ANTIEPILEPTIC DRUGS
Department of Pharmacology NEIGRIHMS, Shillong
HISTORY OF EPILEPSY In 400 B.C., the early physician
Hippocrates suggested that epilepsy was a disorder of the brain
Famous Persons Afflicted: ALEXANDER THE GREAT JULIUS CAESAR NAPOLEON LEWIS CARROLL
WHAT ARE EPILEPSIES? Definition: These are Group of disorders of the CNS
characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes (seizure) of loss of consciousness, with or without characteristic body movements (convulsions), sensory or psychiatric phenomena
What is a seizure? A seizure is a transient alteration of behaviour due to the
disordered, synchronous, and rhythmic firing of populations of brain neurons. Seizure can be non-epileptic and can be evoked in normal brain
A seizure is a paroxysmal behavioral spell generally caused by an excessive disorderly discharge of cortical nerve cells
EPILEPSIES – CLINICALLY• Epilepsy is a syndrome of
two or more unprovoked or recurrent seizures on more than one occasion
• Epileptic seizures range from clinically undetectable (electrographic seizure) to convulsions
• Not to be confused: Remember its Not only falling down and unconsciousness of patients: Alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms
CLASSIFICATION OF EPILEPTIC SEIZURES Generalized:
1. Generalized tonic-clonic seizure2. Absence seizure3. Tonic seizures4. Atonic Seizure5. Myoclonic seizure6. Infantile spasm
TYPES OF SEIZURES – CONTD.
Partial (focal) Seizures: 80% of Adult epilepsies
Simple Partial Seizures Complex Partial Seizures Simple partial or complex partial secondarily
generalized
GENERALIZED SEIZURES1. Generalized tonic-clonic
GTCS/major epilepsy/grand mal Commonest of all Lasts for 1-2 minutes Aura-cry-unconsciousness-tonic phase-clonic phase Usually occurs in both the hemispheres Manifestations are determined by cortical site of seizure
occurrence 2 phases: tonic phase followed by clonic phase 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
EEG CHANGES IN GTCS Tonic: Rythmic high
frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials
Clonic: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials
GENERALIZED SEIZURES – CONTD. Absence seizure:
Also called minor epilepsy/petit mal Usually in Children and lasts for 1-2 minutes Typical generalized spike-and-wave type
discharges at 3 per second (3 Hz) Momentary loss of consciousness (not
convulsion), patient stares at one direction No motor (muscular component) No convulsions Minor muscular twitching restricted to eyelids
(eyelid flutter) and face No loss of postural control.
GENERALIZED SEIZURES – CONTD. Atonic Seizures:
Unconsciousness with relaxation of all muscles Patient falls down Loss of postural tone, with sagging of the head or falling
Myoclonic Seizures: Isolated clonic jerks associated with brief bursts of multiple
spikes in the EEG Momentary contractions of muscles of limbs or whole body No loss of postural control
Infantile spasm: An epileptic syndrome Characterized by brief recurrent myoclonic jerks (muscle spasm)
of the body with sudden flexion or extension of the body and limbs
Progressive mental deterioration
PARTIAL (FOCAL) SEIZURES Simple partial seizure
(Jacksonian) Lasts for 20 – 60 seconds Motor, sensory, vegetative or
psychic symptomatology Typically consciousness is
preserved Confined to a group of
muscles or localized sensory disturbances depending on area of cortex involved
For example – if motor cortex of the left thumb then jerking movement of left thumb, and if it is sensory cortex then paresthesia of left thumb.
No alteration of consciousness
EEG: Excessive synchronized discharge by a small group of neurons. Contralateral discharge
SCHEME OF SEIZURE SPREADSimple (Focal) Partial
Seizures
Contralateral spread
PARTIAL (FOCAL) SEIZURES – CONTD. Complex partial seizure (temporal
lobe/psychomotor epilepsy)
Focus is located in temporal lobe Confused behaviour and purposeless movements and
emotional changes lasting for 30 seconds to 2 minutes An aura often present Automatisms (repetitive coordinated movements)
perioral and hand automatisms Wide variety of clinical manifestations and Consciousness is
impaired
COMPLEX PARTIAL SEIZURE – CONTD.
….Deja vu …
PARTIAL (FOCAL) SEIZURES – CONTD. Secondarily generalized (Jacksonian):
Partial seizures initially Followed by generalized tonic-clonic
seizure
SCHEME OF SEIZURE SPREADComplex Partial Seizures
Complex Secondarily Generalized Partial Seizures
PARTIAL (FOCAL) SEIZURES – CONTD.
STATUS EPILEPTICUS Continuous seizure activity for more than 30
minutes, or 2 or more seizures without recovery of consciousness
Its an Emergency Condition: Recurrent tonic-clonic convulsions without recovery in between
EXPERIMENTAL MODELS
1. Maximal electroshock seizures (MES): tonic phase abolished by drugs effective in GTCS and also Partial seizures
2. PTZ clonic seizures (Pentylenetetrazole): Can be prevented by drugs effective in absence seizure (Petit mal)
3. Kindled seizures: bursts of weak electrical impulses – tonic-clonic seizure
WHY EPILEPSY OCCURS? Children: Birth traumas, infections – meningitis and
congenital abnormalities Middle age: Alcohol, infections, head injury and
Drugs like cocaine, low blood sugar, low oxygeen, low blood Na+ and low Ca+ etc.
Elderly: Stroke, tumors etc. Congenital:
Hippocampus DYSGENESIS (FAILURE OF CORTEX TO GROW PROPERLY)\
VASCULAR MALFORMATIONS AT LEAST EIGHT SINGLE LOCUS GENETIC DEFECTS ARE
ASSOCIATED WITH EPILEPSY – motor cortex, somatosensory cortex, visual cortex, auditory cortex, temporal lobe cortex and olfactory.
CLASSIFICATION OF ANTIEPILEPTIC DRUGS Hydantoins: phenytoin, phosphenytoin Barbiturates: phenobarbitone Iminostilbenes: carbamazepine,
oxcarbazepine Succinimides: ethosuximide Aliphatic carboxylic acid: Valproic acid,
divalproex Benzodiazepines: clonazepam, diazepam,
lorazepam New compounds: gabapentin,
lamotrigine, tiagabine, topiramate, vigabatrin, zonisamide, felbamate
MECHANISMS OF SEIZURE & ANTISEIZURE DRUGS:
Most common ones: Modification of ion conductance
Prolongation of Na+ channel inactivation Inhibition of `T` type Ca++ current
Increase inhibitory (GABAergic) transmission – Cl- Channel.
Glutamate receptor antagonism (NMDA, AMPA, or kainic acid)
Genetic mechanism
The Sodium Channel:
A. Resting State
B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.
C. Refractory State, Inactivation – reduce the rate of recovery.
Na+
Na+
Na+
Sustain channel in this
conformation
Anticonvulsant mechanism – contd.
m gate
h gate
THE SODIUM CHANNEL – CONTD. Drugs acting via this channel: Phenytoin, Sodium Valproate,
Carbamezepine, Lamotrigine, Topiramide and Zonisamide
ANTICONVULSANT MECHANISM – CONTD.T type Ca++ current inhibition: Thalamic neurons exhibit prominent T
current which is a low threshold Ca++ current
T type current is responsible for 3 Hz spike-and-wave
Throughout the thalamus `T` current has large amplitudes – thalamocortical oscillations
Bursts of action potential is by action of T current
In absence seizure Drugs – ethosuximide, valproate and
trimethadione
ANTICONVULSANT MECHANISM – CONTD.
The GABA mediated CL- channel opening
Drugs: barbiturates, benzodiazepines, vigabatrin, gabapentin and valproate
PHENOBARBITONE First effective organic antiseizure agent Mechanism:
Mechanism of CNS depression like other barbiturates, but less effect on Ca++ channel and glutamate release – less hypnotic effect
GABAA receptor mediated like other Barbiturates Continued use – sedation effect lost but not anticonvulsant
action Raises seizure threshold and limits spread Suppresses kindled seizures
Pharmacokinetics: Slowly absorbed and long t1/2 (80 – 120 hrs) Metabolized in liver and excreted unchanged in kidney Single dose after 3 wks. – steady state
PHENOBARBITONE – CONTD.(GARDENAL/LUMINAL) Adverse effects:
Sedation Behavioural
abnormalities Hyperactivity in
children Rashes,
megaloblastic anaemia and osteomalacia
Primidone: Deoxybarbiturate Converted to
Phenobarbitone and PEMA Short half life 6-14 hrs
Uses: Many consider them
the drugs of choice for seizures only in infants
GTC SP and CPS
Dose: 60 mg 1-3 times a
day Child: 3-6
mg/kg/day Available as tabs –
30/60mg, syr. and inj.
PHENYTOIN(DILANTIN/EPSOLIN/EPTOIN)
Pharmacological actions: Not CNS depressant But muscular rigidity and excitement at
toxic doses Abolish tonic phase of GTC seizure No effect on clonic phase Prevents spread of seizure activity Tonic-clonic epilepsy is suppressed but no
change in EEG and aura.. In CVS – depresses ventricular
automaticity, accelerates AV conduction
PHENYTOIN – CONTD. Mechanism of
action: Prevents repetitive
detonation of normal brain cells during `depolarization shift`
Prolonging the inactivation of voltage sensitive Na+ channel
No high frequency discharges
Na+ channel recovers No interference with
kindling – only on high frequency firing
Pharmacokinetics: Slow oral absorption 80-90% bound to plasma
protein Metabolized in liver by
hydroxylation and glucoronide conjugation
Elimination varies with dose – first order to zero order
T1/2 life is 12 to 24 hrs Cannot metabolize by
liver if plasma conc. Is above 10 mcg/ml
Monitoring of plasma concentration
PHENYTOIN – CONTD.
Adverse effects: Hirsutism, coarsening of facial features and acne Gum hypertrophy and Gingival hyperplasia. Hypersensitivity – rashes, lymphadenopathy Megaloblastic anaemia Osteomalacia Hyperglycaemia Cognitive impairment Exacerbates absence seizures Fetal Hydantoin Syndrome
PHENYTOIN SODIUM – CONTD.
Phenytoin Toxicities
Fetal Hydantoin Syndrome
PHENYTOIN SODIUM – CONTD. Uses: It is the first
line antiepileptic for GTCS, no effect in
absence seizure Status epilepticus Trigeminal neuralgia
– 2nd to Carbamazepine
Available as caps/tabs/inj
25 to 100 mg caps and tabs
Drug Interactions: Phenytoin and
carbamazepine increases each others metabolism
Induces microsomal enzyme – steroids, digitoxin etc
Phenytoin metabolism inhibition – by warfarin, isoniazide etc.
Sucralfate – decreases phenytoin ebsorption
CARBAMAZEPINE (TEGRETOL/TEGRITAL) Chemically related to imipramine Trigeminal neuralgia Lithium like action – mood stabilizer Resembles phenytoin in pharmacological actions Unlike phenytoin – inhibits kindling, modifies
electroshock seizures and raises threshold to PTZ and electroshock
MOA: Stabilizes Na+ channel (Voltage gated) in
inactivated state – less excitability Potentiation of GABA receptor
CARBAMAZEPINE – CONTD. Pharmacokinetics
: Poorly water soluble and
oral absorption is low 75% bound to plasma
protein Metabolized in liver:
active 10-11 epoxy carbamazepine
Substrate and inducer of CYP3A4
Half life – 20 to 40hrs. Decreases afterwards due to induction
Adverse effects: Autoinduction of
metabolism Nausea, vomiting,
diarrhoea and visual disturbances
Hypersensitivity – rash, photosensitivity, hepatitis, granulocyte suppression and aplastic anemia
ADH action enhancement – hyponatremia and water retention
Teratogenicity Exacerbates absence
seizures
CARBAMAZEPINE – CONTD. Uses:
Complex partial seizure
GTCS and SPS Trigeminal and
related neuralgias Manic depressive
illness and acute mania
Available as tabs (100mg 200, 400 etc.) and syr.
Oxcarbamazepine
Interactions: Enzyme inducer –
reduce efficacy of OCPs and others
Metabolism is induced by – phenobarbitone, phenytoin, valproate
Inhibits its metabolism – isoniazide and erythromycin
ETHOSUXIMIDE Drug of choice for absence seizures Does not modify maximal electroshock seizure or
inhibit kindling High efficacy and safety Not plasma protein or fat binding Mechanism of action involves reducing low threshold
Ca2+ channel current (T-type channel) in thalamusAt high concentrations: Inhibits Na+/K+ ATPase Depresses cerebral metabolic rate Potentiates GABA
Phensuximide = less effective Methsuximide = more toxic
ETHOSUXIMIDE – CONTD. Toxicity:
Gastric distress, including, pain, nausea and vomiting
Lethargy and fatigue Headache Hiccups Euphoria Skin rashes
Doses: 20-30mg/kg/day Available as syr./caps.
VALPROIC ACID(ENCORATE/VALPARIN) Broad spectrum anticonvulsant Effects on chronic experimental seizure and kindling Potent blocker of PTZ seizure Effective in partial, GTCS and absence seizures Mechanism:
Na+ channel inactivation Ca++ mediated `T` current attenuation Inhibition of GABA transaminase
Pharmacokinetics: well absorbed orally, 90% bound to plasma protein and completely metabolized in liver and excreted in urine t1/2 is 10-15 hrs.
VALPROIC ACID – CONTD. Adverse effects:
Elevated liver enzymes including own – rise in serum transaminase
Nausea and vomiting Abdominal pain and
heartburn Tremor, hair loss, weight
gain Idiosyncratic
hepatotoxicity In Girls – polycystic
ovarian disease and menstrual irregularities
Negative interactions with other antiepileptics
Teratogenicity: spina bifida
Drug Interactions: Valproate and
carbamazepine induce each others metabolism
Inhibits phenobarbitone metabolism and increases its plasma level
Displaces phenytoin from protein binding sites and thereby decreases its metabolism – phenytoin toxicity
Available as tabs. (200/300/500, syr. and inj.)
GABAPENTIN GABA derivative and can cross BBB Enhances GABA release, but not agonist of GABAA Originally designed to be centrally active GABA
agonist – rapid transfer across BBB Binds a protein in cortical membrane – similar to L
type of voltage sensitive Ca++ channel, but do not alter Ca++ currents
Pharmacological Effects: Inhibits hindlimb extension in ME seizure Inhibits clonic seizures induced by PTZ Efficacy is equal to valproic acid but different from
carbamazepine and phenytoin
GABAPENTIN – CONTD. Pharmacokinetics:
Absorbed orally Not metabolized in humans Not bound to plasma proteins and excreted unchanged in
urine Half life is 4 to 6 hrs. No known drug interaction
Uses: Partial seizures with or without secondary generalization in
addition to other drugs 900-1800mg/day is equivalent to 300 mg/day of
carbamazepine if used alone Usual starting dose is 300mg/day
Adverse effects: somnolence, dizziness, ataxia etc.
LAMOTRIGINE Phenyltriazine derivative, newer agent Carbamazepine like action profile and modify MES seizures Originally, as antifolate agent Mechanisms:
Delays recovery from inactivation of Na+ channels prolong Na+ channel inactivation
Glutamate and aspartate inhibition: By directly blocking Na+ channels - stabilizes pre synaptic membrane and prevent release by excitatory neurons
Inhibition of Ca++ in neurons Actions: Broad spectrum activity – action in areas other than Na+
channels, suppresses tonic hind limb extension in ME seizure, no action on PTZ seizures,
Uses: Partial (simple and complex) and secondarily generalized, absence seizure, myoclonic seizure in youngs
LAMOTRIGINE – CONTD. Pharmacokinetics:
Completely absorbed from GIT and metabolized by glucoronidation
Plasma half-life – 15 to 30 hrs Phenobarbitone, carbamazepine and phenytoin –
reduces half life Valproate – increases plasma concentration but its
concentration reduces Together with Carbamazepine – increase in 10,11-
epoxide and toxicity Uses: Monotherapy and add on therapy in simple
partial and secondarily generalized seizures. Daily dose – 100 to 300 mg
TOPIRAMATE Sulfamate substituted monosaccharide Pharmacological effects and MOA:
Broad spectrum antiseizure drug Carbonic anhydrase inhibitor Antiseizure activity against PTZ, ME seizure and partial and
secondarily generalized tonic-clonic kindling Multiple actions – Na+ channel, K+ channel, GABAA, AMPA-
kainate subtypes of glutamate Pharmacokinetics:
Rapidly absorbed orally, 10-20% bound to plasma protein, excreted unchanged in urine
Metabolized by hydroxylation, glucoronidation and hydrolysis
Reduction in estradiol level Uses: GTCS, SP and CPS as supplement drug in
refractory cases
BENZODIAZEPINES Mainly used agents – Clonazepam,
Diazepam, Lorazepam and Clobazam Common Antiseizure properties:
Prevents PTZ induced seizures prominently and modifies electroshock seizure pattern
Clonazepam has potent effect on PTZ induced seizures but almost nil action on ME seiures
Suppress the spread of kindled seizures and generalized convulsions
Do not abolish abnormal discharges at site of stimulation
DIAZEPAM Diazepam:
Commonly used as anticonvulsant in a variety of convulsions
But, not used for long term – sedation effect Mechanism of anticonvulsant is mediated by same
mechanism of sedation: Cl- channel Used in emergency control of convulsion – status
epilepticus, tetanus, febrile convulsion etc. Usually given 0.2 to 0.5 mg/kg body weight IV followed by
repeated doses if required – maximum dose 100 mg/day Rectal diazepam
BENZODIAZEPINES – CONTD. Adverse effects:
Long term use of Clonazepam – drowsiness and lethargy – tolerance to antiseizure effects
Muscular incoordination and ataxia Hypotonia, dysarthria and dizzziness Behavoiural abnormalities in children – aggression,
hyperactivity, irritability and difficulty in concentration Increased bronchial and salivary secretions Exacerbation of seizures
Therapeutic uses: Clonazepam in absence seizure and myoclonic seizure in
children (1 to 6 months) Dose initial – 1.5mg/day, children – 0.01 to 0.03mg/kg/day Status epilepticus – Diazepam, Lorazepam may be used as
alternative
TREATMENT OF EPILEPSIES1. Aim of the treatment:
Control and prevent all seizure activity (seizure - freedom and improvement in quality of life!)
To search the cause of epilepsy Attempts to remove the causes Symptomatic treatment with antiepileptic drugs To consider status epilepticus as medical emergency and treat
efficiently and promptly2. Initiation of treatment:
Initiate therapy even if it is isolated tonic-clonic seizure with family history of seizure, abnormal neurological examination, abnormal EEG and an abnormal MRI
Treat with monotherapy, Substitute another drug if fails Combination therapy – only when all monotherapy fail Therapeutic monitoring of drugs – dose adjustments
3. CHOICE OF DRUGS: ACCORDING TO THE SEIZURE TYPES
Seizure types 1st choice 2nd choiceGeneralized tonic-clonic or simple partial seizure
Carbamazepine, Phenytoin and Valproic acid
Phenobarbitone and Valproate
Absence seizure Valproate EthosuximideComplex partial seizure with or without generalization
Phenytoin, Carbamazepine and Valproate
GabapentinLamotrigine
Myoclonic Valproate LamotrigineTopiramate
Status epilepticus DiazepamLorazepam
Phenytoin IVPhosphenytoin IV
Febrile convulsions Diazepam rectal 0.5mg/kg
-
TREATMENT OF EPILEPSIES – CONTD.4. Withdrawal of drugs:
Gradual withdrawal Prolong therapy – life long/3yrs after last seizure Withdrawal – childhood epilepsy, absence of family history,
primarily generalized tonic-clonic seizure and normal EEG5. Seizure diary6. Antiepileptics and pregnancy
Drugs should not be stopped if conceive – status epilepticus
Fits during pregnancy – birth defects, mental retardation etc.
Folic acid and vit.K supplementation7. Care during attacks: tonic-clonic seizures8. Surgical removal
GENERALIZED ONSET SEIZURES – DRUG THERAPY
Tonic-clonic, myoclonic, and absence seizures: 1st line drug is usually valproate
Generalized seizures: Phenytoin and carbamazepine are
effective on tonic-clonic seizures but not other types of seizures
Absence seizures: Valproate and ethosuximide are equally
effective in children, but only valproate protects against the tonic-clonic seizures that sometimes develop
Risk of hepatoxicity with valproate—should not be used in children under 2
PARTIAL SEIZURES - TREATMENT Without generalization
Phenytoin and carbamazepine may be slightly more effective
With secondary generalization First-line drugs are carbamazepine and
phenytoin (equally effective) Valproate, phenobarbital, and primidone
are also usually effective Phenytoin and carbamazepine can be
used together (but both are enzyme inducers)
PARTIAL SEIZURES – CONTD. Adjunctive (add-on) therapy: newer drugs
gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide
Phenytoin and carbamazepine failure: Lamotrigine, oxcarbazepine, felbamate approved for monotherapy
Refractory partial seizures: Topiramate can be effective
STATUS EPILEPTICUS Goal of therapy:
Rapid termination of seizure activity – more difficult to control – permanent brain damage
Prompt treatment with effective Drugs Attention to hypoventilation and hypotension Treatment is IV only
Diazepam 10mg IV bolus injection (2mg/min) Fractional dose at every 10 min. or titrated dose by slow
infusion Lorazepam: 0.1mg/kg
Followed by Phenobarbitone IM/IV (100-200mg)/min or Phenytoin slow IV in saline (25-50mg/min)
Resistant cases (refractory): IV anaesthetics (Propofol or thiopentone)
General supportive measures
IMPORTANT TO STUDY Mechanism of action and Adverse
effects/Uses of Phenytoin/Valproate/Carbamazepine/ETHSX
Short Notes: Gabapentine, Lamotrigine, Topiramate
Clinical: Pharmacotherapy of Status Epilepticus Pharmacotherapy of GTCS
Reasoning Questions: Valproic acid in absence seizure Phenytoin is not used in absence seizure Benzodiazepines as anticonvulsant
HAVE A NICE DAY !
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