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Chapter 23
Antiepileptic and
Anticonvulsive Drugs
Epilepsy

Epilepsy is a heterogeneous symptom complex
– a chronic disorder characterized by recurrent
seizures.

Most cases - cause is unknown (idiopathic)

When known - termed secondary epilepsy
– trauma, infection, cerebrovascular disorder,
developmental defect, birth injury
Seizure classification

Partial seizures (Simple and Complex)
– short alterations in consciousness, repetitive
unusual movements, psychologic changes,
confusion

Generalized seizures
– both cerebral hemispheres involved, temporary
loss of consciousness, rhythmic movements of
eyes, head or hands

Absence (petit mal)



Most frequent in children/adolescents
Myoclonic


Sudden loss of consciousness, us. Little muscle
contractions, us. Many times/day
Short episodes of muscle contractions
Tonic- clonic (grand mal)

Loss of consciousness, followed by tonic, then
clonic phases

Most commonly encountered form

status epilepticus
Animal model
maximal electroshock seizure （最大电休克 , MES )模型：
主要用于筛选治疗大发作的抗癫痫药。
pentetrazole（戊四唑, PTZ)诱发惊厥模型：
主要用于筛选治疗小发作的抗癫痫药。
kindling seizure (点燃发作)模型：
用于筛选治疗大发作的抗癫痫药。
spontaneously epileptic rat (自发癫痫大鼠，SER)模型：
用于抗癫痫药作用的研究。
SER spontaneously epileptic rat (tm/tm, zi/zi)
Sodium phenytoin 苯妥英钠
（dilantin,大仑丁）
Actions:
 Inhibit the spread ,not suppress
firing from the foci.
 stabilize neuronal membranes,
• Block voltage-dependent Na+ , Ca2+ channel
• Inhibit camdulin kinase system
• Suppress PTP (post tetanic potentiation 强直后增强)
Absorption and Metabolism
Absorption：Oral absorption is slow and irregular
Distribution：plasma protein binding rate 85~90%
Elimination：metabolized by the hepatic
hydroxylation system
an inducer of the hepatic hydroxylation system
blood concentration<10mg/L first-order kinetics
≥10mg/L zero-order kinetics
Therapeutic uses

Antiepileptic: best choice for tonic-clonic
and partial seizures (simple and complex),
not effective for absence seizures

Antiarrhythmic

Relieving peripheral neuralgia
Adverse effects

CNS (dose-related): nystagmus, ataxia

Local irritation: gastrointestinal problems (nausea,
vomiting), gingival hyperplasia

Hematopoietic system: megaloblastic anemia

Anaphylaxis: skin rash, thrombocytopenia

Skeletal system: osteomalacia (adults)

Others: teratogenic effects
phenobarbital 苯巴比妥
（ luminal ,鲁米那）
O
N
O
N
H
Actions


CH2CH3
O
Phenobarbital
Inhibit the spread and suppress firing from the
foci.
The antiseizure effect can be occurred at lower
dosage .
Mechanism


Enhancement of GABA-mediated inhibition
(increase the open time of Cl- channel )
Reduction of glutamate-mediated excitation
Clinical use

Phenobarbital is useful in the treatment of
partial seizures and generalized tonic-clonic
seizures, although the drug is often tried for
virtually every seizure type.
Adverse effects


drowsiness, depressed, ataxia
a potent inducer of the hepatic hydroxylation
system
H5C2
ethosuximide 乙琥胺
C
H3C
First choice in absence seizures
C
O
Mechanism
selectively blocking T-type Ca2+ channels
Adverse effects
gastrointestinal tract irritation
CNS: drowsiness, lethargy, dizziness
C
C
N
H
O
benzodiazepines 苯二氮卓类

diazepam 地西泮
best choice in status epilepticus

nitrazepam 硝西泮
mainly used in absence seizure

clonazepam 氯硝西泮
anti-epileptic spectrum is broad（tolerance
develops）
sodium valproate 丙戊酸钠
broad-spectrum antiepileptic
Mechanism:


Inhibit the spread ,not suppress firing from the
foci.
enhance GABA action; block Na+ and T-type Ca2+
channels
Adverse effects:
gastrointestinal tract irritation; CNS: drowsiness,
lethargy, dizziness; hepatic lesion
Carbamazepine 卡马西平
N
Mechanism
CONH2

Blocks sodium channels and inhibits highfrequency repetitive firing in neurons.

The postsynaptic action of GABA can be
potentiated by carbamazepine.
Clinical use

antiepileptic
partial seizures; tonic-clonic seizures

relieving trigeminal neuralgia

Antimanic

Antiarrhythmic
Adverse effects:
vertigo, nausea, aplastic anemia
Mechanism of Action

Limit the influx of Na+ in neurons, decreasing
their excitability

Potentiate the inhibitory effects of GABAmediated neurons

Block T-type Ca2+ channel
Antiepileptic medication choices
Tonic-clonic (grand mal)： sodium phenytoin,
carbamazepine or phenobarbital
Complex partial ：as above
Absence seizure (petit mal)：ethosuximide,
sodium valproate or clonazepam
Simple partial ： carbamazepine, sodium
phenytoin or phenobarbital
Status epilepticus ：diazepam, phenobarbital
Attention

Most patients take medication for life.

Start with single drug, if fails, two or three, etc.

When removing from one drug and starting
another, taper off first drug as you add the
second.

Most have side effects, serum drug
concentrations are carefully monitored.
Anticonvulsant
Magnesium sulfate 硫酸镁
Mechanism
– decreases release of Ach at neuromuscular
junction (antagonize action of Ca2+)
– depresses central nervous system ( >2-3.5
mg/100ml)
– direct peripheral vasodilation
Indications
(Different routes of administration can cause different actions)
PO. --- diarrhoea action (poorly absorbed)
im or iv --- anticonvulsive action
skeletal muscle relaxation
lower blood pressure
Therapeutic use: hypertensive crise during pregnancy
（eclampsia 子痫）, tetanic 破伤风 convulsion
Adverse effect: respiratory depression, BP decrease,
cardiac arrest
rescue: calcium chloride or calcium gluconate