Anticonvulsant Agents

 1% of planet population afflicted with epilepsies

 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 (-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 Ca+2 channel
 All seizures caused by either a reduction of the inhibitory
synaptic activity or enhancement of excitatory synaptic activity
Anticonvulsant Agents
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
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
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
Seizure Types & Medication
See Goodman Gilman Table 21-1, p.522

 Partial (simple & complex)

 Carbamazepine, Phenytoin, Clonazepam,
Primidone.
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
Anticonvulsant Agents
Barbiturates: First agent discovered
O

NH
C2H5
O

NH

Phenobarbital - Luminol

Indications: Grand mal seizures in pediatric patients, status epilepticus

MOA: Enhances GABA mediated chloride influx (GABA inhibition)
Metabolism: 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 (>50h)
Can cause CNS depression, drowsiness, and associated in decreased IQ
in chronically treated children.
 Anticonvulsant Agents
Hydantoins: Effective against all but absence seizures

H
N
O
N-Na+
O

Phenytoin Sodium - Dilantin®

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!!!
Anticonvulsant Agents
Volume 342:325, February 3, 2000, Number 5
Gingival Hyperplasia Induced by Phenytoin
Figure 1. A 17-year-old boy had generalized tonic–clonic
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.
 Anticonvulsant Agents
Hydantoins
Indications: Grand mal, psychomotor, focal and partial
seizures – for use in patients that are refractory to
less toxic anticonvulsants medications
H
N Hepatic metabolism to an active metabolite: half-life of
H3C O
N
95 hr
O CH3

Mephenytoin - Mesantoin® 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
H infused at a rate of 100-150 PE/minute
N
O
Must monitor respiratory, ECG and BP throughout
N
O OPO(O-Na+)2 administration and for 20 minutes afterward
Used in conjunction with benzodiazepines
Fosphenytoin - Cerebyx®
 Anticonvulsant Agents
Hydantoins
Indications: Tonic-clonic grand mal seizures,
psychomotor seizures
H Hepatic metabolism with renal excretion of metabolites
N -half-life of 3-9 hours
O
N Therapeutic serum concentrations of 15-50 mg/mL
O CH3
Tablet dosage form usually divided to 4-6 per day
Ethotoin - Peganone® Dosage should be individualized with a dose of <2 grams
per day usually ineffective in adults
Given when people have a reaction to phenytoin. Less
effective, but a better toxicity profile.
 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
H3C O seizures that are refractory to all other agents
H3C NH Ethosuximide is preferred for children although the 150 mg half-
O strength methsuximide is marketed for pediatric use

Ethosuximide - Zarontin® 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 – Ca 2+ activity
Metabolism: primarily hepatic with inactive metabolites
excreted renally; Monitor renal and hepatic function since these
O drugs have a profound effect on liver tissue
H3C N Ethoxsuximide half life is 30 hours in children and 60 hours in
CH3
O adults; Methsuximimde half life is 2-4 hours
Monitor for blood dyscrasias
Methsuximide - Celontin®
Ethoxsuximide therapeutic blood levels are 40-100 mg/mL
 Anticonvulsant Agents
Indications: control of absence (petit mal)seizures,
Succinimides INEFFECTIVE in other types of epilepsy
MOA: suppression of the paroxysmal three cycle per second spike
O and wave activity associated with lapses of consciousness - an
increase in the threshold for action potential – Ca2+ activity
N Metabolism: primarily hepatic with inactive metabolites excreted
CH3
O in the bile, half life is 4 hours
Phensuximide - Milontin® Monitor for blood dyscrasias
Succinimides may increase frequency of grand mal seizures
Phensuximide will discolor pink, red or red-brown
Other
Indications: adjunct in partial seizures in adults with epilepsy
O
N MOA: modification of the T-type calcium currents and binds to
GABA BZ receptors raising the action potential threshold
SO2NH2
Half life of 63 hours with most drug excreted as the parent and
Zonisamide - Zonegran® also some glucuronide and acetyl conjugates (renally impaired)
Doesn’t appear to interact with other anticonvulsants
 Anticonvulsant Agents
Oxazolidinediones
H3C O O
H3C N
CH3
O

Trimethadione - Tridione®

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)
 Anticonvulsant Agents
Benzodiazepines
H O
N N
O2N N Cl
Cl
Clonazepam - Klonopin®
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
H3C O
H O N
CO2-K+
Cl N
N
KOH
Diazepam - Valium®
Clorazepate Dipotassium
- Gen-Xene®, Tranxene® Indications: orally-adjunct
in convulsive disorders;
Indications: adjunct in rectally-for refractory
partial seizures, alcohol patients who have
withdrawl occasional bouts of
increased seizure activity;
Do not use in children < 9 parenterally-status
epilepticus and severe
recurrent epilepsy - max
of 30 mg in adults every 2-
4 hours
 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
N benzodiazepine withdrawal

O NH2 Extended release tablet coating will be present in the stool

MOA: reduces polysynaptic responses and blocks post-tetanic
Carbamazepine - Tegretol®, potentials – Na+ channel effects similar to phenytoin
Atretol®, Epitol® Metabolized by CYP3A4 to the epoxide - active metabolite. Half life
of 12 to 17 hours followed by hydrase activity and glucuronidation
O Monitor for blood disorders and hypersensitivity reactions

Indications: monotherapy of adjunct use in adults and children 4-16

years of age suffering from partial seizures, atypical panic disorders
N
Less toxicity than carbamazepine: lack of epoxide metabolite
O NH2
MOA: reduction of the ketone to hydroxy group is the active drug:
produces blockage of the voltage sensitive sodium channels
Oxcarbazepine - Trileptal® Metabolism: glucuronide conjugation and excretion - biphasic half
life: parent = 2 hours, mono-hydroxy = 9 hours
 Anticonvulsant Agents
Other agents
Indications: adjunctive agent in petit mal and other
unlocalized seizure disorders
N N O
Anti-epileptic activity tolerance usually develops quite rapidly
H2NSO2 S N CH3
H MOA: inhibition of carbonic anhydrase in the seizure focal
area and its subsequent acidosis it produced, also loss of Na+
Acetazolamide - Diamox® and K+ inhibits excessive neuronal discharge
Contraindication: 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
Magnesium Sulfate premature labor, asthma in patients refractory to 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
 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)
H2N O O NH2 Monitor for blood disorders and hepatic transaminase levels
every 1-2 weeks, photosensitivity possible
O O MOA: Unknown – Na channel inhibition, GABA component
Metabolism: hepatic with most drug excreted as the parent in
Felbamate - Felbatol®
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;
O
migraine prophylaxis, bipolar disorder
H2N NEW indication July 2002 – management of postherpetic
OH neuralgia (intense burning/tearing pain)
Gabapentin - Neurontin® No hepatic induction or inhibition
In patients > 12 years, dosage is a function of creatinine
clearance—no metabolism—t1/2 5-7 hours by renal elimination
MOA: Unknown - related to GABA but is NOT a GABA
agonist
 Adjunct Anticonvulsant Agents
Indications: Absence and generalized seizures in childhood
(sole in adults, adjunct in pediatrics)
N Warning: serious rashes including Stevens-Johnson syndrome
Cl N
Cl occur in 1% of pediatric patients and 0.3% of adults in the first 2-8
H2N N NH2 weeks of therapy - discontinue used immediately at the first sign of
a rash, avoid during pregnancy or lactation, photosensitization.
Lamotrigine - Lamictal®
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
H3C mal and myoclonic seizures; bipolar manic-depressive illness,
migraine prophylaxis
H3C CO2H
MOA: appears to increase levels of GABA
Valproic acid - Depakene®,
Metabolism: primarily glucuronidation and CYP mediated b-
Depakote®
oxidation, half life of 9-16 hours
Will interfere with urine ketone tests, > 5 years decreased bone
density in young children
 Adjunct Anticonvulsant Agents
Indications: adjunct therapy for partial seizures
CO2H Should be taken with food - dosing titration followed when
H3C
S enzyme-inducing anti-epileptic drugs are taken - optimization

S N MOA: binds to GABA uptake carrier system potentiating the

activity of GABA by preventing reuptake
Hepatic metabolism of the thiophene ring followed by
CH3
glucuronidation—monitor hepatic function
Tiagabine HCl - Gabitril® Tetratogenic in animals; excreted into breast milk

Indications: adjunct therapy for partial seizures in

SO2NH2 adults/kids and Lennox-Gastaut (LGS) in children (10%)
O O Dosage should be titrated as a function of creatinine clearance
O O MOA: a sulfamate monosaccharide that exerts sodium
H3C CH3
O O channel blocking action, increases activity of GABA at its
H3C CH3 receptor and antagonizes the effect of glutamate
Metabolism – primarily excreted as the parent drug into the
Topiramate - Topomax® urine (70%), rest as CYP products and glucuronidation
Maintain fluid intake due to stone formation (1.5%)
 Adjunct Anticonvulsant Agents
Indications: adjunct in partial seizures in adults
Dosage must be individualized based on renal function---
N O
enzymatic amide hydrolysis (non-CYP) to the acid
H3C
NH2 (inactive), half life of 7 hours
H
O MOA: Unknown
Levetiracetam - Keppra®
Possible teratogen – tell patients to advise MD if they
become pregnant or are intending to become pregnant

Indications: grand mal, psychomotor or focal epileptic

O seizures alone or as an adjunct, benign familial tremor
NH Not recommended in children < 8 years
H3C
O N Problem bioequivalence among different manufacturers
H
MOA: Unknown – possibly similar to Phenytoin
Primidone - Mysoline®
Metabolized to phenylethylmalonamide and phenobarbital
with anticonvulsant activity
Seizure Types & Medication
See Goodman Gilman Table 21-1, p.522

 Partial (simple & complex)

 Carbamazepine, Phenytoin, Clonazepam,
Primidone.
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