???? Antiepileptic Drugs

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???? Antiepileptic Drugs

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Definitions in epilepsy

• Epilepsy comprises recurrent episodes of abnormal
  cerebral neuronal discharge. The resulting
  seizures are usually clinically obvious and vary
  in pattern according to which parts of the brain
  are affected.
• Epilepsy can be caused by many neurological
  diseases, including infection, trauma, infarction
  and neoplasia.
• Heredity has an important role (especially in the
  idiopathic generalised epilepsies).

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Normal brain cell
Abnormal high-frequency discharge
Focus
Inhibit discharge
Drug action
Stabilize membrane, inhibit the diffusion of
discharge (primary)
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Common seizure types of Epilepsy

• Generalised seizures.
• Absence (petit mal).
• Tonic/clonic (grand mal).
• Partial seizures.
• Simple partial seizures.
• Complex partial seizures (temporal lobe
  epilepsy).

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Generalised seizures

• Absence (petit mal) These seizures have abrupt
  onset and cessation, with impaired consciousness,
  but with normal posture often retained. The EEG
  shows a typical spike and wave pattern.
• Tonic/clonic (grand mal) Consciousness is
  impaired and the patient usually falls to the
  floor. A phase of muscle contraction (tonic) is
  followed by irregular muscle clonus and then by
  sleep. Injury may occur.

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Partial seizures

• Simple partial seizures features depend on the
  part of the brain affected, result from discharge
  in the precentral gyrus. Consciousness is
  unimpaired.
• Complex partial seizures (temporal lobe
  epilepsy) Consciousness is impaired with
  complex, often repetitive, action.

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The EEG in seizure of Epilepsy
Spike wave
3 Hz Paradoxical discharge
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Epilepsy

• Pathogenesis
• The neuron in brain lesion depolarizes together
  suddenly, and then product high-frequency
  ,out-break discharge. The discharge can diffuse
  to surrounding normal tissue ?extensive
  excitation ?the brain function transient
  aberration.

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Normal brain cell
Abnormal high-frequency discharge
Focus
Inhibit discharge
Drug action
Stabilize membrane, inhibit the diffusion of
discharge (primary)
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Epilepsy

• Therapeutic principle
• Change the permeability of Na, Ca2and K in
  nerve cell membrane, degrade excitement stage,
  extend refractory phase.
• Directly or indirectly increase CNS levels of
  GABA.

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• The primary animal models used in anti-epileptic
  drugs research

• Maximal electroshock seizure (MES ) model
• screen the drugs which used in grand mal.

• Pentetrazole (PTZ) induced convulsion model
  
• screen the drugs which used in petit mal.

• Kindling seizure model screen the drugs
  which used in grand mal.

• Spontaneously epileptic rat (SER) model
  used in anti-epileptic drugs research.

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Classification of Antiepileptic Drugs

• HydantoinsSodium Phenytoin
• BarbituratesPhenobarbital, Primidone
• SuccinimideEthosuximide
• Benzodiazepine Diazepam, Nitrazepam
• Others Sodium Valproate

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Sodium Phenytoin (????)

• ?Physiological disposition?
• Sodium Phenytoin is absorbed slowly after oral
  administration.?After 6-10 days, its plasma
  concentration can achieve effect levels. This
  drug has variable interpatient plasma
  concentration.

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Sodium Phenytoin

• ? Mechanism of action ?
• ?It can block sodium channels (voltage-,
  frequency-, and time dependent fashion) and
  inhibit the generation of action potentials.
• ?It can increase the function of inhibitory
  transmitter GABA, inhibit nerve terminal to
  uptake GABA and induce the increasing of GABA
  receptor, thereby enhance GABA-mediated
  postsynaptic inhibition.

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Sodium Phenytoin

• ?Pharmacologic properties and clinical
  application?
• Anti-epilepticIt can be used for partial
  seizures and tonic/clonic seizures, but not for
  other generalised seizure types.
• Peripheral neuralgiacranial nerve, ischiadic
  nerve and cranial nerve.
• Arrhythmia membrane-stabilizing action.

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Sodium Phenytoin
?Adverse effects?

• Digestive system
• Gingival hyperplasia
• Nervous system
• Hematological system

• Skeletal system
• Allergic response
• Others

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Sodium Phenytoin

• ?Adverse effects?
• Digestive system anorexia, nausea, vomiting and
  abdominal pain (recommend to take it after meal).
  It may cause phlebitis after IV.
• Gingival hyperplasia It common occurs in
  children and teenagers after long term use, the
  incidence rate is about 20. Generally, this
  effect can resolve after drug withdraw 3 to 6
  months.

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Sodium Phenytoin

• ?Adverse effects?
• Nervous system nystagmus, diplopia, vertigo,
  ataxia (usually only at very high
  concentration). Severe patient occurs language
  disorder, mental confusion and cataphora.
• Hematological system Because it can inhibit the
  absorption of folinic acid and accelerate its
  metabolism. This drug also can inhibit folic acid
  reductase. So it may cause megaloblastic anemia
  after long-term use (recommend to pretreat with
  folinic acid).

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Sodium Phenytoin

• ?Adverse effects?
• Skeletal system It can enhance vitamin D
  metabolism, so Phenytoin may increase the risk of
  hypocalcemia, rickets and osteomalacia after
  long-term treatment(pretreat with vitamin D if
  necessary).
• Allergic response rash, thrombocytopenia,
  agranulocytosis and aplastic anemia.
• Others rarely appear male barymastia, female
  hirsutism and lymphadenectasis.

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Phenobarbital (????)

• ? Mechanism of action ?
• Phenobarbital can inhibit the paradoxical
  discharge of epilepsy focus selectively, enhance
  stimulation of surrounding tissues and block
  discharge diffuse to normal tissues.
• Phenobarbital facilitate GABA-mediated inhibition
  of neuronal activity.

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Phenobarbital

• ?Pharmacologic properties ?
• Phenobarbital can be used for all types of
  epilepsy. The effects by turns are grand mal and
  status epilepticsgtlocal psychomotor seizuregtpetit
  mal.
• Take effect rapidly(12 hr), the first choice of
  grand mal.
• Prevent convulsive and eliminate precursory
  symptom.

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Phenobarbital

• ?Adverse effects?
• Somnolence?depression.
• Tolerance develops after long-term treatment.

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Primidone(?????) Primidone(???)

• ?Pharmacologic properties ?
• Absorption after oral administration is rapid,
  and the plasma peak concentration is
  approximately 3 hours at therapeutic doses. It
  can be used for all types of epilepsy except
  petit mal. Its better to use this drug with
  sodium phenytoin. With regard to grand mal, the
  effect of primidone is better than
  phenobarbital,this drug is useless to petit mal.

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Primidone (Primidone)

• ?Adverse effects?
• Common somnolence, vertigo, nausea and vomiting.
• Rare megaloblastic anemia, leucopenia and
  thrombocytopenia.

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Ethosuximide (??? )

• Petit mal (first choice), useless to other types
  of seizure.
• ? Common adverse effect ?
• Gastrointestinal tract anorexia, nausea,
  vomiting.
• CNS headache, dizziness and somnolence.
• Rarely appear agranulemia and aplastic anemia.

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Diazepem(??)
Nitrazepem(????)

• Diazepem
• Diazepem is indicated for status epilepticus.
• Nitrazepem
• Its highly effective in controlling petit mal
  and myoclonus epilepsy.
• Sudden withdrawal of nitrazepem is likely to
  aggravate seizure and induced symptom.

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Sodium Valproate (???? )

• ?Pharmacologic properties ?
• Enhance the enzymatic activity of glutamate
  decarboxylase.?GABA?
• Inhibit GABA reuptake and synapse
  inactivation?synapse frontal membrane GABA??
  enhance GABA postsynaptic inhibition
• Broad spectrum antiepileptic drug, use to all
  types of epilepsy.
• CNS somnolence, disequilibrium, acratia and
  tremor.
• Hepatic lesion (20 patients).
• Gastrointestinal tract nausea, vomiting and
  anorexia.

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Carbamzepine (????)

• ?Pharmacologic properties ?
• Carbamazepine can block sodium channel, inhibit
  paradoxical discharge and discharge diffusion. It
  may relate to the postsynaptic inhibition of
  GABA.
• Broad spectrum antiepileptic drug, use to all
  types of epilepsy.
• Trigeminal neuralgia (therapeutic effect is
  good).
• Antidiuresis-diabetes insipidus.

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Carbamzepine

• ?Adverse effects?
• CNS somnolence, disequilibrium
• Gastrointestinal tract nausea, vomiting and
  anorexia.
• Rash,leucopenia ,thrombocytopenia,aplastic anemia
  and hepatic lesion.

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Principle of Medication

• 12 times/year,no drugs are needed
• Grand pit (first choice) Sodium phenytoin or
  phenobarbital, carbamzepine, Primidone.
• Petit mal (first choice) Ethosuximide,
  clonazepam and sodium valproate.
• Status epilepticusDiazepam or sodium phenytoin
  (IV), phenobarbital, diazepam, clonazepam.
• Psychomotor Sodium phenytoin or combine with
  desoxybarbital or carbamazepine.

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Principle of Medication (I)

• The dose can be gradually increased from a low
  starting dose until reach the best effect.
• In the initial stage, the patients should only be
  treated with a single antiepileptic drug, if the
  drug is useless, then it can be changed. When
  drug changing is necessary, it should be
  gradually withdrawn after the effect of new drug
  occurs.
• After the symptom is fully controlled, the
  patients should continuing be treated for 2 or 3
  years. Sudden withdrawal of drugs are likely to
  precipitate relapse.

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Principle of Medication (II)

• Enhance therapeutic effect dosing individually,
  monitoring drug plasma concentration, examining
  regularly.
• Evaluating efficacy and safety.
• Adjusting drug dosage the therapeutic index of
  antiepileptic drug is low?easy to be poisoning
  Therapeutic dose is get close to toxic dose.

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Anticonvulsant Drugs

• Convulsions are involuntary skeletal muscular
  contractions. Convulsions can arise from
  pathological processes within or outside the
  brain, toxins, drug overdose, or withdrawal from
  drug dependence.
• Commonly used anticonvulsant drugs are sedative
  and hypnotic drugs. Magnesium Sulfate is also
  used on this disease.

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