NEWER ANTI EPILEPTIC DRUGS

1. NEWER ANTIEPILEPTIC DRUGS
OVERVIEW
Dr.Subhashis Sharma
Moderator
Dr.Anurag Jhanjee
Asst.Professor[Pschiatry]

2. OVERVIEW
Seizures are sudden episodes of neurological dysfunction caused by
abnormal electrical activity of the brain
Seizures are common
10% of the population will have a seizure during their lifetime (about
half are seizures with fever in infancy)
Epilepsy: recurrent, unprovoked seizures

3. SEIZURETYPES
Primary Generalized
 Tonic-clonic (“grand mal”)
 Absence (“petit mal”)
 Myoclonic
 Tonic
 Atonic (“drop attacks”)
Partial
 Simple
 Complex
 Secondary generalized

5. “OLDER” AEDS
Phenobarbital 1912
Phenytoin 1938
Primidone 1952
Ethosuximide 1960
Carbamazepine 1974
Valproate 1978
Ethosuximide 1980

6. NEWER AEDS
Felbamate 1993
gabapentin 1994
Lamotrigine 1995
Topiramate 1996
Tiagabine 1998
Levetiracetam 1999
Oxcarbazepine 2000
Zonisamide 2000
Rufinamide 2004
Pregabalin 2005
Lacosamide 2008
Eslicarbazepine 2009
Retigabine 2011

7. MECHANISM OF ACTION OF DIFFERENT
AEDS

8. CARBAMAZEPINE
First line drug for partial szs for years
Two long-acting forms now avail
(2X/day)
Side effects at just above therapeutic
range
Not effective for some seizure types
Must start slowly due to side effects
No IV form
Lots of interactions

9. PHENYTOIN
First line for partial seizures for years
Once a day
IV form
Side effects at just avove therapeutic
range
Not effective for some seizure types
Side effects: imbalance, sedation,
cognitive, gum problems,
osteoporosis
Many interactions

10. VALPROATE
Works for all seizure types
Around for decades
Rare allergic reactions
Helps prevent migraines
New IV form
New long-acting form
Side effects, esp. weight gain & tremor
Menstrual irregularities
Not best for pregnancy
Significant drug interactions

11. BARBITURATES (PRIMIDONE AND
PHENOBARBITAL)
Effective
Once a day (phenobarbital)
cheap
IV form (phenobarbital)
Sedation and cognitive effects
Withdrawal

12. OTHER OLD MEDICATIONS
Acetazolamide
Conazepam & lorazepam
Ethosuximide
Ketogenic diet
ACTH/steroids

13. NEWER AEDS
Equally effective as older AEDs
Most better tolerated than older AEDs
Most have fewer interactions with other medications than older AEDs
All expensive

14. GABAPENTIN
 Binds to the α2-δ protein subunit of voltage-gated
calcium channels
 This closes N and P/Q presynaptic calcium channels,
diminishing excessive neuronal activity
and neurotransmitter release

15. GABAPENTIN
 Generic name: Gabapentin
 Available as: Gabapentin: tablets 600mg, 800mg, capsules 100mg, 300mg, 400mg.
 Average total daily dose: 900mg – 3600mg daily divided into 3 doses, up to 4800mg daily
 Doses per day: 3
 Treatment: Monotherapy and add-on therapy for focal seizures with or without secondary
generalisation (where other treatment has not worked). May make myoclonic and absence
seizures worse.
 Most common possible side effects include the following:
Rash. Diarrhoea, nausea, vomiting, dry mouth, appetite change, weight gain, high blood
pressure, fluid retention, confusion, depression, sleep disturbance, headache, dizziness,
anxiety, tremor, unsteadiness, flu-like symptoms, incontinence, impotence, and double
vision.

16. GABAPENTIN
ADVANTAGES:
.No interaction with other drugs
.Eextremely rare allergic reactions
.Can be started quickly
.Well tolerated
.Treats pain,anxiety,restless leg syndrome,pain due to diabetic neuropathy,post herpetic neuralgia,prophylactic
for migraine.
DISADVANTAGES:
.Three times a day dosing.
.Does not treat all types of seizures

17. LAMOTRIGINE
 Carbamazepine like action profile
 Prolongation of Na+ channel inactivation
 And suppression of high frequency firing
 In addition it may directly block voltage
sensitive Na+ channels thus stabilizing the
presynaptic membrane
 And preventing release of excitatory neurotransmitters mainly glutamate and
mainly glutamate & aspartate
 This may account for broad spectrum of antiseizure
efficacy

18. LAMOTRIGINE
 Generic name: Lamotrigine
 Available as:tablets 25mg, 50mg, 100mg, 200mg, dispersible tablets 5mg, 25mg, 100mg.
 Average total daily dose:Used alone: 100 – 200mg daily divided into 1 – 2 doses, up to 500mg.
With sodium valproate: 100 – 200mg daily divided into 1 – 2 doses.
With enzyme-inducingAEDs and without sodium valproate: 200 – 400mg daily divided into 1 – 2 doses, up
to 700mg.
Without enzyme-inducingAEDs and without sodium valproate: 100 – 200mg daily divided into 1 – 2 doses.
 Doses per day: 1 – 2
 Treatment: Monotherapy and add-on therapy for focal and generalised seizures.Also used for
seizures associated with Lennox-Gastaut syndrome.
 Most common possible side effects include the following:
Serious skin rash and hypersensitivity. Risk minimised with slow introduction. Nausea,
vomiting, diarrhoea, dry mouth, aggression, agitation, headache, drowsiness, dizziness, tremor, difficulty
sleeping, unsteadiness, back pain, joint pain, eye movements, double vision, and blurred vision.

19. LAMOTRIGINE
ADVANTAGES:
 Minimal effect on other medications
 Works for al types of Seizures
 Very wellTolerated
 Minimal sedation
 Safe in pregnancy
 Monotherapy
DISADVANTAGES:
 Rashes if started quickly.Must start slowly

20. TOPIRAMATE
 It appears to act by multiple mechanisms
 Phenytoin like prolongation of Na+ channel inactivation
 GABA potentiation by a postsynaptic effect and antagonism of certain glutamate
receptors

21. TOPIRAMATE
 Generic name:Topiramate
 Available as:tablets 25mg, 50mg, 100mg, 200mg, capsules 15mg, 25mg, 50mg.
 AVERAGE DAILY DOSE:Taken alone: 100mg daily (up to 18 years) or 100 – 200mg daily
(over 18 years).Taken with other AEDs: 5 – 9mg/kg daily (up to 18 years) or 200 – 400mg daily
(over 18 years). All divided into 2 doses.
 Doses per day: 2
 Treatment: Used for focal seizures with or without secondary generalisation and tonic
clonic seizures, where other treatment has not worked.Topiramate has a licence for
monotherapy but is not widely used as a first line drug
 Most common possible side effects include the following:
Rash. Nausea, diarrhoea, vomiting, constipation, indigestion, abdominal pain, dry mouth,
appetite changes, impaired attention, cognition and coordination, movement problems,
tremor, drowsiness, dizziness, anxiety, confusion, mood changes, depression, irritability, and
anaemia.

22. TOPIRAMATE
ADVANTAGES:
 Minimal interaction
 Probably works for all seizure types
 Sprinkle form
 Approved for monotherapy
 Weight loss
 Approved for migraine prevention
DISADVANTAGES:
 Cognitive side effects
 ½% renal stone
 Tingling/pins & needles
 Can decreases the efficacy of OCP

23. TIAGABINE
 Potentiates GABA mediated neuronal inhibition
 by depressing GABA transporter GAT-1
 which removes synaptically released GABA
into neurons and glial cells

24. TIAGABINE
 Generic name:Tiagabine
 Available as:tablets 5mg, 10mg, 15mg.
 Average total daily dose:With enzyme-inducing AEDs: 30 – 45mg daily divided into 2 – 3
doses.Without enzyme-inducing AEDs: 15 – 30mg daily divided into 2 – 3 doses.
 Doses per day: 1 – 3
 Treatment: Add-on therapy for focal seizures with or without secondary generalisation
where other treatment has not worked. May make myoclonic seizures worse.
 Most common possible side effects include the following. Report severe reactions, such
as a skin rash, to your doctor.
Diarrhoea, dizziness, tiredness, nervousness, tremor, concentration problems, emotional
reactions, and speech impairment.

25. TIGABINE
ADVANTAGES:
 Minimal effect on other medications
DISADVANTAGE
.Dose is dependent on concurrent AEDs.
 Anxiety.
 Occasionally makes some seizure typesWorse

26. LEVETIRACETAM
 Binds to synaptic vesicle protein SV2A
which is involved in synaptic vesicle exocytosis

27. LEVITIRACETAM
 Generic name: Levetiracetam
 Available as: Desitrend: granules 250mg, 500mg, 1000mg.
Keppra: tablets 250mg, 500mg, 750mg, 1000mg, oral solution 100mg/ml.
Levetiracetam: tablets 250mg, 500mg, 750mg, 1000mg, oral solution 100mg/ml.
 Average total daily dose: Up to 1500mg twice daily.
 Doses per day: 2
 Treatment: Monotherapy and add-on therapy for focal seizures with or without
secondary generalisation.Add-on therapy for myoclonic seizures in Juvenile Myoclonic
Epilepsy.
 Most common possible side effects include the following:
Anorexia, weight changes, abdominal pain, nausea, vomiting, diarrhoea, drowsiness,
unsteadiness, dizziness, headache, tremor, amnesia, aggression, agitation, depression,
anxiety, and double or blurred vision.

28. LEVETIRACETAM
ADVANTAGES:
 No interactions
 Minimal liver metabolism
 Works for most seizure types
 Can start Quickly
 Well tolerated
 Liquid formulation
DISADVANTAGES:
 Behavioral/psych side effects
 Twice per day

29. OXCARBAZEPINE
 Oxcarbazepine is a prodrug which is activated to eslicarbazepine in the liver.
 Same mechanism as carbamazepine – sodium channel inhibition and is generally
used to treat the same conditions.
 reduce the impact on the liver of metabolizing the drug, and also prevents the
serious forms of anemia or agranulocytosis occasionally associated
with carbamazepine

30. OXCARBAZEPINE
 Generic name: Oxcarbazepine
 Available as:tablets 150mg, 300mg, 600mg, oral suspension 60mg/ml.
 Average total daily dose: Up to 18 years: 30mg/kg daily divided into 2 or 3 doses,
up to 46mg/kg. From 18 years: 600mg – 2400mg daily divided into 2 or 3 doses.
 Doses per day: 2 – 3
 Treatment: Effective for focal seizures, tonic clonic seizures and secondarily
generalised tonic clonic seizures.
 Most common possible side effects include the following.
Skin rash. Nausea, vomiting, constipation, diarrhoea, abdominal pain, dizziness,
headache, drowsiness, agitation, amnesia, hair loss, weakness, unsteadiness,
confusion, depression, and tremor.

31. OXCARBAZEPINE
ADVANTAGES:
 As effective and better tolerated than Carbamazepine
 Fewer interactions than Carbamazepine
 Approved for children > 4
 Approved for first-line monotherapy
DISADVANTAGES:
 Not for all seizure types
 Low sodium, esp if on diuretics also
 Lessens effectiveness of birth control pill

32. ZONISAMIDE
 Weak carbonic anhydrase inhibitory action
 Prolongation of Na+ channel inactivation
resulting in suppression of repetitive neuronal
firing has been observed

33. ZONISAMIDE
 Generic name: Zonisamide
 Available as:capsules 25mg, 50mg, 100mg.
 Average total daily dose: From 18 years: 300mg – 500mg daily divided into 1 or 2
doses.
 Doses per day: 1 – 2
 Treatment: Add-on therapy for focal seizures with or without secondary
generalisation.
 Most common possible side effects include the following:
Skin rash. Nausea, diarrhoea, abdominal pain, constipation, indigestion,
anorexia, weight loss, drowsiness, dizziness, confusion, agitation, irritability,
depression, psychosis, and unsteadiness

34. ZONISAMIDE
ADVANTAGES:
 Used inJapan for many years
 Works for all seizure types
 Approved for children
 Once daily
 Weight loss
 Recent addition of 25 mg capsules
DISADVANTAGES:
 1-2% kidney stones
 Occasional psychiatric or sedative side effects

35. PREGABALIN
 Binds to the α2-δ protein subunit of
voltage-gated calcium channels
 This closes N and P/Q presynaptic calcium channels,
diminishing excessive neuronal activity and
neurotransmitter release

36. PREGABALIN
 Generic Name:Pregabalin
 Available as:tablet
 Average total daily dose: 150–600 mg/DAY
 Doses: Start treatment with 50 mg/day in two divided doses
 Treatment: Adjunctive treatment of partial seizures with or without
secondary generalization in adults
 Most common possible side effects include the following: Somnolence,
dizziness,Ataxia, tremor, dysarthria, paresthesia,Impaired attention,
euphoric mood, irritability, Vomiting, dry mouth, constipation

37. PREGABALIN
ADVANTAGES
 Peripheral and central neuropathic pain
 Generalized anxiety disorders
 Management of pain associated with diabetic peripheral neuropathy
 Management of postherpetic neuralgia
 Management of fibromyalgia
DISADVANTAGES
 Blurred vision, diplopia,Peripheral edema Rare- neutropenia,
 hypoglycemia,
 atrioventricular block
 and congestive heart failure

38. LACOSAMIDE
 Acts by enhancing slow inactivation of
voltage-gated sodium channels
 resulting in stabilization of hyperexcitable
neuronal membranes

39. LACOSAMIDE
 Generic name: Lacosamide
 Available as: Tablets 50mg, 100mg, 150mg, 200mg, syrup 10mg/ml.
 Average total daily dose: From 16 years: 200mg twice a day.
 Doses per day: 2
 Treatment: Add-on therapy for focal seizures with or without secondary
generalisation.
 Most common possible side effects include the following.
Nausea, vomiting, constipation, wind, dizziness, headache, impaired
coordination, drowsiness, tremor, depression, fatigue, abnormal walking, blurred
vision, abnormal eye movements, and itching.

40. LACOSAMIDE
ADVANTAGES:
 Recently been licensed for clinical use.
 Adjunctive treatment of partial onset seizure.
 In patients with epilepsy aged 16 years & older.
DISADVANTAGES:
 Dizziness, headache, balance disorder, abnormal coordination
 memory impairment, somnolence, tremor, nystagmus
 Diplopia
 Nausea, vomiting, constipation
 Pruritus
 Increases PR interval

41. ESLICARBAZEPINE ACETATE
 Acts as a use-dependent blocker of
voltage-sensitive sodium channels
 resulting in stabilization of hyperexcitable
neuronal membranes

42. ESLICARBAZEPINE ACETATE
 Generic name: Eslicarbazepine acetate
 Available as:tablets 800mg.
 Average total daily dose: From 18 years: 800mg once a day, up to 1200mg.
 Doses per day: 1
 Treatment: Effective as an add-on therapy for focal seizures, tonic clonic and
secondarily generalised tonic clonic seizures.
 Most common possible side effects include the following.
Skin rash. Nausea, vomiting, diarrhoea, dizziness, drowsiness, headache,
impaired coordination, tremor, visual problems, and fatigue.

43. ESLICARBAZEPINE ACETATE
ADVANTAGES:
 Adjunctive treatment of partial onset seizures with or without secondary generalization
 in patients with epilepsy aged 16 years and older
 . Oral bioavailability: >90%
 Dosing schedule is once per day
 Dose adjustment is not necessary in Hepatic impairment
DISADVANTAGES:
 Increases PR interval
 Increased risk of suicidal ideation
 Stevens-Johnson syndrome
 Severe renal impairment (CrCL <30 mL/min) results in a 90% decrease in clearance so is not
recommended for these patients

44. RUFINAMIDE
 While the exact mechanism of rufinamide is still unknown, it is thought to act
through modulation of sodium channels resulting in membrane stabilization.
 Rufinamide administration slows recovery after a prolonged prepulse in cortical
neurons and limits sustained repetitive firing of sodium-dependent action
potentials.

45. RUFINAMIDE
 Generic name: Rufinamide
 Available as):tablets 100mg, 200mg, 400mg, oral suspension 40mg/ml.
 Average total daily dose: 900mg – 1600mg (depending on body weight and whether also
taking sodium valproate) twice daily.
 Doses per day: 2
 Treatment: Add-on therapy for Lennox-Gastaut syndrome
 Most common possible side effects include the following.
Hypersensitivity syndrome (possibly including rash and fever) – if concerned seek
immediate medical attention. Nausea, vomiting, diarrhoea, constipation, indigestion,
abdominal pain, weight loss, anorexia, runny nose, nosebleeds, dizziness, headache,
drowsiness, insomnia, anxiety, tiredness, flu-like symptoms, and blurred or double vision.

46. RETIGABINE
 Opens KCNQ2/3 (Kv7.2/7.3) voltage-gated potassium channels on neurons and
activates M-current, which regulates neuronal excitability and suppresses
epileptic activity.

47. RETIGABINE
 Generic name: Retigabine
 Available as:tablets 50mg, 100mg, 200mg, 300mg, 400mg.
 Retigabine is not widely prescribed due to possible side effects.
 Average total daily dose: From 18 years: 600mg – 1200mg daily divided into 3 doses.
 Doses per day: 3
 Treatment: Add-on therapy for focal seizures with or without secondary generalisation.
 Most common possible side effects include the following.skin rash
Dizziness, sleepiness, fatigue, weight gain, confusion, anxiety, tremor, double or blurred
vision, nausea, constipation, and problems urinating. Retigabine can cause problems with
heart rhythm

48. INTRANASAL OR BUCCAL MIDAZOLAM
Safe and effective (studies in UK, Israel): 5-10 mg in adults
Easy to use
Less social stigma
Not approved in US for this usage
Not easy to obtain (controlled substance) in a convenient form
Shorter acting than Diastat

49. CONSIDERATIONS IN CHOOSING AN AED
Side effect profile
Efficacy and correct seizure/syndrome diagnosis
Convenience (doses/day, etc)
 Once/day
Cost
Drug interactions/potential for future problems
Non-epileptic indications for AEDs
 Pain
 Headaches
 Psychiatric
Concurrent medical problems

50. DRUGSTHAT DECREASE EFFICACY OF
ORAL CONTRACEPTIVES
Phenytoin
Carbamazepine
Phenobarbital
Primidone
Topiramate at higher doses
Oxcarbazepine

51. WEIGHT ISSUES
Risk of weight gain
 Valproate
 Gabapentin and Pregabalin
“Risk” of weight loss
 Topiramate
 Zonisamide
 Felbamate

52. LIFESTYLE CHANGESTO MINIMIZE
SEIZURES
Avoid sleep deprivation
Avoid alcohol
Treat fevers quickly
Occasional patients should avoid specific factors such as strobe lights, etc
Pill boxes/reminders

53. SPECIAL CASES
Contraception:
Lamotrigine and oxcarbazepine have little interaction, and
sodium valproate has no interaction with oral contraception.
Pregnancy :
Epilepsy presents specific management problems during
pregnancy.With the exception of gabapentin, treatment with
almost all anticonvulsant drugs is associated with an increased
incidence of fetal congenital abnormalities such as cleft lip, spina
bifida and cardiac defects

54. GUIDELINES FOR ANTICONVULSANT
THERAPY
 Start with one first-line drug
 Start at a low dose; gradually increase dose until effective control of seizures is achieved or side-effects develop (drug
levels may be helpful)
 Optimise compliance (use minimum number of doses per day)
 If first drug fails (seizures continue or side-effects develop), start second first-line drug whilst gradually withdrawing first
 If second drug fails (seizures continue or side-effects develop), start second-line drug in combination with preferred first-
line drug at maximum tolerated dose (beware interactions)
 If this combination fails (seizures continue or side-effects develop), replace second-line drug with alternative second-line
drug
 If this combination fails, check compliance and reconsider diagnosis (is there an occult structural or metabolic lesion or
are seizures truly epileptic?)
 If this combination fails, consider alternative, non-drug treatments (e.g. epilepsy surgery, vagal nerve stimulation)
 Do not use more than two drugs in combination at any one time

55. CONCLUSION
The guideline is intended to act as a working model for managing patients with
epilepsy. Every medical practitioner needs to combine guidelines with his/her own
skill, knowledge and experience keeping in mind the needs of individual patients.
With so many new AEDs in the market, a physician might be tempted in trying
them out but the first-line AEDs still remain the most preferred agents in India
considering their wide availability, known long-term toxicity profile, wide
experience with these agents and cheap price. Since a patient has to take these
drugs for a long time and ensuring drug compliance is a key issue, appropriate
choice of the drug is important.

56. THANKYOU