2. â Some definitions
1- Seizures â«ÙÙۚۧŰȘâŹ
âȘ A seizure means temporary change in brain functions (motor functions, consciousness, sensation, vision,
smell, etc) due to generation of high-frequency impulses by a group of neurons in the brain (epileptic
focus).
âȘ Seizures take various forms _ depending on the site of the epileptic focus
âȘ Symptoms of seizures range from short periods of inattention to a full- convulsive attack lasting for
several minutes.
âȘ A single seizure does not mean epilepsy
2- Epilepsy
âȘ Epilepsy is a neurological disorder characterized by recurrent seizures
3- Convulsions
âȘ Convulsions are rapid, involuntary contraction of the skeletal muscles
âȘ Convulsions are common in epileptic seizures but can also result from infections, fever, and brain trauma.
âȘ Convulsions and seizures are not the same things.
NOTE
âȘ Epilepsy may or may not be accompanied by convulsions
âȘ Abnormal electrical activity during and following a seizure can be detected by electroencephalography
(EEG) 2
3. â The inhibitory and excitatory transmitters of the brain
1- Inhibitory transmitters
âȘ GABA _ it is the main inhibitory transmitter in the brain
âȘ It acts on GABA receptors
2- Excitatory transmitters
âȘ Glutamate and aspartate _ they are the main excitatory transmitters in the brain
âȘ They act on NMDA and AMPA receptors
NOTEs
âȘ In the brain, there is a balance between the levels of the inhibitory and excitatory transmitters
âȘ NMDA receptors = N-Methyl-D-aspartate receptors
âȘ AMPA receptors = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
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4. â Causes of epilepsy
âȘ Often, there is NO known cause.
âȘ Some probable causes of epileptic seizures include :
1- Genetic factors
2- Acquired factors
âȘ Brain damage, such as head trauma or stroke, infection or brain tumor growth,
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5. â Types of seizures
âȘ There are two major classes of seizures: focal onset and generalized onset.
1- Focal
âȘ The onset of focal seizures starts in a localized brain area in which the epileptic impulses remains
localized within one hemisphere.
âȘ Focal epilepsy is of 2 types:
o Focal epilepsy with preserved awareness
o Focal epilepsy with impaired awareness
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7. â Role of brain neurotransmitters in induction of epilepsy
â Epilepsy occurs due to :
1- Decreased level of the inhibitory transmitters (GABA) that give a chance
to the excitatory transmitters to predominate
2- Increased level of the excitatory transmitters (Glutamate & Aspartate)
o Increased level of Glutamate & Aspartate activate NMDA and
AMPA receptors and cause sodium channels to open.
o The passage of Na+ through the sodium channels of neurons
causes depolarization which lead to neuronal firing (generation of
electrical waves)
â Absence seizures
âȘ It is a type of epilepsy that has a completely different mechanism
âȘ This type is caused by the opening of certain type of calcium channels
(T-type Ca2+ channels) in thalamo-cortical neurons at the junctions
between the central area and the cortex of the brain
âȘ Opening these channels separates the connection between the central
area and the cortex of the brain, and the child appears as if he is in a
coma
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8. â MOA of the antiepileptic drugs
âȘ Antiepileptic drugs aim to suppress the abnormal neuronal impulses
âȘ The major antiepileptic drugs are thought to act by 4 main mechanisms
1. Enhancement of the inhibitory transmitter (GABA) action _ this may be achieved by
o enhancing the action of GABA
o inhibiting GABA transaminase enzyme that is responsible for inactivating GABA
2. Inhibition of the excitatory transmitter (Glutamate & Aspartate) action
o Decreasing the release of Glutamate & Aspartate
o Decreasing their actions (by blocking NMDA and AMPA receptors)
3. Blocking sodium channels in the brain _ So reduce the generation of electrical waves
4- Blocking T-type Ca2+ channels (important in controlling absence seizures).
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9. â Antiepileptic drugs
[1] First generation (Classic) drugs
âȘ Phenytoin
âȘ Carbamazepine
âȘ Valproic acid
âȘ Ethosuximide
âȘ Phenobarbital
âȘ Benzodiazepine
[2] Second generation (Newer) drugs
âȘ Vigabatrin
âȘ Lamotrigine
âȘ Topiramate
âȘ Levetiracetam
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NOTES
âȘ First generation drugs work by one of these mechanisms:
1. Enhancement of the inhibitory transmitter (GABA) action
2. Inhibition of sodium channel function _ reducing electrical excitability of cell membranes
3. Inhibition T-type calcium channels (important in controlling absence seizures).
âȘ Second generation drugs work by inhibition of the excitatory transmitter (Glutamate & Aspartate)
action
âȘ Side effects of first-generation drugs are more than those of the second generation
10. [1] First generation antiepileptic drugs (Classic drugs)
â Phenytoin
â Mechanism of action
âȘ It blocks Na+ channels in brain and heart So reduce the generation of electrical waves
â Therapeutic use
âȘ Tonic-clonic seizures only (grand mal epilepsy)
âȘ Cardiac arrythmia
â Adverse effects
âȘ CNS: Nystagmus, diplopia, ataxia
âȘ Liver: microsomal enzyme induction _It activates the liver microsomal enzymes So lowers the plasma
concentration of several other drugs (risk of drug interactions).
âȘ Blood: Megaloblastic anemia, due to increased rate of folic acid metabolism. This can be corrected by
giving folic acid
âȘ Teratogenic_ in the form of cranio-facial anomalies
â Other Adverse effects
âȘ Hirsutism
âȘ Gum hypertrophy
âȘ Oesteomalacia_ due to increased rate of vit D metabolism
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11. â Carbamazepine (Tegratol)
âȘ It is the most widely used antiepileptic drug
â Mechanism of action
âȘ It blocks Na+ channels in brain So reduce the generation of electrical waves
â Therapeutic use
âȘ First line drug in all types of focal seizures
âȘ Second line drug in Tonic-clonic seizures
âȘ Trigeminal neuralgia
â Adverse effects
âȘ CNS: Nystagmus, diplopia, ataxia
âȘ Liver: microsomal enzyme induction _It activates the liver microsomal enzymes So lowers the plasma
concentration of several other drugs (risk of drug interactions).
âȘ Blood: Megaloblastic anemia, due to increased rate of folic acid metabolism. This can be corrected by
giving folic acid
âȘ Teratogenic_ in the form of cranio-facial anomalies
â Other Adverse effects
âȘ Increase ADH secretion _ So lead to hyponatremia and edema
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12. â Valproic acid (Depakin)
â Mechanism of action
âȘ Valproate works by several mechanisms
1- It inhibits GABA transaminase enzyme (the enzyme that inactivates GABA) So increase GABA content of
the brain. GABA reduces the neuronal firing
2- It blocks Na+ channels in brain and heart So reduce the generation of electrical waves
3- It blocks Ca2+ channels, which might explain why it is effective against absence seizures.
â Therapeutic use
âȘ All types of seizures (focal & generalized), including absence seizures
â Adverse effects
âȘ CNS: Nystagmus, diplopia, ataxia
âȘ Liver: microsomal enzyme inhibition _It inhibits the liver microsomal enzymes So increase the plasma
concentration of several other drugs (risk of drug interactions).
âȘ Blood: neutropenia
âȘ Teratogenic_ in the form of cranio-facial anomalies
â Other Adverse effects
âȘ Alopecia (hair loss)
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13. â Ethosuximide
â Mechanism of action
âȘ The mechanism of action of ethosuximide appears to differ
from that of other antiepileptic drugs.
âȘ It blocks T-type Ca2+ channels in thalamo-cortical neurons So
keep the connection between the central area and the cortex of
the brain
â Therapeutic use
âȘ Ethosuximide is used clinically for its selective effect on
absence seizures _ First line drug
â Adverse effects
âȘ GIT upset
âȘ Headache, dizziness
NOTE
âȘ It is the least toxic antiepileptic drug
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14. â Phenobarbital
âȘ It acts mainly as sedative hypnotic
â Mechanism of action
âȘ It acts on GABA receptors, So potentiate GABA effect (GABA agonist)
â Therapeutic use
âȘ It is rarely used now because it causes sedation.
o Tonic-clonic seizures
o Status epilepticus (a life-threatening condition in which epileptic seizures extend for a long time
without a break, 20 min)
â Adverse effects
âȘ CNS: Nystagmus, diplopia, ataxia
âȘ Liver: microsomal enzyme induction _It activates the liver microsomal enzymes So lowers the plasma
concentration of several other drugs (risk of drug interactions).
âȘ Blood: Megaloblastic anemia, due to increased rate of folic acid metabolism. This can be corrected by
giving folic acid
âȘ Teratogenic_ in the form of cranio-facial anomalies
â Other Adverse effects
âȘ The main unwanted effect of phenobarbital is sedation _ This is a serious drawback, because the
drug may have to be used for years.
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15. â Benzodiazepines (Diazepam)
â Mechanism of action
âȘ It acts on GABA receptors, So potentiate GABA effect (GABA agonist)
â Therapeutic use
âȘ First line drug in status epilepticus _ lorazepam, diazepam, or clonazepam are administered
intravenously.
o The advantage in status epilepticus is that they act very rapidly compared with other antiepileptic
drugs.
âȘ First line drug in febrile convulsions in children _ diazepam often being administered rectally
â Adverse effects
âȘ Sedation is the main side effect of these compounds
âȘ Tolerance and physical dependence
âȘ Memory disturbance
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16. [2] Second generation antiepileptic drugs (Newer drugs)
â Vigabatrin
â Mechanism of action
âȘ It inhibits GABA transaminase enzyme (the enzyme that inactivates GABA) So increase GABA content
of the brain. GABA reduces the neuronal firing
â Therapeutic use
âȘ Focal seizures only _ but not as the first choice drug
â Adverse effects
âȘ Visual field defects on long-term therapy (decreased field of vision, not a complete vision loss)
âȘ Sedation
NOTE
âȘ Visual field should be checked every 6 months
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17. â Lamotrigine
â Mechanism of action
1- It blocks Na+ channels in brain and heart So reduce the generation of
electrical waves
2- It inhibits glutamate release
â Therapeutic use
âȘ All types of seizures (focal & generalized) including absence seizures in
children
NOTE
âȘ The mechanism by which Lamotrigine is effective against absence seizures is
not known
â Adverse effects
âȘ Skin rash
âȘ Stevens-Johnson Syndrome (SJS) _ rare
o The risk of SJS is high if combined with valproic acid
NOTE
âȘ Lamotrigine is preferred in pregnancy due to low teratogenic potential
âȘ SJS is a severe type of skin allergy
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18. â Topiramate
â Mechanism of action
1- It enhances the action of GABA
2- It blocks sodium and calcium channels,
3- It blocks AMPA receptors
â Therapeutic use
âȘ All types of seizures (focal & generalized)
â Adverse effects
âȘ Increase the IOP
âȘ Renal stones
âȘ Teratogenic
âȘ Weight loss by decreasing body fat mass
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19. â Levetiracetam
â Mechanism of action
âȘ It binds to SV2A; a synaptic vesicle protein so decreases
glutamate release
â Therapeutic use
âȘ All types of seizures (focal & generalized)
â Adverse effects
âȘ Very low
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