Folic acid

Biochemical Action of Folic Acid:

Folic acid, belonging to the supplement class of water-soluble vitamins, acts as a precursor in coenzyme A (CoA) production, which is crucial for several metabolic processes affecting neurotransmitter synthesis, intermediate metabolism, and cell development.

The synthetic form of folic acid undergoes several transformations before the body can utilise it. Dihydrofolate reductase transforms NADPH from dihydrofolate (DHF) to tetrahydrofolate (THF). The resulting compound is 5-10-methylenetetrahydrofolate (MTHF). This 5-10-MTHF has two potential directions: towards the production of DNA or methionine. Methionine is produced when folate lowers homocysteine levels by giving the MTHFR enzyme a methyl group, forming 5-methyl THF. Methionine synthase provides the remaining methyl group from 5-methyl THF to homocysteine, turning it into methionine. This keeps the cycle continuing by generating THF.

Amino acid metabolism: Folic acid plays a role in the process known as remethylation, which turns homocysteine into methionine. Methionine is essential for DNA methylation and protein synthesis.

DNA methylation: Folic acid facilitates the transfer of methyl groups to DNA molecules, which controls the expression of genes and other epigenetic processes.

Neurotransmitter synthesis: Neurotransmitters such as serotonin, dopamine, and norepinephrine are essential for mental health and mood regulation and are produced predominantly by folic acid.

Onset: PO, 0.5-1 hr

Folic acid is available in the form of tablets and injection solutions.

• Tablets are to be swallowed whole with water/liquid, as applicable.
• Injectable solutions are to be administered parenterally, as applicable.

Folic acid can be used as a supplement to support various biological functions.

• Folic acid is used as a supplement in the prevention and treatment of folate deficiency anemia.
• As a prenatal supplement to protect against neural tube abnormalities in the growing foetus.
• As a supplement to support the treatment of individuals with malabsorption disorders or those using drugs that inhibit the absorption of folate.
• Supplementing with folic acid to meet the increased need for folate in people with certain medical disorders or who are undergoing fast cell division (such as during chemotherapy).

Folic acid may be useful as a supplement for the following health benefits

• Prevention and treatment of deficiency: Folic acid supplements are used to treat or prevent deficits in patients at risk, such as those with malabsorption issues or using medications that block folate, such as macrocytic anemia. Even in the presence of malabsorption, increased oral intake remains effective.
• Preconception and during pregnancy: Neural tube abnormalities (NTD) in newborns are at risk due to inadequate folate intake in the early stages of pregnancy. Increased folate intake reduces the risk of miscarriage, enhances fetal development and birth weight, and may even lessen some of the adverse effects of maternal smoking on neonatal outcomes.
• OCP-induced folate deficiency: With prolonged use of oral contraceptive pills (OCP) (>5 years), serum folate levels gradually decrease, raising concerns related to cognition, mood, anemia, and the risk of NTDs after discontinuation.
• Hyperhomocysteinaemia: Folic acid has been demonstrated to lower high plasma levels of homocysteine (Hcy) when combined with vitamins B12 and B6.
• Bone health and fracture risk: Osteoporotic fracture risk is correlated with high homocysteine (Hcy) levels. Despite decreasing Hcy, the response rate to folate treatment in osteoporotic patients may be as low as 2%.
• Cardiovascular protection and treatment: Patients with CVD who received folic acid supplements had a 10% lower risk of stroke and a 4% lower risk of total CVD. Lower plasma folate levels, no prior CVD, and higher reductions in homocysteine levels were associated with greater benefits.
• Alzheimer’s dementia and impaired cognitive function in the elderly: Age-related rises in Hcy levels, an adverse association between Hcy levels and cognitive function, and the prevalence of folate shortage in the elderly have caused concern about correlating these phenomena to neurodegenerative diseases.
• Diabetes mellitus: Supplemental folic acid does not affect inflammation-related indicators, however, it can improve endothelial dysfunction in type 2 diabetics without lowering homocysteine levels.
• Methotrexate therapy: Patients treated with methotrexate should be prescribed folic acid supplements to reduce the adverse events associated with methotrexate therapy.

• Orally: All oral solid forms of folic acid are often taken before or after meals.
• Parenterally: The injectable solution of folic acid is administered intravenously, intramuscularly, or subcutaneously.

The dosage and duration of treatment should be as per the clinical judgment of the treating healthcare professional.

Vitamins and natural supplements should not replace a balanced diet

This product is not intended to diagnose, treat or prevent any disease(s).

Folic acid tablets are available in various strengths, such as

• Tablet: 400mcg, 800mcg, 1mg
• Injectable solution: 5mg/mL

Dosage Adjustment in Adult Patients

Neural Tube Defects Prophylaxis

Females of childbearing age should take 400 mcg/day orally.

Pregnant women: 600 mcg/day orally

Females with high risk or family history of neural tube defects: 4 mg/day orally

Folic Acid Deficiency

0.4 to 1 mg PO/IV/IM/SC once daily

Methanol Toxicity

50 to 75 mg IV every 4 hours for 24 hr

Methotrexate Toxicity Prophylaxis (Off-label)

1 mg orally qDay but may increase up to 5 mg/day if toxicity occurs.

Folic acid is available in the form of tablets and injectable solutions.

It is sometimes sold in combination with other water-soluble multivitamins.

• Limit the consumption of drinks that include caffeine, such as coffee, tea, chocolate, and alcoholic beverages, as this substance could hinder the absorption of folic acid.
• Avoid the consumption of foods that are high in fat or cholesterol for effective folic acid absorption.
• Stay within your daily calorie needs.
• Avoid spicy foods.

The dietary restriction should be individualized as per patient requirements

Recommended Daily Allowance (RDA)

The RDA for both men and women is 400 μg/day of dietary folate equivalents.

Upper Tolerable Intake (UTL):

The UTL for adults, exclusive of dietary folate is 1,000 g/day of folate with fortified foods or as a supplement.

• Folic acid administration may be contraindicated by an individual's hypersensitivity to the substance or its formulation.
• By treating macrocytic anaemia and slowing the onset of neurological impairment, the use of folate supplements may mask a B12 deficient condition. It is advised that patients undergo screening for vitamin B12 deficiency.
• Folic acid supplementation at high doses may trigger an increase in seizure frequency in individuals with epilepsy.
• Benzyl alcohol is used as a preservative in the injection. Gasping syndrome in newborns is known to be linked to benzoyl alcohol.

The treating healthcare must closely keep a watch and monitor for signs and symptoms like any changes in behaviour or mood as well as prolonged nausea, vomiting, or stomach discomfort.

Folic acid should be used with caution, in case of allergic reactions, breathing problems, or severe dizziness.

Numbness, tingling, or weakness are symptoms of a vitamin B12 shortage that need to be accurately monitored as folic acid can mask the symptoms while leaving the underlying B12 deficiency untreated, potentially leading to neurological damage. If you are taking any additional drugs, let the doctor know and follow the dosage instructions.

Caution is advised when consuming alcohol with folic acid.

Safe to use during breastfeeding. Several studies suggest that the drug does not pass into the breastmilk significantly and is not harmful to the baby.

Folic acid is safe to use during pregnancy.

Folic acid supplementation is generally well-tolerated and safe.

The adverse reactions related to folic acid can be categorized as-

• Common: Nausea, bloating, bitter taste in the mouth, irritability and gas.
• Less Common: Skin reactions, sleep disturbances, and confusion.
• Rare: Generalised urticaria associated with an allergic response, allergic reactions, respiratory issues, and seizures.

• Antacids: Separate dosages by 1-2 hours to decrease the absorption of folic acid.
• Anticonvulsants (phenytoin): Long-term use typically results in decreased folate levels, however, macrocytic anaemia is uncommon. Although medical monitoring is required, supplementation can lower toxicity, which is a favourable interaction.
• Cholestyramine (e.g. Questran): Reduced folate absorption: monitor for signs and symptoms of folate deficiency in the patient, and separate doses by at least 4 hours.
• Gastric acid inhibitors (proton-pump inhibitors): Reduced folic acid absorption — separate doses by 2–3 hours.
• Methotrexate:The medication methotrexate acts as a folate antagonist. Folate supplementation can decrease toxicity, which is a positive interaction; nevertheless, it may lessen methotrexate's effectiveness, hence physicians strongly recommend avoiding its use.
• Oral contraceptives: Increased intakes may be required for women who use OCP long-term since they cause decreased folate levels, especially in those with high oestrogen concentrations.
• Pyrimethamine (e.g.maloprim): Impairs the use of folate and, as such, supplementation with folinic acid may be beneficial.
• Sulfasalazine: Folic acid can reduce drug absorption — separate doses by 2–3 hours.
• Trimethoprim: The medicine trimethoprim works as a folate antagonist. The positive combination of supplementation can lower toxicity; medical monitoring is indicated.
• Zinc: At high doses (>15 mg/day), minor zinc depletion may develop— observe patients for signs and symptoms of zinc deficiency.

The common side effects associated with folic acid include:

• Nausea
• Headache
• Dizziness
• Loss of appetite
• Bloating
• Stomach pain
• Bitter or unpleasant taste in your mouth.
• Sleep disturbances:
• Skin reactions (rash, itching, hives)

The use of folic acid should be prudent in the following group of special populations

• Pregnancy: Folic acid is considered safe in pregnancy.

The RDA of folic acid in pregnant women is 600 mcg/day PO.

Pregnancy category: A; Safe during pregnancy.

• Paediatrics:

Folic acid is vital for neural myelination, brain development, and cognitive function.

The recommended daily intake of folic acid ranges from 65-400 mcg/day PO.

Dosage Adjustment for Paediatric Patients

Folic Acid Deficiency

Infants: 15 mcg/kg/day or 50 mcg/day IV/PO/IM/SC

1 to 10 years: 1 mg/day IV/PO/IM/SC initially, then 0.1 to 0.4 mg/day

Methanol Toxicity

1 mg/kg IV every 4hr for 24 hr

• Geriatrics: There is no sufficient scientific evidence traceable regarding the use and safety of folic acid for use in special populations

• Lactating mothers:

Folic acid enters the breastmilk and is not expected to cause any harm to a breastfed child.

The recommended daily intake for lactating mothers is 500 mcg/day PO.

There is no sufficient scientific evidence traceable regarding the use and safety of folic acid for use in special populations.

Dosage Adjustment in Kidney Impairment

There are no specific dosage adjustments provided.

Dosage Adjustment in Hepatic Impairment

There are no specific dosage adjustments provided.

Overdosage of folic acid supplements is very rare because large doses are excreted in the urine. On extremely high doses may show nausea, diarrhoea, abdominal cramps, and sleep disturbances. Long-term high doses can mask vitamin B12 deficiency and may lead to nerve damage.

There is no specific treatment that is recommended in the event of an overdose. When an overdose is suspected, folic acid should be terminated immediately. Supportive treatment should also be given, along with addressing any symptoms that persist or worsen. Physical treatment might be added if necessary.

Biochemistry action of Folic Acid:

The body's different biochemical processes depend heavily on folic acid, often known as vitamin B9. After consumption, enzymatic processes transform it into 5-methyltetrahydrofolate, which is the active form. For DNA synthesis, repair, and cell division, this active form functions as a coenzyme and takes part in one-carbon transfer processes. Folic acid is essential for the synthesis of amino acids, nucleotides (the building blocks of DNA and RNA), and other biomolecules. It lowers the risk of cardiovascular illnesses by assisting in red blood cell production and homocysteine metabolism. Folic acid is also necessary for foetal development to occur normally throughout pregnancy. Maintaining adequate folic acid levels is important since a deficit can result in megaloblastic anaemia, birth abnormalities, and other health problems.

Kinetic profile of Folic Acid:

• Absorption: Folic acid is largely absorbed in the proximal part of the small intestine through a carrier-mediated process, involving the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT).
• Distribution: After absorption, folic acid is carried in the circulation where it interacts with plasma proteins including albumin and folate-binding proteins to be distributed throughout various physiological tissues and cells.
• Metabolism: Through a sequence of biochemical processes occurring inside the cells, folic acid is transformed into its active form, 5-methyltetrahydrofolate (5-MTHF). This active form acts as a cofactor in one-carbon transfer reactions required for DNA methylation, amino acid metabolism, and nucleotide synthesis.
• Excretion: As a water-soluble vitamin, the majority of excess folic acid is excreted in the urine via the kidneys. During the excretion process, folic acid may also be expelled in the faeces.

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2. https://ods.od.nih.gov/factsheets/Folate-Consumer/
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