Chapter 16

Antiepileptic Drugs

Department of PharmacologyZhang 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.

Normal neurons

Abnormal high-frequency discharge

Epileptic focal

Pathogenesis

sudden, excessive and abnormal high-frequency discharge of neurons diffuses to local or whole brain in a short time → over-excitement →brain dysfunction

EpilepsyEtiology incidence: 50/100,000

Primary epilepsy: 30%

inherited abnormality

Secondary epilepsy: 70%

such as brain tumors, brain infarction,head injury,

hypoglycemia, meningeal infection

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

Partial seizures

(1) Simple partial

Do not lose consciousness and often exhib

it 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 as

sociated with purposeless movents

(1) Generalized tonic-clonic seizures Loss of consciousness and sustained contracti

ons(tonic) of muscles followed by periods of c

ontraction and relaxation (clonic), typically la

sting 1-2m

Continuous episodes with sustained loss of

consciousness is called status epilepticus .

Generalized seizures

(2) Absence seizure

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.

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

Generalized seizures

Mechanism Action of Antiepileptic drugs

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 post- synaptic action of GABA, by inhibiting GABA-transaminase, or by drugs with direct GABA-agonist properties.

Antiepileptic drugs are thought to act by two main mechanisms:

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 DrugsThe 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.

PHARMACOKINETICSBecause 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 uses1.Epilepsy:

all epilepsies but absence seizure

first choice for: generalized tonic-clonic seizures simple partial seizures complex partial seizures

Clinical uses2. 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 Reactions3. CNS symptoms 20g/ml ： drowsiness, dizziness, ataxia,

﹥40g/ml: psychotic, ﹥50g/ml: coma4. 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

Broad–spectrum 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 （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

Luminal

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 （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

1. Gastric distress

2. CNS distress

3. Blood system ： agranulocytosis,

thrombocytopenia, aplastic anemia

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 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 （硝西泮） : 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 evaluation2. The drug choice for initial

treatment of seizures

Therapy for Epilepsy

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

phenytoin phenytoin ,, CarbamazepineCarbamazepine

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

Summary for this chapter

1. choice of drugs for different patterns of

epilepsies

2. effects and uses of phenytoin