Antiepileptic Drugs, 5th Edition

Carbamazepine

20

Mechanisms of Action

Robert L. Macdonald MD, PhD

Professor and Chair, Department of Neurology, Vanderbilt University, Nashville, Tennessee

Carbamazepine (CBZ) is an iminostilbene and a structural congener of the tricyclic antidepressant drug imipramine (Figure 20.1). CBZ has been shown to be effective in the treatment of simple partial, complex partial, and generalized tonic-clonic seizures, but it is ineffective against generalized absence seizures (10,85,89,101). CBZ and the anticonvulsant drug phenytoin (Figure 20.1) have been shown to be effective in treatment of partial seizures and tonic-clonic seizures when they are used alone or as initial therapy (42,83), and both CBZ and phenytoin are drugs of first choice in the treatment of these seizure disorders (60). However, CBZ may be more effective in the treatment of complex partial seizures when complete seizure control is used as an end point (94). CBZ is an effective anticonvulsant drug in experimental animals (30,100), and it has an anticonvulsant profile that is similar to that of phenytoin (39,43). It is effective against maximal electroshock seizures at nontoxic doses but is not active against subcutaneous metrazol-induced seizures. CBZ may also be effective in the short-term and long-term treatment of manic-depressive illness (77), and it is the drug of choice for treatment of trigeminal neuralgia (6). CBZ is administered to adults in doses of 10 to 20 mg/kg/day to achieve total plasma concentrations of 4 to 12 µg/mL (16 to 48 µmol/L) (9, 46). The lower range of plasma concentrations are adequate to control seizures in patients with primary or secondarily generalized tonic-clonic seizures alone, but the higher plasma concentrations are required to treat seizures in patients with partial seizures with or without tonic-clonic seizures (87). CBZ is a lipid-soluble drug that is 65% to 80% bound to plasma proteins (38), and cerebrospinal fluid concentrations vary from 19% to 33% of total plasma concentrations (23). Assuming that 25% of total plasma CBZ is unbound, free plasma and cerebrospinal fluid concentrations are likely to be 1 to 3 µg/mL (4.2 to 12.6 µmol/L) (38).

ACTIONS ON EPILEPTIFORM DISCHARGES

The effect of CBZ has been studied in organized neuronal preparations such as the hippocampal slice. In this preparation, CBZ has been demonstrated to reduce spontaneous bursts recorded from the CA1 region of the rat hippocampal slice that were induced by low-calcium, high-magnesium solutions (29,36,72), low-calcium, low-magnesium solutions (20), and veratridine application (74). These effects were produced in the absence of synaptic transmission because the slices were bathed in a low-calcium solution or veratridine. These results were produced at CBZ concentrations that did not block single antidromically evoked action potentials. Because the effect on paroxysmal bursting in hippocampal pyramidal neurons was produced

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when chemical synaptic transmission was blocked, the antiepileptic effect of CBZ was likely to reduce membrane excitability of pyramidal neurons directly.

The effects of CBZ on hippocampal epileptiform discharges have been shown to be age dependent. CBZ eliminated repetitive afterdischarges in immature rat CA3 hippocampal pyramidal neurons produced by penicillin without altering epileptiform bursts, a finding also suggesting an effect on neuronal excitability (96). Hippocampal slices exposed to the convulsant 4-aminopyridine generate several types of spontaneous discharges, two short-duration bursts and long polyspike bursts (7, 103). In hippocampal slices from adult rats, CBZ abolished long bursts without altering the short “interictal-like” bursts (7,106). Addition of 4-aminopyridine to hippocampal slices from immature animals produced ictal-like and interictal-like discharges, whereas in slices from mature animals, 4-aminopyridine produced only ictal-like activity (26). In immature slices, CBZ blocked ictal-like discharges at relatively low concentrations (50 µmol/L) and blocked interictal-like discharges only at higher concentrations (100 µmol/L). In contrast, CBZ did not block the interictal-like discharges in the adult slices even at the higher concentration. Thus, CBZ appears to have selective actions on convulsant-induced bursting, and the effect is different in developing and mature hippocampus.

MECHANISMS OF ACTION

Multiple mechanisms of action for CBZ have been proposed. However, these can be divided into two basic mechanisms of drug action: (a) an action of CBZ on neuronal sodium channels to reduce sustained, high-frequency repetitive firing of action potentials; and (b) actions of CBZ on synaptic transmission and neurotransmitter receptors including purine, monoamine, acetylcholine, and N-methyl-D-aspartate (NMDA) receptors. Although evidence has been reported supporting both these mechanisms, current experimental evidence suggests that the major mechanism of action of CBZ is to reduce the ability of neurons to fire at high frequency by enhancing sodium channel inactivation. This mechanism and the others are discussed later.

REDUCTION OF SUSTAINED HIGH-FREQUENCY REPETITIVE FIRING

In early studies, CBZ was shown to reduce the excitability of peripheral nerves (35,44). These original observations suggested that CBZ directly reduced the sodium conductance underlying the action potential because increased threshold, decreased conduction velocity, and decreased action potential height occurred. However, it is likely that the CBZ concentrations used in these experiments were supratherapeutic. Schauf et al. (86) demonstrated directly that CBZ reduced sodium current in Myxicola giant axons. This effect was not specific for sodium currents because potassium currents were also reduced. The CBZ effect occurred only at very high CBZ concentrations (0.25 to 1.0 µm). Thus, early studies demonstrated that CBZ directly affected sodium channels, but only at supratherapeutic concentrations.

Early studies also suggested that CBZ may have some effect on spontaneous or evoked repetitive firing recorded from peripheral nerves. Honda and Allen (35) demonstrated that CBZ reduced spontaneous firing of action potentials recorded from peripheral nerves immersed in isotonic sodium oxalate or phosphate solutions. Hershkowitz and Raines (32) studied the effect of CBZ on muscle spindle discharges. These investigators correlated effects on spindle discharges with blood levels and demonstrated that CBZ depressed several aspects of muscle spindle discharges at concentrations that had little or no effect on nerve conduction velocity. These researchers demonstrated that CBZ depressed muscle spindle activity in a manner similar to that produced by local anesthetics. The sustained and prolonged repetitive firing of spontaneous activity and the static stretch response were sensitive to CBZ block, but the brief response to muscle stretch was spared. In addition, CBZ was demonstrated to reduce repetitive afterdischarges originating from small unmyelinated nerves in production of neuromuscular posttetanic potentiation in cat soleus neuromuscular preparations at CBZ concentrations similar to those suppressing spontaneous activity in static stretch responses of muscle spindles (33). This effect on posttetanic repetitive afterdischarges recorded from isolated ventral root filaments occurred at concentrations that did not affect conduction velocity of the motor nerves (33).

The effect of CBZ on repetitive firing was not limited to neuromuscular preparations. CBZ reduced high-frequency repetitive firing of action potentials recorded from mouse spinal cord (Figure 20.2), from neocortical and hippocampal pyramidal neurons grown in primary dissociated cell culture (52,61,64,65), and from hippocampal pyramidal neurons in the slice (36). When depolarized, spinal cord and cortical neurons sustain high-frequency repetitive discharges. In the presence of CBZ at therapeutic free serum concentrations (>1 µmol/L or 4.2 µg/mL), there was a concentration-dependent reduction in the number of action potentials evoked with 500-millisecond depolarizing pulses and in the percentage of neurons manifesting sustained repetitive firing. No effect was produced on single action potentials at concentrations of CBZ <10.6 µmol/L (2.5 µg/mL). In addition to CBZ, its active metabolite, CBZ epoxide (Figure 20.1), was also effective in producing limitation of high-frequency repetitive firing at concentrations comparable to those of CBZ (Figure 20.2). However, an inactive metabolite of CBZ, CBZ diol (Figure 20.1), did not affect high-frequency repetitive firing until concentrations

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were an order of magnitude higher than those effective for CBZ (Figure 20.2). Thus, CBZ and its active metabolite limited sustained high-frequency repetitive firing of action potentials at therapeutic free serum concentrations that did not modify single action potentials.

The effect of CBZ on repetitive firing had three major properties. First, the effect was voltage dependent. The reduction of sustained repetitive firing by CBZ could be enhanced by evoking the action potentials from a reduced membrane potential and could be reversed by evoking the repetitive train after membrane hyperpolarization. Second, the effect wasuse dependent (14). When limitation of repetitive firing was produced, the first action potential in the action potential train was unaffected. However, with successive action potentials in the train there was a reduction in the maximal rate of rise of the action potentials and in the action potential heights until failure of firing occurred. Third, the effect was time dependent. After a train of action potentials was evoked to produce a reduction of firing in the presence of CBZ, subsequent action potentials evoked after the train were also reduced in amplitude and maximum rate of rise. This reduction in action potential properties lasted several hundred milliseconds after the initial conditioning train.

These results suggest that CBZ affects sodium channels. However, the effect is likely to be on the inactivation process of sodium channels. It has been proposed that CBZ binds to sodium channels only in the inactive state, and therefore it limits repetitive firing only when the membrane is depolarized, so a few of the channels are in the inactive state (64). Blockade of repetitive firing can be reversed by hyperpolarizing the membrane to remove all sodium channel inactivation. Furthermore, because inactivation is enhanced by CBZ, initial action potentials in the train are unaffected, but subsequent action potentials in the train are more strongly affected because of the prolonged inactivation of sodium channels opened during early action potentials in the train. Finally, recovery of sodium channels from inactivation is thought to be prolonged, and therefore the reduction in action potentials produced in a train persists for several hundred milliseconds. Thus, it has been proposed that CBZ limits high-frequency repetitive firing by binding to sodium channels in the inactive state and by slowing the rate of recovery of these channels from inactivation. In addition to CBZ, several other antiepileptic drugs that are effective against generalized tonic-clonic and partial seizures, including phenytoin (62) and valproic acid (63), block high-frequency repetitive firing (52,54,55), possibly by a similar mechanism.

The action of CBZ on inactivated sodium channels has been confirmed using voltage-clamp techniques. In studies of peripheral nerve and muscle (15,88), neuroblastoma cells

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in culture (49,115), human NT2-N cells in culture (98), acutely dissociated hippocampal neurons (45,98,104), and rat brain type IIA sodium channels stably expressed in Chinese hamster ovary cells (82), CBZ has been shown to slow the rate of recovery from inactivation and to shift the voltage dependency of steady-state inactivation to more negative voltages and thus to produce a frequency- and voltage-dependent block of sodium channels. The block appears to be selective for the inactive form of the closed channel. Thus, it is likely that CBZ binds preferentially to the inactive form of the sodium channel, an action consistent with the modulated receptor hypothesis of local anesthetic drug action proposed by Hille (34).

In addition to its effect on sodium action potentials and currents, CBZ has been demonstrated to reduce veratridine-stimulated calcium flux (17,24), as well as batrachotoxin-activated sodium influx in N18 neuroblastoma cells and rat brain synaptosomes (116). Veratridine and batrachotoxin both bind to voltage-dependent sodium channels. Therefore, the block of calcium or sodium transport activated by either veratridine or batrachotoxin suggests an action of CBZ on voltage-dependent sodium channels. Furthermore, CBZ inhibited binding of [³H]batrachotoxinin A 20-α-benzoate to sodium channels of rat brain synaptosomes (114). Batrachotoxin causes persistent activation, not block, of sodium channels by binding to high-affinity states of the channel. Thus, it appears that CBZ blocks high-frequency sustained repetitive firing of action potentials and spontaneous burst discharges, veratridine-and batrachotoxin-induced sodium flux, and [³H]batrachotoxinin binding by binding to sodium channels and enhancing voltage-dependent sodium channel inactivation.

SYNAPTIC ACTIONS

In spinal cord, CBZ did not alter monosynaptic reflex discharges at systemic doses that depressed polysynaptic discharges and posttetanic potentiation (39,44,99,100). However, the blood levels required to reduce posttetanic potentiation were supratherapeutic (39), and CBZ failed to alter posttetanic potentiation in the rat hippocampal slice (36). CBZ also reduced synaptic transmission in the spinal trigeminal nucleus of cats (6,25,31,84) and in the nucleus centrum medianum of the thalamus (31). Similarly, the extracellular excitatory postsynaptic potential field potential recorded in hippocampal CA1 apical dendrites and evoked by stratum radiatum stimulation was reduced by CBZ at moderate concentrations (10 to 100 µmol/L) (36). These studies suggest that CBZ may decrease excitatory synaptic transmission. However, these studies do not clarify whether the effect of CBZ is presynaptic or postsynaptic.

In addition to the effects on the process on synaptic transmission, CBZ has been reported to alter neurotransmitter levels, metabolism, and receptors. The primary neurotransmitter receptors studied have included adenosine, monoamine, acetylcholine, γ-aminobutyric acid (GABA), and glutamate receptors.

CBZ may modify excitatory amino acid receptor responses. CBZ did not modify postsynaptic responses to glutamate in a normal magnesium solution (64), and CBZ (400 µmol/L) failed to affect sodium-dependent or [³H]L-glutamate binding to hippocampal synaptic membranes (36). CBZ did not inhibit activation of non-NMDA receptors in cultured rat hippocampal neurons (3), and it attenuated α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor-mediated depolarizations in the rat cortical wedge only at high, supratherapeutic concentrations (76). These data suggest that AMPA-like and kainatelike excitatory amino acid responses are not affected by CBZ.

In contrast, CBZ may alter NMDA receptor responses. CBZ reduced NMDA-activated currents in cultured spinal cord neurons in a concentration-dependent fashion, and it had minimal effects on NMDA-activated currents at relatively low concentrations (>10 µmol/L) (47). Consistent with an effect on NMDA receptors, CBZ reduced NMDA-induced elevation of intracellular calcium concentration in primary cultures of cerebellar granule neurons at a relatively low concentration (50 µmol/L) (8,37), and it reduced NMDA-induced depolarizations in cortical wedges prepared from genetically epilepsy-prone DBA/2 mice at therapeutic CBZ concentrations (1 to 10 µmol/L) (48). Maximal reduction of NMDA-induced depolarizations were produced at CBZ concentrations of 10 to 80 µmol/L, and at higher concentrations (100 to 200 µmol/L), CBZ paradoxically increased the depolarizations. The reduction of NMDA-induced depolarizations by CBZ was noncompetitive, with a reduction in the maximal depolarization but little effect on the half-maximal NMDA concentration. In contrast, the enhancement of the NMDA-induced depolarization at higher NMDA concentrations was “competitive,” with a left shift in the concentration response curve and no alteration in the magnitude of the maximum depolarization. However, in the rat hippocampus, responses to NMDA (97) and NMDA-induced increases in the discharge rate of low-magnesium-induced field potentials (105) were not affected by CBZ, and CBZ did not displace [³H]MK801 to mouse cortical membranes at therapeutic concentrations (28). These data suggest that although CBZ may have anticonvulsant action, at least in part, by reduction of the NMDA receptor current, this mechanism of action remains unproven.

A role of CBZ in modifying adenosine receptor responses was suggested by the finding that CBZ inhibited adenosine-stimulated cyclic adenosine monophosphate accumulation in rat cortical slices (50), and CBZ modified the specific binding of adenosine agonists to rat brain membranes (58,90, 91, 92,108). CBZ specifically displaced the adenosine A1 agonist [³H]cyclohexyl adenosine (CHA) and

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antagonist [³H]diethylphenylxanthine binding (57,58,107, 108), and the inhibition of adenosine receptor binding by CBZ was competitive (58). CBZ was less potent in inhibiting the binding of the adenosine A2 agonist [³H]5′-N-ethylcarboxamidoadenosine (27,91), a finding suggesting that CBZ binds preferentially to Al receptors. Consistent with these results, CBZ was shown to displace an Al adenosine receptor ligand from human hippocampus (19). To determine whether CBZ is an agonist or antagonist at Al adenosine receptors, the effects of the nucleotide guanosine triphosphate and temperature on CBZ binding have been studied. Guanosine triphosphate has been shown to reduce the affinity of agonists for receptors without altering the affinity of antagonists (16,75,102), and antagonist binding potency has been shown to increase at lower temperatures, whereas agonist binding potency increases at higher temperatures (51). Because the potency of CBZ to displace [³H]CHA is unaffected by guanosine triphosphate (91) and is increased at lower temperatures (57), it is likely that CBZ is an A1 adenosine receptor antagonist. The functional significance of CBZ antagonist action at Al adenosine receptors, however, is unclear. In studies in hippocampal slice, CBZ did not appear to have an action mediated by adenosine receptors (72). The depressant effect of adenosine on the population spike recorded in CA1 was completely blocked by caffeine, but the depressant effect of CBZ was not modified by caffeine. Furthermore, a role for adenosine receptors in CBZ action could not be supported in the immature rat hippocampus in vitro (95). Despite a clear demonstration that CBZ is an antagonist at Al adenosine receptors, it is unlikely that this interaction is responsible for the anticonvulsant properties of CBZ. No correlation has been found between the potency of a series of CBZ analogs as inhibitors of either agonist or antagonist binding and their ability to inhibit maximal electroshock seizures (58). Adenosine receptor agonists, not adenosine receptor antagonists, have anticonvulsant effects (1,2,21,22,56,119). Furthermore, in amygdala-kindled seizures in the rat, CBZ, but not CHA, was an anticonvulsant (111), and adenosine receptor antagonists did not block the anticonvulsant effect of CBZ (110). In the striatum, CBZ has been shown to modify extracellular dopamine levels (71). The effect of CBZ is consistent with Al antagonist and A2 agonist activity. Thus, although it appears established that CBZ is an A1 adenosine receptor antagonist, it is unlikely that the anticonvulsant properties of CBZ are derived from actions at adenosine receptors.

Investigators have suggested that monoamines may be involved in the actions of CBZ. The threshold for inducing electroshock seizures was reduced after administration of drugs that deplete brain monoamines (4,11,40,41,81). In contrast, the threshold for inducing electroshock seizures was elevated by administration of monoamine precursors or inhibitors of monoamine catabolism (12,40,78). After an intraventricular injection of 6-hydroxydopamine (6-OHD), which reduced forebrain catecholamines, CBZ was less effective in raising the electroconvulsive threshold current (80,81). Pretreatment with desipramine, which protected noradrenergic neurons from 6-OHD toxicity, blocked the 6-OHD effect on the CBZ anticonvulsant effect. CBZ, however, was shown to increase dopamine, its metabolites, and its precursors in the striatum and hippocampus at therapeutic plasma concentrations (69). Reduction of brain serotonin levels by destruction of raphe neurons did not alter the CBZ anticonvulsant effect (80). However, CBZ has been shown to increase extracellular serotinin levels (18,70). Both the uptake and release of [³H] norepinephrine from brain synaptosomes was inhibited by 100 µmol/L CBZ (79). These results suggest that norepinephrine may be involved in the action of CBZ. However, Westerink et al. (113) found no change in 3,4-dihydroxyphenyl acidic acid and homovanillic acid, the metabolites of dopamine, in corpus striatum, nucleus accumbens, and tuberculum olfactorium of the rat after CBZ treatment. CBZ did not alter extracellular norepinephrine levels in rat hippocampus (118). Furthermore, CBZ did not alter the firing rate of noradrenergic neurons in the locus ceruleus (73). With these conflicting studies, a role for CBZ on catecholamine metabolism remains uncertain.

An effect of CBZ on cholinergic responses in the brain has also been reported. CBZ was shown to produce an increase in striatal and hippocampal acetylcholine levels and a decrease in choline levels (13,66). Neither choline acetyltransferease nor cholinesterase activity was affected by CBZ. CBZ also increased release and synthesis (66).

Certain antiepileptic drugs have been demonstrated to enhance GABAergic synaptic transmission by enhancing the postsynaptic action of GABA at GABA_A receptors (53,54). However, on spinal cord neurons in cell culture, no effect of CBZ was found on postsynaptic responses to iontophoretically applied GABA (64), and CBZ did not alter GABAergic inhibition in the hippocampal slice (36). Furthermore, CBZ did not alter the binding of the GABA_A receptor agonist [³H] muscimol to rat brain synaptic membranes after either short-term or long-term treatment (67,68). These results suggest that CBZ does not modify GABA_A receptor function.

CBZ has been shown to interact with peripheral benzodiazepine sites. Peripheral benzodiazepine binding sites were labeled with [³H]Ro 5-4864 (4′-cholorodiazepam), and CBZ produced a competitive displacement of the labeled ligand with a rather high dissociation constant of 45 µmol/L (58). Furthermore, Ro 5-4864 antagonized the anticonvulsant effect of CBZ, and the effect of Ro 5-4864 was reversed by PK-11195, a compound that displaced Ro 5-4864 binding to peripheral benzodiazepine sites (111). CBZ also upregulated the binding of [³H]PK-11195 to platelets after 4 weeks of treatment (112), and CBZ inhibited the binding of [³H] diazepam to cultured astrocytes but not to cultured neurons (5). In amygdala-kindled rats made tolerant to the anticonvulsant effect of CBZ, cross-tolerance was obtained with

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the anticonvulsant effects of PK-11195, but not to diazepam, a finding consistent with a CBZ interaction with peripheral, but not central, benzodiazepine receptors (109). However, no change in [³H]Ro 5-4864 binding was obtained in rat brain after long-term CBZ treatment (59), and Ro 5-4864 is a convulsant compound that antagonizes GABA_A receptor responses by binding to the TBPS site on the GABA_A receptor (93). Although the available evidence supports an interaction of CBZ with peripheral benzodiazepine sites, it is unclear whether this interaction occurs at a clinically relevant concentration and how CBZ would produce an anticonvulsant action by binding to this site. On balance, it appears unlikely that CBZ exerts it anticonvulsant action by interacting with peripheral benzodiazepine sites.

CONCLUSION

CBZ and its active metabolite CBZ epoxide both limit sustained high-frequency repetitive firing of sodium-dependent action potentials. It is likely that they do so by binding to the inactive form of sodium channels, thereby producing use- and voltage-dependent block of sodium channels. Thus, CBZ is more effective in reducing high-frequency repetitive firing when neurons are depolarized because more channels are in the inactive state. Under normal physiologic conditions, it is likely that vertebrate myelinated and unmyelinated axons have a large negative membrane potential, and therefore, propagated action potentials are relatively resistant to the action of CBZ. In contrast, the cell body of neurons is subject to synaptic depolarization and inward currents that produce burst firing. This is particularly true in neurons undergoing epileptic discharge. CBZ is therefore effective in limiting high-frequency action potentials generated in bursting neurons.

In addition to altering neuronal excitability, CBZ may alter the process of synaptic transmission by affecting presynaptic sodium channels. It has been demonstrated that [³H]BTX-B binding sites are not restricted to cell bodies and axons but are present in synaptic zones with a heterogeneous distribution in the nervous system (117). In the hippocampal slice, stimulation of stratum radiatum elicited extracellular field potentials recorded from the CA1 pyramidal cell layer. The field potentials consisted of a fiber spike, which reflects axonal propagation, and a population spike, which reflects effective synaptic transmission. Veratridine, which displaces [³H]BTX-B binding, produces a specific reduction in the synaptically evoked population spike without affecting the fiber spike. This effect of veratridine is antagonized by CBZ. It is likely therefore that CBZ blocks presynaptic sodium channels and the firing of action potentials; this would secondarily reduce voltage-dependent calcium entry and synaptic transmission.

Although the most likely mechanism of action of CBZ is to block high-frequency repetitive firing of action potentials by interacting with sodium channels, additional actions of CBZ have been suggested. CBZ has been reported to block NMDA receptor currents at therapeutically relevant concentrations. Whereas this observation has not been fully characterized, it is possible that this action of CBZ may act in concert with the effect of CBZ on sodium channels to produce its anticonvulsant effect. At present, it is not possible to determine the relative contribution, if any, of blockade of NMDA currents to the anticonvulsant mechanism of CBZ.

In summary, CBZ is likely to act both presynaptically, to block release of neurotransmitter by blocking firing of action potentials, and postsynaptically, by blocking the development of high-frequency repetitive discharge initiated at cell bodies and possibly by blocking NMDA receptor currents. These combined presynaptic and postsynaptic effects are likely to form the basis of the anticonvulsant actions of CBZ.

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