Epilepsy Tutorial Flashcards
The diagram above represents the inhibitory and excitatory input to a post-synaptic neuron in the temporal lobe. Identify each of the following and write it with the linked number in the box below:
AMPA receptor, GABA receptor, GABA reuptake transporter, GABA transaminase, GABA vesicle, glutamate vesicle, NMDA receptor, succinic semi-aldehyde, synaptic vesicle protein, voltage gated sodium channel, voltage gated calcium channel
- Voltage gated sodium channel
- Voltage gated calcium channel
- Synaptic vesicle protein
- Glutamate vesicle
- NMDA receptor, permeable to sodium and calcium
- AMPA receptor
- GABA receptor
- GABA vesicle
- GABA reuptake carrier
- GABA transaminase
- Succinic semi-aldehyde
There are four ‘classical’ drug target sites. Can you identify an example for each in the diagram above?
receptors, enzymes, ion channels, transport proteins
As a child, Farhat was treated with diazepam for febrile seizures. What is the drug target for diazepam and how would this help treat the seizures?
t 1) what is the drug target, 2) where precisely is the drug target and 3) what is the end result of the interaction between drug and target.
Drug target is the GABAA receptor (specifically the alpha subunit of the GABAA receptor). Drug target is located on the post-synaptic neurons in the temporal lobe (for complex partial, focal seizures) End result – Diazepam binds and increases the effectiveness of GABA activation of this receptor (it doesn’t activate the receptor itself). This leads to chloride ion influx (in the presence of GABA) which would hyperpolarize the temporal lobe neurone and decrease the effects observed in the abstract.
Six months later, Miss F returns to see the consultant neurologist. In the last six months, she has tried the following anti-epileptic drugs. Lamotrigine – which she stopped when she developed a rash and pregabalin – which she didn’t like taking because it made her feel nauseous. The neurologist prescribes a different anti-epileptic drug, levetiracetam, for her to try next.
The drug targets for lamotrigine and pregabalin are shown below. How would these drugs act at these targets to produce an anti-epileptic effect?
Lamotrigine – Voltage gated sodium channel
Pregabalin – Voltage gated calcium channel
Lamotrigine – target is the voltage gated sodium channel. Drug target is located on the glutamatergic neurones in the temporal lobe (for these focal seizures) Blocking the sodium channels reduces neuronal depolaristion which would eventually lead to neurotransmitter release. In this case, glutamate neurotransmission is decreased and there is less excitatory stimulation of the post-synaptic neurone.
Pregabalin – target is the voltage gated calcium channel (in reality, it binds to the alpha 2 delta subunit of the calcium channel i.e. it does not bind to all calcium channels, just the ones with this specific subunit). There is some evidence that this gives pregabalin a degree of selectivity for inhibition of glutamatergic (anticonvulsant) over GABAergic (convulsant action) neurons. Drug target is located on the glutamatergic neurones in the temporal lobe (for these focal seizures) Blocking the calcium channels prevents calcium influx into the neurone which is required to promote vesicle exocytosis and neurotransmitter release. In this case, glutamate neurotransmission is decreased and there is less excitatory stimulation of the post-synaptic neurone
Levetiracetam does not act at one of the classical drug targets. Can you identify the drug target for levetiracetam in the diagram above and explain how the anti-epileptic effect of this drug is produced? [Tip: it also works by reducing glutamate release]
Levetiracetam – target is the synaptic vesicle protein SV2A. Drug target is located with the presynaptic terminal of the glutamatergic neurones in the temporal lobe. This drug interferes with vesicle fusion and therefore reduces exocytosis of glutamate thus decreasing the excitatory activation of the post-synaptic neurone.
which are the two most commonly prescribed drugs to treat epilepsy?
lamotrigine and levetiracetam are the two most commonly prescribed drugs for epilepsy
How to diazepam, lamotrigine and pregabalin each work to treat epilepsy?
Drugs can activate or inhibit a target. Diazepam worked to enhance the GABA response, and due to the fact that it was enhancing an inhibitory effect meant that the post synaptic neurone was less stimulated. Lamotrigine/pregabalin worked to inhibit voltage gated ion channels and thus decreased an excitatory effect also meaning the post synaptic neurone was less stimulated.
Tiagabine and vigabatrin are two medications that can used as add-on (i.e. not first line) therapies for epilepsy. The drug targets for tiagabine and vigabatrin are shown below. How would these drugs act at these targets to produce an anti-epileptic effect?
Tiagabine – GABA reuptake transporter
Vigabatrin – GABA transaminase
Tiagabine: Drug target is the GABA reuptake transporter Drug target is located on the pre-synaptic terminal of the GABAergic neurone in the temporal lobe. End result – Tiagabine prevents GABA from leaving the synapse by blocking the GABA reuptake transporter - reuptake is the major mechanism for GABA removal. Hence GABA remains in the synapse for longer and can then bind to and activate the GABA receptor for a more prolonged period of time leading to greater Cl- influx and hyperpolarization.
Vigabatrin: Drug target is the GABA transaminase enzyme. Drug target is located within the pre-synaptic terminal of the GABAergic neurone in the temporal lobe. End result – A little more complex. Vigabatrin blocks the GABA transaminase enzyme which means GABA is not effectively metabolized in the pre-synaptic terminal (could also take place in glial cells). If GABA builds up in the presynaptic terminal, then there is less of a concentration gradient for GABA reuptake from the synapse. As a result, the reuptake process slows and GABA remains in the synapse for longer, with responses increased as described above.
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?
Valproate is a non-selective drug – it acts on multiple targets within the diagram above i.e. voltage gated sodium channels, GABA transaminase, voltage gated calcium channels, NMDA receptor blockade and even enhances the production of GABA. The biggest problem with non-selective drugs is the propensity for a larger number of side effects due to hitting so many targets. It is also teratogenic – hence its avoidance in females of childbearing age.
what do we look for when we are trying to prescribe a drug with low side effects?
- dose
- selectivity
what does teratogenic mean?
disrupts development of a growing foetus
