1. Antiepileptic drugs

2. Seizures Various forms (depending on the part of the brain affected)
Result from episodic high-frequency discharge of a group of neurons (excitotoxicity)
Starting locally
May then spread to other areas of the brain
recurrent seizures

4. Nature of Epilepsy
The neurochemical basis of the abnormal discharge is not well understood. It may be associated with enhanced excitatory amino acid transmission, impaired inhibitory transmission, or abnormal electrical properties of the affected cells. The glutamate content in areas surrounding an epileptic focus is often raised.

5. Nature of epilepsy
Abnormal electrical activity during seizure can be detected by electroencephalograph (EEG)
Recording from electrodes distributed over the surface of the scalp
Can recognize various types of seizures.

6. Symptoms
Range from a brief lapse of attention to a convulsion (several minutes)
Depends on the function of the region of the brain that is affected

7. Affected brain regions
Motor cortex (convulsion)
Hypothalamus (peripheral autonomic discharge)
Reticular formation in the upper brainstem (loss of consciousness)

8. Epilepsy Recurrent seizures Treated mainly with drugs
Brain surgery may be used for severe cases

9. Causes of epilepsy No recognizable cause
May develop after brain damage
Trauma, infection or tumor growth
Or other kinds of neurological disease

10. Epileptogenesis
Excitatory transmission is facilitated (e.g. glutamate)
Inhibitory transmission is reduced (e.g. GABA)
Abnormal electrical properties of the affected cells

12. EPILEPSY affects 5–10% of the general population.
It is due to sudden, excessive depolarization of
some or all cerebral neurons. This may be:
localized (focal or partial seizure);
spread to cause a secondary generalized seizure;
may affect all cortical neurons simultaneously
(primary generalized seizure).

14. Classification of seizures
EEG
Cortex:
F – frontal
O – occipital
T – temporal
Rang et al.
Pharmacology
– 5th Ed. (2003)
Classification of seizures

15. Types of epilepsy Two major seizure categories:
Partial
Generalized
Both can be classified as:
Simple (if consciousness is not lost)
Complex (if consciousness is lost)
The type of seizure determines the choice of drug!

16. Partial seizures Discharge begins locally (often remain localized)
EEG discharge is normally confined to one hemisphere

17. Partial seizures Symptoms include: Involuntary muscle contraction
Abnormal sensory experiences
Autonomic discharge
Or effects on mood and behavior

18. Simple partial seizures

19. Complex partial seizures
Loss of consciousness
Discharge in the brainstem reticular formation
Are among the commonest types of epilepsy

20. Complex partial seizures

21. Jacksonian epilepsy In motor cortex
Repetitive jerking of particular muscle group
May spread to involve much of the body
Losses voluntary control of the affected parts of the body
Does not necessarily loss consciousness

22. Psychomotor epilepsy In temporal lobe
The attack may consist of movements such as:
Rubbing movements
Dressing or walking or hair-combing
Lasts for a few minutes
Recover with no recollection of the event
The behavior during the seizure can be bizarre and accompanied by a strong emotional response

23. Generalized seizures
Involve the whole brain, including the reticular system
characterized by immediate loss of consciousness
Producing abnormal electrical activity throughout both hemispheres

24. Generalized seizures Two important categories:
Tonic-clonic seizures (grand mal)
Absence seizures (petit mal)

25. Tonic-clonic seizures (grand mal)
EEG shows
Generalized continuous high-frequency activity in the tonic phase (2)
An intermittent discharge in the clonic phase (3)

26. Tonic-clonic seizures (grand mal)
Tonic phase:
An initial strong contraction of the whole musculature, causing a rigid extensor spasm
Respiration stops, defecation, micturition, salivation often occur
Lasts for about 1 minute
Tonic phase (stiffening of the body)

27. Tonic-clonic seizures (grand mal)
Clonic phase:
A series of violent, synchronous jerks after the tonic phase
Gradually dies out in 2-4 minutes
Clonic phase (the body jerks)

28. Tonic-clonic seizures (grand mal)
The patient stays unconscious for a few more minutes and then gradually recovers, feeling ill and confused
Post-convulsive phase (exhaustion)

29. Absence seizures (petit mal)
Occur in children
Much less dramatic
May occur more frequently (many seizures each day) than tonic-clonic seizures

30. Absence seizures (petit mal)
The patient ceases whatever he was doing
Sometimes stopping speaking in mid-sentence
Stares vacantly for a few seconds, with little or no motor disturbance.
The patient is unaware of his surrounding
Recovers with no after-effects

31. Absence seizures (petit mal)
                                                                                 

32. Absence seizures (petit mal)
EEG pattern shows a characteristic rhythmic discharge during the period of seizure
The rhythmicity appears to be caused by oscillatory feedback between the cortex and the thalamus

33. Absence Seizures

34. Absence seizures (petit mal)
Thalamic neurons activity depends on the calcium channels that they express
Treated by blocking calcium channels

35. Lennox-Gastaut Syndrome (LGS: Lennox Syndrome)
Severe kind of epilepsy
Occurs in children
Causes excitotoxic neurodegeneration
Associated with progressive mental retardation

36. Antiepileptic drugs
Effective in controlling seizures in about 70% of patients
Their use is often limited by side-effects

37. Treatment Monotherapy with anticonvulsant
Increase dose gradually until seizures are controlled or adverse effects become unacceptable.
Multiple-drug therapy may be required.
Achieve steady-state kinetics
Monitor plasma drug levels
Avoid sudden withdrawal

38. Primary generalized seizures
AED Treatment Options
Partial seizures
Primary generalized seizures
Tonic- Clonic
Simple
Complex
Secondary Generalized
Tonic
Myoclonic
Atonic
Absence
phenytoin, carbamazepine, phenobarbital,
gabapentin, oxcarbazepine, pregabalin
Ethosuximide
valproic acid, lamotrigine, topiramate,
(levetiracetam, zonisamide)

39. ANTISEIZURE DRUGS 1. Carboxamides (enzyme inductors – CYP450):
Carbamazepine (+ neuropathic pain – n. trigeminus,
postherpetic pain, etc.), Oxcarbazepine
2. Hydantoins: Phenytoin (enzyme inductor),
3. Barbiturates (Phenobarbital – enzyme inductors) and their
analogues (Primidone – prodrug)
4. Succinimides: Ethosuximide (petit mal)
5. Valproates (enzyme inhibitors): Sodium valproate (Depakin®)
6. Benzodiazepines: Clonazepam, Clorazepate, Diazepam
Lorazepam, Nitrazepam
7. GABA analogues: Gabapentin, Tiagabine
8. Hetereogenic anticonvulsants: Lamotrigine, Levetiracetam,
Pregabalin (partial seizures, peripheral neuropathic pain),
Topiramate, Vigabatrin
ANTISEIZURE DRUGS

40. MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or its spread in one or
more of the following ways:
(1) Enhancing GABA synaptic transmission: barbiturates, benzo-
diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira-
mate, valproate; the result is increased permeability to chloride ion,
which reduces neuronal excitability. Valproate and topiramate block
GABA transaminase and tiagabine blocks reuptake of GABA.
(2) Reducing cell membrane permeability to voltage-dependent
sodium channels: carbamazepine, lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate.
(3) Reducing cell membrane permeability to calcium T-channels:
valproate, ethosuximide; the result is diminishing of the generation
of action potential.
(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.

41. Treatment of Seizures Strategies: Modification of ion conductances.
Increase inhibitory (GABAergic) transmission.
Decrease excitatory (glutamatergic) activity.

42. Antiepileptic drugs Three main mechanisms: Other mechanisms include:
Enhancement of GABA action
Inhibition of sodium channel function
Inhibition of calcium channel function
Other mechanisms include:
Inhibition of glutamate release
Block of glutamate receptors

43. GABA Na+ Ca2+ Barbiturates Benzodiazepines Gabapentin Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin
Na+
Ca2+
Carbamazepine
Lamotrigine
Oxcarbazepine
Phenytoin
Topiramate
Valproate
Ethosuximide
Levetiracetam
Pregabalin
Valproate

44. Na+ Channel Inhibitors
blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery
Antiseizure drugs, enhanced Na+ channel inactivation
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

45. Na+ Channel Inhibitors
Phenytoin (Dilantin, Phenytek)
Fosphenytoin (Cerebyx)
Carbamzepine (Tegretol, Carbatrol)
Oxcarbazepine (Trileptal)
Valproic Acid (Valproate; Depakene, Depakote)
Lamotrigine (Lamictal)
Topiramate (Topamax)
Zonisamide (Zonegran)

46. Na+ Channel Inhibitors
Phenytoin (Dilantin, Phenytek):
Oldest nonsedative antiepileptic drug.
Narrow therapeutic window (~ μmol/l)
Well absorbed.
Indications:
First choice for partial and generalized tonic-clonic seizures
Some efficacy in clonic, myoclonic, atonic,
No effect on infantile spasms or absence seizures
Drug Interactions:
Decreases blood levels of many medications
Increases blood levels of phenobarbital & warfarin

47. Na+ Channel Inhibitors
Phenytoin (Dilantin, Phenytek):
Adverse Effects:
Hirsutism & coarsening of facial features
Acne
Gingival hyperplasia (20-40%)
Megaloplastic anemia. (corrected by folic acid)
Decreased serum concentrations of folic acid, thyroxine, and vitamin K with long-term use.
“Fetal hydantoin syndrome”: teratogenic
includes growth retardation, microencephaly, and craniofacial abnormalities (e.g., cleft palate) and is possibly due to an epoxide metabolite of phenytoin.

48. Phenytoin Induced Gingival Hyperplasia
17 year old boy treated with 300mg/day phenytoin for 2 years (unsupervised)
Partial recovery at 3 months after discontinuation

49. Fosphenytoin is a prodrug
rapidly converted to phenytoin in the blood, providing high levels of phenytoin within minutes.
Fosphenytoin may also be administered intramuscularly (IM).
Phenytoin sodium should never be given IM because it can cause tissue damage and necrosis.
Fosphenytoin is the drug of choice and standard of care for IV and IM administration.
Due to sound-alike and look-alike names, there is a risk for medication error to occur.
The trade name of fosphenytoin is Cerebyx®
Celebrex®, the cyclooxygenase-2 inhibitor
Celexa®, the antidepressant.

50. Na+ Channel Inhibitors
Carbamzepine (Tegretol, Carbatrol):
Derived from Tricyclic, antidepressant (bipolar)
Indications:
First choice for complex partial and generalized tonic-clonic seizures.
Contraindications:
May exacerbate absence or myoclonic seizures.
Blood disorders
Liver disorders

51. Na+ Channel Inhibitors
Carbamazepine (Tegretol, Carbatrol):
Drug Interactions: A powerful inducer of hepatic microsomal enzymes
CBZ metabolism is affected by many drugs, and CBZ affects the metabolism of many drugs. oral contraceptives, warfarin, corticosteroids, etc.
Determination of plasma levels and clearance may be necessary for optimum therapy.
Adverse Effects:
Common: Diplopia and ataxia (most common), gastrointestinal disturbances; sedation at high doses
Occasional: Retention of water and hyponatremia; rash, agitation in children
Rare: Idiosyncratic blood dyscrasias and severe rashes

52. Na+ Channel Inhibitors
Oxcarbazepine (Trileptal):
FDA approved in 2000 for partial seizures
Complex partial seizures
Primary & secondarily generalized tonic-clonic seizures
Is a prodrug whose actions are similar to those of carbamazepine; it has a short half-life of 1—2 hour.
Its activity is due to a 10-hydroxy metabolite with a half-life of 10 hours.
Fewer adverse effects than CBZ, phenytoin

53. Na+ Channel Inhibitors
Valproic Acid (Valproate; Depakene, Depakote):
Other Mechanisms of Action:
1) Some inhibition of T-type Ca2+ channels.
2) Increases GABA production and decreases GABA metabolism. (Inhibition of GABA transaminase )
Indications:
Simple or complex partial, & primary generalized tonic-clonic
Also used for absence, myoclonic, and atonic seizures.
Highly effective for photosensitive epilepsy and juvenile myoclonic epilepsy.
Low toxicity and lack of sedative action
Contraindications:
Liver disease

54. Na+ Channel Inhibitors
Valproic Acid (Valproate; Depakene, Depakote):
Drug Interactions:
Affects metabolism of many drugs through liver enzyme inhibition

55. Na+ Channel Inhibitors
Valproic Acid (Valproate; Depakene, Depakote):
Adverse Effects:
Weight gain (30-50%)
Dose-related tremor
Transient hair loss
Polycystic ovary syndrome (PCOS) and menstrual disturbances
Bone loss
Ankle swelling
The most serious side-effect is hepatotoxicity
An increase in serum glutamic oxaloacetic transaminase (sign of liver damage)

56. Na+ Channel Inhibitors
Lamotrigine (Lamictal):
Other Mechanism of Action:
May inhibit synaptic release of glutamate.
Indications:
Adjunct therapy (ages 2 & up):
Simple & complex partial seizures
Generalized seizures of Lennox-Gastaut Syndrome
Monotherapy (adults):
Contraindications:
May make myoclonic seizures worse.  

57. Na+ Channel Inhibitors
Lamotrigine (Lamictal):
Adverse Effects:
Rash (10%)
Rare progression to serious systemic illness
Increased alertness

58. Na+ Channel Inhibitors
Topiramate (Topamax):
Other Mechanism of Action:
Enhances post-synaptic GABAA receptor currents.
Kainate receptor antagonist (blocks a certain type of glutamate channel)
Indications:
Adjunct therapy for partial and primary generalized
seizures in adults and children over 2.
Decreases tonic and atonic seizures in children with Lennox-Gastaut syndrome.
Contraindications:
History of kidney stones, teratogenic

59. Na+ Channel Inhibitors
Topiramate (Topamax):
Drug Interactions:
CBZ, phenytoin, phenobarbital, & primidone decrease blood levels
Adverse Effects:
Nervousness & paresthesias
Psychomotor slowing, word-finding difficulty, impaired concentration, interference with memory
Weight loss & anorexia
Metabolic acidosis

60. Na+ Channel Inhibitors
Zonisamide (Zonegran):
is a sulfonamide derivative that has a broad spectrum of action
Other Mechanism of Action:
Inhibits T-type Ca2+ currents.
Binds to GABA receptors.
Facilitates dopaminergic and serotonergic neurotransmission.

61. Na+ Channel Inhibitors
Zonisamide (Zonegran):
Indications:
Approved for adjunct treatment of partial seizures in adults.
Appears to have a broad spectrum:
Myoclonic seizures
Infantile spasms
Generalized & atypical absence seizures
Lennox-Gastaut Syndrome
Drug Interactions:
Phenytoin and carbamazepine decrease its half-life by half.

62. Na+ Channel Inhibitors
Zonisamide (Zonegran):
Adverse Effects:
Weight loss
Abnormal thinking
Nervousness
Agitation/irritability
Usually well tolerated