Antiepileptics (Autosaved)

Anti-seizure Drugs
Dr. Vishal Singh

Definitions
 Seizure:
Sudden, transitory, and uncontrolled episodes of brain
dysfunction resulting from rapid, rhythmic, synchronous
abnormal firing of neuronal cells with associated motor,
sensory or behavioral changes.
 Epilepsy:
a tendency toward recurrent seizures unprovoked by any
systemic or acute neurologic insults
 Epileptogenesis
sequence of events that converts a normal neuronal network
into a hyperexcitable network
Seizures
 non-epileptic when evoked in a normal brain by
electroshock or chemical convulsants
 epileptic when occurring without evident provocation
Pharmacological agents in current clinical use inhibit

seizures, and thus are referred to as anti-seizure drugs
Whether any of these prevent the development of

epilepsy (epileptogenesis) is uncertain
Causes for Seizures
 Head Trauma  High fever

 Encephalitis  Hypoglycemia
 Drugs  Extreme acidosis
 Birth trauma  Extreme alkalosis
 Abrupt withdrawal from  Hyponatremia
CNS depressants  Hypocalcemia
 Brain Tumor  Idiopathic
 Stroke
Epilepsy
 More than 40 forms of epilepsy have been identified

 Therapy is symptomatic : Majority of drugs prevent
seizures, but neither effective prophylaxis or cure is
available
 Long term therapy, unwanted side effects
 50% cases can be controlled, 25% can be improved
Classification of Epileptic
Seizures
 Focal seizures
Originate within neuronal networks limited to one cerebral

hemisphere
 Generalized seizures
Arise within and rapidly engage neuronal networks
distributed across both cerebral hemispheres
 Unclassifiable
Scheme of Seizure Spread
Focal Seizures
Generalised Seizures
Focal seizures evolving into

generalized seizures
Focal seizures
Depending on the presence of cognitive impairment
 Focal seizures without dyscognitive features
Motor, sensory, autonomic, or psychic symptoms without
impairment of cognition
Focal seizures with dyscognitive features

Accompanied by a transient impairment of cognition
Generalized Seizures
 Tonic - clonic
 Absence : Typical, Atypical
 Tonic
 Clonic
 Atonic
 Myoclonic
Unclassifiable :
 Epileptic ( infantile) spasms
Tonic-clonic (Grand mal)
Tonic phase
Sustained contractions of muscles
throughout the body
Tongue biting, grunting, salivation
increases in HR, BP, pupillary size
Clonic phase
Periods of muscle relaxation
typically lasting 1-2 minutes
Postictal phase
Unresponsiveness, Muscular flaccidity,
Excessive salivation : Stridorous breathing & partial airway
obstruction, Bladder or bowel incontinence
Generalized Seizures
Neuronal Correlates of Paroxysmal
Discharges
Generalized Tonic-Clonic Seizures
Absence Seizures (Petit Mal)
 Sudden, brief lapses of consciousness without loss of

postural control.
 The seizure typically lasts for only seconds, consciousness

returns as suddenly as it was lost, and there is no
postictal confusion.
 May occur dozens of times a day
 Onset is often in childhood (4-8 yrs)

(daydreaming, lack of concentration, decline in school
performance)
Atonic Seizures
 Sudden loss of postural muscle tone lasting 1–2 seconds.
 Consciousness is briefly impaired
 No postictal confusion.
 A brief seizure may cause only a quick head drop or
nodding movement, while a longer seizure will cause the
patient to collapse
Myoclonic Seizures
 Myoclonus is a sudden and brief muscle contraction that
may involve one part of the body or the entire body
 Coexist with other forms of generalized seizures
 Predominant feature of juvenile myoclonic epilepsy
Infantile Spasms
 Characterized by recurrent myoclonic jerks with sudden
flexion or extension of the body and limbs
 90% have their first attack before the age of 1 year
 Most patients are mentally retarded presumably from
the same cause of the spasms
 Infections, kernicterus, tuberous sclerosis ,
hypoglycemia, unknown
Mechanisms of Seizures
Role of synapses in mediating communication
Defective synaptic function – Seizure
 Decrease in inhibitory (GABAergic) transmission.
 Increase in excitatory (glutamatergic) activity
 Alteration in ion conductances

Drugs- Classification
 Anticonvulsants / antiepileptics
 Centrally acting/ on spinal cord/

Skeletal muscle relaxants
 According to MOA
Enhancement of inhibitory
(GABAergic) transmission.
Antiepileptic Drug
 A drug which decreases the frequency and/or

severity of seizures in people with epilepsy
 Treats the symptom of seizures, not the

underlying epileptic condition
 Goal—maximize quality of life by minimizing

seizures and adverse drug effects
 Currently no “anti-epileptogenic” drugs

available
Anti-epileptic drugs
Classical Newer
 Phenytoin  Lamotrigine
 Fosphenytoin  Topiramate
 Phenobarbital  Gabapentin
 Primidone  Tiagabine
 Carbamazepine  Vigabatrin
 Oxcarbazepine  Levetiracetam
 Ethosuximide  Felbamate
 Valproic Acid  Zonisamide
 Benzodiazepines
Mechanisms of action of
Antiepileptic Drugs
Classification
Action on Ion Enhance GABA Inhibit EAA
Channels Transmission Transmission
Na+: Benzodiazepines Felbamate
Phenytoin, Phenobarbitone Topiramate
Carbamazepine, Valproic acid Phenobarbitone
Lamotrigine Gabapentin Lamotrigine
Topiramate Vigabatrin
Valproic acid Topiramate
Ca++: Felbamate
Ethosuximide
Valproic acid
Lamotrigine
Phenytoin
Slows the rate of recovery of inactivated Na+ channels
Stabilising effect on neuronal membranes
↓ paroxysmal depolarisation shift

↓ post tetanic potentiation
↓ seizure spread
↓ duration of after discharge
Anti arrhythmic effect

Phenytoin - pharmacokinetics
 Limited water solubility – not given i.m.
 Particle size and pharmaceutical additives affect

both the rate and the extent of absorption.
 Extensively bound to plasma proteins

 Metabolism by liver parahydroxylase
 Concentrated in bile
 Elimination of phenytoin is dose-dependent

 Pl conc.< 10 mcg/ml – first order kinetics
 Pl conc > 20 mcg / ml – zero order kinetics
 Induces microsomal enzymes
Phenytoin – Untoward effects
 Toxic effects depend on the route of administration, the
duration of exposure, and the dosage.
 Therapeutic plasma concentration: 10-20 µg/ml
 High i.v. rate: cardiac arrhythmias ± hypotension; CNS

depression.
 GIT: nausea & vomiting
 Acute oral overdose: cerebellar and vestibular :
nystagmus, ataxia, diplopia vertigo
 Ocular pain, blurring of vision, delusions,
hallucinations, psychotic episodes
 Peripheral neuropathy
Side effects with chronic treatment
Gingival Osteomalacia
hyperplasia
Cerebellar
effects
Hyperglycemia
Hirsutism Megaloblastic anemia

aplastic anaemia
agranulocytosis
Other untoward effects
Fetal hydantoin syndrome
Pre- and postnatal growth deficiency

with psychomotor retardation,
microcephaly, hypoplastic phalanges,
cleft palate, cardiac defects
Hypoprothrombinemia and hemorrhage in newborns

(increases the metabolism of vitamin K)
Hypersenstivity Reactions : rash

fatal hepatic necrosis,
Stevens-Johnson syndrome.
Fosphenytoin- prodrug of phenytoin
 More soluble form
 Can be given intramuscularly
 Fewer local complications : tissue damage and necrosis
 Compatible with glucose solution

Phenytoin- drug interactions
 With enzyme inhibitors: ↑ phenytoin

 With enzyme inducers: ↓ phenytoin
 PPB- Displacement with salicylates,
sulphonamides
 Folic acid ↓ action of phenytoin
Dose: 100- 400 mg oral

< 50mg / min IV
Phenobarbital
 First effective anti-seizure agent
 GABA facilitatory with selective anticonvulsant effect
Advantages
 Has relatively low toxicity, (↓ TDM req), inexpensive
 Exert maximal anti-seizure action at doses below
those required for hypnosis

 Well tolerated & better compliance
 Inducer of microsomal enzymes – drug interactions.

Phenobarbital -Untoward effects
 Sedation (tolerance develops), lethargy, depression
 Cognitive impairment
 In children: paradoxical irritability, hyperactivity &
behavioral changes.
 Osteomalacia
 Folate deficiency and vit. K deficiency
 Larger doses: nystagmus & ataxia
 Connective tissue abnormalities
Primidone
 Prodrug metabolized to phenobarbital and
phenylethylmalonamide (PEMA), both active
metabolites.
 Effective against focal and GTC seizures
 Start at low dose to avoid sedation
 ADRs : Same as phenobarbital
.
Mephobarbitone: prodrug
Carbamazepine
 Mechanism of action - similar to phenytoin
 Advantage- less cognitive impairment
 Active metabolite – contributes to anti-seizure activity
 Enzyme inducer &Increases its own metabolism (autoinducer)
 Other uses - bipolar mood disorders, trigeminal neuralgia
glossopharyngeal neuralgia, deafferentiation pain
in DM neuropathy , cancer & MS
Carbamazepine – Untoward effects
 More frequent : drowsiness, vertigo, ataxia, diplopia
and blurred vision (tolerance)
 Nausea, vomiting
 Serious hematological toxicity (aplastic anemia,
agranulocytosis, thrombocytopenia) - may require
withdrawal of drug
 hepatic or pancreatic abnormalities
 Hypersensitivity reactions
 peripheral neuritis
 Retention of water & mental/physical sluggishness–
late complication
Carbamazepine -Drug interactions
 With enzyme inhibitors- erythromycin,

INH, valproate, verapamil
 Induce metabolism: OC, steroids,
warfarin
Dose
600-1200mg in epilepsy
400-800 mg in neuralgia
Oxcarbazepine
 prodrug
 less potent enzyme inducer
 Active metabolite –eslicarbazepine
Eslicarbazepine acetate –prodrug

Both are selective inducer of CYP enzymes
that metabolise estrogen
Ethosuximide
 Drug of choice for absence seizures
 Blocks Ca2+ currents (T- type) in the thalamus
 Narrow spectrum: Not effective in other seizure types
 Advantage: no TDM req. & No enzyme induction
 GI complaints : nausea, vomiting, and anorexia
 CNS effects : drowsiness, lethargy, euphoria, dizziness,
headache, and hiccough
 Parkinsonian like symptoms
 Rarely bone marrow toxicity and skin reactions
 Dose : 750 -1000mg single dose
 Divided dosage to prevent nausea or drowsiness
Ethosuximide
GI distress
 SAFE
Aplastic anemia
Leucopenia
SAFE
Valproic Acid
 Effective in multiple seizure types ( broad spectrum )
 Multiple mechanisms (blocks Na2+ channel,  Ca2+ currents, 
GABA levels)
 Advantage: no effect on behaviour, alertness, cognitive function
Dose: started with 10 mg/kg increase upto 60
mg/kg total dose- 500-2000mg
Useful in all epilepsies except cortical focal/ temporal

lobe epilepsy
Valproic Acid - Untoward Effects
GI distress Weight gain

sedation
Alopecia
Fulminant hepatitis
Tremors Age < 2 yrs
Neural tube defects
Monitor LFT
Sodium valproate _ADR
 Hypoalbuminemia
 Ataxia
 Thrombocytopenia
 Pancreatitis
Drug interactions
 Inhibits the metabolism of drugs that are substrates for
CYP2C9 : phenytoin, phenobarbital, carbamazepine,
lamotrigine
 Highly bound to albumin: can displace phenytoin
decreases metabolism & increases toxicity
 Valproate with clonazepam: rarely ppt absence seizures
Benzodiazepines
 MOA - enhance GABA transmission
 Clonazepam :absence, myoclonic seizures, infantile
spasms
 ADR:
 CNS: drowsiness, ataxia,tremor, vertigo, confusion
 Skin eruptions
 Anemia, leucopenia, thrombocytopenia
 Respiratory depression
 dependence
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Anti-seizure Drugs

Dr. Vishal Singh

Pharmacological agents in current clinical use inhibit

Whether any of these prevent the development of

 Head Trauma  High fever

 More than 40 forms of epilepsy have been identified

Originate within neuronal networks limited to one cerebral

Focal seizures evolving into

Focal seizures with dyscognitive features

 Sudden, brief lapses of consciousness without loss of

 The seizure typically lasts for only seconds, consciousness

 May occur dozens of times a day

 Onset is often in childhood (4-8 yrs)

Role of synapses in mediating communication

Defective synaptic function – Seizure

 Decrease in inhibitory (GABAergic) transmission.

 Increase in excitatory (glutamatergic) activity

 Alteration in ion conductances

 Centrally acting/ on spinal cord/

 A drug which decreases the frequency and/or

 Treats the symptom of seizures, not the

 Goal—maximize quality of life by minimizing

 Currently no “anti-epileptogenic” drugs

Stabilising effect on neuronal membranes

↓ paroxysmal depolarisation shift

Anti arrhythmic effect

 Particle size and pharmaceutical additives affect

 Extensively bound to plasma proteins

 Elimination of phenytoin is dose-dependent

 High i.v. rate: cardiac arrhythmias ± hypotension; CNS

Hirsutism Megaloblastic anemia

Pre- and postnatal growth deficiency

Hypoprothrombinemia and hemorrhage in newborns

Hypersenstivity Reactions : rash

 More soluble form

 Can be given intramuscularly

 Fewer local complications : tissue damage and necrosis

 Compatible with glucose solution

 With enzyme inhibitors: ↑ phenytoin

Dose: 100- 400 mg oral

 Exert maximal anti-seizure action at doses below

those required for hypnosis

 Inducer of microsomal enzymes – drug interactions.

 Effective against focal and GTC seizures

 Start at low dose to avoid sedation

 ADRs : Same as phenobarbital

 With enzyme inhibitors- erythromycin,

Eslicarbazepine acetate –prodrug

Useful in all epilepsies except cortical focal/ temporal

GI distress Weight gain

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