Phenobarbital

Brand Names: Donnatal, Solfoton

Clinical Names: Phenobarbital

Summary

generic name: Phenobarbital

trade names: Donnatal®, Solfoton®

note: Primidone is an inactive substance but can exert anticonvulsant effects after the body converts it to phenobarbital.

type of drug: Barbiturate, anticonvulsant.

used to treat: Seizure disorders; as sedative; adjunctive therapy in the treatment of irritable bowel syndrome.

overview of interactions:
• nutrient affected by drug: Folic Acid

• nutrients affected by drug: Vitamin B6 (Pyridoxine) and Vitamin B12 (Cobalamin)

• nutrient affected by drug: Vitamin D

• nutrient affected by drug: Vitamin K

• nutrient affected by drug: Calcium

• nutrient affected by drug: Carnitine



Interactions

nutrient affected by drug: Folic Acid

• adverse drug effects: Nearly all anticonvulsant drugs are known to have a marked impact on levels of folic acid in the body, especially through their effect of reducing folic acid absorption. This is especially important for women who are or might become pregnant. Phenobarbital and related drugs are known to create a high degree of risk for birth defects in and of themselves. Furthermore, folic acid deficiency itself is highly associated with birth defects, especially neural tube defects, and supplementation of folic acid is generally agreed to provide significant benefit in protecting against these types of birth defects. The combination of these two factors creates an extraordinarily high degree of risk for women of child-bearing age who are using phenobarbital. Research on the use of folic acid by pregnant women using phenobarbital has been positive in reducing the frequency and severity of birth defects among children born to women taking phenobarbital. Even so, most physicians caution against such women becoming pregnant.
(Reynolds EH, et al. Epilepsia. 1966 Dec;7(4):261-270; Biale Y, Lewenthan H. Eur J Obstet Gynecol 1984 Nov;18(4):211-216; Ogawa Y, et al. Epilepsy Res 1991 Jan-Feb;8(1):75-78; Yerby MS. Epilepsia 1987;28 Suppl 3:S29-36; Lewis DP, et al. Ann Pharmacother 1998 Jul-Aug;32(7-8):802-817; Dansky LV, et al. Ann Neurol 1987 Feb;21(2):176-182; Smith DB, Racusen LC. Arch Neurol 1973 Jan;28(1):18-22.)

• nutritional support: Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation. A daily supplemental dose of 400-800 mcg folate is probably adequate to compensate for any potential deficiency due to phenobarbital. Folic acid, at a daily dose of 1 mg, should be administered 3 months before conception and during the first trimester to prevent folic acid deficiency-induced malformations. Many nutritionally oriented healthcare professionals advise that every potentially pregnant woman should be taking folic acid.
(Lewis DP, et al. Ann Pharmacother 1998 Jul-Aug;32(7-8):802-817; Nulman I, et al. Drugs 1999 Apr;57(4):535-544.)

A number of anticonvulsants are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. The use of birth control pills or Norplant does not reduce the need for folic acid because many antiepileptic drugs interfere with the efficacy of contraceptives. Studies have shown that the most commonly used antiepileptic medications induce the cytochrome P450 enzymes that metabolize synthetic estrogens (e.g., ethinyl estradiol and mestranol), causing a 40% reduction in serum levels. Thus it becomes even more imperative for a woman using phenobarbital who wishes to become pregnant to add folic acid to her prenatal regimen.
(Nulman I, et al. Drugs 1999 Apr;57(4):535-544; Shane-McWhorter L, et al. Pharmacotherapy 1998 Nov-Dec;18(6):1360-1364; Back DJ, Orme ML. Clin Pharmacokinet 1990 Jun;18(6):472-484; Crawford P, et al. Br J Clin Pharmacol 1990 Dec;30(6):892-896.)

nutrients affected by drug: Vitamin B6 (Pyridoxine) and Vitamin B12 (Cobalamin)

• research: The use of phenobarbital has often been found to be associated with decreased levels of vitamin B6 and vitamin B12, as well as a related elevation in plasma concentrations of homocysteine. Apart from its emerging reputation as a risk factor in cardiovascular disease homocysteine has been used as an experimental convulsant. Several researchers have found elevated levels of homocysteine in epileptics using anticonvulsant medications but at this point evidence is mixed as to whether this is attributable to the underlying disease process, the medication, or both. However, the clinical implications of this potential interaction are uncertain at this time.
(Schwaninger M, et al. Epilepsia 1999 Mar;40(3):345-350.)

• nutritional support: Some nutritionally oriented healthcare professionals might consider supplementation with vitamin B6, vitamin B12, or folate as offering therapeutic potential since nutritional deficiencies of these nutrients are associated with increased homocysteine plasma concentrations. While vitamin B12 is generally considered nontoxic, supplemental use of vitamin B6 at high dosages (200 mg or more per day) carries known risks, including eventual damage to sensory nerves. Individuals taking any anti-convulsant drug should consult their prescribing physician about possible benefits and risks from the simultaneous use of vitamin B6 and/or vitamin B12, and only undertake such use under supervision.

nutrient affected by drug: Vitamin D

• mechanism: Phenobarbital impairs bioavailability of vitamin D.

• research: Phenobarbital and other anticonvulsants are inducers of cytochrome P-450 and the mixed-function oxidase system. Thus, anticonvulsants impair mineralisation, leading to osteomalacia and osteoporosis. Long-term treatment can cause excessive metabolism and deficiency of vitamin D and is believed to be associated with decreased bone mineral density and bone loss. After finding no pattern of low serum levels of vitamin D (25[OH]D) or radiologic evidence of osteomalacia or rickets in over 400 individuals using anticonvulsants in Florida, Williams et al concluded that the climate provided adequate exposure to sunshine and thereby prevented the development of anticonvulsant-induced osteomalacia or rickets.
(Holmes RP, Kummerow FA. J Am Coll Nutr. 1983;2(2):173-199; D'Erasmo E, et al. Recenti Prog Med 1998 Oct;89(10):529-533; Chung S, Ahn C. Brain Dev 1994 Sep-Oct;16(5):382-385; Pluskiewicz W, Nowakowska J. Ultrasound Med Biol 1997;23(4):553-558; Bone HG. JAMA 1983;249:939; Williams C, et al. Southern Med J 1984 Jul;77(7):834-836, 842; Livingston S. JAMA 1983;249:939; Jones G, Sambrook PN. Drug Saf 1994 Jun;10(6):480-489.)

• nutritional support: A moderate dose of 400-1500 IU per day of Vitamin D could exert a protective function for individuals using phenobarbital who are concerned about potential drug-induced osteoporosis. However, as suggested above, regular exposure to sunlight might provide adequate stimulation to enable the body to produce necessary levels of vitamin D. Others have advocated a proactive approach toward the risks of bone loss while voicing caution that given the increased risk of osteomalacia among those taking anticonvulsants, withdrawal from such drugs carries potential for increased risk of seizure-related fractures.
(Tomita S, et al. J Steroid Biochem Mol Biol 1991 Oct;39(4A):479-485; Christiansen C, et al. Br Med J 1973 Dec 22;4(894):695-701; Macallan DC, et al. Postgrad Med J 1992 Feb;68(796):134-136; Duus BR. Injury 1986 Jan;17(1):31-33.)

nutrient affected by drug: Vitamin K

• research: Phenobarbital interferes with vitamin K metabolism as indicated by a raised serum osteocalcin level. This finding may be of importance in the pathogenesis of side effects of these medications. In regard to pregnancy, the use of phenobarbital has been associated with vitamin K deficiencies in newborns.
(Keith DA, et al. Clin Pharmacol Ther 1983 Oct;34(4):529-532; Cornelissen M, et al. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):923-928.)

• nutritional support: At this point research has produced no consensus as to appropriate therapeutic dose of vitamin K to counter the adverse effects of phenytoin. Increasing the amount of green leafy vegetables in the diet could provide multiple benefits, in addition to enhancing vitamin K levels. Further supplementation with 1 mg vitamin K1 daily would also be prudent for most individuals taking phenytoin. Among pregnant women taking anticonvulsants, research indicates that a higher dose of vitamin K1, 10 mg per day, can prevent vitamin K deficiency in their infants.
(Cornelissen M, et al. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):923-928.)

nutrient affected by drug: Calcium

• mechanism: Many anticonvulsants, including phenobarbital, cause reduced calcium absorption with long-term use.
(Wahl TO, et al. Clin Pharmacol Ther. 1981 Oct;30(4):506-512.)

• nutritional support: Individuals taking phenobarbital, especially for periods of greater than two months, would benefit from supplementation with 1000-1500 mg calcium per day. As always it would be valuable to consult with the prescribing physician regarding any supplements being taken at the same time as prescription medications.

nutrient affected by drug: Carnitine

• research: Concern has been expressed as to the possible adverse effects of anticonvulsant drugs upon carnitine levels. However, with regard to phenobarbital the research appears contradictory at this time. While both Zelnick et al and Castro-Gago et al reported decreased serum carnitine levels among individuals using valproic acid, Zelnick found no such association for phenobarbital while Castro-Gago found such an effect.
(Castro-Gago M, et al. J Child Neurol 1998 Nov;13(11):546-549; Zelnik N, et al. Acta Paediatr 1995 Jan;84(1):93-95.)

• nutritional support: The clinical implications of reduced carnitine levels due to this potential interaction are uncertain at this time. in general deficiencies of carnitine are uncommon and there is no conclusive evidence to indicate that most individuals benefit from carnitine supplements. In some therapeutic settings, not necessarily related to the use of anticonvulsants, carnitine has been used at doses in the range of 50 mg/kg per day. However, any individual using phenobarbital or other anticonvulsant medications would be advised to refrain from starting any supplemental use of carnitine without consulting with the prescribing physician and/or a healthcare professional trained in nutrition.

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Do not rely solely on the information in this article.

References

Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990 Jun;18(6):472-484.
Oral contraceptive steroids are used by an estimated 60 to 70 million women world-wide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs. A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol. Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability of ethinylestradiol, a large enterohepatic recirculation and gut flora particularly susceptible to the antibiotic being used. Two drugs, ascorbic acid (vitamin C) and paracetamol (acetaminophen), give rise to increased blood concentrations of ethinylestradiol due to competition for sulphation. The interactions could have some significance to women on oral contraceptive steroids who regularly take high doses of either drug. Although on theoretical grounds adsorbents (e.g. magnesium trisilicate, aLuminium hydroxide, activated charcoal and kaolin) could be expected to interfere with oral contraceptive efficacy, there is no firm evidence that this is the case. Similarly, there is no evidence that smoking alters the pharmacokinetics of oral contraceptive steroids. These agents are now well documented as being able to alter the pharmacokinetics of other concomitantly administered drugs.

Biale Y, Lewenthan H. Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol 1984 Nov;18(4):211-216.
Abstract: A study was conducted to determine the frequency of malformations among newborn infants of mothers receiving anticonvulsive therapy, with and without supplementation of folic acid. In the retrospective part of the study, the frequency of congenital malformations among the 66 newborn of 24 women who received anticonvulsive drugs without the supplementation of folic acid was 15% (10 children). The defects noted were congenital heart disease, cleft lip and palate, neural tube defects and skeletal abnormalities. Three out of the 10 children were stillborn or died immediately after delivery. In the prospective study of the 22 epileptic women with folic acid supplementation to their anticonvulsive regimen, 33 infants were born alive, without congenital malformations and of normal body weight. The teratogenic activity of anticonvulsant drugs seems to be mediated by interference with folic acid metabolism, and such activity might be influenced by hereditary and environmental factors. When an epileptic woman wishes to become pregnant, it is recommended that folic acid be added to her regimen.

Botez MI, Botez T, Ross-Chouinard A, Lalonde R. Thiamine and folate treatment of chronic epileptic patients: a controlled study with the Wechsler IQ scale. Epilepsy Res 1993 Oct;16(2):157-163.
Abstract: Seventy-two epileptic patients receiving phenytoin (PHT) alone or in combination with phenobarbital for more than 4 years were divided into four groups, the first taking two placebo tablets per day; the second folate (5 mg/day) and placebo; the third placebo and thiamine (50 mg/day); and the fourth both vitamins. The clinical trial lasted 6 months. At baseline assessment, 31% of the patients had subnormal blood thiamine levels and 30% had low folate. The vitamin deficiencies were independent phenomena. It was found that thiamine improved neuropsychological functions in both verbal and non-verbal IQ testing. In particular, higher scores were recorded on the block design, digit symbol, similarities and digit span subtests. Folate treatment was ineffective. These results indicate that, in epileptics chronically treated with PHT, thiamine improves neuropsychological functions, such as visuo-spatial analysis, visuo-motor speed and verbal abstracting ability.

Bone HG. Long-term anticonvulsant therapy and vitamin D metabolism. JAMA 1983;249:939. (Review)

Castro-Gago M, Eiris-Punal J, Novo-Rodriguez MI, Couceiro J, Camina F, Rodriguez-Segade S. Serum carnitine levels in epileptic children before and during treatment with valproic acid, carbamazepine, and phenobarbital. J Child Neurol 1998 Nov;13(11):546-549.
Abstract: Serum levels of free, acyl, and total carnitine were determined in 32 patients with seizures, before and after 3, 6, and 12 months of treatment with valproic acid (17 patients), carbamazepine (10 patients), or phenobarbital (5 patients). In all three treated groups, both free and total carnitine levels showed a significant decline with respect to pretreatment levels. This decline was most marked and most consistent in patients treated with valproic acid. In 35% of the patients in this group, carnitine deficiency (ie, total carnitine < 30 micromol/L) was observed by month 12. In none of the three groups were serum carnitine levels significantly correlated with the serum concentration of the drug. These findings suggest a need to monitor serum carnitine levels in children treated with any of these drugs.

Christiansen C, Rodbro P, Lund M. Incidence of anticonvulsant osteomalacia and effect of vitamin D: controlled therapeutic trial. Br Med J 1973 Dec 22;4(894):695-701.

Chung S, Ahn C. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Dev 1994 Sep-Oct;16(5):382-385.
Abstract: In order to assess the bone changes in the subjects receiving anti-epileptic drugs (AEDs), bone mineral densities (BMDs) of the arms, legs, ribs, pelvis, spine, and the whole body were scanned in 78 epileptic children and in 78 controls using dual photon absorptiometry. The study subjects were classified according to the duration of the monotherapy with phenobarbital (PB) or phenytoin (PHT); those who received AEDs for less than 12 months as Group I, for 13-23 months as Group II, and for 24 months as Group III. Group III was subclassified according to the kind of AEDs administered, into those receiving PB as Group IIIp, and those receiving PHT as Group IIId. There was no significant differences in the BMDs of each area, when compared to each control in Groups I and II. In Group III, there were significant differences in ribs and spine, according to the duration of administration. In Group IIIp, there was a significant difference in ribs and spine, and, in Group IIId, there was a significant difference in most of the areas. These results show that the measurement of BMDs in the ribs and spine is necessary for the early detection of subtle bone loss, and it is recommended that vitamin D be administered to children with epilepsy receiving AEDs over 24 months.

Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990 Dec;30(6):892-896.
Abstract: Patients taking oral contraceptive steroids (OCS) are known to suffer contraceptive failure while taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine. We have studied the single dose kinetics of ethinyloestradiol (EE2); 50 micrograms, and levonorgestrel (Ng); 250 micrograms in groups of women before and 8-12 weeks after starting therapy with phenytoin (n = 6) and carbamazepine (n = 4). The area under the plasma concentration-time curve (AUC) was measured over a 24 h period for each steroid and significant reductions were seen with both anticonvulsants. Phenytoin reduced the AUC for EE2 from 806 +/- 50 (mean +/- s.d.) to 411 +/- 132 pg ml-1 h (P less than 0.05) and for Ng from 33.6 +/- 7.8 to 19.5 +/- 3.8 ng ml-1 h (P less than 0.05). Carbamazepine reduced the AUC for EE2 from 1163 +/- 466 to 672 +/- 211 pg ml-1 h (P less than 0.05) and for Ng from 22.9 +/- 9.4 to 13.8 +/- 5.8 ng ml-1 h (P less than 0.05). These changes are compatible with the known enzyme inducing effects of phenytoin and carbamazepine. Patients taking these anticonvulsants will need to be given increased doses of OCS (equivalent to 50-100 micrograms EE2 daily) to achieve adequate contraceptive effects.

D'Erasmo E, Ragno A, Raejntroph N, Pisani D. [Drug-induced osteomalacia]. Recenti Prog Med 1998 Oct;89(10):529-533. [Article in Italian] (Review)
Abstract: The osteomalacia is a metabolic bone disease, characterized by a defect of bone mineralization, due to a lot of causes; among these an important role may be attributed to some drugs. The drugs most frequently associated with osteomalacia are: cholestyramine, phenytoin, phenobarbital, rifampicin, isoniazid, aluminium-containing antacid, saccharated ferric oxide, cadmium, lead, bisphosphonates, fluoride and aluminum. In this review we discuss about the pathophysiologic mechanisms related to drug-induced osteomalacia involving vitamin D metabolism, phosphorus homeostasis and bone mineralization.

Dansky LV, Andermann E, Rosenblatt D, Sherwin AL, Andermann F. Anticonvulsants, folate levels, and pregnancy outcome: a prospective study. Ann Neurol 1987 Feb;21(2):176-182.
Abstract: Folate levels in serum and red cells, as determined by a microbiological assay using Lactobacillus casei, and plasma anticonvulsant concentrations were monitored concurrently in nonpregnant (50 subjects) and pregnant (49 pregnancies in 46 subjects) epileptic women. Twenty-three (46%) nonpregnant women had subnormal serum folate levels and 4 nonpregnant women (8%) showed subnormal red cell folate levels. In pregnant women not taking folate supplements, the incidence of folate deficiency increased as the pregnancy advanced. Pregnant women taking folate supplements achieved normal or supranormal blood folate concentrations. In both nonpregnant and pregnant women, serum and red cell folate levels were inversely correlated with plasma concentrations of phenytoin and of phenobarbital, and with the number of anticonvulsants. In 49 pregnancies, there were 10 abnormal outcomes (20.4%): 4 spontaneous abortions (8.2%) and 6 children with major congenital malformations (12.2%). Blood folate levels were significantly lower in pregnancies with an abnormal outcome than in those with a normal outcome. The results suggest a dose-response relationship among anticonvulsants, folate, and adverse pregnancy outcome.

Duus BR Fractures caused by epileptic seizures and epileptic osteomalacia. Injury 1986 Jan;17(1):31-33.
Abstract: A case of several severe fractures in one patient following epileptic seizures is reported. The patient suffered from epileptic osteomalacia and responded well to vitamin D treatment. The cause of anticonvulsant-induced osteomalacia and its treatment are discussed.

Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Callaghan N. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy. Q J Med 1986 Jun;59(230):569-577.
Abstract: The biochemical parameters associated with vitamin D metabolism, calcium, 25-hydroxy-vitamin D (25OHD) and alkaline phosphatase levels were assessed in 226 out-patients with epilepsy. Patients were grouped depending on the drug treatment; carbamazepine, phenytoin, phenobarbitone and sodium valproate used alone as monotherapy and a combination of these drugs as polytherapy. The most severe alterations occurred in the polytherapy group. Hypocalcaemia was more severe in the phenobarbitone monotherapy group than the carbamazepine or the phenytoin groups. No patient on sodium valproate monotherapy had subnormal levels of calcium (less than 2.1 mmol/l). 25OHD levels were similarly reduced in the carbamazepine, phenytoin and the phenobarbitone groups with no reduction in the sodium valproate group. Significant elevations in alkaline phosphatase levels were evident in all patient groups except the sodium valproate group. This study confirms biochemical evidence for anticonvulsant osteomalacia when the enzyme-inducing drugs are used, the degree of severity depending on the drug regimen.

Hansson O, Sillanpaa M. Letter: Pyridoxine and serum concentration of phenytoin and phenobarbitone. Lancet 1976 Jan 31;1(7953):256.

Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc 1985 Jan;44(1 Pt 1):124-129.
Abstract: Metabolic mechanisms of nutrition and drug interactions include 1) the effects of diet on drug metabolism and action and 2) the effects of drugs on nutritional processes. The type, amount, and timing of foods consumed influence drug dissolution, absorption, distribution, metabolism, and excretion. High-fat meals enhance the absorption of griseofulvin and some other drugs. Milk and other sources of calcium inhibit absorption of tetracycline. High-fat meals increase plasma concentrations of free fatty acids and thereby displace many drugs from binding sites on plasma albumin. High-protein diets increase the activity of the mixed-function oxidase system and enhance the metabolism of numerous drugs. High-electrolyte intakes increase excretion of lithium and also diminish the action of diuretic agents. Bile acid sequestrants and some laxatives decrease lipid digestion and absorption, as well as absorption of the fat-soluble vitamins. Numerous drugs, including tetracycline and cholestyramine, bind iron and decrease its absorption. Coumarins inhibit the function of vitamin K. Phenobarbital and other anticonvulsants are inducers of cytochrome P-450 and the mixed-function oxidase system. Long-term treatment with these inducers can cause excessive metabolism and deficiency of vitamin D. Prooxidant drugs such as chloroquine, drugs detoxified by conjugation with glutathione, and alcohol can deplete reduced glutathione with consequent effects on amino acid transport and the redox status of cells. Acid-forming foods acidify the urine and increase the loss of alkaline drugs such as the amphetamines. Base-forming drugs increase the loss of acidic drugs such as barbiturates. The range of metabolic interactions of drugs and nutrients includes the full scope of physiological processes to which drugs and nutrients are subject.

Holmes RP, Kummerow FA. The relationship of adequate and excessive intake of vitamin D to health and disease. J Am Coll Nutr. 1983;2(2):173-199. (Review)

Iivanainen M, Savolainen H. Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy. Acta Neurol Scand Suppl 1983;97:49-67.
Abstract: Phenobarbital and phenytoin have good antiepileptic effect, but clinically significant untoward effects occur during their long-term use. Phenobarbital may cause hyperactivity, behavioral problems, sedation, and even dementia; these effects are dose related to some extent. Side effects of phenytoin include sedation, a cerebellar syndrome, phenytoin encephalopathy, psychosis, locomotor dysfunction, hyperkinesia, megaloblastic anemia, decreased serum folate level, decreased bone mineral content, liver disease, IgA deficiency, gingival hyperplasia, and a lupus-like hypersensitivity syndrome. Especially susceptible to the neurotoxic effects of phenytoin are epileptic children with severe brain damage who are on multiple drugs. In those children, balance disturbance may develop and be followed by gradual loss of locomotion. Among 131 mentally retarded epileptic patients, phenytoin intoxication occurred in 73 (56%), of whom 18 experienced persistent loss of locomotion. There is experimental evidence that the toxic action of phenytoin lies at the cellular level, predominantly in the cerebellum. Many experts avoid the long-term use of phenytoin because of its insidious and potentially dangerous side effects.

Jiao FY, Gao DY, Takuma Y, Wu S, Liu ZY, Zhang XK, Lieu NS, Ge ZL, Chui W, Li HR, Cao YM, Bai AN, Liu SB. Randomized, controlled trial of high-dose intravenous pyridoxine in the treatment of recurrent seizures in children. Pediatr Neurol 1997 Jul;17(1):54-57.
Abstract: To determine the efficacy of pyridoxine in treating seizures, 90 infants and children with recurrent convulsions primarily due to acute infectious diseases were enrolled in the present study. Forty patients were treated with high-dose pyridoxine (30 or 50 mg/kg/day) by intravenous infusion, and 50 subjects served as controls. Antiepileptic drugs and other therapies were similar in the two groups except for pyridoxine. Clinical efficacy criteria were based on the frequency of convulsions per day and on the duration of individual seizures after therapy was initiated. The results indicated that total response rates in the pyridoxine group and control group were 92.5% and 64%, respectively (chi-square = 14.68, P < .001). After initiation of therapy, seizures resolved after 2.4 +/- 1.4 days in the pyridoxine group and after 3.7 +/- 2.0 days in the control group (t = 3.67, P < .001). No adverse effects of pyridoxine were apparent during the observation period. We conclude that pyridoxine is an effective, safe, well-tolerated, and relatively inexpensive adjunct to routine antiepileptic drugs for treatment of recurrent seizures in children.

Jones G, Sambrook PN. Drug-induced disorders of bone metabolism. Incidence, management and avoidance. Drug Saf 1994 Jun;10(6):480-489.
Abstract: Calcium homeostasis depends upon the interplay of intestinal calcium absorption, renal excretion and skeletal mobilisation of calcium, mediated through bone formation and resorption, which are closely coupled in the adult skeleton. Serum calcium is extremely important for maintenance of normal cellular functions and is regulated by the major calciotropic hormones, parathyroid hormone (PTH), 1,25-dihydroxy-vitamin D and calcitonin. Certain drugs can interfere with calcium metabolism by effects at different stages in calcium metabolism, and a knowledge of the mechanism of drug action is generally helpful in understanding the various resultant clinical skeletal syndromes. Corticosteroids, for example, have profound effects at multiple stages of calcium metabolism, resulting in decreased bone formation and enhanced bone resorption leading to accelerated osteoporosis. Drugs such as aluminium and anticonvulsants impair mineralisation, leading to osteomalacia. Other drugs, such as fluoride, are employed for their known effects on bone, but in excess dosage can be harmful by producing mineralisation defects. Management of these conditions will be discussed in this review.

Keith DA, Gundberg CM, Japour A, Aronoff J, Alvarez N, Gallop PM. Vitamin K-dependent proteins and anticonvulsant medication. Clin Pharmacol Ther 1983 Oct;34(4):529-532.
Abstract: Certain anticonvulsant drugs, especially phenytoin and phenobarbital, interfere with vitamin K metabolism as indicated by a raised serum osteocalcin level. This finding may be of importance in the pathogenesis of side effects of these medications.

Kishi T, Fujita N, Eguchi T, Ueda K. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci 1997 Jan;145(1):109-112.
Abstract: To determine whether the induction of liver enzymes by antiepileptic drugs play a major role in folate depletion, serum concentrations of folate were measured in age-matched control subjects without anemia and in epileptic outpatients who were being treated with a single antiepileptic drug. Two of the four drugs being administered were enzyme inducers. A protein binding radioassay was used to measure folate levels. Compared with serum folate levels in controls (5.14 +/- 1.88 ng/ml: n = 74), mean serum folate levels were reduced significantly in patients treated with phenobarbitone (3.91 +/- 1.73 ng/ml, p < 0.01: n = 33) and carbamazepine (3.85 +/- 1.02 ng/ml, p < 0.01: n = 36): both of which are enzyme-inducing agents. In contrast, patients treated with the non-enzyme-inducer valproate (5.39 +/- 1.71 ng/ml: n = 41) or zonisamide (5.59 +/- 2.60 ng/ml: n = 25) exhibited serum folate levels that did not differ significantly from values in controls. Findings showed that a reduction in serum folate is associated with the induction of enzymes by antiepileptic drugs. Thus, the induction of microsomal liver enzymes may be critical to the depletion of folate by antiepileptic drugs.

Lewis DP, Van Dyke DC, Stumbo PJ, Berg MJ. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother 1998 Jul-Aug;32(7-8):802-817. (Review)
Abstract: OBJECTIVE: Part I of this review examines the relationship between antiepileptic drugs (AEDs) and pregnancy outcomes. Drug-induced folate deficiency and the role of AED metabolism are emphasized. Part II will discuss periconceptional folate supplementation for prevention of birth defects. Part III will discuss the mechanism of folate's protective effect, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted for journal articles published through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included phenytoin, carbamazepine, phenobarbital, primidone, valproic acid, oral contraceptives, clomiphene, drug-induced abnormalities, spina bifida, anencephaly, neural tube defect, folate, folic acid, and folic acid deficiency. STUDY SELECTION: Relevant animal and human studies examining the effects of AEDs, smoking, and oral contraceptives on folate status and pregnancy outcome are reviewed. DATA EXTRACTION: Studies and case reports were interpreted. Data extracted included dosing, serum and red blood cell folate concentrations, teratogenicity of anticonvulsant medications, metabolism of AEDs and folate, and genetic susceptibility to AED-induced teratogenicity. DATA SYNTHESIS: Low serum and red blood cell folate concentrations are associated with adverse pregnancy outcomes. Decreases in serum folate are seen with AEDs, oral contraceptives, and smoking. Since similar birth defects are observed with multiple AEDs, metabolism of aromatic AEDs to epoxide metabolites and genetic factors may play a role in teratogenesis. CONCLUSIONS: Adequate prepregnancy planning is essential for women who have epilepsy. Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation.

Livingston S. Long-term anticonvulsant therapy and vitamin D metabolism. JAMA 1983;249:939.

Macallan DC, Maxwell JD, Eastwood JB. Osteomalacia should be sought and treated before withdrawal of anticonvulsant therapy in UK Asians. Postgrad Med J 1992 Feb;68(796):134-136.
Abstract: Individuals from the Asian sub-continent in the United Kingdom are at particular risk of developing osteomalacia. We report a Gujarati woman who developed osteomalacia whilst taking anticonvulsant drugs; withdrawal of anticonvulsant therapy was followed by a seizure complicated by femoral neck fracture. In patients with other risk factors for osteomalacia, as is the case for Asians living in Britain, anticonvulsant drugs should not be reduced or withdrawn until osteomalacia, which puts the skeleton at increased risk of fracture, and its associated hypocalcaemia, which reduces seizure threshold, have been sought and adequately treated.

Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs 1999 Apr;57(4):535-544.
Abstract: Pregnant women with epilepsy constitute 0.5% of all pregnancies. Proper seizure control is the primary goal in treating women with epilepsy. The commonly used anticonvulsants are established human teratogens. Factors such as epilepsy, anticonvulsant-induced teratogenicity, patient's genetic predisposition and the severity of convulsive disorder may attribute to adverse pregnancy outcome for the children of women with epilepsy. Anticonvulsant interaction with folic acid and phytomenadione (vitamin K) metabolism may lead to an increased risk for neural tube defect and early neonatal bleeding. Psychological, hormonal and pharmacokinetic changes in pregnancy may escalate seizure activity. Preconceptional counselling should include patient education to ensure a clear understanding of risks of uncontrolled seizures and possible teratogenicity of anticonvulsants. Genetic counselling should be performed if both parents have epilepsy or the disease is inherited. Seizure control should be achieved at least 6 months prior to conception and, if clinically possible, by the lowest effective dose of a single anticonvulsant according to the type of epilepsy. The new anticonvulsants are not recommended in pregnancy and require further research to prove their safety in humans. Folic acid 5 mg/day should be administered 3 months before conception and during the first trimester to prevent folic acid deficiency-induced malformations. Antenatal management should include assessment of patients for anticonvulsant-associated birth defects through detailed ultrasound examination and levels of maternal serum alpha-fetoproteins. Therapeutic drug monitoring should be performed monthly, or as clinically indicated. If phenobarbital, carbamazepine or phenytoin is administered, maternal phytomenadione supplementation should begin 4 weeks before the expected date of delivery. In order to prevent convulsions during labour, proper seizure control should be achieved during the third trimester. Benzodiazepines or phenytoin are found to be effective for seizure cessation during labour and delivery. Phytomenadione should be administered immediately after birth to the newborn. The neonate should be assessed carefully for epilepsy and anticonvulsant-associated dysmorphology. Advising the patient on postpartum management regarding contraception and breast-feeding will help maximise the best possible outcome for the newborn and mother. With proper preconceptional, antenatal and postpartum management up to 95% of these pregnancies have been reported to have favourable outcomes.

Ogawa Y, Kaneko S, Otani K, Fukushima Y. Serum folic acid levels in epileptic mothers and their relationship to congenital malformations. Epilepsy Res 1991 Jan-Feb;8(1):75-78.
Abstract: Folic acid levels during pregnancy and in pre-pregnancy were determined in 51 epileptic mothers and those of matched controls. The serum folic acid (SF) levels of epileptic mothers were significantly lower than those of controls in all study periods. The SF levels of mothers of malformed offspring were significantly lower than those of mothers of normal offspring in the 1st and 2nd trimesters of pregnancy. These results suggest that SF concentrations are implicated in congenital malformations in the offspring of epileptic mothers.

Pluskiewicz W, Nowakowska J. Bone status after long-term anticonvulsant therapy in epileptic patients: evaluation using quantitative ultrasound of calcaneus and phalanges. Ultrasound Med Biol 1997;23(4):553-558.
Abstract: The bone status of 25 epileptic female patients on long-term (mean 19 y) anticonvulsant therapy was investigated using quantitative ultrasound of the calcaneus (Lunar Achilles) and phalanges (Igea DBM Sonic 1200). Comparisons were made with a control group of 43 normal healthy women. Radiogrammetric measurements of the second metacarpal bone were also made in the epileptic patients. While all of the ultrasonic parameters were reduced in the epileptic group, differences only achieved statistical significance for speed of sound (SOS) at the phalanges. Phalangeal SOS correlated significantly with cortical thickness of the second metacarpal bone (r = 0.44, p < 0.05). The data suggest that long-term anticonvulsant therapy is associated with significant cortical bone loss. Quantitative ultrasound may have a role in monitoring bone loss in epileptic patients and in guiding suitable preventive therapy.

Reynolds EH, Chanarin I, Milner G, Matthews DM. Anticonvulsant therapy, folic acid and vitamin B12 metabolism and mental symptoms. Epilepsia. 1966 Dec;7(4):261-270.

Salazar T, Barrera F, Capurro MT, Barra C, Salinas A, Novoa F. [Serum concentrations of phenobarbital and the metabolism of calcium and phosphorus in children]. Rev Chil Pediatr 1984 Nov-Dec;55(6):407-410. [Article in Spanish]

Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser PA, Walter-Sack I. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia 1999 Mar;40(3):345-350.
Abstract: PURPOSE: Homocysteine is an experimental convulsant and an established risk factor in atherosclerosis. A nutritional deficiency of vitamin B6, vitamin B12, or folate leads to increased homocysteine plasma concentrations. During treatment with carbamazepine (CBZ), phenytoin, or phenobarbital, a deficiency in these vitamins is common. The objective of the study was to test the hypothesis that antiepileptic drug (AED) treatment is associated with increased homocysteine plasma concentrations. METHODS: A total of 51 consecutive outpatients of our epilepsy clinic receiving stable, individually adjusted AED treatment and 51 sex- and age-matched controls were enrolled in the study. Concentrations of total homocysteine and vitamin B6 were measured in plasma; vitamin B12 and folate were measured in the serum of fasted subjects. RESULTS: Patients and controls differed significantly in concentrations of folate ( 13.5+/-1.0 vs. 17.4+/-0.8 nM and vitamin B6 (39.7+/-3.4 vs. 66.2+/-7.5 nM), whereas serum concentrations of vitamin B12 were similar. The homocysteine plasma concentration was significantly increased to 14.7+/-3.0 microM in patients compared with controls (9.5+/-0.5 microM; p < 0.05, Wilcoxon rank-sum test). The number of patients with concentrations of >15 microM was significantly higher in the patient group than among controls. The same result was obtained if only patients with CBZ monotherapy were included. Patients with increased homocysteine plasma concentrations had lower folate concentrations. CONCLUSIONS: These data support the hypothesis that prolonged AED treatment may increase plasma concentrations of homocysteine, although the alternative explanation that increased homocysteine plasma concentrations are associated with the disease and not the treatment cannot be completely excluded at the moment.

Shafer RB, Nuttall FQ. Calcium and folic acid absorption in patients taking anticonvulsant drugs. J Clin Endocrinol Metab 1975 Dec;41(06):1125-1129.
Abstract: Calcium and folic acid absorption were studied in 28 adult male epileptics on chronic anticonvulsant therapy. In 16 patients on diphenylhydantoin alone, calcium absorption was abnormal in 9. In 12 patients on both diphenylhydantoin and phenobarbital, calcium absorption was abnormal in 3 patients. Folic acid (3H-PGA) absorption was normal in all but one patient, while serum folate (less than 6.4 ng/ml) was reduced in all patients. Hypocalcemia (less than 8.5 mg/100 ml) occurred in only 2 patients, while serum alkaline phosphatase was elevated in 7 patients. These findings support the proposal that rickets and osteomalacia reported in patients on chronic anticonvulsant therapy results from reduced calcium absorption. The effect of these drugs appears to be the acceleration of the metabolism of vitamin D and an increase in the excretion of polar metabolites. This may result in reduced levels of 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol which are necessary for normal absorption of calcium. Since calcium absorption may be impaired secondary to a relative vitamin D deficiency, a supplemental increase in vitamin D intake by patients on anticonvulsant drugs is recommended.

Shane-McWhorter L, Cerveny JD, MacFarlane LL, Osborn C. Enhanced metabolism of levonorgestrel during phenobarbital treatment and resultant pregnancy. Pharmacotherapy 1998 Nov-Dec;18(6):1360-1364.
Abstract: Levonorgestrel implants (Norplant) are an alternative to oral contraceptives and medroxyprogesterone acetate intramuscular injections. An interaction may exist between levonorgestrel and agents that induce the hepatic microsomal enzyme system. A 21-year-old woman with a history of a seizure disorder, treated with phenobarbital, who received levonorgestrel implants became pregnant. After a normal delivery, she took oral contraceptives concomitantly with phenobarbital. Although she was educated about the importance of a backup method of contraception, the woman again became pregnant and delivered twins. A recent national survey of neurologists and obstetricians was conducted evaluating prescriber knowledge of interactions between oral contraceptives and anticonvulsants. Only 4% of neurologists and zero percent of obstetricians knew all the interactions between the six most commonly prescribed anticonvulsants and oral contraceptives. This case supports the importance of continued patient and prescriber education regarding the possibility of drug-drug interactions in women taking anticonvulsants and hormonal contraceptives.

Smith DB, Racusen LC. Folate metabolism and the anticonvulsant efficacy of phenobarbital. Arch Neurol 1973 Jan;28(1):18-22.

Tomita S, Ohnishi J, Nakano M, Ichikawa Y. The effects of anticonvulsant drugs on vitamin D3-activating cytochrome P-450-linked monooxygenase systems. J Steroid Biochem Mol Biol 1991 Oct;39(4A):479-485.
Abstract: The effects of two anticonvulsant drugs, phenytoin and sodium valproate, on the bioactivation of vitamin D3 have been studied with respect to the microsomal and mitochondrial cytochrome P-450-linked monooxygenase systems that contribute to 25-hydroxylation of vitamin D3 in rabbit liver, and the mitochondrial cytochrome P-450-linked monooxygenase system that catalyzes 1 alpha-hydroxylation of 25-hydroxyvitamin D3 in rabbit kidney. These anticonvulsant drugs were found to inhibit the 25-hydroxylase activity on vitamin D3 in liver microsomes and mitochondria, respectively, but not to inhibit the 1 alpha-hydroxylation of 25-hydroxyvitamin D3, even over a wide concentration range. Moreover, the activities of the components of the cytochrome P-450-linked monooxygenase systems: NADPH-cytochrome P-450 reductase, NADPH-ferredoxin reductase and ferredoxin, were never inhibited by these drugs. It is possible that the inhibition of bioactivation of vitamin D3 by these anticonvulsant drugs causes rickets and osteomalacia, and the site of inhibition is expected to be the cytochrome P-450 mediated reactions in liver mitochondria.

Wahl TO, Gobuty AH, Lukert BP. Long-term anticonvulsant therapy and intestinal calcium absorption. Clin Pharmacol Ther. 1981 Oct;30(4):506-512.
Abstract: Twelve patients on anticonvulsant therapy were studied to determine whether or not the drugs induced alterations in gastrointestinal absorption of calcium, response to parathyroid hormone (PTH), or serum 25-hydroxy vitamin D (25-OHD) concentrations. Fractional calcium absorption (FCaA) was determined by giving 45Ca intravenously and orally. The short-term response to PTH was assessed by giving 200 U of parathyroid extract (PTE) intravenously over 15 min and measuring hourly urine cyclic adenosine monophosphate (cAMP) and tubular reabsorption of phosphate (TRP). Calcemic response to PTH was followed by giving intramuscular injections of PTE, 200 U every 6 hr. FCaA was 30.8 +/- 3.7% lower than the normal of 42.2 +/- 2.5% (P less than 0.025), and baseline 25-OHD levels were 30.5 +/- 3.4 ng/ml (normal 15 to 50 ng/ml). Anticonvulsant drugs did not alter renal response to PTE. There was a rise in urinary cAMP from 3.7 +/- 0.23 to 6.1 +/- 0.47 mumol/gm creatinine (P less than 0.005) with a fall in TRP from 87.8 +/- 1.2% to 78.8 +/- 1.6% (P less than 0.005). Serum calcium rose from 9.4 +/- 0.1 to 11.1 +/- 0.3 mg/dl (P less than 0.005). We conclude that FCaA is low in patients receiving anticonvulsant drugs, even when serum 25-OHD levels and the response of bone and kidney to PTH remain normal.

Williams C, Netzloff M, Folkerts L, Vargas A, Garnica A, Frias J. Vitamin D metabolism and anticonvulsant therapy: effect of sunshine on incidence of osteomalacia. Southern Med J 1984 Jul;77(7):834-836, 842.
Abstract: To study the association between anticonvulsant therapy and osteomalacia or rickets, we evaluated 450 epileptic patients receiving anticonvulsants and residing in an institution for the mentally retarded in Florida. Fifty-five of them with increased mean serum alkaline phosphatase and mildly depressed mean serum calcium levels were identified as being at risk for having osteomalacia. None of them, however, had low serum levels of vitamin D (25[OH]D) or radiologic evidence of osteomalacia or rickets. In contrast to reports from northern climates, we found minimal evidence of anticonvulsant-induced bone disease. The study suggests that exposure to sunshine in our patients probably prevented the development of anticonvulsant-induced osteomalacia or rickets.

Yerby MS. Problems and management of the pregnant woman with epilepsy. Epilepsia 1987;28 Suppl 3:S29-36. (Review)
Abstract: Pregnancies occurring in women who are epileptic are considered to be high risk. These women are at increased risk of seizures during pregnancy, labor, and delivery and of pregnancy complications and adverse pregnancy outcomes. Pregnancy alters the pharmacokinetics of anticonvulsant drugs, the levels of which decline as pregnancy advances. Not all drugs are altered in a similar manner, however. The rate of congenital malformations in infants of epileptic mothers is 2.4 times higher than in the general population. Malformations occur with all of the commonly used anticonvulsant drugs. The possible mechanisms of teratogenicity include folic acid antagonism, fetal tissue binding, and toxic effects of metabolic intermediates. Therapy with more than one drug increases the risk of congenital malformations. A unique hemorrhagic phenomenon in the infants of epileptic mothers has been reported and appears to be the result of a deficiency of vitamin K-dependent clotting factors. When taken by a pregnant woman, all antiepileptic drugs except valproic acid manifest themselves in breast milk, but only if the infant exhibits evidence of sedation should breastfeeding be discontinued. The dilemma for the physician treating the pregnant epileptic woman is to protect the mother from seizures and the fetus from unnecessary exposure to anticonvulsant medications.

Zelnik N, Fridkis I, Gruener N. Reduced carnitine and antiepileptic drugs: cause relationship or co-existence? Acta Paediatr 1995 Jan;84(1):93-95.
Abstract: Serum carnitine was measured longitudinally before and after therapy in 15 patients receiving valproic acid, 14 patients receiving carbamazepine and 8 patients receiving phenobarbital. The patients who received valproic acid showed a significant reduction in free (and total) serum carnitine (mean (SE) 37.6 (6.2) mumol/l without valproic acid, 29.1 (1.6) mumol/l with valproic acid (p < 0.001)). Such an effect was not found in patients receiving carbamazepine or phenobarbital.