Download Anti-seizure

Pharmacology: Antiseizure Drugs (Bannon)
SEIZURES:
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Definition: finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
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Types:
Partial Seizures (Simple):
o Consciousness preserved (simple)
o Various manifestations:
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Convulsive jerking
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Paresthesias
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Psychic symptoms (altered sensory perceptions, illusions, hallucinations, affect changes)
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Autonomic dysfunction
Partial Seizures (Complex):
o Impaired consciousness (complex) that is preceded, accompanied, or followed by psychologic
symptoms
Tonic-Clonic Seizures (Generalized):
o Tonic phase involves abrupt LOC, muscle rigidity and respiration arrest (less than 1 minute)
o Clonic phase involves jerking of body muscles, with lip or tongue biting, and fecal and urinary
incontinence (2-3 minutes)
o Formerly called grand mal seizures
Absence Seizures (Generalized):
o Impaired consciousness (often sudden onset and brief)
o Sometimes accompanied by automatisms, loss of postural tone, or enuresis
o Begin in childhood and usually cease by age 20
o Formerly known as petit mal seizures
Myoclonic Seizures:
o Single or multiple myoclonic jerks
Status Epilepticus:
o A series of seizures (usually tonic-clonic) without recovery of consciousness between attacks
o Life-threatening emergency
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Risk Factors:
Children: fever, mental retardation, cerebral palsy, genetics
Adults: trauma, tumors
Elderly: Alzheimer’s Disease, Stroke
DRUGS AND OTHER TREATMENTS FOR SEIZURES:
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General:
First Generation Drugs:
o Use: effective for the treatment of generalized tonic-clonic and partial seizures
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Many rate-dependently prolong inactivation of voltage-gated Na channels (similar to
lidocaine)
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Others potentiate GABA by several mechanism
o Use: effective against generalized (absence) seizures
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Thought to block T-type Ca channel-mediated current in thalamic neurons
Newer Drugs:
o Newer Phenotypic Models: mutant mice, models of kindling or neuropathic pain
o Targeting of Defined Biochemical Mechanisms: GABA uptake, metabolism, receptor effects
o Novel AD Targets: glutamate receptors (NMDA), K+ channels (open to hyperpolarize) or Ca++ channels
Drugs with Broad Spectrum of Action:
o May be due to multiple mechanisms of action and/or novel mechanisms of action
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Drugs for Partial and Generalized Tonic-Clonic Seizures:
Drugs of Choice:
o Phenytoin (Dilantin):
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History: oldest nonsedative antiseizure drug
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MOA: blockade of Na channels is the strongest effect (but not the only effect) at therapeutic
concentrations
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Pharmacokinetics:
 Absorption: highly dependent on the formulation
o Fosphenytoin: soluble prodrug that allows for IM or IV administration
 Elimination: via the liver; dose-dependent and need to titrate dose slowly
Toxicity/Side Effects:
 Nystagmus early
 Diplopia and ataxia are dose-limiting effects
 Gingival hyperplasia and hirsutism are common long-term
 Idiosyncratic reactions are rare
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Use: considered a 2nd line drug by some, but still one of the most widely used drugs in the
world
o Carbamazepine:
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Structure: tricyclic compound related to some antidepressants
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Other Uses (Besides Seizures):
 Treatment of BPD
 Treatment of trigeminal neuralgia
 Drug abuse (?)
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MOA: blockade of Na channels is the primary effect
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Pharmacokinetics:
 Metabolism: significant microsomal induction and may have to adjust dose of this
and other drugs over time (ie. induces its own metabolism)
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Toxicity/Side Effects:
 Diplopia and ataxia (dose-related)
 Idiosyncratic blood dyscrasia in the elderly
 Stevens-Johnson Syndrom (rare but serious skin reaction)
o Genetic risk determined by presence of a specific HLA allele (testing
recommended by FDA)
o 10x higher risk in Asians
 Side effects may be decreased with ER formulation
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Important: may exacerbate myoclonic and absence seizures (do not use for these)
o Valproic Acid:
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Use in Seizures:
 Partial seizures
 Generalized tonic-clonic
 Myotonic seizures
 Atonic seizures
 Generalized (absence) seizures
 Combination seizures
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Other Uses (Besides Seizures):
 Treatment of BPD
 Treatment of migraine (Divalproex sodium ER)

MOA: unclear; broad spectrum of action most likely due to multiple MOA
 Blockade of Na channels possible
 GABA effects may also be relevant
 Histone deacetylation inhibition to INCREASE gene expression (potentiation of Sp
transcription factor family  turns on a bunch of genes)
 May also have effects on Ca++ channels (due to efficacy against absence seizures)
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Side Effects: serious effects are rare, but may not be first line due to these rare events
 Severe idiosyncratic hepatotoxicity (requires monitoring of liver function)
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Formulations:
 Divalproex Sodium ER: used once daily
o Complex partial seizures
o Absence seizures
o Migraine
Alternative Drugs:
o Phenobarbital:
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MOA: potentiate GABA effects
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Use: rapid effects, safety profile and low cost can make it a DOC
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Side Effects: sedative effects can be limiting
o Lamotrigine:
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MOA: blockade of Na channels; may have additional MOAs due to broad spectrum of activity
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-
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Use: shown to be as effective as the DOCs (may now be considered one)
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Side Effects: rare but life-threatening dermatitis possible in infants
o Levetiracetam:
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MOA: binds SV2A to interfere with release of NT

Use: very good for refractory seizures in adults and children (another possible DOC)
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Side Effects: well tolerated
o Gabapentin and Pregabalin (Lyrica):
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MOA: binds voltage gated Ca channel subunit (not related to GABA)
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Other Uses (Besides Seizures):
 Neuropathic pain
 Migraine
 Anxiety
 Surgical analgesia
o Topiramate (Topamax):
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MOA: broad spectrum drug, probably with multiple MOAs
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Use: hot drug for off-label use
 Refractory migraine
 BPD
 Many other disorders
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Side Effects: typical CNS side effects and memory problems
Drugs for Generalized (Absence) Seizures:
Drugs of Choice:
o Ethosuximide:

Use: ONLY a first line drug for absence seizures (no other types)
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MOA: blocks T-type Ca++ channel
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Pharmacokinetics:
 Absorption: good
 Metabolism: complete

Toxicity: well tolerated
 Dose-related gastric distress
 More rare instances of rashes and psychosis
o Valproic Acid: already described
o Clonazepam:

Use:
 Absence seizures (may be less effective that ethosuximide or valproic acid)
 Myoclonic seizures
 Atonic seizures
 Infantile spasms
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Side Effects: typical benzo side effects that limit use
 Sedation
 Development of tolerance
 Withdrawal syndrome
Treatment of Status Epilepticus:
Treatment:
o IV diazepam or lorazepam
o Followed by IV fosphenytoin or phenobarbitol
Important Point: watch for synergistic CNS depression when combining these drugs!
Other Aspects of Antiseizure Drug Therapy:
Teratogenicity:
o Difficult to assess: due to seizures and heterogeneity of these medications
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Most pregnant patients on these drugs deliver normal infants
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Apparent overall 2X increase in risk of congenital malformations when on the drugs (no
increased risk if off the drugs during pregnancy)
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If you choose to keep them an a drug (which is typically done), use the lowest effective dose
of monotherapy
o Specific Known Risks:
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Phenytoin: fetal hydantoin syndrome (?)
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Valproic Acid: risk of spina bifida (1-2%) and possible effect on IQ
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Drug Withdrawal:
o Most difficult for people on benzodiazepines and barbiturates
o ~70% of people with epilepsy enter remission while on medications (>5 years seizure free)
o ~75% of these patients can be successfully and gradually withdrawn from their medications
Other:
o Increased suicide risk (2X)
o Decreased bone density (chronic use)
Future of Pharmacotherapy for Seizures:
Large number of candidate drugs being identified through high-throughput screening
Some have novel MOAs and should be useful/improve the treatment of refractory epilepsy
Improved understanding of genetic and cellular basis for epilepsy will lead to more precisely targeted
therapeutics and new strategies to delay/prevent epileptogenesis
Ketogenic Diet:
History:
o Fasting formerly used to treat epilepsy
o Lost favor because of practical difficulties and antiquated medical theories
Description:
o Low calorie diet with 4 grams of fat per gram of protein or carbs
o Diet creates ketones by fat metabolism (mimics fasting) and ketones replace glucose as fuel
o Not entirely clear what the MOA of this diet is with regard to seizure treatment
o Strict adherence is required (children need to initially be hospitalized to ensure adherence)
Use:
o Treatment of refractory seizures in children (ie. Lennox-Gastaut Syndrome)
Surgery:
Anterior Temporal Lobectomy:
o Use: very effective for refractory and harmful cases of the most common partial seizure of adults
o Results: most patients seizure free for 5 years (enter remission)
Corpus Callostomy:
o Use: Lennox-Gastaut Syndrome (difficult to treat childhood onset form of epilepsy characterized by
frequent and different types of seizures)
Hemispherectomy:
o Use: other severe forms of childhood epilepsy
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Ramussen Syndrome (rare chronic inflammatory neurological disorder)
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Sturge Weber Syndrome (rare congenital neurological and skin disorder)
Vagus Nerve Stimulation (NeuroCybernetic):
o Use:
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Refractor complex partial and generalized seizures
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Poor surgical candidates
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Now being tested in children
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Also used in depression, anxiety and other disorders
o Response: MOA is unclear but clearly effective
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Good response (seizure reduction in 30-75% of patients)
Therapeutic Principles for the Management of Epilepsy:
Pre-Therapy:
o Determine cause of seizures if possible
o For children, wait and see before treating after a single, unprovoked seizure
Therapy:
o Use a drug of choice appropriate for the seizure type
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Partial Seizures and Generalized Tonic-Clonic: phenytoin, carbamazepine, valproic acid
 Possibly: phenobarbital, lamotrigine, levetiracetam
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Generalized (Absence) Seizures: ethosuximide, valproic acid, clonazepam
o Therapeutic index and toxicity not uncommon with most antiseizure drugs, so need to ensure
adequate trial of a single drug AND monitor plasma levels closely
Cases of Treatment Failure:
o Occurs in as many as ½ of patients- first try monotherapy with another first line drug
o If total pharmacological failure (20-30% of patients), consider surgery or vagal nerve stimulation