Session 11 - Epilepsy Flashcards
What is epilepsy?
Epilepsy is an episodic discharge of abnormal high frequency electric activity in the brain leading to seizure.
What does an epilepsy diagnosis require?
evidence of recurrent seizures unprovoked by any other identifiable causes.
Describe four things that happen in epilepsy on a neuronal level
- Increased excitatory activity
- Decreased inhibitory activity
- Loss of homeostatic control
- Spread of neuronal hyperactivity
What are two overarching categories of epilepsy
Partial seizures
Generalized seizures
Give two sub-types of partial seizures - What is the distinguishing feature between the two?
Simple (concious)
Complex (unconscious)
What four things occur in a partial seizure?
o Increased discharged in focal cortical area
Symptoms reflect affected area
Involuntary motor disturbance
Behavioural change
Impending focal spread accompanied by Aura, e.g. unusual smell or taste, déjà vu, jamais vu
What is jamais vu?
Sense of seeing a situation for the first time, despite it happening many times before
What is a generalized seizure?
- Generated centrally and spreads through both hemispheres
- Loss of consciousness
What are two types of generalised seizure?
Tonic-clonic seizure
- Grand mal
Absence seizure
- petit mal
What occurs in a tonic-clonic seizure?
Initial rigidity (tonic) and shaking (clonic)
What occurs in an absence seizure
Loss of expression, stare blankly, patient not aware of them
What is status epilepticus?
Seizure that lasts >5 minutes.
What is the mortality rate in status epilepticus?
20%
What must be excluded in any suspected fit?
Hypoglycaemia
What two drugs do you give in status epilepticus
Benzodiazepines
Phenytoin
What is primary epilepsy
No identifiable cause - 60-65%
What is secondary epilepsy?
Medical conditions affecting the brain 30%
- Vascular disease
- Tumour
What is most common cause of epilepsy in the elderly?
Secondary epilepsy
Give four categories of stimuli which could trigger epileptic fit
Sensory stimuli Brain disease/trauma Metabolic disturbances Infections Therapeutics
Give a sensory stimuli that can cause epileptic fit
Flashing lights/strobes
Give four brain diseases/trauma which can cause epilepsy
Brain injury
Stroke/Haemorrhage
Drugs/alcohol
Structural abnormality
Give three metabolic disturbances which can cause epilepsy
o Hypoglycaemia
o Hypocalcaemia
o Hyponatraemia
What kind of infection causes epilepsy
Febrile convulsions
What therapeutics can cause epilepsy?
Anti-epilectic drugs and polypharmacy
Give four dangers in severe epilepsy
o Physical injury relating to fall/crash o Hypoxia o SUDEP – Sudden death in Epilepsy o Varying degrees of brain dysfunction/damage o Cognitive impairment o Serious psychiatric disease o Significant adverse reactions to medication o Stigma/Loss of livelihood
How do anti-epileptic drugs generally work, generally?
By inhibiting the rapid, repetitive neuronal firing that characterises seizures
How do anti-epileptics work specifically?
o Inhibition of channels involved in neuronal excitability
Voltage gated Sodium channels
Inhibition of Calcium Channel Function (not examined)
o Enhancement of inhibitory activity
GABA-mediated inhibition
How to sodium channel blockers work?
By binding to sodium channels and keeping them in an inactivated state.
Self regulating, as detach from binding site.
How does GABA mediated inhibition work?
an increase in Chloride current into the neurone, increasing the threshold for action potential generation
What are three main pharmacological targets of GABA enhancers?
o Direct GABA agonists
o Benzodiazepine Site – Enhance GABA action
o Barbiturate Site – Enhance GABA action
Name five anti-epileptic drugs
Phenytoin Carbamezapine (will be examined!) Lamotrigine Sodium Valproate Benzodiazepine
What is first line treatments for seizures?
Sodium Valproate and Lamotrigine, then carbamezapine (unless tonic, atonic or myoclonic)
What is first line in partial seizure?
Carbamezapine
What is the indication for phenytoin?
All forms of epilepsy except absence
What is the mechanism of phenytoin?
Prolongs VGSC inactivation state
Stops the spread of excitation from focus
Give some phenytoin ADRs
CNS effects – dizziness, ataxia, headache, Nystagmus, nervousness
Gingival Hyperplasia (20%)
Rashes – Hypersensitivity (Stevens-Johnson Syndrome 2-5%)
Give some phenytoin DDIs
CYP450 Inducer
Many drug interactions, e.g. Warfarin, OCP
Cimetidine Phenytoin
Well absorbed, 90% Protein Bound
Competitive binding, e.g. with Valproate, NSAIDs
Can exacerbate non-linear PKs
What precaution must be taken with phenytoin admin?
Phenytoin displays Non-Linear Pharmacokinetics at Therapeutic concentrations (linear at sub-therapeutic levels). This means close monitoring of free plasma levels is required – saliva often used.
How is carbamezapine administered?
Oral/rectal
What are the indications of carbamexzapine
Second line for most except for absence seizures, tonic, atonic and myoclonic seizures (may make worse)
What is a contraindication for carbamezapine
AV conduction problems
What is the mechanim of action of carbamezapine?
Prolongs VGSC inactivation state
What are some CNS ADRs of carbamezapine?
Dizziness, drowsiness, ataxia, motor disturbances, numbness, tingling
Give three ADRs of carbamezapine other than CNS
Gi -Vomiting
CVS - BP variations
Hyponatremia
Give three DDIs for carbamezapine
CYP450 Enzyme Inducer
Many drug interactions, e.g. Warfarin, OCP
Protein bound
Another protein binding drug can raise Carbamazepine conc.
Antidepressants (SSRIs, MAOIs, TCAs and TCA) interfere with Carbamazepine’s action
What are some therapeutic notes for carbamezapine?
Well absorbed, 75% protein bound
Linear Pharmacokinetics
Initial t½ is ~30hrs, but is a strong inducer of CYP450s and therefore affects its own Phase I metabolism. In repeated use t½ falls to ~15hrs
Drug monitoring required to adjust dosing due to falling t½
What are some indications for lamotrigine?
All forms of epilepsy
Partial seizures
Generalized tonic-clonic and absence seizures (unlike phenytoin and carbamezapine)
What are some contraindications for lamotrigine?
Hepatic impairment
Not first line use in paediatric patients due to ADRs
What is lamotrigines mechanism of action
Prolongs VGSC inactivation state
What are some ADRs for lamotrigine (3)
Less marked CNS dizziness, ataxia, somnolence (drowsiness)
Nausea
Some mild (10%) and serious (0.5%) skin rashes, which limits child use
Give some DDIs for lamotrigine
Adjunct therapy with other anti-epileptic drugs
Oral Contraceptives reduce Lamotrigine plasma levels
Valproate increases Lamotrigine plasma levels (protein binding)
In what situation can you use lamotrigine when you can’t use other AEDs?
Pregnancy
Give three significatn therapeutic notes for lamotrigine
Increasingly first line anti-epileptic drug
Well absorbed, linear PK = 24hrs
No CYP450 induction
What is the mechanism of action of sodium valproate? (3)
Weak inhibition of GABA inactivation enzymes GABAA
Weak stimulus of GABA synthesising enzymes GABA A
Weak VGSC blocker and Weak Ca2+ channel blocker Discharge
Give give ADRs for Sodium valproate
Generally less severe than with other AEDs
CNS sedation – Ataxia, tremor
Weight gain
Hepatic Dysfunction – Transaminases increased in 40% of patients
Rarely hepatic failure
In light of this, what is a major contraindication for sodium valproate?
Acute Liver Disease/Hepatic dysfunction
Give four DDIs with Sod Val
Adjust therapy with other AEDs
Care needed with adjunct therapy, as both Valproate and adjunct PKs are affected. E.g. displaces Lamotrigine and Phenytoin, raising their free plasma concentrations
Antidepressants (SSRIs, MAOIs, TCAs and TCA) inhibit Valproate
Antipsychotics antagonise Valproate, by lowering convulsive threshold
Aspirin displaces Valproate from plasma proteins, raising its free conc
Give three indications for benzodiazepines
Diazepam / Lorazepam – Status Epilepticus
Clonazepam – Absence seizures, short term use
Anxiety
What is a CI for benzos
Respiratory depression
Give mechs of action of Benzos
Act at a distinct receptor site on GABA Chloride channel
Binding of GABA or Benzodiazepines enhance each others binding, acting as positive allosteric effectors
Increases Chloride current into the neurone, increasing threshold for action potential generation
Give three ADRs for Benzos
Sedation Tolerance with chronic use Dependence/Withdrawal with chronic use Confusion, impaired co-ordination Aggression Abrupt withdrawal – seizure trigger Respiratory and CNS depression
What is a DDI for Benzos?
Highly protein bound (85-100%)
Some adjunct use
How can benzos overdose be reversed?
Overdose reversed by IV Flumazenil
Use may precipitate seizure/arrhythmia
What is a basic prescribing rule for AEDs?
Monotherapy is the aim
Systematic use of one drug and replacement if necessary
What is the conundrum in pregnany epileptics?
Will stopping treatment harm mother and baby more than continuing?
What are the risks of AEDs with pregnancy
Neural tube defects
Face and digital hyoplasia
Vit K deficiency (coagulopathy and cerebral haemorrhage)
What can mothers take to avoid birth defects?
Folate supplements
What should be avoided and what should be used as AED in preg?
Sodium valproate should be avoided - neural tube defect
Lamotrigine should be used - 2% defect rate
What is the defet rate with most AEDs?
8%
What is failure rate of contraceptives with Carbamezapine/phenytoin?
5-10%
What is baseline failure rate of contraceptives?
1-2%
Outline phenytoin drug monitoring
o Sub-Therapeutic Levels
Linear Kinetics
o Therapeutic Levels
Non-Linear Kinetics
Saturated enzymes
Plasma t½ increases as dose is increased
Steady State Concentration in Plasma (achieved with a daily dose) varies disproportionately with the dose (see image).
The therapeutic range of Phenytoin is quite narrow, 40-100μmol. Drug monitoring of the plasma levels of Phenytoin is required, as due to its pharmacokinetic properties this therapeutic range can be exceeded quite rapidly, causing adverse effects (see above).
What is status epilepticus?
o Medical emergency
o Adult mortality ~20%
o Risk increases with the length of Status Epilepticus
How do you manage status epilepticus?
o ABC approach
o Exclude hypoglycaemia
o Hypoventilation may result with high AED doses
o ITU for paralysis and ventilation if AEDs are failing
AEDs in Status Epilepticus
o Benzodiazepines
Lorazepam (0.1mg/kg)
Preferred to Diazepam due to longer t½
Given intravenously (rectal if IV access difficult)
o Phenytoin
Zero Order (Non-Linear) kinetics (15-20mg/kg)
Rapidly reaches therapeutic levels IC
Cardiac monitoring – Arrhythmias and hypotension
