Side effects of carbamazepine, valproate and clonazepam during long-term treatment of epilepsy

ABSTRACT Side effects of carbamazepine (CBZ), valproate (VPA) and clonazepam (CZP) are rare during long-term use but rather common and usually transient during the early phases of treatment. The usual side effects of CBZ are drowsiness, dizziness, and diplopia, which are dose dependent in long-term use, but CBZ does not seem to cause cognitive disturbances, as do phenobarbital and phenytoin. Other reactions to CBZ may include leukopenia, hyponatremia, disturbances of vitamin D metabolism and fortunately rarely, agranulocytosis and hepatitis. Use of VPA can lead to gastrointestinal discomfort, weight gain, hair loss, tremor and sedation, but these side effects are rather uncommon, mild, and transient during VPA monotherapy. Potentially hazardous reactions such as hepatitis and pancreatitis have occurred in a few patients on VPA, generally with multidrug therapy. Some of the side effects are dose related. They infrequently lead to withdrawal of VPA. Side effects limited to initiation of CZP therapy include drowsiness, ataxia, and behavioral changes; they are usually transient but can lead to dose reduction or even withdrawal of the drug. Except for development of tolerance, CZP seems to be practically free of long-term side effects.     

Psychotropic effects of carbamazepine in epilepsy: a double-blind comparison with phenytoin.

The "psychotropic" effects of carbamazepine were evaluated with phenytoin (Dilantin) as reference agent in a counterbalanced, crossover study. Forty adult epileptics were given a series of neuropsychologic tests and the MMPI after 4 months on each agent. Most abilities were much the same with either anticonvulsant, but there were fewer errors with carbamazepine on mental tasks requiring attention and problem solving, and some improvement in emotional status was suggested. The findings were consistent with patient reports of improvement in alertness and mental functioning. These results combine with the excellent anticonvulsant properties of carbamazepine to support its use as an anticonvulsant.     

Effects of phenytoin,carbamazepine, and clonazepam on cortex- and amygdala-evoked potentials

Multiple doses of phenytoin, carbamazepine, and clonazepam were tested against single- and double-pulse evoked potentials. Evoked responses were triggered from either the amygdala or the cortex and were recorded in both monosynaptic sites and the mesencephalic reticular formation (MRF). In accordance with previous studies of spinal potentials, it was expected that all three drugs would display a depressant action. Contrary to expectation, only clonazepam had any significant effect, and this drug was effective only against potentials triggered in the amygdala and recorded in the MRF. These data appear inconsistent with the traditional belief that anticonvulsants block seizure spread by antagonizing transmission in neural pathways.     

Effects of carbamazepine, clonazepam, and phenytoin on seizure threshold in amygdala and cortex

This experiment was designed to determine whether or not the stronger effect of anticonvulsants on cortex than on amygdala focal seizures was due to a greater elevation of cortex seizure threshold. The effects of several doses of carbamazepine, clonazepam, and phenytoin were examined on the threshold for electrically induced afterdischarge in amygdala and cortex in 71 rats. All three drugs were found to be effective in increasing the seizure threshold with greater effects being produced in the cortex than in the amygdala. Carbamazepine produced the largest threshold increase in both foci, and clonazepam produced the weakest effects. These data are comparable to previous data on drug action against focal or partial seizures, and suggest that anticonvulsants may control partial attacks through their action on the local seizure threshold. This theory of anticonvulsant drug action adds to the common belief that carbamazepine and phenytoin act primarily by blocking seizure spread.     

Use of phenytoin and carbamazepine in treatment of epilepsy

This article reviews the clinical pharmacology of carbamazepine and phenytoin, widely regarded as the drugs of choice for partial and secondary generalized seizures.     

Effects of phenytoin, carbamazepine, and clonazepam on cortex- and amygdala-evoked potentials in partially kindled rats

The kindling technique has been reported to produce a long-lasting enhancement in both the early and late phases of evoked potentials triggered from the kindled focus. It also alters paired-pulse facilitation and depression in the pathways which support these phenomena. The present experiment was designed to determine whether the drugs which antagonize secondary generalization in the kindling model also antagonize kindling-enhanced excitation in the pathways leading out of the focus. Multiple doses of phenytoin, carbamazepine, and clonazepam were therefore tested against single- and double-pulse evoked potentials triggered from the focus in rats that had been subjected to parital kindling from either the amygdala or the cortex. Responses were recorded in monosynaptic sites and in the mesencephalic reticular formation--a polysynaptic site thought to play an important role in secondary generalization. No drug-related effects were found on early evoked potential components, either in the single-pulse or the double-pulse paradigm. Kindling-enhanced late components ("late waves"), however, were clearly and selectively antagonized by clonazepam.     

Autonomic neuropathy in acute intermittent porphyria.

Autonomic function was assessed in subjects with acute intermittent porphyria and age- and sex-matched controls using five different bedside tests of cardiovascular reflexes. During the acute attack both parasympathetic and sympathetic tests were impaired, but subsequently improved during remission. Early parasympathetic dysfunction was also detected during remission and in latent asymptomatic acute intermittent porphyria.     

Neuropsychological effects of carbamazepine and phenytoin: a reanalysis

We previously reported that carbamazepine had fewer adverse neuropsychological effects than phenytoin, but it is now clear that our patients had much higher phenytoin than carbamazepine serum levels. When persons with high initial phenytoin levels were excluded, the statistical significance of all neuropsychological differences between the drugs disappeared.     

Juvenile acute intermittent porphyria with hypercholesterolemia and epilepsy: a case report and review of the literature

A case of acute intermittent porphyria in a 10-year-old boy with seizures and hypercholesterolemia is presented. The problems of management when seizures and porphyria coincide and discussion of hypercholesterolemia are included. A comprehensive review of the world literature reveals that prepubertal patients with acute intermittent porphyria are predominantly male and show an increased incidence of seizures when compared to older age groups. The principal clinical features in all age groups include abdominal pain, vomiting, fever, and tachycardia in addition to mental changes, limb paresis, and hyporeflexia.     

A comparative study of the cognitive effects of phenytoin and carbamazepine in new referrals with epilepsy

This study compares cognitive function in new referrals with epilepsy well-controlled on single drug therapy with either phenytoin or carbamazepine with that in an untreated control group. Patients receiving phenytoin performed consistently less well on memory tasks than did those untreated or receiving carbamazepine. Although patients on phenytoin overall showed a trend towards poorer performance on a tracking task, higher blood levels of this drug were correlated with better tracking performance. The correlation between blood levels of carbamazepine and tracking performance was the opposite from that of phenytoin. Blood levels of carbamazepine were negatively correlated with measures of anxiety, depression, and fatigue. These findings have implications for the choice of drug in the management of epilepsy and also for the reported claims of a psychotropic effect of carbamazepine.     

Prophylactic effects of phenytoin, phenobarbital, and carbamazepine examined in kindling cat preparations.

Prophylactic effects of phenobarbital, phenytoin (diphenylhydantoin), and carbamazepine were examined in amygdaloid kindling preparations in cats. Daily electrical stimulation was delivered at the time of peak plasma levels. Comparative examination of the chronological pattern of the clinical seizure development, after discharge growth, and formation of distant independent spike foci was made between periods of kindling with chronic drug administration and of rekindling without drugs. Both phenobarbital and carbamazepine were effective, but phenytoin was totally ineffective. Prophylactic action of phenobarbital and carbamazepine was mainly through the suppression of the development of motor seizures manifestations in the former and the same with the development of sustained after discharge in the latter. The kindling preparation appears to possess many desirable features as an ideal model of human epilepsy for the purpose of assessment and recruitment of potential antiepileptic drugs and development of a rational pharmacotherapeutic approach for the management and prevention of seizure disorder.     

Cardiac side effects of phenytoin and carbamazepine. A dose-related phenomenon?

Three patients with dystrophia myotonica and echocardiographic signs of subclinical cardiopathy had cardiac side effects during oral treatment with phenytoin sodium or carbamazepine. These side effects were dose related: ventricular tachycardia appeared at a toxic serum phenytoin level in one patient and disappeared as the concentration fell within the therapeutic range, and atrioventricular block grade 1 developed in two patients at low serum carbamazepine levels, its severity increasing with the drug level. Given the risk of dangerous side effects, cardiac status needs to be carefully assessed before administration of phenytoin or carbamazepine in the treatment of dystrophia myotonica.     

Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy

OBJECTIVE: This open-label study evaluated the efficacy and tolerability of lamotrigine monotherapy compared with monotherapy with conventional antiepileptic drugs in patients converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. METHODS: This study was conducted in 26 neurology clinics and epilepsy centers throughout the United States. The study enrolled 115 patients with epilepsy converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Patients were randomized 1:1 to receive 24 weeks of lamotrigine monotherapy or monotherapy with a conventional antiepileptic drug (carbamazepine, phenytoin, or valproate based on physician's choice). Patients were converted during an 相似文献   

Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial.

Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs, utilised as monotherapy in newly diagnosed epileptic patients. Between 1981 and 1987 243 adult patients aged 16 years or over, newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission. The overall outcome with all of the four drugs was good with 27% remaining seizure free and 75% entering one year of remission by three years of follow up. No significant differences between the four drugs were found for either measure of efficacy at one, two, or three years of follow up. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomised drug, was 10%. For the individual drugs phenobarbitone (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures, the choice of drug will be more influenced by considerations of toxicity and costs.     

Withdrawal symptoms from phenytoin, carbamazepine and sodium valproate.

A prospective, double-blind, placebo-controlled investigation of possible withdrawal symptoms from phenytoin, carbamazepine and sodium valproate is reported in patients with active epilepsy, on combination therapy. There was an increase in seizures on reduction and withdrawal of carbamazepine, but there was no convincing evidence of withdrawal symptoms from any of these drugs.