Transcript Phar 722 Pharmacy Practice III

Phar 722
Pharmacy Practice III
MineralsIron
(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
•
• Functional
– Hemoglobin
– Myoglobin
– Enzymes
Men
2,100 mg
300 mg
50 mg
Women
1,750 mg
250 mg
50 mg
• Storage
– Ferritin, hemosiderin 1000 mg
• Total
3,450 mg
400 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
H3C
O
OH
C
N
O
(CH2)5
H
N
C
(CH2)2
O
OH
C
N
O
(CH2)5
H
N
Deferoxamine (DesferalTM)
OH
O
C
N
N
N
OH
HO
Deferasirox (ExjadeTM)
C
(CH2)2
O
OH
C
N
(CH2)5
NH2
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 Forms
mg 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)
Children (1-3 years)
Children (4-8 years)
Boys (9-13 years)
Girls (9-13 years)
Boys (14-18 years)
Girls (14-18 years)
Men (19-70+ years)
Women (19-50 years)
Women (51-70+ years)
Pregnancy (14-18 years)
Pregnancy (19-50 years)
Lactation (14-18 years)
Lactation (19-50 years)
6.9 mg/day
3 mg/day
4.1 mg/day
5.9 mg/day
5.7 mg/day
7.7 mg/day
7.9 mg/day
6 mg/day
8.1 mg/day
5 mg/day
23 mg/day
22 mg/day
7 mg/day
6.5 mg/day
Iron DRIs-2
• RDA
–
–
–
–
–
–
–
–
–
–
–
–
–
Infants (7-12 months)
Children (1-3 years)
Children (4-8 years)
Boys (9-13 years)
Girls (9-13 years)
Boys (14-18 years)
Girls (14-18 years)
Men (19-70+ years)
Women (19-50 years)
Women (51-70+ years)
Pregnancy (14-50 years)
Lactation (14-18 years)
Lactation (19-50 years)
11 mg/day
7 mg/day
10 mg/day
8 mg/day
8 mg/day
11 mg/day
15 mg/day
8 mg/day
18 mg/day
8 mg/day
27 mg/day
10 mg/day
9 mg/day
Iron DRIs-3
• UL
– Infants (0-12 months)
– Children (1-13 years)
– Adolescents (14-18 years)
– Adults (19+ years)
– Pregnancy (14-50 years)
– Lactation (14-50 years)
40 mg/day
40 mg/day
45 mg/day
45 mg/day
45 mg/day
45 mg/day