Use Of Phenytoin Research Articles

Pharmacogenetics of Epilepsy: One Step Forward?

Genetic Predictors of the Maximum Doses Patients Receive during Clinical Use of the Antieileptic Drugs Carbamazepine and Phenytoin Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, Thom M, Sen A, Shorvon SD, Sander JW, Wood NW, Goldstein DB Proc Natl Acad Sci USA 2005;102:5507–5512. Phenytoin and carbamazepine are effective and inexpensive antiepileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final “maintenance” dose normally determined by trial and error. Although many genes could influence response to these medicines, obvious candidates are known. Both drugs target the α-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin ( P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular use of both carbamazepine and phenytoin ( P = 0.0051, and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5′ splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug-target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.

Pharmacotherapy Overview of Seizure Management in the Adult Emergency Department

Seizures are a common cause of emergency department visits, and approximately 28% of epilepsy patients present to an emergency department annually for treatment. This article will provide an overview of the pharmacotherapeutic management of seizures and anticonvulsant therapy for patients who present to the adult emergency department, including practical information for pharmacists covering or cross-covering this practice area. The benzodiazepines are reviewed as a class, including dosing strategies, pharmacodynamic considerations, and advantages and disadvantages of lorazepam, diazepam, and midazolam. Indications for the use of phenytoin and fosphenytoin will be reviewed, as well as dosing, adverse effects, and cost-effectiveness data. In addition, dosing, administration, pharmacokinetics, and adverse effects of phenobarbital, carbamazepine, and valproate will be discussed. Clinical indications for serum anticonvulsant concentration monitoring and subsequent calculation of loading doses from serum concentrations are reviewed. Since status epilepticus is a life-threatening emergency, its therapeutic management is reviewed, including the use of continuous infusion midazolam, pentobarbital, and propofol. There are many opportunities for clinical pharmacists to collaborate with other members of the health care team to optimize efficacy and minimize adverse effects of anticonvulsant agents in the emergency department setting.

Neuropsychology/Language/Behavior: All Ages

Neuropsychology/Language/Behavior: All Ages

Recrudescence of imported falciparum malaria after quinine therapy: potential drug interaction with phenytoin

Quinine remains a reliable treatment for falciparum malaria in most parts of the world. We report recrudescence of imported Plasmodium falciparum malaria following quinine treatment in the context of concurrent phenytoin use. Supported by a subtherapeutic quinine level, we hypothesise that a drug interaction with phenytoin may compromise the efficacy of quinine in the treatment of malaria.

Use of phenytoin for the long-term treatment of partial seizures: Results of a survey conducted during the 2004 meeting of the American Academy of Neurology

Background: Epilepsy is a chronic disorder that typically requires lifelongpharmacologic treatment. The choice of an antiepileptic drug (AED), therefore, requires careful consideration of efficacy and tolerability. However, the majority of patients with new-onset seizures are initially treated by physicians in the emergency department (ED) or by non-ED physicians (primary care physicians or internists), with phenytoin being the most common AED prescribed for initial therapy, and the long-term adverse effects of AEDs are often overlooked. Objective: The aim of this survey was to examine the perspectives of neurologistsand epileptologists concerning initial therapies prescribed by ED physicians and non-ED physicians for newly diagnosed partial seizures, particularly phenytoin, and the suitability of these therapies for long-term management of the disease. Methods: A computerized survey was conducted during the 2004 AmericanAcademy of Neurology meeting. The survey consisted of 10 questions concerning the use of AEDs in the initial and long-term treatment of newly diagnosed partial seizures. Results: The responses of 268 practitioners were analyzed. Survey participants indicated that 71% of patients referred to them by ED physicians were receiving phenytoin, whereas 59% of patients referred to them by non-ED physicians were receiving phenytoin. Seventy-six percent of survey participants responded that they would switch a patient having partial seizures referred from the ED to another AED. Seventy-eight percent indicated that they did not believe that the medications being received by patients with newly diagnosed partial seizures in the ED were suitable for long-term epilepsy treatment. Conclusion: Although appropriate treatment might vary in the acute and chronic settings, and phenytoin is used as a primary agent for acute treatment of seizures presenting in the ED, the results of the present survey suggest a discrepancy between the medications that primary care and ED physicians prescribe for newly diagnosed partial seizures and those that specialists prescribe for long-term therapy.

Risk of Stevens–Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics

Estimates of risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with some antiepileptic drugs (AEDs) have used denominators based on the number of prescriptions or daily doses. Because the risk of SJS is highest in new users of drugs, the use of denominators reflective of all users can lead to low estimates of risk associated with drugs. In this study, risk in new users is assessed. Data on all hospitalized patients with SJS and TEN with use of carbamazepine (CBZ), lamotrigine (LTG), phenobarbital (PHB), phenytoin (PHT), or valproic acid (VPA) were obtained from the German Registry for Serious Cutaneous Reactions. For 1998-2001, the numbers of new users were estimated from number of dispensed prescriptions in Germany, the average prescribed doses, and the duration of use in the Mediplus database (IMS Health) Germany, and assumptions that relate new use to growth in national dispensings. To minimize the probability of underestimating risk in new users, conservative estimates of new use that were somewhat lower than predicted from national prescription data were used. More than 90% of SJS and TEN cases occurred in the first 63 days of AED use. Over the 4 years, increases in dispensing were 5% for CBZ, 65% for LTG, 6% for PHB, -16% for PHT, and 26% for VPA. Across a range of assumptions about frequency of incident use, the risk estimates vary between 1 and 10 per 10,000 new users for CBZ, LTG, PHT, and PHY and were consistently lower for VPA. Across a range of assumptions used, the risk of hospitalization for Stevens-Johnson syndrome or toxic epidermal necrolysis in new users is low for carbamazepine, lamotrigine, phenytoin, phenobarbital, and valproic acid. Because conservative incidence use fractions were used, it is likely that some risks were overestimated.

Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the alpha-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.

Risk estimates for drugs suspected of being associated with Stevens‐Johnson syndrome and toxic epidermal necrolysis: a case‐control study

The purpose of this case-control study is to estimate the risks of Stevens-Johnson syndrome or toxic epidermal necrolysis associated with the use of specific drugs. The suspected cases were identified from the computerized hospital discharge file. We calculated crude relative risks and adjusted them for confounding by multivariate analysis. The analysis was based on 35 cases and 105 controls. This study showed that the use of carbamazepine, phenytoin and allopurinol is most associated with the risks in the oriental population.

Topiramate-Valproate—Induced Hyperammonemic Encephalopathy Syndrome: Case Report

A 15-year-old boy with inverted duplication of chromosome 15 was admitted for acute onset of irritability, increasing sleepiness, and worsening of seizures. He had been on valproate and other anti-convulsants. However, he was found to have hyperammonemia within 2 weeks after the addition of low-dose topiramate to valproate. He recovered within 7 days after discontinuation of valproate. Topiramate was tailed off. The reintroduction of valproate monotherapy caused hyperammonemia again without clinical features of encephalopathy. He also developed anticonvulsant hypersensitivity syndrome following the use of phenytoin. We propose the term topiramate-valproate-induced hyperammonemic encephalopathy syndrome to include the following features: excessive sleepiness or somnolence, aggravation of seizures, hyperammonemia, and absence of triphasic waves on electroencephalography in any individual on simultaneous topiramate-valproate therapy. The ammonia level ranged from 1.5 to 2 times normal. The serum valproate level might be within the therapeutic range. The possible mechanism is topiramate-induced aggravation of all the known complications of valproate monotherapy. This condition is reversible with cessation of either valproate or topiramate.

Effect of phenytoin on mood and declarative memory during prescription corticosteroid therapy

In humans and animals, corticosteroid excess is associated with impairment in declarative memory and changes in hippocampal structure. In animals, phenytoin pretreatment blocks the effects of stress on memory and hippocampal histology, although no studies have examined the use of phenytoin to prevent corticosteroid-associated memory changes in humans. Mood changes are also common with corticosteroids, but few treatment data are available. This report examines whether phenytoin can prevent mood or declarative memory changes secondary to bursts of prescription corticosteroids. Thirty-nine patients with allergies or pulmonary or rheumatologic illnesses and given systemic corticosteroid therapy were randomized to receive either phenytoin (300 mg/day) or placebo concurrently with the corticosteroids. Mood was assessed with the Hamilton Rating Scale for Depression, Young Mania Rating Scale, and Activation (ACT) subscale of the Internal State Scale; declarative memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT) at baseline and after approximately 7 days of corticosteroid plus phenytoin or placebo therapy. The two groups were similar in age, gender, education, and corticosteroid dose. The phenytoin-treated group showed significantly smaller increases on the ACT, a mania self-report scale, than the placebo-treated group. Groups did not differ significantly on RAVLT change scores. This is the first placebo-controlled study to examine whether a medication can prevent mood and memory changes secondary to corticosteroids. Phenytoin blocked the hypomanic effects of prescription corticosteroids; however, phenytoin did not block the declarative memory effects of corticosteroids.

Drug Therapy in the Heart Transplant Recipient

Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004. With improving survival, the heart transplant recipient faces an increasing number of medical problems caused by both aging and the cumulative complications of immunosuppressive drugs.1 The availability of new drugs to treat infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies has resulted in the heart transplant recipient and their physicians facing an almost overwhelming number of important drug–drug interactions. In parts 1 through 3 of this series, we reviewed commonly used immunosuppressive drugs and their pharmacology, as well as the common medical problems faced by the heart transplant recipient. In this article, we provide an overview of the mechanisms of common and important potential drug–drug interactions and guidelines for avoiding these interactions. The risk for drug–drug interactions is increased by advanced age, polypharmacy, medications with a narrow therapeutic index, or medications requiring intensive monitoring. All of these factors except advanced age are present in the heart transplant recipient. A 10-fold interpatient variability may exist in the magnitude of a drug interaction resulting from patient-related and drug-related factors.2 Patient-related factors predisposing to drug interactions include concomitant diseases, genetics, diet, and environmental exposures. For example, commonly used immunosuppressants, antifungal agents, and lipid-lowering medications are metabolized through the cytochrome P450 (CYP450) enzyme system and effluxed from cells by the multiple drug resistance transporter protein p-glycoprotein (P-gp). Both systems are found in the liver and gastrointestinal tract and exhibit genetic polymorphism.2 The CYP450 enzymes belong to a superfamily of oxygenases; the primary purpose of these oxygenases is to add a functional group to a drug to increase its polarity and to promote its excretion from the body. If enzymes possess >40% homology, they are grouped together into families designated by an Arabic numeral (eg, the …

Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs

The aim of this cross sectional study was to evaluate bone mineral density (BMD) and serum levels of 25-hydroxy vitamin D (25OHD) in a group of patients taking antiepileptic drugs (AED) for a seizure disorder. Between May-2001 and January-2003, we evaluated 58 patients (40 women/18 men), 34.4+/-6 years old living in Curitiba or in its metropolitan area, on antiepileptic therapy for 2 to 38 years (10 on monotherapy /48 on multiple drugs regime). The group was matched by age, gender, and bone mass index to 29 healthy subjects (20 women/ 9 men); 34.2+/-5.9 years old. Medical history and physical exam were performed on all subjects with particular information sought about fractures and risks factors for osteoporosis. Blood samples were collected for total serum calcium, albumin, phosphorus, creatinine, total alkaline phosphatase, and liver function tests. BMD of the lumbar spine, femur and forearm was determined by dual energy X-ray absorptiometry (DXA, Hologic QDR 1000). Between February and April-2003, other blood samples were collected to measure 25OHD, intact paratohormone (PTH) and calcium. Unemployment and smoking history were more frequent among patients than among controls (p<0.05). Fifteen patients had a fracture history, all of which occurred during a seizure. The BMD of the lumbar spine (0.975+/-0. 13 g/cm2 vs. 1.058+/-0.1 g/cm2; p<0.03) and of the total femur (0.930+/-0.1 g/cm2 vs. 0.988+/-0.12 g/cm2; p<0.02) was lower in patients than in controls. In 63.5% of patients and in 24.1 % of controls a T-score < -1.0 in at least one site was seen. The AED users had higher total alkaline phosphatase and lower 25OHD (p<0.02). No correlations between BMD and 25OHD were found. The use of phenytoin was correlated with a greater incidence of fractures (RR: 2.38). We conclude that patients on chronic use of AED have alterations in bone metabolism characterized in this study by lower BMD of the lumbar spine and total femur and lower serum concentrations of 25OHD.

A Complex Interaction between Clozapine and Phenytoin

Objective: As of July 9, 2004, to report the first case of potential pharmacodynamic and pharmacokinetic interactions between clozapine and phenytoin occurring simultaneously in a patient. Case Summary: A 60-year-old African American female treated with clozapine and phenytoin developed neutropenia after the clozapine dose was increased from 650 to 900 mg/day. The neutropenia resolved after phenytoin was discontinued, and the clozapine dose was decreased from 900 to 300 mg/day without any significant change in clozapine levels. Discussion: Neutropenia can be explained on the basis of a potential pharmacodynamic interaction between clozapine and phenytoin. However, neutropenia did not occur until the clozapine dose was increased from 650 to 900 mg/day, corresponding to an increase in clozapine levels from 90 to 114 ng/mL. Neutropenia resolved after phenytoin was discontinued, even though the clozapine concentrations achieved after phenytoin discontinuation (137 ng/mL) were almost the same as those when phenytoin was coadministered (114 ng/mL). This finding suggests that neutropenia was precipitated not only by an increase in the clozapine dose, but also by the concomitant use of phenytoin. On the other hand, the decrease in clozapine concentrations can be explained on the basis of a pharmacokinetic interaction between clozapine and phenytoin. Phenytoin has the potential to decrease clozapine concentrations by inducing the activity of CYP1A2, which provides a primary metabolic pathway for clozapine. Conclusions: Concomitant use of phenytoin may not only decrease clozapine concentrations and compromise its efficacy, but can also precipitate neutropenia. Although based on a single case report, these findings warrant caution when coadministering clozapine and phenytoin.

Seizure prophylaxis in patients with brain metastases from solid tumors: Is phenytoin necessary?

8186 Background: The use of phenytoin as primary seizure prophylaxis in patients with brain metastases from solid tumors is widely practiced at our institution, although this has fallen out of favo...

Prophylactic phenytoin does not improve cerebral edema or survival in acute liver failure—a controlled clinical trial

Background/Aims Seizure activity in patients with acute liver failure (ALF) may increase cerebral oxygen requirements and worsen cerebral edema. Recently, prophylactic phenytoin has been recommended to suppress sub-clinical seizure activity evident on electroencephalographic monitoring. To determine the clinical utility of prophylactic phenytoin therapy in patients with ALF. Methods Forty two patients with ALF were randomized. Twenty two patients were given prophylactic phenytoin and 22 patients acted as controls. The baseline clinical and biochemical features were similar in the two groups and patients with ≥2 poor prognostic variables were equally represented. Results Sixteen patients in the phenytoin group, and 15 in the control group developed cerebral edema ( P=0.38). Mechanical ventilation was required in 10 and 12 patients in the phenytoin and control groups, respectively, ( P=0.77). Seizures occurred in 5 (22.7%) control patients and 5 (25%) phenytoin treated patients ( P=0.86). Fourteen (70%) patients randomized to phenytoin and 15 (68.2%) control patients died ( P=0.89). Conclusions Seizure was common in patients with ALF. Prophylactic use of phenytoin did not prevent cerebral edema, seizures or need for mechanical ventilation, and did not improve survival.

Use of phenytoin in pregnancy for epileptic seizure prevention: a case report

Epilepsy is the most common neurological disorder in women of reproductive age. Phenytoin is one of the most frequently prescribed antiepileptic drugs. Although the vast majority of women with epilepsy have normal pregnancy outcomes, certain fetal anomalies and pregnancy complications are associated with epilepsy and phenytoin use. Appropriate midwifery care of women with epilepsy includes consultation and co-management with an obstetrician and a neurologist. The clinical course of a woman with epilepsy taking phenytoin is presented.

Use of phenytoin in pregnancy for epileptic seizure prevention: a case report

Epilepsy is the most common neurological disorder in women of reproductive age. Phenytoin is one of the most frequently prescribed antiepileptic drugs. Although the vast majority of women with epilepsy have normal pregnancy outcomes, certain fetal anomalies and pregnancy complications are associated with epilepsy and phenytoin use. Appropriate midwifery care of women with epilepsy includes consultation and co-management with an obstetrician and a neurologist. The clinical course of a woman with epilepsy taking phenytoin is presented.

Potentially inappropriate antiepileptic drugs for elderly patients with epilepsy.

To describe prescribing patterns for older veterans with epilepsy, determine whether disparity exists between these patterns and clinical recommendations, and describe those at greatest risk of receiving potentially inappropriate antiepileptic drugs (AEDs). Retrospective administrative database analysis. All outpatient facilities within the Department of Veterans Affairs (VA). All veterans aged 65 and older who had epilepsy diagnosed before the end of fiscal year 1999 (FY99) and who received AEDs from the VA in FY99 (N=21,435). National VA pharmacy data were used to determine the AED regimen based on the AEDs patients received during the year. Administrative data were used to describe demographic variables and to gauge disease severity and epilepsy onset. Approximately 17% of patients received phenobarbital and 54% phenytoin. Patients classified as having newly diagnosed disease were less likely to receive phenobarbital monotherapy and combination therapy and more likely to receive gabapentin or lamotrigine monotherapy (chi2=288.90, P<.001). Logistic regression analyses indicated that, for all patients, those with more severe disease were less likely to receive phenobarbital monotherapy than other monotherapy and phenobarbital combinations than other combinations. Those who received specialty consultation were less likely to receive phenytoin monotherapy than AED monotherapy, which is consistent with clinical recommendations. Most older veterans received potentially inappropriate AED therapy. Hence, the standard of care for older patients with epilepsy should be reevaluated, although the vast use of phenytoin in this population suggests that change in practice patterns may be difficult.

Urolithiasis associated with topiramate

Topiramate is a sulfamate-substituted monosaccharide anticonvulsant used as adjunctive therapy for intractable refractory seizures. It is report a case of topiramate-induced urolithiasis. A 35-year-old man presented with acute, right-sided, colicky flank pain. He denied hematuria or dysuria. He was in use of phenytoin, risperidone, phenobarbital, and topiramate. The total daily dose of topiramate was 375 mg. A CT scan showed a 7 x 1 mm curvilinear density at the right ureterovesical junction with proximal hydrouretronephrosis. He was managed with rigid ureteroscopic stone extraction and the calculus metabolic analysis revealed the stone was composed of carbonate apatite (70%), calcium oxalate dihydrate (20%), and calcium oxalate monohydrate (10%). The present case typifies many features of topiramate-induced urolithiasis. Those who care for patients with urinary stone disease should be aware of this association.

Diabetic neuropathy: an intensive review.

The epidemiology, classification, pathology, and treatment of diabetic neuropathy are reviewed. Diabetic peripheral neuropathy is a common complication of diabetes that can cause significant morbidity and mortality. Some 30% of hospitalized and 20% of community-dwelling diabetes patients have peripheral neuropathy; the annual incidence rate is approximately 2%. The primary risk factor is hyperglycemia. Sensorimotor neuropathy is marked by pain, paresthesia, and sensory loss. Cardiac autonomic neuropathy (CAN) may contribute to myocardial infarction, malignant arrhythmia, and sudden death. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy. Genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder. The pathology of diabetic neuropathy involves oxidative stress, advanced glycation end products, polyol pathway flux, and protein kinase C activation; all contribute to microvascular disease and nerve dysfunction. For symptom management current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications. Citalopram, nonsteroidal antiinflammatory drugs, and opioid analgesics may be used as adjuvant agents. Lamotrigine, oxcarbazepine, paroxetine, levodopa, and alpha-lipoic acid are alternative considerations. Evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal. Complementary therapies have also shown efficacy. The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, and beta-blockers. Gastroparesis may be treated with metoclopramide or erythromycin. The most promising disease-modifying therapy is ruboxistaurin, which is in Phase III trials. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment. Diabetic neuropathy is a many-faceted complication of diabetes that can be managed symptomatically with an array of drugs.