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

EpilepsyEtiology incidence:0.5%~1%

Primary epilepsy Secondary epilepsy

Classifications1. 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) Grand mal epilepsy

Loss of consciousness and myotonia-

myoclonus for a few minutes.

Continuous episodes with sustained loss

of consciousness is called epilepticism.

(2) Absence

Involve a brief, sudden and self-

limiting loss of consciousness.The

patient stare and exhibits rapid eye-

blinking, which lasts for 3 to 5

seconds without any motor disorder.

(3) Myoclonic

Consist of short episode of local

muscle contractions that may reoccu

r 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 Models1. Electric stimulate(maximal electroshock seizu

re, 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) Carba

mazepin(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

Mechanisms2.Modification of ion channel conductance

Inhibitory of Na+ and/or Ca2+ channel

N-typeCa2+ channel 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

Mechanisms2.Promote the stablization of the membrane

a.block voltage-sensitive (use-dependent effect) Na+ channel

b.block voltage-sensitive Ca2+ channel

c. inhibit K+ out

Mechanisms

3.inhibit the activity of camudulin kin

ase

4. Potentiate GABA inhibiting functio

n

Clinical uses1.Epilepsy:

generalized tonic-clonic seizures

simple partial seizures

complex partial seizures

first choice

except absence seizure

Pay attention to children

Clinical uses2. Central pain syndrome: neuralgias

trigeminal neuralgia et al

3. Arrhythmia （心律失常）

Pharmacokinetics1. 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

Pharmacokinetics3. Metabolism :

by hepatomicroenzymes about 60%-70%,

5% unchanged

相互作用4. Elimination : dose-dependent

plasma concentration

less than 10g/ml, FOK, t1/2 6-24hrs

more than 10 g/ml, OOK, t1/2 20-60hrs

Adverse Reactions

Cmax(E) 10g/ml; CTox 20g/ml

1. Gastrointestinal reaction

2. Gingival hyperplasia by increasing the

the induction of collagenase

Adverse Reactions3. CNS symptoms 20g/ml ： drowsiness, dizziness, ataxia,

﹥40g/ml: psychotic, ﹥50g/ml: coma4. Blood system: folic acid dysefficacy

Adverse Reactions4. 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 Reactions6. 心血管反应 arrhythmia

hypotension

Adverse Reactions7.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 Interactions1. 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

Pharmacokinetics1. 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 agentMechanisms:

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 Reactions1. 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 DrugsFlunarizine( 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

2. 5-HT

3. Safe

Lamotrigine( 拉莫三嗪）1. Used as an add-on therapy or monother

apy 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 EpilepsyGeneral Principles and Drug Choice fo

r The Therapy of Epilepsy1. Accurate evaluation2. The drug choice for initial treatme

nt of seizures

Therapy for Epilepsy

(1) grad mal and simple partial seizures:(1) grad mal and simple partial seizures:

Carbamazepine, phenytoinCarbamazepine, phenytoin

Phenobarbital, primidone and valproic Phenobarbital, primidone and valproic acid as alternativeacid 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 Epilepsy3. 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 Sulfate1. 给药途径不同，药理作用不同2. Relaxant of skeletal muscle and CNS dep

ression by iv or im3. Mechanism : calcium antagonism4. Used in convulsion caused by eclampsia ，

高血压危象5. respiratory inhibition and hypotension w

hen overdose.

Thanks!