Newer Anti Epileptic Drugs

NEWER ANTI-EPILEPTIC
DRUGS
DR. AKSHAY KAWADKAR
DR. AKASH KAMBLE

OVERVIEW:-
 EPILEPSY
 TYPES
 OLDER AEDs
 NEWER AEDs
 GUIDELINES FOR ANTICONVULSANT THERAPY
 CONSIDERATIONS IN CHOOSING AN AED
 LIFESTYLE CHANGES TO MINIMIZE SEIZURES

EPILEPSY
 Term epilepsy is derived from the Greek word “Epilepsia”, which means ‘to be seized’, ‘to be taken hold
of’, or ‘to be attacked’
 Epilepsy:
 2 or more unprovoked seizures
 A condition in which a person has recurrent seizures due to chronic, underlying process. Characterized by,
- Recurrent seizures
- Loss of consciousness
- With or without body movements
 Seizure: “Paroxysmal event due to abnormal, excessive, hypersynchronous neuronal activity in the brain.”
(DERIVED FROM LATIN WORD- SACIRE MEANING “TO TAKE POSSESSION OF”)

BURST OF ACTION
POTENTIALS
HYPERSYNCHRONIZATION SEIZURE PROPAGATION
SEIZURE INITIATION

GENERAL CAUSES OF SEIZURE
Ref Harrison 20e pg 3055

REF - https://doi.org/10.1016/j.seizure.2010.10.027.
(https://www.sciencedirect.com/science/article/pii/S105913111000258X)

IDEAL PROPERTIES OF ANTI-EPILEPTIC DRUG
 Broad spectrum activity against all
seizure types
 High Efficacy
 Good tolerability
 No risk of allergic or idiosyncratic
reactions (including teratogenicity)
 Low interaction potential
 Favorable pharmacokinetics (linear
kinetics, half life compatible with once
or twice daily dosage)
 No tolerance to antiepileptic effects
 No withdrawal seizures
 No need for intensive laboratory
monitoring
 Availability of convenient formulations
(pediatric and parenteral )
 Low cost

 Despite a broad range of AEDs currently available, about 30 % of patients
with epilepsy are uncontrolled with available treatment and a further 25 %
suffer from manifestation of drug toxicity.
 In contrast to the relatively large number of anti-epileptics that can
attenuate seizure activity, there are currently no drugs known to prevent
the formation of seizure focus following CNS injury. The eventual
development of such “anti-epileptogenic” drugs will provide an important
means of preventing the emergence of epilepsy following injuries.
An introduction to Antiepileptic drug. Epilepsia 2005; 46 (Suppl 4): 31-37

REF - TEXTBOOK OF
PHARMACOLOGY BY
K.D.TRIPATHI

OLDER AED
 Phenobarbital 1912
 Phenytoin 1938
 Primidone 1952
 Ethosuximide 1960
 Carbamazepine 1974
 Valproate 1978
 Ethosuximide 1980

ADVERSE EFFECTS OF OLD AEDs
 PHENOBARBITONE – Dulling and behavioural changes
 PHENYTOIN - @Theraputic Level – Gum Hypertrophy, Hirsutism,
Hypersensetivity, Megaloblastic Anaemia, Foetal
Hydantoin Syndrome
@High Plasma Level – Cerebellar and Vestibular symptoms
(like ataxia, Diplopia, Nystagmus), Behavioural
alterations, Epigastric pain, Nausea, Vomitting
Phenytoin is potent Enzyme Inducer.
 CARBAMAZAPINE – Dose Related Neurotoxicity, Hypersensetivity, Lupus Like
Syndrome
 VALPROATE – Anorexia, Vomitting, Alopecia, Weight Gain, Fulminant Hepatitis in
Children

NEWER AED
 GABAPENTIN
 PREGABALIN
 LEVETIRACETAM
 FELBAMATE
 LAMOTRIGINE
 TOPIRAMATE
 TIGABAINE
 VIGABATRIN
 LACOSAMIDE
 OXCARBAZAPINE
 ESLICARBAZAPINE
 RUFINAMIDE
 RETIGABINE
 EZOGABINE

GABAPENTIN
 MOA - Modulates neurotransmitter release by binding to α2-δ subunit of voltage
gated Ca channels.
 Primary Indications –
- Adjunctive therapy or monotherapy of Focal or secondary generalized seizures.
- also used in Neuropathic Pain, postherpetic neuralgia, Fibromyalgia and
diabetic neuropathy.

GABAPENTIN
 Usual dosages –
Initial 300-900 mg/day
Maintenance : 900-3600mg/day
 ADR – drowsiness, dizziness, ataxia, headache, tremor, diplopia, nausea, vomiting,
non-pitting pedal edema, weight gain
 IT HAS LESSER DRUG INTERACTIONS AMONGST AEDs

PREGABALIN
 MOA - Binds to the α2- δ subunit of voltage gated calcium channels, causing
decreased calcium influx at nerve terminals and reduced excitatory
neurotransmitter release .
No effect on GABA pathways.
- Adjunctive therapy for partial seizure with or without secondary
generalization.
- also used in Neuropathic pain, Fibromyalgia and generalized anxiety
disorders.

PREGABALIN
Starting dose - 150 mg/day
Maintenance - 150-600 mg/day
 ADR - Dizziness, somnolence, ataxia, asthenia, weight gain, visual disturbances,
attention and concentration difficulties, tremor and peripheral edema
 IT HAS LESSER DRUG INTERACTIONS AMONGST AEDs

LEVETIRACETAM
 MOA – Binds to Synaptic Vesicle 2A (SV2A) protein. Precise mechanism by which
this binding acts is unknown but is likely to involve inhibition of neurotransmitter
release from nerve end terminals.
- First- line and adjunctive therapy of Focal-onset seizures.
- Adjunctive and, possibly, first line therapy of GTCS and Myoclonic seizures
associated with idiopathic generalized epilepsies.

LEVETIRACETAM
 Usual dosages
– Adults :1000-3000 mg/day. T/t may be started with 500 or 1000 mg/day and increased
to target dose by increments of 500 or 1000 mg every 1-2 weeks
Children : 20-60 mg/kg/day. T/t may be started with 10-20mg/kg/day and adjusted
according to response , by increments of 10-20 mg/kg/day every 2 weeks
 ADR - Behavioral and Psychiatric disorders, Nervousness, Irritability, Suicidal behaviour
 LEVETIRACETAM IS AN AED THAT IS MOST FREE FROM ADRs. MOST OF ADRs ARE DOSE
DEPENDENT AND REVERSIBLE.

LEVETIRACETAM
 LEVETIRACETAM IS RELATIVELY FREE FROM DRUG INTERACTIONS WITH OTHER
AED
 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

FELBAMATE
 MOA- Sodium channel blockade, potentiation of GABA a mediated inhibition and
antagonism of NMDA mediated responses
Not indicated as a First line agent.
Add-on treatment of Lennox-Gestaut Syndrome and partial and secondary
generalized seizure refractory to other agents.

FELBAMATE
 Usual dosages – Initial 1200mg/day (adults); 15mg/kg (children)
Maintenance : 1200-3600mg/day (adults);
15- 80mg/kg/day (children)
 ADR - Hepatotoxicity and Aplastic anemia are rare but serious
(due to Toxic Metabolite ATROPALDEHYDE).
 Dose modification is required in hepatic and renal diseases.
Pelleck JM et al. Felbamate :consensus of current clinical experience. Epilepsy
Res 2006;71:89-101

LAMOTRIGINE
 MOA – Blockade of voltage dependent sodium and calcium channels.
AMPA BLOCKER
- Adjunctive therapy and monotherapy of Focal seizures (with or without
secondary generalization) and primary GTCS.
- also useful for other generalized epilepsy syndromes, including Lennox- Gastaut
Syndrome, mostly as adjunctive therapy.
- Depressive Phase of Bipolar Disorder
 Pro-myoclonic effect in syndromes with predominant myoclonic jerks, such as
JME, Dravet syndrome and progressive myoclonic epilepsies.

LAMOTRIGINE
Initial 100-200 mg/day (>12 yrs. of age)
 ADR - Dizziness, diplopia, ataxia, blurred vision, insomnia, headache,
nausea
Skin rash (including serious cutaneous reactions ) lower with a low
starting dose and with a slow dose escalation. (SJS –TEN)
 IMPORTANT INTERACTIONS - Serum Lamotrigine levels are
increased by Valproic acid as Valproate reduces rate of
Lamotrigine elimination . (approx. doubled half life). It explains the
increased incidence of rash seen after starting add-on Lamotrigine in patiets
reveiving Valproate.
 LEAST TERATOGENIC AMONGST AED (SAFE IN PREGNANCY)

TOPIRAMATE
 MOA - Blockade of voltage dependent Na and Ca channels
- Potentiation of GABA mediated inhibition at GABA A receptors,
- Reduction of excitatory action of Glutamate via AMPA receptors
- Adjunctive therapy or monotherapy of Focal and secondary GTCS.
- also useful for Lennox-Gastaut Syndrome and primary generalised tonic
clonic seizures.
- Migraine prophylaxis

TOPIRAMATE
Initial - 25 mg/day
Maintenance - 100-500 mg/day (>12 yrs of age)
 ADRs – Dizziness, ataxia,, Angle closure Glaucoma, cognitive dysfunction,
confusion, diarrhoea, diplopia, Weight Loss, Renal stones, Metabolic acidosis
 SAFE IN PREGNANCY.

TIAGABINE
 MOA – Inhibition of GABA reuptake by
depressing GABA transporter GAT-1 which
removes synaptically released GABA into neurons
and glial cells and thus potentiates GABA
mediated neuronal inhibition.
 Primary Indications
- Adjunctive therapy for partial seizures, with or
without secondary generalization.

TIAGABINE
Starting dose - 5 mg/day, which may be increased by weekly increment of 5
mg/day
 ADR – Dizziness, tremor, attention/ concentration difficulties, depressed mood,
language problems (difficulty in finding words or inititating speech) , seizure
exacerbations (myoclonic and absence seizures)

VIGABATRIN
 MOA – Inhibition of GABA metabolism by inhibiton of GABA Transaminase
- Infantile Spasm in Tuberous Sclerosis
- Adjunctive therapy for Refractory Focal Seizures with Impaired Awareness

VIGABATRIN
Adult - Initial 500 mg Twice a day then increase 500 mg at weekly intervals,
Recommended dose- 1.5 gm twice daily
 ADR –
Bilateral visual field defects, Psychosis

LACOSAMIDE
 MOA – Enhances slow inactivation of voltage- gated sodium channels
resulting in stabilization of hyperexcitable neuronal membranes ;
may interact with Collapsin response mediated protein 2(CRMP2)
- Adjunctive therapy for refractory partial-onset seizure with or without
secondary generalization in adults with epilepsy.

LACOSAMIDE
Starting dose - 100 mg/day
 ADR – Dizziness , headache, Tremor
 Initial concerns were regarding QTc prolongation – but found to have no effect on
QTc at 800mg/day.
 Asymptomatic PR prolongation has been observed but no 2nd or 3rd degree Heart
block has been observed.

ZONISAMIDE
 MOA – Multiple including blockade of voltage gated Na channels, blockade of T-
type calcium channels, potentiation of GABAergic transmission.
- Adjunctive therapy for partial and secondary generalized seizures.
- May also be used as adjunctive therapy in primary generalized seizures.
- Myoclonic Epilepsies (Uncontrolled studies)

ZONISAMIDE
Starting dose - 50 mg/day initially, increased to 100 mg/day after 1 week and
200mg/day after a further 2 weeks. Further dose increments by 100mg/day may
be indicated at intervals of 1-2 weeks, according to clinical response.
 ADR –Attention and concentration difficulties, depression, anorexia, Weight loss,
Nephrolithiasis, skin rashes (including SJS) and hypersensitivity reaction.
Teratogenicity has been reported in animal studies. (cardiovascular defects,
skeletal abnormalities and fetal death)

OXCARBAZAPINE
 MOA – Blockade of voltage gated Na channels and N and P type calcium
channels.
- Adjunctive therapy or monotherapy for partial and secondary generalized
seizures.
- Also useful to treat primary generalized tonic clonic seizures not associated
with absence and myoclonic seizures.

OXCARBAZAPINE
Starting dose - 300 mg/day (5mg/kg/day), which may be increased by weekly
increment of 300 mg/week
Maintenance - 900-1800 mg/day (20-45 mg/kg/day)
 ADR – Dizziness, diplopia, ataxia, somnolence, headache, fatigue, rash,
HYPONATREMIA, gastrointestinal disturbances

ESLICARBAZAPINE
 MOA – Blockade of voltage gated sodium channels resulting in stabilization of
hyper-excitable neuronal membranes
- Adjunctive therapy for Focal seizures. (potential additional indications are
under assessment)

ESLICARBAZAPINE
800 – 1200mg/day (tentative dose range)
 ADR – Dizziness , blurred vision, headache, nausea, diplopia, nausea, vomiting,
Visual Disturbances

RUFINAMIDE
 MOA – Prolongation of the inactive state of sodium channels and slows sodium
channel recovery.
- Focal Epilepsy
- Drop attacks in Lennox Gastaut Syndrome (LGS).

RUFINAMIDE
400 to 800 mg/day in 2 equally divided doses; increase dose by 400 to 800
mg/day every other day to a maximum dose of 3.2 g/day in 2 equally divided doses
 ADR - Dizziness, nausea, diplopia, leukopenia, anaemia, QT shortening
RUFINAMIDE IS CONTRAINDICATED IN PATIENTS WITH FAMILIAL SHORT QT
SYNDROMES.

RETIGABINE AND EZOGABINE
 Mechanism of action – Activation of voltage gated neuronal Potassium channels .
[KCNQ (kv7)]
- Adjunctive therapy for refractory Focal seizure.

RETIGABINE AND EZOGABINE
600-1200 mg/day. Treatment started at 300mg/day and increased at weekly
intervals by 150mg/day upto desired target dose.
 ADR –
Dysarthria, Urinary hesitancy/retention, Blue coloured pigmentation on skin and
lips

PERAMPANEL
 MOA – ANTAGONIST OF AMPA RECEPTOR OF GLUTAMATE
 Primary Indications - Add-on therapy for drug-resistant focal epilepsy
 Usual doses - Initial: 2 mg once daily at bedtime; may increase daily dose by 2 mg
once daily no more frequently than at weekly intervals based on response and
tolerability. Recommended maintenance dose: 8 to 12 mg once daily
 ADR - Serious psychiatric and behavioral reactions, such as aggression, hostility,
irritability, anger, and homicidal ideation

DRUGS IN PIPELINE
 DRUGS DECREASING NEURONAL
EXCITATION
A. Blockade of sodium channel
• Brivaracetam
• Carisbamate
B. Inhibition of glutamate release/ AMPA
antagonist
• NS 1209
• BGG 492
 DRUGS ENHANCING NEURONAL
INHIBITION
• Ganalaxone
• Stiripentol
• CPP 115
• Valrocemide

DRUGS IN PIPELINE
 NOVEL AGENTS -
1. Anti-inflammatory: Belnacasan (VX 765)
2. Pro-drug of Valproic acid: SPD 421, Valnoctamide
3. Chloride importer blockade: Bumetanide
4. Drugs acting on potassium channels
• YKP 3089
• ICA 105665
5. Melatonin
6. 5HT receptor agonist: Naluzotan

BRIVARACETAM
 Pyrrolidone derivative in the same class as levetiracetam that continues to
undergo clinical trials.
 MOA - Like levetiracetam, it binds to the synaptic vesicle protein 2A (SV2A)

CARISBAMATE
 Novel neuromodulator
 Proposed mechanism of action: Inhibit voltage gated sodium channel & modest
inhibition of voltage gated calcium channel

GANOLOXONE
 An allosteric modulator of the GABA-A receptor complex
 Used in Catamenial Epilepsy

STIRIPENTOL
 MOA - It enhances GABA release and prolongs GABA-mediated synaptic events in
a manner similar to phenobarbital.
 Primary Indications
- DRAVET SYNDROME (Severe Myoclonic Epilepsy of Children)
- Stiripentol has some efficacy as an adjunctive therapy in children.
- ADJUVANT TO CLOBAZAM OR VALPROATE
 Usual dosages - 50 mg/kg/day given in 2 or 3 divided doses. Maximum dose: 3
g/day
 ADR – Drowsiness, Ataxia, Decreased Appetite, Aggressive behaviour

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.
 Drug interaction, efficacy and adverse effects are presently unknown.

FLUROFELBAMATE
 Analogue of Felbamate, devoid of toxic metabolite (Atropaldehyde).
 So designed to emulate clinical efficacy of Felbamate without its safety concerns
(aplastic anemia and hepatotoxicity)

JZP-4
 Structural analogue of Lamotrigine with better pharmacokinetic and safety profiles
compared to Lamotrigine.
 Potent sodium and high voltage calcium channel blocker.

SELETRACETAM
 An analogue of Levetiracetam
 Is approximately 10 fold more potent than Levetiracetam in some experimental
models.

NEW FORMULATIONS
 INTRANASAL
- DIAZEPAM
- MIDAZOLAM
 Absorption from nasal mucosa within 2 – 5 minutes
 Rapid penetration into the central nervous system
 Cost effective and feasible to administer to adults as well
Study to Evaluate the Safety and Efficacy of USL261 (Intranasal Midazolam) in Patients with Seizure
Clusters (ARTEMIS1). http://www.clinicaltrials.gov/show/NCT01390220.

AED EFFECTS
 DRUGS THAT DECREASE EFFICACY OF
OCP –
- Phenytoin
- Carbamazepine
- Phenobarbital
- Primidone
- Topiramate at higher doses
- Oxcarbazepine
 RISK OF WEIGHT GAIN
- VALPROATE
- GABAPENTIN AND PREGABALIN
 RISK OF WEIGHT LOSS
- TOPIRAMATE
- ZONISAMIDE
- FELBAMATE

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
firstline 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)

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

When to STOP AED
 Complete Medical Control of seizures for 1-5 years.
 Single Seizure Type. (Generalised better Prognosis than Focal)
 Normal Neurological Examination ( Including Intelligence )
 No Family h/o Epilepsy
 Normal EEG
It seems reasonable to attempt withdrawl of therapy after 2 yrs in patients meeting all
above Criteria.

TRIALS TO COMPARE NEW AND OLD
ANTI EPILEPTICS
1) Standard And New Antiepileptic Drugs (SANAD) Trial
SANAD was an unblinded randomized controlled trial in hospital-based
outpatient clinics in the UK.
2) Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Trial
A prospective observational study of Fetal antiepileptic drug exposure and
cognitive outcomes

CONCLUSION OF TRIALS
 New antiepileptic drugs offer many options in the treatment of epilepsy, each with
unique mechanisms of action as well as adverse effect profiles.
 Although there is no evidence to suggest that the newer medications are more
efficacious, The new antiepileptic drugs are-
1. Well tolerated with few adverse effects,
2. Minimal drug interactions, and
3. A broad spectrum of activity.
LaRoche SM, Helmers SL. The new antiepileptic drugs:
scientific review. JAMA. 2004 Feb 4;291(5):605-14. doi:
10.1001/jama.291.5.605. PMID: 14762040.

LIFESTYLE CHANGES TO MINIMISE SEIZURES
 Avoid sleep deprivation
 Avoid alcohol
 Treat fevers quickly
 Occasional patients should avoid specific factors such as strobe lights, etc
 Pill boxes/reminders

REFERENCES
 Essentials of Medical Pharmacology BY K.D.TRIPATHI
 Basic and Clinical Pharmacology 14th Edition (A & L LANGE SERIES) BERTRAM G. KATZUNG
 Harrison's Principles of Internal Medicine, 20e
 Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e
 Pharacokinetics of Levetiracetam in patients with moderate to severe liver cirrhosis: Clin Pharmaco ther
2005;77;529-541
 Clinical Pharacokinetics of Levetiracetam : Clin Pharmacokinet 2004;43;707-724
 An introduction to Antiepileptic drug. Epilepsia 2005; 46 (Suppl 4): 31-37
 Pelleck JM et al. Felbamate :consensus of current clinical experience. Epilepsy Res 2006;71:89-101
 The SANAD study of effectiveness of carbamazepine, gabapentin, Lamotrigine, oxcarbazepine or
Topiramate for treatment of Partial epilepsy :an unblinded randomised controlled trial LANCET
2007;369;1000-1015
 Zonisamide and renal calculi in patients with Epilepsy : how big an issue? Wroe S. : Curr MedRes Opin
2007;23;1765-1773

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