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Questions and Answers
What is the primary role of voltage-gated sodium channels in seizure activity?
What is the primary role of voltage-gated sodium channels in seizure activity?
Which antiseizure medication is considered the drug of choice for children with absence seizures?
Which antiseizure medication is considered the drug of choice for children with absence seizures?
How do most antiseizure medications exert their effect on abnormal electrical activity?
How do most antiseizure medications exert their effect on abnormal electrical activity?
Which mechanism is NOT associated with the action of GABA in controlling seizure activity?
Which mechanism is NOT associated with the action of GABA in controlling seizure activity?
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What is the definition of status epilepticus?
What is the definition of status epilepticus?
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Which statement accurately describes GABA?
Which statement accurately describes GABA?
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Which medication is primarily used to block high voltage calcium channels?
Which medication is primarily used to block high voltage calcium channels?
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What is a primary adverse effect of many antiseizure medications?
What is a primary adverse effect of many antiseizure medications?
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Which mechanism does levetiracetam utilize to exert its antiseizure effect?
Which mechanism does levetiracetam utilize to exert its antiseizure effect?
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What is an example of a negative psychotropic effect associated with certain antiseizure medications?
What is an example of a negative psychotropic effect associated with certain antiseizure medications?
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What are the main ions that glutamate receptors control to facilitate depolarization?
What are the main ions that glutamate receptors control to facilitate depolarization?
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Which of the following is NOT considered a common CNS adverse reaction of antiseizure medications?
Which of the following is NOT considered a common CNS adverse reaction of antiseizure medications?
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Which antiseizure medication is recommended for managing status epilepticus after lorazepam?
Which antiseizure medication is recommended for managing status epilepticus after lorazepam?
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What type of receptor does phenobarbital primarily activate?
What type of receptor does phenobarbital primarily activate?
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Which of the following antiseizure medications is associated with the highest risk of cognitive dysfunction?
Which of the following antiseizure medications is associated with the highest risk of cognitive dysfunction?
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Which group of receptors does glutamate primarily bind to in the central nervous system?
Which group of receptors does glutamate primarily bind to in the central nervous system?
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Study Notes
Pharmacological Treatment of Epilepsy
- Lecture objective: By the end of the lecture, students will be able to explain medications used for seizures and status epilepticus, describe the mechanism of action, therapeutic uses, adverse effects, and drug interactions of antiseizure medications (ASMs).
Status Epilepticus
- A seizure lasting longer than five minutes; normal mechanisms to terminate the seizure are not functioning.
- Life-threatening, needing emergency treatment.
Established and New Antiseizure Medications
- Established: Phenobarbital, Phenytoin, Ethosuximide, Carbamazepine, Sodium valproate, Clonazepam
- New: Lamotrigine, Gabapentin, Topiramate, Levetiracetam, Pregabalin
Mechanism of Action
- ASMs decrease abnormal electrical activity in the brain (CNS depressants) through various mechanisms:
- Blocking sodium channels
- Blocking calcium channels
- ↑GABA (gamma-aminobutyric acid)
- Glutamate modulation
- Some ASMs have more than one mechanism of action.
- Other mechanisms include modulation of synaptic proteins.
Blockage of Sodium Channels
- Voltage-gated sodium channels control the action potential by regulating the passage of sodium ions across neuronal membranes.
- Many antiseizure medications block sodium channels.
Blockage of Calcium Channels
- Voltage-dependent calcium channels (subtypes: high voltage and low voltage/T-type) are important for neurotransmitter release.
- High voltage calcium channels control calcium influx, governing neurotransmitter release across the synapse.
- Gabapentin and pregabalin block these channels.
- Low-voltage calcium channels (T-type): play a role in absence seizures. Ethosuximide blocks this channel, serving as a drug of choice for absence seizures in children.
GABA Potentiation
- GABA is the most important inhibitory neurotransmitter in the brain.
- Three types of GABA receptors exist (A, B, and C).
- GABA-A receptors are responsible for generating fast inhibitory postsynaptic potentials; controlling seizure activity via ligand-gated chloride channels. Activation of GABA-A receptors increases Cl⁻ influx, leading to hyperpolarization.
- Phenobarbital and benzodiazepines (e.g., clonazepam) activate GABA-A receptors.
- Other antiseizure drugs inhibit GABA aminotransferase or block GABA reuptake.
Glutamate Inhibition
- Glutamate is the main excitatory neurotransmitter in the CNS.
- Glutamate inotropic receptors (NMDA, AMPA, and Kainate) control calcium and sodium ions influx, causing depolarization.
- ASMs can inhibit these receptors.
Other Mechanisms
- Some ASMs modulate synaptic vesicle protein 2A, regulating neurotransmitter exocytosis (particularly glutamate).
- Levetiracetam selectively binds to synaptic vesicle protein 2A.
Status Epilepticus Management
- IV lorazepam (if IV unavailable, use IM midazolam or rectal diazepam). If seizure persists, proceed to IV infusion of fosphenytoin, valproic acid, or levetiracetam.
Other Indications of ASMs
- ASMs can have other indications beyond epilepsy treatment, including psychiatric disorders (e.g., bipolar disorder, anxiety), migraine headaches, and neuropathic pain.
Adverse Drug Reactions of ASMs
- Adverse effects are categorized into CNS symptoms, idiosyncratic reactions, chronic reactions, teratogenicity, and drug interactions.
CNS Adverse Reactions
- Common CNS adverse reactions: sedative effects (tiredness, drowsiness); coordination disturbances (dizziness, ataxia, tremor, diplopia); cognitive dysfunction (e.g., memory problems, word-finding difficulty, most prominent with topiramate); and psychiatric effects.
- Some ASMs have negative psychotropic effects (mood disorders, irritability, aggressiveness, psychosis).
- Some ASMs have positive psychotropic properties and can be used to treat psychiatric disorders (e.g., carbamazepine, valproate, lamotrigine, pregabalin, gabapentin).
Idiosyncratic Reactions
- Rare adverse reactions, specific to certain ASMs. Involve dermatological reactions (range from mild skin rash to severe reactions like Stevens-Johnson syndrome), hematological reactions (e.g., aplastic anemia), and hepatotoxicity.
Chronic Adverse Reactions
- Chronic adverse reactions include weight gain/loss, osteoporosis and reproductive dysfunction, hair loss, and chronic dysmorphic symptoms (e.g., phenytoin).
Teratogenicity
- ASMs can have adverse effects on developing fetuses (birth defects and other adverse effects).
- Valproate has the highest risk for causing birth defects.
- Lamotrigine and levetiracetam have the lowest risk for birth defects.
Drug Interactions
- Drug interactions are an important aspect of using ASMs.
- Valproate is an example of an enzyme inhibitor.
- Several ASMs are enzyme inducers.
- Some ASMs (such as levetiracetam) have no known potential for drug interactions.
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