Induction of Hypersensitivity to a Previously Tolerated Antiepileptic Drug by a Second Antiepileptic Drug

PURPOSE: To describe the induction of hypersensitivity to one antiepileptic drug (AED) by a second AED. METHODS: Case report and review of the relevant literature. RESULTS: A patient is reported who was treated with phenytoin (PHT) for 6 months without adverse effect, but developed a hypersensitivity reaction with rash, fever, elevated liver enzymes, lymphadenopathy, and colitis 6 weeks after the introduction of carbamazepine (CBZ). PHT and CBZ were discontinued. Seizures continued despite treatment with valproic acid and clobazam. A decision was made to cautiously reintroduce PHT. Diffuse skin rash and pharyngitis appeared after two doses of PHT. CONCLUSIONS: The AED hypersensitivity syndrome has been thought to occur as a consequence of preexisting pharmacogenetic and immunologic abnormalities. Our case demonstrates induction of hypersensitivity to an AED that had been formerly well tolerated, after a hypersensitivity reaction to another AED. This is distinct from simple cross-reactivity between one or more drugs. Such induction of hypersensitivity with AEDs has not been previously described.     

Antiepileptic Drug Hypersensitivity Syndrome

Summary: : The antiepileptic drug hypersensitivity syndrome (AHS) is an adverse drug reaction associated with the aromatic antiepileptic drugs (AEDs) phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), and primidone. The syndrome is defined by the triad of fever, skin rash, and internal organ involvement. It can also be caused by other drugs, such as sulfonamides, dapsone, minocycline, terbinafine, azathioprine, and allopurinol. Diagnosis of AHS may be difficult because of the variety of clinical and laboratory abnormalities and manifestations and because the syndrome may mimic infectious, neoplastic, or collagen vascular disorders. The incidence is approximately 1 in 3,000 exposures. AHS starts with fever, rash, and lymphadenopathy, within the fist 2–8 weeks after initiation of therapy. Internal manifestations include, among others, agranulocytosis, hepatitis, nephritis, and myostitis. AHS is associated with a relative excess of reactive oxidative metabolites of the AED. Insufficient detoxification may lead to cell death or contribute to the formation of antigen that triggers an immune reaction. Crossreactivity among PHT, CBZ, and PB is as high as 70–80%.     

Cross-reactivity pattern of rash from current aromatic antiepileptic drugs

We have investigated cross-reactivity of rash among the current aromatic antiepileptic drugs, particularly between the new and the traditional compounds. A retrospective survey of medical records concerning all aromatic antiepileptic drug (AED) treatment in consecutive adult patients with epilepsy was performed. Altogether 663 patients were included comprising 2567 exposures to AEDs. Skin reactions occurred in 93 patients and sequential rashes related to aromatic drugs in 17. Phenytoin (PHT), carbamazepine (CBZ) and oxcarbazepine (OXC) caused rashes in the range of 27-35% in patients with a history of another AED-related rash, whereas lamotrigine (LTG) caused another rash in 17%. A history of an AED-related rash was significantly associated with reactions to PHT, CBZ, and OXC (p<0.001). The association was only borderline significant for LTG (p=0.05). Nevertheless, the occurrence was consistently increased in all subgroups with reactions to other AEDs. A CBZ rash was not significantly associated with an LTG reaction, and vice versa, but the number of patients was limited. Less than one third of patients with a CBZ rash also reacted to OXC. No evidence for increased severity of sequential rashes was found. Clinicians should be aware of the cross-reactivity of the aromatic AEDs regarding cutaneous adverse events, as well as their differences in this respect. LTG appears to be involved in cross-reactions less often than CBZ, OXC and PHT.     

Cytogenetic Effects of Phenytoin and/or Carbamazepine on Human Peripheral Leukocytes

The cytogenetic effects of phenytoin (PHT) and/or carbamazepine (CBZ) were studied to determine clastogenic potential. Comparative analysis of chromosome breakage and sister chromatid exchange (SCE) was performed between 18 patients with epilepsy receiving PHT and/or CBZ and 10 healthy nontreated controls. These studies failed to detect a significant increase in chromosome aberrations or SCEs in groups of treated individuals as compared with controls. No correlation was observed between the rate of either chromosome damage or SCEs and age, sex, drug blood level, or daily dose. The results indicate no detectable chromosome damaging effects of PHT alone, CBZ alone, or a combination of these two antiepileptic drugs (AEDs).     

Gabapentin: Discussion

Summary: Gabapentin (GBP, Neurontin) is a novel anti-epileptic drug (AED) that was shown to be effective against refractory partial seizures in five placebo-controlled trials. However, a number of patients with complex partial seizures experienced an increase in seizure frequency, suggesting that patients suffering from complex partial seizures are not a homogeneous group. In fact, we found that currently available AEDs are likely to be ineffective when staring is a prominent component of complex partial seizures. The poor response of this group of patients may reflect the fact that staring spells are inhibitory seizures and that the AEDs prescribed for partial seizures appear to facilitate inhibitory mechanisms. GBP resembles phenytoin (PHT) and carbamazepine (CBZ) in depressing segmental and reticular excitatory mechanisms and facilitating segmental inhibitory mechanisms, just as it resembles PHT and CBZ in efficacy against some partial seizures and against secondarily generalized seizures. Perhaps the patients in whom GBP increased seizure frequency had complex partial seizures with staring and were therefore unlikely to benefit from drugs such as GBP, CBZ, and PHT, which enhance inhibitory mechanisms in the brain. These findings suggest that future AED trials would greatly benefit from a categorization of complex partial seizures into no-sologically distinct groups.     

Discontinuation of Phenytoin, Carbamazepine, and Valproate in Patients with Active Epilepsy

The effects of discontinuing individual antiepileptic drugs (AEDs) in patients with active epilepsy who are receiving combination therapy have not been studied systematically. We report a double-blind, prospective study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 70 patients with chronic active epilepsy. Each drug discontinuation was randomized to one of two relatively fast rates of reduction, and a control group of 25 patients continued with stable therapy. Patients who had CBZ removed had a significant increase in seizures that was maintained for 4 weeks after the end of drug reduction, and 10 of these 23 patients had to restart therapy with CBZ. There was no significant change in seizure numbers in the other groups. Two patients discontinued from VPA had to restart the drug; none had to restart PHT. The optimal rates of reduction of CBZ remain uncertain. There was no evidence for a clinically or temporally distinct burst of "discontinuation seizures" in any group. Any marked increase in seizures always resolved on reintroduction of the discontinued drug.     

Drug Interaction Profile of Topiramate

Summary: In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cy-tochrome P450 isoforms show an effect of TPM only on the CYP2C_meph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.     

常用抗癫痫药对大鼠胚胎毒性的比较

对临床常用的三种抗癫痫药(AEDs)苯妥英钠(PHT)、丙戊酸内(VPA)和卡马西平(CBZ)进行胚胎毒性的比较,以期找到一种胚胎毒性较低的AEDs。用人类平均治疗量的10倍AEDs给予怀孕母鼠。孕末时,对其胎鼠进行胚胎毒性的鉴定。PHT组除了上枕骨骨化程度低于对照组外,未见其它胚胎毒性。VPA和CBZ组的胚胎毒性高于对照组。VPA组又高于CBZ组。VPA胚胎毒性最强,CBZ次之,PHT最弱。     

Effect of Antiepileptic Drugs on Growth of Murine Lymphoid Tumor Cells in Single-Cell Culture

The effect of three commonly used antiepileptic drugs (AEDs), phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA), on the growth of lymphoid tumor cells was assessed in vitro. A single-cell culture method was used to determine growth rates by direct visualization. The amount of free drug was determined by ultrafiltration to ascertain its correlation to therapeutic drug levels. VPA slowed the growth of B-myeloma (FO) and T-lymphoma (AKR-1) cells significantly within the range of therapeutic drug levels. CBZ and PHT likewise inhibited cell growth in both lineages but at two to four times the therapeutic level of free drug. CBZ was shown to have long-term effects on FO and AKR-1 cells, demonstrated by the reduced growth rates of cloned lines for 2-3 months after drug removal. Cloned sublines of myeloma cells secreting lambda light chain (J558L) treated with CBZ or PHT had a higher frequency of lambda light chain secretion loss mutations than the nontreated parent line.     

Immunologic Aspects of Carbamazepine Treatment in Epileptic Patients

Immune abnormalities have been found in epileptic patients receiving antiepileptic drugs (AEDs). Phenytoin (PHT) produces a decrease in serum IgA and IgM levels and a decrease in blastic transformation of circulating lymphocytes stimulated with phytohemoagglutinin (PHA). The effects of carbamazepine (CBZ) on the immune response are still conflicting. To elucidate the effects of CBZ on some immunologic parameters, serum concentrations of IgA, IgG, IgM, the phagocytosis and killing properties of polymorphonuclear leukocytes (PMNs), the cytotoxic activity of natural killer cells and the response of lymphocytes to mitogenic agents were studied. Forty healthy individuals and 39 epileptic patients treated with carbamazepine (CBZ) monotherapy (age range 18-40 years) entered the study. Student's t test was used to evaluate the data. CBZ had no effect on the serum immunoglobulin concentrations or on lymphocytic reactivity to phytohemoagglutinin (PHA) mitogen. CBZ produced a significant enhancement of phagocytosis and killing properties of PMNs and an increase in natural killer (NK) cell activity. Therefore, a negative effect of CBZ therapy on the immune system was not observed in this study.     

Protein binding of four antiepileptic drugs in maternal and umbilical cord serum.

The total and protein free levels of 4 antiepileptic drugs (AEDs) in serum from 35 maternity patients who had been treated with AED monotherapy throughout pregnancy were studied. Results were compared with those in the umbilical cord serum at the time of delivery, and the placental transfer of AEDs was evaluated from the viewpoint of the protein binding capacity of the drug. The materials consisted of 35 samples of maternal and umbilical cord serum in total and included 13 patients on phenobarbital (PB), 7 on phenytoin (PHT), 7 on carbamazepine (CBZ) and 8 on valproic acid (VPA). The mean fetal/maternal total concentration ratios were 0.86, 0.91, 0.73 and 1.59 for PB, PHT, CBZ and VPA, respectively, only the VPA ratio being above 1. On the other hand, the mean fetal/maternal free fraction ratios were 1.13, 1.10, 1.42 and 0.50 for PB, PHT, CBZ and VPA, respectively, only the VPA ratio being less than 1. Correlation of the 2 ratios showed a reciprocal proportion with a correlation coefficient of -0.90 (P < 0.005). It was considered that the fetal/maternal total concentration ratio of 4 AEDs was regulated by the fetal/maternal free fraction ratio of the corresponding AEDs and that the difference in fetal/maternal free fraction ratio depended on the type of drug being administered.     

Interactions Between Anticonvulsants and Other Commonly Prescribed Drugs

Summary: Many drug interactions can be demonstrated, but only a few are so clinically significant that they necessitate adjusting drug dosages. The same drug combination may produce changes of variable extent or direction in different individuals. The reasons for this variability include genetic control of the rate and inducibility of drug metabolism, and environmental factors such as contact with chemicals. Among antimicrobial agents, chloramphenicol may cause accumulation of phenytoin (PHT) and phenobarbital (PB), and isoniazid may cause PHT, carbamazepine (CBZ), and primidone (PRM) to accumulate. Erythromycin may cause accumulation of CBZ. Among antiulcer agents, antacids may reduce PHT concentration while cimetidine may cause accumulation of PHT, CBZ, and diazepam (DZP). Salicylates displace strongly binding drugs such as PHT, DZP, or valproate (VPA) from the binding sites in plasma proteins, which may lead to some decline of the total plasma level with an increase in the unbound drug percentage. Conversely, anticonvulsants may influence the dosage requirements of oral anticoagulants by inducing their metabolism. Failures of oral contraceptives have been attributed to anticonvulsants in some patients. Probably the most predictable interaction that necessitates dosage adjustment is accumulation of PB caused by VPA. Intentional inhibition of PRM metabolism by nicotinamide serves as an example of attempts to utilize an interaction for improved therapeutic effect.     

Differential effects of antiepileptic drugs on neonatal outcomes

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis

Purpose: Long‐term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long‐term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process. Methods: One hundred sixty adult patients who were receiving AED monotherapy, including two enzyme‐inducers (carbamazepine, CBZ; and phenytoin, PHT), an enzyme‐inhibitor (valproic acid, VPA), and a noninducer (lamotrigine, LTG) for more than 2 years, and 60 controls were enrolled in this study. All study participants received measurement of common carotid artery (CCA) intima media thickness (IMT) by B‐mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index, and serum lipid profile or levels of total homocysteine (tHcy), folate, uric acid, fasting blood sugar, high sensitivity C‐reactive protein (hs‐CRP), or thiobarbituric acid reactive substances (TBARS). Key Findings: Long‐term monotherapy with older‐generation AEDs, including CBZ, PHT, and VPA, caused significantly increased CCA IMT in patients with epilepsy. After adjustment for the confounding effects of age and gender, the CCA IMT was found to be positively correlated with the duration of AED therapy. Patients with epilepsy who were taking enzyme‐inducing AED monotherapy (CBZ, PHT) manifested disturbances of cholesterol, tHcy or folate metabolism, and elevation of the inflammation marker, hs‐CRP. On the other hand, patients on enzyme‐inhibiting AED monotherapy (VPA) exhibited an increase in the levels of uric acid and tHcy, and elevation of the oxidative marker, TBARS. However, no significant alterations in the markers of vascular risk or CCA IMT were observed in patients who received long‐term LTG monotherapy. Significance: Patients with epilepsy who were receiving long‐term monotherapy with CBZ, PHT, or VPA exhibited altered circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process, which is significantly associated the duration of AED monotherapy. This information offers a guide for the choice of drug in patients with epilepsy who require long‐term AED therapy, particularly in aged and high‐risk individuals.     

Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice

Purpose:   Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)–induced seizures in mice.
Methods:   Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone–AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue.
Results:   Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect.
Conclusions:   Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.     

Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population

Purpose: Previous studies found a strong association between HLA‐B*1502 and carbamazepine (CBZ)‐induced Stevens‐Johnson syndrome (SJS) in Han Chinese, but not in Caucasian populations. Even in Han Chinese, the HLA‐B*1502 was not associated with CBZ‐induced maculopapular eruptions (MPE). This study seeks to identify whether HLA‐B*1502 is associated with CBZ‐ or phenytoin (PHT)‐induced SJS or MPE in a Thai population. Methods: Eighty‐one Thai epileptic patients between 1994 and 2007 from the Chulalongkorn Comprehensive Epilepsy Program were recruited. Thirty‐one subjects had antiepileptic drug (AED)‐induced SJS or MPE (6 CBZ‐SJS, 4 PHT‐SJS, 9 CBZ‐MPE, 12 PHT‐MPE), and 50 were AED‐tolerant controls. Results: For the first time, a strong association between HLA‐B*1502 and PHT‐induced SJS was found (p = 0.005). A strong association was also found between the HLA‐B*1502 and CBZ‐induced SJS (p = 0.0005), making Thai the first non‐Chinese population demonstrating such an association. Some patients, who were HLA‐B*1502 and suffered from CBZ‐induced SJS, could be tolerant to PHT and vice versa. This suggests that HLA‐B*1502 may be a common attribute required for a Thai patient to develop SJS from these two AEDs; other different elements, however, are also needed for each AED. In addition, no association between HLA‐B alleles and CBZ‐ or PHT‐induced MPE was found. Conclusions: CBZ‐ and PHT‐induced SJS, but not MPE, is associated with HLA‐B*1502 allele in Thai population.     

Concentration of antiepileptic drugs in persons with epilepsy: a comparative study in serum and saliva

Aim of the study: The monitoring of antiepileptic drugs (AEDs) in clinical setting is important for measuring the efficacy of drugs and their safety and in personalizing drug therapy. We investigated the levels of AED, carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PHB), to understand their association in saliva compared with those in serum during the therapy. Materials and methods: In this study, we performed a prospective study of 116 persons with epilepsy (PWE; mean age 26.90 ± 11.83 years). Serum and saliva samples were collected at trough levels from the patients, who were under the treatment of CBZ, PHT and PHB either alone or in combination of these drugs for at least three months. The drug levels were assessed by high-performance liquid chromatography. Results and conclusions: The number of males (n = 88; 75.86%) was higher than females (n = 28; 24.14%) among the recruited patients. The intake of CBZ, PHT and PHB was observed in 49.14%, 68.10% and 38.79% of PWE, respectively. The levels of these AEDs showed a significant correlation (p < 0.05) between serum and saliva. Interestingly, the levels of mono-therapy or bi-therapy showed a significant association (p < 0.05) between serum and saliva, however, there was no significant association in case of poly-therapy. This is the first report in the Indian population on simultaneous estimation of the three commonly used AEDs, such as CBZ, PHT and PHB in serum and saliva implicating their associations, either in mono-therapy or bi-therapy in PWE.     

The importance of drug interactions in epilepsy therapy

Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)]. The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZ-epoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.     

Effects of Carbamazepine and Phenytoin on EEG and Memory in Healthy Adults

Summary: Using a randomized, double-blind, cross over design, we investigated the effects of carbamazepine (CBZ) and phenytoin (PHT) on memory and spectral EEG components in 15 healthy adults. Each subject was treated with each drug for 1 month, separated by a 1-month washout. Evaluations were conducted at baseline, at the end of each treatment month, and 1 month after the last treatment phase. EEG was collected during an eyes-closed resting condition and a verbal memory activation task. Spectral analysis of the EEG in the nondrug conditions showed that the memory task significantly reduced theta components and increased delta components. As compared with nondrug conditions, the antiepileptic drugs (AEDs) significantly impaired memory performance and produced mild EEG slowing. Memory performance did not differ statistically between the AEDs, but minor differences in spectral EEG components were noted. The results suggest that differences in the cognitive and EEG effects of CBZ and PHT are not clinically significant.