Antiseizure Pharmacotherapy

General concepts
1. Depends on signs presented by patient
2. Low initial dose that is gradually increased until control is achieved or side effects prevent further increase.
3. Serum drug levels may be obtained
4. If seizures continue, a different medication is added in small dose increments while the dose of the first drug is slowly reduced.
5. Meds are discontinued over 6-12 weeks
6. Newer antiseizure meds exhibit fewer troublesome side effects
  1. Limited induction of drug-metabolizing enzymes
    1. Pharmacokinetic profile less complicated
  2. Generally well-tolerated
  3. Less of a health risk in pregnancy
7. Many of the popular drugs have found to double the risk of suicidal ideation in mentally ill patients
  1. Both newer and older drugs can cause this
8. Some antiseizure drug combos can increase incidence of seizures
9. Directed at controlling the movement of electrolytes across neuronal membranes or affecting neurotransmitter balance
10. Antagonism of the excitatory neurotransmitter glutamate.
  1. Glutamate works w/ Na+-K+ ATPase pump
    1. Blocking it indirectly prevents an influx of positive ions into cells
  2. Taurine can antagonize glutamate
    1. Stabilizes neuronal cell membranes by reducing glutamate-induce + ion influx
Drugs that potentiate GABA
1. Mimic effects of GABA by stimulating influx of chloride ions through GABA receptor channel
2. May enhance GABA release, block ruptake of GABA into nerve cells, or block GABA-degrading enzymes
3. These drugs are also used for depression, migraines, neuropathic pain, postherpetic neuralgia, dibromyalgia, spinal cord injury, anxiety and bipolar.
4. Barbiturates
  1. Intensifies effects of GABA in brain
    1. Works against all seizures except absence
    2. Low margin of safety, high potential for dependence, profound CNS depression.
  2. Phenobarbital:
    1. Can suppress optimal neuronal discharges w/o causing sedation.
      1. Inexpensive, long lasting, low incidence of adverse effects.
        Several weeks may be needed for optimal effects.
        Sometimes preferred for neonatal seizures
  3. Primidone (Mysoline)
    1. Potentiates GABA action
      1. Similar pharmacolgic profile to phenobarbital
  4. Although not frequent, it can terminate status epilepticus
5. Benzodiazepines
  1. Bind directly to GABA receptor
    1. Indicated for absence and myoclonic seizures
  2. Diazepam (Valium) and lorazepam (Ativan) are used to terminal status epilepticus.
    1. Tolerance may develop. so dose needs to be readjusted
      1. Generally used in conjunction w/other antiseizure drugs
Drugs that suppress sodium influx
1. Sodium channels are desensitized because complete blocking will cause death
2. Other drugs will affect threshold of neuronal firing, or may interfere w/transduction of glutamate
3. Hydantons & Related Durgs
  1. Phenytoin (Dilantin)
    1. Treats all types except absence seizures
      1. Seizure suppression w/o abuse potential or CNS depression
        Dosages highly indiidualized
        Narrow range between therapeutic and toxic
  2. Valproic acid (Depakene)
    1. Preferred ftor absence & myoclonic seizures.
4. Phenytoin-Like Drugs
  1. Carbamazepine (Tegretol)
    1. Fewer adverse effects than other phenytoin-related drugs
      1. Perferred for tonic-clonic and partial seizures
  2. Oxcarbazepine (Oxtellar XR/Trilepral)
    1. Derivative of carbamazepine, so treatment profile is similar
      1. Slightly better tolerated, though serious skin & organ hypersensitivity have been seen,
  3. Lamotrigine (Lamictal
    1. First-line drugs for partial, absence, and tonic-clonic seizures
      1. Also approved for bipolar
        Duration of action affected by other drugs that change hepatic metabolism.
  4. Levetiracetam (Keppra) & zonisamide (Zonegran)
    1. Adjunctive therapy of partial seizures in adults
      1. Levetiracetam is generally less reactive and has less adverse effects than other antiseizure
  5. Valproic acid derivatives, lamotrigine, felbamate, topiramate, and rufinamide are used for Lennox-Gastaut syndrome.
Drugs that suppress calcium influx
1. Succinimides
  1. Raise seizure threshold by delaying entry of calcium into ions
  2. Ethosuximide (Zarontin)
    1. Preferred choice for absence seizures
2. Amino Acid compounds
  1. Suppress positive ion influxes differently from other antiseizure meds
    1. Effective for paroxysmal and the psychopatholigic component of epilepsy.
  2. Acetazolamide (Diamox) & lacosamide (Vimpat)
    1. Restore ionic, and thus neurologic, imbalances similar to natural amino acids
      1. Acetazolmide can treat absence and myoclonic seizures
        Also used for glaucoma, altitude sickness, nausea, dizziness, drowsiness, and fatigue
        Carbonic anhydrase inhibitor
      2. 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
  3. Drawbacks include allergies, drowsiness, dizziness, irregular heartbeat. and coordination problems

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Antiseizure Pharmacotherapy

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