Anti-epileptics Flashcards
Describe the goals of epilepsy therapy and ladder of treatment
Goal of therapy is
- Prevention of seizures and associated complications.
- Acute treatment of seizures including status epilepticus and febrile seizures
After FIRST seizure:
Start antiepileptic medication when the impact of further seizures outweighs the risks of treatment.
Lowest recurrence rates are associated with a normal EEG and no identifiable cause for seizures or when there is a clear avoidable precipitant (eg sleep deprivation, drugs)
After second seizure
- Treatment is usually indicated when 2 or more seizures
Treatment failure:Before changing drug treatment, check:
-
Compliance
- Therapeutic drug monitoring (drug concentration in blood) can be helpful. ^[ties into secondary learning objectives]
- Noncompliance is a common reason for treatment failure.
-
Dose:
- ensure dose of first-line drug is maximal with minimal adverse effects
Combination treatment:Exhaust all reasonable options for monotherapy before considering long-term treatment with >1drug.
- Evidence for the most appropriate combinations is lacking, a reasonable approach is to combine drugs with differing mechanisms of action.
- Reconsider the diagnosis if the person is apparently refractory to treatment.
- In people with uncontrolled seizures taking >1antiepileptic drug, simplifying and optimising the regimen may improve seizure control.
- An effective dose of 1antiepileptic is better than ineffective doses of 2or more antiepileptics.
Treatment withdrawal:This may be attempted after 2–3years without seizures. Good prognostic signs for remaining seizure-free at the time of withdrawal are
- a history of few seizures
- presence of absence seizures only
- younger age when seizure control achieved
- normal EEG
- normal neurological examination
- absence of brain lesions.
Describe the GABA enhancers
GABA enhancers
e.g. benzodiazepines (midazolam and clonazepam), barbiturates (phenobarbitone)
### Mechanism of action
May have varying modes of action but ultimately increase the activity of GABA
Benzodiazepines: (eg Midazolam, clonazepam) - 1st line for seizure termination in emergencies
- Bind to allosteric modulatory site on GABAA receptor (distinct from GABA binding site) ->increase the affinity of GABA to the receptor
- Main effects:
- reduced anxiety (alpha-2subunit activity) - eg diazepam, alprazolam
- induction of sleep (alpha-1subunit) eg temazepam
- anticonvulsant - (can be used in an emergency to terminate a seizure) eg midazolam, cloncazepam
Barbiturates: (eg Phenobarbitone,Primidone)
- Prolong inhibitory postsynaptic potential by increasing the mean chloride channel opening time and hence the duration of GABA-induced cell membrane hyperpolarisation
- Not routinely used in practice due to long half-life
Role in therapy
Benzodiazepines are first line therapies for seizure termination in emergencies.
### Side effects
- sedation
- respiratory depression
- dependence
- confusion
- anterograde amnesia
- reduced muscle tone
Precautions and contraindications
- Barbiturates are not routinely used due to long half life
Describe the broad MoA of sodium channel blockers
Mechanism of action
- Prevents repetitive neuronal discharge by blocking voltage-dependent and use-dependent sodium channels.
- Preferentiallyblock excitation of cells that fire repetitively
- Many of the sodium channel blockers have other (additional) mechanisms of action, and many aren’t entirely understood.
Describe sodium valproate MoA
Prevents repetitive neuronal discharge by blocking voltage‑ and use-dependent sodium channels. Other actions include enhancement of GABA(competitive inhibition prevents GABA reuptake by glial cells and axonal terminals), inhibition of glutamate and blockade of T-type calcium channels.
List phenytoin MoA
Blocks voltage and use dependent sodium channels
Describe carbamazepine MoA
Prevents repetitive
neuronal discharge by
blocking voltage- and
use-dependent sodium
channels
Describe topiramate MoA
- Stabilises presynaptic neuronal membranes by blocking voltage-dependent sodium channels. Enhances activity of GABA on postsynaptic chloride channels.
List the indications of sodium channel blockers- by type of channel blocker
- sodium valproate indicated in seizures — first line both for acute and chronic, bipolar disorder and migraine
- phenytoin indicated in seizures; sometimes used for status epilepticus but not often used chronically
- carbamazepine for chronic management; indicated in seizures, neuropathic pain, and bipolar or mania
- topiramate for chronic management; indicated in focal seizures, generalised tonic-clonic seizures, and migraine prevention
List the side effects of sodium channel blockers
- sodium valproate: drowsiness, tremors, nausea, paraesthesia, hair thinning usu. temp, weight gain, hepatotoxicity
- phenytoin: drowsiness, dizziness, confusion, gingival hyperplasia, hirsutism
- carbamazepine: CNS depression, hypersensitivity reactions, depressed white cell counts, GIT disorders, fluid retention
- topiramate: somnolence, fatigue, psychiatric effects: depression, emotional lability, nervousness, agitation, hallucinations, psychosis, suicidal ideation, nephrolithiasis, metabolic acidosis: weakly inhibits renal carbonic anhydrase, leads to a dose-related decrease in serum bicarbonate concentrations and rarely to hyperchloraemic, normal anion gap, metabolic acidosis
List considerations of sodium channel blockers
- consider with sodium valproate: there is a poor correlation between therapeutic efficacy and plasma concentration but concentrations may be useful to confirm toxicity or compliance
- PK considerations for phenytoin: - Saturable metabolism (zero-order) non-linear kinetics
- Requires plasma monitoring
- dose plasma concentration relationship non-linear (small rise in dose can cause unexpectedly large rise in drug plasma levels)
- EG: Dose can be increased by 100mg per day if the serum level is less than 5mg/L but only by 30mg per day if the level is above 5mg/L
- Steady state 7-10 days
- Loading dose usually required
- CYPenzyme inducer - many drug interactions
- Highly protein bound (on albumin)
- Toxicity phenytoin: leads to blurred or double vision, slurred speech, clumsiness, dizziness, confusion, hallucinations, cardiovascular collapse
- Monitoring of phenytoin:
- Phenytoin levels are related to efficacy - dose adjustment based on levels can be difficult eg: Dose can be increased by 100mg per day if the serum level is less than 5mg/L but only by 30mg per day if the level is above 5mg/L
- Phenytoin monitoring and dose adjustment are complicated by the drug’s nonlinear pharmacokinetics
- in patients with hypoalbuminaemia (eg in kidney disease, malnutrition, advanced chronic liver disease), a greater proportion of the phenytoin is free (because of lower protein binding) for the same total concentration
- PK carbamazepine: Metabolised by CYP 3A4 (Half life prolonged by drugs that inhibit), It is a CYP enzyme inducer (Increasesmetabolism of other drugs) - lots of drug interactions!, Auto-induction of metabolism (it self-induces it’s own hepatic metabolism), Can take up to a month to reach stable therapeutic levels
Describe the broad MoA of calcium channel modulators
(1) Action potential travels down to the nerve terminal
(2) Voltage-sensitive sodium channel senses the change in voltage, which triggers the channel to open and allows Na+into the cell
(3) Voltage-sensitive calcium channel senses the change in voltage, which triggers the channel to open and allowsCa2+into the cell
(4) Voltage-sensitive calcium channels are associated with a SNARE protein, which essentially mediate vesicular neurotransmitter release
The voltage-sensitive calcium channel contains 5 subunits: namelyα1(pore-forming unit),α2, andδ.
Binding of pregabalin and gabapentin to the α2-δ modulatory site decreases the voltage-induced Ca2+influx, which prevents the release of excitatory neurotransmitters, such as glutamate, therefore decreasing neuronal excitability.
The ‘unknown’ or ‘other’ mechanisms… Becoming increasingly common in practice due to predictable PK and less side effects and drug interactions.
- Antagonismat post-synaptic AMPA glutamate receptors (perampanel)
- Bindingto synaptic vesicle protein2A which may modulate neurotransmitter (glutamate) release (Levetiracetam andBrivaracetam)
- All 3 drugs have been associated with behaviour changes such as aggression and psychiatric effects.
Describe the specific MoAs of calcium channel blockers and their indications
- ethosuximide: Reduces low threshold voltage-dependent calcium conductance in thalamic neurones
- gabapentin and pregabalin: Bind to alpha‑2 delta protein subunit of high threshold voltage-dependent calcium channels, reducing calcium influx and neurotransmitter release. Although structurally related to the neurotransmitter GABA, they are not known to significantly affect GABA or its receptors.
- gabapentin and pregabalin indicated mainly in neuropathic pain, less common for partial seizures
List side effects of calcium channel blockers
- gabapentin and pregabalin: CNS depression, weight gain, oedema, sedation
Describe levetiracetam
- mechanism of action unknown - May modulate neurotransmission (glutatmate) by binding to synaptic vesicle protein2A in the pre-synaptic neuron
- indicated in Seizures - Increasingly common in practice due to being better tolerated than other antiepileptics with less drug interactions.
- side effects: slight sedation, somnolence, headache, altered behaviours inc aggression
List considerations for pregnant women and women of childbearing age
Several antiepileptic drugs (eg phenytoin) induce CYP3A4 and may reduce the efficacy of drugs metabolised by this enzyme:
- Includingcontraceptives,
- Can use levonorgestrel IUD, medroxyprogesterone depot or copper IUD(unaffected by CYP3A4 inducers).
- It is important to look-up drug interactions when prescribing antiepileptic drugs
Pregnancy
- Consider and discuss the possibility of pregnancy before selecting a specific antiepileptic drug
- Some AEDs are potentially teratogenic or can affect cognitive development
- seizure control is high priority during pregnancy as they pose a greater risk to mother and foetus as compared to the adverse effects
- effects of antiepileptics can change during pregnancy due to altered PK
What options are there for managing antiepilectic therapy during pregnancy or for patients planning pregnancy?:
- Consider withdrawal of antiepileptic treatment in women planning pregnancy who have been seizure-free for at least 2years
- Lower the dose of sodium valproatein woman of childbearing age which decreases the teratogenic risk
- Less risk associated with some second generation AEDs
- Tiagabine, Gabapentin, Levetiracetam
- Increase intake of folic acid to 5mg per day commencing at least 1-3 months prior to conception
- Minimises risk of spina bifida
- Shown to have positive outcome on cognitive performance in children
- Some AEDs can impair absorption of folic acid
