Anticonvulsants Flashcards
What is epilepsy?
- A neurological condition causing frequent seizures
- Seizures are “sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex”
Prevelance and Incidence of Epilepsy
- Prevalence between 2-7% of the population
- Incidence increased over the last 30-40 years
Diagnosis of Epilepsy
- Brain activity can be measured using:
- Electroencephalography (EEG)
- Magnetic resonance imaging (MRI)
Seizure types & Symptoms
General
- Tonic-clonic seizures: loss of consciousness -> muscle stiffening -> jerking/twitching -> deep sleep -> wakes up
- Absence seizures: brief staring episodes with behavioural arrest
- Tonic/atonic seizures: sudden muscle stiffening/sudden loss of muscle control
- Myoclonic seizures: sudden, brief muscle contractions
- Status epilepticus: > 5 min of continuous seizure activity
Focal/Partial
a) Simple: retained awareness/consciousness
b) Complex: impaired awareness/consciousness
General seizures
Begins simultaneously in both hemispheres of brain
-> 5 types
Epilepsy for more than 5 minutes
- Status epilepticus
- most dangerous type of seizure
- can be any type of seizure
Partial/focal seizures
Begins within a particular area of brain and may spread out
Glutaminergic synapse: Neurotransmission
- Voltage-gated Na+ channel (VGSC) opens membrane depolarisation
- Voltage-gated K+ channel (VGKC) opens membrane repolarisation
- Ca2+ influx through voltage-gated calcium channels (VGCCs) -> vesicle exocytosis
a) Synaptic vesicle associated (SV2A) protein allows vesicle attachment to presynaptic membrane - Glutamate activates excitatory post-synaptic receptors (e.g. NMDA, AMPA & kainate receptors)
Name voltage gated Na+ channel blockers
Carbamazepine
Lamotrigine
Carbamazepine
Pharmacodynamics
- Stabilises inactive state of Na+ channel -> reducing neuronal activity
- doensn’t close the pore itself, just stabilises inactive state.
Pharmacokinetics
- Enzyme inducer
- lots of drug-drug interactions
- Onset of activity within 1 hour
- 16-30 hour half-life
Indications
- Tonic-clonic seizures; partial seizures
NB: potential severe side-effects (Steven Johnson Syndrome and TEN -> skin complications in individuals with HLA-B*1502 allele
Lamotrigine
Pharmacodynamics
- Inactivates Na+ channels -> reducing glutamate neuronal activity
Pharmacokinetics
- Onset of activity within 1 hour
- 24-34 hour half-life
Indications
- Tonic-clonic seizures; absence seizures
tends to be a better drug than carbamazepine, but also more expesive
Voltage-gated ion channels blockers
e.g. Ethosuximide
Pharmacodynamics
- T-type Ca2+ channel antagonist -> reduces activity in relay thalamic neurones
Pharmacokinetics
- Long half-life (50 hours)
Indications
- Absence seizures
Ethosuximide
Pharmacodynamics
- T-type Ca2+ channel antagonist -> reduces activity in relay thalamic neurones
Pharmacokinetics
- Long half-life (50 hours)
- reasonably fast onset of action
Indications
- Absence seizures
Name drugs targeting glutamate exocytosis and receptors
Levetiracetam
Topiramate
Name drugs targeting glutamate exocytosis and receptors
Levetiracetam
Topiramate
Levetiracetam
Pharmacodynamics
- Binds to synaptic vesicle associated protein (SV2A) -> preventing glutamate release
Pharmacokinetics
- Fast-onset (1 hour)
- half-life (10 hours)
Indications
- Myoclonic seizures
Topiramate
Pharmacodynamics
- Inhibits NMDA & kainate receptors
- Also affects VGSCs & GABA receptors
- > multiple targets
Pharmacokinetics
- Fast-onset (1 hour)
- long half-life (20 hours)
Indications
- Myoclonic seizures
- also used in treatment of some types of neuropathic pain
Glutaminergic synapse neurotransmission
- VGSC -> depolarisation
- VGKC -> repolarisation
- Ca2+ influx through VGCCs -> vesicle exocytosis
- SVA2 allows vesicle attachment to membrane
- Glutamate activates excitatory post synaptic receptor
Drugs acting on the glutaminergic synapse
- VGSC antagonist: e.g Carbamazepine, Phenytoin, Lamotrigine
- VGCC antagonist: Ethosuximide (T-type antagonist);
- SV2A inhibitor: Levetiracetam
- Glutamate receptor antagonist: Topiramate
=> correlates to transmission at. the glutaminergic synapse
=> prevent too much excitation
GABAergic Synapse neurotransmission
- GABA can be released tonically & also following neuronal stimulation
- GABA activates inhibitory post-synaptic GABAA receptors
- GABAA receptors are chloride (Cl-) channels membrane hyperpolarisation
- GABA is taken up by GAT & metabolised by GABA transaminase (GABA-T)
NT secreted most is the brain?
GABA
Diazepam
Pharmacodynamics
- GABA receptor, PAM increases GABA-mediated inhibition
Pharmacokinetics
- Rectal gel - Fast-onset (within 15 min) -> this is very important
- half-life (2 hours)
Indications
- Status epilepticus
What is he only drug that is effective in status epilepticus?
Diazepam
Sodium Valproate
Pharmacodynamics
- Inhibits GABA transaminase -> increases GABA-mediated inhibition
Pharmacokinetics
- Fast onset (1h)
- half-life (12h)
Indications
- Indicated for ALL forms of epilepsy
Which drugs are licensed for tonic-clonic seizures?
Carbamazepine
Lamotrigine
Valproate
Tonic/Atonic seizures - which drug?
Valproate
Which drugs are licensed/used for status epilepticus?
Diazepam
Characteristics of anti-convulsants
- fast onset of action
- long duration of action
What is valproate used for?
Every type of seizure
Which drug can be used for any type of seizure?
valproate
Which drug is used for absence seizures?
Ethosuximide
Lamotrigine
Sodium Valproate
Which drugs are used for partial seizures?
Carbamazepine
Lamotrigine
Levetiracetam
Valproate
Which drugs are used for myoclonic seizures?
Levetiracetam
Topiramate
Valproate
LO2: Anti-convulsants: recognise that anti-convulsant therapy is determined by the seizure type coupled with pharmacodynamics/pharmacokinetic properties of specific anti-convulsant drugs
- Inhibition of VGSCs (e.g. Carbamazepine, lamotrigine) – Tonic-clonic, partial
- Inhibition of VGCCs (e.g. Ethosuximide) – Absence
- Inhibit vesicular release (e.g. Levetiracetam) – Myoclonic
- Inhibit glutamate receptors (e.g. Topiramate) – Myoclonic
- Enhance GABA channel activity (e.g. Diazepam) – status epilepticus
- Inhibit GABA metabolism (e.g. Valproate) – all types
LO1: Seizures
- Tonic-clonic seizures: loss of consciousness -> muscle stiffening -> jerking/twitching -> deep sleep -> wakes up
- Absence seizures: brief staring episodes with behavioural arrest
- Tonic/atonic seizures: sudden muscle stiffening/sudden loss of muscle control
- Myoclonic seizures: sudden, brief muscle contractions
- Status epilepticus: > 5 min of continuous seizure activity
- Simple partial: retained awareness/consciousness
- Complex partial: impaired awareness/consciousness
