Phenytoin should be used with caution in patients with hypotension andor severe myocardial insufficiency. Drugs that activate the pregnane x receptor can disrupt vitamin d metabolism. Effect of antiepileptic drugs on bone density in ambulatory. Vitamin c deficiency decreases activity of drugmetabolizing enzymes, especially in older people. Phenytoin is mainly excreted in the urine as its parahydroxylated metabolite 23 to 70 percent, either free or in conjugated form 5 percent. Pdf calcium and bone metabolism in patients with epilepsy taking. Consideration should be given to screening with bonerelated laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines. Vitamin d 3, is not a vitamin its a hormone but its easier and safer to say vitamin. Warfarin may increase serum phenytoin concentrations. Osteomalacia has been associated with phenytoin therapy and is considered to be due to phenytoins interference with vitamin d metabolism. Comparative study of the relative influence of different.
Phenytoin induced vitamin d deficiency presenting as. An international journal of medicine, volume 59, issue 3, june 1986, pages 569577. Enterohepatic circulation of vitamin d metabolites and their conjugates will be also discussed. Twothirds of the recruited subjects were vitamin d deficient. For vitamin d supplementation, vitamin d 3, the natural form of vitamin d, is preferred over vitamin d 2, because vitamin d 3 is most effective in maintaining adequate levels of vitamin d in the human body. The chemical name is sodium 5,5diphenyl2, 4imidazolidinedione, having the following structural formula. Nutrientdrug interactions and nutritional disorders learn about from the msd manuals medical professional version.
Osteomalacia and phenytoin therapy annals of internal. Phenytoin may also raise the serum glucose level in diabetic patients. Phenytoin is metabolized by hepatic cytochrome p450 enzymes cyp2c9 and cyp2c19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Vitamin d fatsoluble vitamin hormonal regulation of.
The effect of anti epileptic drug therapy on serum 25hydroxyvitamin. Clinically important displacement can be caused by. This may enhance the metabolism of vitamin d and decrease vitamin d levels, which may lead to vitamin d deficiency, hypocalcemia, and hypophosphatemia. Bone mineral density, vitamin d and anticonvulsant therapy scielo. Pdf influence of drugs on vitamin d and calcium metabolism. Phenytoin is a relatively insoluble weak acid, usually administered as the sodium salt. It would be best to discuss the situation and the suggested management plan in detail with your treating neurologist. Vitamin d is a well known fat soluble vitamin that is important for maintaining calcium and phosphate homeostasis, mineralization of the bone, and the modulation of gene expression, cell growth and differentiation.
Dosage adjustment of vitamin d may be necessary when phenytoin is added to or withdrawn from concomitant therapy 195. Effect of phenytoin on bone and vitamin d metabolism. Severe hypocalcemia and resulting seizure caused by vitamin d. Serum calcium, parathormone pth, 25hydroxyvitamin d 25. Treatment for vitamin ddeficiency rickets requires therapeutic doses of calciferol. Phenytoin interferes with the renal activation of vitamin d. In 22 epileptic outpatients treated for at least 1 year with phenobarbitonephenytoin the local and total bone mass, together with serum and urinary indices of calcium metabolism, were measured before and during treatment with either vitamin d 2 or d 3, 4,000 iu daily for 24 weeks. Ligandbound vitamin d receptor binds to consensus sequences on target genes as a heterodimer with the retinoid x receptor and exerts transcriptional regulatory effects. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Because it interferes with vitamin d metabolism, phenytoin can cause weakening of the bones osteomalacia.
It is possible that anticonvulsant drugs alter vitamin d metabolism which results in disturb ance of. In nonlinear kinetics, clearance and halflife fluctuate with plasma concentration. The active hormone, 1,25dihydroxyvitamin d, exerts its effects by binding to the vitamin d receptor, a member of the steroidthyroid hormone superfamily of nuclear receptors. Enzyme induction will continue for as long as the patient takes the inducer and no. There is also increasing awareness of endogenous, mostly steroid, pathways, relevant in particular to vitamin d and cholesterol metabolism, which are targets for this process. Vitamin d is a fatsoluble vitamin that is naturally present in very few foods, added to others, and available as a dietary supplement. The first step in the metabolism of vitamin d, 25 hydroxylation, occurs mainly in the liver 2. Nutrientdrug interactions nutritional disorders msd. Phenytoin sodium is related to the barbiturates in chemical structure, but has a fivemembered ring.
Phenytoininduced changes in the bone mineral metabolism. Vitamin d rich foods and drinks include salmon or mackerel, canned tuna fish, and egg yolks as well as vitamin d fortified foods like cereals, juice, milk and other dairy products see charts at the bottom for detailed amounts per servings. Musculoskeletal effects osteomalacia has been associated with phenytoin therapy and is considered to be due to phenytoins interference with vitamin d metabolism see section 4. Cytochrome p450 3a4 cyp3a4 is a multifunctional enzyme involved in both xenobiotic and endobiotic metabolism. Vitamin d has long been known for its effects on calcium and bone metabolism. Cell differentiation inhibits proliferation and stimulates the normal differentiation of cells immunity the inactive form of vitamin d aids in the formation of active vitamin d which enhances immunity and inhibits the development of autoimmune disease. In vitamin d metabolism, antiepileptic drugs aeds, including phenytoin, are known to interact with cytochrome p450 activity. Each dilantin 100 mg extended oral capsulecontains 100 mg phenytoin sodium. Therapy with phenytoin should be administered cautiously in patients with. Calcium and vitamin d metabolism were evaluated in 5 adult epileptic patients before and during treatment with phenytoin. Calcium phosphate homeostasis mineral bone metabolism halfon m, phan o, teta d. Vitamin d and fall riskgrand rounds presentation final. Dilantin phenytoin can cause vitamin d deficiency date june 11, 2014 author by eric christianson category osteoporosis, seizures dilantin phenytoin is probably one of the dirtiest drugs, but is necessary as it treats an obviously serious condition seizures. Influence of drugs on vitamin d and calcium metabolism.
The objective of this study was to determine the effect of antiepileptic drugs on vitamin d by measuring 25oh vitamin d levels in patients on aeds. It has been suggested that the drugs such as phenytoin accelerate vitamin d metabolism or directly inhibit intestinal calcium absorption. When the level is optimal, vitamin d should be reduced to a supplementation dose of 400800 iuday. Clinical pharmacokinetics of phenytoin springerlink. The rate of metabolism appears to be subject to genetic polymorphism.
Because 25ohd is the predominant circulating form of vitamin d in the normal population, it is considered to be the most reliable index. Interplay between vitamin d and the drug metabolizing. Phenytoin may be prescribed with other seizure medications. In humans, only a small amount of 25ohd is metabolized in the kidney to other dihydroxy metabolites 3, 4. However, this medicine can make absence or petit mal seizures happen more frequently. This medicine is available in different forms, including dilantin, phenytek, or generic phenytoin. Phenytoin and other anticonvulsants that have been shown to induce the cyp450 enzyme are thought to affect bone mineral metabolism indirectly by increasing the metabolism of vitamin d3. Low levels of biologically active vitamin d in patients on aeds have been demonstrated in a number of studies 33, 37, 4446, particularly with use of hepatic enzyme inducing medications like pb, pd, dph and cbz. Subjects who were already on aed, on drug therapy that interfere with vitamin d metabolism, those with hepatic, renal. For reference, 1 cup of milk contains approximately 300 mg of calcium and 100 units of vitamin d. Alterations in calcium, vitamin d and bone tissue metabolism have been associated with the following drugs. Vitamin d vitamin d has been in the news frequently this past year, including an article in the new york times on november 16, 2009. The drug has a moderately large volume of distribution and is approximately 90% bound to plasma proteins.
Vitamin d deficiency causes a lack of bone mineralization, which manifests as rickets in children and osteomalacia in adults. Learn about side effects, warnings, dosage, and more. Deficiency of calcium, magnesium, or zinc may impair drug metabolism. Effects of phenytoin on serum levels of homocysteine. Bioavailability is dependent upon particle size and problems of generic inequivalence have therefore arisen, particularly in scandinavia. It is a medicine that has been approved by the food and drug administration to treat tonic clonic grand mal and complex partial seizures.
Significant decreases occurred in serum concentrations of calcium, albumin, and 25. This may lead to vitamin d deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically. Pdf in the past, interactions between drugs and vitamin d have received only little or no. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Effect of phenytoin on bone and vitamin d metabolism wiley online. Phenytoin can cause the platelet or white blood cell counts to drop, increasing the risk of bleeding or infection, respectively. Reduce your risk of cancer with sunlight exposure by william b. Dilantin phenytoin can cause vitamin d deficiency med. The older aeds are phenobarbital pb, phenytoin pht, carbamazepine cbz, primidone prm, sodium. Phenytoin 100mg filmcoated tablets summary of product. In children, muscle weakness due to vitamin d deficiency is rarely. Serum 25oh vitamin d level testing should be repeated in 3 months after giving pharmacologic doses of vitamin d. Phenytoin therapy in young male patients for 1year causes a bone loss at femur and spine in the absence of vitamin d deficiency and significant bone loss in the cortical bone radius. Several interactions are possible and the net effects are difficult to predict 106 195.
There are few clinicians who use prophylactic calcium or vitamin d for patients taking aed. As the rate of administration increases, the plasma concentration at steady state. Phenytoin follows nonlinear or zeroorder kinetics at therapeutic concentrations, because the rate of metabolism is close to the maximum capacity of the enzymes involved. Significant decreases occurred in serum concentrations of calcium, albumin, and 25hydroxycholecalciferol. The results showed a distinct difference in the action of the two vitamins on bone metabolism during. This can lead to a vitamin d deficiency, as well as low calcium and phosphate. Influence of drugs on vitamin d and calcium metabolism ncbi.
The decreases in serum calcium paralleled those in serum albumin. This effect has been attributed to metabolism of vitamin d to polar inactive metabolites by the hepatic microsomes. Dxa should be done in patients during the treatment with aeds to identify patients who are. Although several studies revealed that pht use was associated with low folate status, the exact mechanism underlying the effect of pht on homocysteine metabolism has not yet been clarified. Bikle1, 1va medical center, department of medicine and dermatology, university of california, san francisco, san francisco, ca 94121, usa correspondence. Increased metabolism of vitamin d, leading to low blood levels of 25hydroxyvitamin d, is seen in individuals given anticonvulsant medications and antituberculous therapy. Previous research showed that phenytoin, as enzyme inducers, can directly regulate the activity of different liver enzymes. Musculoskeletal effects osteomalacia has been associated with phenytoin therapy and is considered to be due to phenytoin s interference with vitamin d metabolism see section 4. It is also produced endogenously when ultraviolet rays from sunlight strike the skin and trigger vitamin d synthesis. A guide to therapeutic drug monitoring melissa faye wu, bsc pharm.
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