Epilepsy, Prolonged Phenytoin Usage, and Its Effects On Bone
Epilepsy, Prolonged Phenytoin Usage, and Its Effects On Bone
Epilepsy, Prolonged Phenytoin Usage, and Its Effects On Bone
INTRODUCTION
Partial seizures are divided into three subtypes:5 simple partial: the patient does not lose consciousness complex partial: the patients consciousness is impaired secondarily generalized The anti-epileptic drug phenytoin (Dilantin, Pfizer) is used to control several types of seizures. Phenytoin is indicated for generalized tonic-clonic (grand mal) seizures and complex partial (psychomotor, temporal lobe) seizures. It is also used to prevent or control seizures occurring during and after neurosurgery.6 Phenytoin, like all drugs, is associated with a number of side effects that must be considered when it is prescribed to patients. A number of articles have been published on the sub________________________________________________________ Dr. Motylev is a Pharmacy Manager in the hospital setting in New York City.
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Renal Activation
Phenytoin interferes with the renal activation of vitamin D. Studies have shown that patients taking phenytoin have low serum levels of 1,25-(OH)2D3 even when their serum levels of 25(OH)D3 are normal, thus suggesting that phenytoin might affect the performance of 1 alpha-hydroxylase in the kidney.6 Furthermore, phenytoin increases the catabolism of activated vitamin D. To avoid vitamin D toxicity and to maintain calcium homeostasis, a feedback mechanism is initiated by cytochrome CYP 24,13 which belongs to the mitochondrial P450 family of enzymes. CYP 24 initiates the process of decomposition of 1,25(OH)2D3 to the inactive product, calcitroic acid (1-alphahydroxy-23 carboxy-24,25,26,27-tetranorvitamin D3).18 Phenytoin activates nuclear receptor pregnane X, which in turn leads to the up-regulation of CYP 24s gene expression.19 This increases the tendency to elevate the decomposition of 1,25(OH)2D3 by the hydroxylation reaction on its side chain. Some extensive studies have been conducted on phenytoins effects on vitamin D. Collective outcomes of several studies lead to the following observations: 1. Phenytoin induces the microsomal enzyme system in the liver, thus increasing 25-hydroxylase production and biliary excretion.10 2. Phenytoins induction of microsomal mixed oxidase system elevates the conversion of active vitamin D, making it more polar and less active11thus leading to the gastrointestinal loss of vitamin D. 3. Unlike the first two processes, which are directly caused by phenytoin, the third process is secondary and is caused by the first two. The effects of phenytoin, described earlier, lead to the unfavorable outcome of poor calcium absorption. If that happens, the parathyroid gland reacts by releasing parathyroid hormone, which in its turn raises the calcium level in the blood by releasing calcium from bones. This step results in the conservation of calcium excretion from the kidneys and leads to the increased absorption of calcium from ingested food.20 In the end, these processes result in bone demineralization, kidney stones, and hypertension. Basically, one can observe signs of phenytoin-induced hyperparathyroidism.
BONE DENSITY
Phenytoins effects on calcium and bone homeostasis lead to the important question of the drugs effects on bone mass density. In fact, in several studies, the use of phenytoin led to decreased bone density in the sites most susceptible to fractures, such as the femoral neck and lumbar spine, in both men and women.10,21
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TREATMENT
The goal of treatment for patients who take phenytoin and experience low BMD is to delay the process of accelerated bone turnover. Calcium and vitamin D supplements are options that may delay bone turnover. In 1994, the National Institutes of Health prepared guidelines for the optimal calcium requirements for patients based on age, sex, and reproductive status27 (Figure 1). Patients who are at high risk for osteoporosis should take 800 IU of vitamin D and 1,500 mg of elemental calcium daily.12
800 mg 8001,200 mg
11 to 24 years
1,2001,500 mg
25 to 65 years Men Older than 65 years 25 to 65 years Older than 50 years (postmenopausal) Older than 65 years Pregnant and nursing
Figure 1 Optimal calcium intake. (Based on data from National Institutes of Health, 1994.27)
1,000 mg 1,500 mg 1,000 mg Taking estrogens Not taking estrogens 1,000 mg 1,500 mg 1,500 mg 1,2001,500 mg
Women
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CONCLUSION
Phenytoin lowers calcium levels in the body by various mechanisms. Careful monitoring and collaborative efforts between physicians and pharmacists can reduce the risk of osteomalacia and bone demineralization in patients undergoing anticonvulsant therapy.
REFERENCES
1. DeLorenzo RJ, Sun DA, Deshpande LS. Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintenance of epilepsy. Pharmacol Ther 2005;105: 229266. 2. Rajpura A, Sethi S. Evidence-based standards of care for adults with epilepsy: A literature review. Seizure 2004;13:4554. 3. Centers for Disease Control and Prevention (CDC). Epilepsy: Increasing awareness and improving care. Available at: www.cdc.gov/programs/chron02.pdf. Accessed May 21, 2006. 4. National Institute of Neurological Disorders and Stroke. Seizure and epilepsy: Hope through research. Available at: www.ninds. nih.gov/disorders/epilepsy/detail-epilepsy.htm. Updated July 17, 2006. Accessed July 18, 2006. 5. McNamara J. Pharmacotherapy of the epilepsies. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill; 2006: 501. 6. Dilantin Kapseals USP (extended phenytoin sodium capsules). Package insert. New York: Parke-Davis/Pfizer. Revised February 2003. 7. Varkey K, Raman PT, Bhartaviziam A, Taori GM. Osteomalacia due to phenytoin sodium. J Neurol Sci 1973;19:287295.
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