Antiepileptic Drugs: Department of Pharmacology Zhang Yan-Mei

Antiepileptic Drugs
Department of Pharmacology
Zhang Yan-mei
Nature of Epilepsy
• Epilepsy affects about 0.5% of the population.
• The characteristic event is the seizure, which is
often associated with convulsion, but may occur in
many other forms.
• The seizure is caused by an abnormal high-
frequency discharge of a group of neurons,
starting locally and spreading to a varying extent
to affect other parts of the brain.
Nature of Epilepsy
• Seizures may be partial or generalised
depending on the location and spread of the
abnormal neuronal discharge. The attack
may involve mainly motor, sensory or
behavioural phenomena. Unconsciousness
occurs when the reticular formation is
involved.
Types of Epilepsy
• Two major categories, namely partial and
generalised seizures; there is some overlap and
many varieties of each.
Partial seizures
– The discharge begins locally, and often
remains localised. Produce relatively
simple symptoms without loss of
consciousness.
Types of Epilepsy
Generalised seizures
– Involve the whole brain, including the reticular system,
thus producing abnormal electrical activity throughout
both hemispheres. Immediate loss of consciousness.
Nature of Epilepsy
• Two common forms of generalised
epilepsy are the tonic-clonic fit (grand
mal) and the absence seizure (petit
mal). Status epilepticus is a life-
threatening condition in which seizure
activity is uninterrupted.
Nature of Epilepsy
• The neurochemical basis of the abnormal
discharge is not well understood. It may be
associated with enhanced excitatory amino
acid transmission, impaired inhibitory
transmission, or abnormal electrical
properties of the affected cells. The
glutamate content in areas surrounding an
epileptic focus is often raised.
Nature of Epilepsy
• Repeated epileptic discharge can cause
neuronal death (excitotoxicity).
• Current drug therapy is effective in 70-

80% of patients.
Mechanism of Action
• Current antiepileptic drugs are thought to act

mainly by two main mechanisms:
Mechanism of Action
– Reducing electrical excitability of cell

membranes, possibly through inhibition of
sodium channel.
– Enhancing GABA-mediated synaptic inhibition.

This may be achieved by an enhanced pre- or
postsynaptic action of GABA, by inhibiting
GABA-transaminase, or by drugs with direct
GABA-agonist properties.
Mechanism of Action
• A few drugs appear to act by a third mechanism,

namely inhibition of T-type calcium channels.
• Newer drugs act by other mechanism, yet to be

elucidated.
• Drugs that block excitatory amino acid receptors

are effective in animal models, but not yet
developed for clinical use.
The Major Antiepileptic Drugs
• The main drugs in current use are:
phenytoin, carbamazepine, valproate and
ethosuximide.
• Secondary drugs include:
– Phenobarbitone: highly sedative
– Various benzodiazepines (e.g. clonazepam);
Diazepam used in treating status epilepticus.
Phenytoin
Mechanism of Action: acts by stabilizing membranes
(1) Blocking voltage-dependence Na+ channel
(2) Blocking voltage-dependence Ca2+ channel
(3) Inhibiting calcium-induced secretory processes,
including release of hormones and neurotransmitters.
(4) Inhibiting post tetanic potentiation (PTP).
PHARMACOKINETICS
• Because phentoin is a weak acid, its
intestinal absorption is variable and plasma
concentration can vary widely. Monitoring
is therefore needed
• It is metabolized by the microsomal system
and is excreted first in the bile and then in
the urine.
Therapeutic uses
• Antiseizure: used in the treatment of grand
mal epilepsy and tonic-clonic seizure
disorders, not in absence seizures.
• Treatment on peripheral neuralgia .
• Antiarrhythmias
Adverse effects
• Gastrointestinal irritation
• Ataxia and diplopia.
• Blood dyscrasias.
• Gingival hyperplasia, hirsutism, increased
collagen proliferation.
Adverse effects
• Hepatitis.
• Fetal malformations: fetal hydantion
syndrome( 胎儿妥因综合症 )
• Drug interactions: increased plasma
concentrations of phenytoin can occur by
concurrent administration of
chloramphenicol( 氯霉素 ), isoniazid （异
烟肼） , cimetidine （甲氰咪胍） ,
dicumarol （双香豆素） , et al.
Carbamazepine
• Derivative of tricyclic antidepressants
• Similar profile to that of phenytoin, but with

fewer unwanted effects
• Effective in most forms of epilepsy (except

absence seizures); particularly effective in
psychomotor epilepsy; also useful in trigeminal
neuralgia and mania.
Carbamazepine
• Strong inducing agent; therefore many drug
interactions
• Low incidence of unwanted effects; principally

sedation, ataxia, mental disturbances, water
retention
Valproate
• Valproate is very effective against absence
seizure.
• Mechanism: facilitate glutamic acid
decarboxylase; inhibit GABA-transaminase;
enhance synaptic responses. some effect on
sodium channels
• Relatively few unwanted effects: anorexia,
nausea, teratogenicity, liver damage (rare,
but serious)
Ethosuximide
• The main drug used to treat absence
seizures, may exacerbate other forms
• Acts by blocking T-type Ca2+-channels
• Relatively few unwanted effects, mainly
nausea and anorexia. (mental disturbances)
Benzodiazepine
• Diazepam: preferred drugs for Status

epilepticus.
• Nitrazepam: petit mal ,especially myoclonic
seizures and infantile spasms.
• Clonazepam: is one of the most effective in
some cases of myoclonic seizures. Used in
petit mal and status epilepticus
Barbiturates
• Phenobarbital, Luminal: is useful in the treatment
of generalized tonic-clonic seizures and statue
epilepticus.
• Mechanism:(1) block Ca2+ currents presynaptic
membrane and decrease neurotransmitter release.
(2) prolong the openings of the Cl- channel in
postsynaptic membrane and decrease it’s response.
• Adverse effects: sedation, depression, drug
interaction.
Clinical Uses of Antiepileptic Drugs
• Tonic-clonic (grand mal) seizures:
carbamazepine preferred because of low
incidence of side-effects, phenytoin, valproate.
Use of single drug is preferred when possible,
because of risk of pharmacokinetic interactions.
• Partial (focal) seizures: carbamazepine,
valproate; clonazepam or phenytoin are
alternatives.
Clinical Uses of Antiepileptic Drugs
• Absence seizures (petit mal): ethosuximide or
valproate. Valproate is used when absence
seizures coexist with tonic-clonic seizures, since
most drugs used for tonic-clonic seizures may
worsen absence seizures.
• Myoclonic seizures: valproate or clonazepam.
• Status epilepticus: must be treated as an
emergency, with diazepam intravenously.
Attentions
• Selection of an appropriate antiseizure
agent
• Use of single drug
• Withdrawal
• Toxicity
• Fetal malformations

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Antiepileptic Drugs

• Current drug therapy is effective in 70-

• Current antiepileptic drugs are thought to act

– Reducing electrical excitability of cell

– Enhancing GABA-mediated synaptic inhibition.

• A few drugs appear to act by a third mechanism,

• Newer drugs act by other mechanism, yet to be

• Drugs that block excitatory amino acid receptors

• Similar profile to that of phenytoin, but with

• Effective in most forms of epilepsy (except

• Low incidence of unwanted effects; principally

• Diazepam: preferred drugs for Status

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