Introduction to Epilepsy and its type and Drugs used in management of Epilepsy.

1. Saddam Ansari
Achiever’s Academy
Introduction and Drugs
used to Treat Epilepsy

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.

5. Classification of Seizures
Partial Seizure
 Simple partial
 Complex partial

6. Continued…
Generalized Seizure
 Tonic-clonic (grand mal)
 Absence (petit mal)
 Myoclonic
 Febrile seizure
 Status epilepticus

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

8. Primary Antiepileptic Drugs
 Phenytoin
 Carbamazepine
 Oxcarbazepine
 Phenobarbital
 Primidone
 Valproic acid
 Ethosuximide
 Benzodiazepines

9. Adjunct Drugs
 Felbamate
 Gabapentin
 Lamotrigine
 Levetiracetam
 Tiagabine
 Topiramate
 Zonisamide

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

31. Continued…
Adverse effects:
 Sedation
 Ataxia
 Nystagmus
 Vertigo
 Acute psychotic reaction with chronic
use

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

36. Continued…
 3% excreted unchanged
 Metabolized by CYP

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

53. Continued…
 t1/2 6–8 h
 Generalized tonic-clonic seizures, partial
seizures,
 Adverse effects: Somnolence, dizziness,
ataxia

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