10. Anti-epileptic drugs Flashcards
Epilepsy epidemiology?
0.5% of population
What is epilepsy?
Epilepsy is a continuing tendency to have seizures
Seizures are sudden discharges of abnormal electrical activity
Epileptic attack can be confused with…
Syncope attack (fainting)
Points to consider in the initial diagnosis of epilepsy before examination?
- History is most important, both from patient and witness.
- ? Aura/warning
- Abnormal movements
- Colour
- Position
- When?
- After effects?
What investigations are used in epilepsy diagnosis?
ECG
EEG
MRI
Difference epileptic classificaitons.
Partial, simple, complex
Generalised, primary or secondary
Presentation of a generalised seizures?
Absence Myoclonic Clonic Tonic Tonic-clonic Atonic
Features of simple partial seizure?
- Focal with minimal spread of abnormal discharge
* normal consciousness and awareness are maintained
Features of complex partial seizures?
Local onset, then spreads Impaired consciousness Clinical manifestations vary with site of origin and degree of spread – Presence and nature of aura – Automatisms – Other motor activity Temporal lobe epilepsy most commonq
Features of secondarily generalised seizures?
Begins focally, with or without focal neurological symptoms
Variable symmetry, intensity, and duration of tonic (stiffening)
and clonic (jerking) phases
Typical duration up to 1-2 minutes
Postictal confusion and somnolence
Which hemispheres are involved in generalised seizures>
Both
Success of epilepsy medications?
- Just under 60% of all people with epilepsy can become seizure free with drug therapy
- In another 20% the seizures can be drastically reduced
Deciding factors for when choosing an anti-epileptic drug?
**exam **
§ Seizure type Epilepsy syndrome Pharmacokinetic profile Interactions/other medical conditions Efficacy Expected adverse effects Cost
AED?
Anti-epileptic durg
What are the targets for AED?
- Increase inhibitory neurotransmitter system— GABA
- Decrease excitatory neurotransmitter system—glutamate
- Block voltage-gated inward positive currents— Na+ or Ca++
- Increase outward positive current—K+
Many AEDs pleiotropic—act via multiple mechanisms
The brain’s major excitatory neurotransmitter, which NT?
Glutamate
What are the two groups of glutamate receptor?
– Ionotropic—fast synaptic transmission • NMDA, AMPA, kainate
• Gated Ca++ and Gated Na+ channels
– Metabotropic—slow synaptic transmission
• Regulation of second messengers (cAMP and Inositol)
• Modulation of synaptic activity
Modulators of glutamate receptors by…
Glycine, polyamine sites, Zinc, redox site
What are the two groups of glutamate receptor?
- Ionotropic—fast synaptic transmission
• NMDA, AMPA, kainate
• Gated Ca++ and Gated Na+ channels - Metabotropic—slow synaptic transmission
• Regulation of second messengers (cAMP and Inositol)
• Modulation of synaptic activity
Which AEDs act primarily on Na+ channels
- Phenytoin, carbamazepine: Block voltage-dependent sodium channels at high firing frequences. Use dependent
- Oxcarbazepine: Block voltage-dependent sodium channels at high firing frequencies. Also effects K_ channels
- Zonisamide: Blocks voltage-dependent Na channels and T-type calcium channel
- Lamotrigine
What are the currently commonly used anti-epileptic drugs?
- Lamotrigine,
- Sodium Valproate,
- Carbamazepine,
- Oxcarbazepine,
- Levetiracetam,
- Topiramate.
Lamotrigine:
MoA?
Side effects?
MoA:
Na+ inhibiting channels
Side effects: Hypersensitivity reactions (esp skin rashes)
Sodium valproate:
MoA?
side effects?
MoA:
Increase in GABA content of the brain
Weak inhibition of GABA transaminase
Side effects: Hair loss Teratogenicity (embryo malaborption causative factor) Foetal syndrome Liver damage
Carbamazepine: relation to anti-depressants? Therapeutic use? Strong enzyme inducting agent, leads to... Side effects?
Relation to anti-depressants?
Tricyclic derivative
Therapeutic use?
Partial seizures
Trigeminal neuralgia
Strong enzyme inducting agent, leads to… drug interactions e.g. Contraceptive pill
Side effects? Sedation Ataxia Mental disturbances Water retention
Oxcarbazepine
- Use?
- MoA?
- Side effects?
Use:
Monotherapy
Add-on therapy in partial seizures
MoA:
- Augments K+ channels
- P450 induction
Side effects: Sedations
Note: Related to carbamazepine but less P450 induction and less toxic
Name 4 newer AEDs?
Levetiracetam
Topiramate
Tiagabine
Zonisamide
Action of levetiracetam?
Use?
Side effects?
Newer AED
MoA:
Inhibit precsynaptic Ca+ channels
Use:
- Analogue of piracetam, a drug used to improve cognitive function
- Used in partial and generalised seizures
- 2nd line in children
Psychiatric side effects
Action of topiramate?
Side effects?
Newer AED, unknown MoA
Side effects:
- Risk of teratogenesis
- Needs slow titration to avoid cognitive side effects (dizziness and confusion)
Which 3 older AED’s should be made aware of as they are still in use?
Phenytoin: Na+ blocker, requires close monitoring as 1st order kinetics, lots of drug interactions and side effects
Ethosuximide: Treated absence seizures in chidlren but may exacerbate other forms
Phenobarbitone: Side effect os osteoporosis
What is the NMDA receptor?
The NMDA receptor is very important for controlling synaptic plasticity and memory function.
The NMDAR is a specific type of ionotropic GLUTAMATE receptor.
NMDA receptor: “N-methyl-D-aspartate (NMDA)” binds selectively to it, and not to other glutamate receptors.
What is the role of benzodiapepines in epilepsy treatment?
E.g. Lorazapam and Diazepam
• Benzodiazepines used as first-line treatment for status epilepticus (delivered IV – fast acting)
• Sedating
Why is felbamate rarely used to treat epilepsy?
Risk of severe hypersensitivity reactions and aplastic anaemia
Why is vagabatrin rarely used to treat epilepsy?
Inhibiting GABA transaminase
Side effects: Drowsiness, behavioural/mood changes, retinal loss
Role of Gabapentin and Pregabalin (2nd generation derivative of gabapentin) as AEDs:
Act specifically…….
Use?
Bonus?
Act specifically on calcium channel subunits called a2d1.
Use: Add-on therapy for partial seizures and tonic-clonic seizures. Neuropathic pain
Bonus: Less sedating
Role of Gabapentin and Pregabalin (2nd generation derivative of gabapentin) as AEDs:
Act specifically…….
Use?
Bonus?
Act specifically on calcium channel subunits called a2d1.
Use: Add-on therapy for partial seizures and tonic-clonic seizures. Neuropathic pain
Bonus: Less sedating
1st and 2nd line treatment for Simple, Complex and Seconary generalised partial seizures?
1st line: Carbamazepine, Lamotrigine oxcarbazepine, Sodium valproate,
levetiracetam
2nd line: Valproic acid, lamotrigine, topiramate, (levetiracetam, zonisamide)
1st line treatment for primary generalised seizures (tonic-clonic, tonic, myoclonic, atonic)?
Valproic acid, lamotrigine, topiramate, (levetiracetam, zonisamide)
treatment for absence seizures (primary generalised)?
Ethosuximide
AEDs in children?
Little RCT evidence
VALPROATE still first line, consider foetal
abnormalities
• Lamotrigine, Levetiracetam increasingly being used
• Ethosuxamide for Primary generalised
What is status epilepticus?
More than 30 minutes of continuous seizure activity
Two or more sequential seizures spanning this period without full recovery between seizures
* Is a medical emergency*
Treatment of status epilepticus?
– Diazepam, lorazapam IV (fast, short acting)
– Followed by phenytoin, fosphenytoin, or phenobarbital (longer acting) when control is established
Baclofen: MoA? Administration? Use? Side effects? Epilepsy?
MoA: Selective agonist on GABA-receptors
Administration: Oral
Use: Spasticity associated with MS or spinal injury
Side effects: Drowsiness, motor inco-ordination, nausea
Epilepsy: NOT USED IN TREATMENT
