2. Introduction
Prior to 1993, the choice of an anticonvulsant medication was limited to
the “traditional” anticonvulsants [Phenobarbital, Primidone,
Phenytoin, Carbamazepine, and Valproate.]
Newer antiepileptic drugs
fewer drug interactions
unique mechanisms of action
broader spectrum of activity.
3. ANTIEPILEPTIC DRUG DEVELOPMENT
1840 1860 1880 1900 1920 1940 1960 1980 2000
0
5
10
15
20
Bromide
Phenobarbital
Phenytoin Primidone
Ethosuximide
Sodium Valproate
Benzodiazepines
Carbamazepine
Zonisamide
Felbamate
Gabapentin
Topiramate Fosphenytoin
OxcarbazepineTiagabine
Levetiracetam
Rufinamide
Lacosamide
Brivaracetam
Pregabalin
Retigabine
?
Calendar Year
NumberofLicensedAntiepilepticDrugs
Lamotrigine
LaRoche SM et al. JAMA, February 4, 2004—Vol 291, No. 5
6. Levetiracetam (1999)
• Monotherapy in the treatment of partial onset seizures with or
without secondary gen. from 16 years of age with newly diagnosed
epilepsy.
• Adjunctive therapy
A.partial onset seizures with or without secondary generalization in
adults, children and infants from 1 month of age with epilepsy
B.myoclonic seizures in adults and adolescents from 12 years of age
with JME
C.primary generalized tonic-clonic seizures in adults and adolescents
from 12 years of age with IGE
7. Mechanism of action
Targets synaptic vesicle protein 2A (SV2A) which has a crucial
role in the regulation of vesicle formation and fusion
8. Advantages
broad spectrum- significance:- clinicians without expertise in
differentiating focal and gen. Sz
good safety profile, no significant idiosyncratic reactions
slow titration not needed, starting dose is often therapeutic for
all forms of seizures and epilepsies.
easier to use as part of polytherapy as it has no significant drug
interactions
No interaction with OCPs
It does not interfere with liver function (a major problem with
most other AEDs that are metabolized in the liver)
9. Main ADRs
somnolence, asthenia and dizziness: dose dependent and reversible
headache, common cold or upper respiratory infections, anorexia
and behavioral disturbances.
interferes with rapid motor learning in humans due to suppression
of excitatory activity in the motor cortex
Need to monitor for changes in behavior, emergence or worsening
of suicidal thoughts/behavior or depression
10. Dosage and titration
Adults
Start - 1000 mg/day (twice-daily dosing), which may be
sufficient for seizure control
can be titrated by 500 mg/week to max 3000 mg/d
Children:
Start with 5–10 mg/kg/day, which may be sufficient for seizure
control.
If needed titrate by 5–10 mg/kg/week to a usual maintenance
dose of 20–40 mg/kg/day given in two divided doses.
11. Considerations in women
Pregnancy: category C
In the UK Epilepsy and Pregnancy Register of 117 pregnancies
exposed to Levetiracetam only three infants (all in the
polytherapy group) had a Major Congenital Malformation.
Breastfeeding: There is an extensive transfer of Levetiracetam
from mother to fetus and into breast milk.
However, breast-fed infants have very-low Levetiracetam plasma
concentrations, suggesting a rapid elimination of Levetiracetam.
Hunt S et al. Neurology 2006;67:1876–9.
12. Drug interactions
does not influence plasma conc. of existing AEDs.
Enzyme inducers may decrease Levetiracetam plasma levels by
20–30%.
Other non-AEDs
no known interactions with other drugs such as OCP, warfarin
and digoxin.
Contin M et al. Ther Drug Monit 2004;26:375–9.
13. Lacosamide (2008)
Tablets are indicated as adjunctive therapy in the treatment of focal
seizures in patients with epilepsy aged 17 years and older.
IV use is indicated as adjunctive in focal seizures in age >17 years
when oral administration is temporarily not feasible
MoA
Lacosamide selectively enhances slow inactivation of voltage-
gated sodium channels, resulting in stabilization of hyper
excitable neuronal membranes and inhibition of repetitive
neuronal firing
Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
14. Dosage and titration
Start with 50 mg twice daily (100 mg/day).
Increase at weekly intervals by 100 mg/day to 200–400 mg/day.
Maximum recommended dose- 400 mg/day because higher doses
may be associated with CNS and gastrointestinal ADRs.
Maximum 300 mg/day for mild or moderate hepatic impairment
15. Main ADRs
Frequent : Dizziness, headache, diplopia, nausea, vomiting and blurred vision.
Serious: A small, asymptomatic, dose-related prolongation of PR interval on
ECG
caution in patients with known conduction problems
severe cardiac disease
in the elderly
in co-medication with drugs known to be a/w PR prolongation.
Considerations in women
Pregnancy: category C
Breastfeeding: unknown but possibly excreted in breast milk (animal data).
No Interactions with hormonal contraception
16. Drug interactions
Minimal, probably of no clinical significance.
does not affect plasma levels of carbamazepine, gabapentin,
lamotrigine, Levetiracetam, oxcarbazepine, phenytoin, valproate.
does not affects plasma concentration of OCPs
On the other hand:-Carbamazepine, phenytoin and
phenobarbital may decrease plasma levels of Lacosamide by 15–
20%
17. Zonisamide
efficacious in focal and generalizes seizures, West syndrome,
Ohtahara, and Unverricht syndrome
Adjunctive therapy in adult patients with focal seizures with or
without secondary generalization.
MOA
Zonisamide blocks the sustained repetitive firing of voltage-
sensitive sodium channels.
Reduces voltage-dependent T-type calcium current
Tosches WA et al. Epilepsy Behav 2006;8:522–6.
18. Dosage and titration
Adults:
Start with 100 mg/day in one or two equally divided doses
After two weeks, the dose may be increased to 200 mg/d
controlled trials suggests doses of 100–600mg/d are effective
Children:
start with 1–2 mg/kg/day for the first week and titrate in
increments of 1–2 mg/kg/day every 2 weeks
childhood maintenance dose is 4–8 mg/kg/d
20. Vigabatrin
structural analogue of GABA, irreversibly inhibits GABA
transaminase
Indications: first line infantile spasms in children with tuberous
sclerosis
Especially in whom use of hormonal treatment (corticosteroids,
ACTH) is contraindicated.
Efficacy: spasm cessation is greatest in tuberous sclerosis complex
(74%) compared with other symptomatic etiologies (50%)
Side effects: bilateral concentric peripheral visual field constriction
21. Dosage
Pediatric doses 50 to 150 mg/kg/day
may be increased by 30-40 mg/kg/d every 4-5 days till maximum
time to response is quite short, within 2 weeks.
If infant shows no improvement in spasms within 2 weeks,
vigabatrin should be discontinued
In good response, consider stopping after 6 months
22. Rufinamide
a triazole derivative with a novel structure
MoA: reduces the recovery capacity of neuronal sodium channels
after inactivation, prolonging their inactive state by limiting
neuronal sodium-dependent action potential firing.
indications - Lennox–Gastaut syndrome in >4 yrs old
Future: probably as adjunctive for intractable focal epilepsies.
Cheng-Hakimian A et al. Int J Clin Pract 2006;60:1497–501.
23. Dosage and titration
Adults and children >30 kg
start - 400 mg/d.
increments of 400 mg/day as frequently as every 2 days.
Maximum -1800 mg/day (in the 30–50 kg weight range)
Palhagen S et al. Epilepsy Res 2001;43:115–24.
24. Main ADRs
Frequent and/or important:
headache, dizziness, fatigue, somnolence, ataxia and gait
disturbances.
Serious:
Status epilepticus
hypersensitivity syndrome
shortening of the QT interval (by up to 20 msec)
contraindicated in familial short QT syndrome
Arroyo S. Neurother 2007;4:155–62.
25. Topiramate
recommended for all types of seizures –
focal or generalized, and idiopathic or symptomatic – in adults and
children including epileptic encephalopathies, such as West syndr and
Lennox–Gastaut syndrome
Initial monotherapy for focal onset or primary GTCSs in patients ≥10 of
age.
Adjunctive therapy for adults and pediatric patients aged 2–16 years with
partial onset seizures, or primary generalized tonic-clonic seizures.
In patients 2 years of age and older with seizures associated with Lennox-
Gastaut syndrome.
26. Mechanisms of action
a. Blockage of voltage-dependent sodium channels.
b. Augmentation of the inhibitory activity of GABA at some
subtypes of the GABA-A receptor
c. Antagonism with the AMPA subtype of the glutamate receptor.
d. Inhibition of the carbonic anhydrase enzyme.
27. Dosage and titration
‘Start very low and go very slow’ is particularly important
Adults and children over 16 years:
start with 25 mg/day for the first week
Titrate in increments of 25 or 50 mg/day in two equally divided doses
at 1 or 2 week intervals.
maintenance dose is 200–400 mg/day.
Children 6–16 years:
start treatment with 25 mg or 1–3 mg/kg/day for the first week.
Titrate with increments of 1–3 mg/kg/day in two divided doses at1- or
2-week intervals.
maintenance dose of 5–9 mg/kg/day in two divided doses.
Renal impairment: half of the usual dose
28. Main ADRs
Somnolence, anorexia, fatigue and nervousness.
Abnormal thinking, mental slowing, word-finding difficulties
Difficulty with concentration/attention, memory impairment,
psychomotor slowing and speech disorders
Weight loss (10% of patients)
paraesthesiae and abdominal pains.
Metabolic acidosis, Nephrolithiasis
Acute myopia with 20
angle-closure glaucoma
Hypohydrosis
Ojemann LM et al. Epilepsy Behav 2001;2:579–84.
29. Drug interactions
In co-medication, phenytoin plasma levels may increase by 25%
and topiramate may decrease by 48%.
probably no interaction with lamotrigine and Levetiracetam,
minimal interactions with valproate
Concomitant use with other carbonic anhydrase inhibitors, such as
zonisamide, should probably be avoided
30. Lamotrigine (1994)
MoA: inhibition of voltage gated sodium channels
all types of seizures except myoclonic jerks
Indications
Adjunctive therapy for focal seizures and primarily GTCS in ≥2 years of
age.
Adjunctive therapy for the generalized seizures of Lennox–Gastaut
syndrome.
Conversion to monotherapy in adults (≥ 16 years of age) with focal
seizures who are receiving treatment with carbamazepine, phenytoin,
phenobarbital, primidone or valproate as the single AED
31. Dosage and titration
Adults and children over 12 years (monotherapy)
Start with 25 mg once daily for 2 weeks.
Followed by 50 mg once daily for 2 weeks.
usual maintenance dose : 100–200 mg/day given OD / BD
32. ADRs
An allergic skin rash MC- approximately 10% of patients.
Stevens–Johnson syndr- approx. 1/300 adults & 1/100 children.
The incidence of skin rash can probably be reduced by starting
treatment with a low dose spread over longer intervals
Significant interactions with other AEDs
Pro-myoclonic effect in syndromes with predominant myoclonic
jerks, such as JME, Dravet syndrome and progressive myoclonic
epilepsies.
33. Drug interactions
Valproate inhibits metabolism of lamotrigine, doubling or tripling
its half-life.
Enzyme inducers, such as carbamazepine, phenytoin and
phenobarbital, accelerate its elimination.
34. Oxcarbazepine
Authorized indication:
monotherapy or adjunctive therapy in focal seizures in adults
monotherapy in focal seizures in children >4 years
Mechanism of action:
Like carbamazepine, blockade of voltage-sensitive sodium channels
is its main mechanism of action.
35. Oxcarbazepine versus carbamazepine
similar to CBZ in efficacy and MoA
better tolerated and fewer interactions with other drugs because it
does not undergo metabolism to epoxide
does not involve hepatic CYP enzymes for its metabolism.
lower incidence of idiosyncratic reactions
Hyponatremia is more common with OXC
36. Dose
Adults: start treatment with 150 mg/day and increase by 150
mg/day every second day until a target dose of 900–1200 mg/day
is reached.
In impaired renal function (creatinine clearance <30 ml/min),
OXC should be initiated at one-half of the usual starting dose.
37. ADRs
MC- headache, dizziness, fatigue, nausea, somnolence, ataxia and
diplopia.
skin rash of OXC is 2% (adults) and 5% (children), vs 5–10% with
carbamazepine.
Hyponatremia (<125 mmol/l) - in 3%
contraindicated in h/o AV block.
38. Disadvantages
contraindicated in generalized seizures, such as absences or
myoclonic jerks in syndromes of IGE
One out of four patients have cross sensitivity to idiosyncratic
reactions with CBZ or other AEDs
Although it is among the first-choice AEDs for monotherapy in
focal epilepsies, its use as polytherapy is less satisfactory because of
drug interactions
39. Tiagabine (1997)
Its authorized indication is adjunctive treatment of partial-onset seizures
in persons 12 years or older.
MoA- blocking reuptake of GABA into neurons and glial cells.
M.C. ADR- dizziness, tremor, impaired concentration.
Tiagabine undergoes extensive hepatic oxidation via the cytochrome P450
system but has not been shown to induce or inhibit hepatic enzyme
function
thus negligible effects on other drugs, including other antiepileptic
drugs.
40. Felbamate (1993)
approved for both monotherapy and adjunctive treatment of
partial-onset seizures in adults and partial- and generalized-onset
seizures a/w LGS in children
acts by potentiation of GABA responses via its interaction with a
site on the GABA-A receptor and inhibition of NMDA receptors via
a channel-blocking action.
M.C. ADRs- GI disturbances, anorexia, insomnia.
Aplastic anemia and hepatic failure are the most serious side
effects, usually seen during first 6–12 months of therapy.
41.
42.
43. SANAD trial
Standard And New Antiepileptic Drugs
SANAD trial randomized 1900 patients with epilepsy into 2 arms ( A & B)
one arm compared new drugs with carbamazepine and the other compared
new drugs with valproate.
Arm A evaluated carbamazepine (CBZ) versus gabapentin (GBP) versus
lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM) in
partial seizures.
Arm B evaluated valproate (VPS) vs LTG vs TPM in generalized seizures
Main outcome measure was Time to treatment failure and time to achieve a
12-month remission of seizures
Marson A.G et al. The SANAD trial. Health Technol Assessm 11: 1–154.
44. Results of SANAD trial
Arm A
LTG had the lowest incidence of treatment failure, statistically
superior to all drugs except OXC.
About 12% fewer patients experienced treatment failure on LTG
than CBZ at 1year after randomization.
Health economic analysis supported LTG being preferred to CBZ for
both cost per seizure avoided and cost per quality-adjusted life-year
gained.
45. ARM B
VPS was the drug least likely to be a/w treatment failure for
inadequate seizure control and was the preferred drug for time to
achieve 12-month remission.
The health economic assessment supported the conclusion that VPS
should remain drug of choice for IGE.
46. Conclusions
LTG may be a clinical and cost-effective alternative CBZ.
In IGE or difficult to classify epilepsy, VPS remains the clinically
most effective drug
Limitation
Since that trial, 3 new AED were licensed (Levetiracetam,
Zonisamide and Pregabalin)
47. Substitution Monotherapy With Levetiracetam vs Older
Antiepileptic Drugs: A Randomized Comparative Trial.
OBJECTIVE To determine whether patients who fail their first antiepileptic
drug (AED) have better neuropsychiatric and quality-of-life (QOL) outcomes
with Levetiracetam monotherapy compared with a second older AED
Participants with partial epilepsy who had failed monotherapy with phenytoin
sodium, carbamazepine, or valproate sodium were randomized to substitution
monotherapy with Levetiracetam or a different older AED.
Result: no differences w.r.t depression scores at 3 months, but a greater
proportion of older AED group improved on the 89-item Quality of Life in
Epilepsy Inventory compared with the Levetiracetam group
Arch Neurol. 2012 Dec;69(12):1563-71
48. AAN and AES- 2004
Efficacy and Tolerability of the New Antiepileptic Drugs, I:
Treatment of New Onset Epilepsy
Question : How does the efficacy and tolerability of the new AEDs
compare with that of older AEDs in patients with newly diagnosed
epilepsy?
Conclusion
new AEDs may be better tolerated than the standard, with equivalent
efficacy.
However new drugs are all substantially more expensive than the old.
There is no literature that addresses the cost-benefit.
49. Under development
Eslicarbazepine acetate, recently licensed as an adjunctive agent
in partial epilepsy is structurally linked to carbamazepine and
oxcarbazepine.
In phase III clinical trials eslicarbazepine was well tolerated, with
the most common AEs reported to include dizziness, headache, and
somnolence.
Elger C et al. Epilepsia 50:454-63.
50. Brivaracetam
pyrrolidone derivative in the same class as levetiracetam that
continues to undergo clinical trials.
Like levetiracetam, it binds to the synaptic vesicle protein 2A.
An exploratory, phase IIb, double-blind, randomized, parallel-
group, placebo controlled study using brivaracetam doses of 5, 20,
or 50 mg/day was performed; tolerability was good, with only 2.6%
of patients discontinuing drug due to ADRs, compared with 3.7% in
the placebo arm.
French JA et al. Neurology 75: 519–525
51. Retigabine
acts by opening the KCNQ potassium channel, leading to neuronal
hyperpolarization.
In a double-blind, randomized, placebo-controlled Phase II clinical trial,
retigabine was added to the treatment regimen of 399 participants with
partial seizures that were refractory to therapy with other antiepileptic
drugs. The frequency with which seizures occurred was significantly
reduced (by 23 to 35%) in participants receiving retigabine.
Brodie M et al. Epilepsia 49(Suppl. 7): 110.
52. Ganaxolone
an allosteric modulator of the GABA-A receptor complex.
In a 3-month pediatric study, subjects with refractory infantile
spasms 25% showed a > 50% reduction in seizures, and one patient
was seizure free
may also have efficacy for catamenial seizures.
53. Stiripentol
As an adjunctive to clobazam and valproate for refractory GTCS as
in Dravet syndrome
enhances central GABA transmission
inhibits metabolism of concurrently AEDs
In a randomized, double-blind, placebo controlled trial it was used
as an adjunctive therapy in refractory Dravet syndrome and was
shown to have better response rate (71%) than placebo (5%)
54. Perampanel
selective, non-competitive antagonist of AMPA-type glutamate
receptors,
currently in clinical development as adjunctive therapy for the
treatment of refractory partial-onset seizures
Efficacy and tolerability as adjunctive in >12 years with refractory
partial-onset seizures has been demonstrated in three phase III,
randomized, doubleblind, placebo-controlled trials
55. 2-DEOXY-D-GLUCOSE
Differs from normal Glucose by lacking an Oxygen atom at 2
position.
MOA- intake into cells is not followed by metabolism-leading to
inhibition of Glycolysis – supposed to decrease epileptogenesis.
Effective in various animal models.
Drug interaction, efficacy and adverse effects are presently
unknown.
The Journal of Neuroscience, 31 October 2007, 27(44): 12007-120117
56. Fluorofelbamate
Analogue of Felbamate, devoid of toxic metabolite (Atropaldehyde).
So designed to emulate clinical efficacy of Felbamate without its safety
concerns ( aplastic anemia and hepatotoxicity)
Exact MOA is unknown, but appears to decrease responses to GABA,
kainate and NMDA and to decrease voltage dependent sodium currents.
Shown to have greater potency than Felbamate in experimental models
Drug interaction, efficacy and adverse effects are presently unknown.
Seizure. 2002 Oct;11(7):423-30
57. JZP-4
Structural analogue of Lamotrigine with better pharmacokinetic
and safety profiles compared to Lamotrigine.
Potent sodium and high voltage calcium channel blocker.
Co adminstration of valproic acid did not result in any significant
change in JZP-4 pharmacokinetics.
Drug interaction, efficacy and adverse effects are presently
unknown.
Pharmacol Biochem Behav. 2008 Jun;89(4):523-34 In vivo pharmacological
effects of JZP-4, a novel anticonvulsant
58. Seletracetem
An analogue of Levetiracetam.
Is approximately 10 fold more potent than Levetiracetam in some
experimental models.
Drug interaction, efficacy are presently unknown.
Well tolerated
Most frequently encountered adverse effect is somnolence,
dizziness, euphoria and nausea.
J Neuro Sci 2005;238 : Matagne et al : Seletracetam (UCB 44212)
59. YKP3089
A novel compound with broad spectrum anticonvulsant activity.
MOA is unknown
Effective in all kinds of experimental models.
Drug interaction, efficacy and adverse effects are presently
unknown.
Epilepsy Res. 2007 Jan;73(1):1-52.
60. Conclusion
It is impossible to conclude that 'all old AEDs are bad' or 'all new
AEDs are good'.
Some of the newer AEDs such as gabapentin, Levetiracetam,
Tiagabine, and Pregabalin are unlikely to cause systemic safety
issues, whereas these were associated with all of the older AEDs.
The absence of hepatic enzyme induction/inhibition with most of
the newer AEDs provides one major advantage.
In the end, drug selection must be based on individual patient and
drug characteristics.
![Introduction
Prior to 1993, the choice of an anticonvulsant medication was limited to
the “traditional” anticonvulsants [Phenobarbital, Primidone,
Phenytoin, Carbamazepine, and Valproate.]
Newer antiepileptic drugs
fewer drug interactions
unique mechanisms of action
broader spectrum of activity.](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)