A Textbook of Clinical Pharmacology and Therapeutics

●Introduction 133

●Mechanisms of action of anti-epileptic drugs 133

●General principles of treatment of epilepsy 133

●Drug interactions with anti-epileptics 139

●Anti-epileptics and pregnancy 139

●Status epilepticus 139

●Withdrawal of anti-epileptic drugs 139

●Febrile convulsions 140

CHAPTER 22

ANTI-EPILEPTICS

INTRODUCTION

Epilepsy is characterized by recurrent seizures. An epileptic
seizure is a paroxysmal discharge of cerebral neurones associ-
ated with a clinical event apparent to an observer (e.g. a tonic
clonic seizure), or as an abnormal sensation perceived by the
patient (e.g. a distortion of consciousness in temporal lobe
epilepsy, which may not be apparent to an observer but which
is perceived by the patient).
‘Funny turns’, black-outs or apparent seizures have many
causes, including hypoglycaemia, vasovagal attacks, cardiac
dysrhythmias, drug withdrawal, migraine and transient
ischaemic attacks. Precise differentiation is essential not only
to avoid the damaging social and practical stigma associated
with epilepsy, but also to ensure appropriate medical treat-
ment. Febrile seizures are a distinct problem and are discussed
at the end of this chapter.

γ-Aminobutyric acid (GABA) acts as an inhibitory neuro-

transmitter by opening chloride channels that lead to hyper-

polarization and suppression of epileptic discharges. In addition

to the receptor site for GABA, the GABA receptor–channel com-

plex includes benzodiazepine and barbiturate recognition sites

which can potentiate GABA anti-epileptic activity. Vigabatrin

(γ-vinyl-γ-aminobutyric acid) irreversibly inhibits GABA transam-

inase, the enzyme that inactivates GABA. The resulting increase

in synaptic GABA probably explains its anti-epileptic activity.

Glutamate is an excitatory neurotransmitter. A glutamate

receptor, the N-methyl-D-aspartate (NMDA) receptor, is

important in the genesis and propagation of high-frequency

discharges. Lamotrigineinhibits glutamate release and has

anticonvulsant activity.

MECHANISMS OF ACTION OF

ANTI-EPILEPTIC DRUGS

The pathophysiology of epilepsy and the mode of action of anti-
epileptic drugs are poorly understood. These agents are not all
sedative, but selectively block repetitive discharges at concen-
trations below those that block normal impulse conduction.
Carbamazepineandphenytoinprolong the inactivated state of
the sodium channel and reduce the likelihood of repetitive
action potentials. Consequently, normal cerebral activity, which
is associated with relatively low action potential frequencies, is
unaffected, whilst epileptic discharges are suppressed.

Key points

• Epilepsy affects 0.5% of the population.


• It is characterized by recurrent seizures.

Key points

Mechanisms of action of anticonvulsants

• The action of anticonvulsants is poorly understood.


• They cause blockade of repetitive discharges at a
  concentration that does not block normal impulse
  conduction.


• This may be achieved via enhancement of GABA action
  or inhibition of sodium channel function.

GENERAL PRINCIPLES OF TREATMENT

OF EPILEPSY

Figure 22.1 outlines the general principles for managing epilepsy.

Before treatment is prescribed, the following questions

should be asked:

• Are the fits truly epileptic and not due to some other
  disorder (e.g. syncope, cardiac dysrhythmia)?


• Is the epilepsy caused by a condition that requires
  treatment in its own right (e.g. brain tumour, brain
  abscess, alcohol withdrawal)?