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PHARMACOTHERAPY OF EPILEPSY

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PHARMACOTHERAPY OF EPILEPSY Powered By Docstoc
					PHARMACOTHERAPY
   OF EPILEPSY
    JUNTIP KANJANASILP
 FACULTY OF PHARMACY, MSU
      9 JANUARY 2008
                  Outline
•   Epidemiology
•   Etiology
•   Pathophysiology
•   Classification
•   Clinical Manifestations
•   Diagnosis
•   Treatment
•   AED withdrawal
•   AED in The Pregnant Women
•   Status epilepticus
          Introduction
• Greek “epilepsia” --> to come
  upon, to be grabbed hold or
  thrown down, to attack, to seize
  hold of
• Hughlings Jackson, 1861: seizures
  were caused by an excessive
  discharge of the gray matter of
  the brain
         Epidemiology
• Thai and worldwide population 1%
• second most common neurologic
  disorder after stroke
• Epilepsy: chronic disorder -->
  recurrent seizures
• newborn and young children
• older than age 65 y
• seizure type and the cause changes
  with age
             Etiology
• Primary or acquired disturbances
  of CNS function
 – benign febrile convulsions of
   childhood
 – idiopathic epilepsy
 – head trauma
 – stroke
 – CNS mass lesion
             Etiology
• Metabolic or systemic disorders
 – hypoxia, meningitis, encephalitis
 – hyponatremia, hypoglycemia,
   hypernatremia or hyperosmolar,
   nonketotic hyperglycemia,
   hypoglycemia
 – hypertensive, uremic, hepatic
   encephalopathy
 – eclampsia, porphyria
 – drug overdose, drug withdrawal
 – hyperthermia
     Drugs cause seizures
• Hx of seizures or impaired drug
  elimination capacity
• antimicrobials (cephalosporins,
  imipenem/cilastatin, penicillin,
  ciprofloxacin, norfloxacin, INH)
• psychotropic agents
  (antidepressants, antipsychotics,
  lithium)
• theophylline
     Drugs cause seizures
• Anesthetic and antiarrhythmic
  agents (lidocaine, tocainide,
  metoprolol, propranolol,
  bupivacaine, procaine)
• radiographic contrast agents
  (diatrizoate meglumine, iohexol,
  iopamidol, meglumine
  metrizoate)
     Drugs cause seizures
• drugs of abuse (amphetamine,
  cocaine, methylphenidate)
• sedative-hypnotic drug
  withdrawal (alcohol,
  barbiturates, benzodiazepines)
• Misc.: cyclosporine, flumazenil,
  ganciclovir
             Etiology
• identifiable cause: drug toxicity,
  metabolic abnormalities
• Hereditary
• elderly: cerebrovascular disease,
  tumor, head trauma, metabolic
  disorders, CNS infections
• incidence of idiopathic epilepsy is
  higher in children
• mental retardation and cerebral
  palsy (increased risk)
              Etiology
• Precipitating factors:
  – hyperventilation --> absence
    seizures
  – sleep, sleep deprivation, sensory
    stimuli, emotional stress
  – hormonal changes, puberty,
    pregnancy
  – theophylline, alcohol,
    phenothiazines, antidepressants,
    overdose AEDs
              Etiology
• Risk factors:
  – severe head trauma
  – CNS infections
  – stroke
  – brain surgery
  – pertussis immunization --> febrile
    seizures
        Pathophysiology
• Paroxysmal discharges occurring
  synchronously in a large
  population of cortical neurons
• seizure originates from the gray
  matter of any cortical or
  subcortical area
• excess excitability spreads
 – locally --> focal seizure
 – widely --> generalized seizure
        Pathophysiology
• Clinical manifestations depend
  on:
 – site of the focus
 – degree of irritability of the
   surrounding area of the brain
 – intensity of the impulse
        Pathophysiology
• Abnormality of potassium
  conductance
• Defect in voltage-sensitive ion
  channels
• deficiency in membrane ATPases
• neuronal membrane instability
  --> seizure
        Pathophysiology
• Excitatory neurotransmitters:
  glutamate, aspartate,
  acetylcholine, NE, histamine,
  corticotropin-releasing factor,
  purines, peptides, cytokines,
  steroid hormones
• Inhibitory neurotransmitters:
  GABA, dopamine
        Pathophysiology
• Deficiency inhibitory
  neurotransmitters: GABA or
  increase excitatory
  neurotransmitters --> abnormal
  neuronal activity
• normal neuronal activity depend
  on: adq. Supply of glucose,
  oxygen, sodium, potassium,
  chloride, calcium, amino acids
        Pathophysiology
• Different physiologic
  abnormalities: systemic pH -->
  seizures
        Pathophysiology
• during seizure: increase demand
  for blood flow to the brain -->
  carry of CO2 and bring
  substrates for neuronal
  metabolic activity --> use more
  energy--> more prolong S -->
  limited increase blood flow -->
  ischemia --> neuronal
  destruction, brain damage
        Pathophysiology
• Failure to control seizures -->
  increase in seizure activity and
  occurrence of other seizure types
  --> appropriate therapy should
  be initiated early after diagnosis
  of epilepsy
          Classification
• The International League Against
  Epilepsy (ILAE)
 – International Classification of
   Epileptic Seizures
 – International Classification of the
   Epilepsies and Epilepsy Syndromes
International Classification of
      Epileptic Seizures
• Partial Seizures
  – simple (without impairment of
    consciousness)
     • with motor symptoms
     • with special sensory or
       somatosensory symptoms
     • with psychic symptoms
International Classification of
      Epileptic Seizures
 – Complex (with impairment of
   consciousness)
    • simple partial onset followed by
      impairment of consciousness
      (with or without automatisms)
    • impaired consciousness at onset
      (with or without automatisms)
 – Secondarily generalized (partial
   onset evolving to generalized tonic-
   clonic seizures)
International Classification of
      Epileptic Seizures
        (ICES: 1981)
• Generalized seizures (bilaterally
  symmetrical and without local
  onset)
  – Absence            •Unclassifed
  – Myoclonic          seizures
 – Clonic
                      • Status
 – Tonic
                      epilepticus
 – Tonic-clonic
 – Atonic
 – Infantile spasms
International Classification of
 the Epilepsies and Epilepsy
Syndromes (ICE: 1985, 1989)
• Partial seizures
   – simple (consciousness preserved)
   – Complex (consciousness impaired)
   – Secondarily generalized seizures
• Generalized-onset seizures
• Localization-related (focal) epilepsies
• Generalized epilepsy
• special syndromes: febrile seizures
    Clinical Manifestations
• Complete history: events during
  attacks (aura, ictal, postictal
  abnormalities) --> Diagnosis
    Clinical Manifestations
• generalized seizures:
  – convulsive and nonconvulsive:
    associated motor disturbances
  – nonconvulsive: absence (petit mal),
    myoclonic, atonic seizures
  – grand mal seizures: clonic and
    tonic-clonic seizures
    Clinical Manifestations
• Generalized tonic-clonic seizures:
• Tonic phase: 15-20 sec
• begin with tonic (rigid) flexion of
  extremities --> extension
• air is forced from larynx -->
  audible cry
    Clinical Manifestations
• quickly followed by clonic
  (jerking) phase: 20-30 sec
• spasms of trunk and extremities
  and often biting of the tongue
• Followed by postictal state: sleep
  or awaken confused and
  disoriented
   Clinical Manifestations

• gradual return of consciousness
  and orientation (15-30 min)
• increased BP and HR,
  incontinence of urine or feces,
  brief interruption of normal
  breathing with cyanosis
    Clinical Manifestations
• Absence (petit mal):
• childhood
• abrupt interruption of
  consciousness --> fixed stare
  and automatisms (lip smacking,
  chewing, grimacing) or mild
  clonic movements
• no loss of postural tone
    Clinical Manifestations
• < 45 sec and ends abruptly
• immediately regaining full
  alertness
• may hundreds of times a day
• family or teachers: daydreaming
• EEG: bilateral 3-Hz spike-wave
  discharges
    Clinical Manifestations
• Onset: Ages of 4-12 y
• Atypical absence seizures: longer
  duration, focal motor
  manifestations, association with
  developmental delay
    Clinical Manifestations
• Atonic seizures: sudden loss of
  muscle tone
• fall abruptly, injuries
• Myoclonic seizures: jerking
  movements of a single or
  multiple muscle groups
• Tonic seizures: similar to GTC,
  lack clonic phase
     Clinical Manifestations
• Partial seizures: limited to one
  hemisphere (underlying focal
  brain lesion: perinatal injury,
  trauma, stroke, CNS tumor)
• simple partial seizures:
  – motor (clonic jerking of one arm)
  – sensory (foul odor or visual distortion)
  – autonomic (piloerection or pupillary
    dilatation)
  – psychic (déjà vu or fear)
    Clinical Manifestations
• Complex partial seizures
  (psychomotor or temporal lobe
  seizures)
• impaired consciousness (2 min)
• stereotypical attacks
• auras
• most common: unusual
  epigastric sensations
    Clinical Manifestations
• During impaired consciousness:
  automatisms (coordinated
  involuntary movements: lip
  smacking, buttoning or
  unbuttoning or wandering
  behavior)
• behavioral abnormalities (less
  often): violent outbursts, crying,
  sexual actions
         Absence and
     complex partial seizures
  Feature          AS            CPS
Pt. affected children         Children
                              and adults
Preictal    No aura;          Aura
symptoms    abrupt            common
            interruption of
            consciousness
          Absence and
      complex partial seizures
  Feature        AS             CPS
Ictal     Automatisms Automatisms
phenomena common        common (more
          Avg. duration complex)
          10 sec        Avg. duration 2
                        min
Postictal None: abrupt  Fatigue,
symptoms  return of     confusion,
          consciousness drowsiness;
                        gradual return of
                        consciousness
        Absence and
    complex partial seizures

  Feature       AS         CPS
Prognosis   Complete   Less
            seizure    favorable
            control    response to
            common     drug
                       therapy
    Clinical Manifestations
• Epileptic syndromes: a
  constellation of S/S that tend to
  occur together
  – childhood absence epilepsy
  – juvenile myoclonic epilepsy
  – Lennox-Gastaut syndrome
    Clinical Manifestations
• Febrile Seizures:
• generalized tonic-clonic seizures
  associated with temperatures
  above 38 C
• occur in the absence of other
  identifiable causes
• 2-5%
    Clinical Manifestations
• Ages of 3 mo-5 y
• neurologically and
  developmentally normal
• simple or complex
• complex febrile seizures:
  prolonged (>15 min), 2 or more
  seizures in 24 hr, associated
  focal seizures
    Clinical Manifestations
• Simple febrile seizures: benign,
  self-limited, 3% recurrent,
  nonfebrile seizures in later life
• treatment: self-limited, no acute
  or long-term neurologic sequelae
  --> not required aggressive
  treatment
    Clinical Manifestations
• febrile seizures occur within 24
  hr of a febrile episode
• prevented by promptly
  instituting antipyretic
• sponge with tepid water 10-15
  min
• acetaminophen q 4 hr if T>38 C
    Clinical Manifestations
• AEDs (phenobarbital, diazepam)
  : seizure continues for > 10 or 15
  min
• chronic admin of AEDs with Hx of
  simple febrile seizures: not
  indicated
   Clinical Manifestations
• Complex febrile seizures:
• preexisting neurologic
  abnormalities, FH of nonfebrile
  epilepsy --> greater risk for
  development of epilepsy in later
  life
• initiate: rectal admin of
  diazepam
• drug prevention: phenobarbital
             Diagnosis
• Medical history, physical, lab -->
  primary, metabolic, systemic
  factors
• Pt history: patient and witness
  – seizure description
     • preictal phenomena (aura)
     • ictal manifestations
     • postictal state
     • provocative factors
            Diagnosis
 – Perinatal and developmental history
 – Hx of febrile seizures
 – Hx of head trauma
 – Hx of CNS infection
 – FH of epilepsy
• Physical examination
             Diagnosis
• Laboratory evaluation
 – CBC                   - BUN
 – Electrolytes          - osmolality
 – Glucose
 – CSF
• EEG (epileptiform abnormalities
  50% after single interictal
  recording)
                Diagnosis
• CT
        } Structural lesions: partial epilepsy
• MRI
• PET: precise localization of areas
  of abnormal blood flow or
  metabolism--> surgical
  intervention
• Seizure onset < 25 y and FH of
  epilepsy --> genetic cause
Disorders that may mimic epilepsy

• Gastroesophageal reflux
• Breath-holding spells
• Migraine
• Sleep disorders (esp.
  parainsomnias)
• Cardiovascular events
• Movements disorders
• Psychological disorders
           Treatment
• Lifestyle adjustment
 – Depend on timing and clinical
   manifestation
 – Driving, swimming, working at ht.,
   operate machinery
 – Seizure precipitants: stress,
   exercise, alcohol, caffeine
   consumption, altered sleep
   schedules, missed meals
             Treatment
• Social issues
   – Problems of self-image and social
     stigma
   – Proper education
• Drug therapy
• Surgical treatment: resection of the
  seizure focus from anterior temporal
  lobe
   – partial seizure (intractable, impair
     functional abilities)
   – MRI, PET: localized the lesion
   – EEG and video monitoring
Behavioral therapies: reflex epilepsies
           Drug Therapy
• Goals:
  – Reduce freq. of recurrent seizures
  – Minimize adverse effects associated
    with AED
• Specific therapeutic endpoints:
  individualized for each pt.
         Drug Therapy
• Choice of AED:
 – Seizure classification
 – Age
 – Sex
 – Concurrent medical conditions
 – Potential ADR
 – Pharmacokinetic features
Principles of AED selection and
             usage
• Preference for monotherapy with
  nonsedating agents
• Monotherapy:
 – Lower cost
 – Reduced ADR and DI
 – Improved compliance
• Monotherapy fail  polytherapy
Principles of AED selection and
             usage
• Sedation and decrease mentation
  : phenobarbital and
  benzodiazepines
            AED DOC based on
           seizure classification
Seizure type       DOC         Alternatives

Partial        Carbamazepine   gabapentin
seizures       Phenytoin       topiramate
               Lamotrigine     levetiracetam
               Valproic acid   zonisamide
               Oxcarbazepine   tiagabine
                               Phenobarbital
                               primidone
                               felbamate
             AED DOC based on
            seizure classification
Seizure type        DOC        Alternatives
Generalized    Valproate       lamotrigine
Tonic-Clonic   Carbamazepine    topiramate
                                felbamate
Seizures       Phenytoin
                               phenobarbital
                               primidone
                               oxcarbazepine
Absence        Ethosuximide    lamotrigine
Seizures       Valproate
Myoclonic      Valproate,      lamotrigine
               clonazepam       topiramate
Seizures                        felbamate
          Antiepileptic Drugs
•   Carbamazepine
•   Phenytoin
•   Phenobarbital
•   Primidone
•   Valproic acid
•   Ethosuximide
•   Benzodiazepins: clonazepam, clorazepate
         Carbamazepine
• generalized tonic-clonic, partial
  seizures
• Sodium channels
• Oral tablet 200 mg, CR
• Dose: int. 100-200 mg bid. --> 1200
  mg/d
         Carbamazepine
• Absorption: time to peak 4-8 hrs
• Hepatic metabolism: carbamazepine
  10,11-epoxide
• half-life 24-45 hrs
• autoinduction: first 1 month
• DI: phenytoin, phenobarbital,
  primidone
         Carbamazepine
• Larger doses and more frequent -->
  minimized fluctuations -->
  breakthrough seizures or transient
  adverse effects
• plasma level monitoring
          Carbamazepine
• ADR:
• dose related: dizziness, drowsiness,
  anorexia, nausea (gradual dose
  titration)
• persistent GI upset: with meals
          Carbamazepine
• hyponatremia and water retention-->
  increase ADH secretion: dose related
  (reduction dose)
• Na < 120 mEq/L: headache,
  confusion, dizziness, loss of seizure
  control (water restriction, reduction
  or disc.or demeclocycline+cont.)
          Carbamazepine
• Cardiac conduction disturbances:
  higher doses, older patients, cardiac
  abnormality
• Overdose: unusual movement
  disorders, induced seizures
          Carbamazepine
• rash: 5% first 1-2 wks -->
  maculopapular, urticaria, morbilliform-
  -> exfoliative dermatitis, Steven-
  Johnson syndrome (drug
  discontinuation, corticosteroids)
• cross-reactivity: phenytoin,
  phenobarbital (used valproate)
          Carbamazepine
• Hepatitis: first few weeks
• SLE: delayed --> after 6-12 mo.
• Aplastic anemia: rare, fatal, during
  the first year (disc. Immediately, not
  challenge): CBC baseline, q 2 wks for
  first 2 mo.--> q 3 mo.
          Carbamazepine
• Leukopenia: first mo. --> CBC q 2
  wks (disc. If absolute neutrophil count
  < 1500/mm3 or infection)
          Carbamazepine
• Potent inducer
• increase clearance of theophylline,
  doxcycline, haloperidol, warfarin,
  corticosteroids, valproate,
  clonazepam, ethosuximide,
  lamotrigine, felbamate, various
  hormones, OC
         Carbamazepine
• Inhibit carbamazepine metabolism
• danazol, dextropropoxyphene,
  erythromycin, isoniazid, verapamil,
  diltiazem, cimetidine
• increase metabolism of carbamazepine
• phenytoin, phenobarbital, primidone
             Phenytoin
• Diphenyl-substituted hydantoin derv.
• 1983
• Partial and generalized tonic-clonic
  seizures
• No : absence and febrile seizures
• Ethotoin, mephenytoin
• Blocks neuronal sodium and calcium
  conductance
             Phenytoin
• Suspension: free acid : 30 mg/5 mL,
  125 mg/5 mL
• Chewable tablets: free acid : 50 mg
• Capsules: sodium salt : 30, 100 mg
• Injectable: sodium salt : 50 mg/mL
             Phenytoin
• Adults MD. 300-400 mg/d
• LD. 15 mg/kg
• Single dose or divided 200-400 mg by
  2-4 hrs
• IV : max. rate 50 mg/min
• Propylene glycol  hypotension,
  cardiac arrhythmias
• Monitor: BP, HR
              Phenytoin
• Avoid changing dosage forms and
  products --> change in bioavailability -->
  changes in seizure control
• Should not IM --> crystallizes --> depot --
  > damage to local tissue and erratically
  absorbed
• Fosphenytoin: water-soluble prodrug
• Phosphatases
             Phenytoin
• 90% bound to albumin
• Renal failure, displacing drugs
• Hepatic metabolism: para-
  hydroxylation
• 5-(p-hydroxyphenyl)-5-phenylhydantoin
• Non-linear pharmacokinetics
             Phenytoin
• ADR:
• acute, dose related: ataxia, diplopia,
  dizziness, drowsiness, encephalopathy,
  involuntary movements (> 30 mg/mL)
• Reversible: discontinued or reduced
  dose
• Nystagmus
• Exacerbate seizures: rare
              Phenytoin
• Long-term: gingival hyperplasia, facial
  coarsening, peripheral neuropathy,
  vitamin deficiencies
• Gingival hyperplasia: oral hygiene,
  reduction dose, gum resection surgery,
  alternative AED
• Chronic: dysmorphic changes,
  hirsutism, acne
             Phenytoin
• Peripheral neuropathy with decreased
  deep tendon reflexes and sensory
  deficits: not reversible
• Induced megaloblastic anemia with
  folic acid deficiency <1%
• Osteomalacia, osteoporosis:
  prophylactic vitamin D, calcium
  supplement : not know
               Phenytoin
• Idiosyncratic: first 8 wks
• Rash, hepatitis, lymphadenopathy,
  hematologic alterations
• Rashes: < 10%, first 14 d + hepatitis,
  lymphadenopathy, fever
•  Steven-Johnson syndrome, erythema
  multiforme, TEN : discontinued
• Hepatitis: first 3 wks: discontinue
• Hepatic injury--> encephalopathy, coma,
  death
             Phenytoin
• Transient depression leukocytes,
  aplastic anemia, agranulocytosis
              Phenytoin
• Drug interaction:
• Potent inducer
• Enhance metabolism: OCs, warfarin,
  corticosteroids, cyclosporine,
  theophylline, carbamazepine, valproate,
  felbamate, lamotrigine, clonazepam
• Reduce phenytoin level: antacids and
  nutritional formulas, nasogastric tube
             Phenytoin
• Displace protein binding: heparin,
  phenylbutazone, tolbutamide, valproate
• Increase phenytoin metabolism: folic
  acid, alcohol, rifampicin
• Reduce phenytoin metabolism:
  valproate, isoniazid, amiodarone,
  cimetidine, omeprazole,
  phenylbutazone, disulfiram,
  sulfonamides, chloramphenicol
           Phenobarbital
• Alternative when monotherapy with
  first-line agents has failed
• partial and generalized tonic-clonic
  seizures
• modulate the inhibitory action of GABA
• attenuate the postsynaptic effects of
  excitatory neurotransmitters
  (glutamine)
            Phenobarbital
• Sodium salt: capsules, tablets, elixir,
  inject
• LD. 15 mg/kg (IV. Not > 100 mg/min)
• MD. : adults 1-3 mg/kg/d
• neonates, children 3-4 mg/kg
• single daily dose at bedtime
• food may delay absorption
• half-life 4 d
          Phenobarbital
• First order kinetics
• not highly bound to proteins
• metabolized to inactive products 30-
  50 %
• ADR:
• dose related: sedation, nystagmus,
  dizziness, ataxia
• Behavior, mood, cognitive
• Reversible hyperactivity and insomnia
  (children > 40%)
         Phenobarbital
• Paradoxical excitation: elderly
• Depression and lack of interest
  or ambition  discontinuation
• Dose related impairment of
  memory, performance on
  intelligence, work performance
• Serious: idiosyncratic ADR
• Morbilliform rash 1-3%
         Phenobarbital
• Steven-Johnson syndrome and
  exfoliative dermatitis (rare)
• With Hepatitis or bone marrow
  suppression
• Cross-reactivity: carbamazepine
  phenytoin
• Megaloblastic anemia with folic
  acid def. (<1%)
• Chronic therapy  osteomalacia
         Phenobarbital
• Accelerates metabolism of:
  theophylline, warfarin,
  cyclosporine, chloramphenicol,
  valproate, felbamate,
  lamotrigine, chlorpromazine,
  haloperidol, TCA
• Enzyme induction: last for days
  to weeks after discontinuation
         Phenobarbital
• Valproate: reduce phenobarbital
  metabolism  toxicity
              Primidone
• Partial and generalized tonic-clonic
  seizures
• Two major metabolites:
  phenobarbital,
  phenylethylmalonamide
• Oral tablets: 50, 250 mg
• Oral suspension: 250 mg/5 mL
• Initiated slowly (acute GI and
  sedative effects)
           Primidone
• Started 125-250 mg bid 
  gradual increase q 4-7 d (125-
  250 mg)
• ADR: similar phenobarbital
• Initial: sedation, dizziness, N
• Decreased libido, impotence
• Long term therapy: neurotoxicity
            Primidone
• Phenytoin: increase
  phenobarbital levels
• Valproate: barbiturate
  intoxication
                Valproate
• short branched-chain fatty acid
• Partial seizures
• Generalized seizures: tonic-clonic, absence
  seizures
• Secondarily generalized tonic-clonic seizures
• potentiation of GABA
              Valproate
• Valproic acid (Depakene): soft gelatin
  capsules 250 mg, syrup 250 mg/5 mL,
  tablet 200 mg, chrono 500 mg
• Divalproex sodium (Depakote): enteric
  coated tablets 125 mg, 250 mg, 500 mg,
  sprinkle capsules 125 mg
                  Valproate
•   Initiated 125-250 mg bid. or tid.
•   Titration 250 mg increments q 3-7 d
•   usual dose: 750-1500 mg divided tid. or qid.
•   Highly bound to albumin
•   > 100 mg/mL albumin saturated
•   half-life 12-16 hrs.
•   major metabolites: active
                 Valproate
• Nausea, vomiting, anorexia, GI discomfort:
  35% --> enteric coated
• dose related:
• fine tremor: reversible, frequently -->
  adjust regimen, propranolol
• Wt. Gain > 50%
• alopecia: transient, initiation of therapy -->
  reduction of dose
                Valproate
• Dose related reduction in platelet count and
  impairment of platelet function --> increase
  bleeding time
• increase hepatic enzymes: 40% -->
  reduction dose or discontinue
       Discontinue Valproate
• Elevation in hepatic enz. 3 times above
  baseline
• elevated bilirubin or PT or decrease serum
  albumin
• S/S of hepatitis
• before initiate: liver enzymes and hepatic
  function tests
               Valproate
• Fulminant hepatotoxicity--> coma, death : 1
  in 49,000 --> discontinue quickly
• the first 6 mo.
• S/S : GI distress, anorexia, sudden loss of
  seizure control
• risk factors:
• age < 2 y
• AED polytherapy
• developmental delay
                Valproate
• Suggestion:
• avoid AED polytherapy in children < 3 y
• avoid preexisting liver disease or FH of
  childhood hepatic disease
• lowest possible dose
                 Valproate
• avoid concomitant salicylates and avoid
  fasting in children with intercurrent illness
• monitor N,V, headache, lethargy, edema,
  jaundice, seizure breakthrough esp. after
  febrile illness
               Valproate
• Drug interaction:
• enzyme inhibitor
• increase phenobarbital levels 80% (0-200%)
• phenytoin: enzyme inhibition and protein
  binding displacement
• phenobarbital, carbamazepine, phenytoin,
  primidone --> decrease valproate levels 30-
  40% --> monotherapy
               Ethosuximide
•   Succinimide: phensuximide, methsuximide
•   absence seizures
•   young children
•   alteration of calcium flux in the thalamus
•   depletion of excitatory neurotransmitter
    stores within the CNS
               Ethosuximide
•   Capsules 250 mg, syrup 250 mg/5 mL
•   3-6 y : 250 mg/d
•   > 6 y : 500 mg/d
•   divided dose: minimize GI distress
•   metabolized hepatically to inactive
             Ethosuximide
• Sedation, nausea, anorexia, headache
• tolerance: the first week
• behavioral disturbances irritability,
  depression, frank psychosis (independent of
  drug dose): rare, history of behavioral or
  psychiatric problems--> discontinue of drugs
             Ethosuximide
• Idiosyncratic: mild, transient leukopenia,
  rare pancytopenia, rash, SLE
• periodic CBC: during 6-12 mo.
• Drug interaction:
• carbamazepine --> reduced ethosuximide
• valproate --> increase ethosuximide
        Benzodiazepines
• Diazepam, clonazepam,
  clorazepate
• Suppress generalized
  epileptiform activity
• Not suppress the primary seizure
  focus
• Enhancing postsynaptic effects of
  GABA
          Clonazepam
• Alone or adjunct
• Lennox-Gastaut syndrome
• Akinetic and myoclonic seizures
• Absence seizures
• Oral tablets : 0.5, 1, 2 mg
• Initiated at low dose
• Infants and children: 0.01-0.003
  mg/kg titrated 3-7 d
           Clonazepam
• Maximum daily dose
• Adults: 20 mg
• Infants and children 0.1 – 0.2
  mg/kg
• Divided doses: avoid transient
  sedative effects at peak
• Chronic therapy: loss of efficacy
  (first 6 months)
          Clonazepam
• Dose-related ADR: drowsiness,
  ataxia
• Mild impairment of cognitive and
  motor skills (persist)
• Behavioral disturbances:
  hyperactivity, irritability,
  restlessness, aggressive or
  violent behavior
          Clonazepam
• Excessive salivation, bronchial
  hypersecretion, wt. gain,
  exacerbate seizures
• Abrupt discontinuation  status
  epilepticus  gradually
  withdrawn
• Phenytoin, carbamazepine,
  phenobarbital: reduce
  cloncazepam conc.
          Clonazepam
• Caution: Clonazepam + valproate
   exacerbate absence seizures
          Clorazepate
• Clorazepate dipotassium
• Adjunct: partial seizures
• Primary active metabolites: N-
  desmethyldiazepam (DMD)
• Maximum dose:
 – Adults 90 mg/d
 – Children 60 mg/d
          Clorazepate
• Sedation, dizziness,
  hypersalivation, behavioral
  changes
• Tolerance: not common , quickly
  as clonazepam
• Antacid: slow rate conversion
  from clorazepate to DMD
• Smoking and AED: accelerate
  metabolism of clorazepate
     New Antiepileptic Drugs
•   Gabapentin
•   Lamotrigine
•   Felbamate
•   Vigabatrin
•   Levetiracetam
•   Tiagabine
•   Topiramate
            Gabapentin
• Cyclohexane derv. of GABA
• inhibitory effects on the CNS
• adjunctive therapy for partial and
  secondarily generalized tonic-clonic
  seizures
• not approved for children or
  monotherapy
• no activity against primary generalized
  tonic-clonic and absence seizures
               Gabapentin
•   Mech. Unknown (gabapentin binding site )
•   oral capsules: 100 mg, 300 mg, 400 mg
•   first day: 300 mg
•   second day: 300 mg twice
•   third day: 300 mg three times
•   bioavailability 60%
•   saturation of the large neutral amino acid
    transport mechanism (system L
    transporter)
              Gabapentin
•   Not metabolized
•   not bound to plasma proteins
•   excreted unchanged in the urine
•   CrCL < 60 mL/min. --> reduction dose
•   half-life: 5-7 hrs.
            Gabapentin
• ADR:
• somnolence 19%, dizziness 17%, ataxia
  12%, fatigue 11%
• rash <1%
• drug interaction:
• antacids, cimetidine --> reduce
  gabapentin levels 12-20%
            Lamotrigine
• Weak antifolate properties
• inhibits voltage-dependent sodium
  channels
• decreased release of excitatory
  neurotransmitters: aspartate, glutamate
• adjunctive therapy for partial and
  secondarily generalized tonic-clonic
  seizures in adults
            Lamotrigine
• Tablets: 25 mg, 100 mg, 200 mg
• with carbamazepine, phenytoin,
  phenobarbital, primidone
• MD. 300-500 mg/d (divided bid.)
• with valproate (with AEDs): 100-200
  mg/d
• F 98%
• protein bound 55%
                 Lamotrigine
•   glucuronic acid conjugation --> inactive
•   half-life 24 hrs. (monotherapy)
•   with inducing AEDs 14 hrs.
•   with inducing AEDs + valproate 27 hrs.
•   with valproate 59 hrs.
            Lamotrigine
• ADR: dizziness, headache, diplopia,
  ataxia, somnolence --> dose reduction
• skin rash (first 4-6 wks) -->
  discontinuation
             Lamotrigine
• DI:
• others AEDs: clinically significant -->
  initiation and titration
• increase valproate conc. 25%
• not effect on carbamazepine,
  phenytoin, phenobarbital, primidone,
  OCs
             Felbamate
• Carbamate derv.
• August 1993
• adults: monotherapy and adjunctive
  therapy for partial seizures
• children: adjunctive therapy for partial
  or generalized seizures associated with
  Lennox-Gastaut syndrome
              Felbamate
• absence, atypical absence, juvenile
  myoclonic seizures
• mechanism: unknown
• life-threatening hematologic and
  hepatic: aplastic anemia, liver failure
• --> only for respond inadequately to
  alternative tx
             Felbamate
• Tablets: 400 mg, 600 mg
• suspension: 600 mg/5 mL
• initiate 1200 mg/d (tid.or qid.)
• increase 1200 mg/d at weekly interval -->
  dose 3600 mg/d
• concomitant AEDs: reduced dose 20-
  30%
               Felbamate
•   Absorbed 90%
•   25% bound to proteins
•   metabolism to inactive products 50%
•   renal excretion 50%
•   half-life 20.5 hrs.
              Felbamate
• Headache, nausea, somnolence,
  anorexia, dizziness, insomnia, fatigue,
  wt. Loss
• idiosyncratic:
• aplastic anemia 1/4000 (the first year)
  mortality rate 30%
• acute hepatic failure (the first year)
  mortality rate 57%
             Felbamate
• CBC no guideline
• LFT: baseline, 1-2 wk interval
• avoid Hx of hematologic or hepatic
  abnormalities
• DI:
• increase phenytoin level-->
• 1200 mg/d : 23%
• 1800 mg/d 47%
             Felbamate
• Decrease carbamazepine level 20-30%
• CBZ-E increase 30-50% --> reduce
  doses of carbamazepine 30%
• increase phenobarbital level
• increase valproate level 20-50% -->
  reduced dose 30%
• phenytoin, carbamazepine reduce
  felbamate level 40-50% : no adjustment
              Vigabatrin
• Irreversible inhibitor of GABA-
  transminase
• adjunctive therapy: refractory partial and
  secondarily generalized tonic-clonic
  seizures
• children with partial seizures,
  generalized seizures, Lennox-Gastaut
  syndrome
               Vigabatrin
•   absorbed 80%
•   not bound to proteins
•   renal excretion >80%
•   First-order kinetics
•   half-life 5-7 hrs.
              Vigabatrin
• ADR:
• Drowsiness, fatigue, depression,
  confusion, GI upset
• psychosis 4-6%--> discontinue
• hallucinations, agitation, paranoia,
  depression, confusion
• onset 5-32 wks
• Hx of psychiatric disturbances
             Vigabatrin
• DI:
• decrease phenytoin conc. 20-30%
• no alteration : carbamazepine,
  valproate, phenobarbital, primidone
          Levetiracetam
• Mech. unknown
• Adjunctive tx of partial seizures in
  adults with refractory epilepsy
• Linear p’ki
• Not inhibitor or inducer
• Dose: 500 mg bid.  max. 3000 mg/d
• ADR: sedation, fatigue
               Tiagabine
•   Inhibit GABA uptake
•   Adjunctive use in partial seizures
•   Dose: 4-8 mg/d Max 80 mg/d
•   Slow titrate to decrease CNS effect
•   ADR: dizziness, tremor, D, depression
•   Carbamazepine, phenytoin  increase
    CL
              Topiramate
• Tab. 25mg, 50 mg, 100 mg
• Mech : Na channels, GABA receptor,
  antagonism AMPA glutamate receptor
• Adjunctive for partial seizures
• Dose: 25-50 mg/d start  200 mg/d 
  1000mg/d
• ADR: ataxia, memory difficult, confusion,
  dizziness, fatigue, somnolence, psychosis,
  wt. loss
• Chronic AFR: kidney stones
• Linear p’ki, few DI
        Withdrawal of Drugs
• Seizure free >= 2 y
    – Relapse rate for childhood-onset 20% and for
      adult-onset 40%
• Rate of drug withdrawal: gradual taper
• Abrupt withdrawal  status epilepticus
• Avoidance of ADR
• Reduction risk of ADR and DI
• Lifestyle not need chronic medication
• Assessment pt.’s work and social
  environment
• Clear explanation to pt. : risk and benefit
  and participate in the decision
• Not drive for several months
 Risk of seizure recurrence after
         AED withdrawal
    Favorable            Unfavorable
    Prognosis             prognosis
Childhood-onset       Adult-onset
Longer seizure free   Freq., severe
interval before       seizures before
drug withdrawal       remission
Absence seizures      Partial seizures
Primary GTC           Atypical febrile
                      seizure
 Risk of seizure recurrence after
         AED withdrawal
    Favorable        Unfavorable
    Prognosis         prognosis
Normal or         EEG abnormalities
improved EEG at   at time of drug
time of drug      withdrawal
withdrawal
                  Abrupt withdrawal
                  of BZD or
                  barbiturate
    The Pregnant Women
Pregnancy:
 – Changes in maternal seizure control
 – Choice of antiepileptic agents (Risk
   of fetal malformations)
 – Alteration of AED pharmacokinetics
 – Potential for AED associated
   coagulopathy in the newborn
     The Pregnant Women
• Changes in maternal seizure
  control
  – No change 50%
  – worsening 40%
  – reduction in seizure 10%
• Several factors:
  – Reduced medication compliance
  – Pharmacokinetic changes
  – Sleep deprivation
    The Pregnant Women
• Choice of antiepileptic agents
  (Risk of fetal malformations)
• 6% (twice in general population)
• Valproate: neural tube,
  cardiovascular and urogenital
  malformations
• Phenytoin: fetal hydantoin
  syndrome
• Carbamazepine: spina bifida
    The Pregnant Women
• Preferred AED: best control
  seizures
• polytherapy  greater risk 
  monotherapy with lowest
  effective dose
• Folate supplements
     The Pregnant Women
• Alteration of AED pharmacokinetics
 – Accelerate hepatic drug metabolism
 – Increased apparent volume of
   distribution
 – Alterations in plasma protein binding
 – Decline in plasma AED conc.  loss of
   seizure control  Monitored at least
   monthly
 – After delivery: determined weekly 
   adjusted dose
     The Pregnant Women
• Potential for AED associated
  coagulopathy in the newborn
• Mothers: phenytoin, phenobarbital,
  primidone  infants: deficient in
  vitamin K-dependent clotting factors
  at birth
• Vitamin K 1 mg IM at birth  monitor
  q 2-4 hr  repeated as needed
        The Pregnant Women
• Mother: vitamin K 20 mg/d orally for
  2 wks or 10 mg IM 4 hr before
  delivery
• Breast milk:
  –   Ethosuximide 80%
  –   Phenobarbital 40-60%
  –   Carbamazepine 40%
  –   Phenytoin 15%
  –   Valproic acid 3%
  –   Monitor infant: lethargic, feeds poorly
    The Pregnant Women
• Prepregnancy planning
• Aware of risk for fetal
  abnormalities
• Potential consequences of
  medication noncompliance
• Need for close therapeutic
  monitoring during pregnancy and
  several weeks after delivery
    Status Epilepticus (SE)
• Medical emergency
• minimize permanent neurologic
  damage and death
• Repetitive clinical convulsions
  without recovery of
  consciousness between attacks
  or repeated electrographic
  seizure activity in a comatose pt.
  , lasting 30 min. or more
    Status Epilepticus (SE)
• CNS injury and neuronal injury 
  Morbidity and mortality
• Fatal: 10-12%
• Noncompliance (most)  Status
  epilepticus
• Goals:
  – Terminate seizures as quickly as possible
    (within at least 90-120 min after onset)
  – Identify and treat reversible causes
  – Manage systemic complications
    (hyperpyrexia, hypoxia)
     Status Epilepticus (SE)
• Lorazepam 0.075 mg/kg IV (2 mg/min) 
• Phenytoin 18 mg/kg IV (50 mg/min)  7
  mg/kg IV 
• Phenobarbital 18 mg/kg (50-75 mg/min) 
  7 mg/kg IV 
• ICU for barbiturate (pentobarbital coma 15-
  20 mg/kg over 1-2 hr + 0.5-1.0 mg/kg/hr)
  or benzodiazepine anesthesia (midazolam:
  ped. 150-200 g/kg + 2.3 g/kg/min)
• Monitor RR, HR, BP
           Bibliography
• Graves NM and Garnett WR. Epilepsy.
  In: Dipiro JT et al., Editors.
  Pharmacotherapy : A
  Pathophysiologic Approach. 4th ed.
  Stamford : Appleton&Lange ; 1999. p.
  952-990.
• Alldredge BK. Seizure Disorders. In:
  Herfindal ET and Gourley DR. editors.
  Textbook of Therapeutics : Drug and
  Disease Management. 6th ed.
  Maryland ; 1996. p. 1005-1033.

				
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