Antiepileptic drugs

Dr. THORAT V. M.
PROFESSOR
Dept.of pharmacology
KIMS KARAD.
Epilepsy:
A group of chronic CNS disorders characterized by
paroxymal cerebral dysrrhythmia manifesting
as brief episodes (seizures) of loss or disturbances
of consciousness with or without characteristic body
movements (convulsions), sensory or psychiatric
phenomena.

Seizures
sudden, transitory, and uncontrolled episodes of
brain dysfunction resulting from abnormal discharge
of neuronal cells with associated motor, sensory or
behavioral changes.

Each episode of neuronal dysfunction is called a

seizure
Causes for Acute Seizures

Trauma
Encephalitis
Drugs
Birth trauma
Withdrawal from depressants
Tumor
High fever
Hypoglycemia
Extreme acidosis
Extreme alkalosis
Hyponatremia
Hypocalcemia
Idiopathic
Classification of seizures
1.Generalized Seizures
Generalized Tonic-Clonic Seizures
Absence Seizures
Tonic Seizures
Atonic Seizures
Clonic Seizures
Myoclonic Seizures
Infantile Spasm
2.Partial (focal) Seizures
Simple Partial Seizures
Complex Partial Seizures
Simple Partial or Complex Partial
secondarily generalised
3. Status Epilepticus
1.GENERALISED SEIZURES
A. Generalised tonic clonic seizures / Grand mal
epilepsy – commomest and lasts 1 – 2 mins
 Aura
 Cry
 Loss of conciousness
 Tonic phase - - Sustained powerful muscle
contraction (involving all body musculature) which
arrests ventilation.
 Clonic phase - Alternating contraction and
relaxation, causing a reciprocating movement
which could be bilaterally symmetrical or “running”
movements.
 Postictal drowsiness and depression of all CNS
functions.
B. Absence Seizures (Petit Mal , Minor
epilepsy )

• Brief and abrupt loss of consciousness, vacant

stare.
• Sometimes with no motor manifestations.
• Minor muscular twitching restricted to eyelids
(eyelid flutter) and face.
• Usually of short duration (5-10 sec), but may
occur dozens of times a day.
• No loss of postural control.
• Often begin during childhood (daydreaming
attitude, no participation, lack of
concentration).
 C.Atonic seizures ( Akinetic )
Unconciousness with Sudden loss of muscle
tone for few seconds – patient may fall
D.Myoclonic seizures.
Shock like momentary contractions of a part or
whole body.
E. Infantile Spasms
seen in infants . An epileptic syndrome.
Attacks , although fragmentary, are often
bilateral and characterized by brief recurrent
myoclonic jerks of the body with sudden
flexion or extension of the body and limbs.
• Progressive mental retardation
2. Partial (Focal) Seizures
A. Simple Partial Seizures (Jacksonian)
• Involves one side of the brain at onset.
• Focal motor, sensory or speech disturbances.
• Confined to a single limb or muscle group.
• No alteration of consciousness.
B. Complex Partial Seizures (Temporal Lobe
epilepsy or Psychomotor Seizures)
• Produces confusion and inappropriate or dazed
behavior.
• Motor activity appears as non-reflex actions.
Automatisms (repetitive coordinated movements).
• Wide variety of clinical manifestations.
• Consciousness is impaired or lost.
C. Partial seizures with secondary Generalised
Experimental Models For Testing Antiepileptics
• Maximal Electroshock Seizure – MES – Brief high
intensity shock ( 140 volts ) is applied to the head
of rodent ----- produces tonic flexion – tonic
extension ---- clonic convulsions
Drugs effective in preventing this – effective in GME
• Phetylene tetrazole ( PTZ ) Clonic seizures – Inj of
this chemical in rats or mice ---- clonic convulsions
---- drugs prevent these convulsions ---- effective
in petit mal epilepsy
• Focal seizures – application of alumina cream or
crystal of cobalt or penicillin in cortical area
• Kindled seizures – weak electrical impulses are
applied to the brain intermittently over days -----
tonic clonic seizures.
 Antiepileptic Drugs
• Hydantoins: Phenytoin, Fosphenytoin ,Methotoin

• Barbiturates: Phenobarbitone , Primidone

• Iminostilbenes : Carbamazepine

• Succinimides: Ethosuximide

• Valproic Acid :Sodium Valproate

• Benzodiazepines : Clonazepam, Diazepam ,

Clobazam

• Other : Lamotrigine, Vigabatrin, Tiagabine ,

Gabapentine , topiramate , Levetiracetam
 pathogenesis

Seizure may arise due to the following

defects -

1. Na or Ca ion conductance of neuronal

membrane.

2. Inhibitory GABAergic transmission.

3. Exitatory glutamatergic transmission.

Major Mechanisms of
Anticonvulsant Action
 Voltage gated
Na+ Na channels
Activation
gate Open

Na+

Inactivation
gate

Na+
 Na+
Block channels
Inactivated
firing at high
channel
frequencies

Na+

Carbamazepine
Phenytoin
Topiramate Felbamate
Sodium valproate
Lamotrigine
GABA Receptor
GABA Gabapentin
Vigabatrin GT
Succinic
Semialdehyde
Valproate SSD
metabolites

Benzodiazepines Gabapentin
Tiagabine
Barbiturates

Topiramate
Cl-
GT: GABA transaminase SSD:Succinic semialdehyde dehydrogenase
October 1, 2021
 Ca++
Voltage regulated
Ca++ current , low
threshold “T”
current in thalamus

Ca++

Gitanjali-14:
 Ca++
Ethosuximide
Sodium Valproate

Ca++
Reduction in the flow of Ca++ through
T - type Ca++ channels in thalamus
Classification
1. Block voltage sensitive Na channels.
Thereby exert neuronal membrane stabilising action &
prevent spread of seizure discharge.
Eg- Phenytoin, Carbamazepine, Valproate , Lamotrigine
2. Enhance inhibitory GABAergic transmission.
a. By facilitating interaction of GABA with GABA receptor.
eg- phenobarbitone, BZD - Diazepam.
b. Inhibiting GABA degradative enzyme GABA transaminase.
eg- Sodium Valproate , vigabatrine
c. Releasing GABA from neuronal endings.
eg- Gabapentin.
3. By blocking T type voltage dependant Ca channels.
eg- ethosuximide, Sodium valproate.
4. Reducing excitatory glutamatergic transmission.
newer drugs eg- lamotrigine.
• Phenytoin
- Primary drug for all types of epilepsies EXCEPT petit
mal epilepsy ( PTZ convulsions – ineffective )

- selective antiepileptic action without causing

drowsiness
MOA
• Blocks voltage sensitive Na channels & cause
Prolongation of Na channel inactivation state
• Have neuronal membrane stabilizing action

• Decreases the intraneuronal concentration of Na –

reduce the paroxysmal depolarization shift in the
abnormally firing neurons & prevent the spread of
seizure discharges.

• It has ability to selectively inhibit high frequency

firing neurons - useful in trigeminal neuralgia and
cardiac arrhythmias
• Stabilizes neuronal membrane. Prolongs
inactivated stage of voltage sensitive sodium
channel. Refractory period of channel is
increased. Spread of repetitive firing from
neurons is prevented.
• Higher doses - Reduction in calcium influx
- Inhibit glutamate action
- Facilitate GABA action.
Pharmacokinetics.
• Oral absorption – slow
• On IM inj it ppts at site of inj – absorption – even
slower than oral
• Bioavailability of different brands may differ- stick
to one brand
• Widely distributed , 70 – 90 % PPB.
• Metabolised by hydroxylation & glucuronide
conjugation
• Kinetics of metabolism is capacity limited-
changes from first order (below 10 µg/ml ) to zero
order above therapeutic range ( above 20 µg/ml )
• Therapeutic concen – 10 - 20 µg /ml- well tolerated
• Potent enzyme inducer- drug interactions (induce
metabolism of other drugs)
Adverse effects.
A] At therapeutic levels.

1. Gum Hypertrophy- commonest S/E. Can be minimised by

maintaining good oral hygiene.

2. Hirsutism & Hypertrichosis ,acne.

3. Hypersensitivity- rashes, lymphadenopathy,DLE,neutropenia

4. Hyperglycemia- may interfere with insulin release.

5. Fetal hydantoin syndrome- if used in pregnancy. (cleft lip, cleft

palate, hypoplastic phalenges, microcephaly).

6. Megaloblastic anaemia- interference with folate abs &metabolism.

7. Osteomalacia- due to interference with Ca metabolism.

8. Hypoprothrombinemia & haemorrhage – increase vit K metabolism

B] At higher levels. -
1. Vestibulo - cerebellar syndrome – Ataxia,
Vertigo , Diplopia , Nystagmus.
2. GIT- epigastric pain , nausea , vomiting.
C] On IV injection- Thrombophlebitis, Fall
in BP, arrhythmias , CVS collapse or
severe CNS depression
FOETAL HYDANTOIN SYNDROME
Drug interactions
1. Phenytoin + Carbamazepine- increase each
others metabolism.
2. Valproate - Displaces phenytoin from PPB &
decrease metabolism - increase plasma levels.
3. Enzyme inhibitors eg cimetidine, isoniazid,
warfarin , chloramphenicol - inhibit metabolism -
toxicity.
4. Phenytoin is enzyme inducer - increases
metabolism of steroids (failure of OCP), digoxin ,
theophylline , warfarin
5.Sucralfate decreases absorption of phenytoin
D0sages & preparations
Phenytoin / Dilantin – 25 mg ,100 mg cap.
- 100 mg / ml oral susp
- 100 mg/2ml inj
Adult 100 mg BD – Max 400 mg / day
Children - 5 - 8 mg / kg
Uses.
A] Epilepsy-
1. 1st choice- GTC, SPS, CPS.
2. 2nd choice to diazepam – in status epilepticus.
B] Non epileptic uses -
1. Trigeminal neuralgia - 2nd choice to
carbamazepine.
2. Ventricular arrhythmias due to digoxin toxicity.
FOSPHENYTOIN-
Prodrug of phenytoin.
Advantage- less damaging to intima so can be
injected IV at a faster rate with saline or
glucose
- 50 mg/ml – 1o ml inj
Carbamazepine
• Initially marketed for trigeminal neuralgia
• Similar MOA like phenytoin but causes less
cognitive impairment than phenytoin.
• Modifies MES as well as raise threshold to
PTZ
• Also inhibits kindling
Mechanism of action
Block voltage sensitive Na channels. Have
neuronal membrane stabilizing action &
prevent the spread of seizure discharges.
Also useful in Trigeminal Neuralgia
characterized by paroxysmal intense pain in
distribution of trigeminal nerve
Pharmacokinetics.
• Oral abs – slow & variable – as poor water soluble
• 70 % PPB & metabolised to active metabolite 10,11 epoxy
Carbamazepine
• initial half life 20-40 hrs but decreases to 10-20 hrs on chronic
use due to autoinduction
• Enzyme inducer.
Adverse effects.
1. Dose related neurotoxicity.
• Sedation, dizziness,ataxia, vertigo, diplopia.
• Vomiting, diarrhoea, worsening of seizures at higher doses.
• Acute intoxication - Coma, convulsions, cardiovascular
collapse.
2. Hypersensitivity- rashes , photosensitivity, hepatitis , SLE
3. Water retention & hyponatremia – enhance ADH action
4. Teratogenicity - minor teratogen but - combination with
valproate doubles teratogenic risk.
Interactions.
1. Due to enzyme induction- may decrease efficacy
of many drugs like OCPs ,warfarin, theophylline ,
Vit D , haloperidol.
2. Enzyme inhibitors like isoniazid , erythromycin ,
Fluoxetine may precipitate toxicity.
Dosage & Preparation
100 ,200 , 400 mg tab. Dose – 200 - 400 mg tid
Uses
1. 1st choice drug for- GTC, SPS, CPS.
2. Trigeminal neuralgia- drug of choice.- FDOC
3. Manic depressive illness & mania- alternative
to lithium
Ethosuximide
1. Important action – antagonism of PTZ induced clonic
seizures
2. Dosenot modifies MES
3. Primary action on thalamocortical syst and Block T
type of Ca channels.
S / Es
gi disturbances , tiredness , mood changes, headache,
drowsiness , inability to concentrate
USE.
Only indication is absense seizures.(shares DOC
status with valproate).
• Valproic acid
• It is a broad spectrum antiepileptic.
• More potent in blocking PTZ seizures than modifying
MES.
• Acts by multiple mechanisms-
1. Blocks voltage sensitive Na channels.
2. Blocks T type voltage dependant Ca channels.
3. Facilitates inhibitory GABAergic transmission by
inhibiting its degradation by enzyme GABA
transaminase.
Pharmacokinetics
Oral absorption – good , 90 % PPB , t ½ 10 -15 hrs
metabolised in liver by oxidation & glucuronide conju.
Adverse effects.
1. commenest- anorexia, vomiting, heartburn.
2. Alopecia , curling of hair,
3. Pancreatitis
4. Dose related - ataxia, tremors.
5. Hypersensitivity- rashes
6. Liver- A symptomatic rise in serum transaminase
(monitoring of LFTs required).
7. Fulminant hepatitis- in children < 3 years age.
8. Teratogenicity – spina bifida, neural tube
defects.
Dosage & Preparation -
200 mg tab & 200 mg / ml liquid
Start with 200 mg tid – max 800 mg.
Children 15 -30 mg / kg / day
Uses
A] Epilepsy.
1. DOC for- Absense seizures. atonic seizures. myoclonic
seizures.
2. Alternative drug for- GTC. SPS, CPS.
B] Non epileptic uses-
1. Mania & bipolar disorder- alternative to lithium.
2. Prophylaxis of migraine.
Drug Interactions
• Valproate inhibit metabolism & increase plasma level of
phenobarbitone.
• It displaces phenytoin from PBS & decrease metabolism of it
– phenytoin toxicity
• Valproate & Carbamazepine induce each others metabolism
• Concurrent administration of clonazepam & valproate is
contraindicated as absence status may ppted
Phenobarbitone - 1st effective antiepileptic
• Used for the Rx of GME & cortical focal epilepsy
• Not effective & not used in petit mal epilepsy –
may even aggravate it
• DOC to treat GME in children below 5 yrs as – no
gum hypertrophy & hirsuitism
• It limits the spread of seizure activity & also
elevate seizure threshold – thus induce complete
remission of generalised tonic clonic seizures &
also eleminate the sensory AURA or other
prodermal signs.
• Can be combined with phenytoin for Rx of GME ,
SPS – reduce SE – low doses required
• Dose – 80 -160 mg in divided doses
October 1, 2021
MOA- Facilitates inhibitory GABAergic transmission.
Advantages-
1. cheap.
2. Least toxic.
Disadvantages-
1. sedation- major drawback.
2. Behavioral abnormalities in children & mental
confusion in adults as AE.
Uses-
1. GTC, SPS, CPS - 2nd choice to carbamazepine &
phenytoin .
2. Status epilepticus - given IM / IV it is 2nd choice to
diazepam.
Primidone
• Effective against all EXCEPT petit mal epilepsy
• Often combined with phenytoin when phenytoin
alone is not effective.
• Converted to 2 active metabolites by liver
1. phenobarbitone
2. Phenyl ethyl malonamide ( PEMA)
• SEs similar to PB
Benzodiazepines
eg- Diazepam , Lorazepam , Clonazepam .
MOA
1. Potentiates GABAergic transmission
2. Higher doses block voltage sensitive Na channels.
Drawbacks-
Not used for long term treatment due to 2 main drawbacks-
1. Tolerance develops to antiepileptic action.
2. Prominent sedative action.
Use-
1. Diazepam & lorazepam are DOC for status epilepticus ,
tetanus , eclampsia , drug induced
2. Rectal diazepam is DOC for febrile convulsions.
3. Clonazepam is alternative drug in absense , atonic ,
myoclonic , Infantile spasm.
 NEWER DRUGS
LAMOTRIGINE -
broad spectrum antiepileptic
Blocks voltage sensitive Na channels.
Inhibits release of excitatory glutamate amino acid.
A/E- severe skin rash (may require withdrawal)
nausea , vomitting , diplopia , ataxia , steven –
Johnson syndrome , DIC
Use-
• Effective in GTC. SPS. CPS, atonic, myoclonic ,
absense seizures.
• Usually used as alternative or add-on drug.
Dosage & Preparation -
Available as 25 , 50 ,100 mg tab
Dose – 50 mg / day – max 300 mg / day
TOPIRAMATE.
MOA- multiple mechanisms-
1. Na channel blockade.
2. GABA potentiation.
3. Glutamate receptor antagonism.
Uses- as add-on drug in GTC, SPS , CPS.
- Prophylaxis of migraine.
GABAPENTIN.
MOA- enhances GABA release - increase GABA
concentration in CNS.
Uses - as add - on drug in GTC, SPS,CPS.
- FDOC pain due to diabetic neuropathy &
post herpetic neuralgia.
Acetazolamide – As adjuvant in resistant petit mal
& GME
• Oxcarbazepine – prodrug of carbamazepine
• Levetiracetam – modifies GABA release
• Zonisamide – inhibits T type Ca current
• Lacosamide – inactivation of Na channels
• Rufinamide - inactivation of Na channels –
adjuvant in Lennox – Gastaut syndrome
• Perampanel – antagonist of AMPA receptors
• Acetazolamide – adjuvant in refractory epilepsy.
Principles of Treatment of Epilepsy
• Drug therapy is prolonged
• DOC and dose depends upon type of epilepsy &
need of individual patient
• Start treatment early and with single drug
preferably at low dose – increase dose till full
control of seizures or SE appear.
• Therapy should be simple – maintain seizure
dairy.
• All drug withdrawal should be gradual . Abrupt
stoppage – status epilepticus.
• Dose regulation – TDM
• Long term follow up to ascertain pt compliance
& neurological examination – EEG.
• When women on antiepileptic therapy
conceive – continue therapy – substitute
sodium valproate
Prophylactic folic acid supplement in 2nd &
3rd trimester – 5 mg daily
• Vit k1 10 mg at 34 and 36 week of pregnancy
- in last month of gestation .
• Carry out investigations carefully – USG ,
alpha fetoprotein at 16 weeks of gestation
• New born - vit k1 1 mg im
Status epilepticus
Seizure occuring continuously for >30 min
or two or more seizures occur without
recovery of consciousness.
MANAGEMENT.
1. Diazepam is DOC- 10 mg IV bolus slowly
over 5 min. Repeat once after 10 min if
needed /
2. Lorazepam is 4 mg i.v sometimes
preferred as effect of single dose lasts
longer ( 8-10 hrs compared to 20-30 min of
diazepam )
3. Fosphenytoin 100 -150 mg/ min i.v infusion
– max 1000 mg under ECG monitoring /
phenytoin sodium – 5-10 mg /kg at rate 25 -
50 mg/min iv/ phenoberbitone 20 – 30
mg/kg at rate of 50 – 60 mg / min iv act
more slowly.
- may be used as alternatives to diazepam
or when convulsions have not been
controlled by diazepam.
4. For refractory cases- who failed to
respond diazepam and fosphenytoin
within 40 min of seizure onset - IV general
anesthetics ( IV midazolam 0.75
mg/kg/min for 20 min / propofol 10 - 40
mg i.v. / thiopentone 3-5 mg/kg i.v ) .
THANK
YOU