Folic Acid
Folic acid
Generic Name
Folic acid
Mechanism
- Enzyme cofactor: Acts as a cofactor for *methylenetetrahydrofolate reductase* (MTHFR) and *dihydrofolate reductase* (DHFR), facilitating conversion of 5,10‑methylenetetrahydrofolate to 5‑methyltetrahydrofolate, the methyl donor for homocysteine remethylation to methionine.
- Nucleic‑acid synthesis: Provides one‑carbon units for the synthesis of *deoxyguanosine monophosphate* (dTMP) and *thymidine triphosphate* (TTP), thus supporting DNA synthesis and cell proliferation.
- Protection of red‑blood‑cell membranes: Maintains phospholipid integrity, reducing risk of megaloblastic anemia.
- Neural‑tube defect (NTD) prevention: Adequate folate levels reduce the likelihood of NTDs by ensuring proper cell division and DNA synthesis during embryogenesis.
Pharmacokinetics
| Parameter | Details |
| Absorption | Rapid, *~90 %* oral bioavailability; uptake via active *folate receptor‑mediated* and passive diffusion; saturation (> 400 µg) may limit absorption. |
| Distribution | Widely distributed; crosses the blood‑brain, placental, and fetal membranes; stores mainly in the liver, kidneys, and bone marrow. |
| Metabolism | Converted to 5‑methyltetrahydrofolate via DHFR; further metabolized by *MTHFR* to active forms. |
| Elimination | Renal excretion unchanged; half‑life *≈ 1–2 h* in healthy adults; prolonged in renal impairment. |
Indications
- Prevention of neural‑tube defects in women of childbearing age (≥ 400 µg/day).
- Treatment of folate‑deficiency anemia (megaloblastic anemia, leukopenia) and *folinic acid‑reversible* megaloblastic changes.
- Adjunctive therapy with *methotrexate* (cancer, rheumatoid arthritis) to reduce mucositis and hepatotoxicity.
- Homocysteine lowering in cardiovascular risk management (≥ 5 mg/day).
- Management of inherited folate‑responsive disorders such as *pyruvate kinase deficiency* and *MTHFR deficiency*.
Contraindications
- Allergy to synthetic folic acid or other B‑vitamins.
- Undiagnosed macrocytic anemia – *rule out B12 deficiency* before initiating therapy.
- Known deficiency of *methionine synthase* or *MTHFR* – monitor for poor response.
- Active folate‑dependent malignancies – high doses may promote tumor proliferation; use cautiously.
- Renal impairment – dose adjustment may be needed; monitor for accumulation.
*Warnings:*
• Large doses may mask *vitamin B12 deficiency* → neurologic damage.
• High folate intake (> 1000 µg/day) may obscure diagnosis of *methylmalonic aciduria*.
• Potential interaction with *anticonvulsants* (e.g., phenytoin) reducing bioavailability.
Dosing
| Situation | Dose & Regimen | Notes |
| Supplementation for healthy adults | 400 µg orally once daily | Equivalent to one prenatal capsule. |
| Pregnancy (first trimester) | 400 µg–800 µg orally daily | Start preconception. |
| NTD prophylaxis | 5 mg orally daily (high‑dose) | For high‑risk patients (prior NTD pregnancy, *folate‑responsive* conditions). |
| Folate‑deficiency anemia | 1–2 mg orally daily or 5–10 mg IV every 3–7 days (as needed) | Once adequate RBC indices achieved, taper to 400 µg. |
| Methotrexate rescue | 5–10 mg orally or IV 24 h after MTX | Administer >24 h post‑MTX to avoid renal toxicity. |
| Renal impairment (CrCl < 30 ml/min) | 2–5 mg orally daily | Observe for accumulation. |
• Route: Oral (tablet, capsule, or liquid); IV for non‑absorptive patients.
• Timing: With or without food; absorption unchanged.
• Duration: Short‑term for deficiency; lifetime for pregnancy prevention.
Adverse Effects
| Category | Frequency | Comments |
| Gastrointestinal | Mild upset, nausea | Dose splitting can mitigate. |
| Dermatologic | Rash, pruritus | Rare, often idiosyncratic. |
| Headache | 5–10 % | May improve with dose adjustment. |
| Allergic reactions | ≤ 1 % | Anaphylaxis rare; severe reactions require prompt discontinuation. |
| Neurologic | Rare (B12 mask)* | Monitor neuro‑status in deficient patients. |
| Serious | • Hemorrhagic stroke (high dose, MTHFR variant), < 0.01 % | Vigilant in high‑risk cardiovascular patients. |
| Miscellaneous | • Hypercalcemia (rare in patients with hyperparathyroidism) | Monitor electrolytes if symptomatic. |
*Adverse effects are rarely dose‑related; most are mediated by masking B12 deficiency or folate‑responsive pathologies.*
Monitoring
- CBC with differential & *reticulocyte count* – assess for macrocytosis, anemia resolution.
- Serum folate & homocysteine – target ≥ 5 ng/mL (folate) & Frequency: CBC every 4–6 weeks until stability; folate/homocysteine every 3–6 months; B12 annually if risk factors present.
Clinical Pearls
- Pregnancy‑prep: Women planning pregnancy should begin 400 µg folic acid at least one month preconception; high‑risk groups *may need 5 mg* to achieve optimal serum levels.
- Methotrexate rescue window: Administer folic acid ≥ 24 h after methotrexate to avoid competitive inhibition of DHFR and hepatotoxicity.
- Differential diagnosis: A patient with macrocytic anemia and neurological deficits may still have B12 deficiency; do not rely solely on folic acid response.
- High‑dose cautions: When using 5 mg/day for NTD prophylaxis, confirm that renal function is normal, as folic acid accumulates in CKD.
- Supplement interactions: Phenytoin, carbamazepine, and other enzyme inducers can lower folate levels; consider higher doses (~1–2 mg/day) in these patients.
- Storage note: Folic acid tablets should be stored at room temperature; avoid exposure to high heat and moisture which can degrade potency.
- Insurance & compliance: Prenatal vitamins are often covered; patients may prefer single‑pill regimens to improve adherence.
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• Key references:
1. National Institutes of Health Office of Dietary Supplements—Folate Fact Sheet.
2. UpToDate: “Folate supplementation in obstetric patients.”
3. Lexicomp Drug Information—Folic Acid.
4. WHO: “Global guidelines on folic acid supplementation.”