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Phenytoin

Trade Names :

  • Dilantin

Phenytoin is an anticonvulsant agent used primarily to prevent seizures in conditions such as epilepsy. Drugs similar to phenytoin are ethotoin (Peganone) and mephenytoin (Mesantoin).

Other anticonvulsant agents include carbamazepine , phenobarbital , primidone , and valproic acid . In some cases, combination therapy with two or more anticonvulsant drugs may be used.

Ginkgo

The herb ginkgo (Ginkgo biloba) has been used to treat Alzheimer's disease and ordinary age-related memory loss, among many other conditions. Seizures have been reported with the use of ginkgo leaf extract in people with previously well-controlled epilepsy; in one case, the seizures were fatal. 43 One possible explanation is contamination of ginkgo leaf products with ginkgo seeds. 1-5 It has also been suggested that ginkgo might interfere with the effectiveness of some anti-seizure medications, including phenytoin. 44 Finally, it has been noted that the drug tacrine (also used to improve memory) has been associated with seizures, and ginkgo may affect the brain in ways similar to tacrine. 45

Glutamine

The amino acid glutamine is converted to glutamate in the body. Glutamate is thought to act as a neurotransmitter (a chemical that enables nerve transmission). Because anticonvulsants work (at least in part) by blocking glutamate pathways in the brain, high dosages of the amino acid glutamine might theoretically diminish an anticonvulsant's effect and increase the risk of seizures.

Ipriflavone

Ipriflavone, a synthetic isoflavone that slows bone breakdown, is used to treat osteoporosis.

Test tube studies indicate that ipriflavone might increase blood levels of the anticonvulsants phenytoin and carbamazepine when they are taken therapeutically. 6 Ipriflavone was found to inhibit a liver enzyme involved in the body's normal breakdown of these drugs, thus allowing them to build up in the blood. Higher drug levels increase the risk of adverse effects.

Because anticonvulsants are known to contribute to the development of osteoporosis, a concern is that the use of ipriflavone for this drug-induced osteoporosis could result in higher blood levels of the drugs, with potentially serious consequences.

People taking either of these drugs should use ipriflavone only under medical supervision.

HopsKavaPassionflowerValerian

The herb kava (Piper methysticum) has a sedative effect and is used for anxiety and insomnia.

Combining kava with anticonvulsants, which possess similar depressant effects, could result in "add-on" or excessive physical depression, sedation, and impairment. In one case report, a 54-year-old man was hospitalized for lethargy and disorientation, side effects attributed to his having taken the combination of kava and the anti-anxiety agent alprazolam (Xanax) for 3 days. 7

Other herbs having a sedative effect that might cause problems when combined with anticonvulsants include: ashwagandha , calendula , catnip , hops , lady's slipper , lemon balm , passionflower , sassafras , skullcap , valerian , and yerba mansa.

Because of the potentially serious consequences, you should avoid combining these herbs with anticonvulsants or other drugs that also have sedative or depressant effects, unless advised by your physician.

White Willow

The herb white willow (Salix alba) , also known as willow bark, is used to treat pain and fever. White willow contains a substance that is converted by the body into a salicylate similar to aspirin.

Higher doses of aspirin may increase phenytoin levels and toxicity during long-term use of both drugs. 8 This raises the concern that white willow might have similar effects on phenytoin, though this has not been proven.

Biotin

Anticonvulsants may deplete biotin, an essential water-soluble B vitamin, possibly by competing with it for absorption in the intestine. It is not clear, however, whether this effect is great enough to be harmful.

Blood levels of biotin were found to be substantially lower in 404 people with epilepsy on long-term treatment with anticonvulsants compared to 112 untreated people with epilepsy. 9 The effect occurred with phenytoin, carbamazepine, phenobarbital, and primidone. Valproic acid appears to affect biotin to a lesser extent than other anticonvulsants.

A test tube study suggested that anticonvulsants might lower biotin levels by interfering with the way biotin is transported in the intestine. 10

Biotin supplementation may be beneficial if you are on long-term anticonvulsant therapy. To avoid a potential interaction, take the supplement 2 to 3 hours apart from the drug.

Note: It has been suggested that the action of anticonvulsant drugs may be at least partly related to their effect of reducing biotin levels. For this reason, it may be desirable to take enough biotin to prevent a deficiency, but not an excessive amount.

Folate

Folate (also known as folic acid) is a B vitamin that plays an important role in many vital aspects of health, including preventing neural tube birth defects and possibly reducing the risk of heart disease. Because inadequate intake of folate is widespread, if you are taking any medication that depletes or impairs folate even slightly, you may need supplementation.

Most drugs used for preventing seizures can reduce levels of folate in the body. 11-16 Phenytoin in particular appears to decrease folate levels by interfering with its absorption in the small intestine, 19 as well as by accelerating its normal breakdown by the body. 20,21

The low blood levels of folate caused by anticonvulsants can raise homocysteine levels, a condition believed to increase the risk of heart disease . 17

Adequate folate intake is also necessary to prevent neural tube birth defects, such as spina bifida and anencephaly (absence of a brain). Because anticonvulsant drugs deplete folate, babies born to women taking anticonvulsants are at increased risk for such birth defects. Anticonvulsants may also play a more direct role in the development of birth defects. 18

However, there can be problems with using folate supplements. High folate levels may speed up the normal breakdown of phenytoin. 22,23 This can lead to breakthrough seizures.

For this reason, folate supplementation during phenytoin therapy should be supervised by a physician.

Calcium

Anticonvulsant drugs may impair calcium absorption and, in this way, increase the risk of osteoporosis and other bone disorders.

Calcium absorption was compared in 12 people on anticonvulsant therapy (all taking phenytoin and some also taking phenobarbital, primidone, and/or carbamazepine) and 12 people receiving no treatment. 24 Calcium absorption was found to be 27% lower in the treated participants.

An observational study found low calcium blood levels in 48% of 109 people taking anticonvulsants. 25 Other findings in this study suggested that anticonvulsants might also reduce calcium levels by directly interfering with parathyroid hormone, a substance that helps keep calcium levels in proper balance.

A low blood level of calcium can itself trigger seizures, and this might reduce the effectiveness of anticonvulsants. 26

Calcium supplementation may be beneficial for people taking anticonvulsant drugs. However, some studies indicate that antacids containing calcium carbonate may interfere with the absorption of phenytoin and perhaps other anticonvulsants. 27,28 For this reason, take calcium supplements and anticonvulsant drugs several hours apart if possible.

Carnitine

Carnitine is an amino acid that has been used for heart conditions, Alzheimer's disease, and intermittent claudication.

Long-term therapy with anticonvulsant agents, particularly valproic acid, is associated with low levels of carnitine. 29 However, it isn't clear whether the anticonvulsants cause the carnitine deficiency or whether it occurs for other reasons. It has been hypothesized that low carnitine levels may contribute to valproic acid's damaging effects on the liver. 30,31 The risk of this liver damage increases in children younger than 24 months, 32 and carnitine supplementation does seem to be protective. 33 However, in one double-blind crossover study, carnitine supplementation produced no real improvement in "well-being" as assessed by parents of children receiving either valproic acid or carbamazepine. 34

L-carnitine supplementation may be advisable in certain cases, such as in infants and young children (especially those younger than 2 years) who have neurologic disorders and are receiving valproic acid and multiple anticonvulsants. 35

Vitamin D

Anticonvulsant drugs may interfere with the activity of vitamin D. As proper handling of calcium by the body depends on vitamin D, this may be another way that these drugs increase the risk of osteoporosis and related bone disorders (see the previous Calcium topic).

Anticonvulsants appear to speed up the body's normal breakdown of vitamin D, decreasing the amount of the vitamin in the blood. 36 A survey of 48 people taking both phenytoin and phenobarbital found significantly lower levels of calcium and vitamin D in many of them as compared to 38 untreated people. 37 Similar but lesser changes were seen in 13 people taking phenytoin or phenobarbital alone. This effect may be apparent only after several weeks of treatment.

Another study found decreased blood levels of one form of vitamin D but normal levels of another. 38 Because there are two primary forms of vitamin D circulating in the blood, the body might be able to adjust in some cases to keep vitamin D in balance, at least for a time, despite the influence of anticonvulsants. 39

Adequate sunlight exposure may help overcome the effects of anticonvulsants on vitamin D by stimulating the skin to manufacture the vitamin. 40 Of 450 people on anticonvulsants residing in a Florida facility, none were found to have low blood levels of vitamin D or evidence of bone disease. This suggests that environments providing regular sun exposure may be protective.

People regularly taking anticonvulsants, especially those taking combination therapy and those with limited exposure to sunlight, may benefit from vitamin D supplementation.

Vitamin K

Phenytoin, carbamazepine, phenobarbital, and primidone speed up the normal breakdown of vitamin K into inactive byproducts, thus depriving the body of active vitamin K. This can lead to bone problems, such as osteoporosis. Also, use of these anticonvulsants can lead to a vitamin K deficiency in babies born to pregnant mothers taking the drugs, resulting in bleeding disorders or facial bone abnormalities in the newborns. 41,42

Mothers who take these anticonvulsants may need vitamin K supplementation during pregnancy to prevent these conditions in their newborns.

Revision Information

  • 1

    Arenz A, Klein M, Fiehe K. Occurrence of neurotoxic 4'-O-methylpyridoxine in Ginkgo biloba leaves, ginkgo medications and Japanese ginkgo food. Planta Med. 1996;62:548-551.

  • 2

    Mizuno N, Kawakami K, Morita E. Competitive inhibition between 4'-substituted pyridoxine analogues and pyridoxal for pyridoxal kinase from mouse brain. J Nutr Sci Vitaminol (Tokyo). 1980;26:535-543.

  • 3

    Wada K, Ishigaki S, Ueda K, et al. An antivitamin B6, 4'-methoxypyridoxine, from the seed of Ginkgo biloba L.Chem Pharm Bull (Tokyo). 1985;33:3555-3557.

  • 4

    Yagi M, Wada K, Sakata M, et al. Studies on the constituents of edible and medicinal plants. IV. Determination of 4-O-methylpyridoxine in serum of the patient with gin-nan food poisoning [in Japanese; English abstract]. Yakugaku Zasshi. 1993;113:596-599.

  • 5

    Arenz A, Klein M, Fiehe K. Occurrence of neurotoxic 4'-O-methylpyridoxine in Ginkgo biloba leaves, ginkgo medications and Japanese ginkgo food. Planta Med. 1996;62:548-551.

  • 6

    Monostory K, Vereczkey L, Levai F, et al. Ipriflavone as an inhibitor of human cytochrome P450 enzymes. Br J Pharmacol. 1998;123:605-610.

  • 7

    Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med. 1996;125:940-941.

  • 8

    Inoue F, Walsh RJ. Folate supplements and phenytoin-salicylate interaction. Neurology. 1983;33:115-116.

  • 9

    Krause KH, Bonjour JP, Berlit P, et al. Biotin status of epileptics. Ann N Y Acad Sci. 1985;447:297-313.

  • 10

    Said HM, Redha R, Nylander W. Biotin transport in the human intestine: inhibition by anticonvulsant drugs. Am J Clin Nutr. 1989;49:127-131.

  • 11

    Kishi T, Fujita N, Eguchi T, et al. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci. 1997;145:109-112.

  • 12

    Reynolds EH. Mental effects of anticonvulsants, and folic acid metabolism. Brain. 1968;91:197-214.

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    Hendel J, Dam M, Gram L, et al. The effects of carbamazepine and valproate on folate metabolism. Acta Neurol Scand. 1984;69:226-231.

  • 14

    Berg MJ, Stumbo PJ, Chenard CA, et al. Folic acid improves phenytoin pharmacokinetics. J Am Diet Assoc. 1995;95:352-356.

  • 15

    Lewis DP, Van Dyke DC, Willhite LA, et al. Phenytoin-folic acid interaction. Ann Pharmacother. 1995;29:726-735.

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    Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998;32:802-817.

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    Ono H, Sakamoto A, Eguchi T, et al. Plasma total homocysteine concentrations in epileptic patients taking anticonvulsants. Metabolism. 1997;46:959-962.

  • 18

    Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998;32:802-817.

  • 19

    Berg MJ, Stumbo PJ, Chenard CA, et al. Folic acid improves phenytoin pharmacokinetics. J Am Diet Assoc. 1995;95:352-356.

  • 20

    Lewis DP, Van Dyke DC, Willhite LA, et al. Phenytoin-folic acid interaction. Ann Pharmacother. 1995;29:726-735.

  • 21

    Kishi T, Fujita N, Eguchi T, et al. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci. 1997;145:109-112.

  • 22

    Berg MJ, Stumbo PJ, Chenard CA, et al. Folic acid improves phenytoin pharmacokinetics. J Am Diet Assoc. 1995;95:352-356.

  • 23

    Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998;32:802-817.

  • 24

    Wahl TO, Gobuty AH, Lukert BP. Long-term anticonvulsant therapy and intestinal calcium absorption. Clin Pharmacol Ther . 1981;30:506-512.

  • 25

    Weinstein RS, Bryce GF, Sappington LJ, et al. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab. 1984;58:1003-1009.

  • 26

    Weinstein RS, Bryce GF, Sappington LJ, et al. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab. 1984;58:1003-1009.

  • 27

    Carter BL, Garnett WR, Pellock JM, et al. Effect of antacids on phenytoin bioavailability. Ther Drug Monit. 1981;3:333-340.

  • 28

    McElnay JC, Uprichard G, Collier PS. The effect of activated dimethicone and a proprietary antacid preparation containing this agent on the absorption of phenytoin. Br J Clin Pharmacol . 1982;13:501-505.

  • 29

    De Vivo DC, Bohan TP, Coulter DL, et al. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia. 1998;39:1216-1225.

  • 30

    Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity [letter]. Lancet. 1984;1:689.

  • 31

    Ater SB, et al. A developmental center population treated with VPA and L-carnitine. In: Update 1993: inborn errors of metabolism in the patient with epilepsy. Sigma-Tau Pharmaceuticals; 1993.

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    Dreifuss FE, Langer DH. Hepatic considerations in the use of antiepileptic drugs. Epilepsia. 1987;28(suppl 2):S23-S29.

  • 33

    Ater SB, et al. A developmental center population treated with VPA and L-carnitine. In: Update 1993: inborn errors of metabolism in the patient with epilepsy. Sigma-Tau Pharmaceuticals; 1993.

  • 34

    Freeman JM, Vining EP, Cost S, et al. Does carnitine administration improve the symptoms attributed to anticonvulsant medications? A double-blinded, crossover study. Pediatrics. 1994;93:893-895.

  • 35

    De Vivo DC, Bohan TP, Coulter DL, et al. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia. 1998;39:1216-1225.

  • 36

    Hahn TJ, Hendin BA, Scharp CR, et al. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med . 1972;287:900-904.

  • 37

    Hahn TJ, Hendin BA, Scharp CR, et al. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med . 1972;287:900-904.

  • 38

    Jubiz W, Haussler MR, McCain TA, et al. Plasma 1,25-dihydroxyvitamin D levels in patients receiving anticonvulsant drugs. J Clin Endocrinol Metab. 1977;44:617-621.

  • 39

    Brodie MJ, Boobis AR, Dollery CT, et al. Rifampicin and vitamin D metabolism. Clin Pharmacol Ther. 1980;27:810-814.

  • 40

    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;77:834-836,842.

  • 41

    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;168:923-928.

  • 42

    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;168:884-888.

  • 43

    Granger AS. Ginkgo biloba precipitating epileptic seizures Age Ageing 2001;30:523-525.

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    Kupiec T, Raj V. Fatal seizures due to potential herb-drug interactions with Ginkgo biloba. J Anal Toxicol . 2006;29:755-758.

  • 45

    Gregory PJ. Seizure associated with Ginkgo biloba? [letter]. Ann Intern Med. 2001;134:344