Welcome to Pharmacology
Chapter 18
Antiepileptic & Anticonvulsive Drugs
Section 1
Antiepileptic Drugs
Epilepsy
Epilepsy is a heterogeneous symptom
complex, a chronic disorder characterized
by sudden, transit and recurrent seizures
which are episodes of brain dysfunction
resulting from abnormal discharge of focal
cerebral neuron and diffusion to normal
neuronal tissues.
Somatic, sensory, automatic and psychotic
Epilepsy
Etiology incidence:0.5%~1%
 Primary epilepsy
 Secondary epilepsy
Classifications
Partial seizures
(1)Simple partial seizures
单纯局限性发作
(2)Complex partial seizures
复合性局限性发作
2. Generalized seizures
(1)Absence seizures(petit mal) 失神发作（小发作）
(2)Myoclonic seizures
肌阵挛性发作
(3)Generalized tonic-clonic seizures (grad mal)
强直-阵挛性发作（大发作）
(4)Status epilepticus
癫痫持续状态
1.
(1) Grand mal epilepsy
Loss of consciousness and myotoniamyoclonus for a few minutes.
Continuous episodes with sustained loss
of consciousness is called epilepticism.
(2) Absence
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.
(3) Myoclonic
Consist of short episode of local
muscle contractions that may
reoccur for several minutes.
Partial
Simple partial
Do not lose conciousness and often
exhibit abnomal activity of a single
limb or muscle group.
Partial
Complex partial
Exhibit motor dysfuntion and loss
of conciousness.
Experimental Models
1. Electric stimulate(maximal electroshock
seizure, MES): grad mal
2. Pentylenetetrazol(PTZ): absence seizure
3. Spontaneously epileptic rat(SER)
4. Kindling response: Complex partial seizures
5. Glutamate
History of Antiepileptic Drugs
1857 potassium bromide(溴化钾)
1912 phenobarbital
1912~1937 35 analogs of phenobarbital
1938 phenytoin
1938~1960
valproate(64), Antiepilepsrin(75)
Carbamazepin(80), gabapentin(90)
The Classifications
Hydantoins
Anticonvulsive barbiturates
Benzodiazepines
Succinimides
New drugs
Electrophysiology of
antiepilepsy drugs
a. inhibit discharge in focus
b. inhibit diffusion in normal neuron
Mechanisms of action of
antiepilepsy drugs
1. To affect inhibitory system involving
GABAergic function
a. Enhancement of GABAergic
transmission: reuptake or metabolism
b. Direct action on the GABA-R
chloride channel complex
Mechanisms
2.Modification of ion channel conductance
Inhibitory of Na+ and/or Ca2+ channel
Ca2+ channel
N-type
L-type
T-type absence
seizures
Mechanisms
c. Diminution of
glutaminergic function
AMPA-R blockade
NMDA-R blockade
Phenytoin Sodium
（苯妥英钠, Dilantin, 大仑丁）
Mechanisms
1.inhibit diffusion in normal neuron
by inhibiting post tetanic potentiation(PTP)
Post tetanic potentiation (PTP) :Increase in amplitude of
EPSP after neuron has received tetanic stimulus, in
neurons refers to any high frequency burst of stimulation
Mechanisms
2.Promote the stablization of the membrane
a.block voltage-sensitive (usedependent effect) Na+ channel
b.block voltage-sensitive Ca2+ channel
c. inhibit K+ out
Mechanisms
3.inhibit the activity of camudulin
kinase
4. Potentiate GABA inhibiting
function
Clinical uses
1.Epilepsy:
generalized tonic-clonic seizures
simple partial seizures
complex partial seizures
first choice
except absence seizure
Pay attention to children
Clinical uses
2. Central pain syndrome: neuralgias
trigeminal neuralgia et al
3. Arrhythmia（心律失常）
Pharmacokinetics
1. Absorption
pKa8.3, slow and unpredictable
after oral administration
Css 5-7d
stimulation by oral and im(pH=10.4)
2. Distribution
PPBR about 90%,Vd 0.6-0.7L/kg
Pharmacokinetics
3. Metabolism :
by hepatomicroenzymes about 60%-70%,
5% unchanged
相互作用
4. Elimination : dose-dependent
plasma concentration
less than 10g/ml, FOK, t1/2 6-24hrs
more than 10 g/ml, OOK, t1/2 20-60hrs
Adverse Reactions
Cmax(E) 10g/ml; CTox 20g/ml
1. Gastrointestinal reaction
2. Gingival hyperplasia by increasing the
the induction of collagenase
Adverse Reactions
3. CNS symptoms
 20g/ml：drowsiness, dizziness, ataxia,
﹥40g/ml: psychotic,
﹥50g/ml: coma
4. Blood system: folic acid dysefficacy
Adverse Reactions
4. Allergy
leukopenia（白细胞减少）,
agranulocytosis（粒细胞缺乏）,
thrombocytopenia（血小板减少）,
aplastic anemia（再生障碍性贫血）
5. Bone system
hypocalcemia,osteomalacia, rachitis
reason：vitamin D
Adverse Reactions
6.心血管反应
arrhythmia
hypotension
Adverse Reactions
7.Others:
a.Teratogenesis
fetal hydantoin syndrome
(胎儿妥因综合征）
b.peripheral neuritis
芬兰 1980～1998年，研究人员追踪了
一家产科诊所中970位怀孕的癫痫妇女，
其中有740位在怀孕初期（前3个月）服
用抗癫痫药物，另外239位则无。结果在
这些服用抗癫痫药物的怀孕妇女中，共
产下28个严重畸形儿（3.8%），未服用
抗癫痫药物组仅产下2个严重畸形儿
（0.8%；P=0.02）
Drug Interactions
1. Hepatomicrosomal enzyme inducer
2. Hepatomicrosomal enzyme inhibiter
3. PPBR
Carbamazepine（卡马西平）
Broad–spectrum antiepileptic agent
Mechanisms
•
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（躁狂症）and depression
4. 尿崩症
Pharmacokinetics
1.
slow and unpredictable after
oral administration
2. PPBR 80%
3. Active metabolite： cyclooxide
4. t1/2 35 hrs at beginning, then may shorten
by 50% due to enzyme induction
Adverse Reactions
1. Gastrointestinal reaction
2. CNS reactions: drowsness, vertigo,
nausea, vomit, ataxia
3. Blood system: leukopenia（白细胞减少）,
agranulocytosis（粒细胞缺乏）,
thrombocytopenia（血小板减少）,
aplastic anemia（再生障碍性贫血）
4. Hepatic intoxication
Phenobarbital
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
Primidone（扑米酮）
Effective for all types of epilepsies
Except absence mal, more effective
than phenobarbital in complex partial
seizures
Mechanism similar to phenobarbital
and  Na+in, K+out
Primidone（扑米酮）
Primidone is metabolized to
phenobarbital and
phenylethylmalonamides(PEMA,
苯乙基丙二酰胺) as active metabolites
Ethosuximide（乙琥胺）
The only indication: absence epilepsy
Mechanisms:
1. reducing the T-type Ca2+ current
2. inhibiting GABA aminotransferase(转
氨酶)，Na+-K+-ATP
Adverse Reactions(safe)
1. Gastric distress
2. CNS distress
3. Blood system ： agranulocytosis,
thrombocytopenia, aplastic anemia
4. SLE
Sodium Valproate（丙戊酸钠）
Broad–spectrum 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,
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（硝西泮）: myoclonic
seizure, atypical absence seizure and
infantile spasm
3. Clonazepam: absence seizure, atonic
and akinetic seizures
Other New Drugs
Flunarizine(氟桂利嗪)
1. Nonselective calcium channel-blocking
drugs
2. Effective for all types of epilepsy,
more effective for grad mal and partial mal
3. inhibit Na+ channel
inhibit L-Ca2+ channel
inhibit T-Ca2+ channel
Antiepilepsirin（抗痫灵）
1. Broad–spectrum antiepileptic agent
5-HT
3. Safe
2.
Lamotrigine(拉莫三嗪）
1. Used as an add-on therapy or
monotherapy in the treatment of
absence or myoclonic seizure
2. The mechanism may related to inhibit
voltage-dependent Na+ channel
Topiramate（托吡酯）
Used in the treatment of partial seizure
with or without generalized tonic-clonic
seizures
• inhibit Na+ channel
• potentiat GABA inhibitory function
• Diminution of glutaminergic function
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:
Carbamazepine, phenytoin
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
Section 2 Anticonvulsants
 Convulsion
 Barbiturates
 Benzodiazepines
 Chloral hydrate
 Magnesium Sulfate
Magnesium Sulfate
1. 给药途径不同，药理作用不同
2. Relaxant of skeletal muscle and CNS
depression by iv or im
3. Mechanism : calcium antagonism
4. Used in convulsion caused by eclampsia，
高血压危象
5. respiratory inhibition and hypotension
when overdose.
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