Chapter 16

Antiepileptic Drugs
Department of Pharmacology
Zhang Xiaojie

Epilepsy
Epilepsy is a heterogeneous symptom
complex, a chronic disorder characterized
by sudden, transient and recurrent seizures
which are episodes of brain dysfunction
resulting from abnormal discharge of focal
cerebral neuron and diffusion to normal
neuronal tissues.

Pathogenesis
Normal neurons
Epileptic focal
Abnormal highfrequency discharge
sudden, excessive and abnormal high-frequency discharge of
neurons diffuses to local or whole brain in a short time
over-excitement brain dysfunction

Epilepsy
Etiology incidence: 50/100,000
Primary epilepsy:

30%

inherited abnormality
Secondary epilepsy: 70%

such as brain tumors, brain infarction,head injury,

hypoglycemia, meningeal infection

Classifications

Partial seizures
(1)Simple partial seizures

(2)Complex partial seizures

2. Generalized seizures
(1)Absence seizures (petit mal)
(2)Myoclonic seizures

(3)Generalized tonic-clonic seizures (grad mal)

-
(4)Status epilepticus

1.

Partial seizures
(1) Simple partial
Do not lose consciousness and often
exhibit abnormal activity of a single limb
or muscle group, lasting 20-60s
Key feature: preservation of
consciousness

Partial seizures
(2) Complex partial
Exhibit motor dysfunction and impaired
consciousness lasting 30s-2m,often
associated with purposeless movents

Generalized seizures
(1) Generalized tonic-clonic seizures
Loss of consciousness and sustained
contractions(tonic) of muscles followed by
periods of contraction and relaxation (clonic),
typically lasting 1-2m
Continuous episodes with sustained loss of
consciousness is called status epilepticus .

Generalized seizures
(2) Absence seizure
Involve a brief, sudden and selflimiting loss of consciousness. The
patient stare and exhibits rapid eyeblinking, which lasts for 3 to 5
seconds without any motor disorder.

Generalized seizures
(3) Myoclonic
a brief (perhaps a second), shocklike
contraction of muscles which may be
restricted to part of one extremity or
may be generalized

Mechanism Action of Antiepileptic drugs

Antiepileptic drugs are thought to act by two main mechanisms:

Reducing electrical excitability of cell membranes,

possibly through inhibition of sodium channel,
then suppressing the repetitive firing of neurons
Enhancing GABA-mediated synaptic inhibition.
This may be achieved by an enhanced pre- or postsynaptic action of GABA, by inhibiting GABAtransaminase, or by drugs with direct GABAagonist 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 (dilantin)
Mechanism of Action: acts by stabilizing membranes
(1) Blocking the voltage-dependence Na+ channel,
limiting the repetitive firing of action potentials
(2) Blocking voltage-dependence Ca2+ channel (L , N)
(3) Inhibiting calcium-induced secretory processes,
including release of hormones and
neurotransmitters.

PHARMACOKINETICS
Because phenytoin is a weak alkali, its
absorption is slow and unpredictable after oral
administration 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.

Clinical uses
1.Epilepsy:
all epilepsies but absence seizure

first choice for:

generalized tonic-clonic seizures
simple partial seizures
complex partial seizures

Clinical uses
2. Treatment of peripheral neuralgia :
trigeminal neuralgia et al
3. Antiarrhythmias ventricular
arrhythmias
First choice for ventricular arrhythmias caused by
cardiac glycoside intoxication

Adverse Reactions
1. Gastrointestinal reaction
2. Gingival hyperplasia by increasing the

the induction of collagenase

Adverse Reactions
3. CNS symptoms
20g/ml drowsiness, dizziness,
ataxia, 40g/ml: psychotic,
50g/ml: coma
4. Blood system:
folic acid deficiency

Megaloblastic anemia
Add leucovorin

Adverse Reactions
5. Bone system
hypocalcemia, osteomalacia, rachitis
reason increase the metabolism of vitamin D

Carbamazepine
Broadspectrum antiepileptic agent
Mechanisms (similar to phenytoin.)

inhibit Na+ channel

potentiat GABA inhibitory function

Carbamazepine
Actions and Uses
1. Antiepileptic effects
grad mal, partial seizures with complex
symptomatology first choice
2. Central algesia: trigeminal neuralgia
more effective than phenytoin
3. Mania and depression
4. diabetes insipidus

Adverse Reactions
1. Gastrointestinal reaction
2. CNS reactions: drowsness, vertigo,
nausea, vomit, ataxia
3. Blood system: leukopenia ,
agranulocytosis ,
thrombocytopenia ,
aplastic anemia
4. Hepatic intoxication

Phenobarbital
Luminal
Broad-spectrum and much effective
in grad mal and partial seizures, but
not drug choice for grad mal, alternative
and iv in the treatment of status
epilepticus

Mechanisms
1. Potentiate the GABA inhibitory

function: pre-synaptic GABA-R

2.

Ca2+

Neurotransmitter

3. Inhibitory of Na+ and Ca2+ channel

Adverse effects: sedation, depression, drug interaction.

Ethosuximide
The only indication: absence epilepsy
Mechanisms:
1. reducing the T-type Ca2+ current
2. inhibiting GABA aminotransferase(
) Na+-K+-ATP

Adverse Reactions
1. Gastric distress
2. CNS distress
3. Blood system agranulocytosis,

thrombocytopenia, aplastic anemia

Sodium Valproate
Broadspectrum antiepileptic agent
Mechanisms:
1.potentiate GABA function
inhibit GABA-T
increase the activity of GAD
2.inhibit Na+ channel
3.inhibit L-Ca2+ channel
inhibit T-Ca2+ channel

uses
Effective for all types of epilepsy,
more effective than ethosuxide for absence
less effective for grad mal and partial mal
grad mal combine with absence seizures

first choice

Adverse Reactions
1. Hepatic intoxication
2. CNS and blood system
thrombocytopenia
3. Teratogenesis

Benzodiazepines
1. Diazepam :first choice for status
epilepticus by iv
2. Nitrazepam : myoclonic
seizure, atypical absence seizure and
infantile spasm
3. Clonazepam: absence seizure, atonic
and akinetic seizures

Therapy for Epilepsy

General Principles and Drug
Choice for The Therapy of
Epilepsy
1. Accurate evaluation
2. The drug choice for initial

treatment of seizures

Therapy for Epilepsy

(1) grad mal and simple partial seizures:
phenytoin , Carbamazepine
Phenobarbital, primidone and valproic
acid as alternative

Therapy for Epilepsy

(2)Absence seizure:
ethosuxide
valproic acid, clonazepam
(3)Complex partial seizures:
Carbamazepine
Phenytoin primidone, valproic acid

Therapy for Epilepsy

(4)Status epilepticus
Diazepam iv, or clonazepam,
phenytoin and phenobarbital
(5)Tonic seizure: valproic acid
(6)Myoclonic seizure:
Glucocorticoids, clonazepam

Therapy for Epilepsy

3. Increase dose gradually
4. Withdrawn or discontinue ---gradually (half year)
5. Change drug or add a second drug
and/or combination
6. Monitoring the serum drug level
7. Adverse reactions
teratogenesis

Summary for this chapter

1. choice of drugs for different patterns of
epilepsies
2. effects and uses of phenytoin