Pharmacology of Antiepileptic Drugs

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Pharmacology of Antiepileptic Drugs

• Melanie K. Tallent, Ph.D.
• tallent_at_drexel.edu

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Basic Mechanisms UnderlyingSeizures and Epilepsy

• ? Seizure the clinical manifestation of an
  abnormal and excessive excitation and
  synchronization of a population of cortical
  neurons
• ? Epilepsy a disease characterized by
  spontaneous recurrent seizures
• ? Epileptogenesis sequence of events that
  converts a normal neuronal network into an
  epileptic network

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Partial Seizures
localized onset can be determined

• ? Simple
• ? Complex
• ? Secondary generalized

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Simple Partial Seizure

• Focal with minimal spread of abnormal discharge
• normal consciousness and awareness are maintained

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Complex Partial Seizures

• Local onset, then spreads
• Impaired consciousness
• Clinical manifestations vary with site of origin
  and degree of spread
• Presence and nature of aura
• Automatisms
• Other motor activity
• Temporal lobe epilepsy
• most common

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Secondarily Generalized Seizures

• ? Begins focally, with or without focal
  neurological symptoms
• ? Variable symmetry, intensity, and duration of
  tonic (stiffening) and clonic (jerking) phases
• ? Typical duration up to 1-2 minutes
• ? Postictal confusion and somnolence

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Generalized Seizures

• In generalized seizures, both hemispheres are
  widely involved from the outset.
• Manifestations of the seizure are determined by
  the cortical site at which the seizure arises.
• Present in 40 of all epileptic Syndromes.

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Generalized seizures

• Absence seizures (Petit mal) sudden onset and
  abrupt cessation brief duration, consciousness
  is altered attack may be associated with mild
  clonic jerking of the eyelids or extremities,
  postural tone changes, autonomic phenomena and
  automatisms (difficult diagnosis from partial)
  characteristic 2.5-3.5 Hz spike-and wave pattern
• Myoclonic seizures myoclonic jerking is seen
  in a wide variety of seizures but when this is
  the major seizure type it is treated differently
  to some extent from partial leading to
  generalized

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Generalized Seizures (cont)

• Atonic seizures sudden loss of postural tone
  most often in children but may be seen in adults
• Tonic-clonic seizures (grand mal) major
  convulsions with rigidity (tonic) and jerking
  (clonic), this slows over 60-120 sec followed by
  stuporous state (post-ictal depression)

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Generalized Tonic-Clonic Seizures

• Recruitment of neurons throughout the cortex
• Major convulsions, usually with two phases
• 1) Tonic phase muscles will suddenly tense up,
  causing the person to fall to the ground if they
  are standing.
• 2) Clonic phase muscles will start to contract
  
• and relax rapidly, causing convulsions
• Convulsions
• motor manifestations
• may or may not be present during seizures
• excessive neuronal discharge
• Convulsions appear in Simple Partial and Complex
  Partial Seizures if the focal neuronal discharge
  includes motor centers they occur in all
  Generalized Tonic-Clonic Seizures regardless of
  the site of origin.
• Atonic and absence Seizures are non-convulsive

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Video
http//www.youtube.com/watch?vfrWcJJkXQFM
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Status Epilepticus

• More than 30 minutes of continuous seizure
  activity
• Two or more sequential seizures spanning this
  period without full recovery between seizures
• Medical emergency

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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
• Goalmaximize quality of life by minimizing
  seizures and adverse drug effects
• Currently no anti-epileptogenic drugs available

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Therapy Has Improved Significantly

• Give the sick person some blood from a pregnant
  donkey to drink or steep linen in it, dry it,
  pour alcohol onto it and administer this.
• Formey, Versuch einer medizinischen Topographie
  von Berlin 1796, p. 193

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Current Pharmacotherapy

• Just under 60 of all people with epilepsy can
  become seizure free with drug therapy
• In another 20 the seizures can be drastically
  reduced
• 20 epileptic patients, seizures are refractory
  to currently available AEDs

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Choosing Antiepileptic Drugs

• ? Seizure type
• ? Epilepsy syndrome
• ? Pharmacokinetic profile
• ? Interactions/other medical conditions
• ? Efficacy
• ? Expected adverse effects
• ? Cost

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General Facts About AEDs

• Good oral absorption and bioavailability
• Most metabolized in liver but some excreted
  unchanged in kidneys
• Classic AEDs generally have more severe CNS
  sedation than newer drugs (except ethosuximide)
• Because of overlapping mechanisms of action, best
  drug can be chosen based on minimizing side
  effects in addition to efficacy

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Classification of AEDs

• Classical
• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine
• Ethosuximide
• Valproate (valproic acid)
• Trimethadione (not currently in use)

• Newer
• Lamotrigine
• Felbamate
• Topiramate
• Gabapentin/Pregabalin
• Tiagabine
• Vigabatrin
• Oxycarbazepine
• Levetiracetam
• Fosphenytoin

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Side effect issues

• Sedation - especially with barbiturates
• Cosmetic - phenytoin
• Weight gain valproic acid, gabapentin
• Weight loss - topiramate
• Reproductive function valproic acid
• Cognitive - topiramate
• Behavioral felbamate, leviteracetam
• Allergic - many

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Cellular Mechanisms of Seizure Generation
emedicine.com
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Targets for AEDs

• Increase inhibitory neurotransmitter systemGABA
• Decrease excitatory neurotransmitter
  systemglutamate
• Block voltage-gated inward positive currentsNa
  or Ca
• Increase outward positive currentK
• Many AEDs pleiotropicact via multiple mechanisms

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EpilepsyGlutamate

• ? The brains major excitatory neurotransmitter
• ? Two groups of glutamate receptors
• Ionotropicfast synaptic transmission
• NMDA, AMPA, kainate
• Gated Ca and Gated Na channels
• Metabotropicslow synaptic transmission
• Regulation of second messengers (cAMP and
  Inositol)
• Modulation of synaptic activity
• ? Modulation of glutamate receptors
• Glycine, polyamine sites, Zinc, redox site

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EpilepsyGlutamate
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Glutamate Receptors as AED Targets

• NMDA receptor sites as targets
• Ketamine, phencyclidine, dizocilpine block
  channel and have anticonvulsant properties but
  also dissociative and/or hallucinogenic
  properties open channel blockers.
• AMPA receptor sites as targets
• Since it is the workhorse receptor can
  anticipate major sedative effects

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Felbamate

• Antagonizes the glycine site on the NMDA receptor
  and blocks Na channels
• Very potent AED lacking sedative effect (unlike
  nearly all other AEDs)
• Associated with rare but fatal aplastic anemia,
  hence is restricted for use only in extreme
  refractory epilepsy

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Topiramate

• Acts on AMPA receptors, blocking the glutamate
  binding site, but also blocks kainate receptors
  and Na channels, and enhances GABA currents
  (highly pleiotropic)
• Used for partial seizures, as an adjunct for
  absence and tonic-clonic seizures (add-on or
  alternative to phenytoin)
• Very long half-life (20h)

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EpilepsyGABA

• ? Major inhibitory neurotransmitter in the CNS
• ? Two types of receptors
• GABAApost-synaptic, specific recognition sites,
  CI- channel
• GABAB presynaptic autoreceptors, also
  postsynaptic, mediated by K currents

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GABAA Receptor
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Clonazapam

• -Benzodiazepine used for absence seizures (and
  sometimes myoclonic) fourth-line AED
• -Most specific AED among benzodiazepines,
  appearing to be selective for GABAA activation in
  the reticular formation leading to inactivation
  of T-type Ca2 channels, hence its useful for
  absence seizures
• -Sedating May lose effectiveness due to
  development of tolerance (6 months)

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Lorazapam and Diazepam

• Benzodiazepines used as first-line treatment for
  status epilepticus (delivered IV fast acting)
• Sedating

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Phenobarbital

• Barbiturate used for partial seizures, especially
  in neonates. Oldest of the currently used AEDs
• Very strong sedation Cognitive impairment
  Behavioral changes
• Very long half-life (up to 5days) Induces P450
  
• Tolerance may arise Risk of dependence
• Primidone, another barbiturate metabolized to
  Phenobarbital, and Phenobarbital are now seldom
  used in initial therapy, owing to side-effects

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AEDs That Act Primarily on GABA

• Tiagabine
• Interferes with GABA re-uptake
• Vigabatrin (not currently available in US)
• elevates GABA levels by irreversibly inhibiting
  its main catabolic enzyme, GABA-transaminase

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Na Channels as AED Targets

• Neurons fire at high frequencies during seizures
• Action potential generation is dependent on Na
  channels
• Use-dependent or time-dependent Na channel
  blockers reduce high frequency firing without
  affecting physiological firing

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Anticonvulsants Mechanisms of Action
Voltage-gated sodium channel
Open
Inactivated
Na
Na
X
I
I
CarbamazepinePhenytoin
LamotrigineValproate
Na
Na
A activation gate I inactivation gate
McNamara JO. Goodman Gilmans. 9th ed.
1996461-486.
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AEDs That Act Primarily on Na Channels

• Phenytoin, Carbamazepine
• Block voltage-dependent sodium channels at high
  firing frequenciesuse dependent
• Oxcarbazepine
• Blocks voltage-dependent sodium channels at high
  firing frequencies
• Also effects K channels
• Zonisamide
• Blocks voltage-dependent sodium channels and
  T-type calcium channels

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Phenytoin

• First-line for partial seizures some use for
  tonic-clonic seizures
• Highly bound to plasma proteins displaced by
  Valproate Induces P450 resulting in increase in
  its own metabolism, but its metabolism is also
  increased by alcohol, diazepam
• Sedating
• Fosphenytoin Prodrug for Phenytoin, used for IM
  injection

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Carbamazapine

• A tricyclic antidepressant used for partial
  seizures some use in tonic-clonic seizures
• Induces P450 resulting in increase in its own
  metabolism
• Sedating Agranulocytosis and Aplastic anemia
  (elderly) Leukopenia (10 of patients)
  Hyponatremia Nausea and visual disturbances

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Oxcarbazapine

• Newer drug, closely related to Carbamazapine,
  approved for monotherapy, or add-on therapy in
  partial seizures
• May also augment K channels
• Some induction of P450 but much less than that
  seen with Carbamazapine
• Sedating but otherwise less toxic than
  Carbamazapine

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Zonisamide

• Used as add-on therapy for partial and
  generalized seizures
• -Also blocks T-type Ca2 channels
• -Very long half-life (1-3days)

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Lamotrigine

• Add-on therapy, or monotherapy for refractory
  partial seizures
• Also inhibits glutamate release and (perhaps)
  Ca2 channels (pleiotropic)
• Metabolism affected by Valproate, Carbamazapine,
  Phenobarbital, Phenytoin
• Less sedating than other AEDs (Severe dermatitis
  in 1-2 of pediatric patients)

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Ca2 Channels as Targets

• General Ca2 channel blockers have not proven to
  be effective AEDs.
• Absence seizures are caused by oscillations
  between thalamus and cortex that are generated in
  thalamus by T-type (transient) Ca2 currents

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Ethosuximide

• Acts specifically on T-type channels in thalamus,
  and is very effective against absence seizures.
• Long half-life (40h)
• Causes GI disturbances Less sedating than other
  AEDs

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Gabapentin and its second generation derivative
Pregabalin

• -Act specifically on calcium channel subunits
  called a2d1. It is unclear how this action leads
  to their antiepileptic effects, but inhibition of
  neurotransmitter release may be one mechanism
• -Used in add-on therapy for partial seizures and
  tonic-clonic seizures
• -Less sedating than classic AEDs

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What about K channels?

• K channels have important inhibitory control
  over neuronal firing in CNSrepolarizes membrane
  to end action potentials
• K channel agonists would decrease
  hyperexcitability in brain
• So far, the only AED with known actions on K
  channels is valproate
• Retiagabine is a novel AED in clinical trials
  that acts on a specific type of voltage-dependent
  K channel (M-channel)

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Valproate (Valproic Acid)

• First-line for generalized seizures, also used
  for partial seizures
• Also blocks Na channels and enhances GABAergic
  transmission (highly pleiotropic)
• Highly bound to plasma proteins Inhibits P450
• CNS depressant GI disturbances hair loss
  weight gain teratogenic (rare hepatotoxic)

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Regulation of Neurotransmitter release

• Several AED have actions that result in the
  regulation of neurotransmitter release from the
  presynaptic terminal, such as lamotrigine, in
  addition to their noted action on ion channels or
  receptors.
• Levetiracetam appears to have as its primary
  action the regulation of neurotransmitter release
  by binding to the synaptic vesicle protein SV2A

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Levetiracetam

• -Add-on therapy for partial seizures
• -Short half-life (6-8h)
• -CNS depression

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Pleiotropic AEDs

• Many AEDs act on multiple targets, increasing
  their efficacy
• Felbamate, lamotrigine, topirmate, valproate

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Drug Interactions

• Many AEDs are notable inducers of cytochrome P450
  enzymes and a few are inhibitors.
• Of the classic AEDs, phenytoin, carbamazipine,
  phenobarbital, and primidone are all strong
  inducers of cytochrome P450 enzymes. They are
  autoinducers, in other words they increase their
  own metabolism.
• Valproate inhibits cytochrome P450 enzymes.

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Pharmacokinetic Considerations

• Most AEDs undergo complete or nearly complete
  absorption when given orally.
• Fosphenytoin (prodrug) may be administered
  intramuscularly if intravenous access cannot be
  established in cases of frequent repetitive
  seizures
• Diazepam (available as a rectal gel) has been
  shown to terminate repetitive seizures and can be
  administered by family members at home.
• Phenytoin, fosphenytoin, phenobarbital, diazepam,
  lorazepam and valproate are available as IV
  preparations for emergency use.
• Most AEDs are metabolized in the liver (P450) by
  hydroxylation or conjugation. These metabolites
  are then excreted by the kidney. Gabapentin
  undergoes no metabolism and is excreted unchanged
  by the kidney.

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Treatment of Epilepsy

• First consideration is efficacy in stopping
  seizures
• Because many AEDs have overlapping, pleiotropic
  actions, the most appropriate drug can often be
  chosen to reduce side effects. Newer drugs tend
  to have less CNS depressant effects.
• Potential of long-term side effects,
  pharmokinetics, and cost are other considerations

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Treatment of Epilepsy

• Monotherapy is preferred better patient
  compliance, less adverse effects
• Add-on therapy is often necessary to eliminate
  break-through or refractory seizures

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AED Treatment Options
Primary generalized seizures
Partial seizures
Simple Complex SecondaryGeneralized
phenytoin, carbamazepine, phenobarbital,
gabapentin, oxcarbazepine, pregabalin
Ethosuximide
Check notes
valproic acid, lamotrigine, topiramate,
(levetiracetam, zonisamide)
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Status Epilepticus

• More than 30 minutes of continuous seizure
  activity
• Two or more sequential seizures spanning this
  period without full recovery between seizures
• Medical emergency

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Status Epilepticus

• Treatment
• Diazepam, lorazapam IV (fast, short acting)
• Followed by phenytoin, fosphenytoin, or
  phenobarbital (longer acting) when control is
  established

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Alternative Uses for AEDs

• Gabapentin/pregabalin, carbamazepineneuropathic
  pain
• Lamotrogine, carbamazepinebipolar disorder
• Leviteracitam, valproate, topirimate,
  gabapentinmigraine

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Questions?