Antiepileptics Flashcards
Nature and Mechanisms of Seizures
Experimental data shows that:
• Antagonists of the GABAA receptor trigger seizures.
• Agonists of glutamate receptors trigger seizures.
• Drugs that enhance GABAergic transmission inhibit seizures.
• Glutamate receptor antagonists inhibit seizures.
The principal mechanisms of action of antiseizure drugs involve:
- Blockade of Voltage-Gated Ion Channels
* Modulation of Synaptic Transmission (newer drugs)
Drugs that Block Voltage-Gated Ion Channels
- Drugs that block Voltage-Gated Na+ channels - block AP
• Phenytoin
• Carbamazepine
• Lamotrigine
• Zonisamide
- may contribute to effects of: Phenobarbital, Valproate, Topiramate - Drugs that block T-type Ca2+ channels
DOC used to tx Absence seizures?
MOA?
Ethosuximide and valproate
• The T-type Ca2+ current governs oscillatory responses in thalamic neurons.
• If tonic-clonic seizures are present valproate is the drug of choice.
• Valproate is also preferred for atypical absence seizures.
• Lamotrigine is probably effective.
Drugs that Affect Synaptic Transmission
- Drugs that enhance GABAergic neurotransmission
- Direct action on the GABA receptor
• Benzodiazepines
• Barbiturates
• Topiramate
Presynaptically:
• Inhibition of the reuptake of GABA: Tiagabine.
• Inhibition of degradation of GABA: Vigabatrin inhibits GABA aminotransferase
Postsynaptically:
• Phenobarbital & topiramate block glutamate receptors.
2
Drugs that Affect Synaptic Transmission
- Drugs that reduce glutamatergic neurotransmission
Presynaptically:
• Gabapentin and pregabalin decrease glutamate release by blocking presynaptic voltage-gated Ca2+ channels.
• Levetiracetam binds to synaptic vesicle glycoprotein 2A (SV2A). This may affect release of glutamate and GABA.
Choice of Drugs for the Therapy of the Epilepsies
- Partial and Secondarily Generalized Tonic-Clonic Seizures
- Carbamazepine
- Oxcarbazepine
- Levetiracetam
- Zonisamide
- Phenytoin
- Valproate
- Lamotrigine
- Topiramate
- Phenobarbital
Generalized Seizures
Tonic-Clonic Seizures
• Main drugs used include:
- Carbamazepine
- Oxcarbazepine
- Valproate
- Lamotrigine
- Phenytoin
- Topiramate
Myoclonic Seizures DOC
- Valproate is the drug of choice.
- Topiramate is also used.
- Levetiracetam is approved for adjunctive therapy.
Atonic Seizures
- Atonic seizures are often refractory to all drugs.
* Valproate and lamotrigine may be beneficial
status Epilepticus managment algorythm
IV lorazepam-(seizure continues)->IV Phenytoin or Fosphenytoin-(s.c.)->IV phenobarbital-(s.c.)->General anesthesia w/ IV midazolam, propofol or barbs.
Drugs induced seizures tx?
controlled with diazepam, lorazepam or phenobarbital.
Breakthrough seizures tx?
Diazepam rectal gel is approved for breakthrough seizures.
AE: Induce cytochrome P450
• Carbamazepine
• Phenobarbital
• Phenytoin
Oxcarbazepine is a weak P450 inducer
Valproate AE
- Hepatotoxicity.
- Inhibits cytochrome P450.
- Inhibits metabolism of several drugs.
- Inhibits its own metabolism.
Phenytoin AE
- Diplopia, ataxia.
- Gingival hyperplasia.**
- Coarsening of facial features in children.
- Hirsutism.
- Rash. Stevens-Johnson Syndrome.
- Zero order kinetics of elimination.
Carbamazepine AE
- Aplastic anemia, agranulocytosis.
* Rash. Stevens-Johnson syndrome
What drug has a BB warning for Rash and SJS
Lamotrigine
Phenobarbtal similar to Primidone AE
- Sedation, drowsiness.
- Rash. Stevens-Johnson syndrome.
- Tolerance, dependence.
- Cognitive impairment, hyperactivity.
- P450 inducer.
What drugs causes Visual field loss as AE
Vigabatrin
Felbamate AE:
- Aplastic anemia
- Hepatotoxicity
- For refractory epilepsy
Discontinuing Antiepileptic Therapy:
- If a patient is seizure-free for 3-5 years discontinuation is warranted.
- Discontinuation should be slow.
- Benzodiazepines and barbiturates should be discontinued very gradually to avoid withdrawal seizures.
- If the patient is on combination therapy, drugs should be withdrawn one at a time.
Overdose Toxicity
- Antiseizure drugs are rarely lethal.
- The most dangerous effect after large overdoses is respiratory depression.
- Treatment is supportive.
- Stimulants should not be used.
Rash and SJS high risk drugs:
- Phenytoin
- Lamotrigine
- Carbamazepine
- Phenobarbital
Other Uses of Antiseizure Drugs:
- Carbamazepine: Neuropathic pain; bipolar disorder.
- Gabapentin: Neuropathic pain.
- Lamotrigine: Bipolar Disorder.
- Pregabalin: Neuropathic pain.
- Topiramate: Migraine.
- Valproate: Bipolar disorder; migraine.
- Primidone: First line for essential tremor (propranolol is also first line).
Nonpharmacologic Approaches
Ketogenic diet
Vagus nerve stimulation
Antiepileptic Drugs and Pregnancy
- Teratogenicity
* Newborn Hemorrhagic Disease
Neuropathic pain tx:
Carbamazepine (also tx. Bipolar disorder)
Gabapentin
Pregabalin
Bipolar disorder tx
Carbamazepine (also neuropathic pain)
Lamotrigine
Valproate (also migraine)
Migraine tx
Topiramate
First lines for essential tremor
Primidone
propranolol
