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 Iron(II) gluconate, or ferrous gluconate, is a black compound often used as an iron supplement. It is the iron(II) salt of gluconic acid. It is marketed under brand names such as ''Fergon'', ''Ferralet'' and ''Simron''. Uses Medical Ferrous glu ...

, and

ferrous fumarate Iron(II) fumarate, also known as ferrous fumarate, is the iron(II) salt of fumaric acid, occurring as a reddish-orange powder, used to supplement iron intake. It has the chemical formula . Pure ferrous fumarate has an iron content of 32.87%, the ...

. It can be administered

orally The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or oral ...

, and by

intravenous injection Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutri ...

, or

intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

. 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 Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic c ...

, iron forms a complex with heme proteins for hemoglobin synthesis.Iron Supplementation.
Nguyen, M. (2021) “Iron Supplementation.” StatPearls nternet, U.S. National Library of Medicine. 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 A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane ...

and released to the bloodstream. Iron in parenteral iron preparation needs to be released by the cleavage of the surrounding complex by macrophages. After reaching the bloodstream, it becomes a part of the endogenous iron pool and establishes normal human iron distribution, metabolism, and elimination. 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. The process of iron toxicity is divided into four clinical stages, which are gastrointestinal damage, improvement in condition,

metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...

and hepatic failure, and intestinal obstruction due to scarring. Whole bowel irrigation and iron chelation are used in the treatment of iron poisoning.

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.

Pharmacokinetics

Oral administration

Non-heme and heme oral iron preparations are absorbed into the

systemic circulation The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

via different mechanisms. Non-heme iron is present in a form of

Fe3+ In chemistry, iron(III) refers to the element iron in its +3 oxidation state. In ionic compounds (salts), such an atom may occur as a separate cation (positive ion) denoted by Fe3+. The adjective ferric or the prefix ferri- is often used to spe ...

and undergoes reduction to

Fe2+ In chemistry, the adjective Ferrous indicates a compound that contains iron(II), meaning iron in its +2 oxidation state, possibly as the divalent cation Fe2+. It is opposed to "ferric" or iron(III), meaning iron in its +3 oxidation state, such as ...

in the

duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...

by duodenal cytochrome b (Dcyt b). Reduced iron is then imported into divalent metal transporter 1(DMT1) into the

enterocyte Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its ...

cytoplasm, either transported into bloodstream by the basolateral transport protein ferroportin or stored as ferritin. 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 Haem or Heme carrier protein 1 (HCP1) was originally identified as mediating heme- Fe transport although it later emerged that it was a folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, w ...

(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. The absorption of heme iron is 2–3 times faster than non-heme iron. 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. The gastrointestinal (GI) absorption process depends on many factors, including the dosage form,

dose Dose or Dosage may refer to: Music * ''Dose'' (Gov't Mule album), 1998 * ''Dose'' (Latin Playboys album) * ''Dosage'' (album), by the band Collective Soul * "Dose" (song), a 2018 song by Ciara * "Dose", song by Filter from the album '' Short ...

, 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. Therefore, oral bioavailability of iron varies greatly, ranging from less than 1% to greater than 50%. Uptake of iron can be enhanced by dietary heme iron and vitamin C, while inhibited by calcium, polyphenols, tannins and

phytates Phytic acid is a six-fold phosphate, dihydrogenphosphate ester of inositol (specifically, of the ''myo'' isomer), also called inositol hexakisphosphate (IP6) or inositol polyphosphate. At physiological pH, the phosphates are partially ionized, re ...

Parenteral administration

Intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

iron is administered directly to the bloodstream, in a form of iron carbohydrate complexes, such as iron dextran and

iron sucrose 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. Chem ...

. The complex is composed of a polynuclear Fe3+ hydroxide core with a surrounding carbohydrate shell. In the body, the iron complex behaves like a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

, 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 Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...

. The fusion of

endosomes Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...

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. 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 Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

for red blood cell synthesis or in the liver as the storage form of ferritin.

Role of iron in hemoglobin synthesis

Hemoglobin synthesis comprises globin and heme synthesis. The heme molecule is formed by the attachment of an Fe2+ ion to protoporphyrin in the

cells.

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. A very limited loss is estimated to be approximately 1 mg/day, mainly by sweating and epithelial cell exfoliation on the skin, genitourinary tract, and

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...

. For women, menstrual bleeding is another route for iron loss.

Iron toxicity and treatment

As a strong catalyst, iron is responsible for conversion of reduced forms of O2 into harmful

hydroxyl radicals The hydroxyl radical is the diatomic molecule . The hydroxyl radical is very stable as a dilute gas, but it decays very rapidly in the condensed phase. It is pervasive in some situations. Most notably the hydroxyl radicals are produced from the ...

in the body. Excessive amount of iron leads to production of high dose of reactive oxygen species (ROS). High doses of ROS are

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...

and can lead to chronic and acute inflammatory conditions. 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.   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. 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 . NTBI is cytotoxic due to its ability to promote the formation of free

, one type of ROS  Such damage results in swelling and

lysis Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

. Iron-loaded cells deplete mitochondrial

ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...

content and die eventually . Other than the mechanism of toxicity, four clinical stages of

iron toxicity 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 Somnolence, drowsiness. In more severe cases, symptoms can include ...

has been classified   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 Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

the mitochondrial inner membrane, resulting in peroxidative damage and upset of

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...

ATP synthesis ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation o ...

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

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 Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an un ...

. 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 .

Examples of iron preparation

Ferrous sulfate

Ferrous sulfate is widely used for both prophylaxis and treatment of iron-deficiency anemia. In 2018, it was the 94th most commonly prescribed drug in the United States, with over eight million prescriptions. ^* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ferrous Gluconate

Ferrous gluconate Iron(II) gluconate, or ferrous gluconate, is a black compound often used as an iron supplement. It is the iron(II) salt of gluconic acid. It is marketed under brand names such as ''Fergon'', ''Ferralet'' and ''Simron''. Uses Medical Ferrous glu ...

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

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

Ferrous fumarate

Ferrous fumarate Iron(II) fumarate, also known as ferrous fumarate, is the iron(II) salt of fumaric acid, occurring as a reddish-orange powder, used to supplement iron intake. It has the chemical formula . Pure ferrous fumarate has an iron content of 32.87%, the ...

is used in both prophylaxis and treatment of iron-deficiency anemia.“Ferrous Furmarate” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020. ^* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name ^* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Carbonyl iron

Carbonyl iron Carbonyl iron is a highly pure (97.5% for grade S, 99.5+% for grade R) iron, prepared by chemical decomposition of purified iron pentacarbonyl. It usually has the appearance of grey powder, composed of spherical microparticles. Most of the impuritie ...

is used in both prophylaxis and treatment of iron-deficiency anemia.

Polysaccharide iron complex

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

Iron sucrose

Iron sucrose 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. Chem ...

is used for patients with iron-deficiency anemia, including those with

chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

, 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.

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.

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.“Haem Derivatives” Martindale: the Complete Drug Reference, by Sean C. Sweetman, Pharmaceutical Press, 2020.

Ferric pyrophosphate

Ferric pyrophosphate is used for hemoglobin mainatence in hemodialysis-dependent

patients. {, class="wikitable" , + Ferric pyrophosphate preparation{{Cite web, title=DailyMed - TRIFERIC- ferric pyrophosphate solution TRIFERIC- ferric pyrophosphate citrate powder, url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=46ec9233-4063-4c48-e054-00144ff8d46c, access-date=2021-08-18, website=dailymed.nlm.nih.gov , - ! Routes !! Dosage forms !! Strengths !! Brand names !! Manufacturer , - , Hemodialysis , , Powder (for reconstitution) , , 272 mg of iron (III) per packet , , TRIFERIC ® , , Rockwell Medical , - , , , Solution , , 27.2 mg of iron (III) per 5 mL ampule , , TRIFERIC ® , , Rockwell Medical , - , Parenteral , , Injection, for IV use , , 6.75 mg iron (III) per 4.5 mL solution , , TRIFERIC ®AVNU , , Rockwell Medical

References

Iron Health care