|Valproic Acid Derivatives|
Valproic acid (VPA) causes carnitine deficiency in infants and children with
epilepsy (Castro-Gago, et al. 1998; Chung et al. 1997; Coulter 1991; Van Wouwe
1995). VPA impairs carnitine hepatic biosynthesis, inhibits fatty acid
oxidation, increases esterification of carnitine, and enhances urinary carnitine
excretion by VPA metabolites (Van Wouwe 1995).
Although carnitine is synthesized by the body, clinical deficiency can occur.
Carnitine deficiency is characterized by inadequate tissue levels, resulting in
impaired tissue fatty acid oxidation (Van Wouwe 1995). VPA-treated patients may
experience anemia, fatigue, hyperammonemia, hypotonia, lethargy, unexplained
stupor, and carnitine-responsive cardiomyopathy; recurrent episodes of a
Reye's-like syndrome with low concentrations of carnitine in liver and muscle,
reduced plasma glucose levels, and ketone bodies may be the most serious
consequence of carnitine depletion (Chung et al. 1997; Van Wouwe 1995).
Carnitine: Patients experiencing fatigue during VPA treatment
should receive carnitine supplements (15 mg/kg); daily administration at this
dosage level reverses clinical symptoms of carnitine deficiency (Van Wouwe
1995). However, daily doses of 100 mg/kg of carnitine have been recommended; up
to 2 g/day may be required for patients experiencing carnitine deficiency
secondary to drug therapy (De Vivo et al. 1998). L-carnitine supplementation (50
mg/kg/day for 7 days) significantly reduces elevated serum ammonia levels
commonly associated with VPA treatment in children; intravenous administration
may be warranted for VPA-induced hepatoxicity (De Vivo et al. 1998; Gidal et al.
1997). Serum carnitine levels should be monitored in patients taking both
divalproex sodium and VPA (Castro-Gago, et al. 1998; Chung et al. 1997).
VPA treatment alters copper and zinc homeostasis in epileptic children. In
one study, serum zinc levels were significantly lower than controls, while serum
copper levels were normal (Sozuer et al. 1995). In a second study, serum zinc
and copper levels were normal, but erythrocyte zinc content was significantly
lower than controls (Lerman-Sagie et al. 1987). In another study serum copper,
but not zinc, levels were significantly lower than controls (Kaji et al. 1992).
None of the children in this study exhibited symptoms of copper deficiency.
Copper: A clinical copper deficiency is rare (National Research
Council 1989). Signs and symptoms of a deficiency include anemia, neutropenia,
changes in structure and appearance of hair, cardiac damage, growth retardation,
impaired collagen formation, bone demineralization, osteoporosis, and emphysema
(Falchuk 1998; National Research Council 1989).
Zinc: Clinically, signs and symptoms of zinc deficiency include
alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to
infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998).
Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune,
nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge
Copper: The reference daily intake value for copper is 2 mg (Covington
1999). Depending on the patient's clinical presentation, doses may need to be
adjusted accordingly to replenish the body's stores of this trace element.
Zinc: Doses of zinc up to 50 mg/day may be recommended (Hambidge
2000). This upper limit includes an adult's total daily intake, which may be
higher than anticipated because of the increasing trend to fortify foods with
zinc. It is important to be mindful of this limit, even if decisions are
deliberately made to temporarily exceed this level for anticipated
The zinc and copper status of epileptic children taking valproate derivatives
should be monitored.
Valproate reduces plasma selenium levels in patients chronically treated with
this drug (Hurd et al. 1984). VPA also decreases levels of glutathione
peroxidase (GSH-Px), a selenium-dependent enzyme, in children experiencing
serious adverse reactions to drug therapy (Graf et al. 1998; Hurd et al. 1984).
Hepatotoxicity and other adverse effects may be related to diminished
antioxidant capacity due to depleted selenium and glutathione
Selenium deficiency may lead to oxidative DNA damage (Ames 2000). Chronically
low levels of this trace element are associated with pathologies such as
cardiovascular disease, rheumatic disorders, muscle, and digestive problems
(Navarro-Alarcon and Lopez-Martinez 2000). In addition, there may be a
connection between depleted selenium levels and cancer, cirrhosis, and
The recommended dietary allowance (RDA) for selenium ranges from 0.70 to 3.50
mg/day (Ames 2000). Doses of 0.02 to 0.05 mg/day have been suggested to prevent
selenium deficiency and its associated disorders (Navarro-Alarcon and
Lopez-Martinez 2000). Optimal and toxic levels of this nutrient have not been
established (Ames 2000). Selenium supplementation may play a role in cancer
prevention, including prostate, breast, colon, and cervical carcinoma.
All anticonvulsant drugs interfere with folate metabolism to different
degrees (Goggin et al. 1987).
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
Although VPA appears to have a minor impact on folate levels, supplementation
may still be warranted, especially for epileptic women who are planning to
become pregnant (Goggin et al. 1987). Daily doses of 5 mg have been recommended
for these women (Robertson 1986). While the recommended dietary allowance (RDA)
of folic acid for adults is 300 to 600 mcg/day (Covington 1999), recommendations
of doses as high as 2000 mcg/day have been reported in the literature (Mayer et
al. 1995). For replacement therapy, doses should be based upon the patient's
individual needs, considering the clinical presentation, age, gender, dietary
habits, and medication regimen.
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
Ames BN. Micronutrient deficiencies: A major cause of DNA damage. Ann NY
Acad Sci. 2000;889:87-106.
Castro-Gago, M, Eiris-Punal J, Novo-Rodriguez MI, et al. Serum carnitine
levels in epileptic children before and during treatment with valproic acid,
carbamazepine, and phenobarbital. J Child Neurol.
Chung S, Choi J, Hyun T, Rha Y, Bae C. Alterations in the carnitine
metabolism in epileptic children treated with valproic acid. JKMS.
Coulter DL. Carnitine, valproate, toxicity. J Child Neurol.
Covington T, ed. Nonprescription Drug Therapy Guiding Patient
Self-Care. St Louis, MO: Facts and Comparisons; 1999:467-545.
De Vivo DC, et al. L-carnitine supplementation in childhood epilepsy:current
perspectives. Epilepsia. 1998;39(11):1216-1225.
Falchuk KH. Disturbances in Trace Elements. In: Fauci A, Braunwald E,
Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine.
14th ed. New York, NY: McGraw-Hill Companies Health Professional
Gidal BE, Inglese CM, Meyer JF, et al. Diet- and valproate-induced transient
hyperammonemia:effect of L-carnitine. Pediatr Neurol.
Goggin T, Gough H, Bissessar A, et al. A comparative study of the relative
effects of anticonvulsant drugs and dietary folate on the red cell folate status
of patients with epilepsy. Q J Med. 1987;65(247):911-919.
Graf WD, Oleinik OE, Glauser TA, et al. Altered antioxidant enzyme activities
in children with a serious adverse experience related to valproic acid therapy.
Hambidge M. Human zinc deficiency. J Nutr. 2000;130(5S
Hurd RW, Rinsvelt HA, Wilder RJ, et al. Selenium, zinc, and copper changes
with valproic acid: possible relation to drug side effects. Neurol.
Kaji M, Ito M, Okuno T, et al. Serum copper and zinc levels in epileptic
children with valproate treatment. Epilepsia. 1992;33(3):555-557.
Lerman-Sagie T, Statter M, Szabo G, et al. Effect of valproic acid therapy on
zinc metabolism in children with primary epilepsy. Clin Neuropharmacol.
Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis.
J Am Coll Cardiol. 1996;27(3):517-527.
National Research Council. Recommended Dietary Allowances.
10th ed. Washington, DC: National Academy Press; 1989.
Navarro-Alarcon M, Lopez-Martinez MC. Essentiality of selenium in the human
body: relationship with different diseases. Sci Total Environ.
Robertson IG. Prescribing in pregnancy. Epilepsy in pregnancy. Clin Obstet
Sozuer DT, Baruteu UB, Karakoe Y, et al. The effects of antiepileptic drugs
on serum zinc and copper levels in children. J Basic Clin Physiol
Van Wouwe JP. Carnitine deficiency during valproic acid treatment. Int J
Vitam Nutr Res.
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