L1 Epilepsy Flashcards
Definition of epileptic seizures
Episodic high frequency discharges by a localised group of neurons in the brain
Symptoms of motor cortex seizure
Convulsions
Symptoms of seizure affecting hypothalamus
Peripheral autonomic effects
Symptoms of seizure in reticular formation
Loss of consciousness
Drug treatment is effective in what percentage of epileptic patients?
~70%
Epilepsy incidence
~0.5% of the general pop (1:200)
Cause of primary epilepsy
Idiopathic
Cause of secondary epilepsy
Result of brain damage, or a tumour acting on a particular brain region
Forms of epilepsy
- Partial seizures (focal): simple or complex
- Generalised seizures: absence or tonic-clonic
Difference between partial and generalised seizures
Partial seizures - discharge localised to one brain region and hemisphere
Generalised seizures - discharge involves both hemispheres and reticular system (consciousness affected)
What percentage of patients with partial seizures can sometimes experience a secondary generalised seizure?
~30%
Absence (petit mal) seizures are most common in __ and are characterised by __
children
staring spells
How is neurotransmission altered in epilepsy?
- increased excitatory neurotransmission
- decreased inhibitory neurotransmission
- repeated discharge (excitotoxicity)
Animal models of epilepsy
- Chemical: ICV Kainate injections (glutamate agonist)
- Physical: Kindling - repeated low intensity brain stimulation (electrodes)
Main aims of AEDs
- Reduce electrical excitability of excitatory neurons (glutamate)
- Increased inhibitory (GABA) neurotransmission
Main mechanisms of AEDs
- Use-dependent Na⁺ channel block
- Ca²⁺ channel inhibition
- Increase GABA-mediated neural inhibition
- Inhibit glutamatergic transmission
List Na⁺ channel blockers used to treat epilepsy
- Carbamazepine
- Oxcarbazepine
- Phenytoin
- Lamotrigine
- Zonisamide
Na⁺ channel blocker stabilises the receptor in its __ state
inactivated
Na⁺ channel blockers mainly affect neurons with __ frequency discharge
high
What is the most widely-used AED?
Carbamazepine
CBZ metabolism
- Epoxidation to CBZ-10,11-epoxide, hydrolysis to CBZ-10,11-trans-dihydrodiol
- Strong inducer of CYP450 enzymes
- Autoinducer of its own metabolism
CBZ increases metabolism of…
phenytoin, warfarin, oral contraceptives
CBZ half-life
30h for single dose, decreased to 15h on repeated dosing
CBZ side effects
- Neurological: drowsiness, dizziness, ataxia, cognitive & motor disturbances
- Hypersensitivity reactions (skin, liver)
Pro-drug analogue of CBZ
Oxcarbazepine
Advantage of oxcarbazepine over CBZ
- Less P450 induction, therefore less drug interactions
- Does not interact with warfarin, cimetidine, erythromycin
Why have CBZ and oxcarbazepine been used for neuropathic pain and schizophrenia?
because they also act as GABA receptor agonists
First-line treatment for partial and secondary generalised seizures
Phenytoin
Phenytoin MOA
Na⁺ and Ca²⁺ channel inhibitor
Combination of phenytoin and __ is not recommended due to toxicity risk
valproate
Phenytoin is highly bound to __
plasma albumin (80-90%)
Why are drug interactions common with phenytoin?
because it’s metabolised by and induces CYP450 enzyme activity, which increases metabolism of CBZ, phenobarbital and valproate
Phenytoin side effects
- Plasma conc. >100µM: vertigo, ataxia, headache
- Plasma conc. >150µM: confusion, intellectual deterioration
- Hypersensitivity reactions (skin, liver)
- Gum hyperplasia
- Vit D def
- Teratogenesis
Safer pro-drug of phenytoin
Fosphenytoin
Sodium-blocking AED that also inhibits presynaptic depolarisation of glutamatergic neurons
Lamotrigine
Lamotrigine is usually combined with __
valproate
Why is Lamotrigine preferred in the elderly?
Low CNS toxicity
Can Lamotrigine be used in pregnancy?
Yes
Zonisamide MOA
- Inhibits both Na⁺ and Ca²⁺ channels
- Neuroprotective by free radical scavenging
- Metabolised by CYP450, then glucuronidation
Half-life of Zonisamide
60h, less when combined with phenytoin, CBZ or valproate
(well-tolerated, not prone to serious DDIs)
Low threshold __ Ca²⁺ channels implicated in periodic discharges of partial seizures
T-type
T-type Ca²⁺ channel blocker used to control absence seizures
Ethosuximide
What is gabapentin?
Pre-synaptic L-type Ca²⁺ channel inhibitor that binds α₂𝛿 subunit of Ca²⁺ channels in cerebral neocortex, hippocampus & SC to decrease release of glutamate and increase GABA levels (by stimulating GAD)
More potent pro-drug of gabapentin
Pregabalin
Valproate MOA
Increases GABA by stimulating glutamate decarboxylase and inhibiting GABA deaminase. Also weak block of Na⁺ and Ca²⁺ channels
Side effects of valproate
Hepatotoxicity, teratogenesis
How does vigabatrin increase GABA in the brain?
by irreversibly inhibiting GABA deaminase
What is tiagabine?
Lipophilic GABA analogue that irreversibly inhibits GAT-1 in neurons & glia to prevent GABA re-uptake, prolonging GABA effect at inhibitory synapses
Pharmacological agents that increase GABAa receptor response to reduce seizure duration
- Phenobarbital
- Benzodiazepines e.g. diazepam, lorazepam, clonazepam
What happens if you overdose on phenobarbital?
Severe respiratory and circulatory depression, coma
When are benzodiazepines used?
in emergency (status epilepticus) - IV admin, fast-acting
Felbamate MOA
NMDA glutamate receptor antagonist. Also weakly blocks Na⁺ and Ca²⁺ channels
Topiramate MOA
AMPA glutamate receptor antagonist. Also blocks Na⁺ channels, raises GABA levels, and weakly blocks carbonic anhydrase
__ channel blockers better in partial seizures
Na⁺
__ channel blockers better in generalised seizures
Ca²⁺
Carbonic anhydrase inhibitor that increases carbonic acid levels to increase seizure threshold
Acetazolamide
Progesterone is __-convulsant
anti (increases GABAa conductance, reduces glutamatergic excitation)
Oestrogen is __-convulsant
pro (reduces GABAa conductance)
What is Dravet syndrome?
Severe myoclonic epilepsy of infancy (SMEI)
What is cannabidiol?
- CBD: non-psychoactive component of cannabis plant
- Oil extracted from a plant high in CBD & low in THC
- Can help in MS, Dravet syndrome, chemo-induced nausea or loss-of-appetite
