Anticonvulsant therapy for status epilepticus

AIMS: To determine whether a particular anticonvulsant is more effective or safer than another or placebo in patients with status epilepticus, and to summarize the available evidence from randomized controlled trials, and to highlight areas for future research in status epilepticus. METHODS: Randomized controlled trials of participants with premonitory, early, established or refractory status epilepticus using a truly random or quasi-random allocation of treatments were included. RESULTS: Eleven studies with 2017 participants met the inclusion criteria. Lorazepam was better than diazepam for reducing risk of seizure continuation [relative risk (RR) 0.64, 95% confidence interval (CI) 0.45, 0.90] and of requirement of a different drug or general anaesthesia (RR 0.63, 95% CI 0.45, 0.88) with no statistically significant difference in the risk of adverse effects. Lorazepam was better than phenytoin for risk of seizure continuation (RR 0.62, 95% CI 0.45, 0.86). Diazepam 30 mg intrarectal gel was better than 20 mg in premonitory status epilepticus for the risk of seizure continuation (RR 0.39, 95% CI 0.18, 0.86). CONCLUSIONS: Lorazepam is better than diazepam or phenytoin alone for cessation of seizures and carries a lower risk of continuation of status epilepticus requiring a different drug or general anaesthesia. Both lorazepam and diazepam are better than placebo for the same outcomes. In the treatment of premonitory seizures, diazepam 30 mg intrarectal gel is better than 20 mg for cessation of seizures without a statistically significant increase in adverse effects. Universally accepted definitions of premonitory, early, established and refractory status epilepticus are required.     

Anticonvulsant use during lactation.

The issue of prescribing anticonvulsant drugs during lactation is clinically important, but also complex. Data for some drugs are completely lacking and for other drugs information is only available from single dose or short term studies or case reports. Moreover, limited knowledge exists about the practical impact of the drug concentrations found in breast milk and there are great methodological problems in the assessment of possible adverse drug reactions in infants. Nevertheless, based on current knowledge, some recommendations can be suggested. Treatment with carbamazepine, valproic acid (sodium valproate) and phenytoin is considered compatible with breastfeeding. Treatment with ethosuximide or phenobarbital (phenobarbitone)/primidone should most probably be regarded as potentially unsafe and close clinical monitoring of the infant is recommended if it is decided to continue breastfeeding. Occasional or short term treatment with benzodiazepines could be considered as compatible with breastfeeding, although maternal diazepam treatment has caused sedation in suckling infants after short term use. During long term use of benzodiazepines, infants should be observed for signs of sedation and poor suckling. Only very limited clinical data are available for the new generation anticonvulsant drugs and no clearcut recommendations can be made until further data are present. If it is decided to continue breast feeding during treatment with these drugs, the infant should be monitored for possible adverse effects. In general, the drug should be given in the lowest effective dose, guided by maternal serum or plasma drug concentration monitoring. If breast feeding is avoided at times of peak drug levels in milk, the exposure of the infant can be reduced to some extent. As breast milk has considerable advantages over formula milk, the benefits of continuing breast feeding should always be taken into consideration in the risk-benefit analysis.     

Anticonvulsant drugs. An update

A considerable amount of information is now available concerning the clinical pharmacology of the anticonvulsant drugs. Some of the more important data are reviewed in this article. In recent years, valproic acid (or sodium valproate) has found a place as a major anticonvulsant agent, while older drugs such as troxidone and sulthiame seem to be disappearing from use. Although much information is available, the essential mechanisms of action of the anticonvulsant drugs are still not understood, either at a molecular or at an electrophysiological level. The pharmacokinetics of the anticonvulsants in common use are now reasonably well documented, though some minor questions are still to be answered. Numerous interactions between anticonvulsants and endogenous substances or other drugs administered concurrently (including other anticonvulsants) have been recorded, but much work still needs to be done to elucidate the frequency and mechanisms of the various interactions. Many adverse effects of the anticonvulsants are known, but further unwanted effects of long-established drugs continue to emerge from time to time, including the still somewhat controversial matter of anticonvulsant-related dysmorphogenesis. The use of valproic acid and its sodium salt has been associated with a worrying incidence of serious liver and pancreatic toxicity. Adequate basic data are now available to put the clinical use of anticonvulsants on a rational basis, but much work remains to be done in this area. In particular, the question of 'therapeutic ranges' of plasma concentrations of the various drugs needs to be reinvestigated in a rigorous statistical fashion, and in relation to different clinical types of epilepsy. The usefulness of monitoring free rather than total drug concentrations also needs further investigation. The ultimate test of the validity of all background scientific pharmacological information about anticonvulsants is its usefulness in the treatment of patients with epilepsy.     

Anticonvulsant and convulsant effects of organic solvents.

Previous studies suggest that organic solvents show anticonvulsant and convulsant effects, respectively at low and high doses. In the present study the first experiment was designed to determine low and high doses of injected acute n-hexane, ethyl acetate and toluene in mice through LD50 estimations. In the second experiment, high doses (around LD50) were employed to evaluate the convulsant effects. Finally, the third experiment evaluated the ability of low doses to prevent electroshock- and PTZ-induced convulsions. Results showed that n-hexane increased the severity of the electroshock-induced seizures only at low doses and had no anticonvulsant effects. Ethyl acetate produced generalized clonic seizures and deaths at high doses and was ineffective to prevent electroshock- and PTZ-induced seizures at low doses. Toluene induced forelimb clonus at high doses and protected against electroshock-induced seizures at low doses. Therefore, the biphasic property on convulsant activity seems to be a feature not shared among organic solvents.     

Inhibition of theophylline elimination by diltiazem therapy

To investigate the effects of diltiazem on theophylline pharmacokinetics, nine healthy male subjects (four smokers and five nonsmokers) received intravenous aminophylline (6 mg/kg) prior to and following 10 days of oral diltiazem therapy. Theophylline half-life increased significantly whereas total body clearance showed a significant decrease following diltiazem. Volume of distribution was unchanged. The small group of smokers had a significantly greater increase in theophylline half-life than the nonsmokers. Inhibition of metabolism of theophylline by diltiazem likely explains the significant changes in theophylline pharmacokinetics. A clinically important drug interaction may occur with theophylline when diltiazem therapy is given concurrently.     

Acute tetrachloroethylene poisoning--blood elimination kinetics during hyperventilation therapy

After ingestion of 12-16 g tetrachloroethylene, a 6-year-old boy was admitted to the clinic in coma. In view of the high initial tetrachloroethylene blood level, hyperventilation therapy was performed. Under this therapeutic regimen, the clinical condition of the patient improved considerably. The tetrachloroethylene blood level profile which was determined under hyperventilation therapy could be computer-fitted to a two-compartment model. Elimination of tetrachloroethylene from the blood compartment occurred via a rapid and a slow process with half-lives of 30 min and 36 hours, respectively. These values compared favourably with the half-lives of 160 min and 33 hours under normal respiratory conditions. During hyperventilation therapy, the relative contribution to the fast elimination process increased from 70% for physiological minute volume to 99.9%. A minor fraction of the ingested dose was excreted with the urine (integral of 1% during the first 3 days). In contrast to previous results, trace amounts of unchanged tetrachloroethylene were detected in the urine besides trichloroacetic acid and trichloroethanol.     

The effect of alternate-day prednisone therapy on cortisol secretion rate in corticosteroid-dependent asthmatics.

The effect of alternate-day prednisone regimen (nine-patients) on cortisol secretion rate was compared with daily therapeutic regimen (ten patients) in corticosteroid-dependent asthmatics. Only the alternate-day regimen did not suppress the adrenal function. The therapeutic efficacy of both regimens was equal. The advantages of alternate-day corticosteroid therapy are presented and the optimal way of starting this therapy discussed.     

Anticonvulsant hypersensitivity syndrome: incidence, prevention and management.

Although the anticonvulsant hypersensitivity syndrome was first described in 1950, confusion still abounds regarding the syndrome. The triad of fever, rash and internal organ involvement occurring 1 to 8 weeks after exposure to an anticonvulsant heralds this rare (1 in 1,000 to 10,000 exposures) but serious reaction. Aromatic anticonvulsants [phenytoin, phenobarbital (phenobarbitone) and carbamazepine] are the most frequently involved drugs; however, there have also been several cases of anticonvulsant hypersensitivity syndrome associated with lamotrigine. Fever, in conjunction with malaise and pharyngitis, is often the first sign. This is followed by a rash which can range from a simple exanthem to toxic epidermal necrolysis. Internal organ involvement usually involves the liver, although other organs such as the kidney, CNS or lungs may be involved. Hypothyroidism may be a complication in these patients approximately 2 months after occurrence of symptoms. The aromatic anticonvulsants are metabolised to hydroxylated aromatic compounds, such as arene oxides. If detoxification of this toxic metabolite is insufficient, the toxic metabolite may bind to cellular macromolecules causing cell necrosis or a secondary immunological response. Cross-reactivity among the aromatic anticonvulsants may be as high as 75%. In addition, there is a familial tendency to hypersensitivity to anticonvulsants. Discontinuation of the anticonvulsant is essential in patients who develop symptoms compatible with anticonvulsant hypersensitivity syndrome. A minimum battery of laboratory tests, such as liver transaminases, complete blood count and urinalysis and serum creatinine, should be performed. Corticosteroids are usually administered if symptoms are severe. Patients with anticonvulsant hypersensitivity syndrome should avoid all aromatic anticonvulsants; benzodiazepines, valproic acid (sodium valproate) or one of the newer anticonvulsants can be used for seizure control. However, valproic acid should be used very cautiously in the presence of hepatitis. There is no evidence that lamotrigine cross-reacts with aromatic anticonvulsants. In addition, family counselling is a vital component of patient management.     

Anticonvulsant effect of allopurinol on hippocampal-kindled seizures.

This study assessed the anticonvulsant effect of allopurinol (5 and 50 mg/kg, IP) on seizures kindled from the feline hippocampus. Allopurinol at a higher dose significantly reduced the behavioral seizures stage, but not afterdischarge duration, without producing any behavioral toxicity. The present results lend experimental support to the contention that allopurinol possesses anticonvulsant efficacy in the treatment of human epilepsy.     

Renal elimination of magnesium as a parameter of bioavailability of oral magnesium therapy.

Magnesium is an important cation in human physiology, especially in the regulation of membrane proteins, as a cofactor for various enzyme systems and in neuromuscular transmission. Magnesium deficiency leads to severe impairment in muscle function, particularly in cardiovascular diseases. Classical bioavailability studies with magnesium cannot be carried out for several reasons. As the magnesium concentration in plasma is extraordinarily well regulated, renal elimination proves to be the best method to determine the absorption of orally administered magnesium. Magnesium pools must first be filled, and the saturation phase of renal elimination then equals the degree of absorption. This parameter of bioavailability shows the percentage of eliminated magnesium in comparison to the administered dose. Eighteen healthy male volunteers were included in this study to compare 5 mg magnesium-DL-hydrogen aspartate with magnesium-L-hydrogen aspartate. After a saturation phase, the test substances were administered in random order. Blood samples for determination of magnesium concentrations were taken, but no typical pharmacokinetic concentration curves were obtained. The areas under the concentration-time curves were equal for both formulations (x = 40.22 [mval*h/l]). The bioavailability of both substances was determined from the renal elimination. No significant difference was found between both treatments. Bioavailability of 5 mg magnesium-DL-hydrogen aspartate was 44.5% and for magnesium-L-hydrogen aspartate 41.7%. It is evident that this method of magnesium determination is practical, comfortable for volunteers and gives reliable results in comparing the absorption of magnesium formulations.     

Plasma cortisol delivery from oral cortisol and cortisone acetate: relative bioavailability.

Plasma cortisol levels were measured before and for 6 h after the intravenous injection of 50 mg cortisol as sodium succinate and oral administration of 50 mg cortisol and 50 mg cortisone acetate in 10 subjects with primary or secondary adrenal failure and in two normal volunteers. Peak cortisol levels of 1518 +/- 190 nmol 1(-1) (mean +/- s.e. mean) and 739 +/- 74 nmol 1(-1) were found 1.46 +/- 0.25 and 1.79 +/- 0.16 h after oral cortisol and cortisone acetate respectively. The relative bioavailability of oral cortisol and cortisone acetate varied widely (cortisol 26-91%, mean 54 +/- 6.9%, cortisone acetate 21-95%, mean 44 +/- 6.5%) but despite this wide variation there was, in individual subjects, a highly significant correlation between the bioavailability of the two steroids (r = 0.870, P less than 0.001). This suggests that the wide interindividual variations in plasma cortisol levels seen after oral cortisone acetate are not related to variations in bioconversion of cortisone.     

Anticonvulsant Hypersensitivity Syndrome

Abstract

Literature pertaining to anticonvulsant hypersensitivity syndrome is reviewed. The regulatory implications of the data for anticonvulsants in particular and also drug products in general are discussed.