AEDs

Antiepleptic Drug Therapy
Presenter-Dr Avinash Singh

Moderator- Lt Col Reema Solanki
The Brain
An extremely complex organ

made up of billions of
connections between neurons.
These connections are each

highly controlled and regulated.
Nerve Cell Communication
 Neurons communicate
between themselves using
small molecules called Sodium
Ions/Channels
neurotransmitters.
Potassium Ions/
Channels
 These neurotransmitters
modulate and regulate the
electrical activity of a given
neuron, and tell it when to fire
an action potential or when
not to.
- Glutamate = excitatory
(tells the neuron to fire)
- GABA = inhibitory (dampens
the neuron firing rate)
 The action potential is an electrical signal that travels down the axon, and is created
using sodium ions (Na+), and inhibited by potassium ions (K+).
 Usually these processes work synergistically to produce normal behavior and activity.
 When dysfunctional, abnormal electrical activity occurs and can produce seizures.
Indications of initiation of AEDs
After 1st seizure episode- if a/w

I. Abnormal neurodevelopmental status
II. Abnormal neurological finding/ focal signs
III. Positive family history
IV. MRI finding
V. EEG abnormality
Introduction
 Most children with new-onset epilepsy achieve seizure freedom with

appropriate AED- Mono/Polytherapy
 However 20% remain symptomatic despite newly developed
antiepileptic molecules which claims to have better efficacy with less
adverse effects
 The superiority of newer AEDs in terms of Efficacy and side effects
have been tested against placebo only till date.
AEDs not Indicated in
 BCECTS (Benign Childhood Epilepsy with Centrotemporal spikes) or
Rolandic epilepsy
 1st episode of generalised seizure without positive clinical sign/ family

history/ EEG or MRI abnormality
Mechanisms of Action
Mechanisms of Action
AEDs primarily acts upon
 At presynaptic membrane on
 Voltage gated Na channel
 High Voltage Activated Ca ion
 SV2A receptor on neurotransmitter (Glutamate) vesicles
 At postsynaptic membrane on
 AMPA receptor
 NMDA receptor
 T-type Ca channel
 GABA receptor
 At postsynaptic inhibitory neuron on
 GABA transporter-GAT-1 & GAT-3
 GABA transaminase inhibition
Molecular targets and indications of AEDs
Choice of AEDs
Choice of AEDs are generally based upon-

 Type of seizure
 Associated syndrome/ risk factor
 Individual factors
Commonly indicated AEDs

 Focal onset- OXC, CBZ, LEV, LTG, PB, PHT, TPM, TPM, VGB
 Primary generalised tonic-clonic- LEV, LTG, TPM
 Juvenile myoclonic epilepsy- LEV, LTG, TPM
 Benign myoclonic epilepsy- VPA
Nelson textbook paediatrics-21st edition

Choice of AEDs in West Syndrome & Infantile Spasm
DOC- Hormonal therapy- ACTH or pulse dose Methylprednisolone or

low dose oral prednisolone
Efficacy- ACTH> Steroids
 Dosage & administration & monitoring:

Inj ACTH- 75 units/m2 IM BD for 02 wks→ 30 units/m2 IM OD
(morning dose) for 03 days → 15 units/m2 IM OD (morning dose) for 03 days →
10 units/m2 IM OD (morning dose) for 03 days → 10 units/m2 IM A/D (morning
dose) for 06 days
 Response observed within 01 week
 If relapse spasm during tapering- Remediation with previously
effective dose for 02 weeks → Taper
 Monitoring with EEG- sleep & awake @1st →2nd →4th wks of therapy with
aim of clearing EEG from hypsarrhythmia
Choice of AEDs in West Syndrome & Infantile Spasm
 DOC: Infantile spasm with Tuberous Sclerosis- Vigabatrin
Adv effect: 30% chance of irreversible retinal toxicity with long term
use (>6 months) leading visual field defects
 3rd line treatment:
 Ketogenic diet
 Other alternatives:
 VPA
 CPZ
 TPM
 Pyridoxine
 IVIg

Choice of AEDs
 Lennox-Gastaut syndrome:
 For drop attacks- tonic/ atonic/ myoclonic astatic: CLB/ VPA/ LTG
 If a/w atypical absence seizure- DOC- VPA
 CZP (Clonazepam) : Effective but limited use due to serious side

effects- sedation, hyperactivity, drooling and due to ↑R/O tolerance
within few months.
 Other alternatives- Ketogenic diet, Levetiracetam, IVIg, Cannabidiol

(in children> 02 yrs of age)

Choice of AEDs
 Dravet Syndrome:
 Clobazam (CLB)
 Valproate (VPA)
 Stiripentol- as adjuvant therapy
 Drug interaction- Stiripentol ↑level of CLB & VPA ↑level of Stiripentol
 Contraindication: LTG, OXC, CBZ, PHT. Barbiturates are
contraindicated in status a/w Dravet syndrome
 Alternative: Cannabidiol

Choice of AEDs
 Absence seizure:
 Ethosuximide (ETS)/ VPA/ LTG
 Efficacy: ETS= VPA >LTG
 Adv. Effects: VPA> ETS> LTG
 DOC: ETS
 EEG monitoring more helpful than observation of care givers
 Other drugs- Acetazolamide, Zonisamide, Clonazepam
 Contraindication: OXC, CBZ & Tiagabine

Special Considerations on Choice of AEDs
 Valproate- Should be avoided in children <02 yrs, as component of

polytherapy and suspected or known cases of liver disease, IEM and
Mitchondriopathy
 GABA-ergic drugs like- PGB, GPT, CLB, CZP, Barbiturates, LEV,
VPA
Should be avoided in children with ADHD and Behavioural problem
 Ease of intiation: IV AEDs are preferred when rapid therapeutic levels are
desired. TPM/ LTG/ Cannabidiol/ CBZ required to be started at low dose and
increased gradually
 Cost/ Availability/ Ease of administration
 Ease of monitoring- Newer AEDs do not require blood level monitoring
 History of Prior response with known AED

 Drug interactions:
 Enzyme inducers- PB, CBZ, PHT→ Reduces levels of VPA, LTG and OCP
 Enzyme inhibitors- VPA → Increases levels of PB, LTG & also ↑plasma free
fraction of PHT by displacing protein bound PHT from its protein binding
site; though total plasma PHT level remains same
 Comorbidity:
 Migraine- preferred AEDs Valproate, Zonisamide, Topiramate
 Obesity- Avoid Valproate. Preferred Topiramate, Zonisamide
 Girls with child bearing potential- Avoid VPA as it can lead to fetal
malformations; like- NTD, Hypospadias, cleft lip-palate
 Co- existing seizures:
e.g- Absence+ generalized tonic-clonic- broad spectrum AEDs like VPA, LTG
are preferred

 Mech. Of actions- in cases where polytherapy is required; AEDs with different
mode of actions are preferred
 Subjective preferences: effective alternatives AEDs might depends on

patient/family; eg some patients might want to avoid hirsutism and gingival
hyperplasia but may tolerate obesity
 Teratogenic profile: Safest in pregnancy LEV & LTG- both are Cat C drugs
 Underlying etiology: Precision therapy
 Genetic predisposition: eg HLA-B1502 a/w high R/O cutaneous reaction and

SCN1A Na channel gene a/w paradoxical aggravation of seizure when treated
with OXC/CBZ/PHT/LTG
Precision therapy
 Targeted therapy against the identified etiology.
 Applies to paediatric epilepsy- defined as patient specific or more

accurately physiology- specific, selection of therapy as determined by
information regarding underlying pathophysiology based on primary
specific genetic, metabolic &/or other cause of epilepsy in patient.

Precision therapy

Use of Non AEDs in Epilepsy
IVIg & Steroids- Used in drug resistant epilepsy syndromes such as

LGS, CSWS, Landau-Kleffner & West Syndrome.
Mechanism of action-
 Both drugs believed to act by reducing inflammation caused due to

cytokines released after seizure probably due to neuronal damage.
 Cytokines increases neuronal excitability by several mech. including

activation of Glutamate receptors.
 In addition; steroids and ACTH might also stimulate brain neurosteroid

receptors that enhances GABA activity and also reduces CRH hormone,
a known Epileptogenic Nelson textbook paediatrics-21st edition
Dose regimen of IVIg & Steroids
IVIg ACTH & Steroids
 Usual regimen- 2g/kg divided  Dose regimen of ACTH (slide no. 13)
over 2-4 consecutive days→ 1  Pre-requisite- to rule out active
g/kg once a month for 06 infection
months.  Monthly IV pulse-
Methylprednisolone- 30 mg/kg for 05
days F/B oral maintenance with taper
for upto 06 months
 Daily steroid regimen- Prednisolone
2 mg/kg P/O for 1-2 month → taper
over 1-3 months
 Pulse steroids are better tolerated
than daily dosing with less incidence
of side effects
 Cannabidiol: Nonpsychoactive extract of cannabis plant
 Indication- Possible adjunct therapy for drug resistant epilepsy

syndrome such as LGS and Dravet syndrome.
 FDA approved for use in children> 02 yrs of age
 Starting dose- 2.5 mg PO BD for 07 days→ 5 mg PO BD as

maintenance. If needed and tolerated; dose can be increased upto 10
mg/kg BD

Other drugs-
 Acetazolamide
• Pyridoxine
• Biotin
• Follinic acid
• Memantine and Dextromethorphan
• Quinidine
• Pyridoxal 5 phosphate
• Thiamine
 mostly used in Precision therapy

Initiation of Therapy
 When Rapid Therapeutic Levels are Desired –
IV AEDs are preferred. Loading dose F/B maintenance dose. Eg PHT, LEV etc
 In nonemergency situations -
Initially started with smaller doses→ gradually increased and titrated to achieve
maintenance dose to Build tolerance to side effects; like sedation. CBZ/ OXC/ TPM/
LTG/ Perampanel etc required to be started at low dose and increased gradually
 Few AEDs are well tolerated even if started with maintenance doses. Eg PB, VPA,
PHT etc.

Monitoring
 Most helpful for the older AEDs for monitoring of effective plasma levels
and to check compliance as well, such as PHT, CBZ, VPA, PB etc.
 Not required in cases of newer molecules as they have wide

therapeutic window. May be done to check compliance.
Indications of Polytherapy
 Indicated only when

 Ineffective even with max tolerated dose or
 Poor control with inacceptable adverse effects
 When 2nd drug is considered
 1st drug tapered with gradual increase of 2nd drug, eventually 1st drug stopped
and 2nd drug continued with min effective and tolerated dosage
 If 2nd drug fails; monotherapy with 3rd drug or Combination/ Polytherapy is
indicated
 Drug resistant epilepsy- those who have failed at least 2 fair trials of
appropriate medications
Na+ Channel Inhibitors
 Phenytoin:
 Indications:
 First choice for partial and generalized tonic-clonic seizures
 Some efficacy in clonic, myoclonic, atonic,
 No effect on infantile spasms or absence seizures
 Drug Interactions:
 Decreases blood levels of many medications
 Increases blood levels of phenobarbital & warfarin
Essentials of medical pharmacology- 6th edition

 Phenytoin:
 Adverse Effects:
 Hirsutism & coarsening of facial features
 Acne
 Gingival hyperplasia (20-40%)

 Brush teeth >8 times per day
 A primary reason not to prescribe for children
 Decreased serum concentrations of folic acid, thyroxine, and
vitamin K with long-term use.

Phenytoin Induced Gingival Hyperplasia
17 year old boy treated with

300mg/day phenytoin for 2
years (unsupervised)
Partial recovery at 3 months

after discontinuation
Images in Clinical Medicine (Feb 2000) 342:325

 Carbamzepine:
 Indications:
 Firstchoice for complex partial and generalized tonic-clonic
seizures.
 Contraindications:
 May exacerbate absence or myoclonic seizures.
 Blood disorders
 Liver disorders

 Carbamazepine:
 CBZ metabolism is affected by many drugs, and CBZ affects
the metabolism of many drugs.
 Mild leukopenia or hyponatremia
 Circulating concentrations of thyroid hormones may be
depressed; TSH remains normal.

 Oxcarbazepine:
 FDA approved in 2000 for partial seizures
 Complex partial seizures
 Primary & secondarily generalized tonic-clonic seizures
 No effect on absence or myoclonic seizures
 Fewer adverse effects than CBZ, phenytoin

 Valproic Acid:
 Other Mechanisms of Action:

 1) Some inhibition of T-type Ca2+ channels.
 2)Increases GABA production and decreases GABA
metabolism.
 Indications:
 Simple or complex partial, & primary generalized tonic-clonic
 Also used for absence, myoclonic, and atonic seizures.
 Highly effective in juvenile myoclonic epilepsy.
 Liver disease
 Valproic Acid:
 Affects metabolism of many drugs through liver enzyme inhibition
 Phenobarbital
 “Drunkenness”
 Clorazepam
 Prolonged absence seizures

 Valproic Acid:
 Weight gain (30-50%)
 Dose-related tremor
 Transient hair loss
 Polycystic ovary syndrome and menstrual disturbances
 Bone loss
 Ankle swelling
Essentials of medical pharmacology- 6 th edition

 Lamotrigine:
 Other Mechanism of Action:
 May inhibit synaptic release of glutamate.
 Indications:
 Adjunct therapy (ages 2 & up):
 Simple & complex partial seizures
 Generalized seizures of Lennox-Gastaut Syndrome
 Monotherapy (adults):
 Simple & complex partial seizures
 May make myoclonic seizures worse.

 Lamotrigine:
 Rash (10%)
 Rare progression to serious systemic illness
 Increased alertness

 Topiramate:

 Enhances post-synaptic GABAA receptor currents.
 Indications:
 Adjunct therapy for partial and primary generalized tonic-clonic seizures in adults
and children over 2
 Decreases tonic and atonic seizures in children with Lennox-Gastaut syndrome.
 History of kidney stones

 Topiramate:
 CBZ, phenytoin, phenobarbital, & primidone decrease blood
levels
 Nervousness & paresthesias
 Psychomotor slowing, word-finding difficulty, impaired
concentration, interference with memory
 Weight loss & anorexia
 Metabolic acidosis

 Zonisamide:

 Inhibits T-type Ca2+ currents
 Binds to GABA receptors
 Facilitates dopaminergic and serotonergic neurotransmission

 Zonisamide:
 Indications:
 Approved for adjunct treatment of partial seizures in adults.
 Appears to have a broad spectrum:
 Myoclonic seizures
 Infantile spasms
 Generalized & atypical absence seizures
 Lennox-Gastaut Syndrome
 Phenytoin and carbamazepine decrease its half-life by half
 Zomisamide:
 Weight loss
 Abnormal thinking
 Nervousness
 Agitation/irritability
 Usually well tolerated

Enhancement of GABA Inhibition
 Barbiturate drugs: Phenobarbital & Primidone
 Mechanism of Action:
 Increases the duration of GABAA-activated Cl- channel
opening.
 Phenobarbital:
 Indications:
 Second choice for partial and generalized tonic-clonic
seizures
 Rapid absorption has made it a common choice for seizures
in infants, but adverse cognitive effects cause it to be used
less in older children and adults
 Status epilepticus
 Absence Seizures

 Primidone:
 Indications:
 Adjuvant or monotherapy for partial and generalized tonic-
clonic seizures
 May control refractory generalized tonic-clonic seizures
 History of porphyria

 Phenobarbital & Primidone:
 Other CNS depressants
 Increased metabolism of vitamin D and K
 Phenytoinincreases the conversion of primidone to
phenobarbital

 Phenobarbital & Primidone :
 Agitation and confusion in the elderly.
 Worsening of pre-existing hyperactivity and aggressiveness in
children
 Sexual side effects
 Physical dependence

 Benzodiazepine drugs:
 Diazepam, lorazepam, clonazepam, clorazepate
 Increases the frequency of GABAA-activated Cl- channel
opening

 Indications:
 Only clonazepam & clorazepate approved for long-term
treatment.
 Clorazepate
 In combination for partial seizures

 Clonazepam
 Lennox-Gastaut Syndrome, myoclonic, atonic, and

absence seizures
 Tolerance develops after about 6 months
Essentials of medical pharmacology- 6th

edition
 Indications:
 Diazepam and lorazepam are used in treatment of status
epileticus.
 Diazepam is painful to inject; lorazepam is more commonly
used in acute treatment.
 Diazepam
 Intermittent use for control of seizure clusters

 Diazepam frequently combined with phenytoin

 Diazepam in children under 9
 Narrow angle glaucoma
 Hypotonia, Dysarthria
 Muscle in-coordination (clonazepam)
 Behavioral disturbances (especially in children)
 Aggression, Hyperactivity, Irritability and Difficulty concentrating
 Tiagabine:
 Inhibition
of GABA transporter (GAT-1) – reduces reuptake of GABA
by neurons and glial cells.
 Indications:
 Approved in 1998 as an adjunct therapy for partial seizures in
patients at least 12 years old.
 Absence seizures

 Tiagabine:
 Interactions:
 Blood levels decreased by CBZ, phenytoin, phenobarbital, &
primidone
 Asthenia
 Abdominal pain

Calcium Channel Blockers
Voltage-Gated Ca2+ Channel T Currents
 Ethosuximide:
 Reduces low threshold Ca2+currents (T currents) in
the thalamic neurons.
 Half-life is ~60 hr in adults; ~30hr in children
 Indications:
 First line for absence seizures
 May exacerbate partial & tonic-clonic seizures
Voltage-Gated Ca2+ Channel T Currents
 Ethosuximide:
 Psychotic behavior
 Blood dyscrasias
 Persistent headaches
 Anorexia
 Hiccups
 Lupus-like syndromes
 Toxicity:
 parkinson-like symptoms
 photophobia
Blockade of Calcium Channels
 Gabapentin:
 Originally designed to be a centrally acting GABA agonist.
 Selective inhibition of v-g Ca2+ channels containing the α2δ1
subunit.
 Indications:
 adjunct
therapy in adults and children with partial &
secondarily generalized seizures.
 Also effective as monotherapy

 Gabapentin:
 Can exacerbate myoclonic & absence seizures.
 Weight Gain (5%) with ankle edema
 Irritability
 Behavioral problems in children (6%)

 Has been associated with movement disorders

 Pregabalin:
 Same as gabapentin
 Indications:
 Approved in 2005
 Adjunct therapy for partial & secondarily generalized seizures
 No effect on absence, myoclonic, or primary generalized tonic-
clonic seizures
 Other uses:
 Prescribed for neuropathic pain, fibromyalgia
Other/Unknown MOA
 Levetiracetam:
 Not exactly known
 Binding affinity to Synaptic Vesicle Protein 2A correlates with its
anticonvulsant activity.
 Also blocks calcium channel N-currents, increases intracellular Ca2+
levels, modulates GABA channel currents
Other/Unknown MOA
 Levetiracetam:
 Renal dysfunction
 Asthenia
 Infection
 Behavioral problems in children

Summary
Na+ Channel Drugs
 Phenytoin
 Cabamazepine
 Valproic Acid
 Lamotrigine
 Topiramate
 Zonisamide
 Lidocaine
GABA Drugs
 Barbiturates: •Tiagabine
 Phenobarbital •Valproic Acid
 Pimidone •Topiramate
 Benzodiazepines:
•Zonisamide
 Diazepam
 Lorazepam
 Clonazepam
 Clorazepate
Ca2+ Channel Drugs
 Ethosuximide
 Valproic Acid
 Zonisamide
 Gabapentin
 Pregabalin
 Levetiracetam
Primary Generalized Tonic-Clonic Seizures
 Drugs of Choice: •Alternatives

 Phenytoin • Lamotrigine
 Carbamazepine • Topiramate
 Oxcarbazepine • Zonisamide
 Valproate • Levetiracetam
• Primidone
• Phenobarbital
• Diazepam
Partial, Including Secondarily
Generalized Seizures
 Phenytoin • Lamotrigine
 Carbamazepine • Topiramate
 Oxcarbazepine • Zonisamide
• Levetiracetam
 Valproate
• Primidone
• Phenobarbital
• Gabapentin
• Pregabalin
• Tiagabine
Absence Seizures

 Ethosuximide • Clonazepam
 Valproate • Zonisamide
Atypical Absence, Myoclonic, Atonic Seizures
 Drug of Choice: •Alternatives
 Valproate • Clonazepam
• Topiramate
• Zonisamide
• Levetiracetam
Adverse Effects
 Rickets –
 Potential side effect with commonly used enzyme inducer AEDs like
PHT, PB, CBZ etc as level of 25(OH)D reduced due to ↑metabolism
 With VPA due to hyperammonemia.
 Skeletal monitoring required for possible osteopenia due to independent

or secondary to ↓ 25(OH)D level with enzyme inducing AEDs
 Treatment- Counseling
Sun exposure
Vit D supplement
Adverse Effects
Adverse Effects
Discontinuation of Therapy
 Can be tried when-
 Seizure free for >2 yrs
 In self limited benign epilepsy syndrome; duration of therapy can as
short as 06 months.
 Prolonged duration of therapy warranted in cases of severe
syndromes and in structural epilepsy
 Most relapses occur during tapering or within 06 months of cessation
Risk factors for relapse:
 EEG abnormality during tapering or after discontinuation
 Structural epilepsy
 Older age of onset
 Longer duration of therapy
 Presence of multiple seizure types
 On Combination/ Polytherapy
Advice before consideration of discontinuation:
 Patient and parent counselling
 Special precaution/ avoid- Driving/ diving/ swimming
 Prescription with P/R Diazepam or Midazolam nasal spray to control
status during or after withdrawal
Thank you..

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Antiepleptic Drug Therapy

Presenter-Dr Avinash Singh

An extremely complex organ

These connections are each

After 1st seizure episode- if a/w

 Most children with new-onset epilepsy achieve seizure freedom with

 1st episode of generalised seizure without positive clinical sign/ family

Choice of AEDs are generally based upon-

Commonly indicated AEDs

Nelson textbook paediatrics-21st edition

DOC- Hormonal therapy- ACTH or pulse dose Methylprednisolone or

 Dosage & administration & monitoring:

Nelson textbook paediatrics-21st edition

 CZP (Clonazepam) : Effective but limited use due to serious side

 Other alternatives- Ketogenic diet, Levetiracetam, IVIg, Cannabidiol

Nelson textbook paediatrics-21st edition

Nelson textbook paediatrics-21st edition

Nelson textbook paediatrics-21st edition

 Valproate- Should be avoided in children <02 yrs, as component of

Nelson textbook paediatrics-21st edition

Nelson textbook paediatrics-21st edition

 Subjective preferences: effective alternatives AEDs might depends on

 Underlying etiology: Precision therapy

 Genetic predisposition: eg HLA-B1502 a/w high R/O cutaneous reaction and

 Targeted therapy against the identified etiology.

 Applies to paediatric epilepsy- defined as patient specific or more

Nelson textbook paediatrics-21st edition

Nelson textbook paediatrics-21st edition

IVIg & Steroids- Used in drug resistant epilepsy syndromes such as

 Both drugs believed to act by reducing inflammation caused due to

 Cytokines increases neuronal excitability by several mech. including

 In addition; steroids and ACTH might also stimulate brain neurosteroid

 Indication- Possible adjunct therapy for drug resistant epilepsy

 FDA approved for use in children> 02 yrs of age

 Starting dose- 2.5 mg PO BD for 07 days→ 5 mg PO BD as

Nelson textbook paediatrics-21st edition

Nelson textbook paediatrics-21st edition

 When Rapid Therapeutic Levels are Desired –

Nelson textbook paediatrics-21st edition

and to check compliance as well, such as PHT, CBZ, VPA, PB etc.

 Not required in cases of newer molecules as they have wide

 Indicated only when

Essentials of medical pharmacology- 6th edition

 Gingival hyperplasia (20-40%)

Essentials of medical pharmacology- 6th edition

17 year old boy treated with

Partial recovery at 3 months

Images in Clinical Medicine (Feb 2000) 342:325

Essentials of medical pharmacology- 6th edition

Essentials of medical pharmacology- 6th edition

 Fewer adverse effects than CBZ, phenytoin

Essentials of medical pharmacology- 6th edition

 Other Mechanisms of Action:

 Prolonged absence seizures

Essentials of medical pharmacology- 6th edition

Essentials of medical pharmacology- 6 th edition

Essentials of medical pharmacology- 6th edition

 Other Mechanism of Action:

Essentials of medical pharmacology- 6th edition

Essentials of medical pharmacology- 6th edition

 Other Mechanism of Action:

Essentials of medical pharmacology- 6 th edition