Carbamazepine Inhibition of Neuronal Na⁺ Currents: Quantitative Distinction from Phenytoin and Possible Therapeutic Implications

Abstract

Carbamazepine and phenytoin, two of the most commonly prescribed antiepileptic drugs, have been proposed to share a similar mechanism of action by use-dependent inhibition of Na+ channels. The proposed similar mechanism of action, however, cannot explain the common clinical experiences that the two drugs are different; in some patients, one drug may be more effective than the other. This may occur even when optimal therapeutic concentrations are reached with both medications in plasma or the cerebrospinal fluid. In this study, we show that the action of the two drugs on Na+ channels are quantitatively very different. The affinity between inactivated Na+ channels and carbamazepine (apparent dissociation constant approximately 25 microM) is approximately 3 times lower than that of phenytoin, yet the binding rate constant of carbamazepine onto the inactivated Na+ channels is approximately 38,000 M(-1)/sec(-1), or approximately 5 times faster than that of phenytoin. It is speculated that carbamazepine may be more effective than phenytoin in treating seizures whose ictal depolarization shift is relatively short, whereas a better response to phenytoin may imply abnormal discharges characterized by more prolonged depolarization.

Carbamazepine inhibits L-type Ca2+ channels in cultured rat hippocampal neurons stimulated with glutamate receptor agonists

“…Since CBZ is known to inhibit voltage-sensitive Na + channels (Kuo et al, 1997;Rush and Elliott, 1997), the effect observed previously could be due to a reduction of the extent of depolarization. Thus, we analyzed the role of TTX-sensitive Na + channels on the increase of the [Ca 2 + ] i induced by kainate, and found that they are not involved in the depolarization caused by kainate, probably because they inactivate after the onset of depolarization.…”

“…CBZ limits sustained high-frequency repetitive-firing of sodium-dependent action potentials of central neurons in cell culture at therapeutic concentrations (MacDonald and Kelly, 1993;Morimoto et al, 1997). This effect is commonly ascribed to a voltage-dependent inhibitory effect on voltage-gated Na + channels (Kapetanovic et al, 1995;Kuo et al, 1997;Rush and Elliott, 1997). However, the mechanisms underlying the effects of this AED have not been completely identified, and are still a matter of debate.…”

“…CBZ is known to inhibit voltage-sensitive Na + channels (VSSCs) (Kuo et al, 1997;Rush and Elliott, 1997). We therefore investigated the role of voltage-sensitive Na + channels on the increase in the [Ca 2 + ] i , induced by kainate.…”

Precision Medicine: SCN8A Encephalopathy Treated with Sodium Channel Blockers

“…Carbamazepine is thought to have a similar working mechanism. However, the affinity of carbamazepine for inactivated sodium channels is around 3 times lower than that of phenytoin [11]. Phenytoin, like all other antiepileptic drugs, has adverse effects, including gingival hyperplasia, skin disorders, cerebellar atrophy, ataxia, polyneuropathy, and impact on liver function.…”

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

“…4 State-dependent block of NaChs is an important mechanism of action of many anticonvulsants, local anesthetics, and antiarrhythmics, [6][7][8][9][10][11][12][13] which generally exhibit greater affinity for the open or inactivated states of the channel than for the resting state ( Fig. 1) and, as such, are considered use-dependent blockers.…”