anti-epileptic drugs

Question 1

Describe different types of epilepsy

Answer 1

• partial
  
  • limited spread between lobes
• generalised seizures (involves both hemispheres of brain)
  - grand mal (tonic/clonic)
  - must be controlled
  - leads to neuronal death
  - lasts for minutes
  - petit mal (absence)
  - developed in childhood
  - specific ion channel
  - seconds
  
  • simple seizures (don’t include loss of consciousness)
  • complex seizures (include loss of consciousness)

Question 2

possible causes of epilepsy

Answer 2

genetics:
- GOF mutations in voltage gated sodium channels can cause familial epilepsy
- K channel mutations = LOF = decreased hyperpolarisation
- change in blood levels
- metabolism
- stress/fatigue
- abnormal high sensory input
- lesions/head injury
- CNS infection

Question 3

characteristics of epilepsy

Answer 3

• depend on location
• e.g motor cortex = convulsions
• e.g hypothalamus = uncontrolled sweating/salivation etc
• e.g reticular formation = loss of consciousness

Question 4

Describe animal models used to better understand the neurobiological basis of epilepsy and evaluate anti-convulsant drugs

Answer 4

• rodents and zebrafish
• chemical models
  
  • if penicillin is applied directly to brain = inhibits GABA receptors in brain ⇒ seizures
  • PTZ → water ⇒ seizures
  • Kainate = agonist of glut = seizures
• genetically modified animals carrying mutations

Question 5

describe anti-epileptics increasing GABA

Answer 5

benzodiazepines
- works directly at GABAa receptor
- after releasing GABA = taken back up = block uptake = more is released into post-synaptic neurone
- e.g diazepam
- e.g barbiturates

uptake inhibitors

metabolic inhibitors
- inhibit breakdown and increase synthesis of GABA
- vigabatrin
- issues = depression
- valproate
- issues = high protein binding, rarely hepatoxic, teratogenic

Question 6

structure and modus operandi of receptors for glutamate and GABA

Answer 6

• glutamate → GABA
• GABA → GABA transaminase/vigabatrin

Question 7

Identify the protein targets of common anticonvulsant drugs, describe their mechanism of action and clinical uses

Answer 7

• Na channel inhibitors
  
  • stabilise inactivated state of V gated Na channels so reduces no. channels available to respond
    = Phenytoin
    = Carbamazepine most widely used anti-epileptic
    = Lamotrigine
• 3-Ca2+ channel blockers
  
  • t-type Ca channels used for absence seizures
    = ethosuximide
  • 4-Ca channel trafficking
    = GABApentin, pregabalin (analgesics)
• GABAa receptor agonists
  
  • similar structure to Nic receptors (5 domains)

Question 8

Describe the main excitatory and inhibitory amino acid neurotransmitters of the central nervous system

Answer 8

GABA = inhibitory
Glutamate = excitatory

Question 9

diazepam

Answer 9

increases GABA transmission at receptor

Question 10

barbituates

Answer 10

increases GABA transmission at receptor

Question 11

valproate

Answer 11

increases transcription of enzymes used in GABA synthesis
= depression

Question 12

vigabatrin

Answer 12

suicide inhibitor of GABA transaminase
= prevents breakdown of GABA -> glutamate
= high protein binding, rarely hepatotoxic

Question 13

phenytoin

Answer 13

decreases sodium transmission at channel
= complex pharmacokinetics and issues

Question 14

carbamazepine

Answer 14

decreases sodium transmission at channel
= most common

Question 15

lamotrigan

Answer 15

decreases sodium transmission at channel
= dizziness, nausea

Question 16

GABApentin

Answer 16

decreases calcium transmission

Question 17

pregabalin

Answer 17

decreases calcium transmission

Question 18

gaba synthesis

Answer 18

glutamate -> glutamic acid oxylase -> GABA