Antiseizure Pharmacotherapy

Antiseizure Pharmacotherapy

1. General concepts

   • Depends on signs presented by patient
   • Low initial dose that is gradually increased until control is achieved or side effects prevent further increase.
   • Serum drug levels may be obtained
   • If seizures continue, a different medication is added in small dose increments while the dose of the first drug is slowly reduced.
   • Meds are discontinued over 6-12 weeks
   • Newer antiseizure meds exhibit fewer troublesome side effects
     • Limited induction of drug-metabolizing enzymes
       • Pharmacokinetic profile less complicated
     • Generally well-tolerated
     • Less of a health risk in pregnancy
   • Many of the popular drugs have found to double the risk of suicidal ideation in mentally ill patients
     • Both newer and older drugs can cause this
   • Some antiseizure drug combos can increase incidence of seizures
   • Directed at controlling the movement of electrolytes across neuronal membranes or affecting neurotransmitter balance
   • Antagonism of the excitatory neurotransmitter glutamate.
     • Glutamate works w/ Na+-K+ ATPase pump
       • Blocking it indirectly prevents an influx of positive ions into cells
     • Taurine can antagonize glutamate
       • Stabilizes neuronal cell membranes by reducing glutamate-induce + ion influx

2. Drugs that potentiate GABA

   • Mimic effects of GABA by stimulating influx of chloride ions through GABA receptor channel
   • May enhance GABA release, block ruptake of GABA into nerve cells, or block GABA-degrading enzymes
   • These drugs are also used for depression, migraines, neuropathic pain, postherpetic neuralgia, dibromyalgia, spinal cord injury, anxiety and bipolar.
   • Barbiturates
     • Intensifies effects of GABA in brain
       • Works against all seizures except absence
       • Low margin of safety, high potential for dependence, profound CNS depression.
     • Phenobarbital:
       • Can suppress optimal neuronal discharges w/o causing sedation.
         • Inexpensive, long lasting, low incidence of adverse effects.
           • Several weeks may be needed for optimal effects.
             • Sometimes preferred for neonatal seizures
     • Primidone (Mysoline)
       • Potentiates GABA action
         • Similar pharmacolgic profile to phenobarbital
     • Although not frequent, it can terminate status epilepticus
   • Benzodiazepines
     • Bind directly to GABA receptor
       • Indicated for absence and myoclonic seizures
     • Diazepam (Valium) and lorazepam (Ativan) are used to terminal status epilepticus.
       • Tolerance may develop. so dose needs to be readjusted
         • Generally used in conjunction w/other antiseizure drugs

3. Drugs that suppress sodium influx

   • Sodium channels are desensitized because complete blocking will cause death
   • Other drugs will affect threshold of neuronal firing, or may interfere w/transduction of glutamate
   • Hydantons & Related Durgs
     • Phenytoin (Dilantin)
       • Treats all types except absence seizures
         • Seizure suppression w/o abuse potential or CNS depression
           • Dosages highly indiidualized
             • Narrow range between therapeutic and toxic
     • Valproic acid (Depakene)
       • Preferred ftor absence & myoclonic seizures.
   • Phenytoin-Like Drugs
     • Carbamazepine (Tegretol)
       • Fewer adverse effects than other phenytoin-related drugs
         • Perferred for tonic-clonic and partial seizures
     • Oxcarbazepine (Oxtellar XR/Trilepral)
       • Derivative of carbamazepine, so treatment profile is similar
         • Slightly better tolerated, though serious skin & organ hypersensitivity have been seen,
     • Lamotrigine (Lamictal
       • First-line drugs for partial, absence, and tonic-clonic seizures
         • Also approved for bipolar
           • Duration of action affected by other drugs that change hepatic metabolism.
     • Levetiracetam (Keppra) & zonisamide (Zonegran)
       • Adjunctive therapy of partial seizures in adults
         • Levetiracetam is generally less reactive and has less adverse effects than other antiseizure
     • Valproic acid derivatives, lamotrigine, felbamate, topiramate, and rufinamide are used for Lennox-Gastaut syndrome.

4. Drugs that suppress calcium influx

   • Succinimides
     • Raise seizure threshold by delaying entry of calcium into ions
     • Ethosuximide (Zarontin)
       • Preferred choice for absence seizures
   • Amino Acid compounds
     • Suppress positive ion influxes differently from other antiseizure meds
       • Effective for paroxysmal and the psychopatholigic component of epilepsy.
     • Acetazolamide (Diamox) & lacosamide (Vimpat)
       • Restore ionic, and thus neurologic, imbalances similar to natural amino acids
         • Acetazolmide can treat absence and myoclonic seizures
           • Also used for glaucoma, altitude sickness, nausea, dizziness, drowsiness, and fatigue
             • Carbonic anhydrase inhibitor
         • Lacosamide is chemically r/t serine
           • Does not produce effects through voltage-gated sodium channels, but other membrane protein channels are involved
             • Used in combo w/other drugs to treat adult patients w/partial onset seizurs
     • Drawbacks include allergies, drowsiness, dizziness, irregular heartbeat. and coordination problems