Lecture 15: Drugs used to Treat Seizure Disorders Flashcards
What are Seizures?
A transient alteration of behavior due to abnormally excessive and synchronous neuronal activity in the brain
What is Epilepsy?
A disorder of brain function characterized by the periodic and unpredictable occurrence of seizures
What does it mean for epilepsy to be symptomatic?
Occur due to a known even such as head trauma or cancer
What does it mean for epilepsy to be asymptomatic?
Generally due to poorly defined genetic factors but don’t really know the cause of the seizures
Do seizures need to be provoked by something?
Seizures can be provoked or unprovoked
With what synchronicity do neurons usually fire in the brain?
They usually fire asynchronously in normal conditions
What is the spread of electrical activity maintained by?
Changes in membrane potential following depolarization (refractory period) and surround inhibition
How is electrical activity insulated in the brain?
- By the refractory period of an action potential
* By surround inhibition
What is Surround Inhibition?
The physiological mechanism that focuses neuronal activity in the central nervous system
What are primary afferents?
Neurons that innervate the skin and any surface of our body
What happens if the receptive field of a neuron is stimulated?
It will produce more action potential than those on the periphery of the receptive field
What happens if the edge of a neuron’s receptive field is stimulated?
It will not produce as many action potentials of those that are stimulated in the center of the receptive field
What happens when a neuron in the receptive field synapses with the interneuron?
The interneuron creates action potentials but also activates GABAergic neurons which inhibits the neighboring neurons to quiet their neuronal activity
How does surround inhibition work?
The neuron that is stimulated inhibits action potentials in the surrounding neurons but activating GABAergic neurons
What are the three steps in seizures?
- Initiation
- Propagation
- Termination
What two events is seizure initiation characterized by?
- High frequency bursts of action potentials
* Hyper synchronization of neuronal population
Which receptors does high frequency stimulation recruit?
NMDA receptors
What flows through NMDA receptors?
Calcium
What are the two main classes of glutamate receptors?
- AMPA receptors
* NMDA receptors
What receptors drive the excitatory effect of glutamate initially?
AMPA receptors
How do AMPA receptors work?
Glutamate binds to the AMPA receptor causing it to open and sodium can flow into the cell causing membrane depolarization
Why are NMDA receptors usually inactive?
Because they have a magnesium block in them that blocks the flow of sodium even when glutamate binds to them
When are NMDA active?
When many AMPA receptors are active allow the magnesium block to dissociate
What ions are NMDA receptors permeable to?
Calcium and sodium
What is the sustained neuronal depolarization in seizures driven by?
Calcium influx through NMDA receptors
What is the propagation of bursting activity in the brain normally prevented by?
Hyperpolarization and surround inhibition
How can the barriers of surround inhibition and hyperpolarization be overcame?
- Increasing extracellular potassium
- Accumulation of calcium
- Activation of the NMDA receptor
What does increasing extracellular potassium do?
Blunts the hyperpolarizing outward potassium currents
What does increased accumulation of calcium do?
In the presynaptic terminals leads to enhanced neurotransmitter release
What does activation of the NMDA receptor do?
Causes more calcium influx and neuronal activation
What happens if the barriers of hyperpolarization and surround inhibition are overacame?
Then seizure activity is propagated through the brain
How do seizures generally resolve?
Spontaneously
The do the mechanisms that terminate a seizure involve?
- loss of ionic gradients
- depletion of ATP
- depletion of neurotransmitters (e.g. glutamate)
- activation of inhibitory circuits (GABA)
What is Status Epilepticus?
A seizure lasting longer than 5 minutes of having more than 1 seizure within a 5 minute period. This is life threatening
What is a postictal period?
The 5-30 minutes after a seizure that is characterized by drowsiness, confusion, depression/anxiety and sometime psychosis
Why does the Postictal period occur?
Because of abnormal electrical activity in the brain resetting
What do the different classification of seizures depend?
- Where in the brain they initiate
* How widely they propagate
What are the three types of seizure classes?
- Focal seizures
- Generalized seizures
- Nonconvulsive (absence) seizures
What do the diverse manifestations of Focal seizures depend on?
Where in the brain it originates
What is the difference between simple and complex Focal seizures?
Simple - Retain consciousness
Complex - Loss of consciousness
What is jerking activity like in Focal seizures?
Jerking activity may start in a specific muscle group and spread to surround muscle groups
What are Automatisms that are seen in Focal seizures?
Unusual activities that are not consciously created like smacking the lips
What is a Focal Seizure?
Abnormal electrical activity that occurs in a very precise part of the brain and doesn’t spread very far
What does the different behavioral manifestation of a Focal seizure indicate?
Where in the brain the seizure is occuring
What is Jacksonian March?
In focal seizures where the jerking activity may start in a certain muscle and spread to surrounding muscle groups
What are Generalized seizures?
Abnormal electrical activity that starts in one precise part of the brain but then migrates or propagates throughout the entire brain
What are the two types of Generalized Seizures?
Tonic-clonic and Myoclonic
How do generalized seizures effect conciousness?
They generally involve loss of consciousness and occur without warning
What are Tonic-clonic generalized seizures?
Sustained contractions (tonic) of muscles throughout the body followed by periods of alternating muscle contraction and relaxation (clonic)
What are Myoclonic generalized seizures?
A brief (~1s) shock like contraction of muscles that may be localized or generalized
What are the two types of Non-convulsive seizures?
Absence and atonic seizures
What are Absence seizures characterized by?
An abrupt onset of impaired consciousness
What are Atonic seizures characterized by?
A sudden loss of muscle strength
How is consciousness affected in atonic seizures?
Usually consciousness is maintained but a person may fall down
What are anti seizure drugs used for?
To prevent the occurrence of seizures in people with epilepsy
When are anti seizure drugs used to treat people without epilepsy?
When people have acute illnesses such as meningitis that may cause seizures
Can epilepsy be cured or prevented?
No
What do anti seizure drugs generally do?
- Enhance inhibitory (GABAergic) neurotransmission
* Diminish excitatory (glutamatergic) neurotransmission
How do antiseizure drugs enhance GABA or decrease glutamate?
- blocking ion conductance (Na, Ca and K)
- blocking neurotransmitter release
- inhibiting/activation the postsynaptic membrane
How do seizure medication effect GABA?
The bind to the GABAa receptor on the postsynaptic membrane
What kind of receptor is the GABAa receptor?
A ligand gated ion channel that allows chloride to flow into the cell hyperpolarize the membrane
What are the two antiseizure drugs that target the GABA system?
- Benzodiazepines
* Barbiturates
What do Benzodiazepines and Barbiturates do?
They enhance the activity of GABA by binding to an allosteric site
What is the difference between Benzos and Barbiturates at the GABA receptor?
Benzos have no effect on the GABA receptor in the absence of GABA while barbiturates can act as GABA agonists at higher concentrations
What kind of ligands are Benzos and barbiturates to GABAa receptors?
They are positive allosteric modulators
What is the difference in frequency of the GABAa channels that Benzodiazepines and Barbiturates act?
- Benzos increase frequency at which GABAa receptor opens
* Barbiturates increase the duration at which the GABAa receptor is open
What is the difference between Benzodiazepines and Barbiturates affect efficacy and potency?
Benzodiazepines increase Potency
Barbiturates increase Efficacy
Why is the risk of overdose higher for barbiturates?
Because it directly gates the GABA receptor
When is there an added risk when taking Benzodiazepines or Barbiturates?
When taken with other CNS depressants like alcohol or opioids
What does Vigabatrin do?
Inhibits GABA aminotransaminase (GABA-T) that is involved in the degradation of GABA
What does Tiagabine do?
Inhibits the GABA transporter (GAT-1 located in neurons and glia) which prolongs the action of the neurotransmitter
What does Carbamazepine do?
Blocks voltage gated sodium channels
How does Carbamazepine block voltage gated sodium channels?
By causing a conformational change of the inactivation gate after entering the cell
What is the Phobicity of Carbamazepine?
It is lipophilic so it enters the the cell
What is the rate of sodium channel blockers like carbamazepine dependant on?
The frequency of cell firing. A cell that fires more is blocked more
What does Gabapentin look like?
A GABA molecule covalently bound to a lipophilic cyclohexane ring
What does Gabapentin do?
Inhibits voltage gated calcium channels by binding to the alpha2delta subunit preventing glutamate neurotransmitter release
What kind of drug a Perampanel?
It is a non-competitive antagonist at the AMPA receptor
What does Perampanel do?
It blocks AMPA receptors so it blocks action potentials
What are the side effects of Perampanel?
- Behavioral changes
- Mood disorders
- Suicidal/homicidal ideation
Why is consideration of pharmacokinetic properties important for seizure medications?
Because the drugs are taken for long periods the need to prevent toxicity
What is the extraction ratio of anti-seizure drugs?
They have a low extraction ratio (can be long acting)
Why are antiseizure drugs very lipophilic?
Because they need to cross the BBB
