Arzneimittelwechselwirkungen mit Antiepileptika

Drug interactions with antiepileptic agents are based in large part on pharmacokinetic mechanisms. Most prominent are induction or inhibition of enzymes of the cytochrome P450 (CYP) system, which is of central importance for metabolic elimination of lipophilic xenobiotics. Potent inductors of CYP isoenzymes are carbamazepine, phenobarbital, phenytoin, and primidone, thereby decreasing not only their own plasma levels and efficacy but also that of other antiepileptics and other drugs. Felbamate, oxcarbazepine, and topiramate are weak inductors of the CYP isoenzyme 3A4, whereas they inhibit CYP2C19. Valproic acid is a potent inhibitor of several CYP isoenzymes and glucuronyltransferases, resulting in an increase in plasma concentrations and toxicity of antiepileptics and other drugs. Antiepileptics that are not involved in drug interactions include gabapentin, levetiracetam, and vigabatrine. The P-glycoprotein may mediate the exit of antiepileptics from the brain. This transport mechanism is inhibited by carbamazepine, which may explain the enhanced clinical efficacy of a combination of carbamazepin with other antiepileptics. Other possible pharmacokinetic interactions are precipitation of antiepileptics in the stomach by antacids or sucralfate and displacement from plasmaprotein binding of one antiepileptic agent by another. Therapeutic drug monitoring (TDM) may be helpful in assessing pharmacokinetic drug interactions. Pharmacodynamic interactions appear to be responsible for the enhanced efficacy of antiepileptic combination therapy. In prescribing drugs, their spectrum of interactions has to be known.     

Long-term use of the major anticonvulsant drugs.

The specific type of epilepsy must be identified. The history and the EEG provide the evidence. Drug selection is then based on the classification of the patient's epilepsy. Major drugs used in the management of epilepsy are phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide and valproic acid. The physician should know their kinetics, interactions and side effects, and the value of monitoring blood levels of these anticonvulsant agents.     

EMIT antiepileptic drug assays adapted to an Abbott-VP Analyzer and compared with a gas-chromatographic procedure

The Abbott-VP Bichromatic Analyzer was used for the determination of four antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, primidone) in serum by means of a modified EMIT homogeneous enzyme immunoassay procedure. The main objective of the work was to examine the precision and the accuracy of the results obtained with this system and its cost effectiveness in comparison to the manual method. Day-to-day precision for all four drugs is excellent with coefficients of variation averaging around 5% in the therapeutic range of concentrations. Results for sera analyzed by this procedure and by a gas chromatographic method do not show any significant difference for phenytoin and phenobarbital. There are however slight differences between the two methods for carbamazepine and primidone. These small differences do not modify significantly the clinical interpretation of the results. The procedure is simple and rapid, and requires only one third of the reagents needed in the recommended manual EMIT procedure using the Gilford Stasar III, thus greatly reducing the operation costs.     

Improved sexual function in three men taking lamotrigine for epilepsy

Little information exists about the effects of newer antiepileptic drugs (AEDs) on sexual function in men with epilepsy. We report a series of three male veterans whose sexual disorders improved with lamotrigine. All three had partial seizures. One patient was taking phenobarbital and gabapentin and complained of decreased potency and anorgasmia. After lamotrigine was added for better seizure control and the dosage of gabapentin was tapered, anorgasmia improved. The second patient complained of impotence after a rash while taking phenytoin and carbamazepine. Impotence persisted with phenobarbital, valproate, and gabapentin. Eight months after gabapentin was replaced with lamotrigine, impotence improved. The third patient complained of long-standing impotence. Treatment with five AEDs had no effect on the dysfunction. Lamotrigine was added to the carbamazepine regimen; impotence improved with decrease in carbamazepine and increase in lamotrigine. The favorable effect of lamotrigine on sexual disorders in these three patients suggests this drug should be considered under appropriate circumstances for men who have sexual dysfunction while taking other antiepileptic agents.     

Pharmacokinetic drug interactions in children taking oxcarbazepine

OBJECTIVE: Our objective was to evaluate the drug-drug interactions of oxcarbazepine with coadministered antiepileptic drugs in children. METHODS: In a clinical trial, pediatric patients receiving an oxcarbazepine dose titrated to 30 to 46 mg. kg(-1). d(-1) given twice daily had 1 to 4 blood samples collected per patient for population pharmacokinetic analysis of oxcarbazepine's major bioactive 10-monohydroxy metabolite. With the use of NONMEM, 7 concomitant antiepileptic drugs and 12 additional covariates were examined for their effects on the pharmacokinetics of 10-monohydroxy metabolite. In addition, for each concomitant antiepileptic drug, the ratio of its mean concentration with coadministration of oxcarbazepine to that without coadministration at baseline was calculated to evaluate the effect of oxcarbazepine on the coadministered antiepileptic drugs. RESULTS: The population pharmacokinetic data for 10-monohydroxy metabolite consisted of a total of 376 observations from 109 patients, aged 3 to 17 years. Body surface area and 3 antiepileptic drugs (carbamazepine, phenobarbital, and phenytoin) were significant predictors of the apparent clearance of 10-monohydroxy metabolite, whereas height was a significant predictor of apparent volume. Weight-normalized clearance of 10-monohydroxy metabolite was higher in young children than in older children and adults. Carbamazepine, phenobarbital, or phenytoin administered with oxcarbazepine increased the apparent clearance of 10-monohydroxy metabolite by 31% to 35%, whereas carbamazepine levels decreased by 15% and phenobarbital levels increased by 14%. CONCLUSIONS: Oxcarbazepine has a low propensity to inhibit or induce oxidative enzymes. Young children could be given higher milligrams-per-kilogram oxcarbazepine doses than older children and adults to achieve the same mean steady-state concentration of 10-monohydroxy metabolite. The adjustment is based simply on body size.     

Clinically significant pharmacokinetic drug interactions between antiepileptic drugs

Pharmacokinetic interactions between antiepileptics represent a major potential complication of epilepsy treatment because drug combinations are common. This review discusses pharmacokinetic drug interactions of clinical significance involving antiepileptics and cytochrome P450 (CYP). Most commonly used antiepileptics are eliminated through hepatic metabolism, catalysed by the enzymes CYP2C9, CYP2C19 and CYP3A4 and uridine diphosphate glucuronosyltransferase (UDGPT). Antiepileptics are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition. Phenytoin, phenobarbiral, primidone and carbamazepine induce CYP and UDPGT enzymes while valproic acid inhibits them. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential and careful dosage adjustments based on serum drug concentration monitoring and clinical observation are the main methods for reducing the risks associated with these interactions.     

Therapeutic drug monitoring of old and newer anti-epileptic drugs.

The aim of the present paper is to provide information concerning the setting up and interpretation of therapeutic drug monitoring (TDM) for anti-epileptic drugs. The potential value of TDM for these drugs (including carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pheneturide, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide) is discussed in relation to their mode of action, drug interactions and their pharmacokinetic properties. The review is based upon available literature data and on observations from our clinical practice. Up until approximately 15 years ago anti-epileptic therapeutics were restricted to a very few drugs that were developed in the first half of the 20th century. Unfortunately, many patients were refractory to these drugs and a new generation of drugs has been developed, mostly as add-on therapy. Although the efficacy of the newer drugs is no better, there is an apparent improvement in drug tolerance, combined with a diminished potential for adverse drug interactions. All new anticonvulsant drugs have undergone extensive clinical studies, but information on the relationship between plasma concentrations and effects is scarce for many of these drugs. Wide ranges in concentrations have been published for seizure control and toxicity. Few studies have been undertaken to establish the concentration-effect relationship. This review shows that TDM may be helpful for a number of these newer drugs.     

Improved isocratic liquid-chromatographic simultaneous measurement of phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, and N-desmethylmethsuximide in serum

We describe an improved "high-pressure" liquid-chromatographic assay for simultaneous determination in serum of the five major antiepileptic drugs (ethosuximide, primidone, phenobarbital, phenytoin, and carbamazepine) and N-desmethylmethsuximide (the compound that must be quantitated for therapeutic drug monitoring of the antiepileptic drug methsuximide). Serum protein is precipitated with an acetone solution containing 5-ethyl-5-(p-methylphenyl)barbituric acid as the internal standard. The centrifuged supernate is injected onto the chromatographic column. Drugs and internal standard are eluted at 30 degrees C with mobile phase containing acetonitrile/methanol/phosphate buffer (17/28/55 by vol) at a flow rate of 0.7 mL/min, monitored at 195 nm. Analysis time is about 20 min. Quantitation is by measurement of peak areas. Analytical and absolute recoveries varied from 95 to 104%. Within-day coefficients of variation ranged from 1.6 to 5.4%, between-day CVs from 0.0 to 3.4% in subtherapeutic, therapeutic, and toxic samples. Resolution of therapeutic concentrations of all six drugs was complete. As yet, we have found no drug or drug metabolite that interferes.     

Simultaneous liquid-chromatographic determination of some bronchodilators, anticonvulsants, chloramphenicol, and hypnotic agents, with Chromosorb P columns used for sample preparation

We describe a simple liquid-chromatographic system for simultaneously measuring bronchodilators, anticonvulsants, hypnotics, and chloramphenicol. Use in therapeutic drug monitoring includes determination of theophylline, caffeine, chloramphenicol, ethosuximide, primidone, phenobarbital, phenacemide, phenytoin, mephenytoin, nirvanol, and carbamazepine and its bioactive metabolites within 13 min. In the "toxicology mode" theophylline, caffeine, barbital, butabarbital, pentobarbital, amobarbital, secobarbital, primidone, phenobarbital, methylprylon, glutethimide, methaqualone, phenytoin, mephenytoin, nirvanol, and carbamazepine and its bioactive metabolites are resolved within 17 min. A reversed-phase C8 column (5-microns particles) is used, with acetonitrile/water (20/80 by vol) as mobile phase. The drugs are extracted from 50 microL of serum with use of a Chromosorb P microcolumn and chloroform/isopropanol (6/1 by vol). The drugs are quantified by absorbance at 208 nm, with tolylphenobarbital as internal standard. Lower limits of detection varied from 0.05 to 0.1 mg/L, analytical recovery from 94% to 106%; CVs were less than 5.6% within run, less than 6.9% between runs.     

Clearance of phenytoin and valproic acid is affected by a small body weight reduction in an epileptic obese patient: a case study

The interaction between clearance of phenytoin, valproic acid, phenobarbital and carbamazepine, and changes in body weight was determined in a 19-year-old obese woman with epilepsy (body weight 93 kg, BMI 36.3 kg/m²). The patient, who was given daily oral doses of 100 mg phenobarbital, 350 mg phenytoin, 800 mg valproic acid and 800 mg carbamazepine over 5 months was hospitalized for obesity treatment. The daily dosage of each drug was held constant during treatment of the obesity. Blood samples were taken five times. Weight reduction was 7 kg (7.5%) over 46 days. Estimation of the pharmacokinetic parameters in each drug was performed by Higuchi's Bayesian program, PEDA Pearson's correlation coefficient ( r ) between clearance and body weight was calculated for each drug. High positive correlations were found between clearance and body weight for phenytoin ( r = 0.800) and valproic acid ( r = 0.785), but not for phenobarbital ( r = - 0.227) and carbamazepine ( r = 0.152). Clearance of phenytoin and valproic acid may be potentially affected by small changes in body weight.     

Clinically relevant anti-epileptic drug interactions

Anti-epileptic drugs frequently interact due to pharmacokinetic features (induction or inhibition of metabolism, production of active metabolites, low therapeutic indices) and the need for prolonged treatment with possible addition of other drugs to treat concomitant diseases. The most important pharmacokinetic interactions are those that inhibit phenytoin, carbamazepine and phenobarbitone metabolism and thus increase their toxicity. Drugs inhibiting metabolism include antibiotic macrolides, chloramphenicol, isoniazide, some sulphonamides, propoxyphene, cimetidine, valproic acid and sulthiame. Anti-epileptic drugs can induce hepatic microsomal enzymes and, therefore, may increase metabolism of corticosteroids, oral contraceptives, oral anticoagulants, cardiovascular agents, antibiotics, chemotherapeutic agents, psychotropic drugs and non-opiate analgesics, thereby reducing their efficacy. Advantageous pharmacodynamic interactions include synergism of ethosuximide plus valproic acid and of carbamazepine plus valproic acid. A pharmacodynamic mechanism may be responsible for the reduced sensitivity of chronically treated epileptics to some neuromuscular blockers.     

Primary standardization of assays for anticonvulsant drugs: comparison of accuracy and precision

BACKGROUND: The accuracy and precision of methods for the measurement of the anticonvulsants phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, and valproate in human serum were assessed in 297 laboratories that were participants in the United Kingdom National External Quality Assessment Scheme (UKNEQAS). METHODS: We distributed lyophilized, serum-based materials containing low, medium, and high weighed-in concentrations of the drugs. The 297 participating laboratories received the materials on two occasions, 7 months apart. Expected concentrations were determined by gas chromatography or HPLC methods in five laboratories using serum-based NIST reference materials as calibrators. RESULTS: In general, bias was consistent across concentrations for a method but often differed in magnitude for different drugs. Bias ranged from -1.9% to 8.6% for phenytoin, -2.7% to 3.1% for phenobarbital, -2.7% to 0.5% for primidone, -8.6% to 0.3% for carbamazepine, -5.6% to 2.0% for ethosuximide, and -7.2% to 0.1% for valproate. Intralaboratory sources of imprecision significantly exceeded interlaboratory sources for many drug/method combinations. The mean CVs for intra- and interlaboratory errors for the different drugs were 6.3-7.8% and 3.3-4.2%, respectively. CONCLUSIONS: For these long-established and relatively high-concentration analytes, the closed analytical platforms generally performed no better than open systems or chromatography, where use of calibrators prepared in house predominated. To improve the accuracy of measurements, work is required principally by the manufacturers of immunoassays to ensure minimal calibration error and to eliminate batch-to-batch variability of reagents. Individual laboratories should concentrate on minimizing dispensing errors.     

Clinical pharmacology and therapeutic use of the new antiepileptic drugs

Although older generation antiepileptic drugs (AEDs) such as carbamazepine, phenytoin and valproic acid continue to be widely used in the treatment of epilepsy, these drugs have important shortcomings such as a highly variable and nonlinear pharmacokinetics, a narrow therapeutic index, suboptimal response rates, and a propensity to cause significant adverse effects and drug interactions. In an attempt to overcome these problems, a new generation of AEDs has been introduced in the last decade. Compared with older agents, some of these drugs offer appreciable advantages in terms of less variable kinetics and, particularly in the case of gabapentin, levetiracetam and vigabatrin, a lower interaction potential. Lamotrigine, topiramate, zonisamide and felbamate protect against partial seizures and a variety of generalized seizure types, vigabatrin is effective against partial seizures (with or without secondary generalization) and infantile spasms, while the use of oxcarbazepine, tiagabine and gabapentin is mainly restricted to patients with partial epilepsy (and, in the case of oxcarbazepine, also primarily generalized tonic-clonic seizures). Levetiracetam, the latest AED to be introduced, has been found to be effective in partial seizures, but its potentially broader efficacy spectrum remains to be determined in clinical studies. Currently, the main use of new generation AEDs is in the adjunctive therapy of patients refractory to older agents. However, due to advantages in terms of tolerability and ease of use, some of these drugs are increasingly used for first-line management in certain subgroups of patients. Due to serious toxicity risks, felbamate and vigabatrin should be prescribed only in patients refractory to other drugs. In the case of vigabatrin, however, first line use may be justified in infants with spasms.     

Seizure prophylaxis in patients with brain tumors: a meta-analysis

OBJECTIVE: To assess whether antiepileptic drugs (AEDs) should be prescribed to patients with brain tumors who have no history of seizures. METHODS: We performed a meta-analysis of randomized controlled trials (1966-2004) that evaluated the efficacy of AED prophylaxis vs no treatment or placebo to prevent seizures in patients with brain tumors who had no history of epilepsy. Summary odds ratios (ORs) were calculated using a random-effects model. Three subanalyses were performed to assess pooled ORs of seizures in patients with primary glial tumors, cerebral metastases, and meningiomas. RESULTS: Of 474 articles found in the initial search, 17 were identified as primary studies. Five trials met inclusion criteria: patients with a neoplasm (primary glial tumors, cerebral metastases, and meningiomas) but no history of epilepsy who were randomized to either an AED or placebo. The 3 AEDs studied were phenobarbital, phenytoin, and valproic acid. Of the 5 trials, 4 showed no statistical benefit of seizure prophylaxis with an AED. Meta-analysis confirmed the lack of AED benefit at 1 week (OR, 0.91; 95% confidence interval [CI], 0.45-1.83) and at 6 months (OR, 1.01; 95% CI, 0.51-1.98) of follow-up. The AEDs had no effect on seizure prevention for specific tumor pathology, including primary glial tumors (OR, 3.46; 95% CI, 0.32-37.47), cerebral metastases (OR, 2.50; 95% CI, 0.25-24.72), and meningiomas (OR, 0.62; 95% CI, 0.10-3.85). CONCLUSIONS: No evidence supports AED prophylaxis with phenobarbital, phenytoin, or valproic acid in patients with brain tumors and no history of seizures, regardless of neoplastic type. Subspecialists who treat patients with brain tumors need more education on this issue. Future randomized controlled trials should address whether any of the newer AEDs are useful for seizure prophylaxis.     

Drug therapy for seizures

Phenytoin, valproic acid, carbamazepine, phenobarbital, primidone, and ethosuximide are important in anticonvulsant therapy. Each drug's structure determines its properties and its activity against particular seizure types. Single-drug therapy is generally preferable to multiple-drug therapy. Absorption, half-life, metabolism, and other pharmacokinetic characteristics are important considerations in the selection of an anticonvulsant drug.     

Side Effects of Antiepileptics— A Review

Abstract:   Older generation antiepileptic drugs like Phenobarbital (Luminal), carbamazepine (Tegretol), phenytoin (Dilantin), and valproic acid (Depakote) have several shortcomings such as suboptimal response rates, significant adverse effects, several drug interactions, and a narrow therapeutic index. New antiepileptic drugs have been developed in the last decade to overcome some of these problems. These newer generation antiepileptics like felbamate (Felbatol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), tiagabine (Gabitril), topiramate (Topamax), and zonisamide (Zonegran) have better tolerability profiles, low interaction potential, and significantly less enzyme inducing or inhibiting properties. As the use of antiepileptic drugs has expanded to include treatment of neuropathic pain, newer side effects have been reported. In addition to the common side effects of antiepileptic drugs, like dizziness, drowsiness, and mental slowing; other side effects like weight gain, metabolic acidosis, nephrolithiasis, angle closure glaucoma, skin rash, hepatotoxicity, colitis, and movement and behavioral disorders, to name a few, have been brought to our attention. This review is an attempt to highlight the features and incidences of some of these side effects.     

Novel anticonvulsant drugs

Principles of complex mechanisms of action of anticonvulsants including latest reports concerning new antiepileptic drugs (AED) are considered. Different aspects of new anticonvulsant drugs (2nd generation) from preclinical and clinical testing, pharmacokinetics, and mono or combination therapy in children and adults are summarized. In the following condensed synopsis pharmacological and clinical characteristics of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB) and tiagabine (TGB) as well as topiramate (TPM) and zonisamide (ZNS) are discussed. In addition to the mechanisms of action, pharmacokinetics, interactions, indications and dosages as well as side effects are considered. Important data concerning the effect and tolerability of anticonvulsant drugs can be obtained from controlled studies. In comparison to drugs of the first generation (phenobarbital [PB], primidon [PRD], phenytoin [PHT], carbamazepine [CBZ] and valproic acid [VPA]) the potential for interactions and side effects due to enzyme induction or inhibition is reduced by most of the anticonvulsant drugs of the second generation. New anticonvulsant drugs increase the spectrum of treatment and represent further steps with regard to the optimization of an individual therapy of the epilepsies.     

ANALYSIS OF THE FACTORS INFLUENCING ANTI-EPILEPTIC DRUG CONCENTRATIONS-VALPROIC ACID

The factors that influence valproic acid (VPA) serum concentrations and level:dose ratios were evaluated, retrospectively, on 51 consecutive routine VPA determinations from 50 chronically treated epileptic patients. The influence of co-medicated anti-epileptic drugs (phenytoin, phenobarbital, carbamazepine), alone or in combination, on total and free levels of VPA was studied. Furthermore, the possible influence of certain physiological and/or pathophysiological factors (age, weight, sex and clinical laboratory data) was considered. The total level:dose ratio was lower when VPA was given in combination with phenytoin or with carbamazepine than when VPA was given alone. The free level:dose ratio also decreased during concomitant treatment with phenytoin. The free fraction of VPA was unaltered when in combination with phenytoin or with carbamazepine, whereas it was decreased by a combination with phenytoin plus carbamazepine. As a whole, strong, positive, correlations existed between the VPA dose (mg/kg/day) and the total and free serum levels of VPA in the range of less than 15 mg/kg/day, but both levels of VPA tended to flatten out at the range of more than 15 mg/kg/day. These findings should therefore be considered when defining dosage regimens or interpreting serum drug concentrations. Stepwise multivariate regression analysis (MVR) showed that the VPA dose, simultaneous carbamazepine intake, serum glutamic oxalacetic transaminase (SGOT) and serum albumin concentration were important determinants of VPA serum concentrations.