Antiepileptic drugs

Antiepileptic drugs
TONY SCARIA 2010 KMC

Principle behind pharmacotherapy of
antiepileptic drugs
• Increase activity of GABA (inhibitory NT)
• Decreased activity of glutamate (excitatory NT)

Drugs acting on GABA

Drugs acting on glutaminergic
transmission

CRMP-2, collapsin-response
mediator protein-2
(lacosamide) SV2A (levetiracetam)
AMPA receptors (blocked by
phenobarbital, topiramate,
and lamotrigine.
NMDA receptors
(blocked by felbamate)
voltage-gated Na+ channels
(phenytoin, carbamazepine,
lamotrigine, and lacosamide)
K+ channels (retigabine)

GABA transporters
(especially GAT-1, tiagabine)
GABA-transaminase (GABA-T, vigabatrin)
GABAA receptors
(benzodiazepines)

Based on MOA of AED
prolongation of—the inactivated state of the Na+
channel
• Phenytoin
• Carbamazepine
• Valproate
• Lamotrigene
• Topiramate
• Zonisamide
Inhibition of T type of ca2+ channels
• Ethosuximide
• Trimethadone
• Valproate
Facilitation of GABA mediated chloride channel
opening
• Barbiturate
• BZD
• Valproate
• Tiagabine
• Vigabatrin
Glutamate antagonist
• NMDA antagonist • felbamate
• AMPA antagonist • topiramate
/phenobarbitone
• Peramapanel /
telampanel
• lamotrigineCRMP2 inhibitors  decrease release of BDNF
• Lacosamide
SV2A protein inhibitor
• levetiracetam
Acting on K + channel
• Retigabine
N type of Ca2+ channel
• Gabapentin
• pregablin

Classification of anti epileptics (chemical)
Hydantoin derivative • Phenytoin
• Fosphenytoin
Barbiturate • Phenobarbitone
Deoxybarbiturate • Primidone
Iminostilbine • Carbamazepine
• Oxcarbamazepine
Succinimide • Ethosuximide
Aliphatic carboxylic acid • Valproate
BZD • Clonazepam / diazepam/lorazepam
Phenyltriazine • Lamotrigine
GABA analogue • Gabapentin
• Vigbatrin
Newer drugs • Topiramte
• Tiagabine
• Zonisamide
• Levitiracetam

Barbiturates
• Phenobarbitone & primidone
• MOA
• GABAagonist  increased chloride conductance
• Reduces Ca2+ dependant release of NT
• Uses
• GTCS & partial seizure
• GTCS in infants (DOC)

Phenytoin
• Nonsedative oral
• Antiarrythmic class Ib (digitalis induced arrhythmia)
• MOA  preferential binding to and prolongation of the inactivated
state of the Na+ channel

PK
• 80 -90 % protein bound  low Vd
• Enzyme inducer
• Metabolised by hydroxylation of CYP 2C19 & 2C9 & as well as by
glucuronide conjugation
• Excreted in urine as glucocoronide conjugate
• Saturation kinetics
• Zero order kinetics at higher dose
• Narrow TI  10 -20 ug/ml

S/E of phenytoin
• Hyperplasia of gums
• Hirsutism
• Hypersensitivity reaction
• Hyperglycemia
• Hypersensitivity
• Hydantoin syndrome
• d/t toxic epoxide metabolism
• Impaired DNA synthesis d/t FA deficeicny
• Cleft palate hypoplastic phalanges microcepahly
• Lymphadenopathy Pseudolymphoma

Gingival hyperplasia d/t phenytoin
• Mc manifestation in
children & adults
• d/t inhibition of
collagenase enzyme
responsible for
breakdown of
collagen

Other drugs causing gingival hyperplasia
• Phenytoin
• CCB
• Sirolimus
• Cyclosporine
• Lamotrigine

Drug interactions of phenytoin
• Induces enzymes
• OCP digitoxin doxycycline theophylline rifampicin levodopa
• carbamazepine & phenytoin
• Increase each others metabolism
• Displacement from PPB of valproate
• Sucralfate binds to phenytoin in GIT  decrease its absorption

Uses of phenytoin
• In all types of seizures
• Except absence seizure & myoclonic seizure
• Trigeminal neuralgia
• 2nd choice
• Cardiac arrhythmia
• d/t digitalis toxicity

Fosphenytoin
• Water soluble
• IV/IM
• Given as slow infusion to Px arrhythmia / CV collapse & coma
• Used in emergency
• Increased risk of hyperphosphatemia

Carbamazepine  PHARmacokinetics
• Oral form only
• Well absorbed
• 80 % protein bound
• Enzyme inducer
• Induces its own metabolism

Carbamazepine
• DOC for partial seizures
• C/I in myoclonic seizure

S/e of carbamazepine
• Hypersensitivity reactions
• Rashes photosensitivity hepatitis
• Lupus like syndrome
• Agranulocytosis
• Aplastic anemia
• Water retention & hyponatremia (SIADH)can occur in elderly

Risk of carbamazepine induced in SJS is
increased in presence of
• HLA B 1502
• May also be allergic to phenytoin lamotrigine & oxcarbazepine

Uses of carbamazepine
• GTCS
• Simple & complex partial seizure
• Trigeminal neuralgia
• Glossopharygengeal neuralgia
• Post herpetic neuralgia
• In Diabetis insipidus

Oxcarbazepine
• Analog of carbamazepine
• Converted to licarbazepine
• No autoinduction
• Enzyme inducer (less than carbamazepine)
• Higher risk of hyponatremia & hepatotoxicity

Drug Moa ADR Use
Lamotrigine Block Na+ & Ca2+ channel Sedation / skin rases / SJS
/ataxia
Partial seizure
Safe drug in pregnancy
Gabapentin Increase release &
inhibits uptake of GABA
(inhibit presynaptiv N
type ca2+ channels)
Sedation ataxia Partial & grandmal
seizure
Neuropathic pain
Vigabatrin inhibits GABA – T Psychosis
Permanent & progressive
painless loss of vision
Partial seizure
LGS (add on)
Infantile spasm with
tuberous sclerosis
Tiagabine Inhibits glial & neuronal
uptake of GABA
Tremors ataxia mental
confusion
Refractory partial seizure

Drug MOA ADR Use
Levitiracetam SV2A protein inhibitor Associated with anger &
aggression
Refractory partial seizure
Felabamate NMDA blocker Hepatotoxicity
Aplastic anemia
Weight loss
Resistant epilepsies
LGS
Zonisamide (sulphonamide derivative)
Voltage gated Na+ & ca2+
channel inhibitor
Renal stone Refractory partial seizure
Topiramate (weak
carbonic anhydrase
activity)
Blocks Na + channel
Increase GABA activity
Decrease glutamate
action
AMPA blocker
Renal stone
Weight loss
Drowsiness dizziness
Partial seizure
Grandmal seizure
Migraine prophylaxis
Alcohol dependence

Drug MOA ADR Use
MgSO4 Toxicity is monitored by
patellar reflex
Eclampsia
Lacosamide Blocks Na channel &
CRMP2
Partial onset seizures
Ganaxolone Neurosteroid • Absence seizure
• Infantile spasm
• Catamenial epilepsy
Rufinamide Block Na+ channel • LGS
Retigabine Block K channel • Add on in partial
seizure
Perampanel
Telampanel
AMPA antagonist • Partial seizure
Pregabalin Inhibit N type Ca2+
channel in presynaptic
neuron
Sedation • Fibromyalgia

Ethosuximide
• Petit mal epilepsy only
• DOC in absence seizures
• Block T type ca2+ channels

Valproate
• Blocks voltage gated Na+ channel
• Blocks T type Ca2+ channels
• facilitate glutamic acid decarboxylase (GAD) increase GABA
• inhibitory effect on the GABA transporter GAT-1
• inhibits GABA transaminase in the brain
• Decrease release of aspartate (excitatory NT) in brain

PK of valproate
• Available as capsule syrup IV capsule
• High oral bioavailability
• Enzyme inhibitor
• All others are inducers

S/E of valproate
• Increased appetite & weight gain
• PCOD
• Acute pancreatitis
• Hepatotoxicity in children <2 yrs
• Therefore in children < 2years  DOC In absence seizure is ethosuximide
• Alopecia
• Teratogenic  NT defect

Valproate can cause hyperammonemia
• d/t blockage of ura
cycle
• Carnitine deficiency

Uses of valproate
DOC in seizure disorder Also used in
• GTCS
• Myoclonic
• Atonic
• Clonic
• Atypical absence
• LGS
• Partial
• Infantile spasm
• Absence
Valproate is also used in
• Bipolar disorder with rapid cycling
• Migraine headache prophylaxis
• Neuropathic pain

Ganoxolone
• Neurosteroid
• Used in absence seizures / infantile spasm / catamenial epilepsy

BZD
• Clonzepam & chlordiazepoxide
• Myoclonic seizure & absence seizures
• Diazepam
• Febrile seizure
• Diazepam & lorazepam
• Status epilepticus

Status epilepticus

Status epilepticus
• DOC  lorazepam

S/E of AED
Antiepileptic causing weight loss  TOFE Antiepileptic causing renal stone  TOPAZ
• Topiramate
• Felbamate
• Topiramate
• Zonismaide

S/E of AED
Lymphadenopathy Phenytoin
Hairloss Valproate
Permanent visual field loss Vigabatrin
Anemia Carbamazeoine
Felbamate (bonemarrow suppression)
Hepatotoxicity Valproate
Carbamazepine
SJS Carbamazepine
Lamotrigine
Weight gain Valproate

First line Second line
Partial seizure with or
with out GTCS
Carbamazepine
valproate
Lamotrigine
Phenobarbital
Lamotrigine
Gabapentin
GTCS Valproate
Lamotrigine
Phenytoin
Topiramate
Absence seizures Valproate
Ethosuximide
Lamotrigine
Clonazepam
Zonisamide
Myoclonic jerks Valproate Lamotigine
Felbamate ]

Infantile spasm
• DOC is ACTH
• Incase of infantile spasm with tuberous sclerosis  vigabatrin is used

Lennox gestaut syndrome
• First line
• Valproate (DOC)
• BZD (clonazepam clobazam)
• Rufinamide
• Second line
• Felbamate
• Topiramate

Treatment of seizures in pregnancy
• Preconception counselling
• To be stabilised under minimum effective dose with same drug
• If new drug has to be started LAMOTRIGINE  DOC
• Folic acid (0.4mg/day) & vitamin K supplementation
• Periodic screening for teratogenicity

Teratogenic effects of AED
Valproate NT defects  spina bifida
Phenytoin Fetal hydantoin syndrome (microcephaly short
phalanges cleft lip)
Carabamazepine Cleft lip & palate
Topiramate Limb agenesis in rodents
Hypospadiasis in males
Zonismaide Teratogenic

• Absence seizures (>2 years)
• GTCS
• Tonic seizure
• Clonic seizure
• Myoclonic seizure
• Atonic
Valproate
• Absence seizure (<2 years) Ethosuximide (d/t hepatotoxicity valproate is not used
)
• Febrile seizure Rectal diazepam
Partial seizure Carbamazepine
Infantile spasm ACTH
Infantile spasm with tuberous sclerosis Vigabatrin
Lennox gastaut syndrome Valproate
Febrile seizure Diazepam (per rectal)
Status epilepticus Lorazepam
Seizure in eclampsia MgSO4
Mesial temporal sclerosis Surgery

Vigabatrine Partial,infantile seizures
Lamotrigene Broad spectrum  partial , absence
Ethosuximide Absence seizure
Phenytoin Tonic clonic atonic akinetic
Carbamazepine Partial tonic clonic atonic akinetic
ACTH West syndrome

Drugs causing seizures
Drug of abuse Anesthetic & analgesic Psychotropics Sedative hypnotic drug
withdrawal
• Amphetamine
• Cocaine
• Phencyclidine
• Methylphenidate
• Meperidine
• Tramadol
• Local anesthetic
• Antidepressants
• Antipsychotics
• Lithium
• Alcohol
• Barbiturate
• BZD

Types of ca2+ channel Drugs acting on them
N type of ca2+ channel • pregabalin
• Gabapentin
T type of Ca2+ channel • Ethosuximide
• Valproate
L type Ca2+ • CCB

Therapeuic drug monitoring

Antiepileptic drugs

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