Snmek 1

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Antiepileptic drugs prof.MUDr Jirina
Martínková, CSc 2006/2007
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Antiepileptic drugs

• Epilepsy affects 0.5-1 of the population. It may
  develop after brain damage (trauma, infection or
  tumour growth), or other kinds of neurological
  disease, including various inherited neurological
  syndromes.
• Epilepsy is treated mainly with drugs.
• Current antiepileptic drugs are effective in
  controlling seizures in about 75 of patients,
  their use is often limited by adverse effects

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Antiepileptic drugs

• The characteristic event in E. is the seizure,
  which is associated with the episodic
  high-frequency discharge of impulses by a group
  of neurones in the brain.
• What starts as a local abnormal discharge
  may then spread to other areas of the brain. The
  site of the primary discharge and the extend of
  its spread determines the symptoms that are
  produced, which range from a brief relapse of
  attention
• to a full-blown convulsive fit lasting for
  several minutes.
• Abnormal electrical activity during a
  seizure can be detected by EEG recording from
  electrodes distributed over the surface of the
  scalp.

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Types of epilepsy
Two major categories partial and generalized,
simple (consciousness is not lost), complex
(consciousness is lost). P a r t i a l s e i
z u r e s the discharge begins locally, and
often remains localised. The symptoms depend on
the brain region(s) involved Psychomotor
epilepsy involuntary muscle contractions,
abnormal sensory experiences or autonomic
discharge, or effects on mood and behaviour. In
the form that is often associated with a focus in
the temporal lobe, the attack may consist of
stereotyped movement such as dressing or walking
or hair-combing Jacksonian epilepsy consists of
repetitive jerking of a particular muscle group,
which spreads and may involve much of the body
within 2 minutes before dying out. The patient
loses voluntary control of the affected parts of
the body but does not necessarily

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Types of epilepsy

• G e n e r a l i s e d s e i z u r e s
  involve the whole brain. Immediate loss of
  consciousness is characteristic of generalised
  seizures.
• Two common forms are
• Tonic- clonic seizures - grand mal - consists of
  an initial strong contraction of the whole
  musculature, causing a rigid extensor spasm.
  Respiration stops and defaecation, micturation
  and salivation often occur. This tonic phase
  lasts for about 1 min and is followed by a series
  of violent, synchronous jerks, which usually dies
  out in 2-4 min. The patient gradually recovers,
  felling ill and confused. Injury may occur during
  the convulsive episode
• Absence seizures petit mal are much less
  dramatic but may occur more frequently. The
  patients abruptly ceases whatever he or she was
  doing, sometimes stopping speaking in
  mid-sentence, and stares vacantly for a few sec,
  with little or no motor disturbance.The patient
  is unaware of his or her surroundings and
  recovers abruptly with no after-effects
• Status epilepticus a life-threatening condition
  in which seizure activity is uninterrupted

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Antiepileptic drugs

• With optimal drug therapy, epilepsy is
  controlled in about 75 of patients, but about
  10 continue to have seizures at intervals of 1
  month or less, which severaly disrupts their life
  and work
• M e c h a n i s m of a c t i o n
• enhancement of GABA action
• phenobarbital, benzodiazepines, vigabatrin,
  gabapentin
• inhibition of sodium channel function
• (reduction of electrical excitability of cell
  membranes)
• phenytoin, carbamazepine, valproate,
  lamotrigine
• inhibition of calcium channel function
• ethosuximide (T-type calcium channels),
  gabapentin (L-type calcium channels)

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Antiepileptic drugsclinical use (tab.1)
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Antiepileptic drugsclinical use

• Pharmacokinetics/pharmacodynamics
• the range of Cpl over which antiepileptic drugs
  are effective without causing excessive adverse
  effects
• is quite narrow
• Cpl is the only predictor of therapeutic
  effectiveness
• large interindividual variability in both Cpl and
  patientsresponse
• therapeutic effects are more related to Cpl (if
  compared to the given dose)

TDM for effective and safe therapy
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Antiepileptic drugsclinical use

• Phenytoin- widely used
• well absorbed from the GIT, and about 80-90 of
  the plasma content is bound to albumin
  (salicylates and valproate inhibit this binding
  competitively)
• metabolised by CYP450, causes enzyme induction
  and thus increases the rate of metabolism of
  other drugs (warfarin) that share the same enzyme
  
• The metabolism shows the characteristic
  of saturation
• (the Css achieved when a patient is given a
  constant daily dose, varies disproportionately
  with the dose)

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Antiepileptic drugsPhenytoin

• Adverse effects Type A (dose-related)
• vertigo, ataxia (low Cpl), confusion with
  intellectual deterioration,
• hyperplasia of the gums (disfiguring), hirsutism
  (androgen secretion), megaloblastic anemia (in
  deficiency of folic acid)
• Adverse effects Type B (not dose-related)
  quite common
• - allergy rashes
• - idiosyncrasy
  hepatitis
• Adverse effects Type D
• the increased incidence of fetal malformations in
  children born to epileptic mothers fetal
  hydantoin syndrom, particularly the occurrence
  of cleft palate (epoxide metabolite?)

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Antiepileptic drugsCarbamazepine

• well absorbed
• a powerful inducer of hepatic microsomal
  enzymes---- accelerates biotransformation of many
  other drugs (phenytoin, warfarin)
• its combination with other
  antiepileptic drugs should be avoided
• Adverse effects Type A (dose-related) low
  incidence
• drowsiness, dizziness, ataxiamore severe
  mental and motor disturbancies, water retention
  
• to avoid it --treatment is usually started
  with a low dose
• Adverse effects Type B (not dose-related)
• severe bone-marrow depression (very rare)

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Antiepileptic drugsValproate

• is effective in many kinds of epilepsy (see
  Tab.1)
• free of adverse effects (low toxicity), absence
  of sedation (!)
• rare but serious hepatotoxicity,
  teratogenicity (spina bifida and other neural
  tube defects), baldness

Ethosuximide The main drug
used to treat absence seizures with relatively
few adverse effects (nauzea, anorexia)
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Antiepileptic drugsPhenobarbital

• is well absorbed, slowly eliminated
• a powerful inducer of hepatic enzymes lowers Cpl
  of several drugs (steroids, warfarin, oral
  contraceptives..)
• Adverse effects Type A (dose-related)
• sedation (!) - impairment of cognition and motor
  performance
• in overdose - respiratory and circulatory failure
  

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Antiepileptic drugsBenzodiazepines

• Diazepam i.v.
• is used to treat status epilepticus - in which
  seizures occur almost without a break
• Advantage very rapid action
• Clonazepam, clobazam (see tab.1)
• have some selective antiepileptic effects
• Sedation is the main adverse effect

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Antiepileptic drugsNewer antiepileptic drugs

• Vigabatrin
• is an irreversible inhibitor of the
  GABA-metabolising enzyme GABA transaminase
• increases the GABA content in the CNS a
  effectively enhances inhibitory transmission
• is effective in a substantial proportion of
  patients resistant to the established drugs
• relatively free of adverse effects
• in a minority of patients occurrence of
  depression and psychotic disturbances

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Antiepileptic drugsNewer antiepileptic drugs

• Lamotrigine
• was shown to have the broad therapeutic profile
  with no pharmacokinetic anomalies
• Gabapentin free of interaction, with limited
  efficacy when used on its own ---useful in
  combinations

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Antiepileptic drugsmonotherapy or combination?

• At present, monotherapy is recommended

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Antiepileptic drugswithdrawal

• can cause increased seizure frequency and
  severity.
• In general, barbiturates and benzodiazepines
• are the most difficult to discontinue. Weeks
  or months may be required, with very gradual
  dosage decrements, to accomplish their complete
  removal.
• Complete discontinuance is an especially
  difficult problem. If a patient is seizure-free
  for 3-4 years, gradual discontinuance is usually
  warranted.

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Antiepileptic drugsand teratogenicity

• The potencial teratogenicity of
  antiepileptic drugs is contraversial and
  important. It is important because teratogenicity
  resulting from long-term drug treatment of
  million of people throughout the world may have a
  profound effect even if the effect occurs in only
  a small percentage of cases. Patients with severe
  epilepsy, in whom genetic factors than drug
  factors may be of greater importance in the
  occurrence of fetal malformations, are often
  receiving multiple antiepileptic drugs in high
  doses.
• In spite of these limitations, it
  appears that children born to mothers taking
  antiepileptic drugs have an increased risk,
  perhaps twofold, of congenital malformation.
  Phenytoin has been implicated in a specific
  sydrome called fetal hydantoin syndrom. A
  similar syndrome has been attributed both to
  phenobarbital and to carbamazepine. Valproate has
  also been implicated in a specific malformation-
  spina bifida.