Epilepsy seizure mechanisms

Chloroquine can cause seizures in patients with epilepsy. The mechanism is uncertain, but it may include reductions in inhibitory neurotransmitters and pharmacokinetic interactions that alter anticonvulsant concentrations. Tonic-clonic convulsions were reported in four patients in whom chloroquine was part of a prophylactic regimen. Antiepileptic treatment was required to control the seizures. None had further seizures after withdrawal of the antimalarial drugs (9). 

There is no shortage of AEDs (Fig. 16.7) but it is not appropriate to consider them in detail in this text other than to see how their mechanisms of action comply with and illustrate those proposed above (Fig. 16.6) for the control of epileptic seizures (see Meldrum 1996 Upton 1994). The decision on which drug to use depends not only on their proven efficacy in a particular type of epilepsy (some drugs are inactive in certain forms) but also what side-effects they have—many are sedative — how they interact with other drugs and how often they need to be taken. Compliance is a problem over a long period if dosing is required more than once a day. It is probably acceptable in reality, if not scientifically, to divide the drugs into old-established AEDs and new AEDs. Only the latter have been developed chemically to modify the known synaptic function of the amino acids. 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Carbamazepine is a tricyclic iminostilbene derivative and structurally related to the tricyclic antidepressants. It is used as a first-line agent for the management of generalized tonic-clonic epilepsy. It is also highly effective for partial seizures but has no efficacy in patients with absence seizures or atonic seizures. In epilepsy it supposedly has the same mechanism of action as phenytoin. An other well... 

Lamotrigine has a broad spectrum of action and is effective in generalized and partial epilepsies. Its primary mechanism of action appears to be blockage of voltage-dependent sodium channels, although its effectiveness against absence seizures indicates that additional mechanisms may be active. Lamotrigine is almost completely... 

Weiss SRB, Post RM, Sohn E, et al Cross tolerance between carbamazepine and valproate on amygdala-kindled seizures. Epilepsy Res 16 37-44, 1993 Weiss SRB, Clark M, Rosen JB, et al Contingent tolerance to the anticonvulsant effects of carbamazepine relationship to loss of endogenous adaptive mechanisms. Brain Res Brain Res Rev 20 305-325, 1995 Weissman MM Panic disorder impact on the quality of life. J Clin Psychiatry 52 [suppl) 6-8, 1991... 

Blockade of the 5-HT7 receptor has been shown to reduce epileptic activity in animal models. Audiogenic seizures induced in DBA/2J mice could be prevented by drugs in a rank order of potency corresponding to their affinity for the 5-HT7 receptor (95). The selective 5-HT7 receptor antagonist SB-258719 has been shown to reduce epileptic activity in an animal model for absence epilepsy, the WAG/Rij rat (65). It is believed to do so by modulating the pacemaker current Ih within the thalamus (96,97). The 5-HT7 receptor has been demonstrated to mediate depolarization within the anterodorsal thalamus by increasing lh through a cAMP-dependent, PKA-independent mechanism (96,97). 

The effects of concomitant carbamazepine, phenytoin, sodium valproate, and zonisamide on the steady-state serum concentrations of clonazepam have been investigated in 51 epileptic in-patients under 20 years of age (14). Serum concentrations of clonazepam correlated positively with the dose of clonazepam and negatively with the doses of carbamazepine and valproic acid, but not with phenytoin or zonisamide. These results confirm that as the oral doses of carbamazepine and sodium valproate increase, the serum concentration of clonazepam falls, but there is no interaction with either phenytoin or zonisamide. In the case of carbamazepine the mechanism of action is thought to be enzyme induction, increasing the metabolism of clonazepam. It is not known what the mechanism is with sodium valproate. In patients with epilepsy, the co-administration of either sodium valproate or carbamazepine will reduce the serum concentration of clonazepam and increase the risk of a seizure. When... 

Ben-Ari, Y. 1985. Limbic seizure and brain damage produced by kainic acid mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14, 375-403. 

McLean, M.J., MacDonald, R.L. (1986). Limitation of sustained high frequency repetitive firing a common anticonvulsant mechanisms of action. In Neurotransmitters, Seizures and Epilepsy III (G. Nistico, P.L. Morselli, K.G. Lloyd, A.G. Fariello, J. Engel, Jr., eds), pp. 23 1. Raven Press, New York. 

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