Iron preparation

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Iron preparation is the formulation for iron supplements indicated in prophylaxis and treatment of iron-deficiency anemia. Examples of iron preparation include ferrous sulfate, ferrous gluconate, and ferrous fumarate. It can be administered orally, and by intravenous injection, or intramuscular injection. [1]

Contents

Early Iron Supplement for Anemia Dr Williams' 'Pink Pills', London, England, 1850-1920 Wellcome L0058211.jpg
Early Iron Supplement for Anemia

Iron preparation stimulates red blood cell production. The action is regulated by various iron-binding proteins in the body, such as ferritin and transferrin. After transferring to the bone marrow cells, iron forms a complex with heme proteins for hemoglobin synthesis. [2]

Different dosage forms of iron preparation have different absorption mechanisms. Iron in oral iron preparations is absorbed in the gut via transporters and carrier proteins and released to the bloodstream. [3] Iron in parenteral iron preparation needs to be released by the cleavage of the surrounding complex by macrophages. [4] After reaching the bloodstream, it becomes a part of the endogenous iron pool and establishes normal human iron distribution, metabolism, and elimination. [5]

Iron poisoning is a fatal medical condition. Due to the saturation of iron-binding protein ferritin, iron in the plasma becomes toxic, promoting peroxidative mitochondrial damage and thus cell death. [6] [7] The process of iron toxicity is divided into four clinical stages, which are gastrointestinal damage, improvement in condition, metabolic acidosis and hepatic failure, and intestinal obstruction due to scarring. [8] [9] Whole bowel irrigation and iron chelation are used in the treatment of iron poisoning. [10]

Mechanism of action

Iron supplements encourage erythropoiesis to increase red blood cell (RBC) production and oxygen transportation in the circulating system. The transportation of non-heme iron across the apical membrane is through divalent metal transporter 1(DMT1) while that of heme iron is through heme carrier protein 1(HCP1) in the small intestine. Iron is then incorporated and stored as ferritin in macrophages, increasing the iron stock in the body. Ferritin is then converted into an absorbable form of Fe2+ to bind to transferrin - an iron transporter in the blood circulation. The raised in transferrin level carried to the bone marrow cells stimulates RBC production, facilitating oxygen transportation in the bloodstream. [2]

Pharmacokinetics

Oral administration

Non-heme and heme oral iron preparations are absorbed into the systemic circulation via different mechanisms.

Non-heme iron is present in a form of Fe3+ and undergoes reduction to Fe2+ in the duodenum by duodenal cytochrome b (Dcyt b). Reduced iron is then imported into divalent metal transporter 1(DMT1) into the enterocyte cytoplasm, either transported into bloodstream by the basolateral transport protein ferroportin or stored as ferritin. [3]

For heme iron, heme oxygenase catalyzes the release of Fe2+ from heme, and Fe2+ enters the enterocyte cytosolic iron pool. However, the uptake mechanism is not well-understood. Haem carrier protein 1(HCP1) has been suggested to transport heme iron into the enterocyte, but has later been proven to have a much higher affinity in the transportation of folate. [11] [12] The absorption of heme iron is 2–3 times faster than non-heme iron. [13]

After absorption, the iron from preparation becomes part of the iron pool in the body. Upon stimulation, the reduction of iron storage Fe3+ in the enterocyte to Fe2+ ferroportin allows the passage of iron through the cell membrane for export. In the blood, ferroportin is then converted to transferrin to reach other tissues. [14]

The gastrointestinal (GI) absorption process depends on many factors, including the dosage form, dose, endogenous erythropoiesis process and diet. The most significant factor regulating iron uptake is the amount of iron present in the body. Iron absorption increases with sufficient iron storage and vice versa. Increased erythrocyte synthesis also stimulates iron absorption in the gut. [15] Therefore, oral bioavailability of iron varies greatly, ranging from less than 1% to greater than 50%. [16] Uptake of iron can be enhanced by dietary heme iron and vitamin C, while inhibited by calcium, polyphenols, tannins and phytates. [13]

Parenteral administration

Iron Sucrose Intravenous Drip Iron sucrose IV drip.jpg
Iron Sucrose Intravenous Drip

Intravenous iron is administered directly to the bloodstream, in a form of iron carbohydrate complexes, such as iron dextran and iron sucrose. The complex is composed of a polynuclear Fe3+ hydroxide core with a surrounding carbohydrate shell. [4] In the body, the iron complex behaves like a prodrug, releasing the iron from the Fe3+ hydroxide core via metabolism.

After the iron complex reaches the bloodstream, macrophages of the reticuloendothelial system will take up the stable complex by endocytosis. The fusion of endosomes and lysosome provides an acidic and reducing environment for iron complex cleavage. Fe2+ released is then transported by the divalent metal transporter 1(DMT1) to the macrophage cytoplasm and incorporated into ferritin. [4]

Ferritin is temporarily stored in the macrophages as part of the iron pool in the body. Upon stimulation, iron can be transported out as ferroportin and oxidized into transferrin in the sites of action, such as the bone marrow for red blood cell synthesis or in the liver as the storage form of ferritin. [4]

Role of iron in hemoglobin synthesis

Hemoglobin Hemoglobin 1hho.gif
Hemoglobin

Hemoglobin synthesis comprises globin and heme synthesis. The heme molecule is formed by the attachment of an Fe2+ ion to protoporphyrin in the bone marrow cells. [17]

Elimination

Iron obtained from iron preparation is eliminated from the body in a similar manner as dietary iron. Iron is mostly conserved and recycled in the body with minimal loss. [18] A very limited loss is estimated to be approximately 1 mg/day, [19] mainly by sweating and epithelial cell exfoliation on the skin, genitourinary tract, and gastrointestinal tract. For women, menstrual bleeding is another route for iron loss. [18]

Iron toxicity and treatment

As a strong catalyst, iron is responsible for conversion of reduced forms of O2 into harmful hydroxyl radicals in the body. Excessive amount of iron leads to production of high dose of reactive oxygen species (ROS). High doses of ROS are cytotoxic and can lead to chronic and acute inflammatory conditions. [20] Therefore, regulation of iron level with iron-binding proteins is essential such as transferrin for the transport and import of iron into cells, and ferritin for iron storage. These iron regulatory proteins prevent the accumulation of toxic cytosolic iron, maintaining a balance between uptake and storage of cellular iron. [15]   

During iron overdose, the protective mechanism is insufficient to limit the cytosolic iron concentration. The massive iron loading fails to match the capacity of ferritin for storage. [15] The high concentration of iron emerges into the bloodstream as toxic non-transferrin-bound plasma iron(NTBI).  In the worst case, high cellular iron concentration accelerates non-transferrin iron uptake, leading to accumulation of NTBI . [21]

NTBI is cytotoxic due to its ability to promote the formation of free hydroxyl radicals, one type of ROS  [22] Such damage results in swelling and lysis of mitochondria. Iron-loaded cells deplete mitochondrial ATP content and die eventually . [7]

Other than the mechanism of toxicity, four clinical stages of iron toxicity has been classified  [4] [9]  

The first stage is the initial stage of excess iron in intestinal system and circulation. High iron concentration causes hemorrhagic necrosis and ulceration of the upper intestine, leading to breakage of intestinal mucosal barrier and blood loss. Moreover, development of NTBI leads to circulatory collapse and reduced consciousness.   

The second stage is relatively stable, with improved consciousness. The decrease in plasma iron level due to cellular uptake creates a false sense of security.

The third stage is the most dangerous phase due to intracellular iron toxicity. Iron catalyzes the mitochondrial inner membrane, resulting in peroxidative damage and upset of oxidative phosphorylation. ATP synthesis is hampered, leading to cellular dysfunction, and even death. Hypotension develops again 2 to 5 days after iron ingestion, in association with severe organ dysfunction involving mainly the liver, heart, and brain. Sudden onset of severe hepatic failure, with hypoglycemia, coagulopathy, and aggravated metabolic acidosis are likely to occur, causing fatal outcome.

The fourth stage is rarely seen as limited cases of iron poisoning can survive the third stage. Patients surviving stage 3 are likely to develop intestinal strictures or obstruction due to scarring.  

Treatment of iron overdose includes gastrointestinal (GI) decontamination, chelation and supportive care. Whole-bowel irrigation can be performed with large amounts of an osmotically balanced polyethylene glycol electrolyte solution to flush out excess iron in the GI tract. In serious cases, iron chelation may be needed by intravenous injection, like deferoxamine. It binds iron and other metal ions with the chelator and is eliminated through the urine. Supportive care may also be necessary for patients with breathing difficulty and GI upset, by offering mechanical ventilation and rehydration respectively . [10]

Examples of iron preparation

Ferrous sulfate

Ferrous sulfate is widely used for both prophylaxis and treatment of iron-deficiency anemia. [23]

In 2018, it was the 94th most commonly prescribed drug in the United States, with over eight million prescriptions. [24]

Ferrous Sulfate Tablet RECALLED - Ferrous Sulfate Tablets, 325 mg (8390240271).jpg
Ferrous Sulfate Tablet
Ferrous sulfate preparations [25]
RoutesDosage formsStrengthsBrand namesManufacturer
BulkPowder
OralSolution220 mg (44 mg iron) per 5 mL*Ferrous Sulfate Elixir
300 mg (60 mg iron) per 5 mLFerrous Sulfate Solution
125 mg (25 mg iron) per mL*Fer-Gen-Sol® DropsTeva
Fer-In-Sol® DropsMead Johnson
Tablets195 mg (39 mg iron)*Mol-Iron®Schering-Plough
300 mg (60 mg iron)*Feratab®Upsher-Smith
325 mg (65 mg iron)*
Tablet, enteric-coated325 mg (65 mg iron)*Ferrous Sulfate Tablets EC
Tablet, film-coated325 mg (65 mg iron)Ferrous Sulfate Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ferrous sulfate, dried preparation [25]
RoutesDosage formsStrengthsBrand NamesManufacturer
OralCapsules190 mg (60 mg iron)
Tablets200 mg (65 mg iron)Feosol®GlaxoSmithKline
Tablets, extended-release160 mg (50 mg iron)Slow FE®Novartis

Ferrous Gluconate

Ferrous gluconate is indicated for both prophylaxis and treatment of iron-deficiency anemia. [26]

Ferrous Gluconate Structure Ferrous gluconate.png
Ferrous Gluconate Structure
Ferrous gluconate preparation [25]
RoutesDosage formsStrengthsBrand namesManufacturer
BulkPowder
OralTablets225 mg (27 mg iron)Fergon®Bayer
Ferrous Gluconate Tablets
300 mg (35 mg iron)Ferrous Gluconate Tablets
320 mg (37 mg iron)*
325 mg (38 mg iron)*

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ferrous fumarate

Ferrous fumarate is used in both prophylaxis and treatment of iron-deficiency anemia. [27]

Ferrous furmarate preparation [25]
RoutesDosage formsStrengthsBrand namesManufacturer
OralTablets200 mg (66 mg iron)Ircon®Kenwood
324 mg (106 mg iron)*Hemocyte®US Pharmaceutical
325 mg (107 mg iron)Ferrous Furmurate Tablets
350 mg (115 mg iron)Nephor-Fer®R&D Labs
Tablets, chewable100 mg (33 mg iron)*Feostat®Forest

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ferrous fumarate combinations [25]
RoutesDosage FformsStrengthsBrand namesManufacturer
OralCapsules, extended-release150 mg (50 mg iron) with Docusate Sodium 100 mg*Ferrous Fumarate with DSS® Timed CapsulesVita-Rx
Tablets, extended-release, film-coated150 mg (50 mg iron) with Docusate Sodium 100 mgFerro-DSS® Caplets®Time-Caps
Ferro-Sequels®Inverness

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Carbonyl iron

Carbonyl iron is used in both prophylaxis and treatment of iron-deficiency anemia. [25]

Carbonyl iron preparation [25]
RoutesDosage formsStrengthsBrand NamesManufacturer
OralSuspension15 mg (of iron) per 1.25 mLIcar® PediatricHawthorn
Tablets45 mg (of iron)Feosol® CapletsGlaxoSmithKline
Tablets, chewable15 mg (of iron)Icar® PediatricHawthorn

Polysaccharide iron complex

Polysaccharide iron complex is used in both prophylaxis and treatment of iron-deficiency anemia. [25]

Polysaccirde-iron complex preparation [25]
RoutesDosage FormsStrengthsBrand namesManufacturer
OralCapsules150 mg (of iron)Ferrex®-150Breckenridge
Fe-Tinic® 150Ethex
Hytinic®Hyrex
Niferex®-150Ther-Rx
Solution100 mg (of iron) per 5 mLNiferex® ElixirTher-Rx
Tablets, film-coated50 mg (of iron)Niferex®Ther-Rx

Iron sucrose

Iron Sucrose Structure Iron Sucrose Structure.jpg
Iron Sucrose Structure

Iron sucrose is used for patients with iron-deficiency anemia, including those with chronic kidney disease, when oral iron therapy is ineffective or impractical. Iron sucrose is given by slow intravenous injection or intravenous infusion. For haemodialysis patients, it may be given into the venous limb of the dialyser. [28]

Iron sucrose preparation [29]
RoutesDosage formsStrengthsBrand namesManufacturer
ParenteralInjection, for IV infusionequivalent to 20 mg of elemental iron per mLVenofer®American Regent

Iron dextran

Iron dextran is given by injection and should be used only in the treatment of proven iron-deficiency anemia where oral therapy is ineffective or impracticable. [30]

Iron dextran preparation [31]
RoutesDosage formsStrengthsBrand namesManufacturer
ParenteralInjection, for IV useequivalent to 50 mg of elemental iron per mLDexferrum®American Regent
Injection, for IV or IM useequivalent to 50 mg of elemental iron per mLINFeD®Watson

Haem iron polypeptide

Haem iron polypeptide is available in oral and parenteral dosage form. Oral formulation is used in both prophylaxis and treatment of iron-deficiency anemia. [32]

Haem iron polypeptide preparation [32]
RoutesDosage formsStrengthsBrand namesManufacturer
OralTablet11 mg (of iron)*Proferrin®Colorado Biolabs
28 mg (of iron)Duofer®Breckenridge
ParenteralInjection, for IV useequivalent to 25 mg of haem per mL*Normosang®Orphan
Injection, for IV infusionequivalent to 350 mg hemin per vialPanhematin®Recordati

Ferric pyrophosphate

Ferric pyrophosphate is used for hemoglobin mainatence in hemodialysis-dependent chronic kidney disease patients. [33]

Ferric pyrophosphate preparation [34]
RoutesDosage formsStrengthsBrand namesManufacturer
HemodialysisPowder (for reconstitution)272 mg of iron (III) per packetTRIFERIC ®Rockwell Medical
Solution27.2 mg of iron (III) per 5 mL ampuleTRIFERIC ®Rockwell Medical
ParenteralInjection, for IV use6.75 mg iron (III) per 4.5 mL solutionTRIFERIC ®AVNURockwell Medical

See also

Related Research Articles

<span class="mw-page-title-main">Iron deficiency</span> State in which a body lacks enough iron to supply its needs

Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key component of the hemoglobin protein, acting as a transport medium for electrons within the cells in the form of cytochromes, and facilitating oxygen enzyme reactions in various tissues. Too little iron can interfere with these vital functions and lead to morbidity and death.

Iron poisoning typically occurs from ingestion of excess iron that results in acute toxicity. Mild symptoms which occur within hours include vomiting, diarrhea, abdominal pain, and drowsiness. In more severe cases, symptoms can include tachypnea, low blood pressure, seizures, or coma. If left untreated, acute iron poisoning can lead to multi-organ failure resulting in permanent organ damage or death.

<span class="mw-page-title-main">Ferritin</span> Iron-carrying protein

Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload.

<span class="mw-page-title-main">Transferrin</span> Mammalian protein found in Homo sapiens

Transferrins are glycoproteins found in vertebrates which bind and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the Fenton reaction. Iron overload is often primary but may also be secondary to repeated blood transfusions. Iron deposition most commonly occurs in the liver, pancreas, skin, heart, and joints. People with iron overload classically present with the triad of liver cirrhosis, secondary diabetes mellitus, and bronze skin. However, due to earlier detection nowadays, symptoms are often limited to general chronic malaise, arthralgia, and hepatomegaly.

<span class="mw-page-title-main">Iron-deficiency anemia</span> Reduced ability of the blood to carry oxygen due to a lack of iron

Iron-deficiency anemia is anemia caused by a lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as feeling tired, weak, short of breath, or having decreased ability to exercise. Anemia that comes on quickly often has more severe symptoms, including confusion, feeling like one is going to pass out or increased thirst. Anemia is typically significant before a person becomes noticeably pale. Children with iron deficiency anemia may have problems with growth and development. There may be additional symptoms depending on the underlying cause.

<span class="mw-page-title-main">Microcytic anemia</span> Medical condition

Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells. The normal mean corpuscular volume is approximately 80–100 fL. When the MCV is <80 fL, the red cells are described as microcytic and when >100 fL, macrocytic. The MCV is the average red blood cell size.

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells. As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">Iron supplement</span> Iron formulation used to prevent or treat iron deficiency anemia

Iron supplements, also known as iron salts and iron pills, are a number of iron formulations used to treat and prevent iron deficiency including iron deficiency anemia. For prevention they are only recommended in those with poor absorption, heavy menstrual periods, pregnancy, hemodialysis, or a diet low in iron. Prevention may also be used in low birth weight babies. They are taken by mouth, injection into a vein, or injection into a muscle. While benefits may be seen in days, up to two months may be required until iron levels return to normal.

Iron-binding proteins are carrier proteins and metalloproteins that are important in iron metabolism and the immune response. Iron is required for life.

<span class="mw-page-title-main">Natural resistance-associated macrophage protein 2</span>

Natural resistance-associated macrophage protein 2, also known as divalent metal transporter 1 (DMT1) and divalent cation transporter 1 (DCT1), is a protein that in humans is encoded by the SLC11A2 gene. DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.

<span class="mw-page-title-main">Iron in biology</span> Use of Iron by organisms

Iron is an important biological element. It is used in both the ubiquitous iron-sulfur proteins and in vertebrates it is used in hemoglobin which is essential for blood and oxygen transport.

<span class="mw-page-title-main">Iron sucrose</span> Intravenous Treatment for Anemia

Intravenous iron sucrose is a commonly used treatment for iron deficiency anemia. Iron sucrose replaces iron in the blood to foster red blood cell production in patients with chronic kidney disease. Iron sucrose has the trade name Venofer.

Latent iron deficiency (LID), also called iron-deficient erythropoiesis, is a medical condition in which there is evidence of iron deficiency without anemia. It is important to assess this condition because individuals with latent iron deficiency may develop iron-deficiency anemia. Additionally, there is some evidence of a decrease in vitality and an increase in fatigue among individuals with LID.

Haem or Heme carrier protein 1 (HCP1) was originally identified as mediating heme-Fe transport although it later emerged that it was the SLC46A1 folate transporter.

<span class="mw-page-title-main">Natural resistance-associated macrophage protein</span> Family of transport proteins

Natural resistance-associated macrophage proteins (Nramps), also known as metal ion (Mn2+-iron) transporters (TC# 2.A.55), are a family of metal transport proteins found throughout all domains of life. Taking on an eleven-helix LeuT fold, the Nramp family is a member of the large APC Superfamily of secondary carriers. They transport a variety of transition metals such as manganese, cadmium, and manganese using an alternating access mechanism characteristic of secondary transporters.

Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people from various ethnic groups. While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage.

Iron(III)-hydroxide polymaltose complex is a medication used to treat iron deficiency / iron deficiency anemia and belongs to the group of oral iron preparations. The preparation is a macromolecular complex, consisting of iron(III) hydroxide (trivalent iron, Fe3+, Fe(OH)3·H2O) and the carrier polymaltose and is available in solid form as a film-coated or chewable tablet and in liquid form as a syrup, drinkable solution, or drops. It is used for treating iron deficiency without anemia (latent iron deficiency) or with anemia (apparent iron deficiency). Prior to administration, the iron deficiency should be diagnostically established and verified via laboratory tests (e.g., low ferritin concentration, low transferrin saturation).

<span class="mw-page-title-main">Ferric maltol</span> Chemical compound

Ferric maltol, sold under the brand names Accrufer (US) and Feraccru (EU), is an iron containing medication for the treatment of adults with low iron stores. It is taken by mouth.

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  32. 1 2 “Haem Derivatives” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020.
  33. ↑ Medical, Rockwell. "TRIFERIC". Rockwell Medical. Retrieved 2021-08-18.
  34. ↑ "DailyMed - TRIFERIC- ferric pyrophosphate solution TRIFERIC- ferric pyrophosphate citrate powder". dailymed.nlm.nih.gov. Retrieved 2021-08-18.
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