Antiepileptic drugs

1. PHL331
Prof. Dr/ Gamal A. Soliman
Pharmacy College
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Lecture-5

2. ▓ Some definitions
1- Seizures ‫نوبات‬
▪ 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).
▪ Seizures take various forms _ depending on the site of the epileptic focus
▪ Symptoms of seizures range from short periods of inattention to a full- convulsive attack lasting for
several minutes.
▪ A single seizure does not mean epilepsy
2- Epilepsy
▪ Epilepsy is a neurological disorder characterized by recurrent seizures
3- Convulsions
▪ Convulsions are rapid, involuntary contraction of the skeletal muscles
▪ Convulsions are common in epileptic seizures but can also result from infections, fever, and brain trauma.
▪ Convulsions and seizures are not the same things.
NOTE
▪ Epilepsy may or may not be accompanied by convulsions
▪ Abnormal electrical activity during and following a seizure can be detected by electroencephalography
(EEG) 2

3. ▓ The inhibitory and excitatory transmitters of the brain
1- Inhibitory transmitters
▪ GABA _ it is the main inhibitory transmitter in the brain
▪ It acts on GABA receptors
2- Excitatory transmitters
▪ Glutamate and aspartate _ they are the main excitatory transmitters in the brain
▪ They act on NMDA and AMPA receptors
NOTEs
▪ In the brain, there is a balance between the levels of the inhibitory and excitatory transmitters
▪ NMDA receptors = N-Methyl-D-aspartate receptors
▪ AMPA receptors = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
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4. ▓ Causes of epilepsy
▪ Often, there is NO known cause.
▪ Some probable causes of epileptic seizures include :
1- Genetic factors
2- Acquired factors
▪ Brain damage, such as head trauma or stroke, infection or brain tumor growth,
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5. ▓ Types of seizures
▪ There are two major classes of seizures: focal onset and generalized onset.
1- Focal
▪ The onset of focal seizures starts in a localized brain area in which the epileptic impulses remains
localized within one hemisphere.
▪ Focal epilepsy is of 2 types:
o Focal epilepsy with preserved awareness
o Focal epilepsy with impaired awareness
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6. 2- Generalized
▪ Generalized seizures affect large brain regions
▪ Generalized seizures can start as focal seizures but the epileptic
impulses spread to both sides of the brain.
▪ Generalized epilepsy is of 3 types:
o Tonic-clonic seizures _ ‫العظمى‬ ‫الدرجة‬ ‫من‬ ‫الصرع‬ _ A tonic–clonic seizure
consists of strong contraction of the whole musculature, causing a
rigid extensor spasm and an involuntary cry.
o Myoclonic seizures _ consisting of repetitive jerking of a particular
muscle group
o Absence seizures _ Epilepsy in the form of inattention (in children)
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7. ▓ Role of brain neurotransmitters in induction of epilepsy
❖ 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)
❖ Absence seizures
▪ It is a type of epilepsy that has a completely different mechanism
▪ 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
▪ 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. ▓ MOA of the antiepileptic drugs
▪ Antiepileptic drugs aim to suppress the abnormal neuronal impulses
▪ 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. ▓ Antiepileptic drugs
[1] First generation (Classic) drugs
▪ Phenytoin
▪ Carbamazepine
▪ Valproic acid
▪ Ethosuximide
▪ Phenobarbital
▪ Benzodiazepine
[2] Second generation (Newer) drugs
▪ Vigabatrin
▪ Lamotrigine
▪ Topiramate
▪ Levetiracetam
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NOTES
▪ 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).
▪ Second generation drugs work by inhibition of the excitatory transmitter (Glutamate & Aspartate)
action
▪ Side effects of first-generation drugs are more than those of the second generation

10. [1] First generation antiepileptic drugs (Classic drugs)
❑ Phenytoin
❖ Mechanism of action
▪ It blocks Na+ channels in brain and heart So reduce the generation of electrical waves
❖ Therapeutic use
▪ Tonic-clonic seizures only (grand mal epilepsy)
▪ Cardiac arrythmia
❖ Adverse effects
▪ CNS: Nystagmus, diplopia, ataxia
▪ Liver: microsomal enzyme induction _It activates the liver microsomal enzymes So lowers the plasma
concentration of several other drugs (risk of drug interactions).
▪ Blood: Megaloblastic anemia, due to increased rate of folic acid metabolism. This can be corrected by
giving folic acid
▪ Teratogenic_ in the form of cranio-facial anomalies
❖ Other Adverse effects
▪ Hirsutism
▪ Gum hypertrophy
▪ Oesteomalacia_ due to increased rate of vit D metabolism
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11. ❑ Carbamazepine (Tegratol)
▪ It is the most widely used antiepileptic drug
❖ Mechanism of action
▪ It blocks Na+ channels in brain So reduce the generation of electrical waves
❖ Therapeutic use
▪ First line drug in all types of focal seizures
▪ Second line drug in Tonic-clonic seizures
▪ Trigeminal neuralgia
❖ Adverse effects
▪ CNS: Nystagmus, diplopia, ataxia
▪ Liver: microsomal enzyme induction _It activates the liver microsomal enzymes So lowers the plasma
concentration of several other drugs (risk of drug interactions).
▪ Blood: Megaloblastic anemia, due to increased rate of folic acid metabolism. This can be corrected by
giving folic acid
▪ Teratogenic_ in the form of cranio-facial anomalies
❖ Other Adverse effects
▪ Increase ADH secretion _ So lead to hyponatremia and edema
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12. ❑ Valproic acid (Depakin)
❖ Mechanism of action
▪ 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.
❖ Therapeutic use
▪ All types of seizures (focal & generalized), including absence seizures
❖ Adverse effects
▪ CNS: Nystagmus, diplopia, ataxia
▪ Liver: microsomal enzyme inhibition _It inhibits the liver microsomal enzymes So increase the plasma
concentration of several other drugs (risk of drug interactions).
▪ Blood: neutropenia
▪ Teratogenic_ in the form of cranio-facial anomalies
❖ Other Adverse effects
▪ Alopecia (hair loss)
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13. ❑ Ethosuximide
❖ Mechanism of action
▪ The mechanism of action of ethosuximide appears to differ
from that of other antiepileptic drugs.
▪ It blocks T-type Ca2+ channels in thalamo-cortical neurons So
keep the connection between the central area and the cortex of
the brain
❖ Therapeutic use
▪ Ethosuximide is used clinically for its selective effect on
absence seizures _ First line drug
❖ Adverse effects
▪ GIT upset
▪ Headache, dizziness
NOTE
▪ It is the least toxic antiepileptic drug
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14. ❑ Phenobarbital
▪ It acts mainly as sedative hypnotic
❖ Mechanism of action
▪ It acts on GABA receptors, So potentiate GABA effect (GABA agonist)
❖ Therapeutic use
▪ 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)
❖ Adverse effects
▪ CNS: Nystagmus, diplopia, ataxia
▪ Liver: microsomal enzyme induction _It activates the liver microsomal enzymes So lowers the plasma
concentration of several other drugs (risk of drug interactions).
▪ Blood: Megaloblastic anemia, due to increased rate of folic acid metabolism. This can be corrected by
giving folic acid
▪ Teratogenic_ in the form of cranio-facial anomalies
❖ Other Adverse effects
▪ 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. ❑ Benzodiazepines (Diazepam)
❖ Mechanism of action
▪ It acts on GABA receptors, So potentiate GABA effect (GABA agonist)
❖ Therapeutic use
▪ 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.
▪ First line drug in febrile convulsions in children _ diazepam often being administered rectally
❖ Adverse effects
▪ Sedation is the main side effect of these compounds
▪ Tolerance and physical dependence
▪ Memory disturbance
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16. [2] Second generation antiepileptic drugs (Newer drugs)
❑ Vigabatrin
❖ Mechanism of action
▪ It inhibits GABA transaminase enzyme (the enzyme that inactivates GABA) So increase GABA content
of the brain. GABA reduces the neuronal firing
❖ Therapeutic use
▪ Focal seizures only _ but not as the first choice drug
❖ Adverse effects
▪ Visual field defects on long-term therapy (decreased field of vision, not a complete vision loss)
▪ Sedation
NOTE
▪ Visual field should be checked every 6 months
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17. ❑ Lamotrigine
❖ Mechanism of action
1- It blocks Na+ channels in brain and heart So reduce the generation of
electrical waves
2- It inhibits glutamate release
❖ Therapeutic use
▪ All types of seizures (focal & generalized) including absence seizures in
children
NOTE
▪ The mechanism by which Lamotrigine is effective against absence seizures is
not known
❖ Adverse effects
▪ Skin rash
▪ Stevens-Johnson Syndrome (SJS) _ rare
o The risk of SJS is high if combined with valproic acid
NOTE
▪ Lamotrigine is preferred in pregnancy due to low teratogenic potential
▪ SJS is a severe type of skin allergy
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18. ❑ Topiramate
❖ Mechanism of action
1- It enhances the action of GABA
2- It blocks sodium and calcium channels,
3- It blocks AMPA receptors
❖ Therapeutic use
▪ All types of seizures (focal & generalized)
❖ Adverse effects
▪ Increase the IOP
▪ Renal stones
▪ Teratogenic
▪ Weight loss by decreasing body fat mass
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19. ❑ Levetiracetam
❖ Mechanism of action
▪ It binds to SV2A; a synaptic vesicle protein so decreases
glutamate release
❖ Therapeutic use
▪ All types of seizures (focal & generalized)
❖ Adverse effects
▪ Very low
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The lecture end
Thank you