P: Antiepileptic Drugs - Week 10 Flashcards
What proportion of the world’s population have epilepsy?
1%
Name 4 genes linked to epilepsy and state what type of receptor they are
KCNQ2 = K+ channel KCNQ3 = K+ channel CHRNA4 = Nicotinic ACh receptor SCN1B = Na+ channel subunit
What is the result of KCNQ2 activation? What about KCNQ3 activation?
both cause repolarization
What is the result of CHRNA4 activation?
reduced GABA release
What is the result of SCN1B activation?
slower inactivation
List 7 causes of seizures
Fever Brain tumour Trauma Abnormalities in CNS development Infection Stroke Hereditary
What does the term “precipitating factor” mean in regards to seizures?
A precipitating factor is one that lowers the overall threshold for excitation, therefore increasing the frequency of Action Potentials and therefore increase the likelihood of seizures
List 7 precipitating factors for seizures
Stress, anxiety Sleep deprivation/fatigue Hormonal changes associated with the menstrual cycle Certain medications Diabetes, blood sugar imbalances Neon or Xenon strobe-flashes Rapid motion
What instrument can you use to measure seizures?
Electroencephalograph (EEG)
What is the function of an EEG?
Measures potential difference between pairs of electrodes (electrical activity)
Does EEG measure the activity of singular neurons?
No, it instead measures groups of neurons in the cerebral cortex
How does the EEG differ between someone having a seizure and someone not having a seizure? (2)
The normal EEG is chaotic. During a seizure, the neurons become hyper-excitable and hyper-synchronised, so you see patterns emerge in the EEG
How can you classify seizures? (2)
- Focal (partial) seizures
2. Generalised seizures
How can you further classify focal seizures? (2) What is the main distinguishing factor between these 2 classifications? (1)
1a. Simple (no loss of consciousness)
1b. Complex (loss of conzciousness)
What sort of changes occur during a simple seizure? (5)
motor, sensory, autonomic, psychic, auras (e.g. feeling of deja-vu)
Describe how the neurons are affected in a focal seizure?
a focal seizure is a seizure that occurs in a discrete population of cortex neurons
Where do most of the changes in a complex seizure occur?
most changes arise from the temporal lobe (part of the brain that controls emotion, behavior, memory)
How can you further classify generalized seizures? (2)
Tonic-clonic (grand mal)
Absence (petit mal)
How is an absence seizure characterized on an EEG?
a 3Hz spike and wave EEG. The wave pattern is widespread.
To an outside observer, what is the difference in the appearance of a Tonic-clonic seizure vs an Absence siezure?
Tonic-clonic seizure: I’m pickle rick!!!! Reeee Reeee. Starts convulsing on floor demanding for szechuan sauce
Absence: Just kind of goes blank. Much more subtle. If in the middle of conversation will pick back up where they left off
How is a tonic-clonic seizure characterized on an EEG?
various phases with widespread excitation and syncrhony to them
How is a partial seizure characterized on an EEG?
Excitation happens only in specific cortical regions (2 in this example)
What are the treatment options for epilepsy? (4)
- Identify the underlying cause
- Avoid precepitants (behavioral modification)
- Antiepileptic drugs
- Surgery
What factor should you consider when trying to identify the underlying cause of epilepsy? (1)
Age
What factors should you consider when thinking about using anti-epileptic drugs? (4)
Does impact of seizure outweigh risk of treatment?
It is palliative rather than curative
It is effective in around 75% of patients, but there are measurable side effects
Consider polytherapy: 1/3rd of patients do not respond to a single antiepileptic
Why might side-effects be an issue when prescribing antiepileptic drugs? (1)
May cause issues with patient compliance
Name 1 way we can modify behavior to help treat epilepsy?
limit stress
Define palliative
relieving pain without dealing with the cause of the condition.
Why is drug treatment for epilepsy only considered a palliative treatment?
Because it does not modify the underlying brain structures underlying the epilepsy
When should we consider surgery for epilepsy?
When medication is not working (i.e. refractory to medication)
Where is the most common surgical resection for epilepsy?
the temporal lobe
What is the aim for antiepileptic drugs?
to inhibit abnormal neuronal discharge
Can a synapse be both excitatory and inhibitory?
No. It can be either but not both
Can a neurotransmitter be both excitatory and inhibitory?
Yes. Serotonin for instance is both excitatory and inhibitory
How does Phenytoin affect epilepsy?
limits excitatory nerve activation – which reduces excitatory input
How do Benzodiazepines affect epilepsy?
enhance GABA receptor activity – i.e. enhances inhibitory input
How can antiepileptic drugs inhibit neuronal discharge? (4)
- inhibit voltage-dependent Na+ channels
- inhibit voltage-dependent Ca2+ channels
- Enhance GABA action
Note: May have more than one mechanism
What is the first line treatment for focal seizures?
Carbamazepine
What is the first line treatment for tonic-clonic seizures?
Valproate
What is the first line treatment for absence seizures? (2)
ethosuximide, valproate
Describe the activation of voltage-gated Na+ channels (8)
- Resting state = channels closed
- Action potential initiated and propagated along axon
- A.P increases positivity, increasing m.p
- Na+ ion channels undergo conformational change when m.p increases over threshold
- Pore opens, allowing a massive influx of Na+ ions
- increased polarity of our membrane and A.P continues
- Na+ ion channel undergoes another conformational change and enters “inactive state”
- Membrane re-polarizes while channel is in inactive state
Name 2 drugs for the treatment of epilepsy that inhibit the voltage-dependent Na+ channel and describe how they do this
Carbamazepine and Phenytoin block the channel in the ‘inactive state’, keeping it in this ‘inactive state’ for a longer period of time such that the ion channel is no longer available to be opened
In what way are the drugs carbamazepine and phenytoin considered “use-dependent” in the treatment of epilepsy?
they only affect high frequency action potentials and not what occurs normally
Name 3 inhibitors of voltage-dependent Na+ channels for the treatment of epilepsy.
Carbamazepine
Lamotrigine
Phenytoin
What form of epilepsy does not respond effectively to voltage-gated Na+ channel inhibitors? (1)
Absence seizures
When treating a patient for epilepsy with phenytoin, in what circumstance can the plasma concentration of phenytoin change drastically? (1)
Can change drastically when the patient is given another drug which displaces phenytoin from the plasma binding proteins
How large is the therapeutic range for phenytoin?
is narrow
How do different patients respond to treatment with phenytoin? (2)
Different patients respond differently. Different doses may be required.
What is the role of T-type Ca2+ channels?
Thalamic relay neuronal firing (i.e. neuronal firing from the thalamus to the cortex)
What form of seizure is associated with abnormalities in T-type Ca2+ channels? (1) What type of EEG pattern does the T-type Ca2+ channel produce in this case? (1)
Absence seizures. The T-type Ca2+ channel generates the characteristic 3 Hz spike and wave pattern
When are T-type Ca2+ channels commonly active?
during sleep
Name 1 T-type Ca2+ channel antagonist
Ethosuximide
What is the effect of enhancing GABA activity on our likelihood to produce seizures? Explain
Enhanced GABA reduce our overall membrane potential, making it harder to reach the threshold for an action potential (thus less likely to have seizures)
What is the receptor for GABA that confers allosteric modulation in epilepsy treatment? Explain (2)
GABA-A receptor: It has multiple binding sites for other substances. These binding sites modulate the ability of this ion channel to open
Name 5 binding sites for the GABA-A receptor
Benzodiazepine site Barbiturate site GABA site Steroid site Picrotoxin site
What must be present for Benzodiazepines and Barbiturates to have any effect on the GABA-A receptor?
GABA
How does Tiagabine enhance GABA action?
Inhibits reuptake of GABA into the neuron by inhibiting the GAT-1 transporter
How does valproate enhance GABA action?
Inhibits (GABA-T and SSADH) the enzymes that breaks down GABA into succinic semialdehyde and then metabolites respectively
What does GABA-T stand for?
GABA transaminase
What does SSADH stand for?
Succinic semialdehyde dehydrogenase
How do Tiagabine and Vigbatrin effect the action of GABA? (2)
Tiagabine: enhances by inhibiting GABA reuptake
Vigabatrin: enhances by irreversibly inhibiting GABA transaminase
For what type of epilepsy are Tiagabine and Vigbatrin used for?
Only used for refractory epilepsy
List 3 effects of valproate
enhance GABA action
inhibit voltage gated sodium channels
inhibit t-type Ca2+ channels
List 4 effects of topiramate
enhance GABA action
inhibit voltage gated sodium channel
activates a hyperpolarizing potassium current
blocks AMPA receptors (glutamate receptors)
Name 5 general side effects of anti-epileptic drugs
sedation unsteadiness diplopia nausea increased fracture risk (phenytoin, carbamazepine, barbiturates, valproate)
What are 3 factors to consider when thinking about using anti-epileptic drugs in women
risk of congenital malformations (pregnancy)
enhanced metabolism of oral contraceptive
consider withdrawal if planned pregnancy (balance risk)
