Chapter 5 Agents for the

treatment of epilepsies
(Antiseizure Drugs)
Overview:
 common CNS disease; pathogenesis is unclear.
 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.
 Symptomatic epilepsy: many neurological diseases:
infection, head injury, infarction and neoplasia
(secondary)
 Idiopathic epilepsy: inherited abnormality (in idiopathic
generalized epilepsies) (primary).>75%

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Pathogenesis: Normal brain cell
 the neuron in brain lesion depolarizes
together suddenly, and then produce Abnormal
high-frequency, out-break discharge. The high-frequency
excessive and abnormal discharge can discharge
diffuse to surrounding normal tissue
→extensive excitation →the brain Local lesion
function transient aberration.

clinic manifestation Inhibit discharge

regional or whole brain dysfunction:
Drug
• motor action Stabilize membrane,
• involuntary and mental episodes inhibit the diffusion
of discharge
• loss of consciousness etc. (primary)

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Seizure type Clinical features Effective drugs

Partial Seizures Part of one lobe of one hemisphere. Consciousness preserved

Simple partial consciousness not impaired, motor signs, special sensory carbamazepine,
signs, psychic symptoms; lasting 20-60s phenytoin,
phenobarbital
Complex partial consciousness impaired, purposeless movements(lip carbamazepine,
smacking,head shaking), lasting 30s phenytoin,
phenobarbital

Generalized seizures Begin locally, both hemisphere. Consciousness lost/no memory

absence seizure abrupt onset of unconsciousness, symmetrical clonic motor ethosuximide,

(petit mal) activity, brief stare, eye flicking, no motion, lasting 30s every clonazepam,
episode valproate,
lamotrigine
Myoclonic seizure brief shocklike contraction of muscles(a second)—restricted glucocorticoids,
to part of one extremity or may be generalized valproate,
lamotrigine
Tonic-clonic major convulsions, tonic spasm of all body musculature, carbamazepine,
seizure (grand mal) synchronous clonic jerking phenytoin,
phenobarbital
Status epilepticus recurrent generalized tonic-clonic seizures without recovery of diazepam,
consciousness, dangerous to life phenytoin, 3
phenobarbital
• Mechanisms of epilepsies
 Defective GABAA inhibition: GABAA-Rs coupled to Cl- channels. Changes in
distribution of GABAA-Rs complex subunits have been shown in animal models of
partial-onset epilepsy and Benzodiazepines can hyperpolarize the GABA neuron by
activation of GABAA-Rs →inhibitory effects
 Defective GABAB inhibition: GABAB-Rs coupled to K+ channels. Alterations or
mutations of GABAB-R might affect seizure threshold or a propensity for recurrent
seizures.
 Activation of NMDA-Rs: the activation of NMDA-Rs is increased in animal models
of epilepsy, some patients with inherited epilepsy showing the fast or longer-lasting
activation of NMDA-Rs
 Ion channel mutation: Na+ channels(SCN1B,SCN1A,SCN2A);
K + channnel(KCNQ2,KCNQ3);
nicotinic Ach receptor mutation
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Therapeutic principle:
• Enhancement of GABAergic transmission directly or indirectly.
• Diminution of excitatory(usually glutamtergic) transmission
• Modification of the permeability of Na+, Ca2+and K+
(conductance), degrade excitement stage,; extend refractory
phase.

Inhibit discharge
Drug
action Stabilize membrane,
inhibit the diffusion of
discharge (primary)

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Molecular targets for antiseizure drugs at
excitatory, glutamatergic synapse:
Presynaptic:
1.VG-Na+ channels:
Phenytoin, carbamazepine, lamotrigine,
lacosamide
2.VG-Ca2+ channels: ethosuximide, lamotrigine,
gabapentin, pregabalin
3.K+ channels: retigabine
Synaptic vesicle proteins:
4.SV2A: levetiracetam,
5.CRMP-2: lacosamide
 Postsynaptic:
6.AMPA-Rs: blockers-phenobarbital, topiramate,
lamotrigine
7.NMDA-Rs: blockers-felbamate
EAAT, exicitatory amino acid transpoter
CRMP, collapsin-response mediator protein 6
Molecular targets for antiseizure drugs
at inhibitory GABAergic synapse:

Specific targets
1.GABA transporters(GAT-1):
tagabine
2.GABA-transaminase(GABA-T):
vigabatrin
3.GABAA-Rs
bezodiazepines
4. GABAB-Rs
Nonspecific targets :
4. VG ion channels.
5. SV2A

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 Phenytoin (Dilantin)
【pharmacokinetics】
 high concentrations in brain,
 high plasma albumin binding,
 half-life: 24 hours.

【mechanism of action】
 to block Na+ current in neurons→to stabilize nervous cellular
membranes→ inhibit propagation of AP→ limit the development of
seizures
 to reduce the influx of Ca2+ during depolarization →suppresses
high-frequency repetitive firing→ halts seizure activity.(large dose)

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【Pharmacologic effects and uses】
1.Antiepileptic effect
 highly effective for all partial seizures, generalized tonic-clonic
seizures and status epilepticus.
 not effective for absence seizure.
2. Anti-peripheral neuralgia
trigeminal neuralgia, glossopharyngeal neuralgia and
sciatic neuralgia etc..
3. Antiarrhythmia
(see antiarrhythmic drugs)

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【adverse effects】

1. gastrointestinal irritation
administration with or after meal.
2. depression of CNS: diplopia, nystagmus, ataxia;
sedation, coma (very higher levels)
3. gingival hyperplasia, hirsutism (most pateints)
4. allergic reaction: skin rash, fever, lymphadenopathy
agranulocytosis
6. osteomalacia:↑Vit. D metabolism (liver enzyme inducer)
7. megaloblastic anemia: low folate levels (long-term use)

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 Barbiturates
1.Characteristics
 Potentiate the inhibitory effects of GABA neurons→prolong Cl-
channel opening;
 ↓Na,Ca influx and depress glutamate excitability (Glu release>AMPA).
 Dose required for antiepileptic action is lower than that of causing
pronounced CNS depression for the patient. More selectivity in
anticonvulsant action than in sedative effect.
2.Uses
 simple partial seizure(50% effective rate) .
 not effective for complex partial seizure.
 first-choice drug for epilepticism in infant and children.
 effective for recurrent generalized tonic-clonic seizures, especially
in patients who do not respond to diazepam plus phenytoin.
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Benzodiazepines
Diazepam & Nitrazepam
Diazepam：fast onset of effect, more safe
 highly effective in controlling status epilepticus.

Clonazepam: higher affinity for the GABAA-Rs than diazepam

 used for absence and myoclonic seizure in children;
 also very effective intravenously in controlling status epilepticus
Nitrazepam:
 highly effective in controlling petit mal and myoclonus epilepsy.
 Sudden withdrawal, likely to aggravate seizure and induced
symptom.
Limitations: sedation, tolerance
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Carbamazepine

Pharmacologic properties:
 block Na+ channel, inhibit discharge and discharge diffusion. It may
relate to the postsynaptic inhibition of GABA.
 broad spectrum antiepileptic drug, use to all types of epilepsy:
highly effective for all partial seizure as first-choice drug,
 highly effective for generalized tonic-clonic seizures.
 trigeminal neuralgia (therapeutic effect is better than phenytoin).
 antidiuresis－diabetes insipidus.

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【Adverse effects】dose-related
more adverse effects,
• Diplopia, ataxia
• CNS: drowsiness, dizziness, disequilibrium
• Gastrointestinal tract: nausea,vomiting and anorexia.
• Rash，leucopenia，thrombocytopenia，aplastic
anemia and hepatic lesion.

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 Ethosuximide
1. effective for absence seizure (first choice---pure petit mal drug),
no effective for other seizures.
 reduce ICa,T in thalamic neurons responsible for generating the
rhythmic discharge of an absence attack.
 t1/2=30～50hrs
2. more adverse effects.
 Gastrointestinal tract: pain, anorexia, nausea, vomiting.
 CNS: headache, dizziness and somnolence.
 Rarely appear agranulemia and aplastic anemia.

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 Sodium valproate
Mechanisms:
 Increase the activity of glutamate decarboxylase → GABA↑
 Inhibit GABA reuptake and synapse inactivation→synapse frontal
membrane GABA↑→enhance GABA postsynaptic inhibition
 Stimulate the degradation of glutamic acid
 Block Na+,Ca2+ channels
Uses: broad spectrum, used for all types of epilepsy:
 most effective for myoclonic seizure to reduce incidence and
severity of tonic-clonic seizures,
 effective for absence seizure but second choice because of its
hepatotoxicity.
Side effects:
• CNS: somnolence, disequilibrium, acratia and tremor.
• Hepatic lesion (20% patients).
• Gastrointestinal tract: nausea, vomiting and anorexia. 16
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 Anticonvulsant drugs

1. pathogenesis
2. anticonvulsant drugs
• Barbiturates/ injection, large dose
• Benzodiazepines / injection, large dose
• chloral hydrate/ enema
• magnesium sulfate injection etc.

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 Magnesium sulfate
【pharmacologic effects】
ADMINISTRATION, DOSE
1.oral administration
laxative effect and promoting bile excretion
2. injection administration
(1)anticonvulsant
 inhibiting CNS by Mg2+ (central mechanism)
 relaxing skeletal muscle (peripheral mechanism)
Ca2+ antagonism; inhibiting Ach release
(2)hypotensive: direct vasodilation

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【therapeutic uses】
 constipation, promoting excretion of toxic substances
and parasites in the intestinal tract. P.O/ large dose
 convulsion and hypertensive emergencies
(crisis, encephalopathy): injection
【adverse effects】
 breath inhibition and hypotention, even death.
 calcium chloride or calcium gluconate should be
administered.

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