Epilepsy (tutorial) Flashcards
What is epilepsy?
Disorder of brain function - characterised by the periodic and unpredictable occurence if serizures
Repeated propensity to seizure activity
Just having one or two seizures does not mean epilepsy - must be recurrent for neurological examination to determine whether it is epilepsy or not
What are seizures?
What are the 2 broad categories of seizures?
A group of disorders
2 types:
- Partial seizures - focally - can identify the point (FOCUS) from where the abnormal activity arises e.g. motor cortex etc.
Simple (might arise in the motor cortex - localised motor activity, conscious during the seizure, lasts about a minute or 2), complex (focus = temporal lobe), secondarily generalised
- Generalised - involve both the hemispheres
tonic - clonic (starts from unconscious to rhythmic jerking - not a medical emergency, self limiting about 3 mins, usually a bit groggy after it), absence (more common in children of schooling age - impaired consciousness, look away, eyelid flicker 10-15 secs, then come back), myoclonic, atonic
What are the general features of epilepsy?
What are the causes?
What is the single common factor found in all patients with epilepsy?
How well can epilepsy be controlled and in what percentage of cases?
Cause often unknown - sometimes due to infection e.g. meningitis, tumours, head trauma
Single common factor - ‘Excessively synchronous or sustained discharge of a group od neurons in the brain’
Generally well controlled by the drugs:
In 50% of cases, well controlled, not many side effects (due to low doses being effective)
In 25% of cases, seizures can be controlled, but patient requires a few drugs / higher doses = more side effects e.g. ataxia, fatigue etc.
In 25% of cases, very difficult to control - space for development of more effective drugs / drugs with fewer side effects
Which neurotransmitter (NT) is responsible for Parkinson’s Disease?
What does the drug therapy for PD involve?
Lack of dopamine
Dopamine replacement therapy - i.e. drugs that administer dopamine to replace the levels
Normally what happens in the brain if glutamate is getting over-fired?
GABA controls this - counteracts the effect of glutamate
In epilepsy, GABA is lacking, cannot control the over activity of glutamate, which causes the rapid, uncontrolled firing of the neurons = seizure
Label the diagram with:
AMPA receptor, GABA receptor, GABA reuptake transporter, GABA transaminase, GABA vesicle, glutamate vesicle, NMDA receptor, succinic semi-aldehyde, synaptic vesicle protein, VG Na+ channel, VG Ca2+ channel
- VG Na+ channel
- VG Ca2+ channel
- Synaptic vesicle proteins
- Glutamate vesicle
- NMDA receptor
- AMPA receptor
- GABA (A) receptor (mediate inhibitory action of GABA)
- GABA vesicle
- GABA reuptake transporter
- GABA transaminase
- Succinic semialdehyde (first metabolate of GABA breakdown, once htis is produced, GABA is inactivated)
What are the 4 ‘classical’ drug target sites?
- Receptors - e.g. the GABA receptors, glutamate receptors
- Ion channels - bind to them to open / close them e.g. VG Ca2+ channels, VG Na+ channels
- Transporter proteins - e.g. GABA reuptake transporter
- Enzymes - e.g. GABA transaminase
Miss F was treated with diazepam for febrile seizures.
What type of drug is diazepam?
What is the drug target site?
Where is the drug working?
What is the end result?
Benzodiazepine
Target = GABAA receptor (diazepam binds to alpha subunit)
Location = post-synaptic neurons in the temporal lobe
End result = binds to and increases effectiveness of GABA at this receptor - enhanced Cl- influx = increased hyperpolarisation of the temporal lobe neruon = lowered activity of the post synaptic neuron
How do benzodiazepines work?
Benzodiazepines = positive allosteric modulators (PAMS) - binds to a diff site on the receptor, which changes the receptors shape to increase its affinity to bind to GABA
Benzodiazepines DO NOT bind directly to the site on the receptor GABA binds to
The drugs Lamotrigine and Pregabalin act to produce an anti-epileptic effect?
What are the drug target sites?
Where do the drugs work?
Lamotrigine:
VG Na+ channels in the glutamatergic neurons in the temporal lobe
Blocking Na+ channels so reduced neuronal depolarisation, reduced Glutamate release = reduced stimulation of the post synaptic neuron
Pregabalin:
VG Ca2+ channel (alpha-2-gamma subunits)
Glutamatergic neurons in the temporal lobe
Blocking Ca2+, reduced Ca2+ influx required for vesicle exocytosis, reduced glutamate released = reduced stimulation of post synaptic neuron
Levetiracetam does not act in one of the classical drug target sites
What is the target site for this drug?
How does it cause an anti-epileptic effect?
Target = synaptic vesicle protein (SV2A)
Location = presynaptic terminal of the glutamatergic neurons in the temporal lobe
Disrupts vesicle function for NT release - intereferes with vesicle fusion, reduces glutamate exocytosis = reduced activation of the post-synaptic neurons
What are the 2 most common epilepsy drugs used currently?
Lamotrigine and Levetiracetam
Tiagabine and vigabatrin are two medications that can used as add-on (i.e. not first line) therapies for epilepsy
What are the drug target sites?
Where and how do the drugs work?
Tiagabine:
Target = GABA reuptake transporters
Location = pre-synaptic GABAergic neurons in the temporal lobe
Tiagabine prevents GABA from leaving the synapse by blocking the GABA reuptake transporter, GABA remains in the synapse for longer so activates the GABA receptor for longer = greater Cl- influx and hyperpolarization
Vigabatrin:
Target = GABA transaminase enzyme
Target = pre-synaptic terminal of GABAergic neurons in the temporal lobe
GABA transaminase enzyme is blocked, which means GABA is not effectively metabolized in the pre-synaptic terminal = increase in conc. of GABA at the pre-synaptic terminal, smaller concentration gradient slows GABA reuptake so GABA remains on receptors longer = increase in Cl- entry in post-synaptic neuron and hyperpolarisation
The neurologist chose not to prescribe sodium valproate to Miss F since it is an anti-epileptic drug that should not be used in female patients with childbearing potential. Sodium valproate has low selectivity. What does this mean and what are the potential consequences of this?
Overlaps on many different target sites - multiple target sites i.e. voltage gated sodium channels, GABA transaminase, voltage gated calcium channels, NMDA receptor blockade and even enhances the production of GABA
More side effects
GABA neurons make up 30% of the neurons in the brain - enhancing GABA can lead to drowsiness, fatigue, impaired motor co-ordination etc.
Selectivity = dose related
Avoid prescribing to females of chldbearing age = teratogenic (fetal abnormalities)
