Clinical Pharmacology and Therapeutics

CHAPTER 22
ANTI-EPILEPTICS
● 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
INTRODUCTION
Epilepsy is characterized by recurrent seizures. An epileptic
seizure is a paroxysmal discharge of cerebral neurones associated
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 treatment.
Febrile seizures are a distinct problem and are discussed
at the end of this chapter.
Key points
• Epilepsy affects 0.5% of the population.
• It is characterized by recurrent seizures.
γ-Aminobutyric acid (GABA) acts as an inhibitory neurotransmitter
by opening chloride channels that lead to hyperpolarization
and suppression of epileptic discharges. In addition
to the receptor site for GABA, the GABA receptor–channel complex
includes benzodiazepine and barbiturate recognition sites
which can potentiate GABA anti-epileptic activity. Vigabatrin
(γ-vinyl-γ-aminobutyric acid) irreversibly inhibits GABAtransaminase,
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. Lamotrigine inhibits glutamate release and has
anticonvulsant activity.
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.
MECHANISMS OF ACTION OF
ANTI-EPILEPTIC DRUGS
The pathophysiology of epilepsy and the mode of action of antiepileptic
drugs are poorly understood. These agents are not all
sedative, but selectively block repetitive discharges at concentrations
below those that block normal impulse conduction.
Carbamazepine and phenytoin prolong 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.
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)?