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Phenobarbital

Also indexed as: Phenobarbitone

Illustration

Phenobarbital is occasionally used as a sedative before surgery, as a hypnotic (sleeping pill) to treat insomnia, and as an anticonvulsant to prevent and treat seizure disorders. Phenobarbital is classified as a barbiturate.

Summary of Interactions with Vitamins, Herbs, and Foods
In some cases, an herb or supplement may appear in more than one category, which may seem contradictory. For clarification, read the full article for details about the summarized interactions.

Beneficial May Be Beneficial: Depletion or interference—The medication may deplete or interfere with the absorption or function of the nutrient. Taking these nutrients may help replenish them.

Biotin

Calcium

Folic acid

L-carnitine

Vitamin A*

Vitamin B12*

Vitamin B6*

Vitamin D

Vitamin K*

Beneficial May Be Beneficial: Side effect reduction/prevention—Taking these supplements may help reduce the likelihood and/or severity of a potential side effect caused by the medication.

Folic acid*

L-Carnitine*

Vitamin B12*

Vitamin D*

Vitamin K*

Beneficial May Be Beneficial: Supportive interaction—Taking these supplements may support or otherwise help your medication work better.

Folic acid*

Avoid Avoid: Reduced drug absorption/bioavailability—Avoid these supplements when taking this medication since the supplement may decrease the absorption and/or activity of the medication in the body.

Vitamin B6

Avoid Avoid: Adverse interaction—Avoid these supplements when taking this medication because taking them together may cause undesirable or dangerous results.

Alcohol

Folic acid*

An asterisk (*) next to an item in the summary indicates that the interaction is supported only by weak, fragmentary, and/or contradictory scientific evidence.

Interaction with Dietary Supplements

Biotin
One controlled study showed that long-term use of phenobarbital increases the breakdown of biotin.1 A test tube study also showed that primidone, a drug that is converted to phenobarbital by the body, prevents the absorption of biotin.2 Further research is needed to determine whether people taking phenobarbital might be at risk for biotin deficiency.

Calcium
Individuals on long-term multiple anticonvulsant therapy may develop below-normal blood levels of calcium, which may be related to drug-induced vitamin D deficiency.3 Two infants born to women taking high doses of phenytoin and phenobarbital while pregnant developed jitteriness and tetany (a syndrome characterized by muscle twitches), cramps, and spasms that can be caused by calcium deficiency during the first two weeks of life.4 Controlled research is needed to determine whether pregnant women who are taking anticonvulsant medications should supplement with additional amounts of calcium and vitamin D.

L-carnitine
One controlled study showed that taking phenobarbital resulted in reduced blood levels of L-carnitine.5 Further research is needed to determine whether people taking phenobarbital might benefit from supplemental L-carnitine. Based on the currently available information, some healthcare practitioners may recommend monitoring L-carnitine blood levels or supplementing with L-carnitine.

Folic acid
Long-term treatment with phenobarbital results in dramatic reductions in folic acid blood levels, though the clinical significance of this effect is unclear.6 Nevertheless, some healthcare practitioners might recommend supplemental folic acid to individuals taking phenobarbital.

One preliminary study showed that pregnant women who use anticonvulsant drugs without folic acid supplementation have an increased risk of having a child with birth defects, such as heart defects, cleft lip and palate, neural tube defects, and skeletal abnormalities. However, supplementation with folic acid greatly reduces the risk.7 Consequently, some healthcare practitioners recommend that women taking multiple anticonvulsant drugs supplement with 5 mg of folic acid daily, for three months prior to conception and during the first trimester, to prevent folic acid deficiency-induced birth defects.8 Other practitioners suggest that 1 mg or less of folic acid each day is sufficient to prevent deficiency during pregnancy.9

One well-controlled study showed that adding folic acid to multiple anticonvulsant therapy resulted in reduced seizure frequency.10 In addition, three infants with seizures who were unresponsive to medication experienced immediate relief following supplementation with the active form of folic acid.11

Despite the apparent beneficial effects, some studies have indicated that as little as 0.8 mg of folic acid taken daily can increase the frequency and/or severity of seizures.12 13 14 15 However, a recent controlled study showed that both healthy and epileptic women taking less than 1 mg of folic acid per day had no increased risk for seizures.16 Until more is known about the risks and benefits of folic acid, individuals taking multiple anticonvulsant drugs should consult with their healthcare practitioner before supplementing with folic acid. In addition, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss folic acid supplementation with their practitioner.

Vitamin A
Anticonvulsant drugs can occasionally cause birth defects when taken by pregnant women, and their toxicity might be related to low blood levels of vitamin A. One controlled study showed that taking multiple anticonvulsant drugs results in dramatic changes in the way the body utilizes vitamin A.17 Further controlled research is needed to determine whether supplemental vitamin A might prevent birth defects in children born to women on multiple anticonvulsant therapy. Other research suggests that ingestion of large amounts of vitamin A may promote the development of birth defects, although the studies are conflicting.

Vitamin B6
One controlled study revealed that supplementing with 200 mg of vitamin B6 daily for four weeks resulted in a 45% reduction in phenobarbital blood levels.18 Therefore, people taking phenobarbital should probably avoid supplementing with large amounts of vitamin B6.

One controlled study revealed that taking anticonvulsant drugs dramatically reduces blood levels of vitamin B6.19 A nutritional deficiency of vitamin B6 can lead to an increase in homocysteine blood levels, which has been associated with atherosclerosis. Vitamin B6 deficiency is also associated with symptoms such as dizziness, fatigue, mental depression, and seizures. People taking multiple anticonvulsant drugs should discuss with their doctor whether supplementing with vitamin B6 is advisable.

Vitamin B12
Anemia is an uncommon side effect experienced by people taking anticonvulsant drugs. Though the cause may be folic acid deficiency in many cases, a deficiency of vitamin B12 may also be a factor in some instances. Deficiencies of folic acid and vitamin B12 can lead to nerve and mental problems. One study revealed that individuals on long-term anticonvulsant therapy, despite having no laboratory signs of anemia, had dramatically lower levels of vitamin B12 in their cerebrospinal fluid (the fluid that bathes the brain) when compared with people who were not taking seizure medications. Improvement in mental status and nerve function was observed in a majority of symptomatic individuals after taking 30 mcg of vitamin B12 daily for a few days.20 Another study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin B12.21 Despite these contradictory findings, people taking anticonvulsant drugs for several months or years might prevent nerve and mental problems by supplementing with vitamin B12.

Vitamin D
Though research results vary, long-term use of anticonvulsant drugs appears to interfere with vitamin D activity, which might lead to softening of bones (osteomalacia). One study showed that blood levels of vitamin D in males taking anticonvulsants were lower than those found in men who were not taking seizure medication.22 In a controlled study, bone strength improved in children taking anticonvulsant drugs who were supplemented with the activated form of vitamin D and 500 mg per day of calcium for nine months.23 Some research suggests that differences in exposure to sunlight—which normally increases blood levels of vitamin D—might explain why some studies have failed to find a beneficial effect of vitamin D supplementation. In one controlled study, blood vitamin D levels in children taking anticonvulsants were dramatically lower in winter months than in summer months.24 Another study of 450 people in Florida taking anticonvulsants found that few had drug-induced bone disease.25 Consequently, people taking anticonvulsant drugs who do not receive adequate sunlight should supplement with 400 IU of vitamin D each day to help prevent osteomalacia.

Vitamin E
Two studies showed that individuals taking phenytoin and phenobarbital had lower blood vitamin E levels than those who received no treatment for seizures.26 27 Though the consequences of lower blood levels of vitamin E are unknown, people taking multiple anticonvulsant drugs should probably supplement with 100 to 200 IU of vitamin E daily to prevent a deficiency.

Vitamin K
Some studies have shown that babies born to women taking anticonvulsant drugs have low blood levels of vitamin K, which might cause bleeding in the infant.28 Though some researchers recommend vitamin K supplementation prior to delivery,29 30 not all agree that supplementation for women taking anticonvulsant drugs is necessary.31 Until more information is available, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss vitamin K supplementation with their healthcare practitioner.

Interaction with Food and Other Compounds

Alcohol
Drinking alcoholic beverages while taking phenobarbital enhances side effects such as drowsiness, confusion, and dizziness.32 Consequently, people taking barbiturates should avoid drinking alcohol, especially when they must stay alert.

References:

1. Mock DM, Mock NI, Nelson RP, Lombard KA. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr 1998;26:245–50.

2. Said HM, Redha R, Nylander W. Biotin transport in the human intestine: inhibition by anticonvulsant drugs. Am J Clin Nutr 1989;49:127–31.

3. Bouillon R, Reynaert J, Claes JH, et al. The effect of anticonvulsant therapy on serum levels of 25-hydroxy-vitamin D, calcium, and parathyroid hormone. J Clin Endocrinol Metab 1975;41:1130–5.

4. Friis B, Sardemann H. Neonatal hypocalcaemia after intrauterine exposure to anticonvulsant drugs. Arch Dis Child 1977;52:239–41.

5. Castro-Gago M, Eiris-Punal J, Novo-Rodriquez MI, et al. Serum carnitine levels in epileptic children before and during treatment with valproic acid, carbamazepine, and phenobarbital. J Child Neurol 1998;13:546–9.

6. Kishi T, Fujita N, Eguchi T, Ueda K. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci 1997;145:109–12.

7. Biale Y, Lewenthal H. Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol Reprod Biol 1984;18:211–6.

8. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999;57:535–44 [review].

9. Hiilesmaa VK, Teramo K, Granstrom JL, et al. Serum folate concentrations during pregnancy in women with epilepsy: relation to antiepileptic drug concentrations, number of seizures, and fetal outcome. Br Med J (Clin Res Ed) 1983;287:577–9.

10. Gibberd FB, Nicholls A, Wright MG. The influence of folic acid on the frequency of epileptic attacks. Eur J Clin Pharmacol 1981;19:57–60.

11. Torres OA, Miller VS, Buist NM, Hyland K. Folinic acid-responsive neonatal seizures. J Child Neurol 1999;14:529–32.

12. Guidolin L, Vignoli A, Canger R. Worsening in seizure frequency and severity in relation to folic acid administration. Eur J Neurol 1998;5:301–3.

13. Lewis DP, Van Dyke DC, Willhite LA. Phenytoin-folic acid interaction. Ann Pharmacother 1995;29:726–35 [review].

14. Berg MJ, Rivey MP, Vern BA, et al. Phenytoin and folic acid: individualized drug-drug interaction. Ther Drug Monit 1983;5:395–9.

15. Reynolds EH. Effects of folic acid on the mental state and fit frequency of drug treated epileptic patients. Lancet 1967;1:1086.

16. Eros E, Geher P, Gomor B, Czeizel AE. Epileptogenic activity of folic acid after drug induces SLE (folic acid and epilepsy). Eur J Obstet Gynecol Reprod Biol 1998;80:75–8.

17. Nau H, Tzimas G, Mondry M, et al. Antiepileptic drugs alter endogenous retinoid concentrations: a possible mechanism of teratogensis of anticonvulsant therapy. Life Sci 1995;57:53–60.

18. Walter-Sack I, Klotz U. Influence of diet and nutrition status on drug metabolism. Clin Pharmacokinet 1996;31:47–64.

19. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999;40:345–50.

20. Frenkel EP, McCall MS, Sheehan RG. Cerebrospinal fluid folate, and vitamin B12 in anticonvulsant-induced megaloblastosis. J Lab Clin Med 1973;81:105–15.

21. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999;40:345–50.

22. Telci A, Cakatay U, Kurt BB, et al. Changes in bone turnover and deoxypyridinoline levels in epileptic patients Clin Chem Lab Med 2000 38:47–50.

23. Jekovec-Vrhovsek M, Kocijancic A, Prezelj J. Effect of vitamin D and calcium on bone mineral density in children with CP and epilepsy in full-time care. Dev Med Child Neurol 2000;42:403–5.

24. Riancho JA, Del Arco C, Arteaga R, et al. Influence of solar irradiation on vitamin D levels in children on anticonvulsant drugs. Acta Neurol Scand 1989;79:296–9.

25. Williams C, Netzloff M, Folkerts L, et al. Vitamin D metabolism and anticonvulsant therapy: effect of sunshine on incidence of osteomalacia. South Med J 1984;77:834.

26. Higashi A, Tamari H, Ikeda T, et al. Serum vitamin E concentration in patients with severe multiple handicaps treated with anticonvulsants. Pediatr Pharmacol (New York) 1980;1:129–34.

27. Higashi A, Ikeda T, Matsukura M, Matsuda I. Serum zinc and vitamin E concentrations in handicapped children treated with anticonvulsants. Dev Pharmacol Ther 1982;5:109–13.

28. Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993;168:923–8.

29. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999;57:535–44 [review].

30. Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol 1993;168:884–8.

31. Hey E. Effect of maternal anticonvulsant treatment on neonatal blood coagulation. Arch Dis Child Fetal Neonatal Ed 1999;81:F208–10.

32. Olin BR, et. Central Nervous System Drugs, Sedatives and Hypnotics, Barbiturates. In: Drug Facts and Comparisons, St. Louis, MO: Facts and Comparisons, 1993, 1398–413.

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