2. Epilepsy?
Second most common neurological
disorder.
Family of different recurrent seizures
disorders that have in common the
sudden, excessive and synchronous
discharge of cerebral neurons.
Abnormal movements or perceptions
that are of short duration but tend to
3. Types of Epilepsy
Primary or Idiopathic Epilepsy:
No specific anatomic cause for the seizure
Inherited abnormality
Treated often for lifetime with antiepileptic
drugs
4. Continued…
Secondary Epilepsy:
Reversible disturbances such as tumors, head
injury , hypoglycemia , meningeal infection or
withdrawal
Antiepileptic are given until primary cause is
corrected
Seizures secondary to stroke or trauma may
cause irreversible CNS damage.
7. Mechanism of action of
antiepileptic drugs
Block the initiation of the electric discharge
from the focal area
Prevent the spread of the abnormal electrical
discharge to adjacent brain areas
Blockade of voltage gated channels
Enhancement of GABAergic impulses
Interference with glutamate transmission
10. Phenytoin
Formerly called as diphenylhydantoin
Effective in suppressing tonic-clonic and
partial seizures
Choice for initial therapy , particularly in
adults
11. Continued…
Mechanism of action:
Blocks voltage – gated sodium channels
Selectively binds to the channels in
inactive state and recovery rate slows
down
At higher concentration – block voltage
dependent calcium channels and
interfere with the release of
monoaminergic neurotransmitters
12. Continued…
Actions:
Reduces the propagation of abnormal
impulses in the brain
Is not a generalized CNS depressant
like the barbiturates
But produces some degree of
drowsiness and lethargy without
progression to hypnosis
13. Continued…
Therapeutic uses:
Highly effective for all partial seizures ,
tonic – clonic seizures and in the status
epilepticus caused by recurrent tonic-
clonic seizures
Not effective in absence seizures , may
worsen if treated with this drug
14. Continued…
Absorption and fate:
Oral absorption is slow but distribution is
rapid and brain concentration are high
Chronic administration of phenytoin is
always oral
Largely bound to plasma albumin
Metabolized by hepatic cytochrome P450
system to an inactive metabolite
15. Continued…
Absorption and fate:
At low doses, half life is 24 hours
Hydroxylation system becomes
saturated as dose increases
Increase in plasma concentration results
in drug induced toxicity
In status epilepticus – IV in form of
fosphenytoin
16. Continued…
Adverse effects:
Depression of CNS particularly in
cerebellum and vestibular system –
nystagmus and ataxia
GIT problems – nausea and vomiting
Gingival hyperplasia particularly in
children
Coarsening of facial features occurs in
children
17. Continued…
Adverse effects:
Megaloblastic anemia – B12 reactions
Confusion, hallucination and drowsiness
Inhibition of antidiuretic hormone
Insulin secretion
Should not be stopped abruptly
18. Continued…
Teratogenic effects:
“Fetal Hydantoin Syndrome” includes
cleft lip, cleft palate and congenital heart
disease
Stunted growth
Mental deficiency
Congenital birth defects in untreated
mothers
Drugs are given at the lowest possible
dose in pregnant women
19. Continued…
Drug Interactions
Drugs that affect phenytoin metabolism:
Chloramphenicol, dicumarol , cimetidine,
sulfonamides and isoniazid
Microsomal metabolism is inhibited by these
drugs in the liver
Phenytoin metabolism is enhanced by
carbamzepine
20. Continued…
Drug Interactions
Increased metabolism of other drugs
caused by phenytoin:
Induces the cytochrome P450 system
Results in increased metabolism of other
antiepileptics, anticoagulants, oral
contraceptives, quinidine, doxycycline,
cyclosporine, mexiletine, methadone, and
levodopa.
21. Carbamazepine
Actions:
Reduces the propagation of abnormal
impulses in the brain by blocking sodium
channels
Inhibits the generation of repetitive
action potentials in the epileptic focus
and preventing their spread
22. Continued…
Therapeutic uses:
Highly effective for all partial seizures ,
first choice drug
Effective in tonic-clonic seizures
Used in treatment of trigeminal neuralgia
Used in manic-depressive patients to
ameliorate the symptoms
23. Continued…
Absorption and Fate:
Absorbed slowly through oral administration
Highly lipid solubility
Half life – 5 to 7 days
Half life decreases with chronic administration
Induces cytochrome P450 system,
cytochrome P450 isozyme, CYP3A4
24. Continued…
Adverse effects:
Chronic administration can cause stupor,
coma and respiratory depression along with
drowsiness, vertigo, ataxia, blurred vision and
rash.
GIT – nausea and vomiting
Liver toxicity
Blood dyscrasias ( 10,11- epoxide metabolite
of drug)
Leukopenia and aplastic anemia
Hyponatremia in elderly people
25. Continued…
Drug interaction:
Hepatic metabolism of carbamazepine is
inhibited by
Cimetidine
Diltiazem
Erythromycin
Isoniazid
Propoxyphene
Toxic symptoms may arise if dose is not
adjusted
26. Oxcarbazepine
10-keto derivative of carbamazepine
Reduces to 10-monohydroxy metabolite
and blocks sodium channels preventing
the spread of the abnormal discharge
Anticonvulsant spectrum and toxicities
are similar to that of carbamazepine
Less potent inducer of drug-
metabolizing enzyme
Reduced effectiveness of oral
contraceptives
27. Phenobarbital
Actions:
Limiting the spread of seizure
discharges in the brain and elevating the
seizures threshold
Exact mechanism is unknown
Believed that potentiation of GABA
neurons
28. Continued…
Therapeutic uses:
50% favorable response rate for simple
partial seizures
Not very effective for complex partial
seizures
First choice of drug for recurrent
seizures in children including febrile
seizure ,diazepam is also effective
29. Continued…
Actions:
Used to treat recurrent tonic-clonic
seizures (if diazepam and phenytoin is
nonresponsive)
Mild sedative to relieve anxiety , nervous
tension, insomnia but benzodiazepines
are superior
30. Continued…
Absorption and Fate:
Well absorbed orally
Freely penetrates the brain
Approximately 75 % drug is inactivated
by the hepatic microsomal system
Remaining drug is excreted unchanged
by the kidney
Potent inducer of cytochrome P450
system
32. Continued…
Adverse effects:
Nausea and vomiting with morbilliform
rash
Agitation and confusion at high doses
Rebound seizures can occur on
discontinuance of phenobarbital
33. Primidone
Related to phenobarbital
Alternate choice in partial and tonic-
clonic seizures
Often used with carbamazepine and
phenytoin
Ineffective in absence seizures
Well absorbed orally but poor protein
binding
Adverse effects is same as
phenobarbital
34. Valproic Acid
Blocks sodium channel
Enhancement of GABAergic
transmission
Broad-spectrum anticonvulsant
Most effective in myoclonic seizures
35. Continued…
Its second choice of drug due its
hepatotoxicity
Reduces the incidence and severity of
tonic-clonic seizures
Effective orally and rapidly absorbed
About 90% bound to plasma proteins
37. Continued…
Adverse effects
Nausea and vomiting
Sedation, ataxia and tremor are
common
Rare hepatic toxicity
Rash and alopecia
Thrombocytopenia
Inhibits the metabolism of other
antiepileptic drugs
38. Ethosuximide
Introduced in 1960 in the USA.
Ethosuximide has very little activity against
maximal electroshock
Considerable efficacy against
pentylenetetrazol seizures; it was introduced
as a "pure petit mal" drug.
39. Continued…
Mechanism of Action
Ethosuximide has an important effect on Ca2+
currents, reducing the low-threshold (T-type)
current.
This effect is seen at therapeutically relevant
concentrations in thalamic neurons.
The T-type calcium currents are thought to
provide a pacemaker current in thalamic neurons
responsible for absence seizures. (INHIBITION of
thalamic neurons)
40. Continued…
Therapeutic uses:
Particularly effective against absence seizures
Very narrow spectrum of clinical activity
Documentation of its effectiveness in human
absence seizures was achieved with long-term
electroencephalographic recording techniques
41. Continued…
Pharmacokinetics
Absorption is complete following administration of
the oral dosage forms.
Peak levels are observed 3–7 hours after oral
administration
Ethosuximide is not protein-bound.
Ethosuximide is completely metabolized,
principally by hydroxylation, to inactive
metabolites.
42. Continued…
The drug has a very low total body clearance
(0.25 L/kg/d)
This corresponds to a half-life of approximately
40 hours, although values from 18 to 72 hours
have been reported.
43. Continued…
Therapeutic Levels & Dosage
Therapeutic levels of 60–100 mcg/mL can be
achieved in adults with dosages of 750–1500
mg/d
Although lower or higher dosages and blood
levels (up to 125 mcg/mL) may be necessary and
tolerated in some patients.
44. Continued…
Drug Interactions
Administration of ethosuximide with valproic acid
results in a decrease in ethosuximide clearance
and higher steady-state concentrations.
No other important drug interactions have been
reported for the succinimides.
45. Continued…
Adverse effects and Toxicity
Gastric distress, including pain, nausea, and
vomiting.
When an adverse effect occur, temporary dosage
reductions may allow adaptation.
Other dose-related adverse effects are transient
lethargy or fatigue and much less commonly,
headache, dizziness, hiccup, and euphoria.
Behavioral changes are usually in the direction of
improvement.
46. Continued…
Phensuximide & Methsuximide
Phensuximide and Methsuximide are
Phenylsuccinimides that were developed and
marketed before Ethosuximide
They are used primarily as anti-absence drugs
Methsuximide is generally considered more toxic,
and Phensuximide less effective, than
Ethosuximide
47. continued…
Unlike Ethosuximide, these two compounds
have some activity against maximal
electroshock seizures
Methsuximide has been used for partial
seizures by some investigators
48. Benzodiazepines
Diazepam Potentiates GABAA responses
Well absorbed orally , rectal administration
gives peak concentration in ~1 h with 90%
bioavailability
IV for status epilepticus , highly protein-bound
, extensively metabolized to several active
metabolites ,t1/2 ~2 d
Status epilepticus, seizure clusters
49. Continued…
Clonazepam Action : As for diazepam
>80% bioavailability extensively metabolized
but no active metabolites , t1/2 20–50 h
Therapeutic uses: Absence seizures,
myoclonic seizures, infantile spasms
Toxicity: Similar to diazepam
50. Felbamate
Blocking voltage-dependent sodium channels
Competing with the glycine-coagonist binding
site on the N-methyl-D-aspartate (NMDA)
glutamate receptor
Blocking calcium channels
51. Continued…
Potentiating the action of GABA. It is an
inhibitor of drugs metabolized by CYP2C19
and â-oxidation, and induces drugs
metabolized by CYP3A4.
It is reserved for use in refractory epilepsies
(particularly Lennox-Gastaut syndrome)
because of the risk of aplastic anemia (about
1:4000)
Hepatic failure.
52. Gabapentin
Decreases excitatory transmission by acting
on Voltage-Gated Ca2+ channels
presynaptically
Bioavailability 50%, decreasing with
increasing doses
not bound to plasma proteins
Not metabolized , excreted through kidney
54. Lamotrigine
Prolongs inactivation of VG-Na+ channels
Acts presynaptically on VG-Ca2+ channels
Decreases glutamate release
Well absorbed orally
No significant protein binding
55. Continued…
Metabolized primarily to the N-2 glucuronide
through the UGT pathway
t1/2 25–35 h
Generalized tonic-clonic seizures, generalized
seizures, partial seizures, generalized seizures,
absence seizures
Adverse effects: Dizziness, headache, diplopia,
rash
Interactions: Valproate, carbamazepine,
oxcarbazepine
56. Levetiracetam
Action on synaptic protein SV2A
Well absorbed orally
Not bound to plasma proteins , t1/2 6–11 h
Generalized tonic-clonic seizures, partial
seizures, generalized seizures
Adverse effects: Nervousness, dizziness,
depression, seizures
Interactions: Phenobarbital, phenytoin,
carbamazepine, primidone
57. Tiagabine
Blocks GABA reuptake in forebrain by
selective blockade of GAT-1
Well absorbed highly bound to plasma
proteins
Metabolism is mainly completed by the
CYP3A family of enzymes
t1/2 4–8 h
Partial seizures
Adverse effects: Nervousness, dizziness,
depression, seizures
58. Topiramate
Broad spectrum antiseizure activity.
Blocks voltage-dependent sodium channels
Increase the frequency of chloride channel
opening by binding to the GABAA receptor
High-voltage calcium currents (L type) are
reduced
59. Continued…
It is a carbonic anhydrase inhibitor and may
act at glutamate (NMDA) sites
Effective and approved for use in partial and
primary generalized epilepsy
It is also approved for treatment of migraine
Topiramate is eliminated renally
t1/2 20 h
60. Continued…
It inhibits CYP2C19 and is induced by
phenytoin and carbamazepine
Lamotrigine is reported to cause an increase
in topiramate concentration
Coadministration of topiramate reduces
ethinyl estradiol
61. Continued…
Adverse effects include somnolence, weight loss,
and paresthesias
Renal stones are reported to occur at a higher
incidence than in a non-treated population
Glaucoma, oligohidrosis, and hyperthermia have
also been reported
62. Zonisamide
sulfonamide derivative that has a broad spectrum
of action. The compound has multiple effects on
neuronal systems thought to be involved in
seizure generation.
These include blockade of both voltage-gated
sodium channels
T-type calcium currents
Its use should be monitored in patients with
reported allergies.
63. Continued…
Approved for use in patients with partial
epilepsy
It is metabolized by the CYP3A4 isozyme and
may, to a lesser extent, be affected by
CYP3A5 and CYP2C19
t1/2 50–70 h
In addition to typical CNS adverse effects, it
may cause kidney stones
Oligohidrosis has been reported
