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PubMed2002

Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate.

BACKGROUND: Case reports suggest that maternal hepatic enzyme-inducing antiepileptic drugs (AED) increase the risk for neonatal bleeding. Antenatal administration of vitamin K(1) to mothers using these drugs therefore is widely recommended. There are, however, no studies on the incidence of this complication. OBJECTIVE: To assess the occurrence of bleeding complications in newborns exposed to maternal enzyme-inducing AED in utero. METHODS: The authors prospectively followed 662 pregnancies in women with epilepsy who used enzyme-inducing AED. Of the 667 neonates, 463 were exposed to carbamazepine, 212 to phenytoin, 44 to phenobarbital, 11 to primidone, and 7 to oxcarbazepine. The control subjects were 1,324 nonepileptic pregnancies (1,334 neonates) matched for maternal age, parity, number of fetuses, and delivery date. None of the mothers received vitamin K(1) during pregnancy, but all infants received 1 mg vitamin K(1) intramuscularly at birth. RESULTS: A bleeding complication was observed in five (0.7%) of the offspring exposed to maternal enzyme-inducing AED and in five (0.4%) control subjects (p = 0.3). After logistic regression analysis was performed, bleeding was associated with birth at <32 weeks of gestation (adjusted OR = 13; 95% CI = 2.7 to 64) and alcohol abuse (adjusted OR = 17; 95% CI = 1.8 to 162) but not with exposure to enzyme-inducing AED (adjusted OR = 1.1; 95% CI = 0.3 to 4.6; p = 0.8). CONCLUSIONS: These data do not support the hypothesis that maternal enzyme-inducing AED increase the risk for bleeding in the offspring. Antenatal administration of vitamin K to these mothers may still be needed in selected cases.

Adult↗
PubMed2002

Effect of antiepileptic drugs on bone density in ambulatory patients.

BACKGROUND: Long-term antiepileptic drug (AED) use causes multiple abnormalities in calcium and bone metabolism that have been most extensively described in institutionalized patients. The objective is to determine the effect of AED on vitamin D levels and bone density in ambulatory patients and to compare the effects of enzyme-inducing and -noninducing AED and of single vs multiple therapy on bone density. METHODS: A cross-sectional evaluation was conducted of 71 patients (42 adults and 29 children/adolescents) on anticonvulsant therapy for at least 6 months who presented to neurologists at a tertiary referral center. Bone mineral density (BMD) as well as serum 25 hydroxy-vitamin D (25-OHD) levels were measured. A detailed questionnaire assessing calcium intake as well as previous and current intake of antiepileptic medications was administered to all patients. RESULTS: Over 50% of adults and children/adolescents had low 25-OHD levels, but this finding did not correlate with BMD. Antiepileptic therapy decreased BMD in adults. Generalized seizures, duration of epilepsy, and polypharmacy were significant determinants of BMD, more so at skeletal sites enriched in cortical bone. Subjects on enzyme-inducing drugs such as phenytoin, phenobarbital, carbamazepine, and primidone tended to have lower BMD than those on noninducers such as valproic acid, lamotrigine, clonazepam, gabapentin, topamirate, and ethosuximide. CONCLUSION: Epilepsy and its therapy, including the newer drugs, are risk factors for low bone density, irrespective of vitamin D levels. Skeletal monitoring with the institution of appropriate therapy is indicated in patients on chronic antiepileptic therapy.

Adolescent↗
PubMed2003

Antiepileptic drug pharmacokinetics during pregnancy and lactation.

The ideal management of women with epilepsy during pregnancy and the postpartum period involves achieving an optimal balance between minimizing fetal and neonatal exposure to the deleterious influences both of antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiologic changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Noncompliance can also be a major factor. The majority of AEDs are characterized by significant increases in clearance during pregnancy. Lamotrigine (LTG) clearance markedly increases throughout pregnancy, to an extent greater than with the older AEDs. Studies during and after birth in mothers taking the older AEDs indicate extensive transplacental transfer and low to moderate excretion into breast milk. Limited studies of the newer AEDs indicate similar extensive transplacental transfer [LTG, oxcarbazepine, topiramate (TPM), zonisamide (ZNS)], and breast milk/maternal plasma concentration ratios less than 1 (LTG, TPM, ZNS). Especially high excretion of levetiracetam into breast milk may occur. Current published guidelines recommend that the ideal AED concentration should be established for each patient before conception and that monitoring of AED concentrations should be performed during each trimester and in the last month of pregnancy. Free concentrations should be measured for phenobarbital, phenytoin, carbamazepine, valproic acid, and primidone. Some authors recommend at least monthly monitoring of AED concentrations, especially for LTG. Future studies of formal pharmacokinetic modeling of AEDs during pregnancy and the postpartum period could provide an important step toward achieving effective drug dosing to maintain therapeutic objectives for the mother but, at the same time, to minimize fetal drug exposure.

Abnormalities, Drug-Induced↗
PubMed2004

Initial treatment of epilepsy: special issues in treating the elderly.

The incidence of new-onset epilepsy is higher among the elderly, the most rapidly growing segment of the population, than in any other age group. New-onset seizures in elderly patients are typically cryptogenic or symptomatic partial seizures that require long-term treatment. Because seizures in the elderly are often readily controlled, considerations of tolerability and safety, including pharmacokinetics and the potential for drug interactions, may be as important as efficacy in the selection of an antiepileptic drug (AED). The newer AEDs introduced during the past decade offer advantages in this respect over older agents. Phenytoin is the most widely used AED in the United States, but its hepatic metabolism and associated enzyme induction, as well as its nonlinear pharmacokinetics, are particular disadvantages for elderly patients. Because of their potential effects on cognitive function, sedating AEDs such as phenobarbital and primidone have little place in the treatment of new-onset seizures in elderly patients. Carbamazepine also is an enzyme-inducing agent with significant potential for drug interactions. Among the newer AEDs, gabapentin and levetiracetam have good safety and cognitive effect profiles and do not interact with other drugs, and lamotrigine offers many of the same benefits. Oxcarbazepine has better tolerability than carbamazepine, and topiramate and zonisamide, although they have more cognitive side effects than the other new AEDs, can be considered for some elderly patients. Forthcoming data from the Veterans Affairs Cooperative Trial 428, as well as recent guidelines from the American Academy of Neurology and the American Epilepsy Society, are likely to provide support for the use of selected second-generation AEDs as first-line agents for the treatment of epilepsy in elderly patients.

Aged↗
PubMed1980

Differential antagonisms of anticonvulsants to various components of maximal seizures induced by electroshock or pentylenetetrazol in mice.

Effects of antiepileptic drugs on various components (TF: tonic extension of forelimb, TH: tonic extension of hindlimb and CL: clonic convulsions or MCL: myoclonus) of maximal seizures induced by electroshock or pentylenetetrazol in mice were examined in order to classify these drugs. In addition, experiment was conducted similarly on the new anti-convulsant agent, 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), in order to assess this compound on the basis of the results with clinically useful antiepileptic drugs. From the results obtained in the present study, irrespective of the method, i.e. chemically or electrically induced seizures, anticonvulsant drugs tested can be classified into four main groups; 1) drugs (trimethadione, ethosuximide, nitrazepam, diazepam, erthotoin and metharbital) with an effect to antagonize all the whole seizure components. (TF, TH and CL or MCL) in an almost same antagonism, 2) drugs (phenacemide, dipropylacetate, pheneturide, acetylpheneturide and phenobarbital) which inhibit all forms of seizures at relatively dissociated doses for the prevention of each component of seizures, 3) drugs (diphenylhydantoin and carbamazepine) which selectively abolish both components (TF and TH) of tonic seizures, and 4) drugs (acetazolamide, sulthiame and primidone) exclusively blocking TH of tonic seizures. AD-810 demonstrated an antagonistic effect on tonic seizures but no on clonic ones with the same manner as seen with diphenylhydantoin and carbamazepine.

Animals↗
PubMed2003

Effects of concomitant antiepileptic drugs on serum carbamazepine concentration in epileptic patients: quantitative analysis based on extracellular water volume as a transforming factor.

The effects of concomitant antiepileptic drugs on the serum carbamazepine concentration (C1) were analyzed quantitatively. Primidone (PRM), phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), zonisamide (ZNS), clonazepam (CZP), and ethosuximide (ETS) were coadministered with carbamazepine (CBZ). Routine therapeutic drug monitoring data, obtained from epileptic patients who were treated with the repetitive oral administration of CBZ fine granules/tablets, were used for the analysis. A total of 119 patients were administered CBZ alone, and 91, 39, 19, and 6 patients were coadministered one, two, three, and more than four different antiepileptic drugs, respectively. Using the data obtained from the patients administered CBZ alone, Ct could be expressed approximately as a function of the daily dose per extracellular water volume (D/VECW) as Ct = A(D/VECW)B (A, B: parameter). By comparing the regression line on log Ct vs. log(D/VECW) for CBZ alone with that for CBZ plus another concomitant drug, Ct was thus found to be affected at each definite ratio by PB and PHT, but not by VPA and ZNS. We postulated a model showing that Ct is affected by each concomitant antiepileptic drug i at each definite ratio. We defined the parameter Ri(i = 1, 2, ..., 7) representing the effect of each concomitant antiepileptic drug on Ct. A linear polynomial expression, in which both members of this model are converted into common logarithms, was used for a multiple regression analysis. The analysis clarified that PB and PHT lowered Ct to 0.770 and 0.710 the value of CBZ alone, respectively. On the other hand, VPA and ZNS did not affect Ct. The number of patients coadministered PRM, CZP, and/or ETS was not sufficient to detect the effect on Ct based on a test of significance. In the case of the addition or discontinuation of concomitant antiepileptic drugs in the same patient, the estimated Ct values were calculated using the value of each Ri and compared with the measured Ct values. Both values were in good agreement, and thus our results appear valid.

Adolescent↗
PubMed1986

[The correlation between concentrations of anticonvulsive drugs in the brain and various parameters of maximal electroshock seizures in mice].

The relationship between concentrations of anticonvulsive drugs in the brain and various parameters of maximal electroshock seizures was investigated in mice. Maximal electroshock seizures were elicited with a current intensity (60 Hz, 50 mA for 0.2 sec) through corneal electrodes. Convulsive movements were detected by an accelerometer, amplified and recorded by a polygraph. Concentrations of anticonvulsive drugs in the whole brain were determined by the method of enzyme immunoassay. With various doses of phenobarbital (PB: 5-35 mg/kg, i.p.), duration of tonic flexion (TF) was prolonged, whereas duration of tonic extension (TE) and clonic convulsion (CL) was shortened in a dose-dependent manner. The correlation coefficient between the PB concentration and the duration of TF, TE or CL was 0.680, -0.882 or 0.409, respectively. The correlation coefficient between the PB concentration and the intensity of TE or CL, measured by the integrated curve of the accelerometer, was -0.847 or 0.440. The correlation coefficient between the PB concentration and the ratio of TE-duration/TF-duration (TE/TF ratio) was -0.901. After administration of phenytoin (PNT), carbamazepine (CBZ) or valproic acid (VPA), a highly negative correlation between the drug level in the brain and the TE/TF ratio was also obtained. In the case of diazepam, clonazepam, ethosuximide or trimethadione, the TE/TF ratio was decreased dose-dependently, but the slope of the dose-response regression line was less steep than that obtained by the administration of PB, PNT, CBZ, VPA or primidone. These results suggest that the TE/TF ratio may be the most reliable parameter for drug evaluation of the anticonvulsive efficacy against tonic-clonic seizures in human patients.

Animals↗
PubMedDate not supplied

Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate.

OBJECTIVE: Part I of this review examines the relationship between antiepileptic drugs (AEDs) and pregnancy outcomes. Drug-induced folate deficiency and the role of AED metabolism are emphasized. Part II will discuss periconceptional folate supplementation for prevention of birth defects. Part III will discuss the mechanism of folate's protective effect, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted for journal articles published through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included phenytoin, carbamazepine, phenobarbital, primidone, valproic acid, oral contraceptives, clomiphene, drug-induced abnormalities, spina bifida, anencephaly, neural tube defect, folate, folic acid, and folic acid deficiency. STUDY SELECTION: Relevant animal and human studies examining the effects of AEDs, smoking, and oral contraceptives on folate status and pregnancy outcome are reviewed. DATA EXTRACTION: Studies and case reports were interpreted. Data extracted included dosing, serum and red blood cell folate concentrations, teratogenicity of anticonvulsant medications, metabolism of AEDs and folate, and genetic susceptibility to AED-induced teratogenicity. DATA SYNTHESIS: Low serum and red blood cell folate concentrations are associated with adverse pregnancy outcomes. Decreases in serum folate are seen with AEDs, oral contraceptives, and smoking. Since similar birth defects are observed with multiple AEDs, metabolism of aromatic AEDs to epoxide metabolites and genetic factors may play a role in teratogenesis. CONCLUSIONS: Adequate prepregnancy planning is essential for women who have epilepsy. Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation.

Anticonvulsants↗
PubMed2004

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.

Anticonvulsants↗
PubMed2000

New anti-epileptic drugs for the 21st century.

Prior to 1993, there were only six major drugs available in the US for the treatment of patients with epilepsy. These included phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), primidone (PRIM), valproic acid/sodium valproate (VPA) and ethosuximide (ESX). Of these drugs, VPA has the broadest spectrum of activity and ESX the most limited. Despite these six agents, as well as several secondary drugs, it is estimated that over 30% of patients have inadequate seizure control, while others, whose disease is adequately controlled, suffer from bothersome adverse events (AEs). Since 1993, ten new drugs have entered the worldwide market (not all in the US). Those released include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LVT), zonisamide (ZNS), clobazam (CLB) and vigabatrin (VGB). The purpose of this article is to review each of the above drugs, looking at efficacy, safety, tolerability and where they may play a role in the current treatment of epilepsy.

Animals↗
PubMed2001

Rapid cycling bipolar disorder.

Rapid cycling bipolar disorder (RCBD) is defined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a type of manic-depressive illness in which the patient experiences four or more episodes of mania and/or major depression per year. It was first reported as a consequence of the reduced effectiveness of lithium carbonate in the treatment and prophylaxis of this form of bipolar disorder (BD) in contrast to those with less frequent cycling. Among the anticonvulsants, there have been reports with different degrees of controlled data concerning carbamazepine, valproate, lamotrigine, topiramate, gabapentin and primidone. There is a paucity of double-blind studies, but what is available supports the use of lamotrigine. There is open data supporting the use of carbamazepine, valproate and topiramate. Regarding other classes, nimodipine may have specific utility in ultradian- (ultra-ultra-) or ultra-RCBD and there is double-blind data regarding the specific utility of olanzapine in RCBD. Low thyroid function may be a factor in development of RCBD; therapies aimed at elevating thyroid levels, even beyond the usual range, have frequently produced benefits in open trials. More research is needed into the possible therapeutic benefits of verapamil, bupropion, choline, light therapy and electroconvulsive therapy (ECT).

Anticonvulsants↗
PubMed2005

Benefits and risks of pharmacological and surgical treatments for essential tremor: disease mechanisms and current management.

Essential tremor (ET) is a neurological disease (and possibly a family of diseases) whose most recognisable feature is an action tremor of the hands and occasionally of the voice and head. Current data support the view that CNS gamma-amino-butyric acid (GABA)-ergic mechanisms may underlie ET and that the tremor may be further modulated by peripheral (muscle) adrenoreceptors. Potential pharmacotherapeutic options, targeted to influence the activity of the neurotransmitter GABA within the CNS and the peripheral adrenergic receptors, are part of the current armamentarium to treat ET. As such, primidone and propranolol remain the mainstays of the therapy for ET. Intramuscular injections of botulinum toxin A may play a role in the treatment of voice and head tremor. Surgical options, which are reserved for patients with severe, medically-refractory tremor, provide adequate tremor control in the majority of patients. As with other progressive neurological disorders of late life, the ability to use neuroprotective medications to intervene in the developing disease to either slow or halt the progression of the pathological process, would involve an understanding of underlying disease mechanisms. The understanding of these mechanisms in ET is limited and further study of these mechanisms is critical for the development of such therapies.

Essential Tremor↗
PubMed1984

Lowering effect of diphenylhydantoin on serum free thyroxine and thyroxine binding globulin (TBG).

To evaluate the effect of anticonvulsants on serum levels of free thyroxine (FT4) and thyroxine-binding globulin (TBG), 32 patients with epilepsy receiving long-term anticonvulsant treatment (mean duration 81.8 +/- 8.9 months) were employed in the present study. The serum levels of total thyroxine (TT4), total triiodothyronine (TT3), T3 resin uptake (T3U) and thyrotrophin (TSH) were also measured. Free thyroxine index (FT4I) was calculated from TT4 and T3U. Mean levels of these thyroid function tests were as follows: 5.52 +/- 1.51 micrograms/dl (TT4), 1.16 +/- 0.32 ng/dl (FT4), 101.5 +/- 16.2 ng/dl (TT3), 27.5 +/- 2.6% (T3U), 19.64 +/- 3.97 micrograms/ml (TBG), 1.50 +/- 0.36 (FT4I) and 2.21 +/- 0.18 microU/ml (TSH). These values except for T3U and TSH were significantly lower than normal values (P less than 0.01). Using correlation analysis, a significant dose-dependency (daily doses) was found between diphenylhydantoin (DPH) and TT4, FT4 and TBG. Other anticonvulsants (barbiturates, carbamazepine, primidone) or duration of treatment were not significantly correlated with thyroid function tests. Therefore serum levels of DPH were also measured in 19 out of 32 patients receiving anticonvulsant treatment. Significant negative correlation was found between serum levels of DPH and FT4 (r = -0.65) and DPH and TBG (r = -0.61).

Adult↗
PubMed1981

[Epilepsy and chronic Chagas disease].

The epileptic syndrome in chronic Chagas' disease is rarely reported in neurological literature. At the present time many papers have demonstrated that histopathological basis of Chagas' disease is a neuronal destruction. The authors studied 167 epileptic patients; 44 out of them had a chronic form of the disease. It was made a comparison of semiologic data between the two groups, and also the evaluation of the therapeutic results with anticonvulsant drugs. The chagasic patients had the onset of epileptic seizures later than the control group, with great predominance of partial seizures of autonomic type. The neurologic examination and cerebrospinal fluid test revealed moderate rates of disturbances, but not sufficient to characterize a neurologic syndrome. The EEG study was performed in 15 of the 44 cases and revealed a suggestive pattern of a diffuse cerebral damage in half of patients. Anticonvulsant therapy based on use of phenylhydantoin, barbituric acid derivates, primidone and benzodiazepines, showed that control of epileptic seizures in Chagas' diseases is more difficult and requires greater quantities of drugs than in the control group.

Adolescent↗
PubMed1994

[Writing tremor: report of a case].

Primary writing tremor is induced by a specific motor activity, generally the handwriting. The case is analyzed under clinic and therapeutic points of view. The patient had a tremor elicited by handwriting without any other concurrent neurologic alteration. He neither presented familiar antecedents nor metabolic, endocrine, iatrogenic, toxic and traumatic ones. As to the therapeutic approach, the tremor did not respond satisfactorily neither to propranolol nor to primidone. But with anticholinergics improvement of the tremor was verified.

Aged↗
PubMed2000

Treatment of epilepsy in the new millennium.

Treatment options for epilepsy have increased markedly since 1990, when only carbamazepine, phenytoin, phenobarbital, primidone, and valproate were used commonly for partial and secondarily generalized seizures. Those with primary generalized seizures received ethosuximide or valproate. Over the past decade, however, additional agents have been introduced, with the promise of improved seizure control and minimal side effects. The new antiepileptic drugs (AEDs)-felbamate, gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin and oxcarbazepine-have demonstrated superior efficacy for some with refractory epilepsy. In addition, the new agents frequently are better tolerated when used as monotherapy or adjunctive therapy. The optimal place for the new AED will require additional studies and careful postmarketing surveillance and assessments. Although these AEDs offer benefits, not all patients with epilepsy have responded. Thus, the search for new AEDs continues.

Animals↗
PubMedDate not supplied

Risk-benefit assessment of anticonvulsants in women of child-bearing potential.

Problems with anticonvulsants in women of child-bearing potential include potential adverse effects on appearance, contraception and pregnancy. These effects must be weighed against the overwhelming benefits of anticonvulsant treatment in the majority of women with epilepsy. Coarsened features, hirsutism and acne may occur in both men and women, particularly if they are exposed to phenytoin. Valproic acid may cause weight gain and hair loss, while carbamazepine treatment carries a significant risk of skin rashes. Anticonvulsants which are liver enzyme inducers (phenytoin, phenobarbital, primidone and carbamazepine) reduce the efficacy of the oral contraceptive pill. No 'pill failure' has been reported with valproic acid. There is a risk of increased seizure frequency in pregnancy irrespective of whether anticonvulsant treatment is taken. Individual seizures carry little risk to the mother or the fetus but status epilepticus has a significant maternal and fetal mortality. The risk of status epilepticus must be taken into account when deciding whether to stop anticonvulsant treatment before pregnancy. There is a 2 to 3 times increased malformation rate in the offspring of epileptic women on treatment. This is primarily due to the drug treatment, but epilepsy itself may also increase the malformation rate. Most malformations are mild and include facial clefts, congenital heart disease and skeletal abnormalities. Valproic acid, however, carries a 1% risk of causing neural tube defects: women receiving this drug who become pregnant should have an ultrasound and alpha-fetoprotein estimation at 16 to 18 weeks of pregnancy. If any abnormality is detected then amniocentesis should be carried out. Women with epilepsy should be counselled before conception and during pregnancy. Before achieving pregnancy a women should be on optimum treatment, preferably on one anticonvulsant. Consideration should be given to withdrawal of anticonvulsant drugs in any woman who has been seizure free for 2 years or who has only mild and infrequent seizures. Folate supplementation should be started prior to conception and should continue during pregnancy. There is a tendency for anticonvulsant drug concentrations to fall during pregnancy, and the dose may need to be increased if clinically indicated. Over 90% of epileptic women who become pregnant will have uneventful pregnancies and will produce healthy infants.

Anticonvulsants↗
PubMed1993

Antiepileptic drugs. A review of clinically significant drug interactions.

Approximately 20 to 30% of patients with active intractable epilepsy are commonly treated with polytherapy antiepileptic drug regimens, and these patients may experience complicated drug interactions. Furthermore, because of the long term nature of treatment, the possibility of drug interactions with drugs used for the treatment of concomitant disease is high. Classically, clinically significant drug interactions, both pharmacokinetic and pharmacodynamic, have been considered to be detrimental to the patient, necessitating dosage adjustment. However, this need not always be the case. With the introduction of new drugs (e.g. vigabatrin and lamotrigine) with known mechanisms of action, the possibility exists that these can be used synergistically. The most commonly observed clinically significant pharmacokinetic interactions can be attributed to interactions at the metabolic and serum protein binding levels. The best known examples relate to induction (e.g. phenobarbital, phenytoin, carbamazepine and primidone) or inhibition [e.g. valproic acid (sodium valproate)] of hepatic monoxygenase enzymes. The extent and direction of interactions between the different antiepileptic drugs are varied and unpredictable. Interactions in which the metabolism of phenobarbital, phenytoin or carbamazepine is inhibited are particularly important since these are commonly associated with toxicity. Some inhibitory drugs include macrolide antibiotics, chloramphenicol, cimetidine, isoniazid and numerous sulphonamides. A reduction in efficacy of antibiotic, cardiovascular, corticosteroid, oral anticoagulant and oral contraceptive drugs occurs during combination therapy with enzyme-inducing antiepileptic drugs. Discontinuation of the enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s) and may necessitate dosage readjustment.

Animals↗