Anti-epileptics Flashcards
What are examples of Benzodiazepines?
- Lorazepam
- Midazolam
- Diazepam
- Clonazepam
- Sodium Valproate
What is the mechanism of action of benzodiazepines?
Act at distinct receptor site on GABA chloride channel. Act as positive allosteric effects. Enhancement of GABA action through:
- Inhibition of GABA inactivation
- Inhibition of GABA re-uptake
- Increase rate of GABA synthesis
This increase chloride current into the neurone which increases the threshold for action potential generation. There is therefore a decreased chance of reaching the seizure threshold
What are the uses of Benzodiazepines?
Used in emergency as first line therapy for acute life-threatening status epilepticus or any acute seizures that has not terminated in 5 mins
How is Lorazepem used?
IV bolus 4mg is first line in emergency such as status epilepticus
How is diazepam used?
Can be given rectally if no access in status epilepticus
How is Midazolam used?
Buccal if no IV access in emergency
How is Clonazepam used?
-Absence seizure in the short term
Describe the pharmacokinetics of Benzodiazepines?
-Well absorbed 90-100% highly plasma bound 85-100%
What are the side effects of Benzodiazepines?
- Sedation
- Tolerance with chronic use
- Confusion impaired co-ordination
- Aggression
- Dependence/Withdrawal with chronic use
- Abrupt withdrawal seizure trigger
- Respiratory and CNs depression
What are some drug interactions of Benzodiazepines?
-Some adjunctive use
How is benzodiazepine overdose reversed?
Overdose reversed by IV flumazenil, but its use may precipitate seizure/arrhythmia
What are examples of sodium channel blockers?
- Lamotrigine
- Phenytoin
- Carbamazepine
What is the mechanism of action of sodium channel blocker?
- Inhibition of voltage gated sodium channels function by binding during depolarisation -hence voltage dependant
- Prolongs inactivation state so cant stimulate another action potential. this is to bring the firing rate back to normal
- Reduces probability of high abnormal spiking (firing lots of action potentials)
- Once neurone membrane potential back to normal VGSC blocker detaches from binding
How is phenytoin used?
- Used for generalised Tonic-Clonic and all partial.
- Used in emergency as a loading dose + infusion when seizure not terminating after 10 mins
How is Carbamazepine used?
-First line therapy for partial seizures (or generalized tonic-clonic seizures).
What is the pharmacokinetic properties of Carbamezipine?
- Strong CYP450 ENZYME INDUCER: increases its own metabolism with repeated doses reducing its half-life from 30 hr to 15 hr
- Well absorbed and 75% protein bound - Linear PK
- Contraindicated with AV conduction problems
How is Lamotrigine used in practice?
- Lamotrigine is the drug of choice for women of childbearing age as LEAST teratogenic
- Lamotrigine is used increasingly as first line
What are some general ADRs of Carbamezipines?
General: Dizziness, Drowsy, Ataxia, Motor Disturbance, Numbness, Tingling, GI upset, Vomiting, Variation in BP, Rashes, Hyponatraemia
Rare: neutropenia
What are the pharmacokinetics of Phenytoin?
- CYP450 inducer
- Well absorbed - but 90% bound in plasma competitive binding can increase levels
- NON LINEAR pharmacokinetics at therapeutic levels so close dose monitoring required. Patients will have a chart and graph to work out dosing.
What are the ADRs associated with phenytoin?
- Gingival Hyperplasia (20%)
- Rashes or hypersensitivity. (Steven Johnson in 2-5%)
- CNS symptoms such as Dizziness, Ataxia, Headache, Nystagmus, Nervousness
What are the pharmacokinetics of Lamotrigine?
- Well absorbed - Linear PK. Half-life is 24 hours
- No CYP450 induction so fewer DDIs
What are the ADRs associated with Lamotrigine?
- Less marked CNs dizziness, ataxia and somnolence
- Nausea
- Some mild and serious skin rashes
What are some drug interactions of Carbamezepines?
- Decreases the effect of many drugs: Warfarin, Systemic Corticosteroids, Oral Contraceptives, Phenytoin
- Contraindicated use with Antidepressants such as SSRIs, MAOIs, & TCA as they interfere with action of Carbamazepine
Adjust Dosing
What are some drug interactions of Phenytoin?
- Competitive binding eg with Valproate, NSAIDS/salicylate Increases plasma level exacerbating Non-Linear PKs
- Decreases the effect of Oral contraceptive
- Increases Cimetidine action
What are some drug interactions of Lamotrigine?
Adjunct therapy with other AEDs
- Oral contraceptive reduce the LTG plasma levels
- Valproate increase LTG in plasma due to competitive binding
What is the mechanism of action of Sodium Valproate?
Mixed sites of Action - Pleiotropic
- Weak inhibition GABA inactivation enzymes increasing GABA
- Weak stimulus of GABA synthesising enzymes increasing GABA
- VGSC blocker + Weak Ca2+ channel block so discharge
How is sodium valproate used in practice?
-First line therapy for primary generalized seizures, (Tonic+Clonic, Absence, Partial Seizures)
What are the pharmacokinetic properties of Sodium Valproate?
- Pharmacokinetics:
- Absorbed 100% - then 90% plasma bound Linear PK t1/2 = 15 hrs
What are some ADRs of Sodium Valproate?
- MOST teratogenic and can lead to sodium valproate syndrome
- Generally less severe ADRs than with other AEDs
- CNS sedation ataxia tremor - weight gain
- Hepatic function affected resulting in elevated Transaminases in 40% patients
- Rarely - hepatic failure
What are the emergency seizure management procedures?
- A to E approach - protect airway, recovery position, give oxygen
- Try benzodiazepines first: either buccal midazolam, IV lorazepam or rectal diazepam
- If not terminating 5 mins later give a further dose
- If still not terminating e.g. have been having a seizure for 10-15 mins then CALL ITU + MED Specialist Registrar and give loading dose of IV phenytoin.
