Anti-epileptics

Question 1

How do voltage-gated sodium channel blockers work in epilepsy

Answer 1

Bind to internal face of sodium channel
Depolarisation of neurone increases proportion of sodium channels in inactivated state
Only bind when channel in inactivated state, so prevent neurone returning to resting state where could continue to depolarise the neurone

Act preferentially on neurones causing high frequency discharge (so don’t interfere with low frequency firing neurones in normal state)

Question 2

Name some examples of voltage gated sodium channel blockers used in epilepsy

Answer 2

Carbamazepine
Phenytoin
Lamotrigine

Question 3

Describe the action of Carbamazepine

Including uses, ADRs & DDIs

Answer 3

One of most widely used anti-epileptic
Strong inducer of CYP450
Affects on phase 1 metab so t1/2 reduces with repeated dosing
Used to treat generalised tonic-clonic & partial seizures

ADRs: CNS (e.g. Drowsiness), GI (e.g. Nausea and vomiting), CVS (e.g. Variation in BP)

DDIs: CYP inducing effects - reduces Phenytoin, Warfarin, corticosteroids, OCP
antidepressants interfere with its action

Question 4

Describe the action of phenytoin

Including uses, ADRs & DDIs

Answer 4

CYP indicer
non-linear PK @ therapeutic levels and linear @ subtherapeutic: needs monitoring
Used to treat generalised tonic-clonic & partial seizures

ADRs: CNS (e.g. Dizziness), gingival hyperplasia, hypersensitivity rashes

DDIs: competitive binding of valproate - increases plasma levels, increases cimetidine levels, reduces levels of OCP

Question 5

Describe the action of lamotrigine

Including uses, ADRs & DDIs

Answer 5

Linear PK
Doesnt induce CYP450 so less DDIs
Used to treat generalised tonic clonic, partial seizures & absence seizures

ADRs less marked: CNS (e.g. Dizziness, ataxia), nausea, skin rashes

DDIs: adjunct therapy with other AEDs & OCP reduce its plasma levels, valproate increases plasma levels due to competitive binding

Question 6

How do GABA enhancers work in epilepsy

Answer 6

GABA a main inhibitory neurotransmitter in the brain
Some Anti-epileptics enhance GABA receptor activation
Facilitates GABA-mediated opening of chloride ion channels
Causes inhibitory effect on neurones (increasing Cl current increases threshold for AP generation)

Question 7

What are the main GABA enhancers used in epilepsy

Answer 7

Valproate sodium

Benzodiazepines

Question 8

Describe the action of valproate sodium

Including what it is used for, ADRs, DDIs

Answer 8

Increasing GABA content in brain: stimulates GABA synthesising enzymes & inhibiting GABA inactivating enzymes
Used to treat partial & generalised seizures

Main ADRs less severe: CNS (e.g. Ataxia, tremor), hepatic (increased transaminases)

DDIs: adjunct therapy - antidepressants & antipsychotics antagonise action, aspirin competitively binds against it

Question 9

Describe the action of benzodiazepines

Including what its is used for, ADRs & DDIs

Answer 9

Act in distant receptor site of GABAa receptor channels
Also has positive allosteric effect: GABA & BZDs enhance one another

Used to treat status epilepticus & absence seizures

Wide range of ADRS: sedation, tolerance, confusion, impaired coordination, aggression, withdrawal seizures, resp and CNS depression

Question 10

What is the basic order of administration when prescribing anti-epileptics

Answer 10

Valproate sodium (first line for primary generalised seizures)
Carbamazepine (mainly for partial seizures)
Lamotrigine (for generalised and partial seizures)
Benzodiazepines or phenytoin (for acute status epilepticus)

Question 11

What is the best use of AEDs in pregnancy

Answer 11

Avoid valproate
Lamotrigine appears to be the safest
Also give folate & vitamin K supplements

Question 12

What are the 4 main classes of anti-epileptic drugs (based on their mechanism of action)

Answer 12

Enhancement of GABAa action
Inhibition of sodium channel function
Inhibition of calcium channel function
Inhibition of glutamate release