1. Emerging drugs for
EpilepsyDr. Priyanka Kumawat

2. Introduction
• Clinical phenomenon rather than a single
disease entity.
• Seizure- A paroxysmal event due to abnormal,
excessive, hypersynchronous, rhythmic
discharges from an aggregate of central
nervous system (CNS) neurons.

3. • Epilepsy- Disorder characterized by recurrent
seizures (also known as “seizure disorder”) due to
chronic underlying process.
• Epilepsy syndrome- Disorders in which epilepsy is a
predominant feature and clinical and pathologic
characteristics are distinctive and suggest a specific
underlying etiology eg: Benign familial neonatal
convulsions, lissencephaly.
• Status epilepticus- Continuous or repetitive,
discrete seizures with impaired consciousness in the
interictal period with duration of seizure activity 15 –
30 min

4. Epidemiology
• The incidence of epilepsy is ~0.3–0.5% in different populations
throughout the world.
• The prevalence of epilepsy has been estimated as 5–10
persons per 1000.
• 5% of the population suffer a single seizure at some time.
• Chance of having a second seizure after an initial unprovoked
episode is 30%.
• 70% well controlled with drugs (prolonged remissions)
• 30% epilepsy at least partially resistant to drug treatments =
INTRACTABLE (PHARMACORESISTANT) EPILEPSY.
• Recurrence rate after the withdrawal of drugs is about 30%.

5. Seizure triggers
• Missed medication (#1 reason)
• Stress, anxiety
• Hormonal changes, Menses
• Dehydration
• Lack of sleep, extreme fatigue
• Photosensitivity
• Alcohol use
• Certain Medications-
(chloroquine,penicillins,quinolones,INH,acyclovir,tramadol,
TCA,Li,theophylline,amphetamine, cocaine,flumazenil)
• Fever in Some Children

6. Pathophysiology of seizures
• Due to shift in normal balance of excitement and inhibition in
CNS.
• Central role for the excitatory neurotransmiter glutamate
(increased) and inhibitory gamma amino butyric acid (GABA)
(decreased)
• Excitability is affected by-
– Alteration in ion channel functioning
– Neurotransmitter level
– Receptor functioning(NMDA & non NMDA)
– Energy metabolism

7. Symptoms that may indicate
seizure disorder
• Periods of blackout or confused memory
• Occasional “fainting spells”
• Episodes of blank staring
• Sudden falls for no apparent reason
• Episodes of blinking or chewing at inappropriate times
• A convulsion, with or without fever
• Clusters of swift jerking movements in babies

8. What if not treated
• Seizures can be potentially life threatening with:
– Brain failure
– Heart failure
– Lung failure
– Trauma
– Accidents
• Sudden Unexpected Death in Epilepsy (SUDEP)
• Even subtle seizures can cause small damage in brain
• Long Term problems:
– Fall in IQ
– Depression
– Suicide
– Social problems
– Quality of life

9. Diagnosis
• Clinical examination and history
• Routine investigation: Haematology, biochemistry, chest X-
ray, electroencephalogram (EEG).
• Neuroimaging :CT/MRI- in all persons aged 25 or more
presenting with first seizure
• Advanced investigations (in pts. with intractable focal epilepsy
where surgery is considered): Neuropsychology, Semiinvasive
or invasive EEG recordings, MR Spectroscopy, Positron
emission tomography (PET) and ictal Single photon emission
computed tomography (SPECT)

10. Classification

11. Current treatment
Medical treatment
• Hydantoin- Phenytoin
• Barbiturates- Phenobarbital, Mephobarbital, primidone
• Iminostilbenes- Carbamazepine,Oxcarbazepine
• Succinimides- Ethosuximide, Methsuximide
• Valproic acid
• Benzodiazepines- Clonazepam,Clorazepate,Midazolam,Diazepam,
Lorazepam
• Other drugs-
Gabapentin,Pregabalin,Vigabatrin,Tiagiban,Levetiracetam,
Topiramate,Felbamate,Zonisamide,Lacosamide,Rufinamide,
Acetazolamide

12. Surgical treatment-
• Curative (resective) procedures:
– Anteromesial temporal resection
– Hemispherectomy.
• Palliative procedures(seizure-related risk decrease and
improvement of the QOL):
– Vagal nerve stimulation (VNS)
– Adenosine releasing implants
Nonpharmacologic treatment-
- Ketogenic diet
- Lifestyle modifications
- Deep brain stimulation
- Brain cooling

13. Basic rules for drug treatment:
• Started in pt with recurrent seizure( and cause is not reversed)
• Single seizure with epileptogenic lesion in the brain
• Drug treatment should be simple, preferably using one
anticonvulsant (monotherapy). “Start low, increase slow“.
• Add-on therapy is necessary in some patients (multiple drugs)
• Withdrawal of drugs-If pt is seizure-free for 2 years with
normal EEG and CNS examination.
• Dose is gradually reduced over 2-3 months

14. MECHANISM OF ACTION OF ANTI-
EPILEPTICS
• Na channel inactivation- Inability of neurons to fire at high frequency eg:
phenytoin, carbamazepine, lamotrigine,felbamate, topiramate, valproic
acid, lacosamide
• Ca+2 channel blockers- Ethosuximide,valproic acid,lamotrigine
• Enhanced GABAergic synaptic transmission – BZD, phenobarbital,
felbamate, topiramate, carbamazepine, Oxcarbazepine
• GABA uptake inhibitors/GABA transaminase inhibitors e.g. Tiagabine,
Vigabatrin
• Promotion of GABA release e.g. Gabapentin
• NMDA receptor antagonist- Felbamate
• AMPA/kianate receptor antagonist- Phenobarbital, topiramate,
lamotrigine
• SV2A(synaptic vesicular protein) ligands- Levetiracetam
• Brain carbonic anhydrase inhibitors- acetazolamide, topiramate,
zonisamaide

16. Specific treatments

20. Newer anti-epileptic drugs
• Brivaracetam
• Carisbamate
• Eslicarbazepine acetate
• Retigabine
• Perampanel
• Ganaxolone
• Clobazam
• Ezogabine
• Stiripentol

21. BRIVARACETAM
• Derivative of levetiracetam
• SV2A ligand-selectively bind to synaptic vesicles in
glutaminergic and GABAergic neurons, glutamate and 
GABA release.
• Also inhibits voltage gated Na-channels.
• More potent and efficacious than levetiracetam
• Trial done in Partial onset seizures,uncontrolled with one or 2
AEDs(anti epileptic drugs)
• Dose 50 mg/day

22. Pharmacokinetics
• Rapidly and almost completely absorbed after oral administration.
• Elimination half life is 7 to 8 hours.
• Weakly bound to plasma protein (<20%)
• Metabolised by non-cytochrome P450 dependent hydrolysis and
hydroxylation.
• Excretion via renal route.
• No dose adjustment is needed when giving concomitantly with other AEDs.
Adverse effects-
– Headache
– Dizziness
– Somnolence
– Fatigue
• Do not change PK of OCPs when used together
• No effects on fertility, pregnancy or early embryonic development in
rat or rabbits in a dose upto 600mg and 120mg/kg respectively.
• Under phase III trial

23. CARISBAMATE
• Derivative of felbamate
• New derivative of this compound, carisbamate, is designed to avoid toxic
metabolites.
• It is a novel neuromodulator.
• Mechanism of action still unknown
• Exhibits disease modifying effects as demonstrated by reduction in neuron
loss and prevention of recurrent seizures in a rodent model of status
epilepticus.
• Dose- 300-1600mg/day.

24. Pharmacokinetics
• Completely absorbed after oral administration, not affected by food.
• Half life is 10.6 to 12.8 hours.
• Protein binding 44%.
• Extensively metabolised, metabolism pathways are O-glucuronidation and
hydrolysis followed by oxidation.
• 1.7% of the dose excreted unchanged in urine.
Adverse effects-
• Most common adverse events are dose dependent(>1000mg) and includes
headache
dizziness
somnolence , and
nausea
• safe in elderly patients.
• Under phase III trial

25. ESLICARBAZEPINE
• Derivative of carbamazepine
• Does not undergo autoinduction.
• Inhibitor of voltage gated Na channels
• Fewer drug interactions
• Less tendency to raised blood cholesterol and lipids
• Dose- 800- 1200 mg/day
Pharmacokinetics
• Protein binding is 30%.
• Half life is 20 -24 hours and is consistent with first order kinetics.
• No relevant effect on the activity of the major cytochrome enzymes.
• Can lead to activation of UGT1A1-mediated glucuronidation of
ethinylestradiol.
• Primarily excreted renally.

26. Tolerability
• Most common adverse effects :
– Headache
– Dizziness
– Nausea
– Sleepiness
– Double vision
– incoordination
• Less neurotoxic than both carbamazepine and oxacarbazepine
in animals studies.
• No abnormal vital signs were seen in clinical laboratory tests.

27. RETIGABINE
• Affect a new target in the synapse,enhance the activity of KCNQ(kv7)
potassium channels.
• Anticonvulsant activity in generalized seizures, partial seizures and
status epilepticus as adjunctive therapy.
• Also have neuroprotective effect.
• Dose- 200-400 mg t.i.d
Pharmacokinetics
• Oral bioavailability : 60%
• Half life : 6- 10 hours
• Protein binding <80%
• Metabolized via N-glucuronidation and N-acetylation/hydrolysis to
inactive metabolite.
• Drug and metabolites are renally excreted.

28. Adverse effects-
• CNS effects
– Dizziness
– Cognitive impairment
– Sedation
– Hyperexcitability
– Headache
• others
– Vertigo
– Diplopia
– Hypothermia
• Low potential of PK drug interactions with concomitant AEDs
• No Pk interaction with OCPs
• Phase III study is ongoing.

29. STIRIPENTOL
• Aromatic allylic alcohols.
• Broad spectrum antiseizure activity
• Cause enhancement of GABAergic neurotransmission by increasing
GABA release, inhibiting GABA reuptake and activation of GABAA
receptors in a barbiturate like manner.
• Approved in 2007 for dravet syndrome in europe
Pharmacokinetics-
• Rapidly absorbed orally with a Cmax 1.5 hours after oral intake.
• 99% bound to plasma protein.
• Clearance increases with increasing dose as it has non-linear
kinetics.
• Potent inhibitor of CYP3A4, CYP1A2, CYP2C19 and thereby affects
numerous other drugs including other AEDs.

30. Adverse effect
• Most commonly reported adverse effect includes:
Loss of appetite,
Drowsiness,
Cognitive impairment,
Diplopia,
Nause and abdominal pain.
• There is a tendency for liver hypertrophy on long term use,
possibly because of its intense drug metabolizing capacity.

31. Ezogabine
• Approved in June 2011 as add-on therapy for the treatment of
partial epilepsy in adults.
• Reduction in seizure rate of 24% to 27%
• Dosage- 200mg to 400mg tds
Adverse effects-
– dizziness
– confusion
– fatigue
– somnolence

32. Perampanel
• Approved in October 2012 as add-on therapy for the treatment of
partial epilepsy in patients 12 years old and older
• Reduction in seizure rate was 28.5%, 35.3%, and 35.0% for 4, 8, and
12 mg, respectively.
• MOA-Highly selective AMPA type glutamate receptor antagonist
Pharmacokinetics-
• Rapid oral absorption
• Vd-77 L
• PPB-95%
• T1/2 ≈ 70 hr(once daily dosing strategy)
• Metabolize by CYP3A4
• Excreted 70% in feces in urine and 30%

33. Adverse effects
– Dizziness
– Fatigue
– Irritability
– Clumsiness
– Weight gain
• Does not affect the plasma concentrations of other AEDs

34. Ganaxolone
• Analog of neurosteroid allopregnanolone(a metabolite of
progesterone)
• Significantly reduce seizure frequency in adults with POSs
• Positive allosteric modulator of GABA
• Useful for absence seizures, Infantile spasms and catamenial
epilepsy
• Dose- 1500 mg/day as adjunctive therapy
Pharmacokinetics
• Lipophilic
• Absorption is higher in fed state
• T1/2- 7-10 hr
• Plasma level rapidly decline due to metabolism and tissue
distribution

35. • No significant drug interactions
• CYP3A4 inhibitor(ketoconazole) blocks its metabolism.
Adverse effects
– Dizziness
– Fatigue
– Somnolence
• Safe and well tolerated in infants at dose up to 54 mg/kg
• Drug is under phase III trial

36. summary
Brivaraceta
m
Carisba
mate
Eslicarba
zepine
acetate
Retigabi
ne
Stiripentol Ganaxolo
ne
Perampan
el
1.Synaptic
vesicle
protein 2A
(SV2A)
ligand
2. inhibits
voltage
gated Na-
channels.
1.neuro
modulat
or.
2. still
unknown
Inhibitor of
voltage
gated Na
channels
(Same
way as of
carbamaz
epine )
Open
voltage-
gated
potassiu
m
channel.
&
Neuropro
tector
Enhancement
of GABAergic
neurotransmi
ssion by
increasing
GABA
release,
inhibiting
GABA
reuptake and
activation of
GABAA
receptors
Positive
allosteric
modulator
of GABA
Highly
selective
AMPA
type
glutamate
receptor
antagonist
Phase III Phase III Phase III Under
review for
approval
Approved Phase III Approved

37. Drugs at early stage of
development
• 2 Deoxy-glucose-chemical analog of sugar but can not undergo
metabolism after being taken up into brain cells and finally
reduce the epileptogenesis.under phase II trial
• Huperazine A-in early phase II studies,derived from a club
moss,used in china to treat Alzheimers,fever,swelling,
scheizophrenia
• Galanin NAX 5055- Neuropeptide found in brain,its increased
activity is related with decreased brain activity
• MPP-021-congnitive enhancer
• NTP-2014-phase I trial,enhances inhibition in brain by a unique
mechanism that may not produce sedation
• ICA-105665-Highly selective Kv7 potassium channel opener

38. • Vigabatrin analog,CPP-115-increase levels of GABA without
loss of vision effects.
• P529,palomid-helpful to treat epilepsy in tuberous sclerosis(it
also has tumour decreasing property)
• Dynamin inhibitors- block dynamin and leads to excitation run
down
• YKP-3089-possible use are epilepsy,nerve pain,anxiety and
bipolar depression

39. Conclusion
• There is a ray of hope for refractory patients with
epilepsy either as monotherapy or add on therapy
• Many of the drugs have advantage over older one of
having less toxicity and lesser drug interactions with
concomitant medications
• Newer drugs are more safe with liver and renal
derangement pts.
• More safer drugs are coming for children,elderly and
pregnant pts.

40. References
• Harrison’s practice 18th edition
• Goodman & Gilman’s 12th edition
• Seizures: Medical Causes and Management Carl J. Vaughan, MD, MRCPI and
Norman Delanty, MB, FRCPI
• Perampanel: newly approved,novel antiepileptic medication for partial-
onset seizures Expert Rev. Neurother. 13(2), 131–134 (2013)
• Basic Mechanisms Underlying Seizures and Epilepsy
• New developments in the treatment of partial-onset
epilepsy.Neuropsychiatric Disease and treatment 2012:8 455-64.
• Biolink.Dynamin inhibitors for epilepsy
• Progress report on new antiepileptic drugs: A summary of the Tenth
Eilat Conference (EILAT X). M. Bialer et al.2010.Elsevier

42. LACOSAMIDE (SPM927)
• Formerly known as harkoseride (ADD 2304037).
• Approved in June 2009 as add-on therapy for the treatment of partial
epilepsy in adults.
• Selectively enhances slow inactivation of voltage-gated Na channel
without affecting the fast inactivation current.
• 100mg twice daily- reduce the median seizure rate by 26%
• 200mg twice daily- reduced the median seizure rate by 39%.
• Synergistic anticonvulsant activity with the AEDs like topiramate,
gabapentin, lamotrigine, levetiracetam, and carbamazepine and less
profound with phenytoin and valproate.

43. Pharmacokinetics
• Rapidly and completely absorbed after oral administration.
• Negligible first pass effect.
• 95% of the oral dose was excreted in urine.
40% - in unchanged form
40% - converted to O-desmethyl
metabolite
• Tmax reached 0.5-4 hours after oral dose.
• t1/2 -13 hours
• Plasma protein binding < 15%
Adverse effects
dizziness
diplopia and blurred vision
nausea and vomiting
headache
tremor

44. RUFINAMIDE
• Triazol derivative
• Mechanisms of action are still under investigation.
• Invitro studies suggest- prolongation of inactivation state of voltage-
gated Na channels like many other AEDs.
Pharmacokinetics
• Oral bioavailability > 85%
• Low protein binding 34%
• Metabolized by enzymatic hydrolysis, independent of CYP
isoenzymes to an inactive metabolite.
• Primarily excreted by renal route.
• Half life : 6 – 10 hours
• It may increase the serum concentration of phenytoin , no interaction
with other AEDs.

45. • Dose - 45mg/kg/d in children (1600mg twice daily in adults) ,resulted
in a 32% reduction in median seizure rate.
• It was approved inapproved in November 2008 as add-on therapy for
the treatment of Lennox-Gastaut Syndrome in patients four years of
age and older
• Adverse effects-
– Dizziness
– Fatigue
– Nausea
– Diplopia
– Vision blurred
– Headache
– Balance difficulties.

46. Need for further advancement
• Treatment resistant seizures remain a problem for
1/3rd of patients despite advancement
• Still requirement to Improving lives of patients with
epilepsy through:
– Improved seizure control
– Improved side effect profiles
– Safer treatment
• Requires a robust pipeline of drugs and devices in
clinical development

47. Summary
• Brivaracetam : Phase III
• Carisbamate : Phase III
• Eslicarbazepine acetate : Phase III
• Retigabine : Under review for FDA approval
• Perampanel : Phase III
• Ganaxolone : Phase III
• Clobazam : Approved
• Ezogabine : Approved in 2011
• Stiripentol : Approved in 2007