Phar 722Pharmacy Practice III

Minerals-Iron

(Updated from Dr. Stennett’s 2004 Iron Lecture)

Spring 2006

Iron Learning Objectives• Know the function of hemoglobin, lactoferrin, transferrin,

ferritin and hemosiderin in relation to function and iron content in the body.

• Rank order various sources of dietary and replacement iron in terms of bioavailability.

• Know processes involved in iron uptake, transport and deposit in cells.

• State which oxidation state of iron is better absorbed and why.• Know the causes, symptoms and treatments for iron deficiency

anemia, hemochromatosis and transfusional hemosiderosis.• Know the oral iron replacement and parenteral iron products

used in the treatment of iron deficiency anemia.• Identify the various drug interactions with oral iron therapy and

their interactions.• List the common side effects of oral iron therapy.• Differentiate iron content among the different available salt

forms.• Know the RDAs for adults and ULs for children and adults.

Iron Distribution – Young Adults• Men Women

• Functional– Hemoglobin 2,100 mg 1,750 mg– Myoglobin 300 mg 250 mg– Enzymes 50 mg 50 mg

• Storage– Ferritin, hemosiderin 1000 mg 400 mg

• Total 3,450 mg 2,450 mg

Iron Absorption-1• Uptake alone regulates body iron stores

– No physiological mechanism of iron excretion exists.

• About 1 to 2 mg of iron is lost per day through sloughing of cells from skin and mucosal surfaces including the lining of the gastrointestinal tract.

• Iron is ingested in three forms (and in this order of bioavailability):– Heme iron from meats – Ferrous iron from supplements– Ferric iron typically from plant sources.

Iron Absorption-2• Uptake of iron may occur at any level of the

small intestine, but it is most efficient in the duodenum. – Sustained release iron product may lose their

effectiveness as they progress down the intestinal tract through the latter portion of the jejunum and onto the ileum.

• Mucosal uptake of iron occurs by two distinct pathways. – Heme (hemoglobin & myoglobin from animal tissue)

• About 25% of the heme iron ingested is absorbed. – Heme is released from its apoproteins by gastric acid and

taken up by the mucosal cells. – Heme is degraded inside the cells to release iron.

– Non-heme iron (next slide)

Iron Absorption-3• Non-Heme Iron (Ferrous salt supplements;

Ferric iron from plants and dairy products)– Only about 1% to 2% of non-heme iron is absorbed– Ascorbic acid enhances iron absorption by forming

chelates and reducing ferric iron to ferrous.– Iron stores determines the rate of non-heme iron

absorption.• The mechanism of absorption of non-heme iron is still not

completely clear. – Ingested inorganic dietary iron, mostly in the ferric state, is

solubilized and reduced to the ferrous state in the presence of gastric acid.

• On average about 10 to 18 percent (depending on diet) of ingested iron is absorbed normally, but absorption increases to 20 to 30 percent in iron deficiency anemia.

Iron Absorption-4• Ferrous iron salts are more soluble than are ferric.

• At physiologic pH, which is approached in the duodenum, and in the presence of oxygen, iron exists in the insoluble ferric state.

• There appears to be a recently identified, at least in rodents, iron-regulated ferric reductase enzyme in the brush border of the intestine that converts ferric iron to ferrous at the extracellular surface to facilitate absorption. – A divalent cation transporter (DCT1) transports the

ferrous ion into the cytosol where it is oxidized to the ferric state.

Iron Transport & Storage-Transferrin• Transferrrin

– The main plasma iron transport protein.– An 80 kDa glycoprotein that transports two irons per protein. – Transferrin binds ferric iron in the presence of an anion, usually

bicarbonate which, is a necessary cofactor for binding.

• The sum of all the transferrin binding sites constitutes the Total Iron Binding Capacity (TIBC) of plasma.– Normally about one-third of the transferrin sites are filled.– At least 80 percent of the iron bound to circulating transferrin is

delivered to the bone marrow to be incorporated into hemoglobin, as the ferrous form, in newly formed erythrocytes.

• Other major sites of iron delivery are the: – Liver which is a primary depot for stored iron– Spleen

Iron Transport & Storage-Fate of Transferrin

• The transferrin-iron complex binds to a cell surface transferrin receptor. – The receptor-transferrin complex is engulfed and forms an

endosome. The pH of the endosome environment is lowered to 5.5 by an ATP-dependent proton pump, which weakens the association between the ferric ion and transferrin.

– In addition, an iron reductase reduces the ferric ion to ferrous which is less strongly bound to transferrin.

– An endosomal, as yet unidentified, iron transporter moves the ferrous iron into the cytosol where a low molecular weight carrier molecule carries ferrous iron to the mitochondria for processing or to ferritin for storage.

• The iron-free transferrin in the endosome is transmitted to the cell surface for recycling rather than being degraded. – The average half-life of a transferrin molecule is 8 days. – During its lifetime it may be recycled for iron transport 100

times.

Iron Transport & Storage-Ferritin

• Iron is stored primarily in the liver bound to ferritin molecules. – Ferritins are complex proteins of 19.7 kDa and 21

kDa.– The subunits of the ferritin molecule form a sphere

with a central cavity containing up to 4500 atoms of crystalline iron providing a flexible reserve of iron.

– How iron is released from ferritin is not clear.

• Hemosiderin– Originates from ferritin molecules that form clusters

over time, are engulfed by lysosomes and finally degraded to an amorphous mass of denatured protein, lipid, and iron oxide.

• The bioavailability of iron from hemosiderin granules is much less that from ferritin.

Iron Transport & Storage-Hemosiderin & Lactoferrin

• Hemosiderin– Originates from ferritin molecules that form clusters

over time, are engulfed by lysosomes and finally degraded to an amorphous mass of denatured protein, lipid, and iron oxide.

• The bioavailability of iron from hemosiderin granules is much less that from ferritin.

• Lactoferrin– A glycoprotein that is part of the transferrin family.– Its name comes from being initially found in milk.– It appears to be a source of iron in breast-fed infants.– It seems to be required for proper functioning of

immune cells where iron binding is required for the immune response, possibly as part of the inflammatory process.

Iron Loss -Menses -Sloughing of skin and intestinal mucosal cells.

Iron Containing Proteins• Iron-containing heme proteins

– Hemoglobin– Myoglobin– Cytochromes

• Iron-sulfur protein– Flavoproteins– Heme-flavoproteins

• Iron storage and transport– Transferrin– Lactoferrin– Ferritin– Hemosiderin

Iron Deficiency Anemia-1• Iron deficiency anemia is considered an

occult bleed in males and postmenopausal females until proven otherwise.

• It is the most common form of anemia and iron deficiency is very common.– 20% females (usually premenopausal)– 50% pregnant females– 3% males

• NOTE: Term infants are born with a • 6-month supply of iron.

Iron Deficiency Anemia-2• Signs and Symptoms

– Iron deficiency anemia usually presents as a microcytic, hypochromic anemia.

• Depending on the severity of the anemia, patients may experience tissue hypoxia manifested as pallor.

– This can be observed easiest in the conjunctiva, mucous membranes, nail beds, and palmar creases.

– Cognitive functioning may be affected. – Routine laboratory evaluation includes hemoglobin,

hematocrit, RBC count, mean cellular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, WBC, platelets, reticulocyte count, bilirubin and LDH, serum iron, TIBC, serum ferritin, peripheral blood smear, and stool for occult blood.

Hemochromatosis-1• Genetic defect predominantly in Caucasians

of N. European descent that causes the person to absorb iron in excess of normal.

• Incidence in the United States– About 0.5% of the population carry two copies of

the defective gene and are at high risk of developing the disease.

– Approximately 10% of the population are carriers and usually do not develop the disease.

Hemochromatosis-2• Gender Differences

– Males begin to develop symptoms in their 30s.

– Females are more likely to show symptoms post-menopausal.

• Organs at risk– Liver– Pancreas– Heart

Hemochromatosis-3• Symptoms

– Arthritis– Liver disease

• Enlarged liver• Cirrhosis• Cancer• Liver failure

– Possibly diabetes from damaged pancreas– Heart abnormalities

• Arrhythmias• Congestive heart failure

– Early menopause and other gonadal abnormalities including loss of libido

– Damaged adrenal gland– Thyroid deficiency

Hemochromatosis-4• Treatment

– Phlebotomy• Depending on severity, a pint of blood will be drawn

once or twice a week for several months to a year or more.

• Goal– Bring blood ferritin levels to the low end of normal and

maintain them there.

• Maintenance– Draw a pint of blood every 2 to 4 months for life.

• Success is based on early detection before organ damage has developed.

– Can the patient’s blood be used by blood banks?• Yes, depending on the status of the blood bank with the

FDA.

Hemosiderosis• Iron intake exceeds iron loss.

– Most common cause is ccumulation of iron from chronic blood transfusions.

• Thalessemias• Sickling Disease

• Treatment– Parenteral deferoxamine (Desferal™)– Oral deferasirox (Exjade™)

Hemosiderosis-Drug Structures

C N (CH2)5HN C (CH2)2 C N (CH2)5

HN C

O

H3C

OH O O OH

(CH2)2

O

C N (CH2)5 NH2

O OH

Deferoxamine (DesferalTM)

N

NN

HOOH

C

OH

O

Deferasirox (ExjadeTM)

Iron Dosing-Oral• The goal of therapy is to normalize hemoglobin,

hermatocrit, red cell indices, and iron stores.– Reticulocyte count responds during the first week, but

therapy should be continued for 3 to 6 months to assure iron stores return to normal.

• The usual adult oral dosing regimen to treat iron deficiency anemia is ferrous sulfate 325mg TID. – Iron is available as :

• Ferrous sulfate 325 mg sugar coated and enteric coated tablets

• Ferrous fumarate 300 mg tablets• Ferrous gluconate 300 mg tablets• Dessicated ferrous sulfate 200 mg tablets • Polysaccharide iron capsules • Most are available as generic products and are relatively

inexpensive. • A number of timed release and combination products

are marketed, but most cases of iron deficiency respond well to the inexpensive generic oral products.

Oral Iron Dosage Formsmg Fe/tablet %Fe

Ferrous Fumarate 60 mg/200 mg 33%

Ferrous Gluconate 35 mg/300 mg 12%

Ferrous Sulfate 60 mg/325 mg 20%

Ferrous Sulfate, Dried 60 mg/200 mg* 32%

Polysaccharide Iron 90-150 mg/capsule

(*“Dried” also is referred to as “Exsiccated”.)

Parenteral Iron Dosage Forms• Iron Dextran

– Indicated when for severe iron deficiency when oral iron administrated is not feasible or rapid enough.

• Iron Sucrose

• Sodium Ferric Gluconate Complex– Both are indicated for iron replacement

therapy for patients on kidney dialysis.

Patient Information• Ferrous sulfate is very irritating to mucosal

surfaces– 5 to 20% of patients commonly encounter adverse

effects include: • nausea, gastric pain, constipation (and sometimes

diarrhea), abdominal cramps, and black stools. – Constipation does not appear to be dose related, but

nausea and epigastric pain are related to the total amount of iron administered.

– To minimize gastric disturbances, therapy can be initiated with one tablet per day and the dosed increased to BID in 2-3 days, and finally to TID in another 2-3 days.

– Note the different salts contain different total amounts of iron even though the milligrams of salt form per tablet are similar.

Iron-Drug Interactions• Any drugs that increase the gastric pH like antacids,

H2 antagonists, or proton pump inhibitors can decrease the absorption of iron by converting it from the ferrous to the less soluble ferric form.– These are commonly encountered in patients whose cause

of the iron deficiency anemia is a bleeding ulcer.

• Drugs that interact with divalent cations, such as tetracycline and ciprofloxacin, should not be administered within two hours of an iron dose.

• NOTE:– Because iron supplements are non-prescription, the fact

that a patient is taking an iron supplement may not show up on the patient profile when a prescription is being filled.

Iron Toxicity• Iron is toxic, especially in infants and

small children. – Many iron tablets mimic common candies

such as M&M type candies.

• Ferrous sulfate tablets are highly toxic. – The lethal dose of iron for a 2-year-old

child is 3 grams, and 1 gram (three 325 mg tablets) leads to severe poisoning.

– Symptoms include gastrointestinal irritation, pain, vomiting, diarrhea, shock, cardiovascular collapse, and death.

Iron DRIs-1• AI

– Infants (0-6 months) 0.27 mg/day

• EAR– Infants (7-12 months) 6.9 mg/day– Children (1-3 years) 3 mg/day– Children (4-8 years) 4.1 mg/day– Boys (9-13 years) 5.9 mg/day– Girls (9-13 years) 5.7 mg/day– Boys (14-18 years) 7.7 mg/day– Girls (14-18 years) 7.9 mg/day– Men (19-70+ years) 6 mg/day– Women (19-50 years) 8.1 mg/day– Women (51-70+ years) 5 mg/day– Pregnancy (14-18 years) 23 mg/day– Pregnancy (19-50 years) 22 mg/day– Lactation (14-18 years) 7 mg/day– Lactation (19-50 years) 6.5 mg/day

Iron DRIs-2• RDA

– Infants (7-12 months) 11 mg/day– Children (1-3 years) 7 mg/day– Children (4-8 years) 10 mg/day– Boys (9-13 years) 8 mg/day– Girls (9-13 years) 8 mg/day– Boys (14-18 years) 11 mg/day– Girls (14-18 years) 15 mg/day– Men (19-70+ years) 8 mg/day– Women (19-50 years) 18 mg/day– Women (51-70+ years) 8 mg/day– Pregnancy (14-50 years) 27 mg/day– Lactation (14-18 years) 10 mg/day– Lactation (19-50 years) 9 mg/day

Iron DRIs-3

• UL– Infants (0-12 months) 40 mg/day– Children (1-13 years) 40 mg/day– Adolescents (14-18 years) 45 mg/day– Adults (19+ years) 45 mg/day– Pregnancy (14-50 years) 45 mg/day– Lactation (14-50 years) 45 mg/day