Anti-Convulsants Flashcards
Voltage-gated Ion Channels
Open and close in response to changes in __ ___.
Once open, these channels recognize and selectively conduct __ __
• These channels can close even while the membrane is still ___ –> inactivation.
These channels subserve a number of functions including the generation and propagation of ___ ___ and the gating of ___ entry into synaptic terminals.
The expression pattern of voltage-gated channels ___ extensively across brain regions
This results in widely varying___ properties across neuronal populations
Voltage-gated Ion Channels
Open and close in response to changes in membrane potential
Once open, these channels recognize and selectively conduct specific ions
• These channels can close even while the membrane is still open –> inactivation.
These channels subserve a number of functions including the generation and propagation of action potential and the gating of calcium entry into synaptic terminals.
The expression pattern of voltage-gated channels varies extensively across brain regions
This results in widely varying electrophysiological properties across neuronal populations
Ligand-gated ion channels can be ___ or ___depending on their ion selectivity
___ is the primary inhibitory neurotransmitter in the central nervous system and activates a class of ion channels called ___ receptors that mediate fast synaptic inhibition - ____
___ is the primary excitatory neurotransmitter in the central nervous system and activates three classes of ion channels (__, ___, ___) that mediate fast synaptic excitation - ____
Ligand-gated ion channels can be excitatory or inhibitory depending on their ion selectivity
• GABA is the primary inhibitory neurotransmitter in the central nervous system and activates a class of ion channels called GABA-A receptors that mediate fast synaptic inhibition - IPSPs
•glutamate is the primary excitatory neurotransmitter in the central nervous system and activates three classes of ion channels (AMPA, Kainate, NMDA) that mediate fast synaptic excitation - EPSPs
Neurons are excitable cells.
Neurons use___ signals to communicate
The distribution of ___- and____-gated ion channels varies between different populations of neurons and these channels influence neuronal firing properties
Neurons are excitable cells.
Neurons use electrical signals to communicate
The distribution of voltage- and ligand-gated ion channels varies between different populations of neurons and these channels influence neuronal firing properties
_____: the clinical manifestation of an abnormal and excessive excitation of a population of neurons.
_____: a tendency toward recurrent seizures that are not a result of systemic or neurological insults.
_____: sequence of events that converts a normal neuronal network into a hyperexcitable network.
Seizure: the clinical manifestation of an abnormal and excessive excitation of a population of neurons.
Epilepsy: a tendency toward recurrent seizures that are not a result of systemic or neurological insults.
Epileptogenesis: sequence of events that converts a normal neuronal network into a hyperexcitable network.
Seizure Classification:
Partial:
- 3.
Primary
- 2.
Seizure Classification:
Partial:
- simple
- complex
- secondarily generalized
Primary
- absence
- myoclonic
Partial Seizure:
•Abnormal electrical activity originating from a __ __ focus.
The seizure focus is a small collection of neurons that act as a trigger for __ __ (epileptiform activity).
There are many factors that can cause a __ __ (e.g. altered cellular properties or synaptic transmission).
The specific symptoms of a simple, partial seizure depend on the ___ of the seizure ___ (e.g. focus in motor cortex - finger twitch; focus in limbic region - unusual behavior or emotional state).
The development and progression of a partial seizure can be divided into discrete phases
- ____ (unusual feelings or sensations that may precede the actual seizure)
- _____ within the seizure focus (____ period). If the seizure will spread, this is where it will happen.
- ___ spread
- ____ generalization (typically lasts minutes)
- ___ period
A partial seizure is characterized by the sudden appearance of ___ ___ of __ groups of neurons within the seizure focus
Partial Seizure:
•Abnormal electrical activity originating from a defined seizure focus.
The seizure focus is a small collection of neurons that act as a trigger for enhanced excitability (epileptiform activity).
There are many factors that can cause a seizure focus (e.g. altered cellular properties or synaptic transmission).
The specific symptoms of a simple, partial seizure depend on the location of the seizure focus (e.g. focus in motor cortex - finger twitch; focus in limbic region - unusual behavior or emotional state).
The development and progression of a partial seizure can be divided into discrete phases
1. Aura (unusual feelings or sensations that may precede the actual seizure)
2. Synchronization within the seizure focus (Ictal period)
3. Seizure spread
4. Secondary generalization
5. Postictal period
A partial seizure is characterized by the sudden appearance of large depolarizations of small groups of neurons within the seizure focus
Explain this picture
If you take the normal cells, experimentally remove GABA-A receptors using a GABA-A antagonsist), instead of getting a nice rhythmic action potential, you get these busrts of ugly APs that normally would not be there if GABA is present.
Large fluctuations in the membrane potential are called Paroxysmal Depolarizing Shifts (PDSs)
The defining features of a PDS are:
a sudden, large, long-lasting depolarization. Our glutamate is doing more than it normally does. It is larger, and it is generating bursts of action potentials. This allows __ ___, and further depolarization. There is a period of inhibition (after hyperpolarization), but it is weakened.The size and duration of the after hyperpolarization is the most important factor that __ the spread of a seizure focus. When that starts to go away, then that is bad. It is not that there is no GABA, it’s because the glutamate is dominating.
Large fluctuations in the membrane potential are called Paroxysmal Depolarizing Shifts (PDSs
The defining features of a PDS are:
a sudden, large, long-lasting depolarization. Our glutamate is doing more than it normally does. It is larger, and it is generating a burst of action potentials. This allows calcium influx, and further depolarization. There is a period of inhibition (afterhyperpolarization), but it is weakened.The size and duration of the after hyperpolarization is the most important factor that limits the spread of a seizure focus. When that starts to go away, then that is bad. It is not that there is no GABA, it’s because the glutamate is dominating.
In most neuronal circuits, GABAergic inhibition exerts a powerful suppression of excitability –> ___ inhibition.
During the development of a focal seizure the ___ ___ is overcome, the ___ ___ in individual neurons gradually disappears and the seizure begins to spread beyond its original ___.
What causes this?
Collapse of GABAergic synaptic inhibition
Changes in ___ structure
Changes in voltage-gated ion channel density
Changes in the levels of ions like K+ and Ca2+.
Although much is known about the cellular mechanisms that cause the surround inhibition to break down, the specific physiological processes that cause a seizure to occur at any given moment are still not known.
In most neuronal circuits, GABAergic inhibition exerts a powerful suppression of excitability –> surround inhibition.
During the development of a focal seizure the surround inhibition is overcome (the GABA cannot suprress the glutamatergic activity), the after hyperpolarization in individual neurons gradually disappears and the seizure begins to spread beyond its original focus.
What causes this?
Collapse of GABAergic synaptic inhibition
Changes in dendritic structure
Changes in voltage-gated ion channel density
Changes in the levels of ions like K+ and Ca2+.
Although much is known about the cellular mechanisms that cause the surround inhibition to break down, the specific physiological processes that cause a seizure to occur at any given moment are still not known.
If activity in the seizure focus is sufficiently intense, the electrical activity ___ and begins to spread to ___ populations of neurons. As the seizure begins to spread, the patient may experience an ___.
Seizure activity can spread across the __ __ to involve the contralateral hemisphere. Once both hemispheres are involved, the seizure has become “____” generalized (Tonic-Clonic or Grand Mal Seizure). At this point, the patient often loses ____.
If activity in the seizure focus is sufficiently intense, the electrical activity synchronizes and begins to spread to neighboring populations of neurons. As the seizure begins to spread, the patient may experience an aura.
Seizure activity can spread across the corpus callosum to involve the contralateral hemisphere. Once both hemispheres are involved, the seizure has become “secondarily” generalized (Tonic-Clonic or Grand Mal Seizure). At this point, the patient often loses consciousness.
During the initial 30 seconds of a secondarily generalized seizure, neurons in the involved area undergo a prolonged ___
This is associated with the ___ phase of muscle contraction
As the seizure evolves, neurons begin to repolarize and the afterhyperpolariztions reappear - ___ phase
Tonic Phase
GABAergic inhibition fails and glutamatergic excitation dominates
Clonic Phase
GABAergic inhibition reappears and glutamatergic excitation is diminished
Following the tonic-clonic phase, there is often a period of decreased electrical activity. This is the post-ictal period (patient is confused or drowsy).
As dramatic as this event is, patients typically do not report any adverse events. They feel tired, weak, and after a few minutes they feel fine.
During the initial 30 seconds of a secondarily generalized seizure, neurons in the involved area undergo a prolonged depolarization
This is associated with the tonic phase of muscle contraction
As the seizure evolves, neurons begin to repolarize and the afterhyperpolariztions reappear - clonic phase
Tonic Phase
GABAergic inhibition fails and glutamatergic excitation dominates
Clonic Phase
GABAergic inhibition reappears and glutamatergic excitation is diminished
Following the tonic-clonic phase, there is often a period of decreased electrical activity. This is the post-ictal period (patient is confused or drowsy).
As dramatic as this event is, patients typically do not report any adverse events. They feel tired, weak, and after a few minutes they feel fine.
(PRIMARY) GENERALIZED SEIZURES
The defining feature of a generalized seizure is a sudden and simultaneous disruption of electrical activity in __ __. e.g. Absence seizure
The typical absence seizure begins suddenly, lasts __ to ___ seconds and produces loss of ___ and minor motor manifestations such as __ and __ smacking.
This period is closely associated with a ___ and __ EEG pattern that appears and disappears as suddenly as the clinical manifestations of the seizure.
Generalized seizures differ from partial or secondarily generalized seizures in that they are not preceded by an ___ and are often not followed by a __-__ period.
(PRIMARY) GENERALIZED SEIZURES
The defining feature of a generalized seizure is a sudden and simultaneous disruption of electrical activity in both hemishperes. e.g. Absence seizure
The typical absence seizure begins suddenly, lasts 10-30 seconds and produces loss of awareness and minor motor manifestations such as blinking and lip smacking.
This period is closely associated with a spike-and-wave EEG pattern that appears and disappears as suddenly as the clinical manifestations of the seizure.
Generalized seizures differ from partial or secondarily generalized seizures in that they are not preceded by an aura and are often not followed by a post-ictal period.
The postictal state is the altered state of consciousness after an epileptic seizure. It usually lasts between 5 and 30 minutes, but sometimes longer in the case of larger or more severe seizures, and is characterized by drowsiness, confusion, nausea, hypertension, headache or migraine, and other disorienting symptoms.
You have these loops between the cells in the thalamus and the cells in the cortex.
The thalamocortical connections that participate in the generation of sleep spindles are thought to be essential for the generation of primary generalized seizures.
The normal bursting properties of thalamic relay neurons are critical - involves ___-___ calcium channels in addition to ___ and ___ receptors.
T-type calcium channels activate and inactivate near the __ __ potential of thalamic relay neurons. In response to a very small depolarization, T-type channels can open (they are excitatory) so when they open they promote depolarization.
T-type calcium channels can be active at the normal ___ ___ potential BUT they inactivate quickly so they do not typically alter basal excitability.
… however this inactivation is relieved when the cells are hyperpolarized, priming the channels to ___ upon return to the normal resting membrane potential
This unique property makes these channels ideally suited to sustain ___ activity associated with __ __
The more you___. the more T channels you reset, and when you go back to resting membrane potential, you get more bursts.
The medication used to treat absence seizures ___ T-type channels
You have these loops between the cells in the thalamus and the cells in the cortex.
The thalamocortical connections that participate in the generation of sleep spindles are thought to be essential for the generation of primary generalized seizures.
The normal bursting properties of thalamic relay neurons are critical - involves T-type calcium channels in addition to GABA and glutamate receptors.
T-type calcium channels activate and inactivate near the resting membrane potential of thalamic relay neurons. In response to a very small depolarization, T-type channels can open (they are excitatory) so when they open they promote depolarization.
T-type calcium channels can be active at the normal resting membrane potential BUT they inactivate quickly so they do not typically alter basal excitability.
… however this inactivation is relieved when the cells are hyperpolarized, priming the channels to activate upon return to the normal resting membrane potential
This unique property makes these channels ideally suited to sustain bursting activity associated with generalized seizures
The more you hyperpolarize, the more T channels you reset, and when you go back to resting membrane potential, you get more bursts.
The medication used to treat absence seizures block T-type channels
Drug Treatment of Seizures:
Epilepsy is a chronic condition that usually requires long-term drug management.
The vast majority of antiepileptic drugs (AEDs) have been developed by screening large numbers of compounds against animal models of seizures.
Chemically induced seizures
Electroshock, Kindling
Genetically engineered mice
In spite of various potential molecular targets, AEDs ultimately must modulate the activity of the ___ channels that mediate neuronal __.
As a result, there will always be a balance between ____ the seizures and tolerating the CNS ___ effects of the drugs.
A considerable advance toward a rational treatment of epilepsy was the realization that not all AEDs are effective against __ types of epilepsy –> correct diagnosis of seizure type is critical for effective treatment
Drug Treatment of Seizures:
Epilepsy is a chronic condition that usually requires long-term drug management.
The vast majority of antiepileptic drugs (AEDs) have been developed by screening large numbers of compounds against animal models of seizures.
Chemically induced seizures
Electroshock, Kindling
Genetically engineered mice
In spite of various potential molecular targets, AEDs ultimately must modulate the activity of the ion channels that mediate neuronal excitability.
As a result, there will always be a balance between controlling the seizures and tolerating the CNS altering effects of the drugs.
•A considerable advance toward a rational treatment of epilepsy was the realization that not all AEDs are effective against all types of epilepsy –> correct diagnosis of seizure type is critical for effective treatment
GABAergic AEDs
Proven effective in the treatment of many types of seizures (__ __, __ ___, __ __ )
Not very effective in the treatment of ___ seizures
Not used much anymore because of ____ side effects
___ - the grand-daddy of all AEDs
Although unknown at the time, it is now well established that ____ (and all barbiturates) binds to __-__ receptors and potentiates the activity of these receptors.
The GABA-A receptor (GABA-AR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major ___ neurotransmitter in the central nervous system. Upon activation, the GABA-A receptor selectively conducts ___ through its pore, resulting in hyperpolarization of the neuron.
Although phenobarbital is no longer used, the GABAergic system has been an important target in the development of new treatments for seizures
GABAergic AEDs
Proven effective in the treatment of many types of seizures (simple complex, partial complex, secondarily generalized)
Not very effective in the treatment of absence seizures
Not used much anymore because of adverse side effects
phenobarbital - the grand-daddy of all AEDs
Although unknown at the time, it is now well established that phenobarbital (and all barbiturates) binds to GABA-A receptors and potentiates the activity of these receptors.
The GABA-A receptor (GABA-AR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABA-A receptor selectively conducts Cl- through its pore, resulting in hyperpolarization of the neuron.
Although phenobarbital is no longer used, the GABAergic system has been an important target in the development of new treatments for seizures
