1. DR.JITENDRA AGRAWAL
FIRST YEAR RESIDENT

2. Epilepsy is among the most common
neurological disorders, affecting approximately
50 million people worldwide. Partial onset seizure
are the most common type of seizures in adults.
SEIZURE: is a paroxysmal event due to
abnormal, excessive, hyper synchronous
discharges from an aggregate of central nervous
system, neurons.
EPILEPSY: describes a condition in which a person
has recurrent seizures due to chronic underlying
process.

3.  1. Partial seizures
a. Simple partial seizures (with motor, sensory,
autonomic, or psychic signs)
b. Complex partial seizures
c. Partial seizures with secondary
generalization

4. 2. Primarily generalized seizures
a. Absence (petit mal)
b. Tonic-clonic (grand mal)
c. Tonic
d. Atonic
e. Myoclonic
3. Unclassified seizures
a. Neonatal seizures
b. Infantile spasms

5.  are those in which the seizure activity is
restricted to discrete areas of the cerebral cortex.
 SIMPLE PARTIAL SEIZURES:
 Clinical manifestation + consciousness is fully
preserved during seizures
 COMPLEX PARTIAL SEIZURES
 focal seizure activity + impairment of
conciousness
 PARTIAL SEIZURES WITH SECONDARY
GENERALIZATION
 seizures that begin as partial seizures and then
spread diffusely throughout the cortex

6.  Pharmacological therapy is initial option for
the treatment of patients with newly
diagnosed epilepsy.
 Focused area is to reduce seizure frequency
with seizure freedom is ultimate goal.
 without side effects.
 Monotherapy is preferable.

7.  First-Line
a. Carbamazepine
b. Phenytoin
c. Lamotrigine
d. Oxcarbazepine
e. Valproic acid
 Alternatives
a. Levetiracetam
b. Topiramate
c. Tiagabine
d. Zonisamide
e. Gabapentin
f. Phenobarbital
g. Primidone
h. Felbamate

8.  Epilepsy a serious and potentially life
threatening condition
 In spite of many approved pharmacological
agents, many patients are not adequately
treated with currently available option.
 Nearly a third patients with epilepsy have
either intractable or uncontrolled seizures or
have significant adverse side effects
secondary to medication.

9.  Monotherapy is preferable to limit drug drug
interactions and side effects… but
 Epilepsy patient need more than one AED to
achieve therapeutics success.
 In spite of that adequate seizure control is
not achieved.
 So the new drug should have minimal drug
interactions and minimal side effect

10. Synonyms:
Retigabine-(INN- international nonproprietary name)
Ezogabine- (USAN- U.S. adopted name)

11.  Recently approved as an adjunctive treatment
for partial onset seizure for patients by
FDA
in June 2011
EMEA
in March 2011

12.  Opening of neuronal voltage-gated potassium
channels, which enhances inhibitory M-type
potassium current.
 The principal mechanism by which membrane
repolarisation occurs after an action potential is
an outward potassium current, termed the M-
current .
 Selectively enhance M-currents through KCNQ2/3
and KCNQ3/5
 No effect on KCNQ1- present in cardiac cells
KCNQ4-present in auditory system

13. Does not directly open the potassium channel
Act as prop or doorstop
Binding into hydrophobic pocket within ‘’gate’’ region of
Kv7.2 and 3 channles
Wihich is the site for molecular ‘’hinge’’
Once lodges within this pocket
It bends the hinge slightly open
Decreasing the angle through which the gate must swing
to full open.

14.  Linear pharmacokinetic profile with dosage
up to 1200mg/day
 Rapidly absorbed after oral administration
 Bioavailibility of oral EZG is about 60%
 Protien binding is approximately 80%
 Volume of distribution at steady state is
about 2-3 L/kg

15.  Metabolized by:
N-acetylation to the mono-acetylated metabolite,
glucuronidation to form N-glucronide structure
 Metabolites have minimal pharmacological activity
 Majority of drug and metabolites excreted through
kidney. Small amount excreted through feces.
 Plasma half life is 8 hrs for drug and metabolites.

16.  May increase the QTc interval.

17.  Low potential for drug interaction
 No potential to inhibit major cytochrome
P450 isoenzyme.
 It is neither substrate nor inhibitor of P-
glycoprotein transporter.

18.  No clinically significant effects of the
following AEDs on Ezogabine
pharmacokinetics:
 Carbamazepine
 Levetiracetam
 Oxcarbazepine
 Phenobarbitol
 Phenytoin
 Topiramate
 Valproate

19.  However lamotrigine increase 15% concentration of
ezogabin
 Ezogabine plasma levels may be reduced by
concomitant administration of phenytoin or
carbamazepine.
 N-acetyl metabolite of ezogabine may inhibit renal
clearance of digoxin

20. Indicated for adjunctive treatment for
 Partial onset seizures
 With or without generalization
 For patients 18 years of age and older.

21. Patients can be considered drug resistant
when
 Failed to have seizure control with 2 or more
AEDs
 Used appropriately
 Tolerated by the patient.

22.  The initial dosage should be 100 mg 3 times
daily (300 mg per day) for 1 week.
 Titrate to maintenance dosage by increasing
the dosage at weekly intervals by no more
than 150 mg per day.
 Optimize effective dosage between 200 mg 3
times daily (600 mg per day) to 400 mg 3
times daily (1,200 mg per day).

23.  When discontinuing EZOGABINE, reduce the
dosage gradually over a period of at least 3
weeks.
 Dosing adjustments are required for geriatric
patients and patients with moderate to severe
renal or hepatic impairment.

24. Most frequent
 Somnolence
 Dizziness
 Confusion
 Asthenia
less frequent
 Speech disorder
 Vertigo
 Tremor
 Amnesia

25.  Urinary retention
 Urinary hesitancy
 This is because of
 Inhibition of bladder contractility secondary
to ezogabine’s effect on KCNQ channels in
detrusor muscle of the bladder.

26.  urologic symptoms should be carefully
monitored.
 Closer monitoring is recommended for,
 benign prostatic hyperplasia [BPH]
 cognitively impaired patients
 anticholinergics

27.  Monitor for dizziness and somnolence
 QT prolongation: QT interval should be
monitored in patients taking concomitant
medications known to increase the QT
interval or with certain heart conditions.
 when EZOGABINE is discontinued, it should
be withdrawn gradually when possible to
minimize the potential of increased seizure
frequency

28.  STUDY 205:A
multicenter, randomized, double-
blind, placebo-controlled trial was performed
of retigabine for partial-onset seizures.
 CONCLUSION: Adjunctive therapy with
retigabine is well tolerated and reduces the
frequency of partial-onset seizures in a dose-
dependent manner.

29.  Study 301: multicenter, randomized, double-
blind, parallel-group trial of ezogabine
(retigabine) in partial epilepsy.
 CONCLUSION: EZG(RTG) is effective as add-
on therapy for reducing seizure frequency in
patients with drug-resistant partial-onset
seizures.

30.  STUDY 302: This was a
multicenter, randomized, double-
blind, placebo-controlled trial in adults with
≥4 partial-onset seizures per month
receiving 1 to 3 antiepileptic drugs.
 CONCLUSIONS: In this dose-
ranging, placebo-controlled trial, adjunctive
EZG (RTG) was effective and generally well
tolerated in adults with refractory partial-
onset seizures

32.  first antiepileptic drug with a very specific
effect on central nervous system potassium
channels.
 Having minimal drug interactions
 Mostly renal excretion
 few safety concerns
 most side effects are those typically seen
with antiepileptic agents.

33.  There are no adequate and well-controlled
studies in pregnant women.

34.  Harrision’s principles of internal
medicine, 17th edition
 Ezogabine: A New Angle On Potassium
Gates.Epilepsy Currents, Vol. 11, No. 3
(May/June) 2011 pp. 75–78© American
Epilepsy Society.
 Porter RJ, Partiot A, Sachdeo R, Nohria
V, Alves WM. Randomized, multicenter, dose-
ranging trail of retigabine for partial-onset
seizures. Neurology. 2007;68:1197-204.

35.  French J, Abou-Khalil B, Leroy R, Yacubian E, Shin
P, et al. Randomized, double-blind, placebo-
controlled trial of ezogabine (retigabine) in
partial epilepsy. Neurology. 2011 May
3;76(18):1555-63.
 Brodie M, Lerche H, Gil-Nagel A, Elger C, Hall
S, et al. Efficacy and safety of adjunctive
ezogabine (retigabine) in refractory partial
epilepsy. 2010 Nov.Neurology. 16:75:1817-24.
 Wikipedia and various internet sites
 Steve chung, kirsten M Kelly, Courtney Schussee;
Neurology research international journal, 20 june
2011.