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
Thank you
