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