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Antiepileptic Drugs
北京协和医学院基础医学院药理学系
叶菜英
Definitions in epilepsy:



Epilepsy comprises recurrent episodes of
abnormal cerebral neuronal discharge.
The resulting seizures are usually
clinically obvious and vary in pattern
according to which parts of the brain
are affected.
Epilepsy
can
be
caused
by
many
neurological
diseases,
including
infection,
trauma,
infarction
and
neoplasia.
Heredity
has
an
important
role
(especially
in
the
idiopathic
Normal brain cell
Abnormal highfrequency
discharge
Focus
Inhibit discharge
Drug action
Stabilize membrane, inhibit the
diffusion of discharge (primary)
Common seizure types of
Epilepsy:


Generalised seizures.
 Absence (petit mal).
 Tonic/clonic (grand mal).
Partial seizures.
 Simple partial seizures.
 Complex
partial
seizures
(temporal lobe epilepsy).
Generalised seizures:


Absence (petit mal): These seizures have
abrupt onset and cessation, with impaired
consciousness, but with normal posture
often retained. The EEG shows a typical
‘spike and wave’ pattern.
Tonic/clonic (grand mal): Consciousness is
impaired and the patient usually falls to
the floor. A phase of muscle contraction
(‘tonic’) is followed by irregular muscle
clonus and then by sleep. Injury may occur.
Partial seizures:


Simple partial seizures: features
depend on the part of the brain
affected, result from discharge in
the precentral gyrus. Consciousness
is unimpaired.
Complex partial seizures (temporal
lobe epilepsy): Consciousness is
impaired
with
complex,
often
repetitive, action.
The EEG in
seizure of Epilepsy
Spike wave
3 Hz Paradoxical discharge
Epilepsy
Pathogenesis:
 The neuron in brain lesion depolarizes
together suddenly, and then product
high-frequency ,out-break discharge.
The
discharge
can
diffuse
to
surrounding normal tissue →extensive
excitation
→the
brain
function
transient aberration.
Normal brain cell
Abnormal highfrequency
discharge
Focus
Inhibit discharge
Drug action
Stabilize membrane, inhibit the
diffusion of discharge (primary)
Epilepsy
Therapeutic principle:
 Change the permeability of Na +,
Ca2+and K+ in nerve cell membrane,
degrade excitement stage, extend
refractory phase.
 Directly or indirectly increase CNS
levels of GABA.
The primary animal models used
in
anti-epileptic
drugs
research
 Maximal electroshock seizure (MES ) model：
screen the drugs which used in grand mal.
 Pentetrazole (PTZ) induced convulsion
model:
screen the drugs which used in petit mal.
 Kindling seizure model:
screen the drugs which used in grand mal.
 Spontaneously epileptic rat (SER) model：
used in anti-epileptic drugs research.
Classification of Antiepileptic
Drugs





Hydantoins：Sodium Phenytoin
Barbiturates
：
Phenobarbital,
Primidone
Succinimide：Ethosuximide
Benzodiazepine:
Diazepam,
Nitrazepam
Others: Sodium Valproate
Sodium Phenytoin (苯妥英钠)
【Physiological disposition】
 Sodium Phenytoin is absorbed slowly
after oral administration.→After
6-10 days, its plasma concentration
can achieve effect levels. This
drug has variable interpatient
plasma concentration.
Sodium Phenytoin
【 Mechanism of action 】
①It can block sodium channels (voltage-,
frequency-, and time dependent fashion)
and inhibit the generation of action
potentials.
②It can increase the function of
inhibitory transmitter GABA, inhibit
nerve terminal to uptake GABA and induce
the increasing of GABA receptor, thereby
enhance GABA-mediated postsynaptic
Sodium Phenytoin
【Pharmacologic properties and clinical
application】



Anti-epileptic：It can be used for
partial seizures and tonic/clonic
seizures, but not for other generalised
seizure types.
Peripheral neuralgia：cranial nerve,
ischiadic nerve and cranial nerve.
Arrhythmia : membrane-stabilizing action.
Sodium Phenytoin
【Adverse effects】




Digestive system
Gingival hyperplasia
Nervous system
Hematological system



Skeletal system
Allergic response
Others
Sodium Phenytoin
【Adverse effects】


Digestive system: anorexia, nausea,
vomiting and abdominal pain (recommend to
take it after meal). It may cause phlebitis
after IV.
Gingival hyperplasia: It common occurs in
children and teenagers after long term use,
the incidence rate is about 20%. Generally,
this effect can resolve after drug withdraw
3 to 6 months.
Sodium Phenytoin
【Adverse effects】


Nervous system: nystagmus, diplopia,
vertigo, ataxia (usually only at very
high concentration). Severe patient
occurs language disorder, mental
confusion and cataphora.
Hematological system: Because it can
inhibit the absorption of folinic acid
and accelerate its metabolism. This drug
also can inhibit folic acid reductase.
So it may cause megaloblastic anemia
after long-term
use (recommend to
Sodium Phenytoin
【Adverse effects】



Skeletal system: It can enhance vitamin D
metabolism, so Phenytoin may increase the
risk of hypocalcemia, rickets and
osteomalacia after long-term
treatment(pretreat with vitamin D if
necessary).
Allergic response: rash, thrombocytopenia
, agranulocytosis and aplastic anemia.
Others: rarely appear male barymastia,
Phenobarbital (苯巴比妥)
【 Mechanism of action 】


Phenobarbital can inhibit the paradoxical
discharge of epilepsy focus selectively,
enhance stimulation of surrounding tissues
and block discharge diffuse to normal
tissues.
Phenobarbital facilitate GABA-mediated
inhibition of neuronal activity.
Phenobarbital
【Pharmacologic properties 】



Phenobarbital can be used for all
types of epilepsy. The effects by
turns are: grand mal and status
epileptics＞local psychomotor
seizure＞petit mal.
Take effect rapidly（1～2 hr), the
first choice of grand mal.
Prevent convulsive and eliminate
precursory symptom.
Phenobarbital
【Adverse effects】
 Somnolence、depression.
 Tolerance develops after long-term
treatment.
Primidone(去氧苯比妥)
Primidone(扑米酮)
【Pharmacologic properties 】
 Absorption after oral administration
is rapid, and the plasma peak
concentration is approximately 3
hours at therapeutic doses. It can
be used for all types of epilepsy
except petit mal. It’s better to use
this drug with sodium phenytoin.
With regard to grand mal, the effect
of
primidone
is
better
than
phenobarbital,this drug is useless
to petit mal.
Primidone (Primidone)
【Adverse effects】
 Common: somnolence, vertigo, nausea
and vomiting.
 Rare: megaloblastic anemia,
leucopenia and thrombocytopenia.
Ethosuximide (乙琥胺 )
Petit mal (first choice), useless to
other types of seizure.
【 Common adverse effect 】
 Gastrointestinal tract: anorexia, nausea,
vomiting.
 CNS: headache, dizziness and somnolence.
 Rarely appear agranulemia and aplastic
anemia.

Diazepem(安定) &
Nitrazepem(硝基安定)
Diazepem :
 Diazepem
is
epilepticus.
indicated
for
status
Nitrazepem :
 It’s
highly effective in controlling
petit mal and myoclonus epilepsy.
 Sudden
withdrawal of nitrazepem is
likely to aggravate seizure and induced
symptom.
Sodium Valproate (丙戊酸钠 )
【Pharmacologic properties 】
 Enhance
the enzymatic activity of glutamate
decarboxylase.→GABA↑
 Inhibit
GABA
reuptake
and
synapse
inactivation→synapse frontal membrane GABA↑→
enhance GABA postsynaptic inhibition
 Broad
spectrum antiepileptic drug, use to all
types of epilepsy.
 CNS:
somnolence, disequilibrium, acratia and
tremor.
 Hepatic lesion (20% patients).
 Gastrointestinal
tract: nausea, vomiting and
anorexia.
Carbamzepine (卡马西平)
【Pharmacologic properties 】
 Carbamazepine can block sodium channel, inhibit
paradoxical discharge and discharge diffusion. It
may relate to the postsynaptic inhibition of
GABA.
 Broad spectrum antiepileptic drug, use to
all types of epilepsy.
 Trigeminal neuralgia (therapeutic effect is good).
 Antidiuresis－diabetes insipidus.
Carbamzepine
【Adverse effects】
 CNS: somnolence, disequilibrium
 Gastrointestinal tract: nausea, vomiting
and anorexia.
 Rash，leucopenia ，thrombocytopenia，
aplastic anemia and hepatic lesion.
Principle of Medication

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
1～2 times/year，no drugs are needed
Grand pit (first choice): Sodium
phenytoin or phenobarbital, carbamzepine,
Primidone.
Petit mal (first choice): Ethosuximide,
clonazepam and sodium valproate.
Status epilepticus:Diazepam or sodium
phenytoin (IV), phenobarbital, diazepam,
clonazepam.
Psychomotor: Sodium phenytoin or combine
with desoxybarbital or carbamazepine.
Principle of Medication (I)



The dose can be gradually increased from
a low starting dose until reach the best
effect.
In the initial stage, the patients
should only be treated with a single
antiepileptic drug, if the drug is
useless, then it can be changed. When
drug changing is necessary, it should be
gradually withdrawn after the effect of
new drug occurs.
After the symptom is fully controlled,
the patients should continuing be
Principle of Medication (II)



Enhance therapeutic effect: dosing
individually, monitoring drug
plasma concentration, examining
regularly.
Evaluating efficacy and safety.
Adjusting drug dosage: the
therapeutic index of antiepileptic
drug is low→easy to be poisoning
Therapeutic dose is get close to
toxic dose.
Anticonvulsant Drugs


Convulsions are involuntary skeletal
muscular contractions. Convulsions can
arise from pathological processes within
or outside the brain, toxins, drug
overdose, or withdrawal from drug
dependence.
Commonly used anticonvulsant drugs are
sedative and hypnotic drugs. Magnesium
Sulfate is also used on this disease.
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