Iron-Dextran: Mechanism of Action, Pharmacokinetics and Adverse Effects

General Description

Iron-dextran is a complex used to treat iron deficiency anemia, functioning through a series of steps. After macrophages uptake iron-dextran from the bloodstream, it is processed in the reticuloendothelial system, releasing iron that binds to transferrin for transport to the bone marrow. Iron-dextran is a non-antigenic prodrug that mimics a ferritin-iron complex, facilitating absorption upon intramuscular injection, with systemic effects typically observed after up to three weeks. Although effective, it has been linked to adverse effects, including infusion reactions and, in rare cases, anaphylaxis, particularly in patients with multiple drug allergies.

Figure 1. Iron-dextran

Mechanism of Action

Iron-dextran is a complex of iron used to treat iron deficiency anemia. The mechanism of action of iron-dextran begins when macrophages remove it from the bloodstream and deliver it to the reticuloendothelial system through endocytosis. In this system, the components of iron-dextran are separated, allowing the release of iron. The released iron binds to transferrin, an essential iron-binding protein responsible for transporting iron to various tissues, particularly the bone marrow. The iron-transferrin complex then binds to transferrin receptor 1, found on erythroid progenitor cells. Following this binding, iron dissociates from transferrin, making it available for the erythroid progenitor cells. These cells utilize the iron to synthesize heme, a vital component of hemoglobin. In the presence of erythropoietin, these progenitor cells mature into erythrocytes, leading to an increase in hemoglobin and, consequently, in red blood cell count, typically observed about seven days post iron-dextran infusion. ¹

Pharmacokinetics

Absorption

Iron-dextran is classified as a prodrug, consisting of an iron carbohydrate complex that effectively provides iron to the body. The carbohydrate component, dextran, is bound to iron and mimics a ferritin-iron complex. Unlike ferritin, which is an antigenic protein that can elicit immune responses when administered intravenously, iron-dextran is designed by substituting ferritin with dextran, making it a non-antigenic compound. This unique structure allows iron-dextran to bypass the typical immune response associated with other forms of iron supplementation. Upon administration, particularly through intramuscular injection, the absorption of iron-dextran can take up to three weeks before systemic effects are observed. It is observed that reticulocyte counts peak between five to ten days after administration, while significant increases in hemoglobin levels are generally noted within two to four weeks. ¹

Distribution, Metabolism, and Elimination

After absorption, iron-dextran distributes throughout the body, where transferrin plays a crucial role in transporting the released iron to the bone marrow for the production of red blood cells. The liver serves as the primary storage site for excess iron, retaining it in the form of ferritin or hemosiderin. The metabolism of iron-dextran involves the degradation of its dextran component, which is primarily excreted in urine, while iron is not actively eliminated from the body. Instead, iron released from the breakdown of red blood cells is recycled to synthesize new red blood cells. Consequently, prolonged infusions of iron-dextran can result in the accumulation of iron in various organs, raising potential concerns about toxicity. The elimination half-life of iron-dextran ranges from one day to 3.5 days, depending on the dosage, but it is important to note that this half-life primarily indicates the duration until phagocytes extract iron-dextran from the plasma, rather than signifying complete elimination from the body. ¹

Adverse Effects

Iron-dextran, despite being an effective treatment for iron deficiency, has been historically associated with significant rates of adverse effects. Most of these adverse drug events were linked to the high-molecular-weight formulation, which has since been withdrawn from the US market. Patients with a history of multiple drug allergies are particularly at an increased risk for allergic reactions to iron-dextran. The main adverse effects include infusion reactions, which may present as complement activation-related pseudoallergy, or CARPA. Symptoms of CARPA typically include flushing, myalgias, arthralgias, back pain, and chest pressure; these reactions are not considered life-threatening and can usually be managed by slowing the infusion rate. More severe reactions, though uncommon, may involve dyspnea, hypotension, angioedema, and neurological symptoms. It is essential to note that while the currently available low-molecular-weight iron-dextran carries a box warning for anaphylaxis risk, evidence on the comparative risk among injectable iron formulations remains controversial. ²

Reference

1. Sebastiano F, Samar N, Mayur P. Iron Dextran. StatPearls. 2024.

2. Burns DL, Pomposelli JJ. Toxicity of parenteral iron dextran therapy. Kidney Int Suppl. 1999 Mar; 69: S119-S124.

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