Chapter 19 Agents used in the

treatment of epilepsies

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.
 can be caused by many neurological diseases, including infection,
head injury, infarction and neoplasia (secondary epilepsy);
 Heredity plays an important role (especially in idiopathic
generalized epilepsies)---inherited abnormality (primary epilepsy).

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

clinic manifestation Inhibit discharge

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

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Seizure type Clinical features Effecttive drugs

Partial Seizures
Simple partial consciousness not impaired, motor signs, special carbamazepine,
sensory 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

absence seizure abrupt onset of unconsciousness, symmetrical clonic ethosuximide,

(petit mal) motor activity, brief stare, eye flicking, no motion, clonazepam,
lasting 30s every episode valproate,
lamotrigine
Myoclonic seizure brief shocklike contraction of muscles(a second)— glucocorticoids,
restricted to part of one extremity or may be valproate,
generalized lamotrigine
Tonic-clonic major convulsions, tonic spasm of all body carbamazepine,
seizure (grand mal) musculature, synchronous clonic jerking phenytoin,
phenobarbital
Status epilepticus recurrent generalized tonic-clonic seizures without diazepam,
recovery of consciousness, dangerous to life phenytoin, 4
phenobarbital
• Mechanisms of epilepsies
 defective GABAA inhibition: GABAA -Rs are 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 are 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:
• Change the permeability of Na+, Ca2+and K+ in
nerve cell membrane; degrade excitement stage;
extend refractory phase.
• increase levels of GABA in CNS directly or
indirectly.
Inhibit discharge
Drug
action Stabilize membrane,
inhibit the diffusion
of discharge
(primary)

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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.

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【pharmacologic effects and uses】
1.antiepileptic effect
 highly effective for all partial seizures, 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
3.cardiovascular collapse
(bradycardia,hypotension, calcium antagonism)
4. gingival hyperplasia
5. hepatitis in the long administration
6. allergic reaction
7. fetal malformation
8. to induce the P-450 system

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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.
 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.use
 simple partial seizure(50% effective rate) .
 not effective for complex partial seizure.
 first-choice drug for epilepticism in infant and children.
 effective for recurrent 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
• Diazepam is highly effective in controlling status epilepticus.
Clonazepam: higher affinity for the GABAA-Rs than diazepam
 is used for absence and myoclonic seizure in children;
 also very effective intravenously in controlling status epilepticus
Nitrazepam:
• It’s highly effective in controlling petit mal and myoclonus
epilepsy.
• Sudden withdrawal of nitrazepam is likely to aggravate seizure
and induced symptom.

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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 tonic-clonic seizures,.
• trigeminal neuralgia (therapeutic effect is better than phenytoin).
• antidiuresis－diabetes insipidus.

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【Adverse effects】
More adverse effects,
• 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 the T-type Ca currents in thalamic neurons
responsible for generating the rhythmic discharge of an
absence attack.
 t1/2=30～50hrs
2. more adverse effects.
 Gastrointestinal tract: 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. 15
 Summary for this chapter

1. choice of drugs for different patterns of

epilepsies
2. effects and uses of phenytoin

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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】
• breathe inhibition and hypotention, even death.
• calcium chloride or calcium gluconate should
be administered.

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 Summary for this chapter

1. drugs used for convulsion

2. effects, mechanism of action, and uses
of magnesium sulfate

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