Antiepileptic drugs benzodiazepines

The major inhibitory neurotransmitter in the cerebral cortex is y-aminobutyric acid (GABA). It attaches to neuronal membranes and opens chloride channels. When chloride flows into the neuron, it becomes hyperpolarized and less excitable. This mechanism is probably critical for shutting off seizure activity by controlling the excessive neuronal firing. Some antiepileptic drugs, primarily barbiturates and benzodiazepines, work by enhancing the action of GABA. 

Antiepileptic drugs are used to prevent the recurrence of seizures. Intravenous phenytoin (or fosphenytoin) and phe-nobarbital are administered after benzodiazepines are given. 

Refractory status epilepticus is seizure activity that is not controlled by first-fine and second-line therapies, including benzodiazepines and antiepileptic drugs. 

Once the first dose of benzodiazepine is given, an antiepileptic drug must be started to prevent further seizures from occurring. AEDs must not be given as first-line therapy since they must be infused relatively slowly to avoid adverse effects, delaying their onset of action. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

From the chemical point of view, formally, antiepileptic drugs could be classified as derivatives of hydantoins (phenytoin, mephenytoin, ethotoin), barbiturates (phenobarbital, mephobarbital, and primidone), succinimides (ethosuximide, methosuximide, phensux-imide), benzodiazepines (diazepam, chlorodiazepoxide, clonazepam, lorazepam), oxazo-lidines (trimethadione, paramethadione), and also valproic acid, carbamazepine, and acetazolamide. 

Refractory status epilepticus that has failed to respond to one of these treatments, and has continued for more than 20-30 min, requires urgent action. The accepted strategy is to paralyze and ventilate the patient and administer an antiepileptic drug in sufficient dosage to suppress EEG evidence of seizure activity. The barbiturate anaesthetic thiopental (thiopentone), the benzodiazepine midazolam, and the anaesthetic propofol have all been used. What little comparative evidence there is remains inconclusive. Such treatment can only be carried out with facilities for artificial ventilation and intensive care, and effects can only be monitored by EEG recording. 

In a retrospective study of cases from the Jefferson County Coroner/Medical Examiners Office, Alabama, USA between January 1982 and December 2000 there were 101 deaths in patients in whom methadone was detected in the blood (35). Methadone was the sole intoxicant in 15 cases, with a mean concentration of 0.27 pg/ml. A benzodiazepine was the most frequently detected co-intoxicant in 60 of the 101 cases and the only co-intoxicant in another 30 cases. In 26 cases methadone had been taken with a range of non-benzodiazepine substances, including antidepressants, antipsychotic drugs, antiepileptic drugs, and cocaine. The high... 

Antiepileptic drugs in Phase III clinical trials are shown in Figure 20.12. Talampanel is a 2,4-benzodiazepine that is a AMPA/KA receptor antagonist. RWJ-333369 is a monocarbamate antagonist at KA receptors. Rufinamide is a 1,2,3-triazole carboxamide that blocks sodium channels. Soretilide has a mechanism of action similar to that of CBZ, and brivaracetam and seletracetam are derivatives of S-(-)-levetiracetam for treatment of myoclonic seizures. 

Drug overdose In a study of 9809 consecutive adults and adolescents with self-poisoning during a 6-month period, there were 474 with non-benzodiazepine antiepileptic drug intoxication [103. The most frequent motivation was intentional intoxication (95.3%). There was no association between antiepileptic drug intoxication and a history of parasuidde, sex, age, or occupation. The most frequent drug involved was carbamazepine ( = 117), followed by phenobarbital ( =77) and sodium valproate ( = 51). 

Uchimura N, Takeuchi N, Kuwahara U et al. (2002) Situation and problem of administration methods and the intermission of hypnotics. Psych ClinNeurosci 56(3) 295-296 Caccia S, Yaratini S (1985) Antiepileptic drug. Springer-Verlag, Berlin, pp 575-593 Hallfors DD, Saxe L (1993) The dependence potential of short half-life benzodiazepines a meta-analysis. Am J Public Health 83(9) 1300-1304... 

The brief duration of a single epileptic fit makes acute drug treatment unfeasible. Instead, antiepileptics are used to prevent seizures and therefore need to be given chronically. Only in the case of status epilepticus (a succession of several tonic-clonic seizures) is acute anticonvulsant therapy indicated — usually with benzodiazepines given i.v. or, if needed, rectally. 

Drugs such as barbiturates and carbamazepine induce certain enzymes and will then trigger faster breakdown of some concomitantly used antipsycho-tics and antidepressants. In contrast, paroxetine, fluoxetine and fluvox-amine, acting by different mechanisms, inhibit the breakdown of other concomitantly administered drugs such as benzodiazepines, antidepressants, antiepileptics and neuroleptics (Table 5.1). 

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