3. Prevalence
• Prevalence- 1 % 0f the
population
• 50 million worldwide
• Higher rates in developing
countries
• 10 million in India
• Incidence – 0.7%
• Incidence is highest in the
young and elderly
6. Background and Justification:
• Between 70 and 80% of individuals are successfully treated with
one of the more than twenty AEDs now available.
• 20-30% of patients have either intractable or uncontrolled seizures
or suffer significant adverse side effects secondary to medication.
• There is no class I evidence comparing the new AEDs to the old, or
the new AEDs to each other in patients with refractory epilepsy.
• Selection of the appropriate drug for a given individual must be
based on understanding of each drug’s pharmacology, side effect
profile, and risks.
9. HISTORY OF AED
• Phenobarbital- Alfred Hauptmann- 1912
• Phenytoin- Tracy Putnam - 1934
• Ethosuximide - Parke, Davis - 1958
• Carbamazepine - Schindler at Geigy - 1953
epilepsy- 1963
• VPA- Pierre Eymard- 1963
• Diazepam - Henry Gastaut - 1965
10. • BEGAN IN 1975 .
• National Institute of Neurological Disorders and Stroke
established the Anticonvulsant Drug Development Programme.
• Screened more than 28,000 new chemical entities.
MORDEN ERA OF AED
17. Characteristics of Older AEDs:
Advantages
Broad familiarity
long-term experience
Known efficacy
Lower cost
What is old is not necessarily outdated
18. Characteristics of Older AEDs:
• Disadvantages
• Cause hepatic enzyme induction (PB, PHT,CBZ, Primidone) or
inhibition (VPA)
• Cause change in internal hormonal compounds (sex steroids,
Vit D)
• Produce interaction with commonly used medications
(warfarin, oral contraceptives, Ca-channel antagonists,
chemotherapy agents)
• Pregnancy Category D
19. Advantages of Newer AEDs
• Greater tolerability
• Fewer side effects
• Fewer drug interactions
• Fewer idiosyncratic reactions
• Minimal influence on metabolic pathways
• Pregnancy category C
20. Selecting an Antiepileptic Drug
Choose antiepileptic drug most suited to the individual
patient based on
seizure/epilepsy type
side effects (anemia, hepatotoxicity, rash, etc.)
patient profile (comorbidity, sex, age, etc,)
ease of use
cost
Balance between efficacy, tolerability and safety
Epilepsy may be a lifelong diagnosis – minimize
chronic side effects from AEDs (cognitive, reproductive,
neuropathy, bone and weight changes, etc.)
22. Reasons for pseudoresistance
Wrong diagnosis Syncope, cardiac arrythmia, PNES
Wrong drug Inappropriate for seizure type,
pharmacokinetic or pharmacodynamic
interactions
Wrong Dose Too low, side effects preventing drug
increase
Life style issue Poor compliance with medication,
alcohol or drug abuse
23. PHARMACORESISTA
NT
The drug faces a modified
target, Interacts less effectively .
Missing the Real Targets
Increased expression or
function of multidrug transporter
proteins
Decreases availability of the
AED at its target versus.
32. Drugs Indication Contra
indication
Minimal
titration
period for
add- on
therapy
Considerations
partial generalised
Felbamate Intractable
partial sz
(add –on
therapy)
LGS when
primary
therapy
failed
Absolute:
hematologic,
autoimmun ds
Relative- renal
1 day Hematologic &
LFT
Gabapentin Add-on None Relative- renal 1 wk TDS , may
combine with
CBZ , well
tolerated
Lamotrigine Mono,add-
on
All sz type
when 1st line
failed
Absolute-SME,
rel- rash, with
PHT,CBZ, liver
ds
>6wk Long titration
may combine
with VPA, well
tolerated
Levetiracetam Add-on GTCS Relative: renal
dis
1wk
33. Drugs Indication Contra
indication
Minimal
titration
period for
add- on
therapy
Considerations
partial generalised
Oxcarbazepine monother/
Add-on
Tonic-clonic
When 1st
line failed
Absol: absence
or myoclonic
relat- renal ds,
hyponatrmic
drug ( lithium
,diuretics )
2wk Fewer SE than
CBZ
Tiagabine Add-on None Abso- absence,
myoclonic ,
Relat- liver ds,
depression
> 6wk Long titration ,
TDS/QID
dosing
Topiramate Add-on All sz except
absence sz
Rela- psych
illness, renal ds
f/h renal calculi
> 6wk Long titration
relatively sever
neurotoxic
effect
34. Drugs Indication Contra
indication
Minimal
titration
period for
add- on
therapy
Considerations
partial generalised
Vigabatrin Add-on
therapy in
adult
West
syndrome in
tuberous
sclerosis
Absolute:
absence/myo
clonic sz
Rela- psy
illness ,renal
ds
1 day Visual field
testing at
regular interval
Zonisamide Add-on All seizure
types when
1st line failed
Rela – psy
illness,renal
ds , h/o renal
calculi
2wk Experience is
still limited
41. • AED exposure – 0.4 – 0.6 % of all pregnancies
• Major malformation – 2-3 % general population
• Epileptic women – 4 – 8% of major malformation, 6 – 20% of
minor malformation
• Still births -1.3% - 14.0 % controls – 1.2 – 7.8 %
• Perinatal death rates – 1.3% -7.8%, controls -1-3.9%
42. CONGENITAL Malformations
MAJOR
• Neural tube defects
• Cong. heart disease
• Orofacial clefts
• Intestinal atresia
• Congenital defects
MINOR
• Cranio-facial dysmorphism
• Distal digit / nail = hypoplasia
• Umbilical / inguinal hernias
• Some improve / disappear later
43. The FDA has categorized AED medications into 2 classes, D and C.
Category C drugs have demonstrated teratogenicity in animals, but
human risk is not known.
The newer AEDs are classified as Category C.
Phenytoin, carbamazepine and valproic acid are category D.
Category D drugs are those drugs for which related to
teratogenicity in both animal and human pregnancies.
In both categories, the recommendation remains the same: selection of
AED in pregnancy should be decided upon risk –benefit ratio to seizure
control.
44.
45. IS Lamotrigine THE antiepileptic in pregnancy ?
Epilepsia 2007
Among 802 exposures the frequency of major
Birth defects was 2.7%
No effect of dose upto 400 mg/day
46. • Epileptic women with difficult to treat seizure
disorder requiring more than 2 antiepileptics
BEST POLYTHERAPY – CARBAMAZEPINE WITH
LAMOTRIGINE
50. LACOSAMIDE
Add-on therapy for adults with partial-onset seizures with
or without secondary generalization
Approved in patients ≥16 years by the European Commission
(August 2008)
In patients ≥17 years by the U.S. Food and Drug Administration
(October 2008)
Mechanisim
1. Enhancing sodium channel slow inactivation
Normalization of activation thresholds
Reduced pathophysiological hyperresponsiveness.
2. Binding to collapsin-response mediator protein 2
(Crmp-2).
Neuronal protection from excitotoxicity and apoptosis
Downregulation of NMDA receptor subunit NR2B
51. PHARMACOKINETIS
Almost completely and rapidly absorbed from the GI tract.
Peak plasma conc 4 hours.
The elimination half-life is around 13 hours
minimally bound to plasma proteins (<15%).
Renal excretion
Dosage adjustments are recommended for pt with mild or moderate
hepatic impairment or severe renal impairment.
Use in severe hepatic impairment patients is not recommended
DRUG INTERACTIONS
• Does not induce or inhibit hepatic enzymes.
• No effect on the plasma concentrations of other AEDS.
52. Current therapy +
Placebo
(n=359)
Current therapy +
Lacosamide 400 mg/day
(n=359)
Lacosamide +
1st generation
AEDs
Lacosamide +
2nd generation
AEDs
50%
responder
rate
from
baseline
with
lacosamide
vs
placebo
Effective regardless of concomitant AED used
53. TRIALS
US multicenter
RCT
(Ben-Menachem E
Epilepsia 2007)
418 patients
European trial
Halasz P (Epilepsia
2009)
485 patients
SP754 Study Group
Chung SS(Epilepsia
2010)
405 patients
Seizure frequency
26% with 200
mg/day,
39% with
400mg/day
40% with
600mg/day,
35.5% with 200
mg/day (p = 0.02)
36.4% with 400
mg/day (p = 0.03)
> 50% reduction
with lacosamide
400 and 600
mg/day
54. Safety and Tolerability
Common adverse effects
• Dizziness, headache, nausea and vomiting.
• Fatigue, ataxia, visual disturbance, diplopia and somnolence also
occurred.
• Rare reports of cardiac events with the drug. (PR prolongation, AF/Afl)
Dosage and Administration
• starting dose is 50 mg twice daily
increased at weekly intervals by 100 mg/day
maintenance dosage of 200 or 400 mg/day
• Recent data suggest intravenous loading doses of lacosamide 200 and
300 mg over 15 minutes were best tolerated.
57. PHARMACOKINETICS
• Following oral administration 85% absorbed
•
• peak plasma concentrations reached in 5–6 hours
• 23–34% bound to plasma proteins.
• t 1/2 - 8 to 12 hours.
• undergoes extensive hepatic metabolism
58. DRUG INTERACTION
• Weak inhibitor of CYP2E1
• weakly induces the CYP3A4 isoenzyme.
• metabolized by carboxylesterases.
• Carbamazepine clearance was increased by 7.9–15.4%, lamotrigine
by 7.7–15.6%.
• phenobarbital and phenytoin clearance decreased by 7.1–11.7%
and 6.5–17.5%, respectively.
• 42% rise in rufinamide concentrations in children, and an 11% rise
in adults with sodium valproate.
• no change with topiramate or lamotrigine.
• Clearance of rufinamide was increased by carbamazepine ,
phenytoin , phenobarbital and primidone.
59. First study
• seizure frequency 41% in pt taking rufinamide 400–1600
mg/day compared with a 52% in those taking placebo (p
= 0.04).
( Palhagan S, Epilepsy Res 2001; 43: 115-24)
Second study
84-day period, with adjunctive rufinamide being administered
to 74 patients with treatment-resistant Lennox-Gastaut
syndrome(including drop attacks and atypical absence attacks)
(Glauser T, Ann Neurol 2008; 70: 1950-8)
60. SEIZURE TYPE RUFINAMIDE PLACEBO
TOTAL SEIZURE 32.7% 11.5%
TONIC-ATONIC 42.5% 1.4%
ATYPICAL ABSENCE &
ATONIC
Decreased
61. THIRD TRIAL
• By Brodie and colleagues in 313 adults and adolescents with partial-
onset seizures,
• rufinamide 1600mg twice daily
• significant median reduction of 20.4% in partial seizure frequency
relative to an increase of 1.6%(p = 0.05).
(Brodie MJ, Epilepsia 2009; 50: 1899-909)
FOURTH TRIAL
• In a retrospective open-label study of rufinamide in 60 patients with
refractory epilepsy of any type,
8.3%became seizure free over 12 weeks.
46.7% had a 50% reduction in seizure frequency.
(Kluger G et al.. Epilepsy Behav 2009; 14: 491-5)
62. Safety and Tolerability
• somnolence, nausea, vomiting,
• anorexia, dizziness, diplopia and ataxia
Dosage and Administration
• available in 100, 200 and 400 mg tablets.
• initially at a dose of 200 mg twice daily.
• increasing in 200 mg twice-daily increments at intervals of
not less than 2 days .
• maximum daily dose of 3200 mg.
63. Eslicarbazepine Acetate
Recently licensed in Europe as adjunctive treatment for partial seizures
with or without Secondary generalization in adults.
In 2010, the licensing application for the AED was not approved by the
US FDA.
64. Mechanisms of Action
competitively interacts with the inactivated state of the voltage-gated
sodium channel.
Pharmacokinetics
not metabolized to carbamazepine 10,11-epoxide, it is therefore not
susceptible to enzyme induction or autoinduction.
half-life is 13–20 hours,
steady-state concentrations being reached within 4–5 days of once-
daily dosing
65. Pharmacokinetics
<40% protein bound.
Inactive by glucuronidation, or excreted unchanged,
mainly by renal elimination.
Not affected by age, sex, food consumption or moderate
hepatic impairment
Dosage reduction may be required if cr cl <60ml/minute.
66. DRUG INTERACTION
• Except with phynetoin ,no pharmacokinetic interactions have been
reported with other AEDs.
• Accelerates the clearance of both hormonal components of the oral
contraceptive pill
• Coadministration with warfarin had no effect on coagulation.
67. EFFICACY
• Seizure reduction varied between 33% and 45% with
eslicarbazepine acetate1200 mg/day,
• Responder rates (>50% seizure reduction vs baseline) ranged
between 38% and 43%).
• Only a few patients in each trial remained seizure free throughout.
Safty and tolerability
• Dizziness and somnolence.
• Headache, abnormal coordination, disturbed attention, diplopia,
blurred vision, vertigo, nausea, vomiting, diarrhoea and rash.
68. Available in 800 mg tablets.
Initial recommended dose is 400 mg
Once daily, increasing after 1–2 weeks to 800 mg once daily.
The drug can be titrated thereafter to a maximum tolerated daily
dose of 1200 mg according to efficacy and tolerability.
69. RETIGABIN
submitted applications to the FDA
European Medicines Agency to have the drug licensed as an
adjunctive treatment for patients with partial-onset seizures.
Mechanisms of Action
opening of neuronal voltage-gated potassium channels, enhancing the
M-type potassium current.
repolarising the membrane back towards resting potential and
suppressing repetitive firing.
70. Pharmacokinetics
Rapidly absorbed following oral administration
Bioavailability 60%.
Peak plasma conc within 60–90 minutes.
Protein binding is <80%.
Half-life 8 hours.
With modest or severe hepatic impairment, clr is decreased by 30–50%.
71. • No interactions between retigabine and enzyme-inducing or non-
inducing agents.
• Five studies (3 phase II and 2 phase III studies) demonstrating the
efficacy and safety of retigabine in pt with partial-onset seizures.
• Median percentage reduction in monthly total partial seizure
frequency from baseline was
23% for 600 mg/day,
29% for 900 mg/day and
35% for 1200 mg/day (p = 0.047)
72. PHASE III TRIAL RESTORE I RESTORE II
DOSAGE 1200mg/d 600,900mg/d
SEIZURE FREQUENCY 44% 28% (600),40% (900)
SIGNIFICANCE P<0.001 P<0.01
74. Safety and Tolerability
• somnolence, confusion, dizziness, tremor, amnesia,
abnormal thinking, vertigo, speech disorders and
asthenia.
• Urinary hesitancy, dysuria and dis colouration
75. BRIVARACETAM
N-propyl analogue of levetiracetam.
Has a 10-fold higher affinity for SV2A than levetiracetam.
inhibits neuronal voltage-gated sodium channels
76. PHARMACOKINETICS
half-life of 7–8 hour
Protein binding is <20%.
Metabolic pathways include
hydrolysis of the acetamide group
hepatic CYP2C8-mediated hydrolysis.
Renal clearance is approximately 3mL/minute through
substantial tubular reabsorption
77. DRUG INTERACTIONS
• reduces plasma concentrations of CBZ and PHT.
• Decreases the estrogen and progestin concentrations of
low dose OCP.
SAFETY AND TOLERABILITY
• Dizziness, headache and somnolence.
• Neutropenia
78.
79. TRIALS STUDY 1
(Neurology® 2010;75:519–525)
STUDY 2
(27th International Epilepsy
Congress; 2007 Jul)
SEIZURE
FREQUENCY
32%
44.2%
55.8%
5mg/d
20mg/d
50mg/d
P<0.047
P<0.002
P<0.001
18.9%
38.2%
30.0%
placebo
50mg/d
150
mg/day
(p = 0.017)
(p = 0.113)
81. PHARMACOKINETICS
• Rapid absorption,
• Peak conc. achieved 1-hour post-dose.
• Long half-life of around 52–129 hours following a single dose (0.2–
8mg)
• 66–90 hours with multiple dosing.
• Pharmacokinetic profile supports once-daily dosing.
• Steady state concentrations are usually reached by day 14.
82. PERAMPANEL
FIRST STUDY
(Krauss G, Epilepsia 2008)
SECOND STUDY
( Eisai Co. Ltd. Status of the E2007
(perampanel) Development Program)
206 PATIENTS
4mg/d
31% decreased seizure
22% in placebo
208 patient
40% decreased seizure
2% increased in pla arm
83.
84. GANAXOLONE
Novel class of neurosteroids called epalons.
Chemically related to progesterone
Devoid of any hormonal activity
potent antiepileptic, anxiolytic, sedative and hypnotic properties
85. MECHANISM OF ACTION
• specifically modulate GABA receptors containing the d-
subunit in the CNS.
• Efficacy in a new, spontaneous model of perimenstrual catamenial
epilepsy.
86. Pharmacokinetics
• partially absorbed following oral administration.
• steady-state plasma concentrations occurred after around 7 days of
dosing
• Safety and Tolerability
• dizziness and somnolence.
• Nervousness, headache, malaise, diarrhoea, constipation and
vomiting.
87. Efficacy
• Phase II studies are being performed to assess the efficacy and
safety of ganaxolone in adult patients with uncontrolled partial-onset
seizures, and in children with infantile spasms.
( Bialer M,Epilepsy Res 2009; 83: 1-43)
• In a randomized,double-blind study, ganaxolone, in dosages up to
1875 mg/day, had significant efficacy for refractory partial-onset
seizures in 52 patients who had other AEDs withdrawn during
epilepsy surgery assessment.
( Laxer K, Epilepsia 2000; 41: 1187-94)
88. STIRIPENTOL
• Granted in the european union in january 2007.
• Use adjunctively to clobazam and valproate in the treatment of
refractory generalized tonic–clonic seizures in patients with severe
myoclonic epilepsy in infancy (SMEI, dravet’s syndrome).
• Acts as a positive allosteric modulator at GABA- A receptors.
91. Principles of Management
• Combination Therapy
• pharmacomechanistic approach based on differing modes of
action
Latest Developments in Drug Therapy
Nondrug Therapy
surgical treatment
vagus-nerve stimulation
ketogenic diet
modified Atkins diet
92. New and Emerging Theapies
• intracranial and extracranial treatment systems of
electrotherapy or pharmacotherapy
• delivers scheduled electrical stimulation bilaterally to the
anterior nucleus of the thalamus. (class I evidence)
• “closed-loop system”:
• when the device detects epileptiform activity, it also
delivers electrical stimulation to the site of this activity
93. We are nearing the end of an era. The new one must
provide answers to at least some of these questions.
‘‘Hope springs eternal in the human breast’’, but
groundbreaking science would also help!