folic acid good one a 2 z
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One of the good knowledge regarding Folic Acid(Vitamine).TRANSCRIPT
Folic Acid
1. NAME
1.1 Substance
1.2 Group
1.3 Synonyms
1.4 Identification Numbers
1.4.1 CAS number
1.4.2 Other numbers
1.5 Brand Names, Trade Names
1.6 Manufacturers, Importers
1.7 Presentation, Formulation
2. SUMMARY
2.1 Main risks and target organs
2.2 Summary of clinical effects
2.3 Diagnosis
2.4 First aid and management principles
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
3.2 Chemical structure
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
3.3.1.2 State/Form
3.3.1.3 Description
3.3.2 Properties of the locally available formulation(s)
3.4 Other characteristics
3.4.1 Shelf-life of the substance
3.4.2 Shelf-life of the locally available formulation(s)
3.4.3 Storage conditions
3.4.4 Bioavailability
3.4.5 Specific properties and composition
4. USES
4.1 Indications
4.1.1 Indications
4.1.2 Description
4.2 Therapeutic dosage
4.2.1 Adults
4.2.2 Children
4.3 Contraindications
5. ROUTES OF ENTRY
5.1 Oral
5.2 Inhalation
5.3 Dermal
5.4 Eye
5.5 Parenteral
5.6 Other
6. KINETICS
6.1 Absorption by route of exposure
6.2 Distribution by route of exposure
6.3 Biological half-life by route of exposure
6.4 Metabolism
6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
7.1.2 Pharmacodynamics
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
7.2.1.2 Children
7.2.2 Relevant animal data
7.2.3 Relevant in vitro data
7.3 Carcinogenicity
7.4 Teratogenicity
7.5 Mutagenicity
7.6 Interactions
7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Sample
8.1.1 Collection
8.1.2 Storage
8.1.3 Transport
8.2 Toxicological analytical methods
8.2.1 Assay for folic acid may be found in the USP XXII, 1990.
8.2.2 Test for biological sample
8.3 Biochemical investigations
8.3.1 Blood
8.3.2 Urine
8.3.3 Others
8.4 Interpretation
8.5 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
9.1.2 Inhalation
9.1.3 Skin exposure
9.1.4 Eye contact
9.1.5 Parenteral exposure
9.2 Chronic Poisoning
9.2.1 Ingestion
9.2.2 Inhalation
9.2.3 Skin exposure
9.2.4 Eye contact
9.2.5 Parenteral exposure
9.3. Course, prognosis, cause of death
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
9.4.2 Respiratory
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
9.4.3.2 Peripheral nervous system
9.4.3.3 Autonomic nervous system
9.4.3.4 Skeletal and smooth muscle
9.4.4 Gastrointestinal
9.4.5 Hepatic
9.4.6 Urinary
9.4.6.1 Renal
9.4.6.2 Other
9.4.7 Endocrine and reproductive systems
9.4.8 Dermatological
9.4.9 Ear, nose and throat: local effects
9.4.10 Hematological
9.4.11 Immunological
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
9.4.12.2 Fluid and electrolyte disturbances
9.4.12.3 Others
9.4.13 Allergic reaction
9.4.14 Other clinical effects
9.4.15 Special risks
9.5 Other
9.6 Summary
10. MANAGEMENT
10.1 General principles
10.2 Relevant laboratory analyses
10.2.1 Sample collection
10.2.2 Biomedical analysis
10.2.3 Toxicological analysis
10.2.4 Other investigations
10.3 Life supportive procedures and symptomatic/specific treatment
10.4 Decontamination
10.5 Elimination
10.6 Antidote treatment
10.6.1 Adults
10.6.2 Children
10.7 Management discussion
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
11.2 Internally extracted data on cases
11.3 Internal cases
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
12.2 Specific preventive measures
12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
1. NAME
1.1 Substance
Folic Acid (INN)
(WHO, 1992)
1.2 Group
ATC classification index
Antianaemic preparations (B03)/Vitamin B12 and folic acid (B03B)/Folic acid and derivatives (B03BB).
(WHO, 1992)
1.3 Synonyms
Acidum Folicum; Folacin; PGA; Pteroylglutamic Acid; Pteroylmonoglutamic Acid; Wills' factor; Vitamin M; liver Lactobacillus casei factor; Folsaure.
(Reynolds, 1993; Budavari, 1989)
(To be completed by each Centre using local data)
1.4 Identification Numbers
1.4.1 CAS number
Folic acid 59-30-3
Sodium folate 6484-89-5
1.4.2 Other numbers
RTECS
LP5425000
1.5 Brand Names, Trade Names
Acfol (Torlan, Spain), Folacid (Netherlands), Folaemin (Netherlands), Folasic (Nelson, Australia), Foldine (France), Folettes (Australia), Folicid (USV, Australia), Folico (Ecobi, Italy), Folina (Tosi, Italy), Folsan (Kali-Chemie, Germany), Folvite (Lederle, Canada)(Lederle, Switzerland)(Lederle, USA), Lexpec (R.P. Drugs, United Kingdom), Nifolin (Denmark), Nivofolacid (Novopharm, Canada), Speciafoldine (Specia, France)
Combination Preparations; Fefol-Ferrous sulfate USP and folic acid (SKF, Philippines), Ferro-Folsan-Ferrous sulfate, succinic acid, folic acid (Phil.), Iberet-Folic-500-Iron,
Vitamin C, Vitamin B Complex, Folic Acid (Philippines).
(To be completed by each Centre using local data)
1.6 Manufacturers, Importers
To be completed by each Centre using local data.
1.7 Presentation, Formulation
Oral
Folic acid tablets (monocomponent) or in combination with other vitamins and minerals. Strengths usually available are 100 mcg, 250 mcg, 400 mcg, 800 mcg, 1 mg and 5 mg.
Syrup 2.5 mg/5 mL
Parenteral
Folate sodium injection; strength usually available is equivalent of folic acid 5 mg/mL
(To be completed by each Centre using local data)
2. SUMMARY
2.1 Main risks and target organs
Folic acid is relatively non-toxic. However, there have been reports of reactions to parenteral injections. Allergic reactions to folic acid have been rarely reported.
2.2 Summary of clinical effects
Severe allergic reactions are characterized by hypotension, shock, bronchospasm, nausea, vomiting, rash, erythema. Itching may also occur.
Adverse gastrointestinal and central nervous system effects have been reported.
Treatment with folic acid is usually well tolerated except for rare reports of allergic reactions.
2.3 Diagnosis
Clinical, haematological and analytical aspects to be addressed. No clinical signs and symptoms are typical for folic acid overdose. Diagnosis should be based on listing and circumstantial evidence.
2.4 First aid and management principles
In case of massive overdose, gastric lavage or induced vomiting could be considered, if seen within 1 to 2 hours after ingestion. Repeat dose activated charcoal to be given, followed by supportive treatment. In case of anaphylaxis, treatment with epinephrine (adrenaline) and support of vital functions should be provided.
For adverse reactions not related to overdose, withdraw drug and provide symptomatic and supportive therapy.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Folic acid was isolated in 1941 by Mitchell and co-workers from green leafy vegetables, liver, yeast and fruits. Synthetic folic acid is commercially available.
3.2 Chemical structure
Structural formula
Molecular formula
C19H19O6
Molecular weight
441.4
Chemical names
N-[4(2-Amino-4-hydroxypteridin-6-ylmethylamino)benzoyl]-L(+)- glutamic acid.
N-{4-[[(2-Amino-1,4-dihihydro-4-oxo-6- pteridinyl)methyl]amino]benzoyl}-L-glutamic acid.
N-{p-[[2-amino-4-hydroxy-6-pteridinyl)methyl]amino]benzoyl}-
glutamic acid.
(Reynolds, 1993; Budavari, 1989)
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
Yellow to orange brown
3.3.1.2 State/Form
Crystalline powder
3.3.1.3 Description
Odourless
Readily soluble in alkali, hydroxides and carbonates. Insoluble in alcohol, acetone, chloroform and ether. Solutions are inactivated by ultraviolet light. Alkaline solutions are sensitive to oxidation and acid solutions are sensitive to heat. Dissociation constant - pKa 4.7, 6.8, 9.0 (30°) (Moffat, 1986).
3.3.2 Properties of the locally available formulation(s)
To be completed by each Centre using local data
3.4 Other characteristics
3.4.1 Shelf-life of the substance
No data available.
3.4.2 Shelf-life of the locally available formulation(s)
To be completed by each Centre using local data.
3.4.3 Storage conditions
Preserve in well closed, light resistant containers. For injection-preserve in single dose or in multiple dose containers, preferably of type 1 glass (USP, 1990). Store between 15 to 30 °C Protect from freezing
(To be completed by each Centre using local data)
3.4.4 Bioavailability
Folic acid is rapidly absorbed from gastrointestinal tract following oral administration. Peak folate activity in blood is 30 to 60 minutes after oral administration.
(To be completed by each Centre using local data)
3.4.5 Specific properties and composition
Commercially available folic acid is prepared
synthetically as yellowish orange crystalline powder.
Folic acid injection is a sterile solution of folic acid in water, prepared with the aid of sodium hydroxide or sodium carbonate which results in formation of sodium folate which is the soluble sodium salt of folic acid. Commercially available folic acid injection has a pH of 8 to 11 and the aqueous solutions are heat sensitive and decompose rapidly in the presence of light and/or riboflavin, so solutions should be protected from light.
Folic acid is incompatible with oxidizing and reducing agents and with heavy metal ions (McEvoy, 1990).
(To be completed by each Centre using local data)
4. USES
4.1 Indications
4.1.1 Indications
For the prevention and treatment of vitamin B deficiency,
For the treatment of megaloblastic anaemia and macrocytic anaemia due to folic acid deficiency.
Folic acid supplements may be required in low birth weight infants, infants breastfed by folic acid deficient mothers, or those with prolonged diarrhoea and infection.
Other conditions which may increase folic acid requirements include alcoholism, hepatic disease, haemolytic anaemia, lactation, oral contraceptive use and pregnancy.
It has been given to pregnant mothers to reduce the risk of birth defects (Klaassen et al., 1986).
Folic acid has been suggested in the management of methanol poisoning, but its efficacy has not been proven (Ellenhorn & Barceloux, 1988).
4.1.2 Description
Not applicable.
4.2 Therapeutic dosage
4.2.1 Adults Folate deficient megoblastic anaemia
Therapeutic dose
5 mg daily orally for 4 months; up to 15 mg daily may be required in malabsorption states.(UK)
250 mcg to 1.0 mg orally daily (USA) Prophylactic dose
200 to 500 mcg orally daily (UK) 400 mcg orally daily (USA) Other indications
Prophylactic dose
5 mg daily or weekly by mouth in thalassaemia or sickle-cell anaemia (and sometimes in patients receiving renal dialysis) Note: Folic acid may also be administered by intramuscular, intravenous or subcutaneous injection as the sodium salt.
(Reynolds, 1993)
4.2.2 Children
Dietary supplements
100 mcg/day may be increased to 500 mcg to 1 mg/day when conditions causing increased requirements are present.
Deficiency states
250 mcg to 1 mg/day until haematological response occurs.
Maintenance
Infants 100 mcg/day. Children up to 4 years up to 300 mcg/day. Children above 4 years 400 mcg/day.
(Reynolds, 1993)
4.3 Contraindications
It should be given with caution to patients with abnormal renal function.
It is also contra-indicated in patients who show hypersensitivity reactions to folic acid.
Caution is advised in patients who may have folate dependent tumours (Reynolds, 1989).
Folic acid should never be given alone or in conjunction with inadequate amounts of Vitamin B12 for the treatment of undiagnosed megaloblastic anaemia. Although folic acid may produce a haematopoietic response in patients with megaloblastic anaemia due to Vitamin B12, it fails to prevent the onset of subacute combined degeneration of the cord (Reynolds, 1989).
5. ROUTES OF ENTRY
5.1 Oral
Tablets
5.2 Inhalation
Not applicable.
5.3 Dermal
Not applicable.
5.4 Eye
Not applicable.
5.5 Parenteral
Aqueous solution.
5.6 Other
Not relevant.
6. KINETICS
6.1 Absorption by route of exposure
Oral
Folic acid is rapidly absorbed from the proximal part of the gastrointestinal tract following oral administration. It is mainly absorbed in the proximal portion of the small intestine. The naturally occurring folate polyglutamate is enzymatically hydrolyzed to monoglutamate forms in the gastrointestinal tract prior to absorption. The peak folate
activity in blood after oral administration is within 30 to 60 minutes (McEvoy, 1990). Enterohepatic circulation of folate has been demonstrated.
6.2 Distribution by route of exposure
Tetrahydrofolic acid and its derivatives are distributed in all body tissues. Folate is actively concentrated in the CSF at about 0.016 to 0.021 mg/ml while the normal erythrocyte level is about 0.175 to 0.316 mg/ml. The liver contains half of the total body stores of folate and is the principal storage site (McEvoy, 1990).
6.3 Biological half-life by route of exposure
No data available.
6.4 Metabolism
Folic acid once absorbed is acted upon by hepatic dihydrofolate reductase to convert to its metabolically active form which is tetrahydrofolic acid.
Following absorption of 1 mg or less, folic acid is largely reduced and methylated in the liver to N-5 methyltetrahydrofolic acid, which is the main transporting and storage form of folate in the body. Larger doses may escape metabolism by the liver and appear in the blood mainly as folic acid.
6.5 Elimination by route of exposure
Oral Following oral administration of single 0.1 to 0.2 mg doses of folic acid in health adults, only a trace amount of the drug appears in urine . Following administration of large doses, the renal tubular reabsorption maximum is exceeded and excess folate is excreted unchanged in urine. Small amounts of orally administered folic acid have been recovered from faeces. About 0.05 mg/day of normal body folate stores is lost by a combination of urinary and faecal excretion and oxidative cleavage of the molecule.
Folic acid is also excreted in the breastmilk.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Folic acid is relatively non-toxic. Toxicity studies in mice showed that folic acid could cause convulsions, ataxia and weakness. Histopathological studies in some strains of mice showed that toxic doses may also cause acute renal tubular necrosis. A possible relationship
between folic acid neurotoxicity and cholinergic receptors in the pyriform cortex and amygdala has been
shown (McGeer et al, 1983).
7.1.2 Pharmacodynamics
Folic acid is transformed into different coenzymes that are responsible for various reactions of intracellular metabolism mainly conversion of homocysteine to methionine, conversion of serine to glycine, synthesis of thymidylate, histidine metabolism, synthesis of purines and utilization or generation of formate.
In man, nucleoprotein synthesis and the maintenance of normal erythropoiesis requires exogenous folate. Folic acid is the precursor of tetrahydrofolic acid which is active and acts as a co-factor for 1-carbon transfer reactions in the biosynthesis of purines and thymidylates of nucleic acids.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
There is little data available on folic acid toxicity in humans. A case of 2 patients who showed exacerbation of psychotic behaviour during treatment with folic acid has been reported (Prakash et al., 1982). The significance of this finding is uncertain since other authors have suggested that folic acid has antipsychotic properties.
Adverse gastrointestinal and central nervous system effects have been reported rarely in patients receiving 15 mg of folic acid daily for one month. However, other studies have failed to confirm these findings (McEvoy, 1990).
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
Toxicity in different strains of mice showed that toxic doses of folic acid may lead to convulsions, ataxia and weakness (Parchure et al., 1985). Histopathological studies in some strains of mice showed acute renal tubular necrosis.
7.2.3 Relevant in vitro data
Cytomorphological effects of folic acid were studied
using in-vitro establishment human oral epithelium. A concentration twice that used clinically (200 mcg/ml of folic acid) did not induce marked cytotoxic reaction in cultured cells. The most pronounced changes were cultures which showed degenerating cells showing oedema, increased translucency of the cytoplasm, flattened cells and atypical filaments (Jainkittivong et al., 1989).
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
No data available.
7.5 Mutagenicity
No data available.
7.6 Interactions
Folic acid therapy may increase phenytoin metabolism in folate deficient patients resulting in decreased phenytoin serum concentration. It has also been reported that concurrent administration of folic acid and chloramphenicol in folate deficient patients may result in antagonism of the haematopoietic response to folic acid.
The use of ethotoin or mephenytoin concurrently with folic acid may decrease the effects of hydantoins by increasing hydantoin metabolism.
Trimethoprim acts as a folate antagonist by inhibiting dihydrofolate reductase, so in patients receiving this drug leucovorin calcium must be given instead of folic acid. Folic acid may also interfere with the effects of pyrimethamine.
Aminopterin (4 aminofolic acid) and methotrexate (4 amino- 10 methylfolic acid) antagonizes reduction of folic acid to tetrahydrofolic acid. Methotrexate continues to be used as an antineoplastic drug whose activity may be dependent on blocking certain syntheses, e.g., of purines, in which folic acid is required, thereby depriving neoplastic cells of compounds essential for their proliferation. Calcium leucovorin is used therapeutically as a potent antidote for the toxic effects of folic acid antagonists used as antineoplastic agents. Methotrexate or pyrimethamine or triamterene also acts as folate antagonist by inhibiting dihydrofolic reductase (USP DI, 1983).
Analgesics, anticonvulsants, antimalarials and corticosteroids may cause folic acid deficiency (USP DI, 1983).
Folic acid precipitates in some proprietary amino acid solutions and in the presence of high concentration of calcium ions, but it appears to be stable and remains in solution provided the pH remains above 5. There have also been reports of folic acid being absorbed by the polyvinyl chloride containers and administration set, however, other studies have not substantiated such observations.
Regarding intravenous incompatibilities, calcium gluconate and folic acid injections have been shown to interact even though a precipitate is not present. The recoverable amount of folic acid from a 10 mg/ml solution declined with increasing concentrations (0.5 to 10 mg/ml) of calcium gluconate. This interaction was reversed by the addition of edetic acid (Trissel, 1986).
7.7 Main adverse effects
Allergic reactions to folic acid have been rarely reported including erythema, rash, itching, general malaise and bronchospasm. Adverse gastrointestinal and central nervous system effects have been reported in patients receiving 15 mg of folic acid daily for one month.
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Sample
8.1.1 Collection
8.1.2 Storage
Pharmaceutical product, should be preserved in well closed, light resistant containers, preferably type 1 glass.
8.1.3 Transport
8.2 Toxicological analytical methods
8.2.1 Assay for folic acid may be found in the USP XXII, 1990.
Identification: Folic acid injection: to a volume of the injection equivalent to about 100 mg of folic acid add water to make about 25 mL. Adjust with hydrochloric acid to a pH of 3.0 cool to 5, then filter, and wash the precipitate of folic acid with cold water until the last washing shows an absence of chloride. Then wash with acetone, and dry at 80 for 1 hour: the ultraviolet absorption spectrum of a 1 in 100,000 solution of the folic acid so obtained in sodium hydroxide solution (1 in 250) exhibits maxima and minima at the same wavelengths as that of a similar solution of USP Folic Acid RS,
concomitantly measured. The ratio A256/A365 is between 2.80 and 3.00.
Folic acid tablet-digest a quantity of powdered tablets, equivalent to about 100 mg of folic acid, with 100 mL of sodium hydroxide solution (1 in 250), and filter. Proceed as directed in the identification test under Folic Acid Injection (USP, 1985).
8.2.2 Test for biological sample
Blood may be used for microbiological assay or competitive binding technique to determine the plasma and red cell folate levels (USP XX11, 1990).
8.3 Biochemical investigations
8.3.1 Blood
BUN, Creatinine-to test for renal function AST, ALT, Alkaline Phosphatase-to test for liver status
8.3.2 Urine
No data available.
8.3.3 Others
No data available.
8.4 Interpretation
Normal serum total folate concentration have been reported to range from 0.005 to 0.015 mg/mL (AHFS Drug Information, 1990). Use of antibiotics may interfere with microbiological assay for serum and erythrocyte folic acid concentration and cause falsely low levels (US XX11, 1990).
8.5 References Position Radical Congener
N -CH CH H PteGlu Methyltetrahydrofolate N -CHO 5-CHOH PteGlu Folinic acid (Citrovorum factor) N -CHO 10-CHOH PteGlu 10 Formyltetrahydrofolate N -CH- 5, 10-CHH PteGlu 5, 10-Methenyltetrahydro- folate N -CH- 5, 10-CH H PteGlu 5, 10 Methylenetetrahydro- folate N -CHNH CH OHH PteGlu Forminiotetrahydrofolate N -CH OH CH OHH PteGlu Hydroxymethyltetrahydro- folate
Structures and Nomenclature of Folic Acid and Congeners (Goodman & Gillman, 1990).
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
No data available.
9.1.2 Inhalation
Not known.
9.1.3 Skin exposure
No data available.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
Therapeutic doses may cause anaphylaxis.
9.2 Chronic Poisoning
9.2.1 Ingestion
Unconfirmed reports of gastrointestinal and central nervous system effects have been reported rarely in patients receiving 15 mg of folic acid daily for one month (McEvoy, 1990). 9.2.2 Inhalation
Not known.
9.2.3 Skin exposure
No data available.
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure No data available.
9.3. Course, prognosis, cause of death
No data available.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Hypertension and shock may be seen as a manifestation of allergic reaction.
9.4.2 Respiratory
Bronchospasm may be seen as a manifestation of allergic reaction.
9.4.3 Neurological 9.4.3.1 Central nervous system (CNS)
No data available. 9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available. 9.4.3.4 Skeletal and smooth muscle
Unconfirmed reports of general malaise and ataxia have been received following therapeutic doses.
9.4.4 Gastrointestinal
Nausea and vomiting as an adverse reaction has been reported.
9.4.5 Hepatic
No data available.
9.4.6 Urinary
9.4.6.1 Renal
No data available.
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
No data available.
9.4.9 Ear, nose and throat: local effects
No data available.
9.4.10 Hematological
No data available.
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid and electrolyte disturbances
No data available.
9.4.12.3 Others No data available.
9.4.13 Allergic reaction
Rash, erythema and itching.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
No data available.
9.5 Other
Unknown
9.6 Summary
Not relevant
10. MANAGEMENT
10.1 General principles
In cases of overdose, treatment is symptomatic and
supportive and is guided by the clinical features.
In case of anaphylactic reaction standard treatment should be given. (See Treatment Guide on Anaphylaxis).
In case of massive ingestion gastric lavage or induced vomiting could be considered if seen within 1 to 2 hours
after ingestion. Activated charcoal should be given repeatedly in view of the enterohepatic circulation of folic acid.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Collect blood for plasma and red cell folate levels.
10.2.2 Biomedical analysis
Request for other test would depend on patient presentation.
There are no confirmed reports of folic acid overdose in humans. In case of an overdose, determination of blood urea nitrogen and creatinine level would be appropriate because of the possibility of renal toxicity which has been reported in experimental mice. Determination of liver function (AST, ALT, Alkaline phosphatase) should also be done due to the possibility of hepatotoxicity, (the liver being the primary storage site of folic acid).
10.2.3 Toxicological analysis
Not relevant
10.2.4 Other investigations
Not relevant
10.3 Life supportive procedures and symptomatic/specific treatment
Treatment is largely supportive. In case of anaphylactic reaction, epinephrine (adrenaline) should be given. Maintain a clear airway and aspirate secretions from airway. Administer oxygen and perform endotracheal intubation when necessary. Support ventilation using appropriate mechanical device. Control convulsions with appropriate drug regimen. Perform cardio-respiratory resuscitation when necessary. Correct hypotension with isotonic fluids and inotropic agents.
10.4 Decontamination
In case of massive ingestion induce vomiting or gastric lavage, if seen within 1 to 2 hours after ingestion. Repeat dose activated charcoal.
10.5 Elimination Adequate hydration would be sufficient to eliminate the drug through the kidneys.
10.6 Antidote treatment
10.6.1 Adults
No antidote.
10.6.2 Children
No antidote.
10.7 Management discussion
Folic acid is relatively non-toxic and management is directed toward symptomatic and supportive therapy.
The only allergic reaction to folic acid, which is life threatening, is anaphylaxis. For anaphylaxis one should give epinephrine (adrenaline) and (if considered necessary) corticosteroids and fluids.
For hypotension unresponsive to volume expansion, one may give dopamine.
Repeated doses of activated charcoal are necessary to remove excess folic acid from the enterohepatic recirculation.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
There is little data available on folic acid toxicity in humans. A case of 2 patients who showed exacerbation of psychotic behaviour during treatment with folic acid has been reported (Prakash et al., 1982). The significance of this finding is uncertain since other authors have suggested that folic acid has antipsychotic properties.
11.2 Internally extracted data on cases Unknown
11.3 Internal cases
To be completed by each Centre using local data 12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
Not relevant
12.2 Specific preventive measures
Not relevant
12.3 Other
Not relevant
13. REFERENCES
Braunwald E, Isselbacher K, Petersdorf R, Wilson J, & Martin J eds. (1987) Harrison's principles of internal medicine, 11 th ed., New York, McGraw-Hill Book Company.
Budavari S ed. (1989) The Merck Index: an encyclopedia of chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey, Merck and Co., Inc. p 660 Ellenhorn MJ & Barceloux DG (1988) Medical toxicology, diagnosis and treatment of human poisoning, New York, Elsevier, pp 30, 79.
Gilman AG, Rall TW, Nies AS & Taylor P eds.(1990) Goodman and Gilman's the pharmacological basis of therapeutics, 8th ed. New York, Pergamon Press, pp 1294-1296, 1302-1306.
Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, & Kulberg AG eds. (1990) Goldfrank's toxicologic emergencies, Norwalk, Appleton-Century- Crofts.
Goth, A Medical Pharmacology: Principles and Concepts, 5th Edition, C.V. Mosby Company, Maruzen Company Limited 1980.
Haddad LM & Winchester JF eds. (1983) Clinical management of poisoning and drug overdose. Philadelphia, Saunders.
Jainkittivong A, Arenholt-Bindsler D, Jepsen A, & Philipsen HP (1989) Effect of folic acid on human oral epithileum in-vitro. J Dent Assoc Thai, 39: 121-127.
Klaassen CD, Amdur MO, & Doull J (1986) Casarett & Doull's toxicology: the basic science of poisons. New York, Macmillan Publishing Company, p 211.
Krupp M, Chatton M & Tierney L (1986) Current medical diagnosis and treatment. Lange Medical Company.
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
Author Dr E.S. Castillo National Poison Control & Information Service Department of Pharmacology UP College of Medicine Manila Philippines
Date August 1991.
Reviewer -
Peer Review Drs Pronczuk, Tempowski, Hartigan-Go, Ten-Ham. Newcastle-upon-Tyne, United Kingdom, February 1992Newcastle-upon-Tyne, United Kingdom, February 1992
See Also: Toxicological Abbreviations