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 . . .