Primidone

Brand Names: Mysoline

Clinical Names: Primidone

Summary

generic name: Primidone

trade name: Mysoline®

type of drug: Anticonvulsant, Antiepileptic drug.

Note: Primidone is an inactive substance until the body converts it to phenobarbital.

used to treat: Seizure disorders.

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

• nutrient affecting drug performance: Nicotinamide

• nutrient affected by drug: Vitamin D

• nutrient affected by drug: Vitamin K

• nutrient affected by drug: Calcium



Interactions

nutrient affected by drug: Folic Acid

• mechanism: Primidone may induce a biochemical or clinical folate deficiency. 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.

• report: Taliani et al reported a case of a patient who developed megaloblastic anemia caused by folate deficiency during treatment with primidone. The serum level of folic acid was significantly low. These researchers suggested that two causes able to produce folate deficiency were involved: chronic assumption of primidone, and low dietary intake of folic acid. The anemia was completely reversed by oral supplementation of folic acid.
(Taliani U, et al. Acta Biomed Ateneo Parmense. 1989;60(5-6):245-248.)

• nutritional concerns: The potential for folate deficiency 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, or primidone which converts into 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.
(Roe DA. 1985: 249; 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 5 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.)

Primidone can interfere with the effectiveness of birth control pills (oral contraceptives). 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. Women who might become pregnant should be advised to use a method of birth control other than oral contraceptives while taking primidone. 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.)

nutrient affecting drug performance: Nicotinamide

• mechanism: Nicotinamide inhibits metabolism of primidone through inhibition of cytochrome P-450.

• research: Bourgeois et al studied the effect of nicotinamide on the conversion of primidone to phenobarbital in mice and in three epileptic patients. In mice, 200 mg per kilogram of nicotinamide increased the half-life of primidone by 47.6%, and decreased the conversion to phenobarbital by 32.4%. Nicotinamide also decreased the conversion of primidone to phenobarbital in patients. The dose of nicotinamide correlated directly with the primidone-phenobarbital ratio.
(Bourgeois BF, et al. Neurology 1982 Oct;32(10):1122-26 )

• nutritional concerns: Individuals taking primidone should avoid taking nicotinamide and should consult their prescribing physician and/or a nutritionally oriented health care professional before starting to supplement with nicotinamide.

nutrient affected by drug: Vitamin D

• mechanism: Primidone may alter vitamin D metabolism and cause a vitamin D deficiency which could manifest as rickets or osteomalacia.
(Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985: 249.)

• 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: Patients taking primidone have been observed to have lower levels of vitamin K. Primidone-derived 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; Cornelissen M, et al. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):884-888.)

• 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 primidone-derived phenobarbital, cause reduced calcium absorption with long-term use, at least partially as a result of alterations in vitamin D metabolism.
(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.


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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

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.

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

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.

Bourgeois BF, Dodson WE, Ferrendelli JA. Interactions between primidone, carbamazepine, and nicotinamide. Neurology 1982 Oct;32(10):1122-1126.
Abstract: The effect of nicotinamide on the conversion of primidone to phenobarbital was studied in mice and in three epileptic patients. In mice, 200 mg per kilogram of nicotinamide increased the half-life of primidone by 47.6%, and the conversion to phenobarbital and phenylethylmalonamide was decreased by 32.4% and 14.5%, respectively. Nicotinamide also decreased the conversion of primidone to phenobarbital in patients. The dose of nicotinamide correlated directly with the primidone-phenobarbital ratio (r = 0.861, p less than 0.01). Nicotinamide also increased carbamazepine levels in two patients treated with this drug. The data demonstrate that nicotinamide inhibits metabolism of primidone in mice and metabolism of primidone and carbamazepine in humans. This probably occurs by inhibition of cytochrome P-450 by nicotinamide.

Carl GF, Gill MW, Schatz RA. Effect of chronic primidone treatment on folate-dependent one-carbon metabolism in the rat. Biochem Pharmacol. 1987 Jul 1;36(13):2139-2144.
Abstract: Rats were treated chronically with primidone (100 mg/kg/12 hr, p.o.) for up to 8 weeks. The effects of this treatment on one-carbon metabolism were determined in brain and liver. Serine hydroxymethyltransferase activity increased in both brain (44%) and liver (50%). Methylenetetrahydrofolate reductase activity increased in liver (26%) with a significant correlation to the length of treatment, but in brain it was unchanged. Methyltetrahydrofolate:homocysteine methyltransferase activity increased in brain (43%) with a significant correlation to length of treatment, but in liver no effect was observed. Methionine adenosyltransferase activity in brain was significantly lower than control at only one point after 8 weeks of chronic treatment. S-Adenosylmethionine concentration in liver increased gradually (23%) during treatment. S-Adenosylhomocysteine concentrations decreased in brain (33%) and increased in liver (23%) with chronic primidone treatment. These data support the hypothesis that chronic primidone treatment leads to folate depletion through interference with folate metabolism.

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.

Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Vogels-Mentink G, Motohara K, De Abreu R, Monnens L. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):923-928.
Abstract: OBJECTIVE: The null hypothesis of our study is that the incidence of vitamin K deficiency in mother-infant pairs exposed to anticonvulsant drugs is not higher than in controls. STUDY DESIGN: In this multicenter observational case-control study, 25 pregnant women receiving anticonvulsant therapy and 25 pregnant controls were studied for PIVKA-II (protein induced by vitamin K absence of factor II) and vitamin K1 concentrations at 32 weeks' gestation and at delivery. RESULTS: PIVKA-II was detectable in 54% of cord samples of the anticonvulsant group and in 20% of controls (chi 2, p = 0.01). In both groups vitamin K1 cord blood levels were predominantly below the detection limit. Maternal vitamin K1 concentrations were lower in women with epilepsy than in controls (Wilcoxon's rank sum test, p < 0.05), but PIVKA-II was rarely present. CONCLUSIONS: The incidence of vitamin K deficiency is increased in neonates exposed to anticonvulsant drugs prenatally. Their mothers, however, are rarely vitamin K deficient.

Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Motohara K, Monnens L. Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol 1993 Mar;168(3 Pt 1):884-888.
Abstract: OBJECTIVE: The null hypothesis of this study is that extra vitamin K administered to pregnant women on a regimen of enzyme-inducing anticonvulsant therapy will not decrease the frequency of symptoms of vitamin K deficiency in their neonates. STUDY DESIGN: A multicenter case-control study was performed on 16 pregnant women on anticonvulsant therapy who received 10 mg of vitamin K1 daily from 36 weeks of pregnancy onward. Concentrations of PIVKA-II (protein induced by vitamin K absence for factor II) and of vitamin K1 were determined in cord blood and compared with those in 20 controls. RESULTS: In none of 17 cord samples was PIVKA-II detectable, compared with 13 of 20 in controls (chi 2, p < 0.001). Median cord vitamin K1 level was 530 pg/ml compared with below detection limit in most controls. CONCLUSIONS: Antenatal vitamin K1 treatment decreases the frequency of vitamin K deficiency in neonates of mothers on anticonvulsant therapy.

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.

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.

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.

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.

Klein GL, Florey JB, Goller VL, Larese RJ, Van Meter QL. Multiple vitamin deficiencies in association with chronic anticonvulsant therapy. Pediatrics 1977 Nov;60(5):767. (Letter )

Krause KH, Bonjour JP, Berlit P, Kochen W. Biotin status of epileptics. Ann N Y Acad Sci 1985;447:297-313.
Abstract: Microbiologically determined plasma biotin levels in 404 epileptics under long-term treatment with anticonvulsants were markedly lower than in 112 controls (p less than 0.0005). Patients with partial epilepsy had lower biotin levels and higher average daily intake of AC than those with generalized epilepsy. Epileptics treated with valproate sodium in monotherapy showed considerably higher biotin levels than epileptics with monotherapy of primidone (PRM), carbamazepine (CBZ), phenytoin (PHT) or phenobarbital (PB). The group of epileptics with high average daily dose of anticonvulsants had lower biotin levels than the group with low dose. In three patients with newly recognized epilepsy biotin levels were normal before starting anticonvulsant medication, increased during the first week and fell under the starting level in the following weeks. Four epileptics treated with PHT, PB, PRM or CBZ had an increased urinary excretion of organic acids, as found in patients with a deficiency of biotin-dependent carboxylases. In 37 epileptics undergoing long-term treatment plasma lactate concentrations were determined; they had a higher mean concentration than that found in controls. Our results suggest, that the lowering of biotin in epileptics is caused by intake of anticonvulsants and has a biochemical effect in these patients. It is discussed, whether this could be a factor in the mode of action of anticonvulsants.

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.
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.

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.

Taliani U, et al. [A clinical case of severe megaloblastic anemia during treatment with primidone]. Acta Biomed Ateneo Parmense. 1989;60(5-6):245-248. [Article in Italian]
Abstract: The case of a patient who developed megaloblastic anemia caused by folate deficiency during treatment with primidone is reported. The serum level of folic acid was significantly low. Two causes able to produce folate deficiency have been discovered: chronic assumption of primidone, and low dietary intake of folic acid. The anemia was completely reversed by oral supplementation of folic acid. It has already been recognized that additional nutritional deficiency is required to precipitate a frank megaloblastic anemia during therapy with antiepileptic drugs.

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.