Yellow to orange, crystalline powder; odourless or almost odourless. Practically insoluble in cold water, ethanol, and most organic solvents. Soluble in dilute acids and in alkaline solutions, and boiling water (to 1 g/100 mL). Chemically, it is pteroylglutamic acid, N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl]-L-glutamic acid. The chemical structure is shown below.

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Folic acid deficiency is defined by WHO as serum folate levels below 3 ng/mL or red cell folate levels below 100 ng/mL. Deficiency may be due to inadequate dietary intake, malabsorption, or increased utilisation of folic acid. Dietary intake may be inadequate in infants fed solely on goat's milk or when diet is poor, particularly when it is low in vegetable constituents. Folates in food are largely present in the form of polyglutamates which are hydrolysed enzymatically at the gastrointestinal mucosa to folic acid. Conditions in which folate utilisation is increased include: pregnancy and lactation; haemolytic anaemia; hyperthyroidism; exfoliative dermatitis; and chronic infection.

Pharmacology

Folic acid is reduced in the body to a number of compounds including tetrahydrofolic acid. In the reduced form, it acts as a coenzyme for various metabolic processes. It is necessary for the synthesis of purine and pyrimidine nucleotides and hence DNA synthesis, and is involved in some amino acid conversions. The maturation of all rapidly proliferating tissues, in particular the bone marrow and the gastrointestinal tract, require folic acid. Folate deficiency leads to megaloblastic anaemia.

Pharmacokinetics

Folic acid is absorbed from the upper gastrointestinal tract. It is generally well absorbed; however, absorption is decreased in chronic alcoholics, in malabsorptive diseases such as tropical and coeliac sprue, in patients with systemic bacterial infection, in patients receiving diphenylhydantoin, and following procedures such as gastrectomy and upper intestinal resection. Folic acid is rapidly metabolised primarily to 5-methyltetrahydrofolate with some 10-formylfolate and some 10-formyltetrahydrofolate formed. It is stored in tissues, especially the liver, predominantly as methylated polyglutamates. 5-methyltetrahydrofolate is also secreted in bile. Enterohepatic recycling of folate may provide as much as 200 g or more folate each day for recirculation to the tissues. Folic acid and 5-methyltetrahydrofolate cross the placenta and accumulate in the foetal liver. 5-methyltetrahydrofolate is also actively transported into the cerebrospinal fluid. Folic acid is excreted in urine unchanged and as a number of metabolites (including 5-methyltetrahydrofolate and pterins). Folic acid is also excreted in faeces.

Indications

Treatment of megaloblastic anaemia due to a deficiency of folic acid; prophylaxis during pregnancy and lactation.

Contraindications

Megaloblastic anaemia due to vitamin B12 deficiency should not be treated with folic acid as the haematological features of vitamin B12 deficiency may be corrected with folic acid but the neurological effects will not be alleviated and may become irreversible.

Warnings

Vitamin B12 deficiency needs to be excluded before folic acid is prescribed (see Contraindications). Large doses of folic acid may counteract the anti-epileptic effect of diphenylhydantoin. Patients receiving diphenylhydantoin treatment should be monitored for possible loss of seizure control following large doses of folic acid. Folic acid does not correct folate deficiency due to dihydrofolate reductase inhibitors (see Interactions). Folinic acid should be used for this purpose.

Folic acid, 5-methyltetrahydrofolate and 10-formyltetrahydrofolate are excreted in breast milk. Therapeutic indications include supplementation in lactating or pregnant women when they are folic acid deficient.

Interactions

Methotrexate has a high affinity for mammalian dihydrofolate reductase and therefore inhibits the reduction of folic acid to tetrahydrofolate. Trimethoprim and pyrimethamine are more selective inhibitors of microbial dihydrofolate reductase: the concentrations required to inhibit the mammalian enzyme are 10,000 to 50,000 times greater than the concentrations required to inhibit the microbial enzyme for trimethoprim and 1,400 times greater for pyrimethamine. Sulphasalazine has been reported to depress folate absorption.

Adverse Reactions

Folic acid is usually well tolerated in humans; however, gastrointestinal disturbances and CNS effects have occasionally been reported following high doses (incidence of less than 1% at dose of 15 mg/day), and isolated reports of allergic sensitivity reactions including bronchospasm and rash have been documented.

Dosage and Administration

1 to 5 mg daily, according to the severity of anaemia and the presence/ absence of malabsorption syndromes.

Composition

Description