Antiepileptic Drugs Aeds

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.

OLD AEDs

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-clonic 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.

Phenytoin and carbamazepine

An effective AED might control seizures and not be too sedative, by stopping a neuron from firing excessively without affecting its ability to respond normally. This is how phenytoin is believed to work. Studies in cultured spinal cord neurons (Macdonald and McLean 1986) have shown that concentrations of phenytoin equivalent to those occurring clinically do not affect the resting membrane potential or the shape of a single-action potential but reduce the rapid discharge induced by depolarising the neuron, while leaving the first action potential intact (Fig. 16.8). It is believed to block voltage-dependent sodium channels (not those mediating the synaptic currents) after their activation, i.e. when they become inactivated, and so maintains them in that inactivated state and unresponsive. These effects, which are also shown by carbamazepine, would explain their effectiveness experimentally against maximal electroshock-induced

Antiepileptic And Neurons

Figure 16.6 Possible sites of action of antiepileptic drugs. Antiepileptic drugs either directly affect ion channels to reduce Na+ (1) or increase Cl_(2) influx, depress glutamate release (3) or its action through NMDA receptors (4), or potentiate the effect of GABA by reducing its destruction by uptake (5) or metabolism by GABA transaminase (6), acting directly on GABAA receptors (7) or potentiating that effect of GABA through an action on benzodiazepine receptors that allosterically alter the GABAA site (8). Currently there are no clinically useful drugs that act as glutamate receptor antagonists

Figure 16.6 Possible sites of action of antiepileptic drugs. Antiepileptic drugs either directly affect ion channels to reduce Na+ (1) or increase Cl_(2) influx, depress glutamate release (3) or its action through NMDA receptors (4), or potentiate the effect of GABA by reducing its destruction by uptake (5) or metabolism by GABA transaminase (6), acting directly on GABAA receptors (7) or potentiating that effect of GABA through an action on benzodiazepine receptors that allosterically alter the GABAA site (8). Currently there are no clinically useful drugs that act as glutamate receptor antagonists seizures and clinically in focal and generalised epilepsy. Also, since they act only on the inactivated channel, they will not affect normal neuronal function, which is why in the experimental study, the first action potential remains unaltered. Neither compound is of any value against absence seizures and may exacerbate them. They have no clear effect on NT function although there is some evidence that in vivo they may potentiate GABA-induced chloride currents.

Ethosuximide

This is really only effective against absence seizures. Experimentally it has no effect on the voltage-gated sodium channels affected by phenytoin but has been reported to suppress the transient T-type calcium currents in the thalamic neurons which are the origin of the 2-3 Hz spike and wave discharge characteristic of this form of epilepsy (see Mody 1998 for detail). Since these discharges are thought to arise from oscillations in excitability induced by changes in the T-type calcium current (see section above on the origin of absence seizures), this would obviously be a neat explanation of its efficacy in that condition. Unfortunately some workers have not been able to repeat this finding at clinically equivalent concentrations and consider ethosuximide to reduce a special persistent Na+ channel and a Ca2+-activated K+ channel.

Barbiturates and benzodiazepines (B & Bs)

As outlined above (see also Chapter 9), these drugs have been found to influence the Cl_ channel of the GABAA receptor. Phenobarbitone acts directly to prolong its

Anticonvulsants Drugs Structures

Figure 16.7 The structure of some established antiepileptic drugs (AEDs) and some newer ones. Note that while the structures of phenytoin and ethosuximide are similar and also close to that of phenobarbitone, they are effective in different forms of epilepsy. Vigabatrin, progabide and gabapentin are clearly related to GABA. Muscimol is a GABAA agonist but is not an effective antiepileptic drug

Figure 16.7 The structure of some established antiepileptic drugs (AEDs) and some newer ones. Note that while the structures of phenytoin and ethosuximide are similar and also close to that of phenobarbitone, they are effective in different forms of epilepsy. Vigabatrin, progabide and gabapentin are clearly related to GABA. Muscimol is a GABAA agonist but is not an effective antiepileptic drug

Table 16.3 Possible mechanisms of action and features of some antiepileptic drugs

Mode of action Comments (half-life, hours)

Established drugs HYDANTOINS Diphenylhdantoin (phenytoin)

DIBENZAPINES Carbamazepine

SUCCINIMIDES Ethosuximide

BARBITURATES Phenobarbitone

Primidone

GM FE TLE

GM/FE GM/PE

BENZODIAZEPINES Diazepam SE

Clonazepam ME SE

Clobazam

SHORT-CHAIN FATTY ACIDS Sodium valproate GM PM

Newer drugs Lamotrigine Gabapentin Vigabatrin

Widely used. Hyperplasia of gums. Anti-folate. Teratogenic. Ineffective in PM (20-80)

Improves mood. Related to tricyclic antidepressants. Drug of choice in FE (10-20)

Drug of choice for PM, with Na valproate (20-60)

Sedative. Withdrawal fits. Little used (50-100) Works partly by conversion to phenobarbitone in body

Given intravenously in SE (<100) Diazepam largely replaced by clonazepam Adjunct to other anti-epileptics. Partly as an anxiolytic

Inhibition of GABA metabolism too slow to explain initial anti-convulsant effect. Increasing use in ME, PM, GM (5-15)

Fewer side effects (24) Excreted unchanged Exacerbates AS (PE)

Notes:

The numbers (1-8) refer to their sites of action as shown in Fig. 16.6. All compounds may produce some overt signs of CNS depression, e.g. ataxia, sedation, dizziness.

opening time (mechanism 2 in Fig. 16.8), while the benzodiazepines modify the GABAA receptor allosterically and increase the likelihood (frequency) of Cl_ channel opening. The benzodiazepines are particularly effective against experimentally induced PTZ seizures.

Phenobarbitone may be as effective as phenytoin and carbamazepine in partial and generalised tonic-clonic seizures but its other central effects such as sedation, depression, listlessness and cognitive impairment mar its usefulness.

Clonazepam, a typical 1:4 benzodiazepine, is effective in absence seizures, myoclonic jerks and tonic-clonic seizures and given intravenously it attenuates status epilepticus. It is less sedative than phenobarbitone but tolerance develops and its withdrawal, as

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