1. School of Pharmacy, University of Nizwa
Antiepileptic Drug
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture-31
April 23, 2012

2. Epilepsy
A common neurological abnormality affecting about 1% of the human population
A chronic, usually life-long disorder characterized by recurrent seizures or convulsions
Epileptic seizures often cause transient impairment of consciousness, leaving the individual at high risk
Therapy is symptomatic, available drugs inhibit seizures, but neither effective prophylaxis nor cure is available

3. Epilepsy: Classification
Epilepsy: Cause
Head trauma, meningitis, childhood fevers, and brain tumors are conditions often associated with the appearance of recurrent seizures
Seizures also may be a toxic manifestation of the action of CNS stimulants and certain other drugs
Epilepsy: Classification
Idiopathic
Symptomatic

4. Idiopathic Epilepsy
When no specific anatomic cause for the seizure, a patient may be diagnosed with idiopathic epilepsy
These seizures may result from an inherited abnormality in the CNS
Patients are treated chronically with antiseizure drugs or vagal nerve stimulation
Most cases of epilepsy are idiopathic

5. Symptomatic Epilepsy
Illicit drug use, tumors, head injury, hypoglycemia, meningeal infection can precipitate seizures
When two or more seizures occur, then the patient may be diagnosed with symptomatic epilepsy
Chronic treatment with antiseizure medications, vagal nerve stimulation and surgery are all appropriate treatments and may be used alone or in combination

6. Seizure: Classification
Partial
Generalized

7. Partial Seizure
Involve only a portion of the brain, only one hemisphere
Symptoms depend on the site of neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain
Simple partial:
Caused by a group of hyperactive neurons exhibiting abnormal electrical activity, which are confined to a single locus in brain
The electrical discharge does not spread, and the patient does not lose consciousness
Complex partial:
Exhibit complex sensory hallucinations, mental distortion, and loss of consciousness

8. Generalized Seizure
Produce abnormal electrical discharges throughout both hemispheres of the brain
May be convulsive or nonconvulsive, and the patient usually has an immediate loss of consciousness
Tonic-clonic:
Loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases
Absence:
Involve a brief, abrupt, and self-limiting loss of consciousness
The onset generally occurs in patients at 3 to 5 years of age
The patient stares and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds

9. Generalized Seizure, continued……
Myoclonic:
Consist of short episodes of muscle contractions that may reoccur for several minutes
Usually begin around puberty or early adulthood.
Febrile seizures:
Develop seizures with illness accompanied by high fever
Status epilepticus:
Two or more seizures recur without recovery of full consciousness between them
Life-threatening and requires emergency treatment

10. Cellular Mechanism of Seizure Generation
Excitation:
Ionic-inward Na+, Ca2+ currents
Neurotransmitter: Glutamate
Inhibition:
Ionic-inward Cl-, outward K+ currents
Neurotransmitter: GABA

11. Mechanism of Action of Antiepileptic Drugs
Blockade of voltage-gated channels (Na+ or Ca2+), enhancement of inhibitory GABAergic impulses, or interference with excitatory glutamate transmission
Some antiepileptic drugs appear to have multiple targets within the CNS, whereas the mechanism of action for some agents is poorly defined

12. Antiepileptic Drugs Drugs that primarily enhance the action of GABA:
Benzodiazepine, Tiagabine, Phenobarbital
Sodium channel blocking agents:
Phenytoin, Carbamazepine, Oxcarbazepine, Topiramate
Agents whose mechanism of action is not known:
Gabapentin, Felbamate

13. Benzodiazepine
Enhance inhibition through their interaction with the GABAA receptor
Diazepam, and lorazepam are most often used for partial and generalized tonic-clonic seizures
Pharmacokinetics:
Well absorbed, and the oral route is preferred
In the emergency, preferred route is intravenous
Metabolized by the microsomal drug-metabolizing system
Use:
In the treatment of absence, myoclonic, and tonic seizures and in the emergency treatment of status epilepticus
Adverse Effects:
Drowsiness

14. Tiagabine Mechanism of action: Use: Pharmacokinetics: Adverse effects:
Blocks the reuptake of GABA, thereby resulting in higher levels of GABA in the synaptic cleft
Use:
In the treatment of partial complex seizures
Pharmacokinetics:
Metabolism by the CYP3A family of enzymes
Adverse effects:
dizziness, nervousness, nausea, and confusion

15. Phenytoin Mechanism of Action: Uses: Pharmacokinetics:
Block sodium channels
Uses:
Effective for treatment of partial seizures and generalized tonic-clonic seizures and in the treatment of status epilepticus
Pharmacokinetics:
After oral administration, absorption is slow but complete
Highly bound (about 90%) to plasma proteins
Displays zero-order (or saturation) kinetics in its metabolism
Adverse Effects:
Ataxia, and vertigo
Higher doses lead to altered levels of consciousness

16. Carbamazepine Mechanism of Action: Uses: Pharmacokinetics:
Block sodium channels
Uses:
Effective for treatment of partial seizures and secondarily generalized tonic-clonic seizures
Pharmacokinetics:
Absorbed slowly following oral administration
Metabolized in the liver
Adverse Effects:
Drowsiness, nausea, headache, dizziness, and vertigo

17. Gabapentin Mechanism of action: Uses: Pharmacokinetics:
Precise mechanism of action is not known
Uses:
Therapy for partial seizures
Pharmacokinetics:
Does not bind to plasma proteins and is excreted unchanged through the kidney
Adverse Effects:
Dizziness, and ataxia