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Antiepileptic Drug Mechanisms of Action E/~l/tp\lo,34(Suppl. 5):Sl-SR. 1993 Raven Press, Ltd.. New York International League Against Epilepsy Antiepileptic Drug Mechanisms of Action *?Robert L. Macdonald and *Kevin M. Kelly Deparlmenls qf*Neurology and tPhysio1og.v. University of Michigan Medical Cmter, Ann Arbor, Michigan. U.S.A Summary: Clinically used antiepileptic drugs (AEDs) de- trigine may decrease sustained high-frequency repetitive crease membrane excitability by interacting with ion channels firing. The mechanisms of action of felbamate are unknown. or neurotransmitter receptors. Currently available AEDs ap- Gabapentin (GBP) appears to bind to a specific binding site pear to act on sodium channels, GABAAreceptors, or calcium in the central nervous system with a restricted regional channels. Phenytoin, carbamazepine, and possibly valproate distribution, but the identity of the binding site and the (VPA) decrease high-frequency repetitive firing of action po- mechanism of action of GBP remain uncertain. Key Words: tentials by enhancing sodium channel inactivation. Benzo- Anticonvulsants- Neuropharmacology -Neurotransmitten- diazepines and barbiturates enhance GABAA receptor- GABA -Phen ytoi n -Carbamazepi ne- Ethosuxi mide-Tri- mediated inhibition. Ethosuximide and possibly VPA reduce methadione-Benzodiazepines-Barbiturates-Valproate- a low-threshold calcium current. The mechanisms of action Felbamate-Gabapentin-Lamotrigine-Neural inhibi- of AEDs currently under development are less clear. Lamo- tion-Sodium-Calcium. A limited number of antiepileptic drugs (AEDs) are PHENYTOIN AND CARBAMAZEPINE available for use in the treatment of patients with epi- lepsy. In the United States, AEDs are limited primarily PHT and CBZ have been shown to interact with to phenytoin (PHT), carbamazepine (CBZ), barbitu- sodium channels at concentrations found free in the rates and primidone (PRM), benzodiazepines (BZDs), plasma of patients being treated for epilepsy (Macdon- valproate (VPA), and ethosuximide (ESM). Three ad- ald, 1989). These AEDs were shown to reduce the fre- ditional AEDs may be available in the United States quency of sustained repetitive firing of action potentials in the near future: felbamate (FBM), gabapentin (GBP), in neurons in cell culture (McLean and Macdonald, and lamotrigine (LTG). It is likely that the currently 1983, 1986b). The characteristic property of these used AEDs as well as the new AEDs have as their pri- AEDs was that they did not reduce the amplitude or mary targets of action neurotransmitter receptors or duration of single action potentials but reduced the ion channels. Three primary neurotransmitter receptor ability of neurons to fire trains of action potentials at or ion channels are targeted by the currently prescribed high frequency. The limitation of high frequency re- AEDs and at least one of the newly developed petitive firing was voltage-dependent, limitation of fir- ones: voltage-dependent sodium channels, voltage- ing being increased after depolarization and reduced dependent calcium channels, and GABAA receptor after hyperpolarization. Once developed, the limitation channels. Basic actions at these ion channels or neu- of firing was prolonged, lasting several hundred milli- rotransmitter receptor channels may be responsible for seconds. The action of the AEDs appeared to be due the clinical actions bf those AEDs. The interaction of to a shift of sodium channels to an inactive state that clinically available AEDs and the three new AEDs was similar to the normally occumng inactive state FBM, GBP, and LTG with those specific neurotrans- but from which recovery was delayed. mitter receptors or ion channels will be the subject of The actions of PHT and CBZ on mammalian my- this review. elinated nerve fibers have been studied (Schwarz and Grigat, 1989). Both AEDs produced a voltage- dependent block of sodium channels that could be re- Address correspondence and reprint requests to Dr. R. L. Mac- donald at Neuroscience Laboratory Building, I103 East Huron, Ann moved by hyperpolarization. PHT produced a shift of Arbor, MI 48104-1607, U.S.A. the steady-state sodium channel inactivation curve to Sl s2 R. L. MACDONALD AND K. M.KELLY more negative voltages. Both PHT and CBZ reduced myelinated nerve, and rat hippocampal pyramidal the rate of recovery of sodium channels from inacti- neurons. vation. In control solutions, sodium channels recovered Thus, evidence from voltage-clamp experiments has from complete inactivation within a few milliseconds confirmed the basic mechanism of action of PHT and after 500-ms depolarization to 25 mV. In the presence CBZ. Both AEDs appear to stabilize the inactive form of 100 pM PHT, recovery was prolonged to 90 ms. of the sodium channel in a voltage-dependent fashion, With 100 pM CBZ, recovery was prolonged to 40 ms. the effect being lessened at large negative membrane At 50 pM, PHT and CBZ each produced a frequency- potentials and increased at less-negative membrane dependent block. At 50 pM, PHT produced an initial potentials. Both AEDs slow the rate of recovery from block of 50%. With repetitive stimulation at 10 Hz, sodium channel inactivation and shift the steady-state the block increased to approximately 80% over 2.5 s. sodium inactivation curve to more negative voltages. Recovery from that block required approximately That stabilization of the inactive form of the receptor 2.5 s. At 100 pM. CBZ also produced a frequency- results in frequency-dependent block of sodium chan- dependent block that was somewhat less pronounced nels and blockade of sustained high-frequency repeti- than that produced by PHT. Thus, PHT and CBZ pro- tive firing of action potentials evoked from reduced duced voltage- and frequency-dependent block of so- membrane potentials. Of interest is the finding that dium channels. Because the concentration-response PHT has a stronger slowing effect than CBZ, which curves could be fitted assuming a first-order reaction, would result in slightly different actions of those AEDs it was suggested that one drug molecule binds to one under different conditions of repetitive firing. receptor near or at the sodium channel. The data also are consistent with PHT and CBZ binding with higher affinity to inactivated sodium channels rather than to ETHOSUXIMIDE AND TRIMETHADIONE open or resting sodium channels. Of interest was the A number of AEDs have been demonstrated to finding that PHT had a longer time dependence for modify the properties of voltage-dependent calcium frequency-dependent block and for recovery from channels (Macdonald, 1989). PHT, barbiturates, and block than did CBZ. This difference would result in a BZDs reduce calcium influx into synaptic terminals more pronounced frequency-dependent block for PHT and block presynaptic release of neurotransmitter. than for CBZ. Thus, although PHT and CBZ have However, those actions have been demonstrated only quulitutivcly similar actions on sodium channels, the at high drug concentrations that are above therapeutic actions are quuntitutivcly somewhat different. That fact free serum concentrations. Thus, it has been concluded may explain, at least in part, differences in the efficacy that AEDs do not have their primary actions on cal- of the two AEDs among patients. cium channels. However, it has been shown that cal- Similar voltage-clamp experiments were performed cium channels are heterogeneous. In primary afferent on isolated mammalian brain neurons (Wakamori et neurons, at least four different types of channels have al., 1989). Hippocampal pyramidal neurons from the been described (Nowycky et al., 1985; Mintz et al., CA 1 region were obtained from 1- and 2-week-old rats. 1992). These channels have been called L channels, T PHT at 200 pM produced a 20-mV negative shift in channels, N channels, and P channels. These channel the steady-state inactivation curve for sodium channels types have different voltage ranges for activation and and produced frequency-dependent block of sodium inactivation and different rates of activation and in- channels. Frequency-dependent block was shown at activation. It also is likely that these are not the only frequencies as low as 1 Hz, and the block increased to types of calcium channels present on neurons. The 50% at 10 Hz. Thus, the ability of PHT to enhance finding that neurons express multiple calcium channels inactivation in neurons in cell culture and in mam- suggests that AEDs may act on specific subtypes of malian myelinated nerve fibers also was present in iso- channels. This fact has been demonstrated for the lated mammalian neurons. AEDs ESM, trimethadione (TMO), and VPA, which The effect of PHT on human sodium channels also are effective in the treatment of generalized absence has been examined (Tomaselli et al., 1989). Total seizures. mRNA was extracted from human brain and injected Generalized absence epilepsy is characterized clini- into Xenopus oocytes. The human brain sodium chan- cally by brief periods of loss of consciousness and elec- nels expressed in oocytes also were blocked by PHT in trically by generalized 3-Hz spike and wave EEG dis- a voltage-, frequency-, and time-dependent fashion. charges. It has been suggested that thalamic relay The effects of PHT on human sodium channels were neurons play a critical role in the generation of the very similar to those on cultured mouse neurons, rat abnormal thalamocortical rhythmicity that underlies Epilepsiu. Vol. 34. Siippl. 5. I993 AED MECHANISMS OF ACTION s3 the 3-Hz spike and wave discharge. Whole-cell voltage- GABA binds to GABAA receptors
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