Epilepsy, Types of Epilepsy, Treatment Strategies and Different Classes of Drugs.

1. By
Dr. Faraza Javaid

2. A group of chronic CNS disorders
characterized by recurrent, periodic and
unpredictable seizures.
 Seizures are sudden, transitory, and uncontrolled
episodes of brain dysfunction resulting from abnormal
discharge of neuronal cells with associated motor,
sensory or behavioral changes.

3.  More than 40 forms of epilepsy have
been identified.
 Therapy is symptomatic in that the
majority of drugs prevent seizures, but
neither effective prophylaxis or cure is
available.

4.  Trauma
 Encephalitis
 Drugs
 Birth trauma
 Withdrawal from
depressants
 Tumor
 High fever
 Hypoglycemia
 Extreme acidosis
 Extreme alkalosis
 Hyponatremia
 Hypocalcemia
 Idiopathic

6. Nature of Epilepsy
 The particular symptoms produced depend on the function
of the region of the brain that is affected. Thus,
 Involvement of the motor cortex causes convulsions,
 Involvement of the hypothalamus causes peripheral
autonomic discharge, and involvement of the reticular
formation in the upper brain stem leads to loss of
consciousness.
 Seizure can be detected by EEG recording from electrodes
distributed over the surface of the scalp.
 Modern brain imaging techniques, such as MRI & PET are
now routinely used in the diagnosis of epilepsy to identify
structural abnormalities (e.g. lesions, tumors) that cause
certain epilepsies.

7. I. Partial (focal) Seizures
A. Simple Partial Seizures
B. Complex Partial Seizures
II. Generalized Seizures
A. Generalized Tonic-Clonic Seizures
B. Absence Seizures
C. Tonic Seizures
D. Atonic Seizures
E. Clonic Seizures
F. Myoclonic Seizures
G. Infantile Spasms

9. A. Simple Partial Seizures
 Involves one side of the brain at onset.
 Focal with motor, sensory or speech
disturbances.
 Confined to a single limb or muscle
group.
 Seizure-symptoms don’t change during
seizure.
 No alteration of consciousness.

10. B. Complex Partial Seizures (Temporal
Lobe epilepsy or Psychomotor Seizures)
 Produces confusion and inappropriate or
dazed behavior.
 Motor activity appears as non-reflex actions.
Automatisms (repetitive coordinated
movements). Purposeless movements like
lips smacking or hand wringing.
 Wide variety of clinical manifestations and
are accompanied by sensory, motor, psychic
symptoms.
 Consciousness is impaired or lost.

12. In Generalized seizures,
both hemispheres are widely
involved from the outset.
Manifestations of the seizure
are determined by the
cortical site at which the
seizure arises.
Present in 40% of all
epileptic Syndromes.

13. Recruitment of neurons throughout the cerebrum
Major convulsions, usually with two phases:
1) Tonic phase
2) Clonic phase
 Convulsions appear in Simple Partial and Complex
Partial Seizures if the focal neuronal discharge
includes motor centers
 They occur in all Generalized Tonic-Clonic Seizures
regardless of the site of origin.
 Atonic, Akinetic, and Absence Seizures are non-
convulsive

14. Tonic phase:
Sustained powerful muscle contraction(involving
all body musculature) which arrests ventilation.
Clonic phase:
Alternating contraction and relaxation, causing a
reciprocating movement which could be bilaterally
symmetrical or “running” movements.

16.  This is the most common and most severe form of
epilepsy.
 It is characterized by an initial rigid extension of
trunk and limbs (tonic phase) lasting 10-20 sec,
followed by a rhythmic contraction of arms and
legs (clonic phase).
 There is loss of consciousness and autonomic
signs
 A period of confusion and exhaustion lasting
several minutes follows the seizure episode; not
usually improved by anticonvulsant therapy.

17.  Brief and abrupt loss of consciousness,
vacant stare.
 Sometimes with no motor manifestations.
 Minor muscular twitching restricted to
eyelids (eyelid flutter) and face.
 Usually of short duration (5-10 sec), but may
occur dozens of times a day.
 No loss of postural control.

18. Often begin during childhood (daydreaming
attitude, no participation, lack of
concentration).
 Attacks may occur up to a hundred times
a day. Age of onset is 3-5 years; may last
till puberty.
 A low threshold Ca2+ current has been
found to govern oscillatory responses in
thalamic neurons (pacemaker)

19. C. Tonic Seizures
 Opisthotonus, loss of
consciousness.
 Marked autonomic
manifestations
D. Atonic Seizures (atypical)
 Loss of postural tone, with
sagging of the head or
falling.
 May loose consciousness.

20. E. Clonic Seizures
 Clonic Seizures: Rhythmic clonic
contractions of all muscles, loss of
consciousness, and marked autonomic
manifestations.
F. Myoclonic Seizures
 Myoclonic Seizures: Isolated clonic jerks,
brief shock like contraction of muscles
restricted to one part/ extremity associated
with brief bursts of multiple spikes in the
EEG.

21. F. Infantile Spasms
 An epileptic syndrome.
 Attacks, although fragmentary, are often
bilateral.
 Characterized by brief recurrent myoclonic
jerks of the body with sudden flexion or
extension of the body and limbs.

22.  Excitation (too much)
• Ionic-inward Na+, Ca++ currents
• Neurotransmitter: glutamate, aspartate
 Inhibition (too little)
• Ionic-inward Cl; outward K+ currents
• Neurotransmitter: GABA

23. Goals:
 Block repetitive neuronal firing.
 Block synchronization of neuronal
discharges.
 Block propagation of seizure.
Minimize side effects with the simplest drug
regimen.
MONOTHERAPY IS RECOMMENDED IN MOST CASES

24. Strategies:
 Modification of ion conductances.
 Increase inhibitory (GABAergic)
transmission.
 Decrease excitatory (glutamatergic) activity.

25. Classification of AEDs
• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine
• Ethosuximide
• Valproate
(valproic acid)
Classical
Newer
Lamotrigine
Felbamate
Topiramate
Gabapentin
Tiagabine
Vigabatrin
Oxycarbazepine
Levetiracetam
Fosphenytoin

26. 28
Chemical basedclassification of AED
Chemical compound class Member Drug
Barbiturate Phenobarbitone
Deoxybarbiturate Primidone
Hydantoin Phenytoin
Iminostilbene Carbamazepine
Succinimide Ethosuximide
Aliphatic carboxylic acid Sodium valproate
Benzodiazepines Clonazepam,Diazepam,Clobazam
Phenyltriazine Lamotrigine
Cyclic GABA analogue Gabapentin
Newer drugs
Vigabatrin , Topiramate,Tiagabine,
Levitiracetam, Zonisamide

27. Largely target partial seizures
Fewer and less severe drug
interactions compared to older
drugs

29. Resting State
Arrival of Action
Potential causes
depolarization and
channel opens
allowing sodium to
flow in.
Refractory State,
Inactivation

30. Na+
Na+
Open
Inactivation
gate
Activation gate

31. Na+
Carbamazepine
Phenytoin
Felbamate
Lamotrigine
Na+
Inactivated
channel
Block channels firing
at high frequencies
Barbiturates
Valproate
Topiramate

32. Ca++
Ca++
Voltage regulated Ca++
current,low threshold “T”
current in thalamus
Gitanjali-14:
Involved in 3 per
second spike and
wave rhythm

33. Ca++
Reduction in the flow of Ca++ through
T - type Ca++ channels in thalamus

35. GABA
metabolites
Succinic
Semialdehyde
Gabapentin
GT: GABA transaminase SSD: Succinic semialdehyde dehydrogenase
GT
SSD
Vigabatrin
Valproate
Benzodiazepines
Barbiturates
Cl-
Gabapentin
Tiagabine
Topiramate

36. .
(From Katzung B.G., 2001)
Block of sustained high frequency repetitive firing of
action potentials.

37. PHENYTOIN (Dilantin)
 Oldest non sedative
antiepileptic drug.
 Fosphenytoin, a more soluble
prodrug is used for parenteral
use.
 “Fetal hydantoin syndrome”
 It alters Na+, Ca2+ and K+
conductances.
 Inhibits high frequency
repetitive firing.
 Alters membrane potentials.
 Alters NTs (NE, ACh, GABA)
Toxicity:
•Ataxia and nystagmus.
•Cognitive impairment.
•Hirsutism
•Gingival hyperplasia.
•Coarsening of facial
features.
•Dose-dependent zero order
kinetics.
•Exacerbates absence
seizures.

39. USES
 Partial seizure
 Generalized (including tonic-clonic) seizures
 Contraindicated in absence seizures
 Nonseizure indications include
- Trigeminal neuralgia
- Manic-depressive disorders

40. Fetal Hydantoin Syndrome
 Pre- and postnatal growth deficiency with
psychomotor retardation, microcephaly with a
ridged metopic suture, hypoplasia of the nails and
finger-like thumb and hypoplasia of the distal
phalanges.
 Radiological skeletal abnormalities reflect the
hypoplasia and fused metopic suture.
 Cardiac defects and abnormal genitalia.
Teratogenicity of several anticonvulsant medications is associated with an elevated
level of oxidative metabolites that are normally eliminated by the enzyme
epoxide hydrolase.

41. CARBAMAZEPINE (Tegretol)
 Tricyclic, antidepressant (bipolar)
 3-D conformation similar to
phenytoin.
 Mechanism of action, similar to
phenytoin. Inhibits high
frequency repetitive firing (Na++)
 Decreases synaptic activity
presynaptically.
 Inh. uptake and release of NE,
but not GABA.
 Potentiates postsynaptic effects of
GABA.
 Metabolite is active.
Toxicity:
•Auto induction of
metabolism.
•Nausea and visual
disturbances.
•Granulocyte suppression.
•Aplastic anemia.
•Exacerbates absence
seizures.

42. OXCARBAZEPINE
 Closely related to
carbamazepine.
 With improved toxicity
profile.
 Less potent than
carbamazepine.
 Mechanism of action, similar
to carbamazepine It alters
Na+ conductance and
inhibits high frequency
repetitive firing.
Toxicity:
•Hyponatremia
•Less hypersensitivity
and induction of hepatic
enzymes than with carb.

43. PHENOBARBITAL
Toxicity:
 Sedation.
 Cognitive
impairment.
 Behavioral changes.
 Induction of liver
enzymes.
 May worsen
absence and atonic
seizures.
 It is the oldest antiepileptic drug.
 Although considered one of the
safest drugs, it has sedative effects.
 Many consider them the drugs of
choice for seizures only in infant
 Useful for partial, generalized tonic-
clonic seizures, and febrile seizures
 Prolongs opening of Cl- channels.
 Blocks excitatory GLU (AMPA)
responses. Blocks Ca2+ currents
(L,N).
 Inhibits high frequency, repetitive
firing of neurons only at high
concentrations.

44. PRIMIDONE
 Metabolized to phenobarbital
and phenylethylmalonamide
(PEMA), both active
metabolites.
 Effective against partial and
generalized tonic-clonic
seizures.
 Should be started slowly to
avoid sedation and GI
problems.
 Its mechanism of action may be
closer to phenytoin than the
barbiturates.
Toxicity:
•Same as phenobarbital
•Sedation occurs early.
•Gastrointestinal complaints.

45. VALPROATE
 Fully ionized at body pH, thus
active form is valproate ion.
 One of a series of carboxylic acids
with antiepileptic activity. Its
amides and esters are also active.
 Mechanism of action, similar to
phenytoin.
  levels of GABA in brain.
 May facilitate Glutamic acid
decarboxylase (GAD).
 Inhibits GAT-1. 
Toxicity:
•Elevated liver enzymes
•Nausea and vomiting.
•Abdominal pain,
•heartburn.
•Tremor, hair loss,
•Weight gain.
•Idiosyncratic,hepatotox
•Teratogen: spina bifida

46. USES
 A broad spectrum anti-seizure drug
(effective against most partial and
generalized seizures, including myoclonic
and absence seizures)
 Non-seizure indications include:
 Migraine (prophylaxis)
 Bipolar disorder

48. ETHOSUXIMIDE
 Drug of choice for absence
seizures.
 High efficacy and safety.
 Mechanism of action involves
reducing low-threshold Ca2+
channel current (T-type channel)
in thalamus.
At high concentrations:
 Inhibits GABA aminotransferase.
 Phensuximide = less effective
 Methsuximide = more toxic
Toxicity:
•Gastric distress,
including, pain, nausea
and vomiting
•Lethargy and fatigue
•Headache
•Hiccups
•Euphoria
•Skin rashes

49. CLONAZEPAM
 A benzodiazepine.
 Long acting drug with efficacy
for absence seizures.
 One of the most potent
antiepileptic agents known.
 Also effective in some cases of
myoclonic seizures.
 Has been tried in infantile
spasms.
 Doses should start small.
 Increases the frequency of Cl-
channel opening.
Toxicity:
• Sedation is prominent.
• Ataxia.
• Behavior disorders.

50. LAMOTRIGINE
 Presently use as add-on therapy with
valproic acid (v.a. conc. are be reduced).
 Almost completely absorbed
 T1/2 = 24 hrs
 Low plasma protein binding
 Also effective in myoclonic and
generalized seizures in childhood and
absence attacks.
 Suppresses sustained rapid firing of
neurons and produces a voltage and use-
dependent inactivation of sodium
channels, thus its efficacy in partial
seizures.
Toxicity:
•Dizziness
•Headache
•Diplopia
•Nausea
•Somnolence
•Rash

52. TOPIRAMATE
Toxicity:
 Somnolence
 Fatigue
 Dizziness
 Cognitive slowing
 Paresthesias
 Nervousness
 Confusion
 Urolithiasis
 Rapidly absorbed, bioav. is > 80%,
has no active metabolites, excreted
in urine.T1/2 = 20-30 hrs
 Blocks repetitive firing of cultured
neurons, thus its mechanism may
involve blocking of voltage-
dependent sodium channels
 Potentiates inhibitory effects of
GABA (acting at a site different
from BDZs and BARBs).
 Depresses excitatory action of
kainate on AMPA receptors.
 Teratogenic in animal models.

53. ZONISAMIDE
 Sulfonamide derivative
 Good bioavailability, low pb.
 T1/2 = 1 - 3 days
 Effective against partial and
generalized tonic-clonic seizures.
 Mechanism of action involves voltage
and use-dependent inactivation of
sodium channels(?).
 May also involve Ca2+ channels.
Toxicity:
•Drowsiness
•Cognitive
impairment
•High incidence of
renal stones (?).

54. FELBAMATE
 Effective against partial seizures
but has severe side effects.
 Because of its severe side effects, it
has been relegated to a third-line
drug used only for refractory cases.
Toxicity:
•Aplastic anemia
•Severe hepatitis

55. VIGABATRIN (-vinyl-GABA)
 Absorption is rapid, bioavailability
is ~ 60%, T 1/2 6-8 hrs, eliminated
by the kidneys.
 Use for partial seizures and
Contraindicated if preexisting
mental illness is present.
 Irreversible inhibitor of GABA-
aminotransferase (enzyme
responsible for metabolism of
GABA) => Increases inhibitory
effects of GABA.
Toxicity:
•Drowsiness
•Dizziness
•Weight gain
•Agitation
•Confusion
•Psychosis

56. TIAGABINE
 100% bioavailable, highly protein
bound.
 T1/2 = 5 -8 hrs
 Effective against partial and
generalized tonic-clonic seizures.
 GABA uptake inhibitor GAT-1.
Toxicity:
•Dizziness
•Nervousness
•Tremor
•Difficulty concentrating
•Depression
•Asthenia
•Emotional lability
•Psychosis
•Skin rash

58. GABAPENTIN (Neurontin)
 Used as an adjunct in partial and
generalized tonic-clonic seizures.
 Does not induce liver enzymes.not
bound to plasma proteins.
 Drug-drug interactions are
negligible.
 Low potency.
 An a.a.. Analog of GABA that does
not act on GABA receptors, it may
however alter its metabolism, non-
synaptic release and transport.
Toxicity:
•Somnolence.
•Dizziness.
•Ataxia.
•Headache.
•Tremor.

60. Status Epilepticus
Status epilepticus exists when seizures recur within a short
period of time , such that baseline consciousness is not
regained between the seizures. They last for at least 30
minutes. Can lead to systemic hypoxia, acidemia,
hyperpyrexia, cardiovascular collapse, and renal shutdown.
 The most common, generalized tonic-clonic status
epilepticus is life-threatening and must be treated
immediately with concomitant cardiovascular, respiratory
and metabolic management.

61. DIAZEPAM (Valium) AND
LORAZEPAM (Ativan)
 Benzodiazepines
 Given I.V.
 Lorazepam may be longer acting.
 1° for treating status epilepticus
 Have muscle relaxant activity.
 Allosteric modulators of GABA
receptors.
 Potentiates GABA function, by
increasing the frequency of channel
opening.
Toxicity
•Sedation
•Children may manifest a
paradoxical hyperactivity.
•Tolerance

62. Treatment of Status Epilepticus in Adults
Initial
 Diazepam, i.v. 5-10 mg (1-2 mg/min)
repeat dose (5-10 mg) every 20-30 min.
 Lorazepam, i.v. 2-6 mg (1 mg/min)
repeat dose (2-6 mg) every 20-30 min.
Follow-up
 Phenytoin, i.v. 15-20 mg/Kg (30-50 mg/min).
repeat dose (100-150 mg) every 30 min.
 Phenobarbital, i.v. 10-20 mg/Kg (25-30mg/min).
repeat dose (120-240 mg) every 20 min.

63. Treatment of Seizures
PARTIAL SEIZURES ( Simple and Complex,
including secondarily generalized)
Drugs of choice: Carbamazepine
Phenytoin
Valproate
Alternatives: Lamotrigine, Phenobarbital,
Oxcarbamazepine.
Add-on therapy: Gabapentin, Topiramate,
Tiagabine, Levetiracetam, Zonisamide.

64. Treatment of Seizures
PRIMARY GENERALIZED TONIC-
CLONIC SEIZURES (Grand Mal)
Drugs of choice: Carbamazepine
Phenytoin
Valproate*
Alternatives: Lamotrigine, Phenobarbital,
Topiramate, Oxcarbamazepine, Primidone,
Levetiracetam, Phenobarbital.
*Not approved except if absence seizure is involved

65. Treatment of Seizures
GENERALIZED ABSENCE SEIZURES
Drugs of choice: Ethosuximide
Valproate*
Alternatives: Lamotrigine, Clonazepam,
Zonisamide, Topiramate (?).
* First choice if primary generalized tonic-clonic seizure is also
present.

66. Treatment of Seizures
ATYPICAL ABSENCE, MYOCLONIC,
ATONIC* SEIZURES
Drugs of choice: Valproate**
Lamotrigine***
Alternatives: Topiramate, clonazepam,
zonisamide, felbamate.
* Often refractory to medications.
**Not approved except if absence seizure is involved.
*** Not FDA approved for this indication.

67. Na+ Channel Blockers Phenytoin
Carbamazepine
Oxcarbamazepine
Primione
Valproic acid
Lamotrigine
Topitramate
Zonisamide
Phenobarbital
Gabapentin
Felbamate
Ca2+ Channel Blockers Ethosuxamide
Phenobarbital
Zonisamide
Drugs that Potentiate
GABA
Increase opening time of channel Phenobarbital
Increase frequency of openings of
channel
Diazepam
Lorazepam
Clonazepam
Increase GABA in synapse Valproic Acid
Increase GABA metabolism Gabapentin
Increase GABA release Gabapentin
Block GABA transaminase Vigabatrin
Block GABA transporter
(GAT-1)
Valproic Acid
Tiagabine