Drug treatment in Epilepsy

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Drug treatment in Epilepsy

• Martin Reed Pharmacy QEPH
• Miriam Wilcher

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Treatment Goals

• No seizures
• No side effects
• Monotherapy
• Once daily dosing
• No blood tests

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What actually happens

• 70 seizure free with one drug
• With careful monitoring and adjustment
• 5 to 10 seizure free with two or more drugs
• 20 still have seizures

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Principals of pharmacological treatment 1

• Use the right drug for the seizure type
• Use one drug and increase the dose until a
  therapeutic effect is gained or toxicity appears
  (maximum tolerated dose)
• Monitor treatment including blood levels
• If required add a second drug.
• If a response consider slowly removing the first
  drug

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Principals of pharmacological treatment 2

• If monotherapy fails use two drugs
• Review and replace the combinations used
• Add in a third drug if necessary
• Be prepared to accept that a significant
  reduction in seizure frequency maybe as good as
  it gets

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Compliance

• For a drug to be effective it has to be taken
• Non compliance is an important issue in poor
  control
• Patients must be fully involved in decisions
• Patients views must be respected
• Better knowledge and respect leads to better
  compliance

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Why dont patients comply?

• Poor communication
• Poor memory
• Poor understanding of instructions
• Mis-information
• Side effects
• Poor dose regimes
• Difficult to swallow/nasty taste medication
• Good information makes medicines work

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When should levels be monitored?

• Uncontrolled seizures
• Recurrence of seizures
• Side effects
• Assessment of compliance
• Confirmation of desired results
• Assessment of therapy when seizures infrequent
• Minor dose adjustments
• Concurrent illness

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But

• Blood concentrations are a guide only
• Timing of sample important
• Never look at the blood level in isolation
• Always consider blood level with respect to
• Side effects
• Seizure frequency

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Modes of action

• 1 Suppress action potential
• Sodium channel blocker or modulator
• Potassium channel opener
• 2 Enhance GABA transmission
• GABA uptake inhibitor
• GABA mimetics
• 3 Suppression of excitatory transmission

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Sodium channels

• Main target for many drugs
• Sodium channels are responsible for the rising
  phase of the action potential in excitable cells
  and membranes
• Examples

Phenytoin Carbamazepine Oxcarbazepine Lamotrigine
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Potassium channels

• Very diverse group of ion channels
• Responsible for resting potential
• Influences excitability of neurones
• Determine potential width

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GABA A and GABA B

• Inhibitory neurotransmitter
• GABA A post synaptic 7 classes
• Dependent upon chloride and bicarbonate ions
• GABA B pre and post synaptic

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GABA A Transmission

• Barbiturates
• primidone
• Benzodiazepines
• Clobazam, clonazepam, diazapam
• Tiagabine
• Vigabatrin

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Calcium channels

• Four main types
• L, P/G, N high voltage
• T low voltage
• Mono amines modulate the circuit
• Nifedipine blocks L

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Calcium channels

• T type
• Ethosuximide, zonisamide
• L type
• Barbiturates, felbamate
• N type
• Lamotrigine, barbiturates , oxcarbazepine
• P/Q type
• Lamotrigine, oxcarbazepine

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Glutamate

• Major excitatory transmitter
• Mainly intracellular
• Three receptor types
• NMDA
• Associated with sodium and calcium ions
• Magnesium ions block
• Other messengers act at NMDA site
• AMPA and kainate receptors
• metabotropic

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Other Mechanisms

• Valproic acid
• Gabapentin
• Piracetam
• Levetiracetam

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BUT

• Why do persistent alterations in neuronal
  circuits or excitability result in a paroxysmal
  disorder like epilepsy?

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Sites of action 1

• Valproate, vigabatrin, tiagabine increase GABA by
  inhibiting reuptake (2) and preventing breakdown
  within the cell (3)
• Benzodiazepines bind to GABA receptors (4)
• Phenobarbital opens chloride channels (4)
• Topiramate blocks sodium channels and is a GABA
  agonist at some sites (4)

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Other modes of action

• Gabapentin, has similar structure to GABA
• Phenytoin,carbamazepine,oxcarbazepine,
  lamotrigine, act on sodium channels
• Ethosuximide, reduces calcium currents
• Levetiracetam, has neuroprotective effect
• Topiramate, acetazolamide, are carbonic anhydrase
  inhibitors
• Zonisamide has weak carbonic anhydrase activity

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Choice of antiepileptic 1
Seizure type Drug of choice Alternatives
Partial simple Partial complex Carbamazepine Phenytoin Valproate Lamotrigine Gabapentin Levetiracetam Topiramate Tiagabine Oxcarbazepine Phenobarbital
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Choice of antiepileptic 2
Seizure type Drug of choice Alternatives
Generalised tonic clonic Carbamazepine Phenytoin Valproate Lamotrigine Topiramate Phenobarbital
Absence Ethosuximide Valproate Lamotrigine Clonazepam
Atypical absence Atonic, myoclonic Valproate Clonazepam
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Carbamazepine 1

• Dose
• 200mg to 1600mg a day in divided doses
• Therapeutic plasma concentration
• 4 to 12 micrograms per ml
• 20 to 50 micromoles/L
• Poor correlation between dose and plasma level in
  children
• Widely distributed in tissues, found in placenta
  and breast milk (40 plasma level)
• t MAX 4 to 8 hours
• Indicated for
• All forms of seizures except absence and
  myoclonic seizures

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Carbamazepine 2

• Common side effects
• Headache, drowsiness, dizziness, ataxia, double
  vision,
• Serious effects
• Osteomalacea, folate deficency, peripheral
  neuropathy, water retention, hyponatraemia, rash,
  blood dyscrasias-leucopaenia
• Comments
• Drug of choice for partial seizures, primary or
  secondary generalised tonic-clonic seizures
• Auto induces own metabolism slow escalation
• Variable half life 25-65 initially 8-18
  chronically
• Active metabolite
• Many drug interactions as enzyme inducer
• Can make myoclonus worse or appear to cause it

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Oxcarbazepine

• Dose
• 600mg to 2400mg daily
• Therapeutic plasma concentration
• Indicated for
• Partial seizures with or without secondarily
  generalised tonic clonic seizures
• Common side effects
• As for carbamazepine less severe
• Comments
• Fewer drug interactions than carbamazepine

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Clonazepam 1

• Dose
• 4 to 8 mg a day
• Therapeutic plasma concentration
• 0.63 to 2.2 mmol/litre
• Indicated for
• Refractory absence and myoclonic seizures

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Clonazepam 2

• Common side effects
• Sedation, ataxia, behaviour problems,
  hyperactivity
• Comments
• Used for partial seizures
• Half life 18 to 50 hours
• Tolerance develops in 30

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Clobazam

• Dose
• 20 to 60mg a day
• Indicated for
• Refractory partial seizures
• Cluster seizures
• Seizures connected with periods
• Common side effects
• As for clonazepam
• Comments
• As for clonazepam

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Ethosuximide 1

• Dose
• 500mg to 1500 mg daily
• Therapeutic plasma concentration
• 300 -700 micromoles/L
• 50 -100 micrograms/L
• Indicated for
• Simple absence seizures

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Ethosuximide 2

• Common side effects
• Gastro intestinal upset, nausea, drowsiness,
  headache, behavioural changes, hiccups, skin
  rashes
• Comments
• Half life 50 to 60 hours in adults
• 30 to 40 hours in children
  
• Administered tds to reduce gastric upset

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Gabapentin 1

• Dose
• 300mg to 2400mg daily (needs tds dose)
• Therapeutic plasma concentration
• Not established
• Indicated for
• Adjunctive treatment for refractory partial
  seizures

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Gabapentin 2

• Common side effects
• Drowsiness, dizziness, fatigue, ataxia, tremor,
  diplopia, nausea and vomiting
• Comments
• Excreted unchanged 95 in urine
• Only 60 of dose absorbed
• Unaffected by food
• Seizure frequency may increase
• No common drug interactions
• Comparatively safe in overdose

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Lamotrigine 1

• Dose
• 100 to 200mg monotherapy or with valproate
• 200mg to 400mg with enzyme inducers
• Therapeutic plasma concentration
• Not clinically relevant
• Indicated for
• All forms of seizures

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Lamotrigine 2

• Common side effects
• Dizziness, ataxia, double vision, nausea,
  somnolence
• Rash (worse in children) less if slow escalation
• Comments
• Complex interaction with valproate very slow
  escalation needed
• Indicated for partial seizures and secondarily
  generalised tonic clonic seizures
• Half life 25 hours shorter with enzyme inducers
• Excreted in breast milk
• Reasonably safe in overdose (10x)

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Levetiracetam

• Dose
• 500mg to 3000mg
• Therapeutic plasma concentration
• Not relevant
• Indicated for
• Partial seizures, Generalised absences
• Common side effects
• Nausea, drowsiness, anorexia, headache, rash,
• Very rarely leucopenia
• Comments
• No drug interactions described

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Phenobarbital 1

• Dose
• 90 to 600mg daily
• Therapeutic plasma concentration
• 60 to 160 micromoles /L
• 20 to 40 micrograms/ml
• Indicated for
• All forms of seizures except absence seizures

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Phenobarbital 2

• Common side effects
• Sedation (tolerance develops), headache,
  hyperkinesia (old young) slurred speech, skin
  reactions, cognitive impairment
• Comments
• Dependency needs very, very slow withdrawal
• Interactions - increases valproate effect
• -enzyme inducer, reduces effects of many other
  drugs
• Half life 2 to 7 days
• Can cause folate deficiency

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Primidone

• Dose
• 50mg to 1500mg daily
• Therapeutic plasma concentration
• No clinical relevance
• Indicated for
• All form of seizures except absence seizures
• Common side effects
• As for phenobarbital
• Comments
• Metabolised to phenobarbital and
  phenyethylmalonamide (PEMA)

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Phenytoin 1

• Dose
• 150mg to 600mg daily
• Therapeutic plasma concentration
• 40 to 40micromoles/L
• 10 to 20 micrograms/ml
• t MAX 4 to 12 hours
• Indicated for
• All forms of seizures except absence seizures
• Common side effects
• Dizziness, nausea, skin rashes, gum tenderness,
  hirsutism in females, peripheral neuropathy,
  tremor, ataxia, osteomalacia, folate deficiency

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Phenytoin 2

• Comments
• Zero order kinetics small increase in dose can
  cause large increase in levels
• Plasma levels (TDM) mandatory
• Many drug interactions including other AEDs
• Enzyme inducer
• Metabolised in the liver
• Half life 22 hours

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Sodium valproate/valproic acid 1

• Dose
• 600mg to 2400mg daily
• Therapeutic plasma concentration
• 300 to 600 micromoles/L
• 50 to 100 micrograms/ml
• But of little clinical value
• Indicated for
• All forms of epilepsy

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Valproic acid/sodium valproate 2

• Common side effects
• Nausea, gastrointestinal irritation, drowsiness,
  ataxia, weight gain also anorexia, alopecia.
• Rare but serious impaired liver function
• thrombocytopenia
• Comments
• Half life 10 to 20 hours, reduced with
  polytherapy
• GI upset reduced by enteric coating
• Interacts with lamotrigine and phenobarbital

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Tiagabine 1

• Dose
• 30 to 45 mg daily with enzyme inducers
• 15 to 30mg daily without enzyme inducers
• Therapeutic plasma concentration
• Not relevant
• Indicated for
• Adjunctive treatment for refractory partial
  seizures
• Common side effects
• Diarrhoea, dizziness, tiredness, concentration
  difficulties, emotional changes, speech
  impairment.

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Tiagabine 2

• Comments
• Short half life (4 to 10 hours)
• Used when add on therapy is required
• Efficacy reduced by enzyme inducing AEDs
• Reduces plasma concentration of sodium valproate

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Topiramate 1

• Dose
• 200mg to 800mg daily
• Therapeutic plasma concentration
• Not clinically relevant
• Indicated for
• Adjunctive treatment for refractory partial
  seizures
• Common side effects
• Nausea, abdominal pain, anorexia, cog.
  impairment, mood disorders (can be aggressive in
  LD)

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Topiramate 2

• Comments
• Watch for weight loss and depressive psychosis
• Ensure adequate hydration increased risk of
  kidney stones. Avoid carbonic anhydrase
  inhibitors e.g. acetazolamide
• Half life 18 to 30 hours reduced where given with
  enzyme inducing drugs

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Vigabatrin 1

• Dose
• 2000mg to 3000mg daily
• Therapeutic plasma concentration
• Not clinically relevant
• Indicated for
• Adjunctive treatment for refractory generalised
  tonic clonic and partial seizures

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Vigabatrin 2

• Common side effects
• Drowsiness, confusion, irritability, fatigue
• Visual field defects
• Psychotic experiences
• Comments
• Irreversible inhibitor of GABA transaminase
• Short half life irrelevant to dosing regime

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Zonisamide 1

• Dose
• 100mg/day increased every 2 weeks to max of 400mg
  
• higher doses in presence of enzyme inducers
• Peak plasma after 2-6hours
• delayed by food but total absorbed not affected.
• Steady state 14days
• Low plasma protein binding but bound to
  erythrocytes
• Indicated for partial seizures

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Zonisamide 2

• Contra indications sulfonamide hypersensitvity
• Cautions
• Renal impairment - excreted in urine
• Tendancy to kidney stones - advise plenty of
  fluids
• Co-administration with enzyme inducers
• Avoid in pregnancy possibly teratogenic

• Very Common Side effects
• - Agitation, confusion, dizziness, somnolence,
  double vision
• Common side effects
• - Diarrhoea, nausea, anorexia, rash

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Zonisamide 3

• Serious but rare effects
• Blood dyscrasias, panreatitis
• Hallucinations, psychosis
• Comment
• - New drug - monitor

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Drug history

• Phenobarbitone 1912
• Phenytoin 1938
• Primidone 1952
• Ethosuximide 1955
• Carbamazepine 1965
• Sod. Valproate 1973
• Valproic acid 1993
• Clonazepam 1974
• Clobazam 1979

• Vigabatrin 1989
• Lamotrigine 1991
• Gabapentin 1993
• Tiagabine
• Topiramate 1995
• Levetiracetam 2000
• Fosphenytoin 2001
• Zonisamide 2005

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others

• Felbamate
• Aplastic anaemia
• Liver failure
• Remacemide
• Piracetam

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Drugs to be used with care

• Aminophylline
• Amphetamines
• Analgesics
• Antibiotics
• Antidepressants
• Antimuscarinics
• Antipsychotics
• Baclofen
• Bupropion
• Donepezil etc

• Cyclosporin
• Cocaine
• Isoniazid
• Lignocaine
• Mefloquine
• NSAIDs
• Opioids
• Oral contraceptives
• Vincristine

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Web sites

• www.BNF.org
• www.e-epilepsy.org.uk/
• www.medicines.org.uk