Sodium channel, concentration-dependent effects

Introduced initially for absence seizures, this drug is now known to be effective in and used to treat tonic lonic seizures and most types of epilepsy. It was found to inhibit GABA transaminase and so elevate GABA concentrations and inhibition. This is achieved, however, over a slower time-course than its anti-seizure effect, especially experimentally, which is now thought to be due to its phenytoin-like, use-dependent block of sodium channels. Since, unlike phenytoin, the full effect of valproate takes some weeks to develop, its slower effect on GABA metabolism and activity should not be ignored. 

Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Sodium channel block is modest with verapamil, and still less marked with diltiazem. It is negligible with nifedipine and other dihydropyridines. Verapamil and diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines. (See Chapter 14 for additional details.) On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects they are therefore less depressant on the heart than verapamil or diltiazem. 

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

Current efforts in these studies involve a detailed characterization of pyrethroid-activator interactions and the examination of a broader range of pyrethroids and other compounds as enhancers of activation. Recently, we have found that cismethrin is one of the most effective pyrethroids in this system, producing enhancement at high concentrations equal to or greater than that observed with deltamethrin (Figure 2). The action of cismethrin in the mouse brain system is quite different from its action on neuroblastoma cell sodium channels, where it has no effect on veratridine-dependent activation but is able to antagonize the enhancement produced by other pyrethroids (5). 

We have also defined both the effect of veratridine concentration on sodium channel activation in this system and the impact of , -DDT on the concentration-effect curve for veratridine-dependent activation (Figure 5). Half-maximal activation by veratridine oc-cured at approximately 50 PM, a value very close to that found for the action of this compound in mouse brain synaptosomes (7. , -... 

Sodium channel blockade At therapeutic concentrations, phenytoin, carbamazepine, and lamotrigine block voltage-gated sodium channels in neuronal membranes. This action is rate-dependent (ie, dependent on the frequency of neuronal discharge) and results in prolongation of the inactivated state of the Na" channel and the refractory period of the neuron. Phenobarbital and valproic acid may exert similar effects at high doses. 

FIGURE 31.2 At 10 nM, palytoxin-induced a rapid increase in the intracellular sodium concentration in cultured cerebellar granule cells. This effect of palytoxin was sensitive to the voltage-dependent sodium channel blocker saxitoxin. Data are means sem of three independent experiments, each performed in duplicate. Drugs were added at the time points indicated by the arrows. 

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