected by Iron
Al-, Mg-, and Ca +2 -containing antacids
Levodopa ↓ (chelates with iron)
Tetracycline and doxycycline Methyldopa ↓ (decreases efficacyof methyldopa)
Histamine2 antagonists Levothyroxine ↓ (decreased efficacyof levothyroxine)
Proton pump inhibitors Penicillamine ↓ (chelates with iron)
Cholestyramine Fluoroquinolones ↓ (forms ferricionquinolone complex)Tetracycline and doxycycline ↓ (whenadministered within 2 hours of iron salt)Mycophenolate ↓ (decreasesabsorption)
Drug interactions of iron
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
ParenteralIron
Preparations• Iron-dextran• Iron-sorbitol-citric
acid• Ferrous-sucrose• Ferric
carboxymaltose• Sodium ferric
gluconate• Ferumoxytol
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)
• 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
• 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)
Therapeutic concerns about iron dextranIntramuscular 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.
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
Adverse Drug Reactions of iron dextranLocal :• 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
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)
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)
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
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.
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
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
• 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
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 ironoxide that is coated witha carbohydrate shell
Ferric oxide hydrate bondedto sucrose chelates withgluconate in a molar rate of2 iron molecules to 1 gluconatemolecule
Complex of ferric hydroxide anddextran
Complex of polynuclear ironhydroxide in sucrose
Indication
Treatment of iron deficiencyanemia for adult patientswith chronic kidney disease(CKD)
Treatment of iron-deficiencyanemia for patients undergoingchronic hemodialysis whoare receiving supplementalerythropoietin therapy
Treatment of patients withdocumented iron deficiencyin whom oral therapy isunsatisfactory or impossible
Treatment of iron-deficiencyanemia for patientsundergoing chronichemodialysis who arereceiving supplementalepoetin alfa therapy
Ferumoxytol Sodium Ferric Gluconate Iron Dextran Iron Sucrose
Usual dose
• Initial 510 mg intravenousInjection
⇓• 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 atinjection site, flushing,hypotension, fever, chills,
Leg cramps, hypotension
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.
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
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
Darbepoetin • Recently introduced• Hyperglycosylated modified EPO
Advantages:
• t½ >24 hours,• Longer acting• Can be administered once every 2–4 weeks
AcuteIron
Poisoning
• 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
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.
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 urineoAdvantage:
• It removes loosely bound iron as well as that from haemosiderin and ferritin, but
• Not from haemoglobin or cytochrome
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
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.
TherapeuticConsiderations
To startIron Therapy . . .
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.
Take – Home Message The advantages and disadvantages of
the various preparations and routes of administration should be ful ly weighed before selecting the form of therapy.
In the first instance, Under normal circumstances, oral iron is the treatment of choice s ince it is s imple, effective, safe and cheap.
However, the ult imate decision depends on patient’s condit ion & compliance.
Thank You . . .