Therapeutics: Anti-Epileptics
Our favourite pharmacist Kunal Gohil rejoins the podcast to take us through anti-epileptic medications!
Epilepsy is a neurological condition where abnormal electrical brain activity causes uncontrolled movements, behaviour and sometimes loss of awareness. It affects around 600,000 people in the UK. This means that almost 1 in 100 people in the UK have epilepsy. Around 87 people are diagnosed with epilepsy in the UK every day.
In the UK every year about 1000 people die due to epilepsy. One cause is status epilepticus. Status epilepticus describes a seizure which lasts longer than 5 minutes or recurrent seizures without recovery between them. Sometimes there is no clear cause and this is called sudden unexplained death in epilepsy (SUDEP).
Epilepsy causes unprovoked seizures. Provoked seizures are caused by space occupying lesions, infections or electrolyte abnormalities.
Pharmacology
Excitatory neurones (the accelerator) cause a positive charge in the post-synaptic neurone through sodium influx while inhibitory neurones (the brake) cause a negative charge through chloride influx.
The basis of epilepsy treatment is therefore either to reduce the accelerator or increase the brake.
The three mechanisms of treatment
Modulate Ion Influx
These drugs block the action of ion channels either on the pre-synaptic or post-synaptic neurone.
Sodium valproate, lamotrigine, carbamazepine and phenytoin block pre-synaptic sodium channels.
Lamotrigine, Pregabalin and Gabapentin block calcium channels on the pre-synaptic neurone.
Type 2 calcium channels are on the post-synaptic membrane; these are blocked by sodium valproate.
GABA Propagation
This is all about increasing inhibition by reducing membrane positivity and reducing the propagation of action potentials. Chloride channels have a benzodiazepine and barbiturate receptor so these drugs can be used. This is the basis of treatment for status epilepticus.
Novel Mechanism
Levetiracetam doesn’t work on ion channels or affect GABA. It works by stopping the release of glutamate from vesicles and so reduces NDMA action and so reduces transmission.
Sodium Valproate (Epilim)
Works on sodium and calcium channels and does have some action on GABA receptors. First line in generalised, partial and absence seizures. Also used in status epilepticus refractory to benzodiazepines.
Teratogenic; can cause spina bifia. In female patients of childbearing potential need to be on pregnancy prevention.
Can cause acute pancreatitis, hepatitis, blood dyscrasia and hyperammonemia.
Phenytoin (Epanutin)
One of oldest anti-epileptics. Non-specific for cardiac sodium channels and so can cause arrhythmia and so needs monitoring.
Very narrow therapeutic index with saturation kinetics. Enzyme inhibitor. Albumin bound. Causes gingival hyperplasia.
Doses differ depending on administration.
Carbamazepine (Tegratol)
Useful in partial seizures but poor for absence seizures. Powerful enzyme inducer. Associated with Stevens-Johnson Syndrome especially in Korean/Japanese populations.
Levetiracetam (Keppra)
Good for partial seizures and second line in generalised. Now being used in status epilepticus. Was the focus of the EcLiPSE trial which we have previous podcasted about. Can also be given IV.
Lamotrigine (Lamictal)
Also associated with Stevens-Johnsons Syndrome but has a lower rate of adverse drug reactions if dose started low and gradually increased. Can only be given orally.
Clobazam/Clonazepam
Lorazepam, Midazolam and Diazepam are reserved for rescue use in status. Clobazam and Clonazepam are safer for longer term temporary use.
Kunal also emphasised how important the brand of Anti-Epileptic is. In January 2014, the Medicines and Healthcare products Regulatory Authority (MHRA) issued guidance on the safe prescription of anti-epileptics and which brands can and can’t be substituted:
Category 1 Phenytoin, carbamazepine, phenobarbital and primidone. Specific measures are necessary to ensure consistent supply of a particular product. This means that individuals should not be switched between versions of these AEDs, but should always kept on the same version.
Category 2 Sodium valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine acetate, topiramate and zonisamide. The need for continued supply of a particular product should be based on ‘clinical judgement’ (the doctors judgement of the risk of problems) and in consultation with the individual.This means that a doctor should decide, with the individual, whether it is important to always stay on the same version or whether it is ok to switch between different versions.
Category 3 Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide and vigabatrin. No specific measures are normally required and these AEDs can be prescribed generically.This means that individuals can be switched between different versions of their AEDs.
Kunal recommended the Epilepsy Society website
You can find our episode on Seizures here
The NICE Guidelines for Epilepsy diagnosis and management can be found here
Here is the Take Visually for this episode: