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Anticonvulsant Medications
Hydantoin Derivatives


Depletions
Calcium; Vitamin D
Mechanism

Hypocalcemia and subsequent bone loss during anticonvulsant therapy may be the result of vitamin D deficiency (Foss et al. 1979; Gough et al. 1986; Reunanen et al. 1976; Shafer and Nuttall 1975). Phenytoin accelerates the metabolism of vitamin D and increases the excretion of metabolites. Patients on long-term anticonvulsant therapy have reduced serum concentrations of 25-hydroxycholecalciferol (Bell et al. 1979; Gascon-Barre et al. 1984) and 1-25-dihydroxycholecalciferol (Somerman et al. 1986), which are necessary for calcium absorption (Shafer and Nuttall 1975; Valimaki et al. 1994). One study found that epileptic patients receiving long-term anticonvulsant therapy who were exposed to regular sunshine had normal serum vitamin D (25(OH)D) levels with no evidence of osteomalacia or rickets (Williams et al. 1984).


Significance of Depletion

Calcium:Osteoporosis is the primary disease associated with chronic calcium deficiency; it can result in pathologic fractures associated with bone pain, spinal deformity, and premature morbidity and mortality (Cashman and Flynn 1999; Covington 1999). Other signs and symptoms of depleted serum calcium levels include arrhythmias, neuromuscular irritability, and mental status changes such as depression and psychosis (Potts 1998).

Vitamin D: Because vitamin D is fat-soluble, prolonged periods of deficiency are required to produce symptoms (National Research Council 1989). While the long evolution is often asymptomatic (Rao 1999), depleted levels are characterized by inadequate mineralization of the bone, which could lead to rickets (in children) and osteomalacia (in adults) (Covington 1999; National Research Council 1989; Rao 1999). Other signs and symptoms of low levels of vitamin D include increased risk of fractures, osteoporosis, phosphaturia, hyperparathyroidism, chronic muscle weakness, hypovitaminosis D, bone pain, pseudofractures, waddling gait, or severe, chronic hypocalcemia (Holick et al. 1998; National Research Council 1989; Rao 1999; Vieth 1999). Subclinical vitamin D deficiency has been reported in postmenopausal women with osteoporosis (Rao 1999). The prevalence of vitamin D deficiency is more common in women, certain ethnic populations, and increases with age.


Replacement Therapy

Calcium: Calcium supplementation in the form of citrate, malate, gluconate, or carbonate salts may range from 1000 mg to 1500 mg or more daily (Adler and Rosen 1999; Covington 1999). Doses as high as 3000 mg/day with 10 to 50 mcg/day of 25-OH-D3 may be appropriate if plasma calcium and phosphate levels are stable and within normal range (DrŁeke 1999). In cases where calcium deficits are associated with vitamin D deficiency, up to 6000 mg/day of calcium (acetate or carbonate) may be warranted. These values should be adjusted on an individual basis depending upon the patient's age, gender, clinical presentation, serum calcium levels, dietary habits, and medication regimen. Calcium replacement should be part of a comprehensive approach to the evaluation and treatment of osteoporosis.

Vitamin D:†Doses of vitamin D3 ranging from 1000 to 2000 IU/day or 25-OH-D3 ranging from 10 to 25 mcg/day have been used to treat vitamin D deficiency, which is characterized by low plasma levels of 25-OH-D3 (DrŁeke 1999). Other recommendations involve doses between 200 to 800 IU/day for adults (Rao 1999) and 50,000 IU/month for elderly patients with osteomalacia (Holick et al. 1998).


Vitamin B1 (Thiamine)
Mechanism

Long-term phenytoin therapy significantly reduces blood thiamine levels (Botez et al. 1982; Botez et al. 1993).


Significance of Depletion

Early nonspecific manifestations of depleted thiamine levels include weakness, fatigue, anorexia, constipation, nystagmus, and mental status changes such as memory loss, confusion, and depression (Covington 1999). Beriberi is the classic condition associated with thiamine deficiency. Symptoms include polyneuritis, cardiac disturbances (bradycardia, heart failure, hypertrophy), and possibly edema. Thiamine deficiency rarely occurs alone; it is usually accompanied by deficiencies in other B vitamins.


Replacement Therapy

Although the recommended dietary allowance (RDA) for this nutrient ranges from 1.1 to 1.5 mg for adults depending on gender, treatment of beriberi requires oral doses as high as 5 to 10 mg/day for one month to achieve tissue saturation and replenish body stores of thiamine (Covington 1999). Treatment of deficiency secondary to alcoholism may require up to 40 mg/day of thiamine orally; cardiovascular disease may warrant a total daily intake of 90 mg (Marcus and Coulston 1996). Replacement therapy should be tailored to the patient's needs depending on age, gender, clinical presentation, serum vitamin B1 levels, dietary habits, and medication regimen.

In one clinical study, supplementation with thiamine (50 mg/day) in patients receiving phenytoin therapy improved performance on both verbal and non-verbal IQ tests (Botez et al. 1993).


Vitamin B9 (Folic Acid)
Mechanism

Phenytoin therapy decreases serum folate levels (Berg et al. 1995; Dastur and Dave 1987; Schwaninger et al. 1999). Folate may be a cofactor in phenytoin metabolism (Berg et al. 1992; Lewis et al. 1995).


Significance of Depletion

Low levels of folate have been linked to colon cancer, heart disease, cognitive deficits, and birth defects, specifically neural tube defects (Ames 2000; Covington 1999). Deficiency increases chromosome breakage and elevates serum homocysteine. Vitamin B9 deficiency may also lead to megaloblastic anemia.


Replacement Therapy

The recommended dietary allowance (RDA) for adults is 300 to 600 mcg/day (Covington 1999). However, recommendations of doses of folic acid as high as 2000 mcg/day have been reported in the literature (Mayer et al. 1996). For replacement therapy, doses should be based upon the patient's individual needs, considering the clinical presentation, age, gender, dietary habits, and medication regimen.

Warning: While supplementation with folic acid prevents depletion, it also alters phenytoin pharmacokinetics, leading to lower serum concentrations and loss of seizure control (Ladjimi and Gounelle 1994; Rivey et al. 1984).Folic acid doses as low as 1 mg/day may disturb phenytoin metabolism (Seligmann et al. 1999). Supplementation with folate may be initiated at the commencement of phenytoin therapy, which would allow for appropriate adjustment of the phenytoin dose (Lewis et al. 1995). There is great variability in tolerance to folate supplementation in epileptic patients (Ch'ien et al. 1975). A clinical case involving a patient who developed symptomatic phenytoin-induced folate deficiency was treated with 5 mg/day folic acid (Seligmann et al. 1999). Although serum levels normalized within 6 weeks, the folate caused serum phenytoin levels to become subtherapeutic, resulting in a breakthrough seizure. Titration of phenytoin dosage was required.

Those taking phenytoin together with folate should be consistent about the amount of folate ingested. Monitoring serum folate and phenytoin concentrations throughout the course of therapy is warranted.


Vitamin H (Biotin)
Mechanism

Long-term phenytoin treatment accelerates biotin catabolism (Mock et al. 1998) and significantly reduces plasma biotin levels (Krause et al. 1982; Krause et al. 1985).


Significance of Depletion

Although biotin deficiency is uncommon, nonspecific symptoms such as changes in skin color as well as the development of nonpruritic dermatitis, alopecia, and muscle pain may be indicative of depleted biotin levels (Covington 1999). Additionally, low levels of this nutrient may be associated with hypercholesterolemia, anemia, anorexia, depression, and insomnia.


Replacement Therapy

Biotin deficiency is treated with doses between 1 mg and 10 mg to resolve symptoms and prevent recurrence (Mock 1996).


Editorial Note

This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.


References

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Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY Acad Sci. 2000;889:87-106.

Bell RD, Pak CY, Zerwekh J, et al. Effect of phenytoin on bone and vitamin D metabolism. Ann Neurol. 1979;5(4):374-378.

Berg MJ, Fincham RW, Ebert BE, et al. Phenytoin pharmacokinetics: before and after folic acid administration. Epilepsia. 1992;33(4):712-720.

Berg MJ, Stumbo PJ, Chenard CA, et al. Folic acid improves phenytoin pharmacokinetics. J Am Diet Assoc. 1995;95(3):352-356.

Botez MI, et al. Thiamine and folate treatment of chronic epileptic patients: a controlled study with the Wechsler IQ scale. Epilepsy Res. 1993;16(2):157-163.

Botez MI, Joyal C, Maag U, et al. Cerebrospinal fluid and blood thiamine concentrations in phenytoin-treated epileptics. Can J Neurol Sci. 1982;9(1):37-39.

Cashman K, Flynn A. Optimal nutrition: calcium, magnesium and phosphorus. Proc Nutr Soc. 1999;58:477-487.

Ch'ien LT, Krumdieck CL, Scott CW Jr., et al. Harmful effect of megadoses of vitamins: electroencephalogram abnormalities and seizures induced by intravenous folate in drug-treated epileptics. Am J Clin Nutr. 1975;28(1):51-58.

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Dastur D, Dave U. Effect of prolonged anticonvulsant medication in epileptic patients: serum lipids, vitamins B6, B12 and folic acid, proteins and fine structure of liver. Epilepsia. 1987;28:147-159.

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Foss MC, Meneghelli UG, Verissimo JM. The effect of the anticonvulsants phenobarbital and diphenylhydantoin on intestinal absorption of calcium. Acta Physiol Lat Am. 1979;29(4-5):223-228.

Gascon-Barre M, Villeneuve JP, Lebrun LH. Effect of increasing doses of phenytoin on the plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations. J Am Coll Nutr. 1984;3(1):45-50.

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Holick MF, Krane SM, Potts JT. Calcium, phosphorus, and bone metabolism: calcium-regulating hormones. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2221-2222.

Krause KH, Berlit P, Bonjour JP, et al. Impaired biotin status in anticonvulsant therapy. Ann Neurol. 1982;12(5):485-486.

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

Ladjimi H, Gounelle JC. Phenytoin treatment and folate supplementation affect concentrations of folates in tissues of cobalamin-deficient rats. Arch Int Physiol Biochim Biophys. 1994;102(3):189-193.

Lewis DP, Van Dyke DC, Willhite LA, et al. Phenytoin-folic acid interaction. Ann Pharmacother. 1995;29(7-8):726-735.

Marcus R, Coulston AM. Water-soluble vitamins. In: Hardman JG, Limbird LE, et al, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill Health Professions Division; 1996:1557-1558.

Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27(3):517-527.

Mock DM. Biotin. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington, DC: ILSI Press; 1996:231.

Mock DM, Mock NI, Nelson RP, et al. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroenterol Nutr. 1998;26(3):245-250.

National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989.

Potts JT. Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill Companies Health Professional Division; 1998:2241.

Rao DS. Perspective on assessment of vitamin D nutrition. J Clin Densitom. 1999:2(4):457-464.

Reunanen MI, Sotaniemi EA, Hakkarainen HK. Serum calcium balance during early phase of diphenylhydantoin therapy. Int J Clin Pharmacol Biopharm. 1976;14(1):15-19.

Rivey MP, Schottelius DD, Berg MJ, et al. Phenytoin-folic acid: a review. Drug Intell Clin Pharm. 1984;18(4):292-301.

Schwaninger M, Ringleb P, Winter R, et al. Elevated concentrations of homocysteine in antiepileptic drug treatment. Epilepsia. 1999;40(3):345-350.

Seligmann H, Potasman I, Weller B, et al. Phenytoin-folic acid interaction: a lesson to be learned. Clin Neuropharmacol. 1999;:22(5):268-272.

Shafer RB, Nuttall FQ. Calcium and folic acid absorption in patients taking anticonvulsant drugs. J Clin Endocrinol Metab. 1975;41(6):1125-1129.

Somerman MJ, Rifkin BR, Pointon-Miska S, et al. Effect of phenytoin on rat bone resorption in vitro. Arch Oral Biol. 1986;31(4):267-268.

Valimaki MJ, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. Bone Miner Res. 1994;9(5):631-637.

Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842-856.

Williams C, Netzloff M, Folkerts L, et al. Vitamin D metabolism and anticonvulsant therapy: effect of sunshine on incidence of osteomalacia. South Med J. 1984;77(7):834-836, 842.


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