Pharmacology of Hematinics (Iron, Vitamin B12, Folic Acid)

1. Introduction/Overview

Hematinics constitute a fundamental class of therapeutic agents employed to correct deficiencies in essential substrates required for normal erythropoiesis. These agents—primarily iron, vitamin B12 (cobalamin), and folic acid—are critical for the synthesis of hemoglobin and the proper maturation of red blood cells. Deficiencies in any of these hematinic factors lead to distinct forms of anemia, characterized by impaired oxygen-carrying capacity and subsequent systemic manifestations. The clinical management of these anemias is a cornerstone of hematological therapeutics, requiring a precise understanding of the underlying pathophysiology to guide appropriate replacement therapy. This chapter provides a systematic examination of the pharmacology of these essential nutrients, detailing their mechanisms, kinetic profiles, therapeutic applications, and associated risks.

The clinical relevance of hematinics extends beyond the simple correction of anemia. Iron is integral to numerous cellular processes beyond hemoglobin synthesis, including oxidative metabolism and enzyme function. Vitamin B12 and folic acid are cofactors in one-carbon metabolism, essential for DNA synthesis and neurological integrity. Consequently, deficiencies can manifest with diverse clinical pictures, from fatigue and pallor to neurological deficits and developmental abnormalities. The importance of accurate diagnosis and appropriate pharmacological intervention cannot be overstated, as improper use can lead to treatment failure or, in the case of iron, significant toxicity.

Learning Objectives

• Describe the biochemical roles and molecular mechanisms of action of iron, vitamin B12, and folic acid in erythropoiesis and cellular metabolism.
• Compare and contrast the pharmacokinetic profiles, including routes of administration, absorption mechanisms, distribution, and elimination, for oral and parenteral iron, vitamin B12, and folic acid.
• Identify the approved clinical indications, dosing strategies, and monitoring parameters for hematinic agents in the treatment of corresponding deficiency states.
• Analyze the spectrum of adverse effects, contraindications, and major drug interactions associated with iron, vitamin B12, and folic acid therapy.
• Evaluate special considerations for the use of hematinics in populations such as pregnant women, pediatric and geriatric patients, and individuals with renal or hepatic impairment.

2. Classification

Hematinics are classified based on the specific nutrient they supply. This classification aligns directly with the underlying deficiency they are intended to treat.

Iron Preparations

Iron supplements are categorized by their chemical form and route of administration.

• Oral Iron Salts:
  • Ferrous Salts: These are the first-line agents for oral iron supplementation due to superior bioavailability compared to ferric salts. Common examples include ferrous sulfate, ferrous gluconate, and ferrous fumarate. They differ primarily in their elemental iron content per salt molecule.
  • Ferric Salts: Examples include ferric citrate and ferric maltol. Their absorption is generally less efficient than ferrous salts, but some newer formulations are designed for improved tolerability or specific clinical settings (e.g., in chronic kidney disease).
• Parenteral Iron Formulations:
  • Iron Dextran: A complex of ferric oxyhydroxide and dextran polymers. It carries a risk of dextran-induced anaphylaxis and requires a test dose.
  • Iron Sucrose: A complex of ferric hydroxide and sucrose. It is associated with a lower risk of serious hypersensitivity reactions compared to iron dextran.
  • Ferric Carboxymaltose: A stable complex allowing for larger single doses (up to 1000 mg) administered over 15 minutes.
  • Ferumoxytol: A superparamagnetic iron oxide nanoparticle approved for intravenous use, which also has properties detectable by magnetic resonance imaging.
  • Iron Isomaltoside: Allows for high-dose, rapid intravenous infusion.

Vitamin B12 (Cobalamin) Preparations

• Cyanocobalamin: The most common synthetic form used in supplements and injections. It is stable and converted in the body to active coenzymes, methylcobalamin and adenosylcobalamin.
• Hydroxocobalamin: Often used in injectable formulations, particularly outside the United States. It has a longer tissue retention time than cyanocobalamin and is also used as an antidote for cyanide poisoning.
• Methylcobalamin and Adenosylcobalamin: These are the active coenzyme forms of vitamin B12. They are available in some oral and sublingual supplements, marketed for direct utilization.

Folic Acid and Folates

• Folic Acid (Pteroylmonoglutamic Acid): The fully oxidized, synthetic monoglutamate form used in supplements and food fortification. It is more stable and bioavailable than dietary folates.
• Folinic Acid (Leucovorin): A reduced, formyl derivative of folic acid that is metabolically active without requiring reduction by dihydrofolate reductase. It is used clinically to “rescue” normal cells from the effects of methotrexate and other antifolate drugs.
• Dietary Folates: Found naturally in foods as polyglutamate conjugates (e.g., methyltetrahydrofolate, formyltetrahydrofolate), which must be deconjugated to monoglutamates for absorption.
• L-Methylfolate (5-MTHF): The predominant circulating and biologically active form of folate. It is available as a medical food or supplement, potentially bypassing metabolic steps impaired by genetic polymorphisms (e.g., in MTHFR enzyme).

3. Mechanism of Action

Iron

The primary pharmacodynamic action of iron is to serve as an essential component of heme, the oxygen-binding prosthetic group of hemoglobin, myoglobin, and cytochromes. At the molecular level, iron in its ferrous (Fe²⁺) state is incorporated into protoporphyrin IX by the enzyme ferrochelatase to form heme. Heme synthesis occurs in the mitochondria of erythroid precursor cells in the bone marrow. Beyond erythropoiesis, iron is a critical cofactor for numerous enzymes involved in the electron transport chain (cytochromes), DNA synthesis (ribonucleotide reductase), and detoxification (cytochrome P450 enzymes). Therapeutic iron administration aims to replete body stores, normalize serum ferritin levels, and support the increased demand for heme synthesis during the compensatory erythroid hyperplasia that follows anemia.

Vitamin B12 (Cobalamin)

Vitamin B12 functions as a coenzyme for two crucial enzymatic reactions in human metabolism. Its mechanism is intimately linked with folate metabolism.

• Methionine Synthase Reaction: Methylcobalamin serves as a cofactor for methionine synthase, which catalyzes the conversion of homocysteine to methionine. This reaction simultaneously regenerates tetrahydrofolate (THF) from methyltetrahydrofolate (5-methyl-THF). This is a critical step because the accumulation of 5-methyl-THF, due to B12 deficiency, leads to a functional folate deficiency known as the “methylfolate trap,” impairing DNA synthesis.
• Methylmalonyl-CoA Mutase Reaction: Adenosylcobalamin is a cofactor for methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA, an intermediate in the tricarboxylic acid (TCA) cycle. Deficiency in this pathway leads to the accumulation of methylmalonic acid, which may contribute to the neurological manifestations of B12 deficiency, including myelopathy and neuropathy.

The correction of vitamin B12 deficiency restores the activity of these enzymes, normalizing homocysteine and methylmalonic acid levels, resolving the megaloblastic hematopoiesis, and potentially halting or reversing neurological damage.

Folic Acid

Folic acid, after metabolic activation, acts as a carrier of one-carbon units in numerous biosynthetic reactions. Its primary pharmacodynamic role in hematopoiesis is to provide one-carbon moieties for the de novo synthesis of purines and thymidylate, which are essential precursors for DNA and RNA synthesis. Specifically, derivatives of tetrahydrofolate (THF) are involved in:

• The conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by thymidylate synthase, requiring 5,10-methylenetetrahydrofolate.
• The de novo synthesis of purine rings, where 10-formyl-THF contributes carbon atoms.

In folate deficiency, impaired DNA synthesis leads to slowed nuclear maturation while cytoplasmic development proceeds normally, resulting in large, immature erythroid precursors (megaloblasts) and macrocytic red cells. Folic acid administration is converted intracellularly to dihydrofolate (DHF) and then to the active cofactor THF by dihydrofolate reductase (DHFR), thereby replenishing the folate pool and restoring normal DNA synthesis and erythroid maturation.

4. Pharmacokinetics

Iron

Absorption: Iron absorption is a tightly regulated process occurring primarily in the duodenum and proximal jejunum. Heme iron from animal sources is absorbed more efficiently (15-35%) than non-heme inorganic iron (1-15%). For medicinal ferrous salts, absorption is influenced by luminal factors: ascorbic acid and gastric acid enhance reduction to Fe²⁺ and solubility, while phytates, phosphates, tannins (in tea), and antacids can form insoluble complexes, reducing absorption. The divalent metal transporter 1 (DMT1) mediates the uptake of ferrous iron across the apical enterocyte membrane. Intracellular iron is either stored as ferritin or exported into the circulation via ferroportin, a process facilitated by the oxidation of Fe²⁺ to Fe³⁺ by hephaestin and ceruloplasmin. Hepcidin, a liver-derived peptide hormone, is the master regulator of iron homeostasis; it binds to ferroportin, inducing its internalization and degradation, thereby inhibiting iron absorption and release from stores.

Distribution: In plasma, iron is bound to transferrin, which delivers it to bone marrow for hemoglobin synthesis or to storage sites (liver, spleen, bone marrow) where it is incorporated into ferritin. The total body iron is approximately 3-5 grams, with about two-thirds in hemoglobin, one-quarter in storage, and the remainder in myoglobin and enzymes.

Metabolism and Excretion: Iron has no specific excretory pathway. Minimal amounts are lost through sloughing of enterocytes, skin cells, and in urine and bile (≈1 mg/day). The primary route of elimination is through blood loss, such as menstruation. This lack of an active excretory mechanism underlies the risk of iron overload with excessive intake or repeated transfusions.

Pharmacokinetics of Parenteral Iron: Intravenous iron complexes are taken up by the reticuloendothelial system (RES), primarily in the liver and spleen. Iron is released from the carbohydrate shell within macrophages, enters the plasma transferrin pool, and is then distributed like endogenous iron. The half-life of the iron-carbohydrate complex itself is short (hours), but the released iron incorporates into body stores with a biological half-life of weeks to months. The maximum rate of iron utilization for erythropoiesis is approximately 40 mg/day.

Vitamin B12

Absorption: Vitamin B12 absorption is a complex, multi-step process requiring intact gastric, pancreatic, and ileal function. Dietary B12 is released from food proteins by gastric acid and pepsin. It then binds to R-binders (haptocorrins) from saliva. In the duodenum, pancreatic proteases degrade the R-binders, releasing B12 to bind with intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells. The B12-IF complex is resistant to digestion and travels to the distal ileum, where it binds to cubam receptors (cubilin and amnionless) on ileal enterocytes, mediating receptor-mediated endocytosis. Approximately 1-2% of an oral dose can be absorbed by passive diffusion across the entire intestinal mucosa, which is the basis for high-dose oral therapy in pernicious anemia. Following absorption, B12 is released into the portal blood bound to transcobalamin II (TCII), the delivery protein.

Distribution: Vitamin B12 is transported to tissues via the TCII receptor. The liver is the primary storage organ, holding several milligrams—enough to last 3-5 years even if absorption ceases completely. The total body store is 2-5 mg.

Metabolism and Excretion: Vitamin B12 undergoes intracellular conversion to its active coenzyme forms, methylcobalamin and adenosylcobalamin. It is excreted primarily in the bile, but most of this is reabsorbed via the enterohepatic circulation (≈3-8 µg/day). A small amount is lost in urine (≈0.1% of body stores per day). The plasma elimination half-life of injected cyanocobalamin is approximately 6 days, but the biological half-life from hepatic stores is much longer.

Folic Acid

Absorption: Dietary folates are polyglutamates that must be hydrolyzed to monoglutamates by the brush-border enzyme glutamate carboxypeptidase II (GCPII, also called folylpoly-γ-glutamate carboxypeptidase) prior to absorption. This occurs primarily in the proximal jejunum. Folic acid from supplements and fortified foods is already a monoglutamate and is absorbed directly via the proton-coupled folate transporter (PCFT) and the reduced folate carrier (RFC). At pharmacological doses (>400 µg), passive diffusion also becomes significant. Absorption is rapid and efficient, with bioavailability approaching 85-100% for folic acid on an empty stomach, compared to approximately 50% for food folates.

Distribution: Absorbed folates are reduced and methylated in the enterocyte to 5-methyl-THF, which is the primary form released into the portal circulation. Folates are widely distributed throughout body tissues. The liver contains about half of the total body stores of approximately 10-30 mg.

Metabolism and Excretion: Folic acid is a prodrug. It is reduced to DHF and then to THF by DHFR in a two-step, NADPH-dependent process. THF is then converted to various one-carbon substituted forms, including 5-methyl-THF. Folates are actively reabsorbed in the renal proximal tubule. Excess amounts are excreted unchanged in the urine, particularly after large intravenous doses. Significant amounts are also lost in bile but undergo enterohepatic recirculation. The half-life of folate in plasma is short (≈3 hours), but the turnover of body stores is slower; deficiency can develop within weeks to months on a folate-deficient diet due to limited storage capacity.

5. Therapeutic Uses/Clinical Applications

Iron

• Iron Deficiency Anemia (IDA): The principal indication. Oral ferrous salts are first-line. Parenteral iron is reserved for specific situations: intolerance or inadequate response to oral iron, malabsorption disorders (e.g., celiac disease, post-gastrectomy), chronic inflammatory bowel disease, chronic kidney disease (especially in patients on erythropoiesis-stimulating agents), heavy uterine bleeding where oral replacement is impractical, and during the late second or third trimester of pregnancy if severe anemia is present.
• Prophylaxis in High-Risk Groups: Routine supplementation is recommended during pregnancy (typically 27-30 mg elemental iron daily). It may also be considered in preterm infants, children with rapid growth, and individuals with chronic blood loss (e.g., menorrhagia).
• Heart Failure: Intravenous iron (e.g., ferric carboxymaltose) is indicated in patients with chronic heart failure and iron deficiency (with or without anemia) to improve exercise capacity and symptoms, as per recent clinical guidelines.

Vitamin B12

• Pernicious Anemia and Other Causes of B12 Deficiency: This includes autoimmune gastritis (destroying parietal cells and intrinsic factor), gastric surgery, ileal resection or disease (e.g., Crohn’s), and pancreatic insufficiency. Lifelong replacement is typically required for pernicious anemia.
• Megaloblastic Anemia due to B12 Deficiency: Treatment corrects the anemia and may prevent or partially reverse neurological complications (subacute combined degeneration of the spinal cord, peripheral neuropathy, cognitive changes).
• Nutritional Deficiency: Less common but seen in strict vegans who consume no animal products over many years.
• Prophylaxis: Following total gastrectomy or ileal resection.
• High-Dose Oral Therapy: An effective alternative to injections for dietary deficiency and even for pernicious anemia, utilizing the passive diffusion pathway (typical doses of 1000-2000 µg daily).

Folic Acid

• Megaloblastic Anemia due to Folate Deficiency: Causes include nutritional deficiency (alcoholism, poor diet), malabsorption (celiac disease, tropical sprue), increased demand (pregnancy, lactation, hemolytic anemias, exfoliative skin diseases), and drugs (methotrexate, phenytoin, trimethoprim).
• Neural Tube Defect (NTD) Prevention: Periconceptional folic acid supplementation (400-800 µg daily) significantly reduces the risk of NTDs (e.g., spina bifida, anencephaly). Higher doses (4-5 mg daily) are recommended for women with a previous NTD-affected pregnancy.
• Homocystinuria/Methotrexate Rescue: High-dose folic acid may lower homocysteine levels in some disorders. Folinic acid (leucovorin) is used to “rescue” normal cells from the folate-antagonist effects of methotrexate in cancer chemotherapy or to treat methotrexate overdose.
• Prophylaxis in Chronic Hemolytic Anemias: Conditions like sickle cell disease or hereditary spherocytosis have increased folate turnover, warranting daily supplementation (typically 1 mg).

6. Adverse Effects

Iron

Oral Iron: Gastrointestinal side effects are common and dose-related, including nausea, epigastric pain, constipation, diarrhea, and dark-colored stools. These effects often lead to poor adherence. Strategies to improve tolerance include dose reduction, taking with food (though this decreases absorption), or switching to a different salt (e.g., from sulfate to gluconate or fumarate, which have lower elemental iron content per tablet).

Parenteral Iron: Adverse reactions can be classified as:

• Hypersensitivity/Infusion Reactions: Symptoms range from mild (pruritus, flushing, arthralgias, myalgias, chest pain) to severe anaphylaxis. The risk varies among formulations, historically highest with high-molecular-weight iron dextran. Premedication with antihistamines or corticosteroids is not routinely recommended but may be considered in high-risk patients. A test dose is required for iron dextran.
• Physiologic Reactions: Self-limiting symptoms like headache, dizziness, nausea, and hypotension may occur, possibly related to the rate of infusion or free iron release.
• Long-Term Toxicity (Iron Overload): Repeated unnecessary parenteral dosing or hereditary hemochromatosis can lead to hemosiderosis, with iron deposition causing damage to the liver (cirrhosis), heart (cardiomyopathy), and endocrine glands (diabetes, hypogonadism).

Acute Iron Toxicity: Primarily a risk in pediatric accidental ingestion. Doses exceeding 20 mg/kg of elemental iron can cause severe gastroenteritis, hemorrhagic necrosis, metabolic acidosis, shock, and hepatic failure. Chelation therapy with deferoxamine is the treatment for systemic toxicity.

Vitamin B12

Vitamin B12 is generally considered extremely safe, even at high doses, due to its water-soluble nature and the body’s ability to excrete excess.

• Injection Site Reactions: Mild pain or erythema can occur with intramuscular or subcutaneous administration.
• Hypersensitivity: Rare allergic reactions to injectable formulations or to cobalt have been reported.
• Hypokalemia: A potential complication during the initial treatment of severe megaloblastic anemia. Rapid erythroid hyperplasia consumes potassium, which may require monitoring and supplementation.
• Acneiform Eruptions: Rarely reported with high-dose therapy.

There are no known black box warnings for vitamin B12.

Folic Acid

Folic acid is also very well-tolerated. Adverse effects are uncommon and usually mild.

• Gastrointestinal Disturbances: Nausea, anorexia, bloating, or flatulence may occur at high doses.
• Allergic Reactions: Rash, pruritus, and bronchospasm are rare.
• Neurological Effects: A major concern is the potential for folic acid to correct the hematological abnormalities of vitamin B12 deficiency while allowing the underlying neurological damage to progress unnoticed. This underscores the imperative to rule out B12 deficiency before initiating folic acid therapy for megaloblastic anemia.
• Potential Cancer Risk: Epidemiological studies have yielded conflicting data on whether high-dose folic acid supplementation might promote the growth of pre-existing colorectal neoplasia. This remains an area of investigation and caution.
• Interaction with Antiepileptic Drugs: Folic acid can reduce serum levels of phenytoin, carbamazepine, and phenobarbital, potentially leading to increased seizure frequency.

7. Drug Interactions

Iron

• Antacids, H2-Receptor Antagonists, Proton Pump Inhibitors: By increasing gastric pH, these agents reduce the solubility and conversion of ferric iron to the absorbable ferrous form, decreasing iron absorption.
• Tetracyclines, Bisphosphonates (e.g., alendronate), Levothyroxine, Mycophenolate Mofetil: Oral iron can form insoluble complexes with these drugs in the gastrointestinal tract, significantly impairing the absorption of both agents. Dosing should be separated by at least 2-4 hours.
• Quinolone Antibiotics (e.g., ciprofloxacin): Similar chelation interactions can occur, reducing antibiotic absorption and efficacy.
• Ascorbic Acid (Vitamin C): Enhances iron absorption by reducing ferric iron to ferrous iron and forming a soluble complex.
• Chloramphenicol: May delay the hematological response to iron therapy by inhibiting erythroid maturation.

Vitamin B12

• Metformin, Proton Pump Inhibitors, H2-Receptor Antagonists: Long-term use of these agents is associated with an increased risk of vitamin B12 deficiency, likely due to interference with calcium-dependent IF-B12 complex formation or alterations in gut flora. Monitoring of B12 status may be warranted.
• Aminoglycosides, Colchicine, Para-Aminosalicylic Acid, Slow-Release Potassium: These drugs may impair B12 absorption, potentially through mucosal damage or other mechanisms.
• Nitrous Oxide: This anesthetic gas oxidizes and inactivates the cobalt core of methylcobalamin, inhibiting methionine synthase. Acute or chronic exposure can precipitate or exacerbate B12 deficiency, leading to megaloblastic anemia or neurological dysfunction.

Folic Acid

• Antiepileptic Drugs (Phenytoin, Carbamazepine, Phenobarbital, Valproate): A bidirectional interaction exists. Antiepileptics can induce folate deficiency via multiple mechanisms. Conversely, folic acid supplementation can reduce serum concentrations of phenytoin, carbamazepine, and phenobarbital, potentially reducing seizure control. Valproate may also reduce folate levels.
• Methotrexate, Trimethoprim, Pyrimethamine: These drugs are folate antagonists. They inhibit dihydrofolate reductase (DHFR), blocking the conversion of folic acid to its active forms. High-dose folic acid or folinic acid may be used to counteract these effects in specific clinical protocols (e.g., methotrexate rescue).
• Sulfasalazine: Inhibits the absorption and cellular uptake of folates, potentially leading to deficiency.
• Oral Contraceptives: Early studies suggested a link with lowered folate levels, but the clinical significance is likely minimal with modern low-dose formulations.

8. Special Considerations

Pregnancy and Lactation

Iron: Supplementation is almost universally recommended during pregnancy (27-30 mg elemental iron daily) to meet increased maternal and fetal demands and prevent deficiency. Intravenous iron may be used in the second or third trimester for severe, refractory IDA. Iron is excreted in breast milk, but the concentration is not significantly increased by maternal supplementation.

Vitamin B12: Deficiency during pregnancy is associated with adverse outcomes, including neural tube defects and developmental delay. Vegan and vegetarian mothers are at particular risk. Supplementation is safe and recommended for deficient mothers. B12 is present in breast milk, and adequate maternal intake ensures sufficient levels for the infant.

Folic Acid: Periconceptional supplementation (starting at least one month before conception) with 400-800 µg daily is a standard public health recommendation to prevent neural tube defects. Higher doses (4-5 mg daily) are used in high-risk pregnancies. Folic acid is considered safe during lactation.

Pediatric Considerations

Iron: Full-term infants are born with adequate stores for 4-6 months. Supplementation for breastfed infants may begin at 4 months. Preterm infants often require earlier and more aggressive supplementation. Liquid formulations are used, but care must be taken to prevent accidental overdose, which can be fatal. Dosing is typically 2-6 mg/kg/day of elemental iron.

Vitamin B12: Deficiency in infants, while rare, is serious and usually results from maternal deficiency (e.g., in vegan mothers) or an inborn error of metabolism. It presents with failure to thrive, developmental regression, and megaloblastic anemia. Prompt diagnosis and treatment are critical to prevent permanent neurological damage.

Folic Acid: Supplementation in children is generally only indicated for documented deficiency, certain hemolytic anemias, or during treatment with antifolate drugs. Dosing is weight-based.

Geriatric Considerations

Elderly patients are at increased risk for all hematinic deficiencies due to factors like poor nutrition, atrophic gastritis (affecting both iron and B12 absorption), polypharmacy, and chronic diseases. A high index of suspicion is required. The presentation of B12 deficiency may be predominantly neurological or cognitive (pseudo-dementia). Careful dosing of oral iron is needed due to increased susceptibility to GI side effects and constipation.

Renal Impairment

Iron: Patients with chronic kidney disease (CKD), especially those on dialysis, frequently have functional iron deficiency due to inflammation and elevated hepcidin. Intravenous iron is a mainstay of therapy, often co-administered with erythropoiesis-stimulating agents. Dosing schedules vary; some formulations are approved for use in CKD. Iron overload is a concern with long-term use.

Vitamin B12 and Folic Acid: These are water-soluble and removed by dialysis. Patients on hemodialysis often require supplementation. High-dose folic acid is sometimes used to lower homocysteine levels, though the clinical benefit on cardiovascular outcomes remains unproven.

Hepatic Impairment

Severe liver disease can affect the metabolism and storage of hematinics. Iron overload disorders (hemochromatosis) directly cause hepatic damage. Vitamin B12 and folate stores are primarily hepatic, so liver disease may alter their kinetics. No specific dose adjustments are routinely recommended, but monitoring is prudent.

9. Summary/Key Points

• Hematinics (iron, vitamin B12, folic acid) are essential for DNA synthesis and hemoglobin production. Deficiencies lead to microcytic (iron) or macrocytic (B12/folate) anemias, with B12 deficiency also causing potentially irreversible neurological damage.
• Iron absorption is tightly regulated by hepcidin via ferroportin. Oral ferrous salts are first-line for IDA; parenteral iron is used for intolerance, malabsorption, or rapid correction. GI upset is common with oral therapy, while parenteral iron carries a risk of hypersensitivity.
• Vitamin B12 absorption requires intrinsic factor and ileal receptors. Deficiency most commonly results from pernicious anemia or malabsorption. Treatment involves intramuscular injections or high-dose oral supplements. It is extremely safe.
• Folic acid is absorbed in the proximal small intestine and activated by DHFR. Its primary uses are treating folate deficiency anemia and preventing neural tube defects. It can mask the hematological signs of B12 deficiency.
• Significant drug interactions exist, particularly for oral iron (which chelates many drugs) and folic acid (which interacts with antiepileptics and antifolates).
• Special populations require attention: routine iron and folic acid in pregnancy, vigilance for B12 deficiency in the elderly and vegans, and aggressive IV iron management in CKD.

Clinical Pearls

• Anemia should be fully characterized (mean corpuscular volume, reticulocyte count, iron studies, B12/folate levels) before initiating hematinic therapy to ensure correct treatment.
• A lack of response to oral iron may indicate non-adherence (often due to GI side effects), continued blood loss, malabsorption, incorrect diagnosis (e.g., anemia of chronic disease), or concomitant B12/folate deficiency.
• Neurological symptoms in the setting of macrocytic anemia should raise strong suspicion for B12 deficiency over folate deficiency. Always measure B12 and methylmalonic acid/homocysteine levels before giving folic acid.
• For pernicious anemia, high-dose oral cyanocobalamin (1000-2000 µg daily) is as effective as monthly injections and may be preferred by patients, provided adherence is assured.
• The goal of iron therapy is not only to correct hemoglobin but also to replete stores (ferritin >50 µg/L). Continue oral iron for 3-6 months after hemoglobin normalizes.

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