MOA Provides iron, an essential component in hemoglobin, myoglobin, and various enzymes [L2239].; Iron combines with porphyrin and globin chains to form hemoglobin, which is critical for oxygen delivery from the lungs to other tissues [L2263].

INDICATION For the prevention and treatment of iron deficiency anemia [L2252].;

ROE Mostly recycled; small daily losses occurring via desquamation, sweat, urine, and bile [L2240]. Some iron is lost during menstrual bleeding.; ; About 1–2 mg of iron is lost every day, through skin and gastrointestinal desquamation and minor blood losses. This loss is balanced by intestinal absorption. Therefore, iron recycling accounts for most of the iron homeostasis in human. ;

ABSORPTION Approximately 5 – 10% of dietary iron is absorbed (increased up to 30% in iron deficiency states). Therapeutically ingested oral iron is up to 60% absorbed via active and passive transport processes [L2240].; ; The median time to maximum serum concentration (Tmax) occurs 4h post administration. Between 2 and 8 h post administration, average serum iron concentrations fluctuate by only 20%, according to one study [A32500].; ; It is advised to consume ferrous sulfate along with ascorbic acid, as this practice has been known to increase its absorption [A32506]. Reduced absorption with antacids, Zn, Ca, phosphorus, trientine, and cholestyramine has been observed [L2253].

PHARMACODYNAMICS The pharmacodynamics of ferrous sulfate can be summarized as follows: oxygen transport and storage, electron transport and energy metabolism, antioxidant and beneficial pro-oxidant functions, oxygen sensing, and DNA replication and repair [L2259].; ; Ferrous sulfate facilitates oxygen transport by hemoglobin (Hb). It is utilized as an iron supply as it replaces the Fe found in Hb, myoglobin and other enzymes [L2253].; ; Iron is needed by the human body to maintain optimal health, particularly for helping to form red blood cells (RBC) that carry oxygen around the body. A deficiency in iron may indicate that the body cannot produce enough normal red blood cells (RBC). This is also known as iron deficiency anemia and can lead to fatigue, breathlessness, palpitations, dizziness, and headache [L2254].; ; Iron deficiency anemia occurs when body stores of iron decrease to very low levels, and the stores are unable to support normal red blood cell (RBC) production. Insufficient dietary iron, impaired iron absorption, bleeding, or loss of body iron in the urine may lead to iron deficiency. The homeostasis of iron normally is regulated carefully by the body to ensure that an adequate supply of iron is absorbed in order to compensate for normal body losses of iron [L2251]. Iron is found naturally in certain foods and adequate amounts may be obtained through the diet. For individuals who do not receive enough iron from their diet, an iron supplement is necessary. Various conditions can also cause iron deficiency anemia, such as pregnancy or heavy menstrual flow [L2236]. ; ; Taking iron in supplement form, such as ferrous sulfate, allows for more rapid increases in iron levels when dietary supply is not sufficient [L2175].

TOXICITY Oral LD50 is 319 mg/kg in rat and 680 mg/kg in mouse [MSDS].; ; Iron is toxic to the gastrointestinal system, cardiovascular system, and central nervous system. The exact mechanisms of toxicity are unclear, however, it appears that excess free iron is inserted into enzymatic processes and interferes with the oxidative phosphorylation process, leading to metabolic acidosis. In addition, iron catalyzes free radical formation, and serves as an oxidizer [L2234].; ; Toxicity depends on the amount of elemental iron that has been ingested. Up to 20 mg/kg of elemental iron is not toxic, 20 to 60 mg/kg is mildly-moderately toxic, and > 60 mg/kg can cause severe symptoms and morbidity [L2233].; ; Gastrointestinal adverse effects are the most commonly reported effects associated with oral iron ingestion, and include nausea, flatulence, abdominal pain, diarrhea, constipation, and black/tarry stools [L2234].; ; Early symptoms of overdose include: abdominal pain, fever, nausea, vomiting (may contain blood), and diarrhea. Late symptoms of overdose include bluish lips, fingernails, and palms; drowsiness; weakness; tachycardia; seizures; metabolic acidosis; hepatic injury; and cardiovascular dysfunction. The patient may have the appearance of being recovered before the onset of the later symptoms. Hospitalization should continue for 24 h after the patient becomes asymptomatic to monitor for delayed onset of shock/gastrointestinal bleeding. Later sequelae of iron sulfate overdose include intestinal obstruction, pyloric stenosis, and gastric scarring [L2240].; ; When plasma protein binding is saturated, iron combines with water to form iron hydroxide and free H+ ions, compounding the metabolic acidosis. Coagulopathy may appear as an earlier sign of toxicity because of interference with the coagulation cascade and later because of hepatic injury [L2234].; ; If the patient is comatose or seizing, gastric lavage with sodium bicarbonate should be performed. Deferoxamine is the antidote for iron poisoning. Other supportive treatments to support fluid and electrolyte balance and correct metabolic acidosis are also advised [L2240].;

METABOLISM Iron usually exists in the ferrous (Fe2+) or ferric (Fe3+) state, but since Fe2+ is oxidized to Fe3+, which, in neutral aqueous solutions rapidly hydrolyzes to insoluble iron(III)-hydroxides, iron is transported and stored while bound to plasma proteins. Efficacious binding of iron is imperative not only to ensure that stores are available when required but also due to the fact that Fe2+ may catalyze the formation of reactive oxygen species, which leads to oxidative stress, damaging cellular constituents [L1825]. ; ; Three important proteins regulate the transport and storage of iron. _Transferrin_ transports iron in the plasma and the extracellular fluid compartment [L1825].; ; The transferrin receptor, which is expressed by cells that require iron and present in their membranes, binds the transferrin di-iron complex and internalizes this complex into the cell. _Ferritin_ is a protein that stores iron, maintaining it in a readily available state [L1825]. ; ; Approximately 60% of iron is found in the erythrocytes within hemoglobin, the oxygen transport protein. The remainder of the iron is located in myoglobin in the muscles, in a variety of different enzymes (‘heme’ and ‘non-heme’), and in storage form. The majority of stored iron is in the form of ferritin, found in the liver, bone marrow, spleen and, and the muscles [L1825]. ; ; Serum iron (i.e., iron bound to transferrin) represents a very small proportion of total body iron (<0.2%). The relationship between physiological iron compartments is quite dynamic, and the process occurs as follows [L1825]:; ; Erythrocytes are broken down both in the liver and in the spleen, and new red blood cells are produced in the bone marrow. The total serum iron pool is approximately 4 mg, but the normal daily turnover is no greater than 30, and therefore, minor alterations in serum level due to exogenous iron administration are clinically meaningless. Conventional measurements of serum iron concentrations offer no relevant information about the availability of functional iron for physiological processes and other evaluation strategies must be followed through [L1825].