Lesson 1.2. Iron Pharmacology

Hemoglobin, Myoglobin, and DNA

Iron is an essential trace element required for:

1. __________________________ synthesis

2. Oxygen ______________________

3. Electron transport and _____ production

4. Activity of several enzymes, including _____________________________

1 = ?

transport and storage

Iron is an essential trace element required for:

1. __________________________ synthesis

2. Oxygen ______________________

3. Electron transport and _____ production

4. Activity of several enzymes, including _____________________________

2 = ?

ATP

Iron is an essential trace element required for:

1. __________________________ synthesis

2. Oxygen ______________________

3. Electron transport and _____ production

4. Activity of several enzymes, including _____________________________

3 = ?

cytochromes and ribonucleotide reductase

Iron is an essential trace element required for:

1. __________________________ synthesis

2. Oxygen ______________________

3. Electron transport and _____ production

4. Activity of several enzymes, including _____________________________

4 = ?

iron deficiency and iron-deficiency anemia

Pharmacologically, iron is mainly used to prevent or treat a._____________________________ however excessive iron can promote b._____________________________.

a = ?

oxidative tissue injury

Pharmacologically, iron is mainly used to prevent or treat a._____________________________ however excessive iron can promote b._____________________________.

b = ?

60-70%

MAJOR DISTRIBUTION OF BODY IRON

• Hemoglobin

15-30%

MAJOR DISTRIBUTION OF BODY IRON

• Ferritin/Hemosiderin Stores

10%

MAJOR DISTRIBUTION OF BODY IRON

• Myoglobin

Small amount

MAJOR DISTRIBUTION OF BODY IRON

• Enzymes/other proteins

<1%

MAJOR DISTRIBUTION OF BODY IRON

• Plasma transferrin-bound iron

Hemoglobin

Iron forms the nucleus of the iron-porphyrin heme ring, which, together with globin chains forms __________________.

active iron excretion

The body has no regulated pathway for a.___________________________. Therefore, iron balance is primarily controlled at the level of b._______________. This can cause c._________________________.

a = ?

intestinal absorption

The body has no regulated pathway for a.___________________________. Therefore, iron balance is primarily controlled at the level of b._______________. This can cause c._________________________.

b = ?

acute iron toxicity

The body has no regulated pathway for a.___________________________. Therefore, iron balance is primarily controlled at the level of b._______________. This can cause c._________________________.

c = ?

Ferrous iron (Fe²⁺)

IRON EXISTS MAINLY AS:

• more soluble and absorbed through intestinal transporters

Ferric iron (Fe³⁺)

IRON EXISTS MAINLY AS:

• predominant form in many foods and storage complexes

• reduced first before absorption

Heme iron

IRON EXISTS MAINLY AS:

• from meat and is absorbed efficiently

Non-Heme Iron

IRON EXISTS MAINLY AS:

• from plants and requires reduction to be absorbed

FR

COMMON SYMBOLS:

• ferric reductase

• convert dietary Ferric ion (Fe³⁺) into ferrous iron (Fe²⁺)

DMT1

COMMON SYMBOLS:

• Divalent Metal Transporter 1

• uptake of Fe²⁺ into intestinal cells

HCP1

COMMON SYMBOLS:

• Heme carrier protein 1

• uptake of heme iron

AF

COMMON SYMBOLS:

• apoferritin

• ferritin without iron

F

COMMON SYMBOLS:

• Ferritin

• iron-storage protein

FP

COMMON SYMBOLS:

• ferroportin

• major iron-exporter

• exports iron from the organ to the blood

Tf

COMMON SYMBOLS:

• Transferrin

• main iron transport protein in blood

• distributes iron to the bone marrow or hepatocytes

TfR

COMMON SYMBOLS:

• transferrin receptor

• receives iron in the organ sites (ex: bone marrow and hepatocytes)

duodenum and proximal jejunum

ABSORPTION AND REGULATION OF IRON:

• absorption occurs mainly in the ____________________________.

Ferric Reductase (FR)

ABSORPTION AND REGULATION OF IRON:

• Inorganic/Non-Heme Iron is reduced first from Ferric Ion to Ferrous iron using a.____________________.

• Then, the reduced iron is absorbed in the intestinal epithelial cells through b._________________________.

a = ?

divalent metal transporter 1 (DMT1)

ABSORPTION AND REGULATION OF IRON:

• Inorganic/Non-Heme Iron is reduced first from Ferric Ion to Ferrous iron using a.____________________.

• Then, the reduced iron is absorbed in the intestinal epithelial cells through b._________________________.

b = ?

Heme Carrier Protein 1 (HCP1)

ABSORPTION AND REGULATION OF IRON:

• Heme Iron which is a ferrous iron is absorbed in the intestinal epithelial cells through ________________________.

transferrin

DISTRIBUTION AND STORAGE OF IRON:

• Iron is transported by a.____________________ to b.________________ in the bone marrow for the synthesis of hemoglobin in RBCs and c.____________ for storage as ferritin.

a = ?

erythroid precursors

DISTRIBUTION AND STORAGE OF IRON:

• Iron is transported by a.____________________ to b.________________ in the bone marrow for the synthesis of hemoglobin in RBCs and c.____________ for storage as ferritin.

b = ?

hepatocytes

DISTRIBUTION AND STORAGE OF IRON:

• Iron is transported by a.____________________ to b.________________ in the bone marrow for the synthesis of hemoglobin in RBCs and c.____________ for storage as ferritin.

c = ?

Transferrin Receptors (TfR)

DISTRIBUTION AND STORAGE OF IRON:

• The transferrin-iron complex binds to ___________________ in erythroid precursors and hepatocytes, allowing the iron to be internalized.

cell membrane

DISTRIBUTION AND STORAGE OF IRON:

• After iron is released, the transferrin-transferrin receptor complex is recycled back to the a.___________ while the transferrin is released back into the b._______ to bind with another iron.

a = ?

plasma

DISTRIBUTION AND STORAGE OF IRON:

• After iron is released, the transferrin-transferrin receptor complex is recycled back to the a.___________ while the transferrin is released back into the b._______ to bind with another iron.

b = ?

Hepcidin

liver-produced peptide allowing the body to store iron

iron homeostasis

Hepcidin is a central key regulator to maintain ______________________.

degradation of ferroportin

High hepcidin causes:

1. internalization and _______________________

2. reducing intestinal _______________________

3. reducing _________________ from macrophages

1 = ?

iron absorption

High hepcidin causes:

1. internalization and _______________________

2. reducing intestinal _______________________

3. reducing _________________ from macrophages

2 = ?

iron release

High hepcidin causes:

1. internalization and _______________________

2. reducing intestinal _______________________

3. reducing _________________ from macrophages

3 = ?

ferroportin activity

Low hepcidin causes:

1. permit ________________________

2. increased __________________________________

1 = ?

iron delivery to plasma

Low hepcidin causes:

1. permit ________________________

2. increased __________________________________

2 = ?

Hepcidin Synthesis

HIGH IRON STORES:

1. Increased iron in hepatocytes stimulates ________________________

2. This ___________ ferroportin

3. This also reduces ________________________________

1 = ?

inhibits

HIGH IRON STORES:

1. Increased iron in hepatocytes stimulates ________________________

2. This ___________ ferroportin

3. This also reduces ________________________________

2 = ?

iron absorption and release from storage

HIGH IRON STORES:

1. Increased iron in hepatocytes stimulates ________________________

2. This ___________ ferroportin

3. This also reduces ________________________________

3 = ?

Vitamin C and Acidic Gastric pH

Absorption is enhanced by:

Food, Antacids, Calcium, Tea, Coffee, and Proton Pump Inhibitors

Absorption of Iron is reduced by:

Liver, Spleen, and Bone Marrow

Excess iron is stored as ferritin and hemosiderin in the __________________________________.

intestinal mucosal cells, skin, sweat, and menstruation

Excretion is minimal mainly through shedding of:

anemia

INDICATIONS:

1. Iron deficiency ___________

2. Pregnancy and _______________

3. ex: gastrointestinal bleeding, heavy menstrual bleeding

4. ____________________ deficiency

5. especially with erythropoietin therapy

6. _______________ anemia

7. Gastrectomy or severe small bowel disease leasing to _______________

1 = ?

lactation

INDICATIONS:

1. Iron deficiency ___________

2. Pregnancy and _______________

3. ex: gastrointestinal bleeding, heavy menstrual bleeding

4. ____________________ deficiency

5. especially with erythropoietin therapy

6. _______________ anemia

7. Gastrectomy or severe small bowel disease leasing to _______________

2 = ?

Chronic Blood Loss

INDICATIONS:

1. Iron deficiency ___________

2. Pregnancy and _______________

3. ex: gastrointestinal bleeding, heavy menstrual bleeding

4. ____________________ deficiency

5. especially with erythropoietin therapy

6. _______________ anemia

7. Gastrectomy or severe small bowel disease leasing to _______________

3 = ?

Nutritional Iron

INDICATIONS:

1. Iron deficiency ___________

2. Pregnancy and _______________

3. ex: gastrointestinal bleeding, heavy menstrual bleeding

4. ____________________ deficiency

5. especially with erythropoietin therapy

6. _______________ anemia

7. Gastrectomy or severe small bowel disease leasing to _______________

4 = ?

Chronic Kidney Disease

INDICATIONS:

1. Iron deficiency ___________

2. Pregnancy and _______________

3. ex: gastrointestinal bleeding, heavy menstrual bleeding

4. ____________________ deficiency

5. especially with erythropoietin therapy

6. _______________ anemia

7. Gastrectomy or severe small bowel disease leasing to _______________

5 = ?

Postpartum

INDICATIONS:

1. Iron deficiency ___________

2. Pregnancy and _______________

3. ex: gastrointestinal bleeding, heavy menstrual bleeding

4. ____________________ deficiency

5. especially with erythropoietin therapy

6. _______________ anemia

7. Gastrectomy or severe small bowel disease leasing to _______________

6 = ?

malabsorption

INDICATIONS:

1. Iron deficiency ___________

2. Pregnancy and _______________

3. ex: gastrointestinal bleeding, heavy menstrual bleeding

4. ____________________ deficiency

5. especially with erythropoietin therapy

6. _______________ anemia

7. Gastrectomy or severe small bowel disease leasing to _______________

7 = ?

Ferrous sulfate, ferrous fumarate, ferrous gluconate, ferric complexes

IRON PREPARATIONS

• Common Oral Preparations

Iron sucrose, ferric carboxymaltose, ferric derisomaltose, ferumoxytol, iron dextran

IRON PREPARATIONS

• Common Intravenous Preparations

inexpensive

IRON PREPARATIONS:

Main Pharmacologic Characteristics of Oral Route:

1. Convenient and ____________

2. Absorption is regulated and __________________________ are common

1 = ?

gastrointestinal effects

IRON PREPARATIONS:

Main Pharmacologic Characteristics of Oral Route:

1. Convenient and ____________

2. Absorption is regulated and __________________________ are common

2 = ?

intestinal absorption

IRON PREPARATIONS:

Main Pharmacologic Characteristics of Intravenous Route:

1. Bypasses _________________________

2. ___________________________ more rapidly

3. Requires monitoring for ___________________________________

1 = ?

Replenishes iron

IRON PREPARATIONS:

Main Pharmacologic Characteristics of Intravenous Route:

1. Bypasses _________________________

2. ___________________________ more rapidly

3. Requires monitoring for ___________________________________

2 = ?

hypersensitivity and other infusion reactions

IRON PREPARATIONS:

Main Pharmacologic Characteristics of Intravenous Route:

1. Bypasses _________________________

2. ___________________________ more rapidly

3. Requires monitoring for ___________________________________

3 = ?

gastrointestinal absorption is normal

IRON PREPARATIONS:

Indications of Oral Route:

1. effective for correcting anemia when ______________________________

tolerate or absorb

IRON PREPARATIONS:

Indications of Intravenous Route:

1. For patients who cannot _________________ oral iron

2. Those with _______________ due to chronic kidney disease patients on hemodialysis

3. ___________________ is present

4. ______________________ is clinically desirable

5. Ongoing __________________

1 = ?

chronic anemia

IRON PREPARATIONS:

Indications of Intravenous Route:

1. For patients who cannot _________________ oral iron

2. Those with _______________ due to chronic kidney disease patients on hemodialysis

3. ___________________ is present

4. ______________________ is clinically desirable

5. Ongoing __________________

2 = ?

Malabsorption

IRON PREPARATIONS:

Indications of Intravenous Route:

1. For patients who cannot _________________ oral iron

2. Those with _______________ due to chronic kidney disease patients on hemodialysis

3. ___________________ is present

4. ______________________ is clinically desirable

5. Ongoing __________________

3 = ?

Rapid repletion

IRON PREPARATIONS:

Indications of Intravenous Route:

1. For patients who cannot _________________ oral iron

2. Those with _______________ due to chronic kidney disease patients on hemodialysis

3. ___________________ is present

4. ______________________ is clinically desirable

5. Ongoing __________________

4 = ?

Blood loss

IRON PREPARATIONS:

Indications of Intravenous Route:

1. For patients who cannot _________________ oral iron

2. Those with _______________ due to chronic kidney disease patients on hemodialysis

3. ___________________ is present

4. ______________________ is clinically desirable

5. Ongoing __________________

5 = ?

Nausea, Epigastric discomfort, Constipation or diarrhea, Metallic taste, Black stools, andTeeth staining (liquid preparations)

IRON PREPARATIONS:

• Side Effects of Oral Route

Pain at injection site, Hypotension, Fever, Arthralgia, Allergic reactions (rare), and Anaphylaxis (most commonly associated with older high-molecular-weight iron dextran formulations)

IRON PREPARATIONS:

• Side Effects of Intravenous Route

Acute Iron Toxicity

occurs primarily in young children who accidentally ingest iron tablets and as few as 10 tablets can be lethal

necrotizing gastroenteritis, vomiting, abdominal pain, and bloody d iarrhea

Acute Iron Toxicity Symptoms:

1. early signs include:

2. severe symptoms may include:

1 = ?

shock, lethargy, dyspnea, metabolic acidosis, coma, and death

Acute Iron Toxicity Symptoms:

1. early signs include:

2. severe symptoms may include:

2 = ?

Chronic Iron Toxicity

also known as Iron Overload

Inherited Hemochromatosis

Causes of Chronic Iron Toxicity:

• Excessive iron absorption due to a genetic disorder

Frequent Blood Transfusions

Causes of Chronic Iron Toxicity:

• Often seen in patients with conditions like β-thalassemia

Excess iron deposits in organs such as the heart, liver, and pancreas, leading to organ failure and death

Consequence of Chronic Iron Toxicity

Phlebotomy

CHRONIC IRON TOXICITY TREATMENT

• most efficient treatment when anemia is not present

• one unit of blood is removed weekly until excess iron is depleted

Iron Chelation Therapy

CHRONIC IRON TOXICITY TREATMENT

• uses IV deferoxamine, oral chelators deferasirox and deferiprone

efficient

CHRONIC IRON TOXICITY TREATMENT

Iron Chelation Therapy Challenges

1. less _____________

2. more ___________________

3. carries risk such as ________________

1 = ?

complex and expensive

CHRONIC IRON TOXICITY TREATMENT

Iron Chelation Therapy Challenges

1. less _____________

2. more ___________________

3. carries risk such as ___________________

2 = ?

agranulocytosis

CHRONIC IRON TOXICITY TREATMENT

Iron Chelation Therapy Challenges

1. less _____________

2. more ___________________

3. carries risk such as ________________

3 = ?

Regular CBC monitoring

CHRONIC IRON TOXICITY TREATMENT

Iron Chelation Therapy

• _____________________ must be done to detect potential side effects