Anticonvulsants for Pharmacology and Therapeutics Flashcards
What is an epileptic seizure?
Seizures are “sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex”
Either too much glutamate or too little GABA
What is epilepsy?
A neurological condition causing frequent seizures
What are the two main types of epilepsy?
Partial/Focal – the excess discharge is localised to one area of the brain Generalised – the synchronised discharge affects all brain areas
When are the two peaks in incidence of epilepsy and what are they usually caused by?
Young adults – where genetic predispositions begin to manifest Later years – when patients start getting brain injuries e.g. stroke
What are the main mechanisms of anti-epileptic drugs?
Enhancing GABA-mediated inhibition Inhibiting glutamate-mediated excitation Na+ channel blockade (blocking nerve conduction) Calcium channel blockade
Give an example of a group of drugs that enhance GABA-mediated inhibition.
Benzodiazepines
What does Levatiracetam bind to in order to inhibit glutamate release?
SV2A
What are the 3 main excitatory receptors?
AMPA and Kainate (Na+/Ca2+ channel) NMDA
Describe the effects of important AEDs on hepatic enzymes.
Phenytoin and Carbamazepine – hepatic enzyme INDUCERS Valproate – hepatic enzyme INHIBITORS
What are the 2 ways of diagnosing epilepsy?
Electroencephalography (EEG) Magnetic resonance imaging (MRI)
What are the different types of general seizure?
Tonic-clonic Absence Tonic/atonic Myoclonic Status epilepticus
What are the features of a tonic clonic seizure?
loss of consciousness -> muscle stiffening -> jerking/twitching -> deep sleep -> wakes up
What are the features of a absence seizures?
brief staring episodes with behavioural arrest can lead to loss of muscle tone and falling over
What are the features of a tonic/atonic seizures?
sudden muscle stiffening/sudden loss of muscle control
What are the features of a myoclonic seizures?
sudden, brief muscle contractions similar to tonic by less severe
What are the features of a status epilepticus?
> 5 min of continuous seizure activity Doesn’t necessarily manifest of any of the 4 but can have parts of each or just be one
Describe the types of focal seizure
Simple: retained awareness/consciousness Complex: impaired awareness/consciousness
How does the glutamatergic synapse work?
- 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
- Glutamate activates excitatory post-synaptic receptors
What receptors does glutamate act on at the post synaptic membrane?
NMDA, AMPA & kainate receptors
What protein allows vesicle attachment to the presynaptic terminal in glutamernergic synapses?
Synaptic vesicle associated (SV2A) protein
What are 2 drugs that act on VGSC?
Carbamazepine
Lamotrigine
What are the pharmacodynamics and pharmacokinetics of carbamazepine?
Pharmacodynamics
- Stabilises inactive state of Na+ channel
- Reduces neuronal activity
Pharmacokinetics
- Enzyme inducer
- Onset of activity within 1 hour
- 16-30 hour half-life
What are the potential consequences of carbamazepine treatment?
- Potential severe side-effects
- SJS & TEN - potentially fatal skin conditions
- in individuals with HLA-B*1502 allele
What are the pharmacodynamics and pharmacokinetics of lamotrigine?
Pharmacodynamics:
- Inactivates Na+ channels -> reducing glutamate neuronal activity
Pharmacokinetics:
- Onset of activity within 1 hour
- 24-34 hour half-life
What drug blocks VGCC?
Ethosuximide
What are the pharmacodynamics and pharmacokinetics of ethosuximide?
Pharmacodynamics
- T-type Ca2+ channel antagonist
- Reduces activity in relay thalamic neurones
Pharmacokinetics
- Long half-life (50 hours)
What drugs target glutamate exocytosis?
Levetricetam
What are the pharmacodynamics and pharmacokinetics of levetiracetam?
Pharmacodynamics
- Binds to synaptic vesicle associated protein (SV2A)
- Preventing glutamate release
Pharmacokinetics
- Fast-onset (1 hour); half-life (10 hours)
What drug targets glutamate receptors?
Topiramate
What are the pharmacodynamics and pharmacokinetics of topiramate?
Pharmacodynamics
- Inhibits NMDA & kainate receptors
- Also affects VGSCs & GABA receptors
Pharmacokinetics
- Fast-onset (1 hour); long half-life (20 hours
What is topiramate used for?
- Mainly neuropathic pain
- Also epilepsy
Summarise the sites of action for drugs effecting the Glutamatergic Synapse
- VGSC antagonist: e.g Carbamazepine
- VGCC antagonist: Ethosuximide (T-type antagonist);
- SV2A inhibitor: Levetiracetam
- Glutamate receptor antagonist: Topiramate
Describe the GABA synapse
- 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)
What epilepsy drugs target the GABA synapse?
- Diazepam
- Sodium valoprate
What are the pharmacodynamics and pharmacokinetics of diazepam?
Pharmacodynamics
- GABA receptor, PAM
- Increases GABA-mediated inhibition - positive allosteric action
Pharmacokinetics
- Rectal gel - Fast-onset (within 15 min); half-life (2 hours)
What are the pharmacodynamics and pharmacokinetics of sodium valporate?
Pharmacodynamics
- Inhibits GABA transaminase ® increases GABA-mediated inhibition
Pharmacokinetics
- Fast onset (1h); half-life (12h
What drugs should you use for the treatment of absence seizures?
- Ethosuximide
- Lamotrigine
- Valproate
What drugs should you use for the treatment of tonic clonic seizures?
- Carbamazepine
- Lamotrigine
- Valproate
What drugs should you use for the treatment of tonic/atonic seizures?
Sodium valporate
What drugs should you use for the treatment of myoclonic seizures?
- Levetiracetam
- Topiramate
- Valproate
What drugs should you use for the treatment of status epilepticus?
- Diazepam
What drugs should you use for the treatment of Focal seizures?
- Carbamazepine
- Levetiracetam
- Lamotrigine
- Valproate
