Anticonvulsive action

Cj jH,2N202. Used as its sodium salt, which is a white hygroscopic powder. Unstable, readily absorbing carbon dioxide and liberating phenytoin. Made by treating a-bromodi-phenylacetylurea with alcoholic ammonia. It has a mild hypnotic and strong anticonvulsant action, and is used in the treatment of grand-mal and focal epilepsy. 

Primidone [125-33-7] C22H24N2O2 (39) is an analogue of phenobarbital that is used for the treatment of generalized tonic-clonic seizures. It is metabolized in humans to phenobarbital (6) and phenylethyLmalondiamide [7206-76-0J, C22H24N2O2 (40) and these metaboUtes are probably responsible for its anticonvulsant actions. Primidone has many of the side effect HabiUties seen with phenobarbital. 

Benzodiazepines. Several BZs have anticonvulsant activity and ate used for the treatment of epilepsy producing their anticonvulsant actions via interactions with the GABA /BZ receptor complex to enhance inhibitory GABAergic transmission (1). The anticonvulsant actions of the BZs tend to tolerate upon chronic usage in six months, and BZs also lead to withdrawal symptomatology. Other side effects include sedation, ataxia, and cognitive impairment. 

In addition to inhibiting fast voltage-dependent Na+ currents, many anticonvulsants also suppress persistent Na+ currents, in some cases even more efficiently. This mechanism may also be important in the anticonvulsant action of these substances because persistent Na+ currents are thought to give rise to high frequency burst discharges in some neurons. 

Clearly since a reduction in GABA function causes convulsions, then augmenting its function should provide an anticonvulsant action. This may be achieved in a number of ways as listed in Table 16.2 and indicated in Fig. 16.6. For more detail see Chapter 9. 

A complete dose-response analysis was generated for PCP for doses from 0.625 to 20 mg/kg IP (data not shown). PCP exhibited dose-related anticonvulsant action when day one minus day three differ ence scores were compared for all doses tested. When retested with saline only on day five, no reduction in convulsant sever it or super-sensitive response was observed (day one minus day five), indicating no carryover drug effect 48 hours after dosing. At behavioral ly equivalent doses, all compounds assayed were clearly anticonvulsant (table 3). TCP was most potent at the doses tested. PCA was the most efficacious, and reduced convulsant severity by 2.58 points. As with PCP, none of the other phencycli-noids had any carryover effects 48 hours after dosing (day one minus day five). 

Anticonvulsant action of the nucleoside transport inhibitor, soluflazine, on synaptic and non-synaptic epileptogenesis in the guinea-pig hippocampus. Epilepsy Res. 2 (2), 65-71. 

Yunger, L. M., Fowler, P. J., Zarevics, P., and Seder, P. E. (1984) Novel inhibitors of gamma-aminobutyric acid (GABA) uptake anticonvulsant actions in rats and mice../. Pharmacol. Exp. Ther. 228,109-115. 

Gleitz J, Friese J, Beile A, Ameri A, Peters T. (1996a). Anticonvulsive action of (+/-)-kavain estimated from its properties on stimulated synaptosomes and Na-i- channel receptor sites. EurJ Pharmacol. Nov. 7. 315(1) 89-97. 

Turkanis SA, Smiley KA, Borys FIK, Olsen DM, Karler R. (1979). An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats. Epilepsia. 20(4) 351-63. Tyrey L. (1984). Endocrine aspects of cannabinoid action in female subprimates search for sites of action. NIDA Res Monogr. 44 65-81. 

The anxiolytic properties of 5-HT3 receptor antagonists have been demonstrated in several animal models of anxiety. In these models, the 5-HT3 antagonists mimic the anxiolytic effects of the benzodiazepines but differ from the latter in their lack of sedative, muscle relaxant and anticonvulsant action. These compounds appear to be extremely potent... 

Topiramate, derived from D-fruc-tose, has complex, long-lasting anticonvulsant actions that cooperate to limit the spread of seizure activity it is effective in partial seizures and as an add-on in Lennox-Gastaut syndrome. 

It should be pointed out that neuroleptics do not exert an anticonvulsant action, on the contrary, they may lower seizure thershold. 

Diazepam exhibits anxiolytic, sedative, soporific, central myorelaxant, and anticonvulsant action. It suppresses feelings of fear, worry, and stress. It is nsed for nervons stress, excitement, anxiety, sleep distnrbance, neurovegetative disorders, psychonenrosis, obsessive neurosis, hysterical or hypochondriac reactions, and phobias. The most freqnently used synonyms are sednxen, relaninm, valium, sibazon, apaurin, and many others. 

In psychiatric practice, chlorpromazine is used in various conditions of psychomotor excitement in patients with schizophrenia, chronic paranoid and also manic-depressive conditions, neurosis, alcohol psychosis and neurosis accompanied by excitement, fear, stress, and insomnia, hi comparison with other neuroleptics, chlorpromazine is unique in that it has an expressed sedative effect. It is sometimes used in anesthesiological practice for potentiating narcosis. It also has moderate anticonvulsant action. The most common synonyms are aminazine, megaphen, largactil, thorazine, prompar, and others. 

This drug not only exhibits anticonvulsant action, but also betters the mental condition of the patient. 

Pharmacokinetics Approximately 1 % to 2% of total body magnesium is located in the extracellular fluid space. Magnesium is 30% bound to albumin. With IV use, the onset of anticonvulsant action is immediate and lasts approximately 30 minutes. With IM use, onset occurs in 1 hour and persists for 3 to 4 hours. Magnesium is excreted by the kidney. 

The anticonvulsant activity of diazepam, assessed by its protection against pentylenetetrazole-induced tonic convulsions, was strongly reduced in ai-(HIOIR) mice compared to wild-type animals (Rudolph et al. 1999). Sodium phenobarbital remained fully effective as anticonvulsant in ai(HlOlR) mice. Thus, the anticonvulsant activity of benzodiazepines is partially but not fuUy mediated by ai receptors. The anticonvulsant action of zolpidem is exclusively mediated by ai receptors, since its anticonvulsant action is completely absent in ai(HlOlR) mice (Crestani et al. 2000). 

Anticonvulsant action In anaesthetic dose all barbiturates e.g. phenobarbitone, mephobarbitone possess anticonvulsant action. Phenobarbitone is drug of choice for the treatment of grandmal epilepsy (details are given in chapter Antiepileptic drugs ). 

The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24-4). It also acts presynaptically to decrease synaptic transmission. These effects probably account for the anticonvulsant action of carbamazepine. Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known. 

Retigabine which is in phase II clinical trials for epilepsy, is a derivative of the analgesic flupirtine which also has anticonvulsant activity. The anticonvulsant action of retigabine is greater than that of flupirtine, however retigabine is not effective in models of acute pain. 

Benzodiazepines. Benzodiazepines have anticonvulsant actions, especially intravenous diazepam and oral clonazepam. They are also sedating. Both of these actions have led to the use of benzodiazepines for the treatment of mood disorders, especially as adjunctive treatment for agitation and psychotic behavior during the phase of acute mania. Benzodiazepines are also broadly used in anxiety and sleep disorders. 

FIGURE 7-27. Shown here is an icon of topiramate s pharmacologic actions. By interfering with calcium channels and sodium channels, topiramate is thought both to enhance the inhibitory actions of gamma aminobutyric acid (GABA) and to reduce the excitatory actions of glutamate. Topiramate is also a carbonic anhydrase inhibitor (CAI) and as such has independent anticonvulsant actions. 

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