Anticonvulsant Agents

1
Anticonvulsant Agents

• 2.5 million Americans are afflicted with
  epilepsies
• more than 40 types identified (wear a Medic-Alert
  id)
• 80 are treatable (leaving almost 500k
  uncontrolled)
• No effective prophylaxis nor cure ? drugs only
  inhibit seizures
• Compliance a problem long-term use with many
  side effects
• General physiological mechanisms of
  anticonvulsants
• Limit the sustained repetitive firing of a neuron
  by promoting the inactivated state of
  voltage-activated Na channels
• Enhance the GABA (g-amino butyric acid) mediated
  synapatic inhibition (some drugs act pre- and
  others post-synaptically)
• Less common forms of epileptic seizures called
  absence seizures are controlled by limiting the
  activation the T-current which is a
  voltage-activated Ca2 channel
• All seizures caused by either a reduction of the
  inhibitory synaptic activity or enhancement of
  excitatory synaptic activity

2
Anticonvulsant Agents
3
Seizure Types

• Seizures transient alteration of behavior due
  to the disordered, synchronous and rhythmic
  firing of a population of brain neurons
• Epilepsy disorder of brain function
  characterized by the periodic and unpredictable
  occurrence of seizures
• The type of seizure determines the drug selected
  for therapy
• Partial seizures account for 60 of epileptic
  attacks
• Caused by a cortex lesion, tumor, developmental
  malformation, damage due to stroke or trauma, etc
  ? can be visualized by MRI
• Simple Single focal area, preservation of
  consciousness
• Complex Start focal and spread, loss of
  consciousness occurs
• Generalized seizures account for 40 of
  epileptic attacks
• Etiology is most often genetic inheritance of
  multiple mutant genes
• Grand Mal (tonic-clonic) muscle contractions,
  whole-body jerks
• Petit Mal (absence) blank, absent stare.
  Dissociation.
• Status Epilepticus Continuous series of seizures
  without reawakening

4
Anticonvulsant Agents

• General considerations for anti-seizure
  medications
• The physicians dilemma is to chose an
  agent/agents that that controls the seizures with
  minimal side-effects
• Long-term nature of the treatment creates
  problems with respect to toxicity multiple
  agents may be needed, especially if the patient
  suffers from more than one type of seizure
• Plasma concentrations should be routinely
  measured initiation of therapy, following
  dosage adjustments, in event of therapeutic
  failure, signs of toxicity and when multiple
  drugs are used
• The cause of the seizure should be pursued - can
  a correctable structural lesion or metabolic
  problem be fixed?
• Drug therapy should be initiated with a single
  drug - loading dose is only utilized in cases of
  extreme urgency
• Pregnancy and anti-seizure meds are associated
  with increased stillbirth, mortality and birth
  defects
• 7 risk versus 2-3 for the general population
• Metabolic epoxides and low epoxide hydrase
  activity

5
Anticonvulsant Agents

• General considerations for anti-seizure
  medications
• Develop tolerance to sedation and side effects
• IF a single drug fails to control seizures at
  maximum dosage and compliance is confirmed then
  another drug should be substituted
• Gradually reduce discontinued drug to prevent
  status epilecticus
• Third drug should be tried BEFORE instituting
  combination therapy
• Patient or relative should fill out a seizure
  chart - document compliance
• Monitoring plasma levels useful in multi-drug
  cases offending agent??
• No clear guidelines for medication cessation
  following long periods of absence of seizures -
  if done it MUST be done over a period of months
• 3-35 of status epilepticus patients will die -
  immediate diazepam IV followed by IV phenytoin
  due to rapid redistribution of diazepam to fatty
  tissues with attention to hypoventilation and
  hypotension

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Seizure Types Medication
See Goodman Gilman Table 21-1, p.522

• Partial (simple complex)
• Carbamazepine, Phenytoin, Clonazepam, Primidone.
  Valproic acid as adjunct.
• Petit mal (absence seizure)
• Ethosuximide, valproic acid, clonazepam,
  trimethadione
• Grand mal (tonic-clonic seizure)
• Phenytoin, diazepam, carbamazepine,
  phenobarbital, primidone
• Status Epilepticus
• IV diazepam, phenytoin, phenobarbital

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Anticonvulsant Agents
Barbiturates First agent discovered
Indications Grand mal seizures in pediatric
patients, status epilepticus MOA Enhances GABA
mediated chloride influx (GABA inhibition) Metabol
ism Liver metabolism. Stimulates P450 enzymes
that increases the metabolism of MANY
drugs! Given IV or PO with slow onset and a very
long half-life (gt50h) Can cause CNS depression,
drowsiness, and associated in decreased IQ in
chronically treated children.
8
Anticonvulsant Agents
Hydantoins Effective against all but absence
seizures
Indications tonic-clonic (grand mal), partial
seizure, status epilepticus cardiac
arrhythmias INEFFECTIVE in absence seizures, USE
a single manufacturers product! MOA (All
Hydantoins) Produces a sustained depolarization
by slowing the rate of voltage-activated Na
channels - prevents hyperexcitability 90 protein
bound - hepatic metabolism to inactive
hydroxylated cpd - half-life of 20-60 hours,
serum therapeutic level of 5-20 mg/mL No
sedative properties in normal doses, chronic use
toxicity includes gingival hyperplasia (20 and
reversible), hirsutism and overdosage is manifest
by ataxia (30 mg/mL), nystagmus, vertigo, blurred
vision, confusion, lethargy (40 mg/mL),
hallucinations Many drug interactions!
Injection (never IM-precip), chewable tablets,
oral suspension, prompt acting capsules, extended
release capsules Generics shown to have
bioavailability problems!!!
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Anticonvulsant Agents
10
Volume 342325, February 3, 2000, Number
5 Gingival Hyperplasia Induced by
Phenytoin Figure 1. A 17-year-old boy had
generalized tonicclonic seizures for four years.
When the seizures began, a computed tomographic
scan of his brain and an electroencephalogram
were normal. Treatment with 300 mg of phenytoin
per day was subsequently begun and continued
unsupervised for a period of two years.
Examination revealed coarsening of facial
features and severe gingival hyperplasia (Panel
A), brisk deep-tendon reflexes, and cerebellar
ataxia. Withdrawal of phenytoin was followed by
marked regression of the gingival hyperplasia
within three months (Panel B) however, ataxia
persisted.
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Anticonvulsant Agents
Hydantoins
Indications Grand mal, psychomotor, focal and
partial seizures for use in patients that are
refractory to less toxic anticonvulsants
medications Hepatic metabolism to an active
metabolite half-life of 95 hr Indications
status epilepticus Water soluble injectable
phosphate prodrug whose dosage is expressed as
phenytoin equivalents (PE) Must be diluted into
5 dextrose of normal saline and infused at a
rate of 100-150 PE/minute Must monitor
respiratory, ECG and BP throughout administration
and for 20 minutes afterward Used in conjunction
with benzodiazepines
12
Anticonvulsant Agents
Hydantoins
Indications Tonic-clonic grand mal seizures,
psychomotor seizures Hepatic metabolism with
renal excretion of metabolites -half-life of 3-9
hours Therapeutic serum concentrations of 15-50
mg/mL Tablet dosage form usually divided to 4-6
per day Dosage should be individualized with a
dose of lt2 grams per day usually ineffective in
adults Given when people have a reaction to
phenytoin. Less effective, but a better toxicity
profile.
13
Anticonvulsant Agents
Succinimides
Indications control of absence (petit
mal)seizures, INEFFECTIVE in other types of
epilepsy Note Methsuximide should only be used
for petit mal seizures that are refractory to all
other agents Ethosuximide is preferred for
children although the 150 mg half-strength
methsuximide is marketed for pediatric
use Succinimides may increase frequency of grand
mal seizures MOA suppression of paroxysmal three
cycle per second spike and wave activity
associated with lapses of consciousness - an
increase in the threshold for action potential
Ca2 activity Metabolism primarily hepatic with
inactive metabolites excreted renally Monitor
renal and hepatic function since these drugs have
a profound effect on liver tissue Ethoxsuximide
half life is 30 hours in children and 60 hours in
adults Methsuximimde half life is 2-4
hours Monitor for blood dyscrasias Ethoxsuximide
therapeutic blood levels are 40-100 mg/mL
14
Anticonvulsant Agents
Indications control of absence (petit
mal)seizures, INEFFECTIVE in other types of
epilepsy MOA suppression of the paroxysmal three
cycle per second spike and wave activity
associated with lapses of consciousness - an
increase in the threshold for action potential
Ca2 activity Metabolism primarily hepatic with
inactive metabolites excreted in the bile, half
life is 4 hours Monitor for blood
dyscrasias Succinimides may increase frequency of
grand mal seizures Phensuximide will discolor
pink, red or red-brown Indications adjunct in
partial seizures in adults with epilepsy MOA
modification of the T-type calcium currents and
binds to GABA BZ receptors raising the action
potential threshold Half life of 63 hours with
most drug excreted as the parent and also some
glucuronide and acetyl conjugates (renally
impaired) Doesnt appear to interact with other
anticonvulsants
Succinimides
Other
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Anticonvulsant Agents
Oxazolidinediones
Warning Tetratogenic Indications Control of
absence (petit mal) seizures refractory to other
agents MOA UNKNOWN! Different pcol than
hydantoins and barbiturates - does NOT raise the
seizures threshold caused by electroconvulsive
therapy Metabolism hepatic demethylation to
active metabolite slowly excreted renally -
parent drug half life of 16-24 hours but the
demethylated drug half-life of 6-13 days Target
therapeutic serum concentration of approximately
700 mg/mL Monitor for blood disorders (approx.
20), considerable sedative effect - may progress
to ataxia (inform MD of any sign of visual
disturbances or infection)
16
Anticonvulsant Agents
Benzodiazepines
Indications orally-adjunct in convulsive
disorders rectally-for refractory patients who
have occasional bouts of increased seizure
activity parenterally-status epilepticus and
severe recurrent epilepsy - max of 30 mg in
adults every 2-4 hours
Indications petit mal, or partial seizures
alone or as adjunct Therapeutic concentrations in
children 20-80 ng/mL Adult dosage or no more
than 20 mg/day Be aware of sedative effects
Indications adjunct in partial seizures,
alcohol withdrawl Do not use in children lt 9
17
Anticonvulsant Agents
Other agents
Warning aplastic anemia and agranulocytosis at
5-8X normal Indications partial seizures -
best response rate, grand mal and mixed seizure
patterns trigeminal neuralgia pain relief other
unlabeled uses psychiatric disorders, alcohol,
cocaine and benzodiazepine withdrawal Extended
release tablet coating will be present in the
stool MOA reduces polysynaptic responses and
blocks post-tetanic potentials Na channel
effects similar to phenytoin Metabolized by
CYP3A4 to the epoxide - active metabolite. Half
life of 12 to 17 hours followed by hydrase
activity and glucuronidation Monitor for blood
disorders and hypersensitivity reactions Indicati
ons monotherapy of adjunct use in adults and
children 4-16 years of age suffering from partial
seizures, atypical panic disorders Less toxicity
than carbamazepine lack of epoxide
metabolite MOA reduction of the ketone to
hydroxy group is the active drug produces
blockage of the voltage sensitive sodium
channels Metabolism glucuronide conjugation and
excretion - biphasic half life parent 2 hours,
mono-hydroxy 9 hours
18
Anticonvulsant Agents
Other agents
Indications adjunctive agent in petit mal and
other unlocalized seizure disorders Anti-epileptic
activity tolerance usually develops quite
rapidly MOA inhibition of carbonic anhydrase in
the seizure focal area and its subsequent
acidosis it produced, also loss of Na and K
inhibits excessive neuronal discharge Contraindica
tion sulfonamide allergy Indications
convulsions due to hypomagnesiumia or severe
pre-eclampsia or eclampsia without producing CNS
depression in mother or infant, acute nephritis
in children, inhibition of premature labor,
asthma in patients refractory to
b-agonists Injection only either IV or IM MOA
prevents convulsions by blocking neuromuscular
transmission and decreased the amount of
acetylcholine liberated at the end plate caused
by motor nerve transmission
19
Adjunct Anticonvulsant Agents
Indications NOT first line agent (aplastic
anemia)! Use in patients refractory to all other
therapies in partial seizures in adults or
Lennox-Gastaut syndrome (severe epilepsy) Monitor
for blood disorders and hepatic transaminase
levels every 1-2 weeks, photosensitivity
possible MOA Unknown Na channel inhibition,
GABA component Metabolism hepatic with most
drug excreted as the parent in the urine -
half-life of 20-23 hours Indications adjunct
therapy in children 3-12 years of age for partial
seizures, tremors associated with multiple
sclerosis migraine prophylaxis, bipolar
disorder NEW indication July 2002 management of
postherpetic neuralgia (intense burning/tearing
pain) No hepatic induction or inhibition In
patients gt 12 years, dosage is a function of
creatinine clearanceno metabolismt1/2 5-7 hours
by renal elimination MOA Unknown - related to
GABA but is NOT a GABA agonist
20
Adjunct Anticonvulsant Agents
Indications Absence and generalized seizures in
childhood (sole in adults, adjunct in
pediatrics) Warning serious rashes including
Stevens-Johnson syndrome occur in 1 of pediatric
patients and 0.3 of adults in the first 2-8
weeks of therapy - discontinue used immediately
at the first sign of a rash, avoid during
pregnancy or lactation, photosensitization. MOA
Unknown - appears to modulate sodium
channels Metabolism predominately by glucuronide
conjugation Warning Hepatotoxicity,
Terratogenic, pancreatitis Indications Petit
mal and mixed seizures with absence, grand mal
and myoclonic seizures bipolar manic-depressive
illness, migraine prophylaxis MOA appears to
increase levels of GABA Metabolism primarily
glucuronidation and CYP mediated b-oxidation,
half life of 9-16 hours Will interfere with urine
ketone tests, gt 5 years decreased bone density in
young children
21
Adjunct Anticonvulsant Agents
Indications adjunct therapy for partial
seizures Should be taken with food - dosing
titration followed when enzyme-inducing
anti-epileptic drugs are taken -
optimization MOA binds to GABA uptake carrier
system potentiating the activity of GABA by
preventing reuptake Hepatic metabolism of the
thiophene ring followed by glucuronidationmonitor
hepatic function Tetratogenic in animals
excreted into breast milk Indications adjunct
therapy for partial seizures in adults/kids and
Lennox-Gastaut (LGS) in children (10) Dosage
should be titrated as a function of creatinine
clearance MOA a sulfamate monosaccharide that
exerts sodium channel blocking action, increases
activity of GABA at its receptor and antagonizes
the effect of glutamate Metabolism primarily
excreted as the parent drug into the urine (70),
rest as CYP products and glucuronidation Maintain
fluid intake due to stone formation (1.5)
22
Adjunct Anticonvulsant Agents
Indications adjunct in partial seizures in
adults Dosage must be individualized based on
renal function---enzymatic amide hydrolysis
(non-CYP) to the acid (inactive), half life of 7
hours MOA Unknown Possible teratogen tell
patients to advise MD if they become pregnant or
are intending to become pregnant Indications
grand mal, psychomotor or focal epileptic
seizures alone or as an adjunct, benign familial
tremor Not recommended in children lt 8
years Problem bioequivalence among different
manufacturers MOA Unknown possibly similar to
Phenytoin Metabolized to phenylethylmalonamide
and phenobarbital with anticonvulsant activity
23
Seizure Types Medication
See Goodman Gilman Table 21-1, p.522

• Partial (simple complex)
• Carbamazepine, Phenytoin, Clonazepam, Primidone.
  Valproic acid as adjunct.
• Petit mal (absence seizure)
• Ethosuximide, valproic acid, clonazepam,
  trimethadione
• Grand mal (tonic-clonic seizure)
• Phenytoin, diazepam, carbamazepine,
  phenobarbital, primidone
• Status Epilepticus
• IV diazepam (Lorazepam), phenytoin,
  phenobarbital