Our story wrt pharmacotherapy

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Our story- wrt pharmacotherapy

• Katherine (Delargy)Duncombe

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Rob, Katherine and Anthony

• Parents both pharmacists who met at college
• Anthony was born in Feb 1996 40 weeks 3.78kg.
  Difficult delivery,ceph-haematoma, by six months
  old he was diagnosed with a squint.
• Aged 10 months old has 1st seizure (tonic-clonic)
  after chicken pox
• He has 10 more febrile convulsions

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1st major event

• September 2000 starts school- behaviour worsens
• December 2000 becomes very ill lose speech and
  goes into a catotonic state. Regression of
  skills and language
• Stay as in patient in local hospital
• Referred to GOSH

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Treatment at local hospital

• Non Convulsive SE and convulsive SE
• Phenytoin IV Diazepam rectally as emergency
  drugs
• Started on valproate then a few days later on
  carbamazepine
• Evidence now show that monotherapy should be tried

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Tertiary care

• Prednisolone- high dose course for 6 weeks
• Intermittent high dose steroid
• Very good result- return of language
• Increased appetite, activity, aggression

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Behaviour

• ADHD diagnosis
• Anthony tried methyl phenidate
• Didnt work
• Possibly behaviour related to epilepsy not ADHD
• Reduced appetite, caution in epilepsy

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Clobazam

• Benzodiazepine like valium but medium duration
  of action
• Lowers seizure threshold
• Used intermittently
• Problem with dependance and tolerance, withdrawal
  seizures, also can disinhibit in some cases
• CAMHs psychiatrist advised to withdraw due to
  sedation

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Emergency treatment of convulsive status
epilepticus

• We had a supply of rectal diazepam- easy to use.
• BUT undignified and more difficult as child grow
  heavier
• Tolerance- when he was using clobazam noticed it
  took two doses of rectal diazepam to cease the
  seizures
• Nowadays buccal midazolam is an option-more
  dignified, possibly easier

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Getting off carbamazepine

• We found that it caused myoclonus
• Tried to withdraw 1st time too quickly- led to
  seizures
• We came off really slowly the second time
  reducing by 100mg every 2 weeks
• Enzyme inducer- induces own metabolism and that
  of valproate

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Addition of Lamotrigine

• Lamotrigine given with valproate
• Anthony experienced rash within a month of
  commencing.
• Seemed to reduce seizures
• But that rash was potentially serious a Stevens
  Johnsons type reaction
• On allergy list.

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Topiramate

• Again we still had valproate
• Disaster for us- Anthony was ill with an
  exacerbation anyway BUT he also had
  neuropsychiatric adverse reaction to topiramate
• Depressed and very aggressive-gave his favourite
  teaching assistant a chinese burn

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Addition of levetiracetam

• Valproate still there
• Unlicensed in kids at the time and only
  recommended for adjunctive treatment BUT we had
  heard case reports of successful monotherapy
• So..built dose up slowly to minimise side
  effects and.

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Withdrawal of valproate (Epilim)

• This was uneventful thankfully
• Valproate need for 6 monthly blood tests
  especially liver function.

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Hurray levetiracetam monotherapy!

• Anthony has now been well and free of clinical
  seizures for over 2 years.

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What does this mean for you?

• No two epilepsies are the same
• Anti-convulsant medication is not curative but
  can reduce or cease seizures
• Disease process independent of anti-convulsant
  medication
• Monotherapy is often best option and should be
  tried before 2 or more AEDs are prescribed

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What does this mean?

• Having pharmacist parents does not mean you get
  optimal treatment or protect you from adverse
  drug reactions
• We mainly muddled through
• Hindsight is 2020

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Ethosuximide

• Reduces calcium conductance in neurones which
  have been implicated in the pathophysiology of
  absence seizures
• Doses are increased slowly every three to four
  days
• Blood disorders

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Drugs that can lower seizure threshold
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Vigabatrin

• Is an irreversible inhibitor of
  GABA-transaminase, leads to an increased amount
  of GABA in the brain
• Renally excreted
• Visual field defects

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Phenytoin

• Acts on voltage dependent Na channels to prolong
  inactive state, it reduces Ca entry into neurones
  which blocks neurotransmitter release and
  enhances action of inhibitory neurotransmitter
  GABA
• Not used first line
• adverse effects.
• non-linear kinetics, a narrow therapeutic range
  and is highly protein bound
• Small dose adjustments can produce large changes
  in serum concentration
• Metabolism varies between individuals
• Standard adult dose of 300mg on can be toxic or
  subtherapeutic in 50
• Different oral formulations have different F
• Liver disease can lead to accumulation and
  toxicity
• Fosphenytoin is a pro-drug converted to phenytoin
  
• Blood or skin disorders

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• Oxcarbazepine
• Is functionally a pro-drug activated by liver
  metabolism
• Piracetam
• Unknown mechanism
• Licensed as add-on therapy

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Lamotrigine

• Prolongs the inactivation of voltage sensitive
  sodium channels
• Is sensitive to enzyme inducers and inhibitors
• Avoid in liver disease and caution is needed in
  renal impairment
• Slow titration of dosage is essential
• Blood disorders
• Skin reactions

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Tiagabine

• It acts by selectively inhibiting GABA reuptake
  into presynaptic neurones and glial cells, thus
  prolonging its inhibitory effects
• Hepatic metabolism
• Use with caution in liver impairment and avoided
  in severe liver disease
• Affected by enzyme inducers
• In patients taking enzyme inducing drugs the
  maintenance dose is usually 30mg to 45mg per day.
  In other patients the maintenance dose is 15mg to
  30mg

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Carbamazepine

• Thought to prevent the repetitive firing of
  action potentials in depolarised neurones by
  blocking sodium channels and prolonging inactive
  state
• Suppositories are reserved for short-term use
  when no other route is available, note
  bioavailability difference with oral preparation.
  
• Carbamazepine is an enzyme inducer and also
  undergoes autoinduction
• Doses should be reduced in severe liver disease
  and used with caution in renal impairment.
• Blood hepatic and skin disorders

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Sodium valproate

• Multiple mechanisms of action.
• inhibiting GABA-degrading enzymes,
• stimulating activity of enzymes that break down
  the excitatory neurotransmitter glutamic acid
• limiting repetitive neuronal firing by blocking
  sodium channels
• Enzyme inhibitor
• No need to build up dose gradually
• Adverse effects include fatal pancreatitis and
  thrombocytopenia
• Counselled on recognising these symptoms
• Avoided in patients with liver disease because of
  its hepatotoxicity (normally first 6 months)

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Barbiturates

• Reduces action of glutamic acid and enhances
  action of GABA at receptor
• Oldest antiepileptics still in use
• Phenobarbitone is now reserved for patients who
  cannot tolerate other antiepileptics
• Phenobarbitone is potent enzyme inducer
• Barbiturates accumulate in liver disease and in
  severe renal impairment

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Benzodiazepines

• Their site of action on GABAA receptor
• Diazepam is first line treatment in status, given
  either IV or PR.
• Lorazepam and midazolm are alternatives
• Clonazepam is mainly used as an adjunct.
• Few patients have a good response to the drug and
  tolerance, associated with worsening of all
  seizure types, is common
• Clobazam is less sedating than diazepam or
  clonazepam and is used as an adjunct.
• Tolerance is a problem
• All benzodiazepines can precipitate coma in liver
  disease and are best avoided

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Gabapentin

• Unknown mechanism
• The drug is not metabolised and is excreted
  unchanged by the kidneys.
• Dose reduction in renal impairment
• No interactions
• Dose can be increased to 2,400mg/day and beyond

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• Levetiracetam
• Is an analogue of piracetam but has broader
  spectrum of seizure activity
• No pharmacokinetic interactions
• Pregabalin
• Unknown mechanism
• Renally excreted
• No interactions

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Zonisamide

• Adjuctive treatment for refractory partial
  seizures
• Side effects GI disturbance
• Interacts with carbamazepine

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Interactions between antiepileptics

• Are complex and may enhance toxicity without a
  corresponding increase in antiepileptic effect
• Interactions are usually caused by hepatic enzyme
  induction or inhibition
• Significant interactions that occur between
  antiepileptics themselves are listed in the BNF
  and you need to watch out for them

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Which drug?
Efficacy
Toxicity
Seizure type, dosing, formulation, age, cost,
teratogenicity